The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with ...chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.
This report is to complement the original Fleischner Society recommendations for incidentally detected solid nodules by proposing a set of recommendations specifically aimed at subsolid nodules. The ...development of a standardized approach to the interpretation and management of subsolid nodules remains critically important given that peripheral adenocarcinomas represent the most common type of lung cancer, with evidence of increasing frequency. Following an initial consideration of appropriate terminology to describe subsolid nodules and a brief review of the new classification system for peripheral lung adenocarcinomas sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS), six specific recommendations were made, three with regard to solitary subsolid nodules and three with regard to multiple subsolid nodules. Each recommendation is followed first by the rationales underlying the recommendation and then by specific pertinent remarks. Finally, issues for which future research is needed are discussed. The recommendations are the result of careful review of the literature now available regarding subsolid nodules. Given the complexity of these lesions, the current recommendations are more varied than the original Fleischner Society guidelines for solid nodules. It cannot be overemphasized that these guidelines must be interpreted in light of an individual's clinical history. Given the frequency with which subsolid nodules are encountered in daily clinical practice, and notwithstanding continuing controversy on many of these issues, it is anticipated that further refinements and modifications to these recommendations will be forthcoming as information continues to emerge from ongoing research.
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those ...requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta PA:A ratio of >1) would be associated with severe COPD exacerbations.
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval CI, 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.).
Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. ...The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African-Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African-American populations, and combined these results in a meta-analysis. More females and African-Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57 × 10(-6)) and SOX5 (rs59569785, p=1.61 × 10(-6)) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18 × 10(-7)) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management.
There is an unmet need for blood biomarkers in diagnosis and prognosis of chronic obstructive pulmonary disease (COPD). The search for these biomarkers has been revolutionized by high-throughput ...sequencing techniques and multiplex platforms that can measure thousands of gene transcripts, proteins, or metabolites. We review COPDGene (Genetic Epidemiology of COPD) project publications that include DNA methylation, transcriptomic, proteomic, and metabolomic blood biomarkers and discuss their impact on COPD. Key contributions from COPDGene include identification of DNA methylation effects from smoking and genetic variation, new transcriptomic signatures in the blood, identification of protein biomarkers associated with severity and progression (e.g., sRAGE soluble receptor for advanced glycosylation end products, inflammatory cytokines IL-6 and IL-8), and identification of small molecules (ceramides and sphingomyelin) that may be pathogenic. COPDGene studies have revealed that some of the COPD genome-wide association study polymorphisms are strongly associated with blood biomarkers (e.g., rs2070600 in
is a pQTL protein quantitative trait locus for sRAGE), underscoring the importance of combining omics results. Investigators have developed molecular networks identifying lower CD4
resting memory cells associated with COPD. Genes, proteins, and metabolite networks are particularly important because the explanatory value of any single molecule is small (1-10%) compared with panels of multiple markers. COPDGene has been a useful resource in the identification and validation of multiple biomarkers for COPD. These biomarkers, either combined in multiple biomarker panels or integrated with other omics data types, may lead to novel diagnostic and prognostic tests for COPD phenotypes and may be relevant for assessing novel therapies.
Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV1 and FVC, is a heterogeneous population with frequent ...transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (eg, whether transitions merely reflect measurement variability or noise).
Are individuals with PRISm enriched for transitions associated with substantial changes in lung function?
Current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV1 < 80% predicted with FEV1/FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7), and obstruction (FEV1/FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV1 % predicted and/or FVC % predicted between consecutive visits. Ever-PRISm was present if a subject had PRISm at any visit. Logistic regression examined the association between significant transitions and ever-PRISm status, adjusted for age, sex, race, FEV1 % predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response.
Among subjects with complete data (N = 1,775) over 10.1 ± 0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted OR, 14.9; 95% CI, 10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV1 alone (regardless of change in FVC % predicted) was used to define significant transitions.
PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time.
ClinicalTrials.gov; No.: NCT000608764; URL: www.clinicaltrials.gov
Airway wall thickening in cigarette smokers is thought to be a result of inflammatory changes and airway remodeling. This study investigates if CT-derived airway wall thickening associates to disease ...severity in smokers with and without COPD and if airway wall thickening is reversible by smoking cessation.
We examined 2000 smokers and 46 never-smokers who returned for a 5-year follow-up visit in the COPDGene-study. Multivariable regression analyses were performed at visit 1 to associate airway wall thickness (expressed as Pi10) with percent predicted forced expiratory volume in 1 s (FEV1%-predicted), 6-min walking distance (6MWD), and St. George Respiratory Questionnaire (SGRQ). Longitudinal analyses were performed to assess the effect of smoking cessation on Pi10 using linear mixed models.
A higher Pi10 was significantly associated with worse FEV1%-predicted, 6MWD, and SGRQ in all GOLD-stages. Longitudinal analyses showed that subjects that quit smoking significantly decreased in Pi10 (ΔPi10 = −0.18 mm, p < 0.001). Subjects that started smoking had a significant increase in Pi10 (ΔPi10 = 0.14 mm, p < 0.001).
Pi10 is a clinically relevant biomarker of smoking-related airway injury in smokers with and without COPD. The change in Pi10 with change in smoking status suggests that it can quantify a reversible component of smoking-related airway inflammation.
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Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD ...was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis.
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