Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation.

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 (FEV1) 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 FEV1 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.).

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts.

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 (FEV1) 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 FEV1 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.).

Myeloid Heterogeneity Mediates Acute Exacerbations of Pulmonary Fibrosis.

Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF. In addition to accelerating the rate of lung function decline, exposure to fine particulate matter (particulate matter smaller than 2.5 µm [PM2.5]) is a risk factor for increased mortality in subjects with IPF. In this article, we show that exposure to PM2.5 mediates monocyte recruitment and fibrotic progression in mice with established fibrosis. In mice with established fibrosis, bronchoalveolar lavage cells showed monocyte/macrophage heterogeneity after exposure to PM2.5. These cells had a significant inflammatory and anti-inflammatory signature. The mixed heterogeneity of cells contributed to the proinflammatory and anti-inflammatory response. Although monocyte-derived macrophages were recruited to the lung in bleomycin-injured mice treated with PM2.5, recruitment of monocytes expressing Ly6Chi to the lung promoted progression of fibrosis, reduced lung aeration on computed tomography, and impacted lung compliance. Ly6Chi monocytes isolated from PM2.5-exposed fibrotic mice showed enhanced expression of proinflammatory markers compared with fibrotic mice exposed to vehicle. Moreover, IPF bronchoalveolar lavage cells treated ex vivo with PM2.5 showed an exaggerated inflammatory response. Targeting Ly6Chi monocyte recruitment inhibited fibrotic progression in mice. Moreover, the adoptive transfer of Ly6Chi monocytes exacerbated established fibrosis. These observations suggest that enhanced recruitment of Ly6Chi monocytes with a proinflammatory phenotype mediates acute exacerbations of pulmonary fibrosis, and targeting these cells may provide a potential novel therapeutic target to protect against acute exacerbations of IPF.

A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease: An Official American Thoracic Society Research Statement.

Background: Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes. Objectives: To prioritize a list of research topics related to the diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease, and atrial fibrillation) by summarizing existing evidence and using consensus-based methods. Methods: A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real time on the basis of their potential for advancing the field. Results: Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) clinical trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac and pulmonary rehabilitation; and 10) health equity. Seventeen experts participated, and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after two rounds of voting. The range of summative Likert scores was -15 to 25. The highest priority was "Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements." Health equity was identified as an important topic that should be embedded within all research. Conclusions: We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Association of Ground Glass Opacities with Systemic Inflammation and Progression of Emphysema.

RATIONAL: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied. OBJECTIVE: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema. METHODS: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBC, changes in %emphysema, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGOAMFM and one-year FEV1 decline but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGOAMFM was associated with progression to COPD at one-year follow-up. CONCLUSIONS: Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes.

INTRODUCTION: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. METHODS: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. RESULTS: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). CONCLUSION: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

Airway Tapering in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Luminal narrowing is a hallmark feature of airway remodeling in COPD, but current measures focus on airway wall remodeling. Quantification of the natural increase in cumulative cross-sectional area along the length of the human airway tree can facilitate assessment of airway narrowing. METHODS: We analysed the airway trees of 7641 subjects enrolled in the multicenter COPDGene cohort. Airway luminal tapering was assessed by estimating the slope of the change in cumulative cross-sectional area along the length of the airway tree over successive generations (T-Slope). We performed multivariable regression analyses to test the associations between T-Slope and lung function, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea score, 6-minute walk distance (6 MWD), FEV1 change, exacerbations, and all-cause mortality after adjusting for demographics, %CT emphysema, and total airway count. RESULTS: The T-Slope decreased with increasing COPD severity: 2.69 (0.70) in nonsmokers and 2.33 (0.70), 2.11 (0.65), 1.78 (0.58), 1.60 (0.53), and 1.57 (0.52) in GOLD stages 0 through 4 respectively (Jonckheere-Terpstra p=0.04). On multivariable analyses, the T-Slope was independently associated with FEV1 (ß=0.13 L, 95% CI 0.10 to 0.15, p<0.001), 6MWD (ß=15.0 m, 95%CI 10.8 to 19.2, p<0.001), change in FEV1 (ß=-4.50 ml·year-1, 95% CI -7.32 to -1.67; p=0.001), exacerbations (IRR=0.78, 95% CI 0.73 to 0.83, p<0.001), and mortality (HR=0.79, 95% CI 0.72 to 0.86, p<0.001). CONCLUSION: T-Slope is a measure of airway luminal remodeling and is associated with respiratory morbidity and mortality.

FEV1/FVC Severity Stages for Chronic Obstructive Pulmonary Disease.

Rationale: The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a low FEV1/FVC ratio, but the severity of COPD is classified using FEV1% predicted (ppFEV1). Objectives: To test a new severity classification scheme for COPD using FEV1/FVC ratio, a more robust measure of airflow obstruction than ppFEV1. Methods: In COPDGene (Genetic Epidemiology of COPD) (N = 10,132), the severity of airflow obstruction was categorized by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (ppFEV1 of ⩾80%, ⩾50-80%, ⩾30-50%, and <30%). A new severity classification (STaging of Airflow obstruction by Ratio; STAR) was tested in COPDGene-FEV1/FVC ⩾0.60 to <0.70, ⩾0.50 to <0.60, ⩾0.40 to <0.50, and <0.40, respectively, for stages 1-4-and applied to the combined Pittsburgh SCCOR and Emphysema COPD Research Registry for replication (N = 2,017). Measurements and Main Results: The agreements (weighted Bangdiwala B values) between GOLD and the new FEV1/FVC ratio severity stages were 0.89 in COPDGene and 0.88 in the Pittsburgh cohort. In COPDGene and the Pittsburgh cohort, compared with GOLD staging, STAR provided significant discrimination between the absence of airflow obstruction and stage 1 for all-cause mortality, respiratory quality of life, dyspnea, airway wall thickness, exacerbations, and lung function decline. No major differences were noted for emphysema, small airway disease, and 6-minute-walk distance. The STAR classification system identified a greater number of adults with stage 3/4 disease who would be eligible for lung transplantation and lung volume reduction procedure evaluations. Conclusions: The new STAR severity classification scheme provides discrimination for mortality that is similar to the GOLD classification but with a more uniform gradation of disease severity. STAR differentiates patients' symptoms, disease burden, and prognosis better than the existing scheme based on ppFEV1, and is less sensitive to race/ethnicity and other demographic characteristics.

Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease.

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.

Pulmonary Rehabilitation for Adults with Chronic Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.

Background: Despite the known benefits of pulmonary rehabilitation (PR) for patients with chronic respiratory disease, this treatment is underused. Evidence-based guidelines should lead to greater knowledge of the proven benefits of PR, highlight the role of PR in evidence-based health care, and in turn foster referrals to and more effective delivery of PR for people with chronic respiratory disease. Methods: The multidisciplinary panel formulated six research questions addressing PR for specific patient groups (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) and models for PR delivery (telerehabilitation, maintenance PR). Treatment effects were quantified using systematic reviews. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel made the following judgments: strong recommendations for PR for adults with stable COPD (moderate-quality evidence) and after hospitalization for COPD exacerbation (moderate-quality evidence), strong recommendation for PR for adults with interstitial lung disease (moderate-quality evidence), conditional recommendation for PR for adults with pulmonary hypertension (low-quality evidence), strong recommendation for offering the choice of center-based PR or telerehabilitation for patients with chronic respiratory disease (moderate-quality evidence), and conditional recommendation for offering either supervised maintenance PR or usual care after initial PR for adults with COPD (low-quality evidence). Conclusions: These guidelines provide the basis for evidence-based delivery of PR for people with chronic respiratory disease.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Supporting delivery of remote pulmonary rehabilitation across different healthcare contexts: A multi-national study.

Purpose: This study aimed to understand factors that health professionals, from a variety of healthcare contexts and countries, believed support remote delivery of pulmonary rehabilitation (PR); and to develop a targeted intervention to support implementation of remote PR. Methods: A 3-phase participatory action-research process was employed, across three study hubs in three countries (NZ, India, USA), representing diverse healthcare delivery contexts. Phase 1 employed focus groups of health professionals working in PR; data were analysed qualitatively with transcripts coded against two implementation frameworks (Theoretical Domains Framework (TDF) and Consolidated Framework for Implementation Research (CFIR)). Findings informed development of an online toolbox to support delivery of remote PR (Phase 2), which was evaluated using semi-structured interviews (Phase 3). Results: 20 health professionals participated across all study phases. Factors considered to influence implementation of remote PR were consistent across diverse healthcare contexts and related to staffing availability, skills and confidence, and equipment and technology accessibility. An online toolbox provided support for enhancing knowledge and confidence, but was not able to address all implementation barriers. Discussion: Key factors to support clinicians deliver remote PR are common across different healthcare contexts, suggesting broader telerehabilitation implementation strategies may be applicable across healthcare environments.

Lung Function in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Prior studies have found that human immunodeficiency virus (HIV) infection is associated with impaired lung function and increased risk of chronic lung disease, but few have included large numbers of women. In this study, we investigate whether HIV infection is associated with differences in lung function in women. METHODS: This was a cross-sectional analysis of participants in the Women's Interagency HIV Study, a racially and ethnically diverse multicenter cohort of women with and without HIV. In 2018-2019, participants at 9 clinical sites were invited to perform spirometry. Single-breath diffusing capacity for carbon monoxide (DLCO) was also measured at selected sites. The primary outcomes were the post-bronchodilator forced expiratory volume in 1 second (FEV1) and DLCO. Multivariable regression modeling was used to analyze the association of HIV infection and lung function outcomes after adjustment for confounding exposures. RESULTS: FEV1 measurements from 1489 women (1062 with HIV, 427 without HIV) and DLCO measurements from 671 women (463 with HIV, 208 without HIV) met standards for quality and reproducibility. There was no significant difference in FEV1 between women with and without HIV. Women with HIV had lower DLCO measurements (adjusted difference, -0.73 mL/min/mm Hg; 95% confidence interval, -1.33 to -.14). Among women with HIV, lower nadir CD4 + cell counts and hepatitis C virus infection were associated with lower DLCO measurements. CONCLUSIONS: HIV was associated with impaired respiratory gas exchange in women. Among women with HIV, lower nadir CD4 + cell counts and hepatitis C infection were associated with decreased respiratory gas exchange.

Radiomics for Improved Detection of Chronic Obstructive Pulmonary Disease in Low-Dose and Standard-Dose Chest CT Scans.

Background Approximately half of adults with chronic obstructive pulmonary disease (COPD) remain undiagnosed. Chest CT scans are frequently acquired in clinical practice and present an opportunity to detect COPD. Purpose To assess the performance of radiomics features in COPD diagnosis using standard-dose and low-dose CT models. Materials and Methods This secondary analysis included participants enrolled in the Genetic Epidemiology of COPD, or COPDGene, study at baseline (visit 1) and 10 years after baseline (visit 3). COPD was defined by a forced expiratory volume in the 1st second of expiration to forced vital capacity ratio less than 0.70 at spirometry. The performance of demographics, CT emphysema percentage, radiomics features, and a combined feature set derived from inspiratory CT alone was evaluated. CatBoost (Yandex), a gradient boosting algorithm, was used to perform two classification experiments to detect COPD; the two models were trained and tested on standard-dose CT data from visit 1 (model I) and low-dose CT data from visit 3 (model II). Classification performance of the models was evaluated using area under the receiver operating characteristic curve (AUC) and precision-recall curve analysis. Results A total of 8878 participants (mean age, 57 years ± 9 [SD]; 4180 female, 4698 male) were evaluated. Radiomics features in model I achieved an AUC of 0.90 (95% CI: 0.88, 0.91) in the standard-dose CT test cohort versus demographics (AUC, 0.73; 95% CI: 0.71, 0.76; P < .001), emphysema percentage (AUC, 0.82; 95% CI 0.80, 0.84; P < .001), and combined features (AUC, 0.90; 95% CI: 0.89, 0.92; P = .16). Model II, trained on low-dose CT scans, achieved an AUC of 0.87 (95% CI: 0.83, 0.91) on the 20% held-out test set for radiomics features compared with demographics (AUC, 0.70; 95% CI: 0.64, 0.75; P = .001), emphysema percentage (AUC, 0.74; 95% CI: 0.69, 0.79; P = .002), and combined features (AUC, 0.88; 95% CI: 0.85, 0.92; P = .32). Density and texture features were the majority of the top 10 features in the standard-dose model, whereas shape features of lungs and airways were significant contributors in the low-dose CT model. Conclusion A combination of features representing parenchymal texture and lung and airway shape on inspiratory CT scans can be used to accurately detect COPD. ClinicalTrials.gov registration no. NCT00608764 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vliegenthart in this issue.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

Influence of Pulsatility and Inflow Waveforms on Tracheal Airflow Dynamics in Healthy Older Adults.

Tracheal collapsibility is a dynamic process altering local airflow dynamics. Patient-specific simulation is a powerful technique to explore the physiological and pathological characteristics of human airways. One of the key considerations in implementing airway computations is choosing the right inlet boundary conditions that can act as a surrogate model for understanding realistic airflow simulations. To this end, we numerically examine airflow patterns under the influence of different profiles, i.e., flat, parabolic, and Womersley, and compare these with a realistic inlet obtained from experiments. Simulations are performed in ten patient-specific cases with normal and rapid breathing rates during the inhalation phase of the respiration cycle. At normal breathing, velocity and vorticity contours reveal primary flow structures on the sagittal plane that impart strength to cross-plane vortices. Rapid breathing, however, encounters small recirculation zones. Quantitative flow metrics are evaluated using time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI). Overall, the flow metrics encountered in a real velocity profile are in close agreement with parabolic and Womersley profiles for normal conditions, however, the Womersley inlet alone conforms to a realistic profile under rapid breathing conditions.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.