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Jill Ohar,1 Robert Tosiello,2 Thomas Goodin,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294). Methods: Patients were grouped by baseline predicted post-bronchodilator FEV1 (

Brendan Clark,1 Brian J Wells,2 Amit K Saha,3 Jessica Franchino-Elder,1 Asif Shaikh,4 Bonnie MK Donato,1 Jill A Ohar5 1Health Economics and Outcomes Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 2Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 5Department of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USACorrespondence: Jill A Ohar, Department of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA, Tel +1 336-406-6733, Fax +1 336-716-7277, Email johar@wakehealth.eduBackground: Patients with chronic obstructive pulmonary disease (COPD) can have low peak inspiratory flow (PIF), especially after hospitalization for acute exacerbation of COPD (AECOPD).Purpose: To characterize patients hospitalized for AECOPD, and to assess the prevalence of low PIF, changes in PIF after hospitalization, and the association of low PIF with healthcare resource utilization (HRU) outcomes.Patients and Methods: A retrospective cohort study was conducted using electronic health record data of hospitalized COPD patients in the Wake Forest Baptist Health system (01/01/2017 through 06/30/2020). Patients with a first eligible AECOPD hospitalization (index hospitalization) who were discharged before 05/31/2020 were included. PIF was measured using the In-Check DIAL™ at both medium-low resistance (R-2) and high resistance (R-5) during the index hospitalization. For R-2 and R-5, PIF was divided into low PIF (< 60 L/min; < 30 L/min) and high PIF (≥ 60 L/min; ≥ 30 L/min) groups. The primary outcome was the prevalence of low PIF. The stability of PIF after hospitalization was described. Adjusted regression models evaluated associations between low PIF and subsequent 30-day readmissions, 90-day readmissions, and HRU outcomes, including hospitalizations, emergency department visits, inpatient days, and intensive care unit (ICU) days.Results: In total, 743 patients with PIF measured at R-2 and R-5 during a AECOPD hospitalization were included. The prevalence of low PIF was 56.9% at R-2 and 14.7% at R-5. PIF values were relatively stable after hospitalization. Adjusted analyses showed significant increases in HRU (all-cause hospitalizations [31%], COPD hospitalizations [33%], COPD inpatient days [46%], and COPD ICU days [24%]) during the follow-up period among patients with low PIF (< 60 L/min) at R-2. The 30- and 90-day readmission risks were similar between patients with low PIF and high PIF.Conclusion: Low PIF is common among patients hospitalized for AECOPD, relatively stable after hospital discharge, and associated with increased HRU.Keywords: AECOPD, electronic health records, healthcare utilization, PIF

Jill A Ohar,1 Gary T Ferguson,2 Donald A Mahler,3 M Bradley Drummond,4 Rajiv Dhand,5 Roy A Pleasants,4,6 Antonio Anzueto,7 David MG Halpin,8 David B Price,9,10 Gail S Drescher,11 Haley M Hoy,12 John Haughney,9 Michael W Hess,13 Omar S Usmani14 1Section of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA; 2Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 3Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 4Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 6Department of Quality, University of Michigan, Ann Arbor, MI, USA; 7Pulmonology Section, University of Texas Health, and South Texas Veterans Health Care System, San Antonio, TX, USA; 8University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 9Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 10Observational and Pragmatic Research Institute, Singapore; 11Pulmonary Services Department, MedStar Washington Hospital Center, Washington, DC, USA; 12Transplant Center, Vanderbilt University Medical Center, Nashville, TN, USA; 13COPD Foundation, Kalamazoo, MI, USA; 14National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UKCorrespondence: Jill A OharSection of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USATel +1 336-716-8426Fax +1 336-716-7277Email johar@wakehealth.eduAbstract: Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.Keywords: chronic obstructive pulmonary disease, dry powder inhalers, peak inspiratory flow

Jill A Ohar,1 Ayca Ozol-Godfrey,2 Thomas Goodin,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest University, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Jill A OharDepartment of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1054, USATel +1 336 716 7765Email johar@wakehealth.eduPurpose: The clinical manifestation of COPD can differ by gender, with women experiencing worse lung function and health-related quality of life than men. Additionally, women tend to report more symptoms given the same disease severity. Accordingly, the impact of gender on efficacy and safety in patients with moderate-to-very-severe COPD was examined following 12 weeks of nebulized glycopyrrolate (GLY) 25 μg twice daily (BID) or placebo.Patients and Methods: GLY and placebo pooled data from the replicate 12-week GOLDEN 3 and 4 studies (n=861) were grouped by gender. Endpoints reported were change from baseline in trough forced expiratory volume in 1 second (FEV1), St George’s Respiratory Questionnaire (SGRQ) and EXAcerbations of COPD Tool-Respiratory Symptoms (EXACT-RS) total scores. Safety was evaluated by reviewing the incidence of adverse events (AEs) and serious AEs.Results: Men (placebo: 54.7%; GLY: 56.1%) were generally older with a greater proportion of high cardiovascular risk and use of background long-acting β2-agonists or inhaled corticosteroids. GLY treatment resulted in significant, clinically important improvements in trough FEV1, regardless of gender. Patients treated with GLY reported significant improvements in SGRQ total score, irrespective of gender; however, the improvement was numerically higher in women. Although EXACT-RS improved in both genders, only women experienced a significant improvement. Overall, GLY was well tolerated with a numerically lower incidence of AEs in men than women.Conclusion: Treatment with nebulized GLY resulted in lung function, SGRQ total score, and EXACT-RS total score improvements regardless of gender. However, only EXACT-RS showed significantly greater improvements in women compared with men. Treatment with GLY was generally well tolerated across genders. These data support the efficacy and safety of GLY 25 μg BID in patients with moderate-to-very-severe COPD, independent of gender. Gender similarities in airflow improvement and differences in symptom-reporting augment the evidence supporting the consideration of individualized treatment plans for COPD patients.Keywords: COPD, gender, LAMA, nebulized glycopyrrolate

Sohini Ghosh,1 Roy A Pleasants,2 Jill A Ohar,3 James F Donohue,1 M Bradley Drummond1 1Division of Pulmonary Diseases and Critical Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Durham VA Medical Center, Durham, NC, USA; 3Department of Medicine, Section of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA Purpose: Adequate peak inspiratory flow rate (PIFR) is required for drug dispersion with dry powder inhalers (DPIs). Prevalence of PIFR discordance (suboptimal PIFR with prescribed inhalers) and factors influencing device-specific PIFR are unclear in COPD. The objective of this study was to determine the prevalence of PIFR discordance and associated clinical factors in a stable COPD population. Patients and methods: An observational, single-center, cohort study was conducted including 66 outpatients with COPD. PIFR was measured using the In-Check™ Dial with applied resistance of prescribed inhalers. Participants were defined as discordant if measured PIFR was Results: The median age of the COPD participants was 69.4 years, 92% were white and 47% were female. A total of 48% were using low–medium resistance DPIs (Diskus®/Ellipta®) and 76% used high-resistance DPI (Handihaler®). A total of 40% of COPD participants were discordant to prescribed inhalers. Female gender was the only factor consistently associated with lower PIFR. Shorter height was associated with reduced PIFR for low–medium resistance (r=0.44; P=0.01), but not high resistance (r=0.20; P=0.16). There was no correlation between PIFR by In-Check™ dial and PIFR measured by standard spirometer. Conclusion: PIFR is reduced in stable COPD patients, with female gender being the only factor consistently associated with reduced PIFR. Discordance with prescribed inhalers was seen in 40% of COPD patients, suggesting that many COPD patients do not generate adequate inspiratory force to overcome prescribed DPIs resistance in the course of normal use. Keywords: pulmonary disease, chronic obstructive, dry powder inhaler, peak inspiratory flow rate, drug delivery systems

Jill A Ohar,1 Alyssa Bowling,2 Thomas Goodin,2 Barry Price,2 Ayca Ozol-Godfrey,2 Sanjay Sharma,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc, Marlborough, MA, USA Purpose: Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies. Patients and methods: Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV1. FEV1 area under the curve from 0 to 12 hours (AUC0–12 h), trough FEV1, St George’s Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed. Results: Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV1 AUC0–12 h, trough FEV1, SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV1 AUC0-12 h (0.165 vs 0.078 L; P

Ohar JA, Ozol-Godfrey A, Goodin T, Sanjar S. Int J Chron Obstruct Pulmon Dis. 2020;15:995–1004. The authors have advised there is an error in Figure 4B on page 1000. For EXACT-RS responder rates, the OR for both genders are shown to be significant at p

Smoking cessation is still the most important intervention in patients with chronic obstructive pulmonary disease (COPD), regardless of sex. There is some evidence that nicotine replacement therapy may be less effective in women than in men. However, women may derive greater benefits from a sustained quit attempt. For example, one study found that compared with men, women who were sustained quitters had a greater initial rise and a slower age-related decline in forced expiratory volume in 1 second. Men and women do not appear to differ in their response to bupropion or to the various types of bronchodilators. A number of factors contribute to the increased risk of osteoporosis in women with COPD. Both smoking and the degree of airflow obstruction have been identified as important risk factors for osteoporosis. Women may be particularly susceptible to the effects of smoking on bone metabolism. Immobility and decreased physical activity have also been shown to accelerate bone loss. [ABSTRACT FROM AUTHOR]

The increase in cigarette smoking among women is now being reflected in an increased incidence of chronic obstructive pulmonary disease (COPD). Since 1985, the rate of COPD-related deaths in women has steadily risen, and it nearly tripled from 1980 to 2000. There continues to be debate about whether women are more susceptible than men to COPD. Women on average have airways that are 17% smaller, and further narrowing of the airways by COPD may make women more vulnerable to symptomatic airways obstruction. There also is some evidence of greater bronchial hyperreactivity in women, although conflicting findings have been re-ported. Gender bias appears to exist in the diagnosis and workup of COPD. For example, there is some evidence that clinicians are more likely to consider the diagnosis of COPD in men than in women. One study showed that women who had symptoms consistent with COPD were significantly less likely than men to undergo spirometric assessment. [ABSTRACT FROM AUTHOR]

Joshua S Cohen,1 Matthew C Miles,2 James F Donohue,3 Jill A Ohar2 1United Lung and Sleep Clinic, Saint Paul, MN, USA; 2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3University of North Carolina Chapel Hill, Chapel Hill, NC, USA Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and health care expenditure worldwide. Relaxation of airway smooth muscle with inhaled bronchodilators is the cornerstone of treatment for stable COPD, with inhaled corticosteroids reserved for those with a history of exacerbations. Tiotropium has occupied center stage in COPD treatment for over 10 years and improves lung function, quality of life, exercise endurance, and reduces the risk of COPD exacerbation. Long-acting β2-agonists (LABAs) improve lung function, reduce dynamic hyperinflation, increase exercise tolerance, health-related quality of life, and reduce acute exacerbation of COPD. The combination of long-acting muscarinic antagonists (LAMAs) and LABAs is thought to leverage different pathways to induce bronchodilation using submaximal drug doses, increasing the benefits and minimizing receptor-specific side effects. Umeclidinium/vilanterol is the first combination of LAMA/LABA to be approved for use in stable COPD in USA and Europe. Additionally, indacaterol/glycopyrronium and aclidinium/formoterol have been approved in Europe and in numerous locations outside USA. Several other agents are in the late stages of development, most of which offer once-daily dosing. The benefits of new LAMA/LABA combinations include improved pulmonary function, dyspnea, and health-related quality of life, and in some cases, reduced exacerbations. These evolving treatments will provide new opportunities and challenges in the management of COPD. Keywords: bronchodilator, fixed-dose combination, chronic bronchitis, emphysema, COPD treatment

Yong Liu,1 Roy A Pleasants,2 Janet B Croft,1 Anne G Wheaton,1 Khosrow Heidari,3 Ann M Malarcher,4 Jill A Ohar,5 Monica Kraft,6 David M Mannino,7 Charlie Strange8 1Division of Population Health, Centers for Disease Control and Prevention, Atlanta, GA, 2Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, NC, 3Chronic Disease Epidemiology Office, Department of Health and Environmental Control, South Carolina, SC, 4Office of Smoking and Health, Centers for Disease Control and Prevention, Atlanta, GA, 5Section on Pulmonary, Critical Care, Allergy and Immunologic Disease, Wake Forest University, Winston Salem, NC, 6Department of Medicine, University of Arizona, Phoenix, AZ, 7Division of Pulmonary, Critical Care, and Sleep Medicine, Pulmonary Epidemiology Research Laboratory, University of Kentucky, Lexington, KY, 8Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA Background: The purpose of this study was to assess the relationship of smoking duration with respiratory symptoms and history of chronic obstructive pulmonary disease (COPD) in the South Carolina Behavioral Risk Factor Surveillance System survey in 2012.Methods: Data from 4,135 adults aged ≥45 years with a smoking history were analyzed using multivariable logistic regression that accounted for sex, age, race/ethnicity, education, and current smoking status, as well as the complex sampling design.Results: The distribution of smoking duration ranged from 19.2% (1–9 years) to 36.2% (≥30 years). Among 1,454 respondents who had smoked for ≥30 years, 58.3% were current smokers, 25.0% had frequent productive cough, 11.2% had frequent shortness of breath, 16.7% strongly agreed that shortness of breath affected physical activity, and 25.6% had been diagnosed with COPD. Prevalence of COPD and each respiratory symptom was lower among former smokers who quit ≥10 years earlier compared with current smokers. Smoking duration had a linear relationship with COPD (P

Abstract Background Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers. Methods Caucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio ≥ 70% and ppFEV1 ≥ 80% (n = 311) despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders. Results Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile → Val: p < 0.003; S2, Gly → Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25–75 (p values 0.001 – 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities. Conclusion Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.

Background/objectives: Both aging and chronic obstructive pulmonary disease (COPD) are strongly associated with changes in the metabolome; however, it is unknown whether there are common aging/COPD metabolomic signatures and if accelerated aging is associated with COPD., Methods: Plasma from 5704 subjects from the Genetic Epidemiology of COPD study (COPDGene) and 2449 subjects from Subpopulations and intermediate outcome measures in COPD study (SPIROMICS) were profiled using the Metabolon global metabolomics platform (1013 annotated metabolites). Post-bronchodilator spirometry measures of airflow obstruction (forced expiratory volume at one second (FEV 1 )/forced vital capacity (FVC) < 0.7) were used to define COPD. Elastic net regression was trained on never and former smokers with normal spirometry and no emphysema to create a metabolomic age score which was validated in SPIROMICS subjects., Results: Our metabolic age score was strongly associated with chronic age in the validation cohort (correlation coefficient = 0.8). COPD subjects with accelerated aging (>7 years difference between metabolic and actual age) had more severe disease compared with those who had decelerated aging (<-7 years difference between metabolic and actual age). COPD and aging metabolites were shared more than expected ( p < 0.001), with amino acid and glutathione metabolism among pathways overrepresented., Conclusions: These findings suggest a common mechanism between aging and COPD and that COPD is associated with accelerated metabolic aging.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation ( n  = 1,367) versus above 4,000 ft (1,219 m) elevation ( n  = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV 1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

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.)

Rationale: Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSAD TLC )., Objectives: To evaluate an AI model for estimating fSAD TLC and study its clinical associations in chronic obstructive pulmonary disease (COPD)., Methods: We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a subset ( n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSAD TLC in the remaining 1458 SPIROMICS participants. We compared fSAD TLC with dual volume, parametric response mapping fSAD PRM . We investigated univariate and multivariable associations of fSAD TLC with FEV 1 , FEV 1 /FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV 1 decline. The results were validated in a subset ( n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV 1 , smoking pack years, smoking status, and percent emphysema., Measurements and Main Results: Inspiratory fSAD TLC was highly correlated with fSAD PRM in SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. In SPIROMICS, fSAD TLC was associated with FEV 1 (L) (adj.β = -0.034, P < 0.001), FEV 1 /FVC (adj.β = -0.008, P < 0.001), SGRQ (adj.β = 0.243, P < 0.001), and FEV 1 decline (mL / year) (adj.β = -1.156, P < 0.001). fSAD TLC was also associated with FEV 1 (L) (adj.β = -0.032, P < 0.001), FEV 1 /FVC (adj.β = -0.007, P < 0.001), SGRQ (adj.β = 0.190, P = 0.02), and FEV 1 decline (mL / year) (adj.β = -0.866, P = 0.001) in COPDGene. We found fSAD TLC to be more repeatable than fSAD PRM with intraclass correlation of 0.99 (95% CI: 0.98, 0.99) vs. 0.83 (95% CI: 0.76, 0.88)., Conclusions: Inspiratory fSAD TLC captures small airways disease as reliably as fSAD PRM and is associated with FEV 1 decline.

Introduction: The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs)., Methods: High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting β 2 -agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates., Results: The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65-5.09 m/s; duration: 227-270 ms) and DPIs (velocity: 1.43-4.60 m/s; duration: 60-757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration., Conclusions: Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate., (© 2024. The Author(s).)

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies., Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS)., Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021., Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls., Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema., Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001)., Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Background: In this study, we compare management of patients with high-risk chronic obstructive pulmonary disease (COPD) in the United States to national and international guidelines and quality standards, including the COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST)., Methods: Patients were identified from the DARTNet Practice Performance Registry and categorized into three high-risk cohorts in each year from 2011 to 2019: newly diagnosed (≤12 months after diagnosis), already diagnosed, and patients with potential undiagnosed COPD. Patients were considered high-risk if they had a history of exacerbations or likely exacerbations (respiratory consult with prescribed medication). Descriptive statistics for 2019 are reported, along with annual trends., Findings: In 2019, 10% (n = 16,610/167,197) of patients met high-risk criteria. Evidence of spirometry for diagnosis was low; in 2019, 81% (n = 1228/1523) of patients newly diagnosed at high-risk had no record of spirometry/peak expiratory flow in the 12 months pre- or post-diagnosis and 43% (n = 651/1523) had no record of COPD symptom review. Among those newly and already diagnosed at high-risk, 52% (n = 4830/9350) had no evidence of COPD medication., Interpretation: Findings suggest inconsistent adherence to evidence-based guidelines, and opportunities to improve identification, documentation of services, assessment, therapeutic intervention, and follow-up of patients with COPD., Funding: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution., Competing Interests: Alan Kaplan is a member of the advisory board of, or speakers bureau for, AstraZeneca, Behring, Boehringer Ingelheim, Covis, Grifols, GlaxoSmithKline, Merck Frosst, Novo Nordisk, Novartis, Pfizer, Purdue, Sanofi, Teva, and Trudel. M. Bradley Drummond has received grant support from the NIH, Department of Defense, Boehringer-Ingelheim, Midmark and Teva; consultancy fees from Astra Zeneca, GlaxoSmithKline, Boehringer-Ingelheim, Chiesi, Verona, and Teva in the prior 18 months. Catherine Meldrum reports no conflict of interest. Douglas Mapel has received grant funding from Boehringer Ingelheim Pharmaceuticals, GlaxoSmithKline, Sunovion; and consultancy fees from Boehringer Ingelheim Pharmaceuticals, Mylan, Theravance Biopharma, and Novartis. Fernando Martinez has received personal fees and non-financial support from the American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, ConCert, Genentech, GSK, Inova Fairfax Health System, Miller Communications, National Society for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rico Respiratory Society, Chiesi, Sunovion, Theravance, Potomac, University of Alabama Birmingham, Physicians Education Resource, Canadian Respiratory Network, Teva and Dartmouth; non-financial support from ProterrixBio, Gilead, Nitto and Zambon; and personal fees from Columbia University, Integritas, MD magazine, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Patara/Respivant, PlatformIQ, American Thoracic Society, Rockpointe, Rare Disease Healthcare Communications and France Foundation; grant support from NIH; and is a member of steering committees for Afferent/Merck, Biogen, Veracyte, Prometic, Bayer, Bridge Biotherapeutics and ProMedior. Jill Ohar has participated in advisory boards for Sunovion Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Mylan, and Theravance and has received grant funding from Sunovion Pharmaceuticals Inc and Boehringer Ingelheim. MeiLan Han 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. Nicola Hanania served as an advisor or consultant for Astra Zeneca, GSK, Sanofi, Genentech, Teva, Verona, Amgen and his institution received research grant support from Astra Zeneca, GSK, Sanofi, Genentech and Teva. Wilson Pace is on the advisory board for Mylan; stock from Novo Nordisk, Pfizer, Novartis, Johnson & Johnson, Stryker, Amgen, Gilead, and Sanofi. Michael Pollack, Hana Muellerova, Norbert Feigler and Hitesh Gandhi are employees of AstraZeneca and hold stock and/or stock options in the company. AstraZeneca is a co-funder of the CONQUEST initiative. Konstantinos Kostikas has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, GILEAD, GSK, Menarini, Novartis, Sanofi, Specialty Therapeutics; (paid to the University of Ioannina); his department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir (paid to the University of Ioannina); KK is a member of the GOLD Assembly. Marije van Melle, Maja Kruszyk, Alex Federman, Juan Wisnivesky, Yasir Tarabichi, Dennis Williams reports no conflict of interest. Margee Kerr is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Victoria Carter is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Alexander Evans is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Ruth Murray is an employee of Optimum Patient Care Ltd, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Rachel Pullen is an employee of the Observational and Pragmatic Research Institute, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. Amy Couper is an employee of the Observational and Pragmatic Research Institute, which is a research collaborator of the CONQUEST initiative with Optimum Patient Care and AstraZeneca. David Price has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline., (© 2023 The Author(s).)

Background: Limited data are available regarding marijuana smoking's impact on the development or progression of chronic obstructive pulmonary disease (COPD) in middle-aged or older adults with a variable history of tobacco cigarette smoking., Methods: We divided ever-tobacco smoking participants in the SubPopulations and InteRmediate Outcomes In COPD Study (SPIROMICS) into 3 groups based on self-reported marijuana use: current, former, or never marijuana smokers (CMSs, FMSs or NMSs, respectively). Longitudinal data were analyzed in participants with ≥2 visits over a period of ≥52 weeks., Measurements: We compared CMSs, FMSs, and NMSs, and those with varying amounts of lifetime marijuana use. Mixed effects linear regression models were used to analyze changes in spirometry, symptoms, health status, and radiographic metrics; zero-inflated negative binomial models were used for exacerbation rates. All models were adjusted for age, sex, race, baseline tobacco smoking amount, and forced expiratory volume in 1 second (FEV 1 ) %predicted., Results: Most participants were followed for ≥4 years. Annual rates of change in FEV 1 , incident COPD, respiratory symptoms, health status, radiographic extent of emphysema or air trapping, and total or severe exacerbations were not different between CMSs or FMSs versus NMSs or between those with any lifetime amount of marijuana use versus NMSs., Conclusions: Among SPIROMICS participants with or without COPD, neither former nor current marijuana smoking of any lifetime amount was associated with evidence of COPD progression or its development. Because of our study's limitations, these findings underscore the need for further studies to better understand longer-term effects of marijuana smoking in COPD., (JCOPDF © 2023.)

Introduction: Data collected through ongoing, state-based, cross-sectional health surveys could be used to better understand the contribution of respiratory symptoms to impaired health among the US adult population., Methods: We used the 2015 Behavioral Risk Factor Surveillance System telephone health survey in four states (Kentucky, Florida, South Carolina, Texas) to describe the relationship between symptoms, associated factors such as tobacco smoking, and health impairments. Self-reported productive cough, shortness of breath (SOB), and dyspnea on exertion (DOE) were categorized as minimal, moderate, or severe. Data were analyzed using multiple logistic regression models with age as a covariate to assess relationships of symptoms with other factors., Results: Among adults ≥ 18 years, respiratory impairment [current asthma, chronic obstructive pulmonary disease (COPD), or a current moderate or severe symptom] occurred in 39.1% of the population. More than half of adults reporting moderate or severe symptoms had not been diagnosed with asthma or COPD, particularly with DOE and productive cough. Subjects were at greater risk of moderate and severe SOB or productive cough with increasing age, prolonged smoking duration (≥ 20 years), being an ever-smoker, or if reporting COPD, current asthma, or any other comorbidity except cancer. Morbid obesity [body mass index (BMI) > 35 kg/m 2 ] was associated with severe DOE at a rate similar to current asthma or COPD (25.6%, 95% CI 20.9-30.3%; 20.8%, 95% CI 16.4-25.1%; 21.3%, 95% CI 17.5-25.1%, respectively); it was the most common cause of DOE. SOB was associated with worse general health impairment and limited ambulation compared with other symptoms. Tobacco smoking prevalence and race varied among states, affecting symptom prevalence., Conclusion: In the largest US survey in decades, we provide a current perspective of respiratory symptoms among adults of all ages. While known risk factors were apparent, low-risk persons also frequently reported symptoms and impairments., (© 2022. The Author(s).)

Rationale/Objective: The Behavioral Risk Factor Surveillance System (BRFSS) health survey has been used to describe the epidemiology of chronic obstructive pulmonary disease (COPD) in the US. Through addressing respiratory symptoms and tobacco use, it could also be used to characterize COPD risk., Methods: Four US states added questions to the 2015 BRFSS regarding productive cough, shortness of breath, dyspnea on exertion, and tobacco duration. We determined COPD risk categories: provider-diagnosed COPD as self-report, high-risk for COPD as ≥10 years tobacco smoking and at least one significant respiratory symptom, and low risk was neither diagnosed COPD nor high risk. Disease burden was defined by respiratory symptoms and health impairments. Data were analyzed using multiple logistic regression models with age as a covariate., Results: Among 35,722 adults ≥18 years, the overall prevalence of COPD and high-risk for COPD were 6.6% and 5.1%. Differences among COPD risk groups were evident based on gender, race, age, geography, tobacco use, health impairments, and respiratory symptoms. Risk for disease was seen early where 3.75% of 25⁻34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly >20 years. Seventy-nine percent of persons ≥45 years-old with frequent shortness of breath (SOB) reported having or being at risk of COPD, reflecting disease burden., Conclusion: These data, representing nearly 18% of US adults, indicates those at high risk for COPD share many, but not all of the characteristics of persons diagnosed with the disease and demonstrates the value of the BRFSS as a tool to define lung health at a population level.

Background: "Transitions of care" have been the focus of readmission reduction strategies for acute exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD). Wake Forest Baptist Medical Center (WFBMC) implemented a comprehensive care plan for AECOPD admissions in 2014 that also seeks to improve the diagnosis/treatment of COPD, strives for the optimal management of co-morbidities, and emphasizes hospice/palliative care in appropriate patients., Methods: A retrospective, electronic health record (EHR) based, observational cohort study was used to evaluate AECOPD admissions between 5/12/2014 to 6/28/2016. An existing AECOPD registry was used to determine care plan status, readmissions were identified from the EHR, and mortality information was obtained from the state of North Carolina. Propensity weighted, multiple logistic regression was used to compare the care plan (n = 597) versus usual care (n = 677) on readmission and mortality outcomes after covariate adjustment., Results: Enrollment in the care plan was associated with a reduced odds of 30-day all-cause readmission (OR 0.84, 95% CI 0.71-0.99), 30-day mortality (OR 0.63, 95% CI 0.44-0.88), and the composite endpoint of 30-day, all-cause readmissions and mortality (OR 0.78, 95% CI 0.67-0.92). The plan also reduced AECOPD-specific readmissions at 90 days (OR 0.78, 95% CI 0.63-0.96)., Conclusion: A comprehensive care plan for patients hospitalized for AECOPD reduced the odds of all-cause readmission, mortality, and AECOPD specific readmission risk. This exploratory study reinforces the use of the AECOPD Care Plan at WFBMC. Future research should focus on a randomized, pragmatic clinical trial to further evaluate the impact of this plan on clinical outcomes., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study aims to assess the relationship of body mass index (BMI) status with respiratory conditions, asthma, and chronic obstructive pulmonary disease (COPD) in a state population., Methods: Self-reported data from 11,868 adults aged ≥18 years in the 2012 South Carolina Behavioral Risk Factor Surveillance System telephone survey were analyzed using multivariable logistic regression that accounted for the complex sampling design and adjusted for sex, age, race/ethnicity, education, smoking status, physical inactivity, and cancer history., Results: The distribution of BMI (kg/m(2)) was 1.5% for underweight (<18.5), 32.3% for normal weight (18.5-24.9), 34.6% for overweight (25.0-29.9), 26.5% for obese (30.0-39.9), and 5.1% for morbidly obese (≥40.0). Among respondents, 10.0% had frequent productive cough, 4.3% had frequent shortness of breath (SOB), 7.3% strongly agreed that SOB affected physical activity, 8.4% had current asthma, and 7.4% had COPD. Adults at extremes of body weight were more likely to report having asthma or COPD, and to report respiratory conditions. Age-adjusted U-shaped relationships of BMI categories with current asthma and strongly agreeing that SOB affected physical activity, but not U-shaped relationship with COPD, persisted after controlling for the covariates (p < 0.001). Morbidly obese but not underweight or obese respondents were significantly more likely to have frequent productive cough and frequent SOB than normal weight adults after adjustment., Conclusion: Our data confirm that both underweight and obesity are associated with current asthma and obesity with COPD. Increased emphasis on exercise and nutrition may improve respiratory conditions., (Published by Elsevier Ltd.)

Chronic obstructive pulmonary disease (COPD) has historically been considered a disease of older, white, male smokers, as illustrated in Frank Netter's classic images of the 'pink puffer' and 'blue bloater'. However, women may be more susceptible to COPD than men, and the disease course may be reflective of that increased susceptibility. From a review of epidemiological data of COPD, we found differences in the way men and women present with COPD symptoms, a bias in the way COPD symptoms are treated in men and women, and differences in susceptibility to airway obstruction based on age, sex, and smoking history. These data show that classic stereotypes of COPD - including male predominance - should be abandoned, and that there are not two but multiple COPD phenotypes, which are characterised by differences between women and men in susceptibility, symptoms, and disease progression. These differences impact on physician perception. Although further research into this concept is needed, the differences we found should prompt, in the short term, changes in the way (and in whom) COPD is evaluated, diagnosed, and treated; in the long term, these differences should prompt research into the prognosis of COPD based on sex differences.

Background: Competing interests occur frequently in health care. This results in the potential for conflict of interest (COI). COI can lead to biased generation or assessment of evidence and misinform healthcare decision makers. Declaration of COI is insufficient to neutralize potentially harmful effects. Medical professional societies are obliged to develop robust mechanisms to "manage" COI, particularly in the development of official guidance documents that affect health care., Purpose: This document describes the background, methods, and content of the new "American Thoracic Society (ATS) Policy on Management of COI in Official ATS Documents, Projects, and Conferences.", Methods: We used existing reviews on COI policies that were prepared for the World Health Organization and for an ATS guideline methodology workshop as the evidence base for this work. We reviewed existing policies of selected organizations and other relevant literature. Members of the ATS Documents Development and Implementation Committee and the ATS Ethics and COI Committee collaborated to draft a COI policy. We used face-to-face meetings, electronic correspondence, and teleconferences to finalize the draft. The policy then underwent review and ultimate approval by the ATS Board of Directors., Results: The ATS developed a new policy and procedures for declaration and management of COI. These procedures include: (1) self declaration of COI, (2) review of potential participants' COI, (3) disclosure of COI to project participants, (4) refusal or excusal from certain decisions or recommendations when appropriate, (5) disclosure of COI to users of documents or attendees of conferences, (6) handling disputes in COI resolution. This policy includes a tool that may be useful for supporting decision makers in management of COIs as they assess the value and relevance of conflicts., Conclusions: The ATS Policy on Management of COI in Official ATS Documents, Projects, and Conferences, in effect since March 2008, promises greater organizational transparency. Application and ongoing evaluation of the policy will give the ATS the opportunity to determine its usefulness in specific settings.

The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

Asbestos pollution is a global problem. Asbestos exposure induced mesothelioma does not require an 'occupational' type of exposure. Bystander exposures may result in earlier age of disease onset and more aggressive disease progression as described in the following 3 case reports., (Copyright 2007 Wiley-Liss, Inc.)

Study Objectives: To determine patterns in asbestos-induced lung diseases found in older, less exposed workers., Design: Review of a database evaluating lung function, smoking status, form of asbestos-induced lung disease, and radiograph abnormalities., Setting: Outpatient clinic., Participants: A total of 3383 asbestos-exposed workers referred for independent medical evaluation, including control subjects who lacked asbestos-specific radiograph abnormalities (n = 243), subjects with low International Labor Organization (ILO) scores (n = 2,685), high ILO scores (n = 312), bronchogenic cancer (n = 63), and mesothelioma (n = 80). Of these, 3,327 workers have specific smoking status information and 3,312 workers have lung volume measures., Interventions: Chest radiographs were interpreted by a certified B-reader, and abnormalities were quantified according to the ILO scoring system. Spirometry and lung volume measurement were performed. Subjects completed a self-administered questionnaire that was reviewed at the time of examination. Control subjects were screened on two separate occasions at least 10 years apart to exclude subclinical or slowly progressive asbestos-induced lung disease., Measurements and Results: The mean age of the population was 65.1 +/- 9.9 years, and the latency was 41.4 +/- 10.1 years (+/- SD). Most subjects (41.8%) had normal pulmonary function. Obstruction was the most common pulmonary function abnormality (25.4%), followed by restriction (19.3%) and a mixed pattern (6.0%). Most subjects (79.4%) had low ILO scores. Benign pleural abnormalities were the only findings in 54% of subjects with low ILO score. Subjects with high ILO scores were older, smoked more, and had a longer latency than subjects with low ILO scores and control subjects. Smokers were younger, had a shorter latency, and had paradoxically greater ILO scores than nonsmokers. Subjects with bronchogenic cancer and mesothelioma had longer latencies than control subjects and subjects with benign asbestos-induced lung disease., Conclusions: Asbestos-induced lung disease today is characterized by low ILO scores, long latencies, greater disease magnitude in smokers, and a normal or obstructive pattern of pulmonary function abnormality. Spirometric evaluation in the absence of lung volume measurements caused misclassification that resulted in overestimation of the presence of a restrictive pattern of pulmonary function.

Background: Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified., Methods: We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided., Results: The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001)., Conclusions: Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Testing for serum prostate-specific antigen (PSA) levels has been widely used to screen for prostate cancer. However, PSA testing has low specificity and sensitivity because PSA is not prostate cancer-specific. PSA is encoded by the APS gene, and the expression of this gene is regulated by androgens. W. Xue et al. Cancer Res., 60: 839-841, 2000 reported recently that serum PSA levels are associated with a G/A polymorphism at androgen responsive element 1 (ARE1) of APS and/or the CAG repeats in exon 1 of the androgen receptor (AR) gene. This result, if confirmed, may significantly increase the specificity and sensitivity of PSA testing by incorporating genotype-specific thresholds. In this study, we tested for the association between serum PSA levels and these single nucleotide polymorphisms (SNPs) in a large sample of 518 men. For the AR gene, we observed slightly (but not statistically significant) higher mean serum PSA levels in men with shorter CAG repeats (

Recent availability of computerized image analysis has fostered hope that barium injection and landmarking of pulmonary arteries would be unnecessary for morphometric assessment when using this technique. We reasoned that if barium injection altered morphometric variables, it would do so in a linear fashion correlating with incremental increases in injection pressure of the barium. The two goals of the present study were to determine whether barium injection into arteries affected morphometric measurements and to determine whether incremental increases in injection pressure correlated with alterations in morphometric measurements in a linear fashion. Computerized image analysis was used to measure the internal elastic lamina (IEL) and external elastic lamina (EEL). Medial area (MA), luminal area (LA), percentage of medial thickness, IEL square root of MA, and idealized LA were calculated. Barium injection did not alter morphometric variables in a linear fashion correlating with incremental increases in injection pressure of the barium except the percentage of arteries that filled with barium. Maximum recruitment for pre-acinar arteries occurred at 40 mmHg pressure and 60 mmHg distending pressure for intra-acinar arteries. Incremental increases in injection pressure did not affect IEL, EEL, or calculated morphometric variables. However, IEL, medial thickness, and MA were all smaller in injected vessels than in uninjected vessels. IEL square root of MA and the ratio of measured vs. idealized LA were both increased in injected lungs. We suspect that vascular injection selects for evaluation, a population of smaller, thin-walled vessels, which in the uninjected lungs are collapsed and hence excluded from analysis.

Proteolytic enzymes have been proposed to play a role in the pathogenesis of various inflammatory pulmonary diseases accompanied by parenchymal remodeling. To assess the role of inflammatory cells and proteolytic enzymes in the development of chronic allograft rejection after lung transplantation, bronchoalveolar lavage fluid (BALF) samples from clinically stable lung transplant (LT) recipients (i.e., without evidence of active infection or rejection), heart transplant (HT) recipients, and healthy volunteers (NL) were analyzed for total white blood cell (WBC) count and differential cell count, along with gelatinolytic/type IV collagenolytic activity. The LT group displayed a significantly increased total WBC count, neutrophil count, and percent neutrophils compared with the NL group, confirming the presence of inflammation. Furthermore, gelatin zymography revealed a significant increase in activity of the 72 and 92 kD gelatinases in the LT group compared with the NL group. A positive correlation existed between neutrophil counts and the increase in proteolytic activity. Immunosuppressive therapy did not account for the findings, since no significant difference in cell counts or proteolytic activity existed between the NL and HT control groups. These findings, together with those of others that relate chronic lung allograft dysfunction to an increase in BALF neutrophils and collagen matrix remodeling, collectively indicate that up-regulated proteolytic activity may have a role in chronic rejection after lung transplantation.

Context: Chronic bronchitis, estimated to affect more than 13 million adults in the United States, is characterized in part by retention of airway secretions, but no approved or effective therapy for airway mucus retention in patients with chronic bronchitis has been established. Surfactant reduces sputum adhesiveness, which contributes to difficulty in clearing secretions, but surfactant has not been tested in patients with chronic bronchitis., Objective: To examine the effects of exogenous surfactant on sputum clearance and pulmonary function in patients with stable chronic bronchitis., Design: A prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled comparison of the effects of 2 weeks of treatment with 3 doses of aerosolized surfactant (palmitoylphosphadidylcholine [DPPC]) or saline (placebo)., Setting: Four US teaching hospitals., Participants: A total of 87 adult patients with the diagnosis of stable chronic bronchitis., Main Outcome Measures: Pulmonary function, respiratory symptoms, and sputum properties before treatment (day 0), after 2 weeks of treatment (day 14), and 7 days after stopping treatment (day 21)., Results: A total of 66 patients were randomized to surfactant treatment and 21 to saline treatment. Patient demographic characteristics between groups were similar at baseline. In patients who received a DPPC dose of 607.5 mg/d for 2 weeks, prebronchodilator forced expiratory volume in 1 second (FEV1) increased from 1.22 L (SEM, 0.08 L) at day 0 to 1.33 L (SEM, 0.09 L) at day 21 (P=.05), an improvement of 11.4%; postbronchodilator FEV1 improved 10.4% by days 14 and 21 (P=.02); and the ratio of residual volume to total lung capacity, a measure of thoracic gas trapping, decreased 6.2% by day 21 (P=.009). In the surfactant groups, there was a dose-dependent increase in the ability of sputum to be transported by cilia in vitro., Conclusion: Aerosolized surfactant improved pulmonary function and resulted in a dose-related improvement in sputum transport by cilia in patients with stable chronic bronchitis.