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Background Post-surgical hypoparathyroidism (PoSH) is often long term, with significant associated morbidity and ongoing treatment. A recent systematic review found impaired quality of life (QoL) in patients with PoSH, despite stable treatment. Most studies did not include an appropriate control arm and further studies were recommended, taking into account underlying disease and comorbidities. This study aims to compare QoL in patients with PoSH with appropriate control groups. Methods This was a cross-sectional observational study using the general quality of life SF-36 tool and a hypocalcaemia symptom score (HcSS) to assess QoL in patients with PoSH and controls (who had similar surgery but without PoSH). Participants were identified from two patient groups (the Butterfly Thyroid Cancer Trust and the Association for Multiple Endocrine Neoplasia Disorders) and a single tertiary centre in the UK. Results Four hundred and thirty-nine responses (female n = 379, PoSH n = 89) were included with a median (range) age of 52 (19–92) years. Reported dates of surgery ranged from 1973 to 2019. HcSS scores showed significantly more associated symptoms in patients with PoSH than those without (p p = 0.008) in the energy/fatigue subdomain of the SF-36. Conclusion Patients with PoSH reported significantly more fatigue and loss of energy compared to appropriately matched controls, but overall QoL was not significantly different. Standardised QoL measures may not be sensitive enough to highlight the impact on QoL in these patients. A disease-specific tool may be required.

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4

BACKGROUND: Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. PURPOSE: To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 ((3)He) MRI. MATERIALS AND METHODS: In this secondary analysis of a Health Insurance Portability and Accountability Act–compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized (3)He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. RESULTS: Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th–75th percentile, 7.3%–38.3%) versus 1.4% (25th–75th percentile, 0.1%–5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th–75th percentile, 7.1%–18.9%) versus 3.1% (25th–75th percentile, 1.1%–4.4%) in those without plugs (P < .001). CONCLUSION: Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Hip fractures are associated with significant morbidity and mortality in smokers with lung disease, but whether lung-specific factors are associated with fracture risk is unknown. Our goal was to determine whether lung-specific factors associate with incident hip fracture and improve risk discrimination of traditional fracture risk models in smokers. The analysis consisted of a convenience sample of 9187 current and former smokers (58,477 participant follow-up years) participating in the Genetic Epidemiology of chronic obstructive pulmonary disease (COPD) longitudinal observational cohort study. Participants were enrolled between 2008 and 2011 with follow-up data collection through July 2018. Traditional risk factors associated with incident hip fracture (n = 361) included age, female sex, osteoporosis, prevalent spine and hip fracture, rheumatoid arthritis, and diabetes. Lung-specific risk factors included post-bronchodilator percent forced expiratory volume in 1 s (FEV1 %) predicted (OR, 0.95; 95% CI, 0.92-0.99 for each 10% increase), Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification (OR, 1.09; 95% CI, 1.002-1.19 for each higher stage), presence of CT-determined emphysema (OR, 1.34; 95% CI, 1.06-1.69), symptom scores (OR, 1.10; 95% CI, 1.03-1.19 for each higher unit score), 6-min walk distance (OR, 0.92; 95% CI, 0.90-0.95 for each 30-m increase), body mass index, airflow obstruction, dyspnea, and exercise (BODE) index (OR, 1.07; 95% CI, 1.01-1.13 for each higher unit score), total exacerbations (OR, 1.13; 95% CI, 1.10-1.16 per exacerbation), and annual exacerbations (OR, 1.37; 95% CI, 1.21-1.55 per exacerbation). In multivariable modeling, age, black race, osteoporosis, prevalent hip and spine fracture, rheumatoid arthritis, and diabetes were associated with incident hip fracture. The presence of emphysema, 6-min walk distance, and total number of exacerbations added to traditional models improved risk discrimination (integrated discrimination improvement [IDI] values 0.001 [95% CI, 0.0003-0.002], 0.001 [95% CI, 0.0001-0.002], and 0.008 [95% CI, 0.003-0.013], corresponding to relative IDIs of 12.8%, 6.3%, and 34.6%, respectively). These findings suggest that the incorporation of lung-specific risk factors into fracture risk assessment tools may more accurately predict fracture risk in smokers. © 2020 American Society for Bone and Mineral Research.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. Objectives: To perform a genome-wide association study (GWAS) of ILAs. Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10(−27)) and subpleural ILAs (P = 1.6 × 10(−29)). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10(−8)) and FCF1P3 (rs73199442, P = 4.8 × 10(−8)) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10(−8)) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

Background Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. Methods sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). Results Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P 1 (P 10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

Background Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. Methods Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC Results Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, –2.2; 95% CI, –4.1 to –0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, –1.1; 95% CI, –1.9 to –0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, –14.3 to 15.6). Conclusions Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. Trial Registry ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

The Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, which began in 2007, is an ongoing multicenter observational cohort study of more than 10,000 current and former smokers. The study is aimed at understanding the etiology, progression, and heterogeneity of chronic obstructive pulmonary disease (COPD). In addition to genetic analysis, the participants have been extensively characterized by clinical questionnaires, spirometry, volumetric inspiratory and expiratory computed tomography, and longitudinal follow-up, including follow-up computed tomography at 5 years after enrollment. The purpose of this state-of-the-art review is to summarize the major advances in our understanding of COPD resulting from the imaging findings in the COPDGene study. Imaging features that are associated with adverse clinical outcomes include early interstitial lung abnormalities, visual presence and pattern of emphysema, the ratio of pulmonary artery to ascending aortic diameter, quantitative evaluation of emphysema, airway wall thickness, and expiratory gas trapping. COPD is characterized by the early involvement of the small conducting airways, and the addition of expiratory scans has enabled measurement of small airway disease. Computational advances have enabled indirect measurement of nonemphysematous gas trapping. These metrics have provided insights into the pathogenesis and prognosis of COPD and have aided early identification of disease. Important quantifiable extrapulmonary findings include coronary artery calcification, cardiac morphology, intrathoracic and extrathoracic fat, and osteoporosis. Current active research includes identification of novel quantitative measures for emphysema and airway disease, evaluation of dose reduction techniques, and use of deep learning for phenotyping COPD.

Early stages of chronic obstructive pulmonary disease (COPD) are characterized by the loss and narrowing of terminal bronchioles in the lung, resulting in “air-trapping,” often occurring before overt emphysema manifests. Individuals with an airway-predominant phenotype of COPD display extensive lung air-trapping and are at greater cardiovascular disease (CVD) risk than COPD patients with an emphysema-predominant phenotype. We hypothesized that the degree of computed tomography (CT)-quantified lung air-trapping would be associated with greater aortic and carotid artery stiffness and lower endothelial function, known biomarkers of CVD risk. Lung air-trapping was associated with greater aortic stiffness (carotid femoral pulse wave velocity, CFPWV) ( r = 0.60, P = 0.007) and carotid β-stiffness ( r = 0.75, P = 0.0001) among adults with ( n = 10) and without ( n = 9) a clinical diagnosis of COPD and remained significant after adjusting for blood pressure (BP) and smoking history (pack-years) (carotid β-stiffness: r = 0.68, P < 0.01; CFPWV r = 0.53, P = 0.03). The association between lung air-trapping and carotid β-stiffness remained significant after additionally adjusting for age and forced expiratory volume 1(FEV1) ( r = 0.64, P = 0.01). In the COPD group only ( n = 10), lung air-trapping remained associated with carotid β-stiffness ( r = 0.82, P = 0.05) after adjustment for age, pack-years, and FEV1. In contrast, no association was observed between CFPWV and lung air-trapping after adjustment for BP, pack-years, age, and FEV1 ( r = 0.12, P = 0.83). Lung air-trapping was not associated with endothelial function (brachial artery flow-mediated dilation) in the entire cohort ( P = 0.80) or in patients with COPD only ( P = 0.71). These data suggest that carotid artery stiffness may be a mechanism explaining the link between airway-predominant phenotypes of COPD and high CVD risk. NEW & NOTEWORTHY Previous cross-sectional studies have demonstrated greater large elastic artery stiffness and lower endothelium-dependent dilation in chronic obstructive pulmonary disease (COPD) patients compared with controls. Furthermore, COPD patients with emphysema have greater aortic stiffness than non-COPD controls, and the degree of stiffness is associated with emphysema severity. The present study is the first to demonstrate that even before overt emphysema manifests, lung air-trapping is associated with carotid artery stiffness in COPD patients independent of blood pressure, age, or smoking history.

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

Background:Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publication have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n=1,443), SPIROMICS (n=1,623); ECLIPSE (n=2,349); Pittsburgh COPD SCCOR (n=399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P1 (P < 0.001), and emphysema severity (P10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Contains fulltext : 220761.pdf (Publisher’s version ) (Open Access) Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue-->Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway-->Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P < 0.001] in the Tissue-->Airway group; r = -0.14 [P = 0.011] in the Airway-->Tissue group). SuStaIn placed 30% of smokers with normal lung function at elevated stages, suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up.Conclusions: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One third of healthy smokers have detectable imaging changes, suggesting a new biomarker of "early COPD."

Publisher's version (útgefin grein), Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P, R.J.A. is an Action for Pulmonary Fibrosis Research Fellow. L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). I.N. is supported by the NHLBI (R01HL130796). B.G.-G. is funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (TESIS2015010057) cofunded by European Social Fund. J.M.O. is supported by the NHLBI (K23HL138190). C.F. is supported by the Spanish Ministry of Science, Innovation and Universities (grant RTC-2017-6471-1; Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea) cofinanced by the European Regional Development Funds “A way of making Europe” from the European Union and by agreement OA17/008 with Instituto Tecnológico y de Energías Renovables to strengthen scientific and technological education, training, research, development and innovation in Genomics, Personalized Medicine and Biotechnology. The Spain Biobank array genotyping service was performed at CEGEN-PRB3-ISCIII, which is supported by PT17/0019, of the PE I+D+i 2013–2016, funded by Instituto de Salud Carlos III, and cofinanced by the European Regional Development Funds. P.L.M. is an Action for Pulmonary Fibrosis Research Fellow. M.O. is a fellow of the Parker B. Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research. B.D.H. is supported by NIH K08 HL136928, Parker B. Francis Research Opportunity Award. M.H.C. and G.M.H. are supported by NHLBI grants R01HL113264 (M.H.C.), R01HL137927 (M.H.C.), R01HL135142 (M.H.C. and G.M.H.), R01111024 (G.M.H.), and R01130974 (G.M.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. T.M.M. is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). M.D.T. is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health. I.P.H. was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. I.S. is supported by Medical Research Council (G1000861) and Asthma UK (AUK-PG-2013-188). D.F. was supported by an Intermediate Fellowship from the Wellcome Trust (097152/Z/11/Z). This work was partially supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. V.N. is funded by an NIHR Clinical Lectureship. G.G. is supported by project grant 141513-051 from the Icelandic Research Fund and Landspitali Scientific Fund A-2016-023, A-2017-029, and A-2018-025. D.J.L. and A.M. are supported by Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SNP Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California) and the Broad Institute of Harvard and Massachusetts Institute of Technology (Boston, Massachusetts) using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was supported by NIH grants R01 HL131565 (A.M.), R01 HL103676 (D.J.L.), and R01 HL137234 (D.J.L.).

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Purpose Quantitative computed tomography (QCT)-derived measures of lung density are valued methods for objectively characterizing lung parenchymal and peripheral airways disease and are being used in a growing number of lung disease focused trials. Detector and reconstruction improvements in CT technology have allowed for significant radiation dose reduction in image acquisition with comparable qualitative image quality. We report the impact of detector type and reconstruction type on QCT lung density measures in relation to decreasing dose indices. Methods Two sets of studies were completed in an in vivo pig model with a SOMATOM Definition Flash CT system: (a) prior to system upgrade with conventional detectors (UFC) and filtered back projection (FBP), and (b) post system upgrade with integrated electronic detectors (STELLAR) and iterative reconstruction (SAFIRE). CT data were acquired across estimated CT volume dose indices (CTDIvol ) ranging from 0.75 to 15 mGy at both inspiratory and expiratory breath holds. Semiautomated lung segmentations allowed calculation of histogram median, kurtosis, and 15th percentile. Percentage of voxels below -910 HU and -950 HU (inspiratory), and -856 HU (expiratory) were also examined. The changes in these QCT metrics from dose reduction (15 mGy down to 0.75 mGy) were calculated relative to paired reference values (15 mGy). Results were compared based on detector and reconstruction type. Results In this study, STELLAR detectors improved concordance with 15 mGy values down to 3 mGy for inspiratory scans and 6 mGy for expiratory scans. The addition of SAFIRE reconstruction in all acquired measurements resulted in minimal deviation from reference values at 0.75 mGy. Conclusion The use of STELLAR integrated electronic detectors and SAFIRE iterative reconstruction may allow for comparable lung density measures with CT dose indices down to 0.75 mGy.

Rationale: Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear.Objectives: In this work, we sought to determine the independent association between rural residence and COPD-related outcomes, including COPD exacerbations, airflow obstruction, and symptom burden.Methods: A total of 1,684 SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) participants with forced expiratory volume in 1 second/forced vital capacity < 0.70 had geocoding-defined rural-urban residence status determined (N = 204 rural and N = 1,480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes, including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of the home address to the block level at the time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures. The primary outcome measures were exacerbations determined over a 1-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. The odds ratio (OR) and incidence rate ratio (IRR) of exacerbations that required treatment with medications, including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates.Results: Rural residence was independently associated with a 70% increase in the odds of total exacerbations (OR, 1.70 [95% confidence interval (CI), 1.13-2.56]; P = 0.012) and a 46% higher incidence rate of total exacerbations (IRR 1.46 [95% CI, 1.02-2.10]; P = 0.039). There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation in the analysis attenuated the association between rural residence and the odds and incidence rate of total exacerbations (OR, 1.52 [95% CI, 1.00-2.32]; P = 0.05 and IRR 1.39 [95% CI, 0.97-1.99]; P = 0.07). There was no difference in symptoms or airflow obstruction between rural and urban participants.Conclusions: Rural residence is independently associated with increased odds and incidence of total, but not severe, COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of the increased risk of COPD exacerbations in the rural population.

Lung imaging is increasingly being used to diagnose, quantify, and phenotype chronic obstructive pulmonary disease (COPD). Although spirometry is the gold standard for the diagnosis of COPD and for severity staging, the role of computed tomography (CT) imaging has expanded in both clinical practice and research. COPD is a heterogeneous disease with considerable variability in clinical features, radiographic disease, progression, and outcomes. Recent studies have examined the utility of CT imaging in enhancing diagnostic certainty, improving phenotyping, predicting disease progression and prognostication, selecting patients for intervention, and also in furthering our understanding of the complex pathophysiology of this disease. Multiple CT metrics show promise for use as imaging biomarkers in COPD.

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment–based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%–80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01718197","term_id":"NCT01718197"}}NCT01718197, {"type":"clinical-trial","attrs":{"text":"NCT01606826","term_id":"NCT01606826"}}NCT01606826, {"type":"clinical-trial","attrs":{"text":"NCT01750411","term_id":"NCT01750411"}}NCT01750411, {"type":"clinical-trial","attrs":{"text":"NCT01761058","term_id":"NCT01761058"}}NCT01761058, {"type":"clinical-trial","attrs":{"text":"NCT01761630","term_id":"NCT01761630"}}NCT01761630, {"type":"clinical-trial","attrs":{"text":"NCT01759186","term_id":"NCT01759186"}}NCT01759186, {"type":"clinical-trial","attrs":{"text":"NCT01716494","term_id":"NCT01716494"}}NCT01716494, and {"type":"clinical-trial","attrs":{"text":"NCT01760915","term_id":"NCT01760915"}}NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109146","term_id":"1051682664"}}HL109146, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109164","term_id":"1051682685"}}HL109164, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109172","term_id":"1051682699"}}HL109172, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109086","term_id":"1051682577"}}HL109086, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109250","term_id":"1051682815"}}HL109250, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109168","term_id":"1051682692"}}HL109168, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109257","term_id":"1051682826"}}HL109257, U10 {"type":"entrez-nucleotide","attrs":{"text":"HL109152","term_id":"1051682671"}}HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

Background Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions. Methods Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at Results Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans. Conclusions Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period. Trial Registry ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov.

Contains fulltext : 194255.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. METHODS: We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. RESULTS: Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. CONCLUSIONS: Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD.

Summary Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low ( 1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV 1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute.

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Rationale: The American Thoracic Society (ATS)/European Respiratory Society defines a positive bronchodilator response (BDR) by a composite of BDR in either forced expiratory volume in 1 second (FEV(1)) and/or forced vital capacity (FVC) greater than or equal to 12% and 200 ml (ATS-BDR). We hypothesized that ATS-BDR components would be differentially associated with important chronic obstructive pulmonary disease (COPD) outcomes. Objectives: To examine whether ATS-BDR components are differentially associated with clinical, functional, and radiographic features in COPD. Methods: We included subjects with COPD enrolled in the COPDGene study. In the main analysis, we excluded subjects with self-reported asthma. We categorized BDR into the following: 1) No-BDR, no BDR in either FEV(1) or FVC; 2) FEV(1)-BDR, BDR in FEV(1) but no BDR in FVC; 3) FVC-BDR, BDR in FVC but no BDR in FEV(1); and 4) Combined-BDR, BDR in both FEV(1) and FVC. We constructed multivariable logistic, linear, zero-inflated negative binomial, and Cox hazards models to examine the association of BDR categories with symptoms, computed tomography findings, change in FEV(1) over time, respiratory exacerbations, and mortality. We also created models using the ATS BDR definition (ATS-BDR) as the main independent variable. Results: Of 3,340 COPD subjects included in the analysis, 1,083 (32.43%) had ATS-BDR, 182 (5.45%) had FEV(1)-BDR, 522 (15.63%) had FVC-BDR, and 379 (11.34%) had Combined-BDR. All BDR categories were associated with FEV(1) decline compared with No-BDR. Compared with No-BDR, both ATS-BDR and Combined-BDR were associated with higher functional residual capacity %predicted, greater internal perimeter of 10 mm, and greater 6-minute-walk distance. In contrast to ATS-BDR, Combined-BDR was independently associated with less emphysema (adjusted beta regression coefficient, −1.67; 95% confidence interval [CI], −2.68 to −0.65; P = 0.001), more frequent respiratory exacerbations (incidence rate ratio, 1.25; 95% CI, 1.03–1.50; P = 0.02) and severe exacerbations (incidence rate ratio, 1.34; 95% CI, 1.05–1.71; P = 0.02), and lower mortality (adjusted hazards ratio, 0.76; 95% CI, 0.58–0.99; P = 0.046). Sensitivity analysis that included subjects with self-reported history of asthma showed similar findings. Conclusions: BDR in both FEV(1) and FVC indicates a COPD phenotype with asthma-like characteristics, and provides clinically more meaningful information than current definitions of BDR.

BackgroundObesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown.MethodsWe performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height.2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD.ResultsA total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD.ConclusionsSubcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Background Chronic bronchitis (CB) increases risk of COPD exacerbations. We have shown that the St. George's Respiratory Questionnaire (SGRQ) CB definition identifies patients with a similar clinical phenotype as classically defined CB. Whether the SGRQ CB definition is a predictor of future COPD exacerbations is unknown. Methods We analyzed 7,557 smokers with normal spirometry and Global Initiative for Chronic Obstructive Lung Disease stage 1-4 COPD in the Genetic Epidemiology of COPD study with longitudinal follow-up data on exacerbations. Subjects were divided into classic CB+ or classic CB–, using the classic definition. In addition, subjects were divided into SGRQ CB+ or SGRQ CB–. Exacerbation frequency and severe exacerbation frequency were determined in each group. Multivariable linear regressions were performed for exacerbation frequency with either classic CB or SGRQ CB and relevant covariates. Results There were 1,434 classic CB+ subjects and 2,290 SGRQ CB+ subjects. The classic CB+ group had a greater exacerbation frequency compared with the classic CB– group (0.69 ± 1.26 vs 0.36 ± 0.90 exacerbations per patient per year; P Conclusions The SGRQ CB definition identified more subjects at risk for future exacerbations than the classic CB definition. SGRQ CB was at least a similar if not better predictor of future exacerbations than classic CB.

Background Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. Methods We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between −600 and −250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. Results In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected. Conclusions RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.

The objective of this study was to increase the spatial and temporal resolution of dynamic 3-dimensional (3D) magnetic resonance imaging (MRI) of lung volumes and diaphragm motion. To achieve this goal, we evaluate the utility of the proposed blind compressed sensing (BCS) algorithm to recover data from highly undersampled measurements.We evaluated the performance of the BCS scheme to recover dynamic data sets from retrospectively and prospectively undersampled measurements. We also compared its performance against that of view-sharing, the nuclear norm minimization scheme, and the l1 Fourier sparsity regularization scheme. Quantitative experiments were performed on a healthy subject using a fully sampled 2D data set with uniform radial sampling, which was retrospectively undersampled with 16 radial spokes per frame to correspond to an undersampling factor of 8. The images obtained from the 4 reconstruction schemes were compared with the fully sampled data using mean square error and normalized high-frequency error metrics. The schemes were also compared using prospective 3D data acquired on a Siemens 3 T TIM TRIO MRI scanner on 8 healthy subjects during free breathing. Two expert cardiothoracic radiologists (R1 and R2) qualitatively evaluated the reconstructed 3D data sets using a 5-point scale (0-4) on the basis of spatial resolution, temporal resolution, and presence of aliasing artifacts.The BCS scheme gives better reconstructions (mean square error = 0.0232 and normalized high frequency = 0.133) than the other schemes in the 2D retrospective undersampling experiments, producing minimally distorted reconstructions up to an acceleration factor of 8 (16 radial spokes per frame). The prospective 3D experiments show that the BCS scheme provides visually improved reconstructions than the other schemes do. The BCS scheme provides improved qualitative scores over nuclear norm and l1 Fourier sparsity regularization schemes in the temporal blurring and spatial blurring categories. The qualitative scores for aliasing artifacts in the images reconstructed by nuclear norm scheme and BCS scheme are comparable.The comparisons of the tidal volume changes also show that the BCS scheme has less temporal blurring as compared with the nuclear norm minimization scheme and the l1 Fourier sparsity regularization scheme. The minute ventilation estimated by BCS for tidal breathing in supine position (4 L/min) and the measured supine inspiratory capacity (1.5 L) is in good correlation with the literature. The improved performance of BCS can be explained by its ability to efficiently adapt to the data, thus providing a richer representation of the signal.The feasibility of the BCS scheme was demonstrated for dynamic 3D free breathing MRI of lung volumes and diaphragm motion. A temporal resolution of ∼500 milliseconds, spatial resolution of 2.7 × 2.7 × 10 mm, with whole lung coverage (16 slices) was achieved using the BCS scheme.

Purpose: A test object (phantom) is an important tool to evaluate comparability and stability of CTscanners used in multicenter and longitudinal studies. However, there are many sources of error that can interfere with the test object-derived quantitative measurements. Here the authors investigated three major possible sources of operator error in the use of a test object employed to assess pulmonary density-related as well as airway-related metrics. Methods: Two kinds of experiments were carried out to assess measurement variability caused by imperfect scanning status. The first one consisted of three experiments. A COPDGene test object was scanned using a dual source multidetector computed tomographic scanner (Siemens Somatom Flash) with the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) inspiration protocol (120 kV, 110 mAs, pitch = 1, slice thickness = 0.75 mm, slice spacing = 0.5 mm) to evaluate the effects of tilt angle, water bottle offset, and air bubble size. After analysis of these results, a guideline was reached in order to achieve more reliable results for this test object. Next the authors applied the above findings to 2272 test object scans collected over 4 years as part of the SPIROMICS study. The authors compared changes of the data consistency before and after excluding the scans that failed to pass the guideline. Results: This study established the following limits for the test object: tilt index ≤0.3, water bottle offset limits of [−6.6 mm, 7.4 mm], and no air bubble within the water bottle, where tilt index is a measure incorporating two tilt angles around x- and y-axis. With 95% confidence, the density measurement variation for all five interested materials in the test object (acrylic, water,lung, inside air, and outside air) resulting from all three error sources can be limited to ±0.9 HU (summed in quadrature), when all the requirements are satisfied. The authors applied these criteria to 2272 SPIROMICS scans and demonstrated a significant reduction in measurement variation associated with the test object. Conclusions: Three operator errors were identified which significantly affected the usability of the acquired scan images of the test object used for monitoring scanner stability in a multicenter study. The authors’ results demonstrated that at the time of test object scan receipt at a radiology core laboratory, quality control procedures should include an assessment of tilt index, water bottle offset, and air bubble size within the water bottle. Application of this methodology to 2272 SPIROMICS scans indicated that their findings were not limited to the scanner make and model used for the initial test but was generalizable to both Siemens and GE scanners which comprise the scanner types used within the SPIROMICS study.

Background: Although the relation between radiographic abnormalities and spirometric impairment in people with asbestosis has been studied extensively, the extent of spirometric impairment associated with milder radiographic abnormalities is not established.Objective: To test associations between mild radiographic abnormalities and Lower Limit of Normal (LLN)-based spirometry interpretation.Methods: Spirometry and CXRs were collected for 1,026 at low risk of exposure to pneumoconiotic agents participants in a medical screening program.Results: Individuals with each type of isolated or combined International Labour Organization (ILO) abnormalities had up to over sixfold statistically significant increase in odds of LLN-based restrictive pattern physiology (OR = 1.96, 95%CI 1.03–3.73 for parenchymal to OR = 6.09, 95%CI 1.94–19.10 for parenchymal and pleural) compared to those with normal films.Conclusions: The findings from this study confirm the association of mild profusion abnormalities with clinically r...