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

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

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.

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

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.

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.

Although high resolution computed tomography (HRCT) is commonly used to assess interstitial lung disease (ILD), relatively little is known about interrater reliability and construct validity of HRCT-reported nodules, ground-glass opacity, or other typical findings. We determined the interobserver and intraobserver variability of HRCT findings and correlated HRCT abnormalities with physiologic measures in 57 patients with chronic beryllium disease (CBD). Reliability of HRCT scan measurements were assessed using weighted kappa (K(W)) and intraclass correlation coefficients. We correlated HRCT with spirometry, body plethysmographic lung volumes, diffusing capacity for carbon monoxide (DL(CO)), maximal exercise testing with measurement of arterial blood gases, and bronchoalveolar lavage (BAL). Interobserver agreement for three of the HRCT abnormalities found in CBD was moderate: the K(W) for nodules, septal lines, and ground-glass attenuation were 0.53, 0.44, and 0.53, respectively. Agreement was poor for bronchial wall thickening (K(W) = 0.15). HRCT scores correlated significantly with DL(CO), gas exchange at rest and at maximal exercise, and lung volume. This study demonstrates that HRCT has good interrater reliability and correlates with indices of the severity of granulomatous lung diseases such as CBD.

Pulmonary lymphangiomyomatosis has been associated with renal angiomyolipoma in case reports, but the prevalence of this association has not been well documented. The objective of this study was to determine the frequency of renal angiomyolipoma in a series of subjects with pulmonary lymphangiomyomatosis. Eighteen consecutive patients with pulmonary lymphangiomyomatosis were seen at a single institution between 1989 and 1994. Of these, one patient was excluded because she did not have an abdominal computed tomographic (CT) scan. We found eight out of 17 (47%) patients with pulmonary lymphangiomyomatosis to have renal angiomyolipomas. These were found either at surgery or on abdominal CT scanning. Thus, renal angiomyolipomas occur commonly in association with pulmonary lymphangiomyomatosis. Consequently, the early detection of renal angiomyolipoma by abdominal CT may be important, because lesions with dimensions larger than 4 cm may present an increased risk for complications related to tumor growth or hemorrhage. Serial follow-up by ultrasonography or CT scanning is important in identifying and monitoring high-risk patients. Prophylactic treatment (partial or total nephrectomy) may be considered for patients with tumors that show significant growth or other complications, such as hemorrhage.