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1.  Sources of Variation in Quantitative Computed Tomography of the Lung 
Journal of thoracic imaging  2013;28(5):10.1097/RTI.0b013e31829efbe9.
The goal of quantitative analysis of computed tomography (CT) scans is to understand the anatomic structure that is responsible for the physiological function of the lung. While the gold standard for structural analysis requires the examination of tissue this is not practical in most studies. Quantitative CT allows a method to obtain valuable information on lung structure without having to remove tissue from the body thereby allowing longitudinal studies of chronic lung diseases. This review briefly discusses CT analysis of the lung and some of the sources of variation that can cause differences in the CT metrics used for analysis of lung disease. While there are many sources of variation the purpose of this review will show that if the study is properly designed to take into account these variations and the CT scanner is properly calibrated valuable information can be obtained from CT scans that should allow us to study the pathogenesis of lung disease and the effect of treatment.
PMCID: PMC3823539  PMID: 23934141
Quantitative CT; COPD; Asthma
2.  Quantitative Pulmonary Imaging Using Computed Tomography and Magnetic Resonance Imaging 
Respirology (Carlton, Vic.)  2012;17(3):432-444.
Measurements of lung function, including spirometry and body plethesmography, are easy to perform and are the current clinical standard for assessing disease severity. However, these lung functional techniques do not adequately explain the observed variability in clinical manifestations of disease and offer little insight into the relationship of lung structure and function. Lung imaging and the image based assessment of lung disease has matured to the extent that it is common for clinical, epidemiologic, and genetic investigation to have a component dedicated to image analysis. There are several exciting imaging modalities currently being used for the non-invasive study of lung anatomy and function. In this review we will focus on two of them, x-ray computed tomography and magnetic resonance imaging. Following a brief introduction of each method we detail some of the most recent work being done to characterize smoking-related lung disease and the clinical applications of such knowledge.
PMCID: PMC3312990  PMID: 22142490
Radiology and other Imaging; COPD; Asthma; Emphysema
3.  Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus 
BMC Pulmonary Medicine  2014;14(1):164.
Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.
Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%).
Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5–10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study.
Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa.
Trial registration identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-164) contains supplementary material, which is available to authorized users.
PMCID: PMC4216374  PMID: 25341556
Airway disease; CT scan; Diabetes mellitus; Emphysema; Spirometry
4.  Fluticasone Induces Epithelial Injury and Alters Barrier Function in Normal Subjects 
The airway epithelium has a number of roles pivotal to the pathogenesis of asthma, including provision of a physical and immune barrier to the inhaled environment. Dysregulated injury and repair responses in asthma result in loss of airway epithelial integrity. Inhaled corticosteroids are a corner stone of asthma treatment. While effective in controlling asthma symptoms, they fail to prevent airway remodeling. Direct cytopathic effects on the airway epithelium may contribute to this.
This study examined the effects of a 4-week treatment regimen of inhaled fluticasone 500 μg twice daily in healthy human subjects. Induced sputum was collected for cell counts and markers of inflammation. Barrier function was examined by diethylenetriaminepentacetic acid (DTPA) clearance measured by nuclear scintillation scan, and albumin concentration in induced sputum.
Steroid exposure resulted in epithelial injury as measured by a significant increase in the number of airway epithelial cells in induced sputum. There was no change in airway inflammation by induced sputum inflammatory cell counts or cytokine levels. Epithelial shedding was associated with an increase in barrier function, as measured by both a decrease in DTPA clearance and decreased albumin in induced sputum. This likely reflects the normal repair response.
Inhaled corticosteroids cause injury to normal airway epithelium. These effects warrant further evaluation in asthma, where the dysregulated repair response may contribute to airway remodeling.
PMCID: PMC4196246  PMID: 25324978
Airway epithelial cell; Asthma; Asthma-medication; corticosteroids
5.  The Effect of Azithromycin in Adults with Stable Neutrophilic COPD: A Double Blind Randomised, Placebo Controlled Trial 
PLoS ONE  2014;9(8):e105609.
Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.
Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15).
Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed.
In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted.
Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12609000259246
PMCID: PMC4141795  PMID: 25148049
6.  DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):97.
Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.
We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7 and FEV1 < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.
Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10−8).
In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0097-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4169636  PMID: 25134640
Pulmonary disease; Chronic obstructive; Hyperinflation; Genome-wide association analysis; Total lung capacity; DNAH5
7.  Quantitative Assessment of the Airway Wall Using Computed Tomography and Optical Coherence Tomography 
Ever since the site and nature of airflow obstruction in chronic obstructive pulmonary disease was described by Hogg, Thurlbeck, and Macklem, investigators have been looking for methods to noninvasively measure the airway wall dimensions. Recent advances in computed tomography technology and new computer algorithms have made it possible to visualize and measure the airway wall and lumen without the need for tissue. However, while there is great hope for computed tomographic assessment of airways, it is well known that the spatial resolution does not allow small airways to be visualized and there are still concerns about the sensitivity of these measurements obtained from these airways. Optical coherence tomography is a new bronchoscopic imaging technique that has generated considerable interest because the spatial resolution is much higher than computed tomography. While relatively more invasive than computed tomography, it has the advantage of not exposing the patient to ionizing radiation. This review discusses some of the data surrounding these two imaging techniques in patients with chronic obstructive pulmonary disease. These imaging techniques are extremely important in the assessment of patients with chronic obstructive pulmonary disease because therapy that is designed to modulate the inflammation in airways may be contraindicated in subjects with the emphysema phenotype and visa versa. Therefore, these new imaging techniques are very likely to play a front-line role in the study of chronic obstructive pulmonary disease and will, hopefully, allow clinicians to phenotype individuals, thereby personalizing their treatment.
PMCID: PMC2731804  PMID: 19687216
computed tomography; airways; optical coherence tomography; chronic obstructive pulmonary disease
8.  Quantitative Computed Tomography Assessment of Airway Wall Dimensions 
Airway remodeling is extremely important in the pathophysiology of chronic obstructive pulmonary disease (COPD). Since the site and nature of airflow obstruction was described by Hogg, Thurlbeck, and Macklem, investigators have been looking for methods to noninvasively measure the airway wall dimensions in subjects with and at risk for COPD. The advent and proliferation of computed tomography (CT) initially allowed investigators to quantify changes in lung parenchymal structure in subjects with emphysema, and more recently attention has turned to the measurement of airway wall dimensions. Unfortunately, while the lung density is relatively easy to quantify, reliable airway measurements have proven to be more difficult to obtain. However, recent advances in CT technology and new computer algorithms have changed the way investigators have measured airways using CT, and it is now hoped that many of the early issues surrounding airway measurements can be resolved. The measurement of airway wall dimensions is important because it is well known that chronic airflow limitation can be caused by a combination of airway and parenchymal changes. The phenotypic expression of these different subtypes of COPD is vital because a therapy designed to modulate the inflammation in airways may be contraindicated in subjects with the emphysema phenotype and visa versa. Therefore, these new imaging techniques are very likely to play a front-line role in the study of COPD and will, hopefully, allow clinicians to phenotype individuals, thereby personalizing their treatment.
PMCID: PMC2720108  PMID: 19056721
computed tomography; airways; emphysema; chronic obstructive pulmonary disease
9.  Chairman's Summary 
PMCID: PMC2720105  PMID: 19137669
10.  Validation of Airway Wall Measurements by Optical Coherence Tomography in Porcine Airways 
PLoS ONE  2014;9(6):e100145.
Examining and quantifying changes in airway morphology is critical for studying longitudinal pathogenesis and interventions in diseases such as chronic obstructive pulmonary disease and asthma. Here we present fiber-optic optical coherence tomography (OCT) as a nondestructive technique to precisely and accurately measure the 2-dimensional cross-sectional areas of airway wall substructure divided into the mucosa (WAmuc), submucosa (WAsub), cartilage (WAcart), and the airway total wall area (WAt). Porcine lung airway specimens were dissected from freshly resected lung lobes (N = 10). Three-dimensional OCT imaging using a fiber-optic rotary-pullback probe was performed immediately on airways greater than 0.9 mm in diameter on the fresh airway specimens and subsequently on the same specimens post-formalin-fixation. The fixed specimens were serially sectioned and stained with H&E. OCT images carefully matched to selected sections stained with Movat’s pentachrome demonstrated that OCT effectively identifies airway epithelium, lamina propria, and cartilage. Selected H&E sections were digitally scanned and airway total wall areas were measured. Traced measurements of WAmuc, WAsub, WAcart, and WAt from OCT images of fresh specimens by two independent observers found there were no significant differences (p>0.05) between the observer’s measurements. The same wall area measurements from OCT images of formalin-fixed specimens found no significant differences for WAsub, WAcart and WAt, and a small but significant difference for WAmuc. Bland-Altman analysis indicated there were negligible biases between the observers for OCT wall area measurements in both fresh and formalin-fixed specimens. Bland-Altman analysis also indicated there was negligible bias between histology and OCT wall area measurements for both fresh and formalin-fixed specimens. We believe this study sets the groundwork for quantitatively monitoring pathogenesis and interventions in the airways using OCT.
PMCID: PMC4064993  PMID: 24949633
11.  Airway Wall Thickness Assessed Using Computed Tomography and Optical Coherence Tomography 
Rationale: Computed tomography (CT) has been shown to reliably measure the airway wall dimensions of medium to large airways. Optical coherence tomography (OCT) is a promising new micron-scale resolution imaging technique that can image small airways 2 mm in diameter or less.
Objectives: To correlate OCT measurements of airway dimensions with measurements assessed using CT scans and lung function.
Methods: Forty-four current and former smokers received spirometry, CT scans, and OCT imaging at the time of bronchoscopy. Specific bronchial segments were identified and measured using the OCT images and three-dimensional reconstructions of the bronchial tree using CT.
Measurements and Main Results: There was a strong correlation between CT and OCT measurements of lumen and wall area (r = 0.84, P < 0.001, and r = 0.89, P < 0.001, respectively). Compared with CT, OCT measurements were lower for both lumen and wall area by 31 and 66%, respectively. The correlation between FEV1% predicted and CT and OCT measured wall area (as percentage of the total area) of fifth-generation airways was very strong (r = −0.79, r = −0.75), but the slope of the relationship was much steeper using OCT than using CT (y = −0.33x + 82, y = −0.1x + 78), indicating greater sensitivity of OCT in detecting changes in wall measurements that relate to FEV1.
Conclusions: OCT can be used to measure airway wall dimensions. OCT may be more sensitive at detecting small airway wall changes that lead to FEV1 changes in individuals with obstructive airway disease.
PMCID: PMC2408438  PMID: 18310475
chronic obstructive pulmonary disease
12.  Expression of Matrix Metalloproteinase-1 in Alveolar Macrophages, Type II Pneumocytes, and Airways in Smokers: Relationship to Lung Function and Emphysema 
Lung  2014;192(4):467-472.
An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema.
We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs’ surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema.
There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT.
These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.
Electronic supplementary material
The online version of this article (doi:10.1007/s00408-014-9585-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4104162  PMID: 24792232
Computed tomography; Emphysema; Expression; Immunohistochemistry; Metalloproteinase; Lung
13.  A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment 
Rationale: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.
Objectives: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.
Methods: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.
Measurements and Main Results: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.
Conclusions: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.
PMCID: PMC3707363  PMID: 23471465
chronic obstructive pulmonary disease; gene expression profiling; biologic markers
14.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13 
Human Molecular Genetics  2011;21(4):947-957.
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
PMCID: PMC3298111  PMID: 22080838
15.  Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype 
PLoS ONE  2012;7(5):e37483.
Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).
Methods and Findings
Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.
Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.
PMCID: PMC3356313  PMID: 22624038
16.  Small-Airway Obstruction and Emphysema in Chronic Obstructive Pulmonary Disease 
The New England journal of medicine  2011;365(17):1567-1575.
The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD.
We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles.
On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P = 0.001), GOLD stage 2 disease (P = 0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001).
These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3238466  PMID: 22029978
17.  Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema 
Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.
Objectives: To identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.
Methods: We performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than –950 Hounsfield units) in all three cohorts.
Measurements and Main Results: We identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10−7 with at least mild emphysema vs. control subjects; P = 4.8 × 10−8 with moderate and more severe emphysema vs. control subjects).
Conclusions: Our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema.
Clinical trial registered with (NCT00292552).
PMCID: PMC3040393  PMID: 20709820
emphysema; chronic obstructive pulmonary disease; BICD1; single-nucleotide polymorphism
18.  Loci Identified by Genome-wide Association Studies Influence Different Disease-related Phenotypes in Chronic Obstructive Pulmonary Disease 
Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.
Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.
Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).
Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.
Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.
PMCID: PMC3029936  PMID: 20656943
COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema
19.  Persistent Pneumocystis colonization leads to the development of chronic obstructive pulmonary disease (COPD) in a non-human primate model of AIDS 
The Journal of infectious diseases  2010;202(2):302-312.
HIV-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with sub-clinical infection has been postulated to promote COPD. Persistence of Pneumocystis (Pc) is associated with HIV and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results support the concept that an infectious agent contributes to development of HIV-associated lung disease and suggests that Pc colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression thus identifying potential therapeutic targets for COPD.
PMCID: PMC2946196  PMID: 20533880
Pneumocystis; COPD; SHIV; AIDS; HIV
20.  Quantitative CT: Associations between Emphysema, Airway Wall Thickness and Body Composition in COPD 
Pulmonary Medicine  2011;2011:419328.
The objective of the present study was to determine the association between CT phenotypes—emphysema by low attenuation area and bronchitis by airway wall thickness—and body composition parameters in a large cohort of subjects with and without COPD. In 452 COPD subjects and 459 subjects without COPD, CT scans were performed to determine emphysema (%LAA), airway wall thickness (AWT-Pi10), and lung mass. Muscle wasting based on FFMI was assessed by bioelectrical impedance. In both the men and women with COPD, FFMI was negatively associated with %LAA. FMI was positively associated with AWT-Pi10 in both subjects with and without COPD. Among the subjects with muscle wasting, the percentage emphysema was high, but the predictive value was moderate. In conclusion, the present study strengthens the hypothesis that the subgroup of COPD cases with muscle wasting have emphysema. Airway wall thickness is positively associated with fat mass index in both subjects with and without COPD.
PMCID: PMC3100107  PMID: 21647214
21.  Quantification of lung surface area using computed tomography 
Respiratory Research  2010;11(1):153.
To refine the CT prediction of emphysema by comparing histology and CT for specific regions of lung. To incorporate both regional lung density measured by CT and cluster analysis of low attenuation areas for comparison with histological measurement of surface area per unit lung volume.
The histological surface area per unit lung volume was estimated for 140 samples taken from resected lung specimens of fourteen subjects. The region of the lung sampled for histology was located on the pre-operative CT scan; the regional CT median lung density and emphysematous lesion size were calculated using the X-ray attenuation values and a low attenuation cluster analysis. Linear mixed models were used to examine the relationships between histological surface area per unit lung volume and CT measures.
The median CT lung density, low attenuation cluster analysis, and the combination of both were important predictors of surface area per unit lung volume measured by histology (p < 0.0001). Akaike's information criterion showed the model incorporating both parameters provided the most accurate prediction of emphysema.
Combining CT measures of lung density and emphysematous lesion size provides a more accurate estimate of lung surface area per unit lung volume than either measure alone.
PMCID: PMC2976969  PMID: 21040527
22.  Micro–Computed Tomography Measurements of Peripheral Lung Pathology in Chronic Obstructive Pulmonary Disease 
Background: The smaller airways, < 2 mm in diameter, offer little resistance in normal lungs, but become the major site of obstruction in chronic obstructive pulmonary disease (COPD).
Objective: To examine bronchiolar remodeling and alveolar destruction in COPD using micro–computed tomography (micro-CT).
Methods: Micro-CT was used to measure the number and cross-sectional lumen area of terminal bronchioles (TB) and alveolar mean linear intercept (Lm) in 4 lungs removed from patients with very severe (GOLD-4) COPD and 4 unused donor lungs that served as controls. These lungs were inflated with air to a transpulmonary pressure (PL) of 30 cm H2O and held at PL 10 cm H2O while they were frozen solid in liquid nitrogen vapor. A high resolution CT scan was performed on the frozen specimen prior to cutting it into 2-cm thick transverse slices. Representative core samples of lung tissue 2 cm long and 1 cm in diameter cut from each slice were fixed at −80°C in a 1% solution of gluteraldehyde in pure acetone, post-fixed in osmium, critically point dried, and examined by micro-CT.
Results: A 10-fold reduction in terminal bronchiolar number and a 100-fold reduction in their minimal cross-sectional lumen area were measured in both emphysematous and non-emphysematous regions of the COPD lungs.
Conclusions: The centrilobular emphysematous phenotype of COPD is associated with narrowing and obliteration of the terminal bronchioles that begins prior to the onset of emphysematous destruction.
PMCID: PMC3136953  PMID: 19741267
COPD, small airway obstruction; termination bronchioles, reduction of; emphysematous destruction
23.  Characterisation of COPD heterogeneity in the ECLIPSE cohort 
Respiratory Research  2010;11(1):122.
Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).
We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.
COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.
The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.
PMCID: PMC2944278  PMID: 20831787
24.  Transforming Growth Factor-β Receptor-3 Is Associated with Pulmonary Emphysema 
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
PMCID: PMC2742752  PMID: 19131638
betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism
25.  The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2009;4(8):e6865.
Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.
Methodology/Principal Findings
Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.
Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.
PMCID: PMC2730536  PMID: 19718453

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