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1.  Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy? 
Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.
PMCID: PMC4722841  PMID: 26562761
wall area percent; wall thickness; wall area; lumen area; branching generation number
2.  β-blockers are associated with a reduction in COPD exacerbations 
Thorax  2015;71(1):8-14.
While some retrospective studies have suggested that β-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful.
Subjects with GOLD stage 2 to 4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicenter observational cohort of current and former smokers, were recruited. Total and severe exacerbation rates were compared between groups categorized by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on computed tomography, respiratory medications, presence of coronary artery disease, congestive heart failure, and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers.
3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (Incidence risk ratio, IRR 0.73,95%CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67,95%CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33,95%CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35,95%CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use.
β-blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomized, placebo-controlled trial.
PMCID: PMC5154678  PMID: 26283710
β-blockers; COPD; exacerbations; cardiac
3.  Association Between Expiratory Central Airway Collapse and Respiratory Outcomes Among Smokers 
JAMA  2016;315(5):498-505.
Central airway collapse greater than 50% of luminal area during exhalation (Expiratory Central Airway Collapse, ECAC) is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, its prevalence and clinical significance are unknown.
To determine whether ECAC is associated with respiratory morbidity in smokers independent of underlying lung disease.
Design, Setting and Participants
We analyzed paired inspiratory-expiratory computerized tomography (CT) images from a large multicenter study (COPDGene) of current and former smokers aged 45–80 years. Participants were enrolled from January 2008 to June 2011, and followed longitudinally till October 2014. Images were screened using a quantitative method to detect at least a 30% reduction in minor axis tracheal diameter from inspiration to end-expiration. From this sample of screen positive scans, cross-sectional area of the trachea was measured manually for confirmation of ECAC at three predetermined levels (aortic arch, carina and bronchus intermedius) in the inspiratory-expiratory scans. Participants with ≥50% reduction in cross-sectional area were diagnosed with ECAC.
Expiratory Central Airway Collapse
Main Outcome(s) and Measure(s)
Primary outcome was baseline respiratory quality of life [St George’s Respiratory Questionnaire (SGRQ) scale 0 to 100, 100 represents worst health status, minimum clinically important difference MCID 4 units] and secondary outcomes were dyspnea [modified Medical Research Council (mMRC) scale 0 to 4, 4 represents worse dyspnea, MCID 0.7 units] and six minute walk distance [MCID 30 m] at enrollment and exacerbation frequency (events per 100 person-years) on longitudinal follow-up.
8820 current and former smokers with and without COPD were included. The prevalence of ECAC was 5%. On multivariable analyses, ECAC was associated with older age [65.0 vs. 59.4 years, absolute difference = 5.6, 95%CI 4.8 to 6.4, adjusted Odds Ratio, OR for every 1-year increase 1.06,95%CI 1.04–1.07;p<0.001], female sex [297 (67%) vs. 3856 (46%), absolute difference = 21.0%, 95%CI 16.4 to 25.4, OR 2.08,95%CI 1.63–2.63;p<0.001], white race compared to African American [374 (84.4%) vs. 5654 (67.5%), absolute difference = 16.9%, 95%CI 13.1 to 20.2, OR 1.85,95%CI 1.38–2.48;p<0.001], higher BMI [31.2 vs. 28.7, absolute difference = 2.5, 95%CI 1.9 to 3.1, OR for every 1 unit increase 1.07,95%CI 1.06–1.09;p<0.001] and lower FEV1 [1.82 vs. 2.28 L, absolute difference = −0.46, 95%CI −0.54 to −0.38, OR for every 1L decrease 0.74,95%CI 0.62–0.89;p<0.001]. ECAC was associated with worse SGRQ scores [30.9 vs. 26.5 units, p<0.001, absolute difference =4.4, 95%CI 2.2 to 6.6)] and mMRC [median 2, Interquartile range IQR 0–3 vs. 1, IQR 0–3, p<0.001] and independent of age, sex, race, BMI, FEV1, smoking burden and emphysema. On follow-up, participants without COPD but with ECAC had increased frequency of total (54 vs. 35 events per 100 person-years, IRR 2.19; 95%CI 1.78 to 2.71;p<0.001) and severe respiratory events requiring hospitalization (16 vs. 10 events per 100 person-years, IRR 2.95; 95%CI 2.20 to 3.95;p<0.001).
Conclusions and Relevance
In a cross-sectional analysis of current and former smokers, the presence of expiratory central airway collapse was associated with worse respiratory quality of life. Further studies are needed to assess long-term effects on clinical outcomes.
Trial Registration Identifier: NCT00608764
Phase 1 protocol available here:
Phase 2 protocol available here:
PMCID: PMC5173387  PMID: 26836732
Expiratory Central Airway Collapse; CT; lung function; respiratory morbidity
Density masking is the de-facto quantitative imaging phenotype for emphysema that is widely used by the clinical community. Density masking defines the burden of emphysema by a fixed threshold, usually between −910 HU and −950 HU, that has been experimentally validated with histology. In this work, we formalized emphysema quantification by means of statistical inference. We show that a non-central Gamma is a good approximation for the local distribution of image intensities for normal and emphysema tissue. We then propose a test statistic in terms of the sample mean of a truncated non-central Gamma random variable. Our results show that this approach is well-suited for the detection of emphysema and superior to standard density masking. The statistical method was tested in a dataset of 1337 samples obtained from 9 different scanner models in subjects with COPD. Results showed an increase of 17% when compared to the density masking approach, and an overall accuracy of 94.09%.
PMCID: PMC5153356  PMID: 27974952
Emphysema quantification; statistical test; non-central Gamma; truncated random variable
The Agatston score, computed from ECG-gated computed tomography (CT), is a well established metric of coronary artery disease. It has been recently shown that the Agatston score computed from chest CT (non ECG-gated) studies is highly correlated with the Agatston score computed from cardiac CT scans. In this work we present an automated method to compute the Agatston score from chest CT images. Coronary arteries calcifications (CACs) are defined as voxels contained within the coronary arteries with a value greater or equal to 130 Hounsfield Units (HU). CACs are automatically detected in chest CT studies by locating the heart, generating a region of interest around it, thresholding the image in such region and applying a set of rules to discriminate CACs from calcifications in the main vessels or from metallic implants. We evaluate the methodology in a large cohort of 1500 patients for whom manual reference standard is available. Our results show that the Pearson correlation coefficient between manual and automated Agatston score is ρ = 0.86 (p < 0.0001)
PMCID: PMC5153357  PMID: 27974951
Agatston score; object detection; computed aided detection; segmentation; heuristics
6.  Comparing algorithms for automated vessel segmentation in computed tomography scans of the lung: the VESSEL12 study 
Medical image analysis  2014;18(7):1217-1232.
The VESSEL12 (VESsel SEgmentation in the Lung) challenge objectively compares the performance of different algorithms to identify vessels in thoracic computed tomography (CT) scans. Vessel segmentation is fundamental in computer aided processing of data generated by 3D imaging modalities. As manual vessel segmentation is prohibitively time consuming, any real world application requires some form of automation. Several approaches exist for automated vessel segmentation, but judging their relative merits is difficult due to a lack of standardized evaluation. We present an annotated reference dataset containing 20 CT scans and propose nine categories to perform a comprehensive evaluation of vessel segmentation algorithms from both academia and industry. Twenty algorithms participated in the VESSEL12 challenge, held at International Symposium on Biomedical Imaging (ISBI) 2012. All results have been published at the VESSEL12 website The challenge remains ongoing and open to new participants. Our three contributions are: (1) an annotated reference dataset available online for evaluation of new algorithms; (2) a quantitative scoring system for objective comparison of algorithms; and (3) performance analysis of the strengths and weaknesses of the various vessel segmentation methods in the presence of various lung diseases.
PMCID: PMC5153359  PMID: 25113321
Thoracic computed tomography; Lung vessels; Algorithm comparison; Segmentation; Challenge
7.  Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study 
BMC Pulmonary Medicine  2016;16:169.
Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD
We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia.
Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05–22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58–0.85), self-reported heart failure (OR 6.92, 95%CI 1.56–30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17–6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38–7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up.
Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia.
Trial registration
COPDGene is registered at NCT00608764 (Registration Date: January 28, 2008)
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0331-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5131397  PMID: 27903260
8.  Pulmonary Predictors of Incident Diabetes in Smokers 
Diabetes mellitus and its complications are a large and increasing burden for health care worldwide. Reduced pulmonary function has been observed in diabetes (both type 1 and type 2), and this reduction is thought to occur prior to diagnosis. Other measures of pulmonary health are associated with diabetes, including lower exercise tolerance, greater dyspnea, lower quality of life (as measured by the St. George’s Respiratory Questionaire [SGRQ]) and susceptibility to lung infection and these measures may also predate diabetes diagnosis.
We examined 7080 participants in the COPD Genetic Epidemiology (COPDGene) study who did not report diabetes at their baseline visit and who provided health status updates during 4.2 years of longitudinal follow-up (LFU). We used Cox proportional hazards modeling, censoring participants at final LFU contact, reported mortality or report of incident diabetes to model predictors of diabetes. These models were constructed using known risk factors as well as proposed markers related to pulmonary health, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, respiratory exacerbations (RE), 6-minute walk distance (6MWD), pulmonary associated quality of life (as measured by the SGRQ), corticosteroid use, chronic bronchitis and dyspnea.
Over 21,519 person years of follow-up, 392 of 7080 participants reported incident diabetes which was associated with expected predictors; increased body mass index (BMI), high blood pressure, high cholesterol and current smoking status. Age, gender and accumulated smoking exposure were not associated with incident diabetes. Additionally, preserved ratio with impaired spirometry (PRISm) pattern pulmonary function, reduced 6MWD and any report of serious pulmonary events were associated with incident diabetes.
This cluster of pulmonary indicators may aid clinicians in identifying and treating patients with pre- or undiagnosed diabetes.
PMCID: PMC5084840  PMID: 27795984
chronic obstructive pulmonary disease; COPD; diabetes; pulmonary predictors
9.  A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes 
Rationale: Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.
Objectives: To identify genetic determinants of quantitative imaging phenotypes.
Methods: We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD.
Measurements and Main Results: The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes.
Conclusions: Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci.
PMCID: PMC4595690  PMID: 26030696
emphysema; airway; genetics; chronic obstructive pulmonary disease
10.  Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline 
Environmental Health Perspectives  2016;124(9):1436-1442.
Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined.
We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT).
The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis.
Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (–1.3%) in percent emphysema (LAAI-950), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAAI-950 were highly correlated with 15th percentile density (correlation –1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (–6.1 mL) of FEV1 (p = 0.001) between 1981 and 2011.
There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAAI-950 may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline.
Lai PS, Hang J, Zhang F, Sun J, Zheng BY, Su L, Washko GR, Christiani DC. 2016. Imaging phenotype of occupational endotoxin-related lung function decline. Environ Health Perspect 124:1436–1442;
PMCID: PMC5010398  PMID: 27138294
11.  Regional Emphysema of a Non–Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival Rates 
Rationale: Chronic obstructive pulmonary disease is associated with a worse overall survival in non–small cell lung cancer. Lung emphysema is one component of chronic obstructive pulmonary disease. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival.
Methods: We evaluated 304 cases of non–small cell lung cancer from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low-attenuation areas less than −950 Hounsfield units (%LAA−950) and measured for each region. Whole-lung %LAA−950 was defined as the emphysema score of the entire lung parenchyma, whereas regional %LAA−950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor %LAA−950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival.
Measurements and Main Results: Increasing tumor %LAA−950 was associated with larger tumors (P = 0.024). Survival, stratified by stage, was significantly worse in those with tumor %LAA−950 greater than or equal to the 50th percentile versus less than the 50th percentile (P = 0.046). Whole-lung %LAA−950 and regional %LAA−950 (e.g., regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor %LAA−950 was associated with an increased risk of death (adjusted hazard ratio, 1.36; confidence interval, 1.09–1.68; P = 0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: (1) exclusion of cases with central tumor location, (2) exclusion of cases where surgery was performed, (3) exclusion of cases where radiation therapy was performed, (4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and (5) inclusion of only stage IV disease.
Conclusions: Increasing emphysema of the region in which a non–small cell lung cancer tumor occurs is associated with increasing tumor size and worse overall survival.
PMCID: PMC4566414  PMID: 26039412
non–small cell lung cancer; emphysema
12.  Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases 
Respiratory Research  2016;17:92.
Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function.
Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.
The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.
Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.
Trial registration
Trial registration number NCT01701869.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0402-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4962504  PMID: 27460105
COPD; Emphysema; CT; Imaging; MMPs
13.  Paraseptal Emphysema: Prevalence and Distribution on CT and Association with Interstitial Lung Abnormalities 
European journal of radiology  2015;84(7):1413-1418.
To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities.
Materials and Methods
We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated.
Of the 2633 participants, 86 (3%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71% male, mean 36 pack-years, p<0.001) and had significantly decreased FEV1/FVC% (p=0.002), and diffusion capacity of carbon monoxide (DLCO) (p=0.002). There was a significant association between pure paraseptal emphysema and interstitial lung abnormalities (p<0.001).
The prevalence of pure paraseptal emphysema was 3% in the FHS population, predominantly affects the upper lung zone, and contributes to decreased pulmonary function. Cigarette smoking, aging, and male gender were the factors associated with the presence of paraseptal emphysema. Significant association between paraseptal emphysema and interstitial lung abnormalities was observed.
PMCID: PMC4450117  PMID: 25868675
Paraseptal emphysema; Interstitial lung abnormalities; CT
14.  Detection of Rheumatoid Arthritis–Interstitial Lung Disease Is Enhanced by Serum Biomarkers 
Rationale: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.
Objectives: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD.
Methods: Subjects enrolled in Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR.
Measurements and Main Results: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.
Conclusions: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.
PMCID: PMC4476561  PMID: 25822095
interstitial lung disease; rheumatoid arthritis; subclinical; biomarkers; risk prediction
15.  Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk 
Rationale: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered.
Objectives: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women.
Methods: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use.
Measurements and Main Results: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures.
Conclusions: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.
PMCID: PMC4418341  PMID: 25719895
low bone density; COPD; vertebral fractures; quantitative computed tomography; smoking
16.  Normal Thymus in Adults: Appearance on CT and Associations with Age, Sex, BMI and Smoking 
European radiology  2015;26(1):15-24.
To investigate the CT appearance and size of the thymus in associations with characteristics of participants.
Materials and Methods
2540 supposedly healthy participants (mean age 58.9 years, 51% female) were evaluated for the CT appearance of thymic glands with four-point scores (according to the ratio of fat and soft tissue), size, and morphology. These were correlated with participants’ age, sex, BMI, and smoking history.
Of 2540 participants, 1869 (74%) showed complete fatty replacement of the thymus (Score 0), 463 (18%) predominantly fatty attenuation (Score 1), 172 (7%) half fatty and half soft-tissue attenuation (Score 2), and 36 (1%) solid thymic gland with predominantly soft-tissue attenuation (Score 3). Female participants showed less fatty degeneration of the thymus with higher thymic scores within age 40-69 (P<0.001). Participants with lower thymic scores showed higher BMI (P<0.001) and were more likely to be former smokers (P<0.001) with higher pack-years (P=0.04).
Visual assessment with four-point thymic scores revealed a sex difference in the fatty degeneration of the thymus with age. Women show significantly higher thymic scores than men, suggesting less fat content of the thymus, during age 40-69. Cigarette smoking and high BMI are associated with advanced fatty replacement of the thymus.
PMCID: PMC4847950  PMID: 25925358
Computed tomography; Thymus Gland; Adult; Body Mass Index; Smoking
17.  Pulmonary cysts identified on chest CT: Are they part of aging change or of clinical significance? 
Thorax  2015;70(12):1156-1162.
To investigate the prevalence and natural course of pulmonary cysts in a population-based cohort and to describe the CT image characteristics in association with participant demographics and pulmonary functions.
Materials and Methods
Chest CT scans of 2633 participants (mean 59.2 years; 50% female) of the Framingham Heart Study (FHS) were visually evaluated for the presence of pulmonary cysts and their image characteristics. These findings were correlated with participant demographics and results of pulmonary function tests as well as the presence of emphysema independently detected on CT. The interval change was investigated by comparison with previous CT scans (median interval, 6.1 years).
Pulmonary cysts were seen in 7.6% (95% CI, 6.6-8.7; 200/2633). They were not observed in participants younger than 40 years old, and the prevalence increased with age. Multiple cysts (≥5) were seen in 0.9% of all participants. Participants with pulmonary cysts showed significantly lower BMI (P<0.001). Pulmonary cysts were most likely to appear solitary in the peripheral area of the lower lobes and remain unchanged or slightly increase in size over time. Pulmonary cysts showed no significant influence on pulmonary functions (P=0.07-0.6) except for DLCO (P=0.03) and no association with cigarette smoking (P=0.1-0.9) or emphysema (P=0.7).
Pulmonary cysts identified on chest CT may be a part of the aging changes of the lungs, occurring in asymptomatic individuals older than 40 years, and are associated with decreased BMI and DLCO. Multiple pulmonary cysts may need to be evaluated for the possibility of cystic lung diseases.
PMCID: PMC4848007  PMID: 26514407
CT; Lung; Cysts; the Framingham Heart Study
18.  Association Between Interstitial Lung Abnormalities and All-Cause Mortality 
JAMA  2016;315(7):672-681.
Interstitial lung abnormalities have been associated with decreased six-minute walk distance, diffusion capacity for carbon monoxide and total lung capacity; however to our knowledge, an association with mortality has not been previously investigated.
To investigate whether interstitial lung abnormalities are associated with increased mortality.
Prospective cohort studies of 2633 participants from the Framingham Heart Study (FHS) (CT scans obtained 9/08–3/11), 5320 from the Age Gene/Environment Susceptibility (AGES)-Reykjavik (recruited 1/02–2/06), 2068 from COPDGene (recruited 11/07–4/10), and 1670 from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) (between 12/05–12/06).
Interstitial lung abnormality status as determined by chest CT evaluation.
All cause mortality over approximately 3 to 9 year median follow up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
Interstitial lung abnormalities were present in 177 (7%) of the participants from FHS, 378 (7%) from AGES-Reykjavik, 156 (8%) from COPDGene, and in 157 (9%) from ECLIPSE. Over median follow-up times of ~3–9 years there were more deaths (and a greater absolute rate of mortality) among those with interstitial lung abnormalities compared to those without interstitial lung abnormalities in each cohort; 7% compared to 1% in FHS (6% difference, 95% confidence interval [CI] 2%, 10%), 56% compared to 33% in AGES-Reykjavik (23% difference, 95% CI 18%, 28%), 16% compared to 11% in COPDGene (5% difference, 95% CI −1%, 11%) and 11% compared to 5% in ECLIPSE (6% difference, 95% CI 1%, 11%). After adjustment for covariates, interstitial lung abnormalities were associated with an increase in the risk of death in the FHS (HR=2.7, 95% CI, 1.1–65, P=0.030), AGES-Reykjavik (HR 1.3, 95% CI 1.2–1.4, P<0.001), COPDGene (HR=1.8, 95% CI, 1.1, 2.8, P=0.014), and ECLIPSE (HR=1.4, 95% CI, 1.1–2, P=0.022) cohorts. In the AGES-Reykjavik cohort the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
In four separate research cohorts, interstitial lung abnormalities were associated with a higher risk of all-cause mortality. The clinical implications of this association require further investigation.
PMCID: PMC4828973  PMID: 26881370
Idiopathic pulmonary fibrosis; interstitial lung disease; interstitial lung abnormalities (ILA); undiagnosed; subclinical
19.  A randomised trial of lung sealant versus medical therapy for advanced emphysema 
The European respiratory journal  2015;46(3):651-662.
Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.
Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.
57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalization (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.
Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.
PMCID: PMC4826269  PMID: 25837041
20.  Pulmonary Artery Enlargement is Associated with RV Dysfunction and Loss of Blood Volume in Small Pulmonary Vessels in Chronic Obstructive Pulmonary Disease 
Circulation. Cardiovascular imaging  2015;8(4):10.1161/CIRCIMAGING.114.002546 e002546.
COPD causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. CT-detected relative pulmonary artery enlargement defined as a pulmonary artery to ascending aorta diameter ratio greater than one (PA:A>1) is a marker for pulmonary hypertension and predicts COPD exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function.
Methods and Results
A single-center prospective cohort study of COPD patients was conducted. Clinical characteristics and CT metrics, including the PA:A and pulmonary blood vessel volume were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac magnetic resonance imaging (cMRI) with 3D analysis. Linear regression examined the relationships between clinical characteristics, CT and cMRI metrics, and 6-minute walk distance (6MWD). Twenty four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (EF) (52±7% vs 60±9%, p=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross sectional area of <5 mm2. Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RVEF. Both PA diameter and reduced RVEF were independently associated with reduced 6MWD.
The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on CT. CMRI detects early RV dysfunction and remodeling in non-severe COPD patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance.
PMCID: PMC4392846  PMID: 25855668
cardiac MRI; CT; pulmonary hypertension; pulmonary heart disease; smoking; COPD
21.  Long-Term Exposure to Traffic Emissions and Fine Particulate Matter and Lung Function Decline in the Framingham Heart Study 
Rationale: Few studies have examined associations between long-term exposure to fine particulate matter (PM2.5) and lung function decline in adults.
Objectives: To determine if exposure to traffic and PM2.5 is associated with longitudinal changes in lung function in a population-based cohort in the Northeastern United States, where pollution levels are relatively low.
Methods: FEV1 and FVC were measured up to two times between 1995 and 2011 among 6,339 participants of the Framingham Offspring or Third Generation studies. We tested associations between residential proximity to a major roadway and PM2.5 exposure in 2001 (estimated by a land-use model using satellite measurements of aerosol optical thickness) and lung function. We examined differences in average lung function using mixed-effects models and differences in lung function decline using linear regression models. Current smokers were excluded. Models were adjusted for age, sex, height, weight, pack-years, socioeconomic status indicators, cohort, time, season, and weather.
Measurements and Main Results: Living less than 100 m from a major roadway was associated with a 23.2 ml (95% confidence interval [CI], −44.4 to −1.9) lower FEV1 and a 5.0 ml/yr (95% CI, −9.0 to −0.9) faster decline in FEV1 compared with more than 400 m. Each 2 μg/m3 increase in average of PM2.5 was associated with a 13.5 ml (95% CI, −26.6 to −0.3) lower FEV1 and a 2.1 ml/yr (95% CI, −4.1 to −0.2) faster decline in FEV1. There were similar associations with FVC. Associations with FEV1/FVC ratio were weak or absent.
Conclusions: Long-term exposure to traffic and PM2.5, at relatively low levels, was associated with lower FEV1 and FVC and an accelerated rate of lung function decline.
PMCID: PMC4384780  PMID: 25590631
air pollution; respiratory function tests; particulate matter; chronic obstructive pulmonary disease; asthma
22.  Clinical and Radiologic Disease in Smokers With Normal Spirometry 
JAMA internal medicine  2015;175(9):1539-1549.
Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free.
To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0.
Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011.
Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life.
One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George’s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease.
Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.
PMCID: PMC4564354  PMID: 26098755
23.  Anterior Mediastinal Masses in the Framingham Heart Study: Prevalence and CT Image Characteristics 
To investigate the prevalence and CT image characteristics of anterior mediastinal masses in a population-based cohort and their association with the demographics of the participants.
Materials and Methods
Chest CT scans of 2571 Framingham Heart Study participants (mean age 58.9 years, 51% female) were evaluated by two board-certified radiologists with expertise in thoracic imaging for the presence of anterior mediastinal masses, their shape, contour, location, invasion of adjacent structures, fat content, and calcification. For participants with anterior mediastinal masses, a previous cardiac CT scan was reviewed for interval size change of the masses, when available. The demographics of the participants were studied for any association with the presence of anterior mediastinal masses.
Of 2571, 23 participants (0.9%, 95% CI: 0.6 to 1.3) had anterior mediastinal masses on CT. The most common CT characteristics were oval shape, lobular contour, and midline location, showing soft tissue density (median 32.1 HU). Fat content was detected in a few cases (9%, 2/23). Six out of eight masses with available prior cardiac CT scans demonstrated an interval growth over a median period of 6.5 years. No risk factors for anterior mediastinal masses were detected among participants’ demographics, including age, sex, BMI, and cigarette smoking.
The prevalence of anterior mediastinal masses is 0.9% in the Framingham Heart Study. Those masses may increase in size when observed over 5–7 years. Investigation of clinical significance in incidentally found anterior mediastinal masses with a longer period of follow-up would be necessary.
PMCID: PMC4332399  PMID: 25705709
Anterior mediastinal masses; CT; Prevalence; the Framingham Heart Study
24.  Morphologic Response of the Pulmonary Vasculature to Endoscopic Lung Volume Reduction 
Endoscopic Lung Volume Reduction has been used to reduce lung hyperinflation in selected patients with severe emphysema. Little is known about the effect of this procedure on the intraparenchymal pulmonary vasculature. In this study we used CT based vascular reconstruction to quantify the effect of the procedure on the pulmonary vasculature.
Intraparenchymal vasculature was reconstructed and quantified in 12 patients with CT scans at baseline and 12 weeks following bilateral introduction of sealants in the upper lobes. The volume of each lung and each lobe was measured, and the vascular volume profile was calculated for both lower lobes. The detected vasculature was further labeled manually as arterial or venous in the right lower lobe.
There was an increase in the volume of the lower lobes (3.14L to 3.25L, p=0.0005). There was an increase in BV5, defined as the volume of blood vessels with cross sectional area of less than 5mm2, (53.2ml to 57.9ml, p=0.03). This was found to be correlated with the increase in lower lobe volumes (R=0.65, p=0.02). The changes appear to be symmetric for veins and arteries with a correlation coefficient of 0.87 and a slope of near identity.
In the subjects studied, there was an increase, from baseline, in BV5 in the lower lobes that correlated with the change in the volume of the lower lobes. The change appeared to be symmetric for both arteries and veins. The study illustrates the use of intraparenchymal pulmonary vascular reconstruction to study morphologic changes in response to interventions.
PMCID: PMC4648543  PMID: 26587564
25.  Childhood-Onset Asthma in Smokers. Association between CT Measures of Airway Size, Lung Function, and Chronic Airflow Obstruction 
Rationale and Objectives: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma.
Methods: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models.
Measurements and Main Results: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models.
Conclusion: In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction.
Clinical trial registered with (NCT00608764).
PMCID: PMC4298990  PMID: 25296268
airway wall volume; airway lumen volume; wall area percent

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