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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

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.

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

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.

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

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.).

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 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. Electronic supplementary material The online version of this article (10.1186/s12931-019-1121-z) contains supplementary material, which is available to authorized users.

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.

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.

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.

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...

Endothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT.We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil.Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree.After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P0.01).These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.

Rationale and Objectives We evaluated the role of automated quantitative computed tomography (CT) scan interpretation algorithm in detecting interstitial lung disease (ILD) and/or emphysema in a sample of elderly subjects with mild lung disease. We hypothesized that the quantification and distributions of CT attenuation values on lung CT, over a subset of Hounsfield units (HUs) range (−1000 HU, 0 HU), can differentiate early or mild disease from normal lung. Materials and Methods We compared the results of quantitative spiral rapid end-exhalation (functional residual capacity, FRC) and end-inhalation (total lung capacity, TLC) CT scan analyses of 52 subjects with radiographic evidence of mild fibrotic lung disease to the results of 17 normal subjects. Several CT value distributions were explored, including (1) that from the peripheral lung taken at TLC (with peels at 15 or 65 mm), (2) the ratio of (1) to that from the core of lung, and (3) the ratio of (2) to its FRC counterpart. We developed a fused-lasso logistic regression model that can automatically identify sub-intervals of −1000 HU and 0 HU over which a CT value distribution provides optimal discrimination between abnormal and normal scans. Results The fused-lasso logistic regression model based on (2) with 15-mm peel identified the relative frequency of CT values of over −1000 HU and −900 and those over −450 HU and −200 HU as a means of discriminating abnormal versus normal lung, resulting in a zero out-sample false-positive rate, and 15% false-negative rate of that was lowered to 12% by pooling information. Conclusions We demonstrated the potential usefulness of this novel quantitative imaging analysis method in discriminating ILD and/or emphysema from normal lungs.

BackgroundCOPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD.MethodsCAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow-up were recorded. Accuracy of the CAC scores was measured by using receiver-operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events.ResultsCAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r= 0.84; P< .001). Over 5 years of follow-up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c-indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack-years, FEV1, percent emphysema, and CT scanner type, a Weston score≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 [95%CI, 1.32 to 3.53]; P= .002), but a Agatston score≥ 400 was not (hazard ratio, 1.75 [95%CI, 0.99-3.09]; P= .053).ConclusionsA simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD.Trial registryClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

BACKGROUND:Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE:We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS:Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n=1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n=1,895). Asubset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS:COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS:Patients with moderate-to-severe COPD and blood eosinophil counts of 300cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study.

A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known.To identify subthreshold structural disease in normal-appearing lung regions in smokers.We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity.The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEVSubthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Introduction Quantitative CT (QCT) imaging-based metrics have quantified disease alterations in asthma and chronic obstructive pulmonary disease (COPD), respectively. We seek to characterise the similarity and disparity between these groups using QCT-derived airway and parenchymal metrics. Methods Asthma and COPD subjects (former-smoker status) were selected with a criterion of post-bronchodilator FEV1

The new third-generation dual-source computed tomographic (CT) scanners and third-generation iterative reconstruction software enable substantial reductions in radiation dose to the patient.1 This is of great importance to the medical imaging community because the recent increase in the use of x-ray CT has greatly increased the amount of ionizing radiation received by populations in the United States and other countries around the world.2,3 The recently published National Lung Cancer Screening Trial study showed a 20% decrease in mortality from lung cancer with the use of screening CT scans of the thorax in patients at high risk for lung cancer.4–7 The use of CT for lung cancer screening will further increase the number of x-ray CT studies performed on the thorax. Reducing the CT radiation dose to the thorax would be of great benefit to patients enrolled in lung cancer screening programs. Computed tomography is also increasingly being used to establish quantitative phenotypes to subtype lung diseases such as COPD and asthma,8–15 and reducing the CT dose in these CT studies would also be beneficial. The medical imaging community has been trying to reduce the amount of ionizing radiation to the general population using a number of approaches. These include using medical imaging studies only when they are known to be beneficial to the patient, substituting nonionizing radiation studies such as ultrasound and magnetic resonance imaging for x-ray CT studies whenever possible, lowering the radiation dose of both radiographic and x-ray CT studies as much as possible while still maintaining adequate image quality and image noise levels, and, finally, encouraging CT manufacturers to pursue advanced technological solutions for reducing the radiation exposures necessary to provide diagnostic images of the thorax and other body parts. It is very important for quantitative CT scanning of the lung to maintain the accuracy of the CT attenuation values with acceptable levels of image noise. This is accomplished using carefully designed CT protocols.16 It is also important to monitor the performance of CT scanners that are used for obtaining quantitative measurements over time. This is typically achieved using CT test objects (CT phantoms) that are made up of nonbiologic materials that simulate different in vivo tissue CT densities such as soft tissue, water, lung tissue, and air. The COPDGene 1 test object in the COPDGene phase 1 multicenter National Institutes of Health study is one of the commonly used CT test objects that is used for CT quality control.17 This CT test object has been used in a number of National Institutes of Health and privately sponsored multicenter lung research studies that use quantitative CT to phenotype lung disease including COPDGene, multi-ethnic study of atherosclerosis, severe asthma research program, and subpopulations and intermediate outcome measures in COPD study. We have recently described18 the effects of reducing dose on CT attenuation values in the COPDGene 2 test object using a second-generation dual-source CT scanner, SOMATOM Definition FLASH, and second-generation iterative reconstruction software, SAFIRE.19 In that study, we showed that the COPDGene 2 test object can be used to assess the effects of decreasing dose on the mean attenuation values of the 8 materials in the COPDGene 2 test object using weighted filtered back projection (WFBP) and using the SAFIRE iterative reconstruction method. In this study, we have sought to evaluate the quantitative stability of measures derived from the COPDGene 2 test object while lowering imaging to ultralow doses, taking advantage of advances in third-generation dual-source CT technologies including third-generation iterative reconstruction methods.

RationaleThe demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined.ObjectivesWe evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema.MethodsThe study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report.Measurements and main resultsPneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33).ConclusionsAmong smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Purpose Quantitative computed tomography (CT) measures are increasingly being developed and used to characterize lung disease. With recent advances in CT technologies, we sought to evaluate the quantitative accuracy of lung imaging at low and ultra-low radiation doses with the use of iterative reconstruction (IR), tube current modulation (TCM), and spectral shaping. Methods We investigated the effect of five independent CT protocols reconstructed with IR on quantitative airway measures and global lung measures using an in-vivo large animal model as a human subject surrogate. A control protocol was chosen (NIH-SPIROMICS + TCM) and five independent protocols investigating TCM, low and ultra-low radiation dose, and spectral shaping. For all scans quantitative global parenchymal measurements (mean, median and standard deviation of the parenchymal HU, along with measures of emphysema) and global airway measurements (number of segmented airways and pi10) were generated. In addition, selected individual airway measurements (minor and major inner diameter, wall thickness, inner and outer area, inner and outer perimeter, wall area fraction, and inner equivalent circle diameter) were evaluated. Comparisons were made between control and target protocols using difference and repeatability measures. Results Estimated CT volume dose index (CTDIvol) across all protocols ranged from 7.32 mGy to 0.32 mGy. Low and ultra-low dose protocols required more manual editing and resolved fewer airway branches; yet, comparable pi10 whole lung measures were observed across all protocols. Similar trends in acquired parenchymal and airway measurements were observed across all protocols, with increased measurement differences using the ultra-low dose protocols. However, for small airways (1.9 ± 0.2mm) and medium airways (5.7 ± 0.4mm) the measurement differences across all protocols were comparable to the control protocol repeatability across breath-holds. Diameters, wall thickness, wall area fraction, and equivalent diameter had smaller measurement differences, than area and perimeter measurements. Conclusions In conclusion, the use of IR with low and ultra-low dose CT protocols with CT volume dose indices down to 0.32 mGy maintains selected quantitative parenchymal and airway measurements relevant to pulmonary disease characterization. This article is protected by copyright. All rights reserved.

Summary Background Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. Methods In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40–80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1–4) on the basis of post-bronchodilator FEV 1 . Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. Findings 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations. Interpretation Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute.

Background Traditional metrics of lung disease such as those derived from spirometry and static single-volume CT images are used to explain respiratory morbidity in patients with COPD, but are insufficient. We hypothesised that the mean Jacobian determinant, a measure of local lung expansion and contraction with respiration, would contribute independently to clinically relevant functional outcomes. Methods We applied image registration techniques to paired inspiratory-expiratory CT scans and derived the Jacobian determinant of the deformation field between the two lung volumes to map local volume change with respiration. We analysed 490 participants with COPD with multivariable regression models to assess strengths of association between traditional CT metrics of disease and the Jacobian determinant with respiratory morbidity including dyspnoea (modified Medical Research Council), St Georges Respiratory Questionnaire (SGRQ) score, 6-min walk distance (6MWD) and the Body Mass Index, Airflow Obstruction, Dyspnoea and Exercise Capacity (BODE) index, as well as all-cause mortality. Results The Jacobian determinant was significantly associated with SGRQ (adjusted regression coefficient β=−11.75,95% CI −21.6 to −1.7; p=0.020), and with 6MWD (β=321.15, 95% CI 134.1 to 508.1; p 1 , smoking pack-years, CT emphysema, CT gas trapping, airway wall thickness and CT scanner type. The mean Jacobian determinant was also independently associated with the BODE index (β=−0.41, 95% CI −0.80 to −0.02; p=0.039) and mortality on follow-up (adjusted HR=4.26, 95% CI 0.93 to 19.23; p=0.064). Conclusions Biomechanical metrics representing local lung expansion and contraction improve prediction of respiratory morbidity and mortality and offer additional prognostic information beyond traditional measures of lung function and static single-volume CT metrics. Trial registration number NCT00608764; Post-results.

ObjectivesExtra-thoracic tumors send out pilot cells that attach to the pulmonary endothelium. We hypothesized that this could alter regional lung mechanics (tissue stiffening or accumulation of fluid and inflammatory cells) through interactions with host cells. We explored this with serial inspiratory computed tomography (CT) and image matching to assess regional changes in lung expansion.Materials and methodsWe retrospectively assessed 44 pairs of two serial CT scans on 21 sarcoma patients: 12 without lung metastases and 9 with lung metastases. For each subject, two or more serial inspiratory clinically-derived CT scans were retrospectively collected. Two research-derived control groups were included: 7 normal nonsmokers and 12 asymptomatic smokers with two inspiratory scans taken the same day or one year apart respectively. We performed image registration for local-to-local matching scans to baseline, and derived local expansion and density changes at an acinar scale. Welch two sample t test was used for comparison between groups. Statistical significance was determined with a p value < 0.05.ResultsLung regions of metastatic sarcoma patients (but not the normal control group) demonstrated an increased proportion of normalized lung expansion between the first and second CT. These hyper-expanded regions were associated with, but not limited to, visible metastatic lung lesions. Compared with the normal control group, the percent of increased normalized hyper-expanded lung in sarcoma subjects was significantly increased (p < 0.05). There was also evidence of increased lung "tissue" volume (non-air components) in the hyper-expanded regions of the cancer subjects relative to non-hyper-expanded regions. "Tissue" volume increase was present in the hyper-expanded regions of metastatic and non-metastatic sarcoma subjects. This putatively could represent regional inflammation related to the presence of tumor pilot cell-host related interactions.ConclusionsThis new quantitative CT (QCT) method for linking serial acquired inspiratory CT images may provide a diagnostic and prognostic means to objectively characterize regional responses in the lung following oncological treatment and monitoring for lung metastases.

Purpose Overweight and underweight conditions are considered relative contraindications to lung transplantation due to their association with excess mortality. Yet, recent work suggests that body mass index (BMI) does not accurately reflect adipose tissue mass in adults with advanced lung diseases. Alternative and more accurate measures of adiposity are needed. Chest fat estimation by routine computed tomography (CT) imaging may therefore be important for identifying high-risk lung transplant candidates. In this paper, an approach to chest fat quantification and quality assessment based on a recently formulated concept of standardized anatomic space (SAS) is presented. The goal of the paper is to seek answers to several key questions related to chest fat quantity and quality assessment based on a single slice CT (whether in the chest, abdomen, or thigh) versus a volumetric CT, which have not been addressed in the literature. Methods Unenhanced chest CT image data sets from 40 adult lung transplant candidates (age 58 ± 12 yrs and BMI 26.4 ± 4.3 kg/m2), 16 with chronic obstructive pulmonary disease (COPD), 16 with idiopathic pulmonary fibrosis (IPF), and the remainder with other conditions were analyzed together with a single slice acquired for each patient at the L5 vertebral level and mid-thigh level. The thoracic body region and the interface between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in the chest were consistently defined in all patients and delineated using Live Wire tools. The SAT and VAT components of chest were then segmented guided by this interface. The SAS approach was used to identify the corresponding anatomic slices in each chest CT study, and SAT and VAT areas in each slice as well as their whole volumes were quantified. Similarly, the SAT and VAT components were segmented in the abdomen and thigh slices. Key parameters of the attenuation (Hounsfield unit (HU) distributions) were determined from each chest slice and from the whole chest volume separately for SAT and VAT components. The same parameters were also computed from the single abdominal and thigh slices. The ability of the slice at each anatomic location in the chest (and abdomen and thigh) to act as a marker of the measures derived from the whole chest volume was assessed via Pearson correlation coefficient (PCC) analysis. Results The SAS approach correctly identified slice locations in different subjects in terms of vertebral levels. PCC between chest fat volume and chest slice fat area was maximal at the T8 level for SAT (0.97) and at the T7 level for VAT (0.86), and was modest between chest fat volume and abdominal slice fat area for SAT and VAT (0.73 and 0.75, respectively). However, correlation was weak for chest fat volume and thigh slice fat area for SAT and VAT (0.52 and 0.37, respectively), and for chest fat volume for SAT and VAT and BMI (0.65 and 0.28, respectively). These same single slice locations with maximal PCC were found for SAT and VAT within both COPD and IPF groups. Most of the attenuation properties derived from the whole chest volume and single best chest slice for VAT (but not for SAT) were significantly different between COPD and IPF groups. Conclusions This study demonstrates a new way of optimally selecting slices whose measurements may be used as markers of similar measurements made on the whole chest volume. The results suggest that one or two slices imaged at T7 and T8 vertebral levels may be enough to estimate reliably the total SAT and VAT components of chest fat and the quality of chest fat as determined by attenuation distributions in the entire chest volume.

Expiratory computed tomography (CT) imaging of the lungs without any contrast media has been used for several decades to assess lung ventilation by looking for areas of air trapping in the lungs. This method has been amenable to quantitative CT (QCT) lung analysis techniques and has been used in several large NIH multicenter research studies of airway disease including CanCOLD, COPDGene, SPIROMICS, and SARP. Contrast enhanced lung ventilation imaging by having the patient inhale an inert gas and then imaging with either CT or magnetic resonance imaging (MRI) have been done to assess lung ventilation imaging and these more advanced and costly methods are reviewed in this article. The future of CT or MRI ventilation imaging of the lung rests on developing safe methods that have robust imaging signals that are amenable to computer analysis, validation, and the prevailing economic model in medical imaging.

The purpose of this review article is to review the process of developing optimal computed tomography (CT) protocols for quantitative lung CT (QCT). In this review, we discuss the following important topics: QCT-derived metrics of lung disease; QCT scanning protocols; quality control; and QCT image processing software. We will briefly discuss several QCT-derived metrics of lung disease that have been developed for the assessment of emphysema, small airway disease, and large airway disease. The CT scanning protocol is one of the most important elements in a successful QCT. We will provide a detailed description of the current move toward optimizing the QCT protocol for the assessment of chronic obstructive pulmonary disorder and asthma. Quality control of CT images is also a very important part of the QCT process. We will discuss why it is necessary to use CT scanner test objects (phantoms) to provide frequent periodic checks on the CT scanner calibration to ensure precise and accurate CT numbers. We will discuss the use of QCT image processing software to segment the lung and extract the desired QCT metrics of lung disease. We will discuss the practical issues of using this software. The data obtained from the image processing software are then combined with those from other clinical examinations, health status questionnaires, pulmonary physiology, and genomics to increase our understanding of obstructive lung disease and improve our ability to design new therapies for these diseases.

OBJECTIVES The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them. MATERIALS AND METHODS Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m(2)) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAA(I-950)). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAA(E-856)). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLC(CT) and FRC(CT)), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10). RESULTS Mean (SD) %LAA(I-950) was 2.0% (2.7%), and mean (SD) %LAA(E-856) was 9.2% (6.8%). Mean (SD) %LAA(I-950) was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P < 0.001). The %LAA(I-950) did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAA(E-856) did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAA(I-950) showed a direct relationship to TLC(CT) (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAA(E-856) was related to age (P = 0.001), FRC(CT) (P = 0.007), and scanner type (P < 0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLC(CT) (P < 0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P < 0.001). CONCLUSIONS Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution.

Background: Pulmonary blood volume(PBV) changes with lung inflation and this can be measured as a change in non-air volume via quantitative CT, assuming that tissue volume remains constant. Methods: 40 subjects(20 female, 20 male) were selected across various COPD classes from SPIROMICS multicenter research study. TLC and RV pair was acquired for each subject. Lobar segmentation for TLC was obtained via Apollo lung analytics platform(VIDA Diagnostics, US) with occasional edits from expert analysts. RV lobar mask was obtained via VIDA9s automatic image registration whereby TLC lobar mask was warped into the RV domain. Lung tissue mass (parenchyma plus blood) was derived from Hounsfield units. Results: PBV is greater at TLC compared to RV: mean relative tissue mass difference of 3.5% (95% confidence interval:[2.1%, 5.0%]) for the whole lung. Relative tissue mass (thus PBV) changes between TLC and RV are similar across all lobes with a mean value of 6.0%(significantly different from whole lung, p=0.001). In addition, as seen in, there is considerable difference in distribution of PBV changes across subjects. Conclusion: Decreases in PBV with lung inflation demonstrate subject variability when a mixed COPD population is evaluated suggesting lung volume effects must be considered when reporting regional PBV, especially when using blood volume as a surrogate for regional perfusion as is done with Dual Energy CT.

Multidetector row computed tomography (MDCT) is increasingly taking a central role in identifying subphenotypes within chronic obstructive pulmonary disease (COPD), asthma, and other lung-related disease populations, allowing for the quantification of the amount and distribution of altered parenchyma along with the characterization of airway and vascular anatomy. The embedding of quantitative CT (QCT) into a multicenter trial with a variety of scanner makes and models along with the variety of pressures within a clinical radiology setting has proven challenging, especially in the context of a longitudinal study. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), sponsored by the National Institutes of Health, has established a QCT lung assessment system (QCT-LAS), which includes scanner-specific imaging protocols for lung assessment at total lung capacity and residual volume. Also included are monthly scanning of a standardized test object and web-based tools for subject registration, protocol assignment, and data transmission coupled with automated image interrogation to assure protocol adherence. The SPIROMICS QCT-LAS has been adopted and contributed to by a growing number of other multicenter studies in which imaging is embedded. The key components of the SPIROMICS QCT-LAS along with evidence of implementation success are described herein. While imaging technologies continue to evolve, the required components of a QCT-LAS provide the framework for future studies, and the QCT results emanating from SPIROMICS and the growing number of other studies using the SPIROMICS QCT-LAS will provide a shared resource of image-derived pulmonary metrics.

Medical imaging is a rapidly advancing field enabling the repeated, noninvasive assessment of physiological structure and function. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In addition, swine may serve as a human surrogate, facilitating the development and comparison of new imaging protocols for translation to humans. This study presents methods for pulmonary imaging developed for monitoring pulmonary disease initiation and progression in a pig exposure model with computed tomography and magnetic resonance imaging. In particular, a focus was placed on systematic processes, including positioning, image acquisition, and structured reporting to monitor longitudinal change. The image-based monitoring procedure was applied to 6 Yucatan miniature pigs. A subset of animals ( n = 3) were injected with crystalline silica into the apical bronchial tree to induce silicosis. The methodology provided longitudinal monitoring and evidence of progressive lung disease while simultaneously allowing for a cross-modality comparative study highlighting the practical application of medical image data collection in swine. The integration of multimodality imaging with structured reporting allows for cross comparison of modalities, refinement of CT and MRI protocols, and consistently monitors potential areas of interest for guided biopsy and/or necropsy.

Through interior tomography, high-resolution microcomputed tomography (μCT) systems provide the ability to nondestructively assess the pulmonary acinus at micron and submicron resolutions. With the application of systematic uniform random sampling (SURS) principles applied to in situ fixed, intact, ex vivo lungs, we have sought to characterize morphometric differences in central vs. surface acini to better understand how well surface acini reflect global acinar geometry. Lungs from six mice (A/J strain, 15-20 wk of age) were perfusion fixed in situ and imaged using a multiresolution μCT system (Micro XCT 400, Zeiss). With the use of lower-resolution whole lung images, SURS methods were used for identification of central and surface foci for high-resolution imaging. Acinar morphometric metrics included diameters, lengths, and branching angles for each alveolar duct and total path lengths from entrance of the acinus to the terminal alveolar sacs. In addition, acinar volume, alveolar surface area, and surface area/volume ratios were assessed. A generation-based analysis demonstrated that central acini have significantly smaller branch diameters at each generation with no significant increase in branch lengths. In addition to larger-diameter alveolar ducts, surface acini had significantly increased numbers of branches and terminal alveolar sacs. The total path lengths from the acinar entrance to the terminal nodes were found to be higher in the case of surface acini. Volumes and surface areas of surface acini are greater than central acini, but there were no differences in surface/volume ratios. In conclusion, there are significant structural differences between surface and central acini in the A/J mouse.

The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE).1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a -950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p0.001; for WA%, 1.20-fold increase, p0.001; for pi10, 1.16-fold increase, p0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26-fold increase, p0.001).Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.

The purposes of this study were: to describe chest CT findings in normal nonsmoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9-11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial interobserver variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Many patients with chronic obstructive pulmonary disease (COPD) have marked discordance between forced expiratory volume in 1 second (FEV1) and degree of emphysema on computed tomography (CT). Biomechanical differences between these patients have not been studied. We aimed to identify reasons for the discordance between CT and spirometry in some patients with COPD.Subjects with Global initiative for chronic Obstructive Lung Disease stages I-IV from a large multicenter study (The Genetic Epidemiology of COPD) were arranged by percentiles of %predicted FEV1 and emphysema on CT. Three categories were created using differences in percentiles: Catspir with predominant airflow obstruction/minimal emphysema, CatCT with predominant emphysema/minimal airflow obstruction, and Catmatched with matched FEV1 and emphysema. Image registration was used to derive Jacobian determinants, a measure of lung elasticity, anisotropy, and strain tensors, to assess biomechanical differences between groups. Regression models were created with the previously mentioned categories as outcome variable, adjusting for demographics, scanner type, quantitative CT-derived emphysema, gas trapping, and airway thickness (model 1), and after adding biomechanical CT metrics (model 2).Jacobian determinants, anisotropy, and strain tensors were strongly associated with FEV1. With Catmatched as control, model 2 predicted Catspir and CatCT better than model 1 (Akaike information criterion 255.8 vs. 320.8). In addition to demographics, the strongest independent predictors of FEV1 were Jacobian mean (β = 1.60,95%confidence intervals [CI] = 1.16 to 1.98; P 0.001), coefficient of variation (CV) of Jacobian (β = 1.45,95%CI = 0.86 to 2.03; P 0.001), and CV of strain (β = 1.82,95%CI = 0.68 to 2.95; P = 0.001). CVs of Jacobian and strain are both potential markers of biomechanical lung heterogeneity.CT-derived measures of lung mechanics improve the link between quantitative CT and spirometry, offering the potential for new insights into the linkage between regional parenchymal destruction and global decrement in lung function in patients with COPD.

The relationship between quantitative airway measurements on computed tomography (CT) and airflow limitation in individuals with severe alpha (1)-antitrypsin deficiency (AATD) is undefined. Thus, we planned to clarify the relationship between CT-based airway indices and airflow limitation in AATD. 52 patients with AATD underwent chest CT and pre-bronchodilator spirometry at three institutions. In the right upper (RUL) and lower (RLL) lobes, wall area percent (WA%) and luminal area (Ai) were measured in the third, fourth, and fifth generations of the bronchi. The severity of emphysema was also calculated in each lobe and expressed as low attenuation area percent (LAA%). Correlations between obtained measurements and FEV(1)% predicted (FEV(1)%P) were evaluated by the Spearman rank correlation test. In RUL, WA% of all generations was significantly correlated with FEV(1)%P (3rd, R = -0.33, p = 0.02; 4th, R = -0.39, p = 0.004; 5th, R = -0.57, p < 0.001; respectively). Ai also showed significant correlations (3rd, R = 0.32, p = 0.02; 4th, R = 0.34, p = 0.01; 5th, R = 0.56, p < 0.001; respectively). Measured correlation coefficients improved when the airway progressed distally from the third to fifth generations. LAA% also correlated with FEV(1)%P (R = -0.51, p < 0.001). In RLL, WA% showed weak correlations with FEV(1)%P in all generations (3rd, R = -0.34, p = 0.01; 4th, R = -0.30, p = 0.03; 5th, R = -0.31, p = 0.03; respectively). Only Ai from the fifth generation significantly correlated with FEV(1)%P in this lobe (R = 0.34, p = 0.01). LAA% strongly correlated with FEV(1)%P (R = -0.71, p < 0.001). We conclude therefore that quantitative airway measurements are significantly correlated with airflow limitation in AATD, particularly in the distal airways of RUL. Emphysema of the lower lung is the predominant component; however, airway disease also has a significant impact on airflow limitation in AATD.