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.

Mucus plugs in the airways of asthmatic subjects and smoking status.

BACKGROUND: Mucus plugs have been described in the airways of asthmatic subjects, particularly those with associated with type 2 inflammation and sputum eosinophilia. In the current study we addressed the question of whether smoking, neutrophilic inflammation and airway dimensions affected the prevalence of mucus plugs. METHODS: In a cohort of moderate to severe asthmatics (n = 50), including a group of ex-smokers and current smokers, the prevalence of mucus plugs was quantified using a semi-quantitative score based on thoracic computerized tomography. The relationships between mucus score, sputum inflammatory profile and airway architecture were tested according to patient's smoking status. RESULTS: Among the asthmatics (37% former or active smokers), 74% had at least one mucus plug. The median score was 3 and was unrelated to smoking status. A significant but weak correlation was found between mucus score, FEV1 and FEV1/FVC. Mucus score was significantly correlated with sputum eosinophils. Among former and active smokers, mucus score was correlated with sputum neutrophils. Mucus score was positively associated with FeNO in non-smoking subjects. The lumen dimensions of the main and lobar bronchi were significantly inversely correlated with mucus score. CONCLUSION: Airway mucus plugs could define an asthma phenotype with altered airway architecture and can occur in asthmatic subjects with either neutrophilic or eosinophilic sputum according to their smoking status.

Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

Associations of hiatus hernia with CT-based interstitial lung changes: the MESA Lung Study.

BACKGROUND: Hiatus hernia (HH) is prevalent in adults with pulmonary fibrosis. We hypothesised that HH would be associated with markers of lung inflammation and fibrosis among community-dwelling adults and stronger among MUC5B (rs35705950) risk allele carriers. METHODS: In the Multi-Ethnic Study of Atherosclerosis, HH was assessed from cardiac and full-lung computed tomography (CT) scans performed at Exam 1 (2000-2002, n=3342) and Exam 5 (2010-2012, n=3091), respectively. Percentage of high attenuation areas (HAAs; percentage of voxels with attenuation between -600 and -250 HU) was measured from cardiac and lung scans. Interstitial lung abnormalities (ILAs) were examined from Exam 5 scans (n=2380). Regression models were used to examine the associations of HH with HAAs, ILAs and serum matrix metalloproteinase-7 (MMP-7), and adjusted for age, sex, race/ethnicity, educational attainment, smoking, height, weight and scanner parameters for HAA analysis. RESULTS: HH detected from Exam 5 scans was associated with a mean percentage difference in HAAs of 2.23% (95% CI 0.57-3.93%) and an increase of 0.48% (95% CI 0.07-0.89%) per year, particularly in MUC5B risk allele carriers (p-value for interaction=0.02). HH was associated with ILAs among those <80 years of age (OR for ILAs 1.78, 95% CI 1.14-2.80) and higher serum MMP-7 level among smokers (p-value for smoking interaction=0.04). CONCLUSIONS: HH was associated with more HAAs over time, particularly among MUC5B risk allele carriers, and ILAs in younger adults, and may be a risk factor in the early stages of interstitial lung disease.

Impaired Ventilatory Efficiency, Dyspnea, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease: Results from the CanCOLD Study.

Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [[Formula: see text]e/[Formula: see text]co2]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1) the association between high [Formula: see text]e/[Formula: see text]co2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o2 ([Formula: see text]o2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co2 (r = -0.38; P < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co2 above the ULN was associated with greater dyspnea and low [Formula: see text]o2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.

Ambient Air Pollution and Dysanapsis: Associations with Lung Function and Chronic Obstructive Pulmonary Disease in the Canadian Cohort Obstructive Lung Disease Study.

Rationale: Outdoor air pollution is a potential risk factor for lower lung function and chronic obstructive pulmonary disease (COPD). Little is known about how airway abnormalities and lung growth might modify this relationship. Objectives: To evaluate the associations of ambient air pollution exposure with lung function and COPD and examine possible interactions with dysanapsis. Methods: We made use of cross-sectional postbronchodilator spirometry data from 1,452 individuals enrolled in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study with linked ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) air pollution estimates. Dysanapsis, or the ratio of the airway-to-lung volume calculated from thoracic computed tomography images, was used to examine possible interactions. Measurements and Main Results: In adjusted models, 101.7 ml (95% confidence interval [CI], -166.2 to -37.2) and 115.0 ml (95% CI, -196.5 to -33.4) lower FEV1 were demonstrated per increase of 2.4 ug/m3 PM2.5 and 9.2 ppb NO2, respectively. Interaction between air pollution and dysanapsis was not statistically significant when modeling the airway-to-lung ratio as a continuous variable. However, a 109.8 ml (95% CI, -209.0 to -10.5] lower FEV1 and an 87% (95% CI, 12% to 213%) higher odds of COPD were observed among individuals in the lowest, relative to highest, airway-to-lung ratio, per 2.4 µg/m3 increment of PM2.5. Conclusions: Ambient air pollution exposure was associated with lower lung function, even at relatively low concentrations. Individuals with dysanaptic lung growth might be particularly susceptible to inhaled ambient air pollutants, especially those at the extremes of dysanapsis.

Race/Ethnicity, Spirometry Reference Equations, and Prediction of Incident Clinical Events: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study.

Rationale: Normal values for FEV1 and FVC are currently calculated using cross-sectional reference equations that include terms for race/ethnicity, an approach that may reinforce disparities and is of unclear clinical benefit. Objectives: To determine whether race/ethnicity-based spirometry reference equations improve the prediction of incident chronic lower respiratory disease (CLRD) events and mortality compared with race/ethnicity-neutral equations. Methods: The MESA Lung Study, a population-based, prospective cohort study of White, Black, Hispanic, and Asian adults, performed standardized spirometry from 2004 to 2006. Predicted values for spirometry were calculated using race/ethnicity-based equations following guidelines and, alternatively, race/ethnicity-neutral equations without terms for race/ethnicity. Participants were followed for events through 2019. Measurements and Main Results: The mean age of 3,344 participants was 65 years, and self-reported race/ethnicity was 36% White, 25% Black, 23% Hispanic, and 17% Asian. There were 181 incident CLRD-related events and 547 deaths over a median of 11.6 years. There was no evidence that percentage predicted FEV1 or FVC calculated using race/ethnicity-based equations improved the prediction of CLRD-related events compared with those calculated using race/ethnicity-neutral equations (difference in C statistics for FEV1, -0.005; 95% confidence interval [CI], -0.013 to 0.003; difference in C statistic for FVC, -0.008; 95% CI, -0.016 to -0.0006). Findings were similar for mortality (difference in C statistics for FEV1, -0.002; 95% CI, -0.008 to 0.003; difference in C statistics for FVC, -0.004; 95% CI, -0.009 to 0.001). Conclusions: There was no evidence that race/ethnicity-based spirometry reference equations improved the prediction of clinical events compared with race/ethnicity-neutral equations. The inclusion of race/ethnicity in spirometry reference equations should be reconsidered.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

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.

Exertional dyspnoea in patients with mild-to-severe chronic obstructive pulmonary disease: neuromechanical mechanisms.

In patients with chronic obstructive pulmonary disease (COPD), exertional dyspnoea generally arises when there is imbalance between ventilatory demand and capacity, but the neurophysiological mechanisms are unclear. We therefore determined if disparity between elevated inspiratory neural drive (IND) and tidal volume (VT ) responses (neuromechanical dissociation) impacted dyspnoea intensity and quality during exercise, across the COPD severity spectrum. In this two-centre, cross-sectional observational study, 89 participants with COPD divided into tertiles of FEV1 %predicted (Tertile 1 = FEV1 = 87 ± 9%, Tertile 2 = 60 ± 9%, Tertile 3 = 32 ± 8%) and 18 non-smoking controls, completed a symptom-limited cardiopulmonary exercise test (CPET) with measurement of IND by diaphragm electromyography (EMGdi (%max)). The association between increasing dyspnoea intensity and EMGdi (%max) during CPET was strong (r = 0.730, P < 0.001) and not different between the four groups who showed marked heterogeneity in pulmonary gas exchange and mechanical abnormalities. Significant inspiratory constraints (tidal volume/inspiratory capacity (VT /IC) ≥ 70%) and onset of neuromechanical dissociation (EMGdi (%max):VT /IC > 0.75) occurred at progressively lower minute ventilation ( V ̇ E ${\dot{V}}_{{\rm{E}}}$ ) from Control to Tertile 3. Lower resting IC meant earlier onset of neuromechanical dissociation, heightened dyspnoea intensity and greater propensity (93% in Tertile 3) to select qualitative descriptors of 'unsatisfied inspiration'. We concluded that, regardless of marked variation in mechanical and pulmonary gas exchange abnormalities in our study sample, exertional dyspnoea intensity was linked to the magnitude of EMGdi (%max). Moreover, onset of critical inspiratory constraints and attendant neuromechanical dissociation amplified dyspnoea intensity at higher exercise intensities. Simple measurements of IC and breathing pattern during CPET provide useful insights into mechanisms of dyspnoea and exercise intolerance in individuals with COPD. KEY POINTS: Dyspnoea during exercise is a common and troublesome symptom reported by patients with chronic obstructive pulmonary disease (COPD) and is linked to an elevated inspiratory neural drive (IND). The precise mechanisms of elevated IND and dyspnoea across the continuum of airflow obstruction severity in COPD remains unclear. The present study sought to determine the mechanisms of elevated IND (by diaphragm EMG, EMGdi (%max)) and dyspnoea during cardiopulmonary exercise testing (CPET) across the continuum of COPD severity. There was a strong association between increasing dyspnoea intensity and EMGdi (%max) during CPET across the COPD continuum despite significant heterogeneity in underlying pulmonary gas exchange and respiratory mechanical impairments. Critical inspiratory constraints occurred at progressively lower ventilation during exercise with worsening severity of COPD. This was associated with the progressively lower resting inspiratory capacity with worsening disease severity. Earlier critical inspiratory constraint was associated with earlier neuromechanical dissociation and greater likelihood of reporting the sensation of 'unsatisfied inspiration'.

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

Asthma and fixed airflow obstruction: Long-term trajectories suggest distinct endotypes.

BACKGROUND: Long-term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. OBJECTIVE: We investigated whether measures of asthma control and airway inflammation and remodelling differed by long-term FAO status in moderate-to-severe asthma. METHODS: Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post-bronchodilator forced expired volume in one second (FEV1 )-to-forced vital capacity ratio below 0.70. RESULTS: Sixty-two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow-up assessment (median interval 7.9 years; IQR: 5.4-8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long-term follow-up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long-term follow-up. Sputum eosinophils, ACQ and long-term FEV1 decline did not differ. Participants with incident FAO at long-term follow-up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1 , whereas baseline ASM was similar to those without FAO. CONCLUSION: In moderate-to-severe asthma, long-term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long-term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline.

Human airway branch variation and chronic obstructive pulmonary disease.

Susceptibility to chronic obstructive pulmonary disease (COPD) beyond cigarette smoking is incompletely understood, although several genetic variants associated with COPD are known to regulate airway branch development. We demonstrate that in vivo central airway branch variants are present in 26.5% of the general population, are unchanged over 10 y, and exhibit strong familial aggregation. The most common airway branch variant is associated with COPD in two cohorts (n = 5,054), with greater central airway bifurcation density, and with emphysema throughout the lung. The second most common airway branch variant is associated with COPD among smokers, with narrower airway lumens in all lobes, and with genetic polymorphisms within the FGF10 gene. We conclude that central airway branch variation, readily detected by computed tomography, is a biomarker of widely altered lung structure with a genetic basis and represents a COPD susceptibility factor.

Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.

Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown.Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT).Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general population-based cohort, and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). A weighted GRS was calculated from 83 SNPs that were previously associated with lung function. Lung density, spatially matched airway dimensions, and airway counts were assessed on full-lung CT. Generalized linear models were adjusted for age, age squared, sex, height, principal components of genetic ancestry, smoking status, pack-years, CT model, milliamperes, and total lung volume.Measurements and Main Results: MESA Lung and SPIROMICS contributed 2,517 and 2,339 participants, respectively. Higher GRS was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways, without effect modification by smoking. Adjustment for CT lung structure, particularly small airway measures, attenuated associations between the GRS and FEV1/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P < 0.0001), but not the GRS (P > 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone.Conclusions: A GRS associated with COPD susceptibility was associated with CT lung structure. Lung structure may be an important mediator of heritability and determinant of personalized COPD risk.

Description of Participation in Daily and Social Activities for Individuals with COPD.

This study described the participation in daily and social activities and the perceived barriers and facilitators to participation of individuals with chronic obstructive pulmonary disease (COPD). Individuals, recruited from outpatient clinics, responded to a survey on their participation in, and barriers and facilitators towards, 26 daily and social activities, divided into 3 categories: (1) physical activity and movement (PAM); (2) self-care; and (3) social engagement. For each activity, chi-square analyses were used to examine participation differences by individuals': quartiles of airflow obstruction [percent predicted forced expiratory volume in 1 second (FEV1%predicted)] and breathlessness burden and exacerbation risk. Of the 200 participants (47% women; mean ± standard deviation age = 68 ± 9 years), most wanted to increase their participation in PAM activities (range 21-75%) and significant differences were found in 5/10 PAM activities for individuals' breathlessness burden and exacerbation risk (e.g., more individuals than expected in group A (modified Medical Research Council breathlessness score <2 and 0-1 exacerbations in past 12 months) participated in regular exercise as much as they wanted (χ(9)2=20.43, Cramer's V=.23)). Regardless of the degree of airflow obstruction or breathlessness burden and exacerbation risk, the most common barrier to participation was breathlessness (p<.001, η2p=.86) and the most common facilitator was engaging as part of their routine (p<.001, η2p=.75). Individuals with COPD want to increase their participation in daily and social activities but are limited by breathlessness. Strategies to alleviate breathlessness should be identified/prioritized and incorporated into individuals' daily routines to meet their self-reported participation objectives in daily and social activities.

Association of Dysanapsis With Chronic Obstructive Pulmonary Disease Among Older Adults.

Importance: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), yet much of COPD risk remains unexplained. Objective: To determine whether dysanapsis, a mismatch of airway tree caliber to lung size, assessed by computed tomography (CT), is associated with incident COPD among older adults and lung function decline in COPD. Design, Setting, and Participants: A retrospective cohort study of 2 community-based samples: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, which involved 2531 participants (6 US sites, 2010-2018) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD), which involved 1272 participants (9 Canadian sites, 2010-2018), and a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which involved 2726 participants (12 US sites, 2011-2016). Exposures: Dysanapsis was quantified on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio). Main Outcomes and Measures: Primary outcome was COPD defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function. All analyses were adjusted for demographics and standard COPD risk factors (primary and secondhand tobacco smoke exposures, occupational and environmental pollutants, and asthma). Results: In the MESA Lung sample (mean [SD] age, 69 years [9 years]; 1334 women [52.7%]), 237 of 2531 participants (9.4%) had prevalent COPD, the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV1 decline was -33 mL/y (31 mL/y). Of 2294 MESA Lung participants without prevalent COPD, 98 (4.3%) had incident COPD at a median of 6.2 years. Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 vs 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81 to 17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1 to 9.2; P < .001) but no significant difference in FEV1 decline (-31 vs -33 mL/y; difference, 2 mL/y; 95% CI, -2 to 5; P = .30). Among CanCOLD participants (mean [SD] age, 67 years [10 years]; 564 women [44.3%]), 113 of 752 (15.0%) had incident COPD at a median of 3.1 years and the mean (SD) FEV1 decline was -36 mL/y (75 mL/y). The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (-34 vs -36 mL/y; difference, 1 mL/y; 95% CI, -15 to 16; P=.97). Among 1206 SPIROMICS participants (mean [SD] age, 65 years [8 years]; 542 women [44.9%]) with COPD who were followed up for a median 2.1 years, those in the lowest airway to lung ratio quartile had a mean FEV1 decline of -37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (-55 mL/y [16 mL/y ]; difference, -17 mL/y; 95% CI, -32 to -3; P = .004). Conclusions and Relevance: Among older adults, dysanapsis was significantly associated with COPD, with lower airway tree caliber relative to lung size associated with greater COPD risk. Dysanapsis appears to be a risk factor associated with COPD.

Inhalation Toxicology of Vaping Products and Implications for Pulmonary Health.

E-cigarettes have a liquid that may contain flavors, solvents, and nicotine. Heating this liquid generates an aerosol that is inhaled into the lungs in a process commonly referred to as vaping. E-cigarette devices can also contain cannabis-based products including tetrahydrocannabinol (THC), the psychoactive component of cannabis (marijuana). E-cigarette use has rapidly increased among current and former smokers as well as youth who have never smoked. The long-term health effects are unknown, and emerging preclinical and clinical studies suggest that e-cigarettes may not be harmless and can cause cellular alterations analogous to traditional tobacco smoke. Here, we review the historical context and the components of e-cigarettes and discuss toxicological similarities and differences between cigarette smoke and e-cigarette aerosol, with specific reference to adverse respiratory outcomes. Finally, we outline possible clinical disorders associated with vaping on pulmonary health and the recent escalation of acute lung injuries, which led to the declaration of the vaping product use-associated lung injury (EVALI) outbreak. It is clear there is much about vaping that is not understood. Consequently, until more is known about the health effects of vaping, individual factors that need to be taken into consideration include age, current and prior use of combustible tobacco products, and whether the user has preexisting lung conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Imaging-based clusters in former smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and intermediate outcome measures in COPD study (SPIROMICS).

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. RESULTS: We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. CONCLUSIONS: QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.