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Katerina L Byanova,1,* Rebecca Abelman,2,* Crystal M North,3 Stephanie A Christenson,1 Laurence Huang1,2 1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 2Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Laurence Huang, HIV, Infectious Diseases, and Global Medicine Division, Room 2807, UCSF Pride Hall, 2540 23rd Street, San Francisco, CA, 94110, USA, Tel +1 (415) 476-4082, Extension 406, Fax +1 (415) 476-6953, Email laurence.huang@ucsf.eduAbstract: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation and persistent respiratory symptoms. People with HIV (PWH) are particularly vulnerable to COPD development; PWH have demonstrated both higher rates of COPD and an earlier and more rapid decline in lung function than their seronegative counterparts, even after accounting for differences in cigarette smoking. Factors contributing to this HIV-associated difference include chronic immune activation and inflammation, accelerated aging, a predilection for pulmonary infections, alterations in the lung microbiome, and the interplay between HIV and inhalational toxins. In this review, we discuss what is known about the epidemiology and pathobiology of COPD among PWH and outline screening, diagnostic, prevention, and treatment strategies.Keywords: HIV, COPD, tuberculosis, air pollution, immune activation, smoking, pulmonary infections

Igor Z Barjaktarevic,1 Russell G Buhr,1,2 Xiaoyan Wang,3 Scott Hu,1 David Couper,4 Wayne Anderson,4 Richard E Kanner,5 Robert Paine III,5 Surya P Bhatt,6 Nirav R Bhakta,7 Mehrdad Arjomandi,7 Robert J Kaner,8 Cheryl S Pirozzi,5 Jeffrey L Curtis,9,10 Wanda K O’Neal,4 Prescott G Woodruff,7 MeiLan K Han,9 Fernando J Martinez,8 Nadia Hansel,11 James Michael Wells,6 Victor E Ortega,12 Eric A Hoffman,13 Claire M Doerschuk,4 Victor Kim,14 Mark T Dransfield,6 M Bradley Drummond,4 Russell Bowler,15 Gerard Criner,14 Stephanie A Christenson,7 Bonnie Ronish,5 Stephen P Peters,12 Jerry A Krishnan,16 Donald P Tashkin,1 Christopher B Cooper1 On behalf of the NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)1Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; 2Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA; 3Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, CA, USA; 4Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; 5Department of Medicine, University of Utah, Salt Lake City, UT, USA; 6Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 7Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; 8Department of Medicine, Weill Cornell Weill Cornell Medical Center, New York, NY, USA; 9Department of Medicine, University of Michigan, Ann Arbor, MI, USA; 10Medicine Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA; 11Department of Medicine, John Hopkins University, Baltimore, MD, USA; 12Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 13Department of Medicine, University of Iowa, Iowa City, IA, USA; 14Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 15Department of Medicine, National Jewish Health Systems, Denver, CO, USA; 16Department of Medicine, University of Illinois at Chicago, Chicago, IL, USACorrespondence: Christopher B CooperDepartments of Medicine and Physiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095, USAEmail ccooper@mednet.ucla.eduObjective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.Results: A majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.Conclusion: With advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registration: ClinicalTrials.gov: NCT01969344T4.Keywords: bronchodilator responsiveness, inspiratory capacity, FVC, FEV1, SPIROMICS

Barjaktarevic IZ, Buhr RG, Wang X, et al. Int J Chron Obstruct Pulmon Dis. 2019;14:2927– 2938. The authors have advised that there is an error in the Funding section on page 2935. The correct funding statement is as follows: FundingThis study was supported by R01HL125432-01A1 (MBD), T32HL007106-41 (RMB), and TL1TR001883-01 (RGB). SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN2682009 00014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200 900019C, and HHSN268200900020C) and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals, Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute, Inc., GlaxoSmithKline, Grifols Therapeutics, Inc., Ikaria, Inc., Nycomed GmbH, Takeda Pharmaceutical Company, Novartis Pharmaceuticals Corporation, ProterixBio; Regeneron Pharmaceuticals, Inc., Sanofi, and Sunovion. The PRM analyses were supported by NHLBI HL122438 and HL138188. Mehrdad Arjomandi was supported by a grant from the Flight Attendant Medical Research Institute. The authors apologize for this error. Read the original article

Background: As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying bloo

Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, which has shown increased expression in patients with chronic obstructive pulmonary disease (COPD) compared with healthy individuals. We aimed to assess the efficacy and safety of tezepelumab in patients with moderate to very severe COPD despite receiving triple inhaled therapy., Methods: COURSE was a double-blind, randomised, placebo-controlled, phase 2a trial across 90 sites in ten countries in Asia, Europe, and North America. Eligible participants were aged 40-80 years, had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least two moderate to severe COPD exacerbations in the 12 months before enrolment. Patients were randomly assigned (1:1) to receive tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. Randomisation was stratified by geographical region and by number of exacerbations in the 12 months before enrolment. Participants, investigators, site staff, and the study sponsor were masked to treatment assignment. The primary endpoint was the annualised rate of moderate or severe COPD exacerbations over 52 weeks. A prespecified subgroup analysis assessed the primary endpoint in patients grouped by baseline blood eosinophil counts (BECs). Efficacy and safety were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04039113 (completed)., Findings: Between July 30, 2019, and Oct 4, 2022, 333 patients (mean age 67·2 years [SD 7·0]; 145 [44%] female and 188 [56%] male; 293 [88%] White, 34 [10%] Asian, and four [1%] Black or African American) were randomly assigned and treated with tezepelumab (n=165) or placebo (n=168). The annualised rate of moderate or severe COPD exacerbations over 52 weeks was 1·75 for tezepelumab versus 2·11 for placebo (rate ratio 0·83 [90% CI 0·64-1·06]; p=0·10 [one-sided]; the primary endpoint was not met). In prespecified subgroup analyses, the annualised rate of moderate or severe COPD exacerbations over 52 weeks was 2·04 with tezepelumab versus 1·71 with placebo (rate ratio 1·19 [95% CI 0·75-1·90]) in patients with a baseline BEC of less than 150 cells per μL, 1·64 versus 2·47 (0·66 [0·42-1·04]) in patients with a baseline BEC of 150 cells per μL to less than 300 cells per μL, and 1·20 versus 2·24 (0·54 [0·25-1·15]) in patients with a baseline BEC of 300 cells per μL or higher. Adverse events occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group. Serious adverse events occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group. Five patients died while receiving study treatment: two in the tezepelumab group and three in the placebo group. No deaths were determined to be causally related to study treatment by investigator assessment., Interpretation: A significant reduction was not observed in the annualised rate of moderate or severe COPD exacerbations with tezepelumab versus placebo. Further studies are required to evaluate the efficacy of tezepelumab in patients with moderate to very severe COPD, particularly in patients with a baseline BEC of 150 cells per μL or higher. Tezepelumab was well tolerated, with no safety concerns identified., Funding: AstraZeneca and Amgen., Competing Interests: Declaration of interests DS has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo Pharmaceuticals, Genentech, Glenmark Pharmaceuticals, Gossamer Bio, GSK, Kinaset Therapeutics, Menarini Group, Novartis, PULMATRiX, Sanofi, Synairgen, Teva Pharmaceuticals, Theravance Biopharma, and Verona Pharma, and has a leadership or fiduciary role in the Global Initiative for Chronic Obstructive Lung Disease (science committee). CEB has received grants and consultancy fees from 4D Pharma, Areteia Therapeutics, AstraZeneca, Chiesi, Genentech, Global Access Diagnostics, GSK, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi. KFR has received payment or fees for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Roche, and Sanofi, and has received fees for advisory board participation from AstraZeneca, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Sanofi. MKH has received grant support from the American Lung Association, AstraZeneca, Biodesix, Boehringer Ingelheim, the COPD Foundation, Gala Therapeutics, Novartis, Nuvaira, Sanofi, Sunovion, and the US National Institutes of Health; has received royalties from Norton Publishing, Penguin Random House, and UpToDate; has received consultancy fees from Aerogen, Altesa BioPharma, Amgen, Apreo Health, AstraZeneca, Boehringer Ingelheim, DevPro Biopharma, Genentech, GSK, Merck, Mylan, Novartis, Polarian, Pulmonx, Regeneron Pharmaceuticals, Roche, RS Biotherapeutics, Sanofi, Teva Pharmaceuticals, and Verona Pharma; has received personal fees from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis; has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, Integrity, Medscape, MedWiz Pharmacy, and NACE; has received fees for advisory board participation from Novartis and Medtronic; owns stock in Alesa BioPharma and Meissa Vaccines; and has leadership or fiduciary roles in the COPD Foundation (scientific committee and board member), the American Lung Association (advisory committee and volunteer spokesperson), the American Thoracic Society (journal editor), the Global Initiative for Chronic Obstructive Lung Disease (science committee), and the Emerson School Board, Ann Arbor, MI, USA. SAC has received fees for advisory board participation from AstraZeneca, Glenmark Pharmaceuticals, and Regeneron Pharmaceuticals; has received consultancy fees from Sanofi; has received fees for authorship from UpToDate for an article about Genomic Tools; and has received fees for non-branded talks by AstraZeneca, GSK, Regeneron Pharmaceuticals, and Sanofi. MBD has received grants from Boehringer Ingelheim, Midmark, and Teva Pharmaceuticals, and has received personal fees from AstraZeneca, Becker Pharma, Boehringer Ingelheim, Chiesi, GSK, Midmark, Optimum Patient Care, Polarean, Teva Pharmaceuticals, and Verona Pharma. AP has received grants from AstraZeneca, Chiesi, GSK, the Italian Medicines Agency, and Sanofi; has received consultancy fees from AstraZeneca, Avillion, Chiesi, ELPEN Pharmaceuticals, GSK, Novartis, and Sanofi; has received presentation fees from AstraZeneca, Avillion, Chiesi, Edmond Pharma, ELPEN Pharmaceuticals, GSK, IQVIA, Menarini Group, Mundipharma, Novartis, Sanofi, and Zambon; has participated in advisory boards for AstraZeneca, Avillion, Chiesi, ELPEN Pharmaceuticals, GSK, IQVIA, MSD, Novartis, and Sanofi; and has a leadership or fiduciary role in the Global Initiative for Chronic Obstructive Lung Disease (science committee). IDP has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva Pharmaceuticals; has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva Pharmaceuticals; and has a leadership or fiduciary role in the Global Initiative for Chronic Obstructive Lung Disease (science committee). NAM is an employee of Amgen and owns stock in Amgen. GA, AK, ÅH, MG, NSS, and SSP are employees of AstraZeneca and own stock or stock options in AstraZeneca., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, reduced exacerbations and improved lung function in patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation in the phase 3 BOREAS trial., Objective: To assess clinical outcomes in patients from BOREAS by emphysema status., Methods: Patients with COPD and type 2 inflammation (screening blood eosinophils ≥300 cells/μL) on maximal inhaled therapy were randomized to add-on dupilumab 300 mg or placebo every 2 weeks for 52 weeks. We assessed the annualized moderate/severe COPD exacerbation rates over 52 weeks and change from baseline to Week 12 in prebronchodilator forced expiratory volume in 1 s (FEV 1 ) in patients with and without investigator-reported emphysema., Results: Investigator-reported emphysema was present in 306/939 patients (32.6 %) at baseline. Dupilumab reduced exacerbation rates vs placebo by 29 % (relative risk [RR] 0.71 [95 % CI 0.53-0.95]) and 31 % (RR 0.69 [95 % CI 0.53-0.89]) in patients with and without emphysema, respectively. Prebronchodilator FEV 1 least squares mean difference from baseline to Week 12 for dupilumab vs placebo was 0.07 L ([95 % CI 0.002-0.14]) and 0.09 L ([95 % CI 0.04-0.14]) in patients with and without emphysema, respectively. No treatment by emphysema interaction effect was observed for the annualized rate of exacerbations (P value for interaction = 0.8296) or change in prebronchodilator FEV 1 (P value for interaction = 0.6438)., Conclusion: Dupilumab efficacy was similar in patients with COPD and type 2 inflammation, with or without investigator-reported emphysema., Competing Interests: Declaration of competing interest Bhatt SP: Apreo, Boehringer Ingelheim, Chiesi, Genentech, Medscape, Sanofi, Verona Pharma – consultant; Genentech, Nuvaira, Sanofi – grants (to institution); GSK, Regeneron Pharmaceuticals Inc. – advisory board; Horizon CME, Integrity CME – honoraria. Rabe KF: AstraZeneca, Chiesi Farmaceutici, CSL Behring, Sanofi – consultant; AstraZeneca, Boehringer Ingelheim – travel fees; Boehringer Ingelheim, Sanofi, Novartis – grants. Hanania NA: Amgen, AstraZeneca, Boehringer Ingelheim, Genentech USA, GSK – consultant; AstraZeneca, Genentech, GSK, Sanofi, Teva Pharmaceuticals – grants (to institution); Sanofi, Teva Pharmaceuticals – advisory board; Elsevier Publishing – Editor in Chief, Respiratory Medicine. Vogelmeier CF: AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, CSL Behring, GSK, Grifols, Insmed, Novartis, Roche, Sanofi – advisory board and speaking engagements; AstraZeneca – data and safety monitoring board. Bafadhel M: AstraZeneca, Roche – grant funding to institution; AstraZeneca, Chiesi, GSK – consultancy and speaker honoraria; Albus Health, ProAxsis – scientific advisor. Christenson SA: Amgen, Apogee Therapeutics, Atheneum Consulting, Axon Advisors, Genentech, Verona Pharma – consultant; AstraZeneca, GSK, Regeneron Pharmaceuticals Inc., Sanofi – advisory boards/non-branded medical teaching; BMJ Publishing Group – Associate Editor for Thorax; CME Consultants, Horizon CME, Medscape, MJH Life Sciences – non-branded medical teaching; Glenmark Pharmaceuticals – advisory boards; UpToDate – compensation for authorship. Papi A: AstraZeneca, Avillion, Chiesi Farmaceutici, Edmond Pharma, GSK, Mundipharma, Roche, Sanofi – consultant/advisory boards; IQVIA – advisory board; Mundipharma – speaker; Sandoz, Zambon – lecture fees. Singh D: Aerogen, AstraZeneca, BIAL, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla USA, CSL Behring, EpiEndo, Glenmark, GSK, Kinaset, Menarini, Novartis Pharma, Orion Corporation, Pulmatrix, Sanofi, Therevance, Verona Pharma – consultant; NIHR Manchester Biomedical Research Centre – research grants (to institution). Laws E, Lu X, Bauer D, Robinson LB: Sanofi – employees, may hold stock and/or stock options in the company. Dakin P, Maloney J, Bansal A: Regeneron Pharmaceuticals Inc. – employees and shareholders. Abdulai RM: Sanofi – former employee., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition., Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression., Methods/discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture., Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis., (JCOPDF © 2024.)

Background: Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility., Objectives: We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker., Methods: Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation., Results: Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10 -3 ). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10 -3 ) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of T H 2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of T H 1 and inflammation genes (IL12A, MUC5B, and CC16) and T H 17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10 -6 )., Conclusions: Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma., Competing Interests: Disclosure statement Supported by National Institutes of Health grants HL142769 and AI149754. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Exacerbations in COPD can be life-threatening and can lead to irreversible declines in lung function and quality of life. Medications that reduce exacerbation burden are an unmet need, because exacerbations put patients at risk of more exacerbations and decrease quality of life. Ensifentrine is a novel, first-in-class, selective, dual inhibitor of phosphodiesterase 3 and 4 with demonstrated nonsteroidal antiinflammatory activity and bronchodilatory effects., Research Question: Does ensifentrine reduce the rate or risk of COPD exacerbations?, Study Design and Methods: A prespecified, pooled analysis of the phase 3 clinical trials ENHANCE-1 (ClinicalTrials.gov Identifier: NCT04535986) and ENHANCE-2 (ClinicalTrials.gov Identifier: NCT04542057) was conducted to assess the effect of ensifentrine on exacerbation rate and risk (time to first exacerbation). The trials included symptomatic patients 40 to 80 years of age with moderate to severe COPD who received 3 mg tid ensifentrine over 24 weeks or placebo. Subgroup analyses and frequent exacerbator transition risk assessment were conducted post hoc., Results: In total, 975 patients treated with ensifentrine and 574 patients who received placebo were included in the pooled analysis, including 62% of patients receiving concomitant long-acting muscarinic antagonist or long-acting β 2 -agonist therapy and 18% receiving concomitant inhaled corticosteroid therapy. Ensifentrine was associated with significant reductions in the rate (rate ratio, 0.59; 95% CI, 0.43-0.80; P < .001) and risk (hazard ratio, 0.59; 95% CI, 0.44-0.81; P < .001) of moderate to severe exacerbations compared with placebo. Reductions in the rate and risk of exacerbations generally were consistent across patient subgroups, including age, sex, race, background maintenance medication use, chronic bronchitis, eosinophil count, COPD severity, and exacerbation history. Ensifentrine was associated with a numerical delay in transitioning from an infrequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease [GOLD] group B) to a frequent exacerbator (GOLD group E) compared with placebo., Interpretation: Ensifentrine reduced the rate of exacerbations and increased the time to first exacerbation among patients with COPD across a broad range of clinically relevant subgroups., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: F. C. S. has received grant or contract support from Agency for Healthcare Research and Quality, AstraZeneca, the COPD Foundation, Gala Therapeutics, Nuvaira, Pulmonx, Sanofi/Regeneron, and Verona Pharma; and consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi/Regeneron. S. A. C. has participated in advisory boards and/or received consulting fees from AstraZeneca, Amgen, Apogee Therapeutics, Axon Advisors, DevPro Pharma, Genentech, Kymera, Regeneron, Sanofi, and Verona Pharma; has received nonbranded speaking and/or writing honoraria from AstraZeneca, Daedalus Enterprises, GSK, Horizon CME, MJH Holdings, Regeneron, Sanofi, UpToDate, and WebMD; and has received travel fees from Sanofi and Regeneron. T. R. is an employee of Verona Pharma plc and may hold stock or stock options. T. B. is a paid statistical consultant for Verona Pharma. K. R. is an employee of Verona Pharma plc and may hold stock or stock options. I. Z. B. has received grant or contract support from Aerogen, Takeda, Theravance, and Viatris and consulting fees and paid honoraria from AstraZeneca, Grifols, Inhibrx, Sanofi/Regeneron, Takeda, and Verona Pharma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. Objectives: To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). Methods: Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. Measurements and Main Results: Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations ( P  < 0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included Alloprevotella , Oribacterium , and Veillonella species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of Streptococcus , Actinobacillus , Actinomyces , and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV 1 regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in Prevotella , Leptotrichia , and Neisseria species. In contrast, the rapid decline group (FEV 1 slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in Streptococcus species. Conclusions: In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Background: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear., Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV 1 ) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52., Results: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV 1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab., Conclusions: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.)., (Copyright © 2024 Massachusetts Medical Society.)

Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that IL-13-activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibited viscoelastic liquid behavior and that mucus secreted by IL-13-activated HAECs exhibited solid-like behavior caused by mucin cross-linking. In addition, IL-13-activated HAECs shows increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that was prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), was increased in IL-13-activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings was increased in patients with asthma with high airway mucus plug scores. Together, our results show that IL-13-activated HAECs autonomously generated pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.

Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1 . Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2'-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

Objective: Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP)., Methods: Correlation analyses of mRNA expression of six candidate genes ( AP2A2 , MUC6 , MUC2 , MUC5AC , MUC5B , and TOLLIP ) and asthma phenotypes were performed in the longitudinal cohort ( n  = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort ( n  = 155). eQTL ( n  = 114) and genetic association analysis of asthma severity (426 severe vs. 531 non-severe asthma) were performed, and compared with previously published GWASs of IIPs and asthma., Results: Higher expression of AP2A2 and MUC5AC and lower expression of MUC5B in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers ( P  < 0.01). SNPs associated with asthma and IIPs in previous GWASs were eQTL SNPs for MUC5AC , MUC5B , or TOLLIP , however, they were not in strong linkage disequilibrium. The risk alleles for asthma or protective alleles for IIPs were associated with higher expression of MUC5AC and lower expression of MUC5B . rs11603634, rs12788104, and rs28415845 associated with moderate-to-severe asthma or adult onset asthma in previous GWASs were not associated with asthma severity ( P  > 0.8)., Conclusions: SNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of MUC5AC and lower expression of MUC5B are risk for asthma but protective for IIPs.

Background: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation., Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV 1 ) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms)., Results: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV 1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups., Conclusions: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.)., (Copyright © 2023 Massachusetts Medical Society.)

COPD is a heterogeneous condition, the onset and trajectory of which is influenced not only by tobacco exposure but also an individual's genetics and the exposures they accumulate over their life course. In such a complex chronic disease, phenotyping individuals based on similar clinical or molecular characteristics can aid in guiding appropriate therapeutic management. Treatable traits, characteristics for which evidence exists for a specific favorable treatment response, are increasingly incorporated into COPD clinical guidelines. But the COPD phenotyping literature is evolving. Innovations in lung imaging and physiologic metrics, as well as omics technologies and biomarker science, are contributing to a better understanding of COPD heterogeneity. This review summarizes the evolution of COPD phenotyping, the current use of phenotyping to direct clinical care, and how innovations in clinical and molecular approaches to unraveling disease heterogeneity are refining our understanding of COPD phenotypes., Competing Interests: Dr Christenson discloses relationships with AstraZeneca, Sanofi/Regeneron, and GlaxoSmithKline., (Copyright © 2023 by Daedalus Enterprises.)

Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822-1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EKS received grant support from GlaxoSmithKline and Bayer. ESW received honoraria from Pri-Med. JAK reports a grant from U.S. National Institutes of Health (NIH) paid to the institution during the conduct of the study. He also reports personal fees from GlaxoSmithKline consulting on antibodies for acute COVID-19; personal fees from AstraZeneca consulting on antibodies for severe asthma, paid to the institution; personal fees from CereVu Medical consultant for medical device for dyspnea, paid to the institution; and personal fees from BData consultant for severe asthma registry outside the submitted work. JLC reports grants from NIH/NHLBI and the COPD Foundation for the current work and paid to his institution; grants from NIH/NHLBI, the COPD Foundation, NIH/NIAID, and the Departments of Veterans Affairs and of Defense, outside the current work and paid to his institution; and consulting fees from CSL Behring, LLC, AstraZenca, and Novartis Corp., outside the current work and paid to his institution. MCN has received grant support from GlaxoSmithKline. MHC has received grant support from GlaxoSmithKline and Bayer, consulting fees from AstraZeneca, and speaking fees from Illumina. MK received consulting fees from Arrowhead pharmaceuticals and has a patent pending for mucin measurements in chronic bronchitis. MKH reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Amgen, UpToDate, Altesa Biopharma, Medscape, NACE, MDBriefcase, Integrity and Medwiz. 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 has received stock options from Meissa Vaccines and Altesa Biopharma. MVDB reports research grants paid to their institution by GlaxoSmithKline, Novartis, AstraZeneca, Roche and Genentech. SAC received consulting fees from Sanofi/Regeneron, GlaxoSmithKline, AstraZeneca, Glenmark Pharmaceuticals, and Amgen; honoraria from Sanofi/Regeneron, MJH Holdings LLC: Physicians? Education Resource, Sunovion, UpToDate, and Wolters Kluwer Health; travel support from AstraZeneca and GlaxoSmithKline; and sits on the data safety board or advisory boards of Sanofi/Regeneron, and AstraZeneca, and GlaxoSmithKline. TL has stock options from Variant Bio. VEO is on the Data Safety Monitoring Board or Advisory Board for Sanofi and Regeneron. ATH, EVB, GR, HD, SG, SL, SK, SNPK, WKO, and YL have no competing interests to declare., (Copyright: © 2023 Buren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication., Objective: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs., Methods: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression., Results: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs., Conclusions: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV 1 ) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV 1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD., (© 2023. The Author(s).)

E-cigarette use has rapidly increased as an alternative means of nicotine delivery by heated aerosolization. Recent studies demonstrate nicotine-containing e-cigarette aerosols can have immunosuppressive and pro-inflammatory effects, but it remains unclear how e-cigarettes and the constituents of e-liquids may impact acute lung injury and the development of acute respiratory distress syndrome caused by viral pneumonia. Therefore, in these studies, mice were exposed one hour per day over nine consecutive days to aerosol generated by the clinically-relevant tank-style Aspire Nautilus aerosolizing e-liquid containing a mixture of vegetable glycerin and propylene glycol (VG/PG) with or without nicotine. Exposure to the nicotine-containing aerosol resulted in clinically-relevant levels of plasma cotinine, a nicotine-derived metabolite, and an increase in the pro-inflammatory cytokines IL-17A, CXCL1, and MCP-1 in the distal airspaces. Following the e-cigarette exposure, mice were intranasally inoculated with influenza A virus (H1N1 PR8 strain). Exposure to aerosols generated from VG/PG with and without nicotine caused greater influenza-induced production in the distal airspaces of the pro-inflammatory cytokines IFN-γ, TNFα, IL-1β, IL-6, IL-17A, and MCP-1 at 7 days post inoculation (dpi). Compared to the aerosolized carrier VG/PG, in mice exposed to aerosolized nicotine there was a significantly lower amount of Mucin 5 subtype AC (MUC5AC) in the distal airspaces and significantly higher lung permeability to protein and viral load in lungs at 7 dpi with influenza. Additionally, nicotine caused relative downregulation of genes associated with ciliary function and fluid clearance and an increased expression of pro-inflammatory pathways at 7 dpi. These results show that (1) the e-liquid carrier VG/PG increases the pro-inflammatory immune responses to viral pneumonia and that (2) nicotine in an e-cigarette aerosol alters the transcriptomic response to pathogens, blunts host defense mechanisms, increases lung barrier permeability, and reduces viral clearance during influenza infection. In conclusion, acute exposure to aerosolized nicotine can impair clearance of viral infection and exacerbate lung injury, findings that have implications for the regulation of e-cigarette products., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maishan, Sarma, Chun, Caldera, Fang, Abbott, Christenson, Langelier, Calfee, Gotts and Matthay.)

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.

We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a transcriptional signature of sepsis with several genes previously reported as sepsis biomarkers, and a bSVM sepsis diagnostic classifier (AUC = 0.97 training set; AUC = 0.77 validation set). Pathogen detection performance of plasma mNGS varied on the basis of pathogen and site of infection. To improve detection of virus, we developed a secondary transcriptomic classifier (AUC = 0.94 training set; AUC = 0.96 validation set). We combined host and microbial features to develop an integrated sepsis diagnostic model that identified 99% of microbiologically confirmed sepsis cases, and predicted sepsis in 74% of suspected and 89% of indeterminate sepsis cases. In summary, we suggest that integrating host transcriptional profiling and broad-range metagenomic pathogen detection from nucleic acid is a promising tool for sepsis diagnosis., (© 2022. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment., Competing Interests: Declaration of interests SAC reports grant funding paid to her institution from the National Institutes of Health (NIH) and Merck; consulting fees paid from AstraZeneca, GlaxoSmithKline, and Glenmark Pharmaceuticals; payment and honoraria paid from AstraZeneca, Sanofi/Regeneron, Genentech, and Sunovion; and participation in advisory boards or Data and Safety Monitoring Boards (DSMBs) for AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron, and Glenmark Pharmaceuticals. BMS reports grants paid to their institution from NIH, Canadian Institutes of Health Research, Canadian Lung Association, Quebec Respiratory Health Research Network, and McGill University Health Centre Foundation, and leadership as director for the Centre for Outcomes and Research Evaluation of the McGill University Health Centre Research Institute. MB reports grants paid to their institution from AstraZeneca and Roche; consulting fees paid to their institution from AstraZeneca and GlaxoSmithKline; honoraria paid to their institution from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline; and participation in advisory boards or DSMBs with fees paid to their institution from AstraZeneca and GlaxoSmithKline. NP reports research funding paid to their institution from NIH and CSL Behring, and participation in advisory boards for CSL Behring and Pharmacosmos., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale: It has been suggested that patients with chronic obstructive pulmonary disease (COPD) experience considerable daily respiratory symptom fluctuation. A standardized measure is needed to quantify and understand the implications of day-to-day symptom variability., Objectives: To compare standard deviation with other statistical measures of symptom variability and identify characteristics of individuals with higher symptom variability., Methods: Individuals in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Exacerbations sub-study completed an Evaluating Respiratory Symptoms in COPD (E-RS) daily questionnaire. We calculated within-subject standard deviation (WS-SD) for each patient at week 0 and correlated this with measurements obtained 4 weeks later using Pearson's r and Bland Altman plots. Median WS-SD value dichotomized participants into higher versus lower variability groups. Association between WS-SD and exacerbation risk during 4 follow-up weeks was explored., Measurements and Main Results: Diary completion rates were sufficient in 140 (68%) of 205 sub-study participants. Reproducibility (r) of the WS-SD metric from baseline to week 4 was 0.32. Higher variability participants had higher St George's Respiratory Questionnaire (SGRQ) scores (47.3 ± 20.3 versus 39.6 ± 21.5, p =.04) than lower variability participants. Exploratory analyses found no relationship between symptom variability and health care resource utilization-defined exacerbations., Conclusions: WS-SD of the E-RS can be used as a measure of symptom variability in studies of patients with COPD. Patients with higher variability have worse health-related quality of life. WS-SD should be further validated as a measure to understand the implications of symptom variability., (JCOPDF © 2022.)

Altered redox biology challenges all cells, with compensatory responses often determining a cell's fate. When 15 lipoxygenase 1 (15LO1), a lipid-peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine-binding protein 1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase 4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter SLC7A11 critically restores/maintains intracellular GSH. We hypothesized that high 15LO1, PEBP1, and GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG) ratios, to enhance type 2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11, and T2 biomarkers (Western blot and RNA-Seq) were measured in asthmatic and healthy control (HC) cells and fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared with HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, a T2 cytokine (IL-13) induced 15LO1 generation of hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers, and worsened clinical outcomes. Thus, 15LO1 pathway-induced redox biology perturbations worsen T2 inflammation and asthma control, supporting 15LO1 as a therapeutic target.

Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem mass spectrometry (MS/MS) analysis. We identified one membrane-bound protein, myeloid-associated differentiation marker (MYADM), as a candidate SP-A binding partner. Blocking MYADM on mouse and human eosinophils ex vivo prevented SP-A from inducing apoptosis; blocking MYADM in vivo led to increased persistence of eosinophilia and airway hyper-responsiveness in an ovalbumin (OVA) allergy model and increased airways resistance and mucus production in a house dust mite (HDM) asthma model. Examination of a subset of participants in the Severe Asthma Research Program (SARP) cohort revealed a significant association between epithelial expression of MYADM in asthma patients and parameters of airway inflammation, including: peripheral blood eosinophilia, exhaled nitric oxide (FeNO) and the number of exacerbations in the past 12 months. Taken together, our studies provide the first evidence of MYADM as a novel SP-A-associated protein that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane protein in patients with asthma., (© 2021. The Author(s).)

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach., Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m 2 ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data., Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 -8 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling., Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD., Methods: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV 1 , forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF 25-75% ). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344)., Findings: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV 1 and FEF 25-75% , and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV 1 , FEV 1 /FVC, FEF 25-75% , and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years., Interpretation: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents., Funding: National Institutes of Health; National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests RGB reports grants from the National Institutes of Health (NIH), Foundation for the NIH (FNIH), and the COPD Foundation, during the study, and grants from NIH outside the submitted work. ERB has undertaken clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Johnson & Johnson (Janssen), Novartis, Regeneron, and Sanofi Genzyme. ERB has also served as a paid consultant for AstraZeneca, MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron, and Sanofi Genzyme, outside the submitted work. SAC reports personal fees from AstraZeneca, GlaxoSmithKline, Amgen, Glenmark, Sunovion, Genentech, and UpToDate, outside the submitted work. CBC reports grants from NIH/National Heart, Lung, and Blood Institute (NHLBI), FNIH, and COPD Foundation, during the conduct of the study. CBC reports personal fees from PulmonX, Nuvaira, and MGC Diagnostics, and is a Global Medical Expert for GlaxoSmithKline, outside the submitted work. MKH reports grants from NHLBI during the conduct of the study, personal fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Merck, Mylan, Teva, and Verona, and research support from Sanofi, Sunovion, and Novartis, outside the submitted work. NNH reports grants from NIH and COPD Foundation, grants and personal fees from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim, and personal fees from Mylan, outside the submitted work. ATH reports grants from NHLBI and FNIH during the conduct of the study. EAH reports grants from NIH during the conduct of the study. EAH is a founder and shareholder of VIDA Diagnostics, outside the submitted work. FJM reports personal fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Raziel, during the conduct of the study. FJM reports personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Miller Communications, National Society for Continuing Education, PeerView Communications, Chiesi, Sunovion, Physicians Education Resource, Canadian Respiratory Network, Teva, CSL Behring, and Sanofi/Regeneron; non-financial support from ProterixBio, Gilead, Nitto, Zambon, and twoXAR; personal fees, non-financial support, and non-personnel travel support from Genentech; personal fees from MD Magazine, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Patara/Respivant, Bayer, American Thoracic Society, Rockpointe, CME Outfitters, Dartmouth University, DevPro, Gala, Integritas, IQVIA, Projects in Knowledge, Vindico, and Academy for Continuing Healthcare Learning; IPF Study Steering Committee for Afferent/Merck, Biogen, Veracyte, Prometic, and Bayer; IPF Advisor for Bridge Biotherapeutics; IPF teleconference with AbbVie; and grants from NIH, Rare Disease Healthcare Communications, and Promedior/Roche, outside the submitted work. RP reports grants from NHLBI and COPD Foundation, during the conduct of the study. RP reports grants from the Department of Veterans Affairs, and personal fees from Partner Therapeutics, outside the submitted work. PGW reports personal fees from Sanofi, Regeneron, Glenmark Pharmaceuticals, Theravance, GlaxoSmithKline, and NGM Pharma, outside the submitted work. WKO'N reports grants from NIH/NHLBI, during the conduct of the study. RCB reports grants from NIH, during the conduct of the study; and personal fees from Parion Sciences, outside the submitted work. MK reports grants from NIH, during the conduct of the study; contracts from Genentech, Gala Therapeutics, AstraZeneca, Ionis Pharmaceuticals, and personal fees from Boehringer Ingelheim and Amgen, outside the submitted work. In addition, MK has a patent (methods for diagnosing or predicting chronic bronchitis) pending. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease who have minimal or no airflow obstruction. Objectives: To develop a multidimensional definition of a lung-related "resilient smoker" that is useful in research studies and then identify a resilient smoker subgroup in the SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) cohort using this definition. Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ⩾80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. Results: Consensus was achieved on 6 of 12 diagnostic items, which include cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in forced expiratory volume in 1 second. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of CRP (C-reactive protein) and sTNFRSF1A (soluble tumor necrosis receptor factor1A) was lower in resilient than nonresilient smokers ( P = 0.02 and P = 0.03). Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "nonresilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from nonresilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS., (© 2021. The Author(s).)

Introduction: COPD exacerbations are heterogeneous and can be triggered by bacterial, viral, or noninfectious insults. Exacerbations are also heterogeneous in neutrophilic or eosinophilic inflammatory responses. A noninvasive peripheral biomarker of COPD exacerbations characterised by bacterial/neutrophilic inflammation is lacking. Granulocyte-colony stimulating factor (G-CSF) is a key cytokine elevated during bacterial infection and mediates survival, proliferation, differentiation and function of neutrophils., Objective: We hypothesised that high peripheral G-CSF would be indicative of COPD exacerbations with a neutrophilic and bacterial phenotype associated with microbial dysbiosis., Methods: Serum G-CSF was measured during hospitalised exacerbation (day 0 or D0) and after 30 days of recovery (Day30 or D30) in 37 subjects. In a second cohort, serum and sputum cytokines were measured in 59 COPD patients during stable disease, at exacerbation, and at 2-weeks and 6-weeks following exacerbation., Results: Serum G-CSF was increased during exacerbation in a subset of patients. These exacerbations were enriched for bacterial but not viral or type-2 biologies. The median serum G-CSF level was 1.6-fold higher in bacterial exacerbation compared to nonbacterial exacerbation (22 pg·mL -1 versus 13 pg·mL -1 , p=0.0007). Serum G-CSF classified bacterial exacerbations with an area under the curve (AUC) for the receiver operating characteristic (ROC) curve equal to 0.76. Exacerbations with a two-fold or greater increase in serum G-CSF were characterised by neutrophilic inflammation, with increased sputum and blood neutrophils, and high sputum interleukin (IL)-1β, IL-6 and serum amyloid A1 (SAA1) levels. These exacerbations were preceded by dysbiosis, with decreased microbiome diversity and enrichment of respiratory pathogens such as Haemophilus and Moraxella . Furthermore, serum G-CSF at exacerbation classified neutrophilic-dysbiotic exacerbations (AUC for the ROC curve equal to 0.75)., Conclusions: High serum G-CSF enriches for COPD exacerbations characterised by neutrophilic inflammation with underlying bacterial dysbiosis., Competing Interests: Conflict of interest: A. Chakrabarti reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work. Conflict of interest: J.S. Mar reports personal fees from and equity in Genentech, Inc., outside the submitted work. Conflict of interest: D.F. Choy is an employee of Genentech, Inc. Conflict of interest: Y. Cao reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work. Conflict of interest: N. Rathore reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work. Conflict of interest: X. Yang reports personal fees from Genentech, Inc., during the conduct of the study and outside the submitted work. Conflict of interest: G.W. Tew reports personal fees from Genentech, Inc., during the conduct of the study and outside the submitted work. Conflict of interest: O. Li is a salaried employee of Genentech, Inc. and received nonfinancial support from Genentech, Inc., during the conduct of the study. Conflict of interest: P.G. Woodruff reports consulting fees from Regeneron, Sanofi, Glenmark Pharma, Theravance and NGM Pharma, and visiting professor honoraria from Amgen and Genentech, outside the submitted work. Conflict of interest: C.E. Brightling is an employee of the University of Leicester. Conflict of interest: M. Grimbaldeston is an employee of Genentech, Inc., and reports personal fees and nonfinancial support during the conduct of the study. Conflict of interest: S.A. Christenson reports consulting fees from AstraZeneca, GlaxoSmithKline, Amgen and Glenmark; personal fees for invited lectures from Sunovion and Genentech; and personal fees for writing for UpToDate, all outside the submitted work. Conflict of interest: M. Bafadhel reports grants from AstraZeneca; honoraria for consulting and advisory boards, as well as travel to conferences, from AstraZeneca, Chiesi and GSK. She is a scientific advisor to and minor shareholder in AlbusHealth, all outside the submitted work. Conflict of interest: C.M. Rosenberger reports personal fees from and stock in Genentech, Inc., during the conduct of the study and outside the submitted work., (Copyright ©The authors 2021.)

Introduction: Continuing inhaled corticosteroid (ICS) use does not benefit all patients with COPD, yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions., Methods: We performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature versus sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-sequencing data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine coregulatory networks related to the onset of COPD exacerbations after ICS withdrawal., Results: In multivariate analyses, we identified a gene signature ( LGALS12 , ALOX15 , CLC , IL1RL1 , CD24 , EMR4P ) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three coregulatory gene networks as well as sex to be related to an early versus late/nonexacerbation phenotype., Conclusion: We identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients., Competing Interests: Conflict of interest: B. Ditz has nothing to disclose. Conflict of interest: A. Sarma reports grants from National Heart, Lung, and Blood Institute, during the conduct of the study. Conflict of interest: H.A.M. Kerstjens reports a grant from AstraZeneca as well as grants and fees for consultancy or advisory board participation from GlaxoSmithKline, Boehringer Ingelheim, and Novartis, and a grant from Chiesi, all outside of the submitted work and all paid to his institution. Conflict of interest: J.J.W. Liesker has nothing to disclose. Conflict of interest: E. Bathoorn has nothing to disclose. Conflict of interest: J.M. Vonk has nothing to disclose. Conflict of interest: V. Bernal has nothing to disclose. Conflict of interest: P. Horvatovich has nothing to disclose. Conflict of interest: V. Guryev has nothing to disclose. Conflict of interest: S. Caldera has nothing to disclose. Conflict of interest: C. Langelier has nothing to disclose. Conflict of interest: A. Faiz has nothing to disclose. Conflict of interest: S.A. Christenson reports consulting fees from AstraZeneca, GlaxoSmithKline, Amgen and Glenmark; personal fees for invited lectures from Sunovion and Genentech; and personal fees for writing for UpToDate, all outside the submitted work. Conflict of interest: M. van den Berge has nothing to disclose., (Copyright ©The authors 2021.)

Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression., Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants., Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections., Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD. Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression. Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV 1 and peripheral oxygen saturation ( P  < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema ( P  < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) ( P  < 0.001). Conclusions: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD). Objectives: To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes. Methods: Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially. Measurements and Main Results: After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness). Conclusions: Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium., Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program., Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed., Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 -9  -4 ). Higher expression levels of GSDMB correlated with asthma and greater number of exacerbations (P < .05). Expression levels of GSDMB correlated with genes involved in IFN signaling, MHC class I antigen presentation, and immune system pathways (false-discovery rate-adjusted P < .05). rs1031458 and rs3902920 in GSDMB colocalized with IFN regulatory factor binding sites and associated with GSDMB expression, asthma severity, and asthma exacerbations (P < .05)., Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF 25-75 ). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log 10 transformed values. Log 10 GCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log 10 GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high log 10 GCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.

Ratrionale: The antimicrobial peptide cathelicidin, also known in humans as LL-37, is a defensin secreted by immune and airway epithelial cells. Deficiencies in this peptide may contribute to adverse pulmonary outcomes in chronic obstructive pulmonary disease (COPD)., Objectives: Using clinical and biological samples from the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we assessed the associations of plasma cathelicidin levels with cross-sectional and longitudinal COPD outcomes., Methods: A total of 1609 SPIROMICS participants with COPD and available plasma samples were analyzed. Cathelicidin was modeled dichotomously (lowest quartile [< 50 ng/ml] versus highest 75% [≥ 50 ng/ml]) and continuously per 10 ng/ml. Fixed-effect multilevel regression analyses were used to assess associations between cathelicidin and cross-sectional as well as longitudinal lung function. The associations between cathelicidin and participant-reported retrospective and prospective COPD exacerbations were assessed via logistic regression., Measurements and Main Results: Cathelicidin < 50 ng/ml (N=383) was associated with female sex, black race, and lower body mass index (BMI).At baseline,cathelicidin < 50 ng/ml was independently associated with 3.55% lower % predicted forced expiratory volume in 1 second (FEV 1 )(95% confidence interval [CI] -6.22% to -0.88% predicted; p =0.01), while every 10 ng/ml lower cathelicidin was independently associated with 0.65% lower % predicted FEV 1 (95% CI -1.01% to -0.28% predicted; p < 0.001). No independent associations with longitudinal lung function decline or participant-reported COPD exacerbations were observed., Conclusions: Reduced cathelicidin is associated with lower lung function at baseline. Plasma cathelicidin may potentially identify COPD patients at increased risk for more severe lung disease., Competing Interests: RMB is supported through grants from the National Institutes of Health. APC receives grants from the National Institutes of Health and receives consulting fees from VIDA. JMW receives grants from the National Institutes of Health. GJC receives grants from the National Institutes of Health and receives consulting fees from Novartis, AstraZeneca, Respironics, MedImmune, Actelion, Forest, and Pearl. REK receives contracts and grants from the National Institutes of Health. RP receives grants from the National Institutes of Health and research monies from the COPD Foundation. SAC receives grants from the National Institutes of Health and consulting fees from GlaxoSmithKline, Amgen, Glenmark, Sunovion, Genetech and MedImmune. CBC receives grants from the National Institutes of Health and contracts from the National Institutes of Health Foundation. IZB has consulting fees from Amgen, Theravance, GE Healthcare, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim and Verona Pharma. JAK receives grants from the National Institutes of Health and the Patient-Centered Outcomes Research Institute and consulting fees from Inogen. MKH receives grants from the National Institutes of Health. JLC receives grants from the National Institutes of Health. NNH receives grants from the National Institutes of Health and the COPD Foundation and has contracts from AstraZeneca, Boehringer Ingelheim and Mylan. RAW receives consulting fees from AstraZeneca, Boehringer Ingelheim, Contrafect, Pulmonx, Roche, Spiration and Sunovion. MBD receives grants from the National Institutes of Health. ASC, DJC, SPP, and WWL have nothing to declare., (JCOPDF © 2020.)

Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV 1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV 1  % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 238 patients with COVID-19, other viral or non-viral acute respiratory illnesses (ARIs). Compared to other viral ARIs, COVID-19 was characterized by a diminished innate immune response, with reduced expression of genes involved in toll-like receptor and interleukin signaling, chemokine binding, neutrophil degranulation and interactions with lymphoid cells. Patients with COVID-19 also exhibited significantly reduced proportions of neutrophils and macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 26-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.980, 0.950 and 0.871, respectively. Classifier performance was stable at low viral loads, suggesting utility in settings where direct detection of viral nucleic acid may be unsuccessful. Taken together, our results illuminate unique aspects of the host transcriptional response to SARS-CoV-2 in comparison to other respiratory viruses and demonstrate the feasibility of COVID-19 diagnostics based on patient gene expression.

Purpose of Review: The biology underlying asthma and chronic obstructive pulmonary disease (COPD) is heterogeneous. Targeting therapies to patient subgroups, or 'molecular phenotypes', based on their underlying biology is emerging as an efficacious treatment strategy. This review summarizes the role of airway sample gene expression profiling in understanding molecular phenotypes in obstructive lung disease., Recent Findings: Recent gene expression studies have reinforced the importance of Type two (T2) inflammation in asthma and COPD subgroups. Studies in asthma also suggest that the molecular phenotype with enhanced T2 inflammation is itself heterogeneous with a subgroup that has steroid-refractory inflammation. Other inflammatory pathways are also emerging as implicated in asthma and COPD molecular phenotypes, including Type one and Type 17 adaptive immune responses and proinflammatory cytokines, such as interleukin-6., Summary: Genomic profiling studies are advancing our understanding of the complex biology contributing to asthma and COPD molecular phenotypes. Recent studies suggest that asthma and COPD subgroups may benefit from different treatment strategies than those currently in practice.