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Craig P Hersh,
George R Washko,
Raúl San Estépar,
Sharon Lutz,
Paul J Friedman, Meilan K Han,
John E Hokanson,
Philip F Judy,
David A Lynch,
Barry J Make,
Nathaniel Marchetti,
John D Newell,
Frank C Sciurba,
James D Crapo,
Edwin K Silverman
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ABSTRACT: BACKGROUND: Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease. METHODS: Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < -950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp-856, the percent of lung < -856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between -856 and -950 HU; and (4) Residuals from the regression of Exp-856 on percent emphysema. RESULTS: In 8517 subjects with complete data, Exp-856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp-856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables. CONCLUSIONS: Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
Respiratory research 04/2013; 14(1):42. · 3.36 Impact Factor
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Alejandro A Diaz, Meilan K Han,
Carolyn E Come,
Raúl San José Estépar,
James C Ross,
Victor Kim,
Mark T Dransfield,
Douglas Curran-Everett,
Joyce D Schroeder,
David A Lynch,
Juerg Tschirren,
Edwin K Silverman,
George R Washko
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ABSTRACT: In CT scans of smokers with COPD, the subsegmental airway wall area percent (WA%) is greater and more strongly correlated with FEV1 % predicted than WA% obtained in the segmental airways. Because emphysema is linked to loss of airway tethering and may limit airway expansion, increases in WA% may be related to emphysema and not solely to remodeling. We aimed to first determine whether the stronger association of subsegmental vs segmental WA% with FEV1 % predicted is mitigated by emphysema and, second, to assess the relationships among emphysema, WA%, and total bronchial area (TBA).
We analyzed CT scan segmental and subsegmental WA% (WA% = 100 × wall area/TBA) of six bronchial paths and corresponding lobar emphysema, lung function, and clinical data in 983 smokers with COPD.
Compared with segmental WA%, the subsegmental WA% had a greater effect on FEV1% predicted (-0.8% to -1.7% vs -1.9% to -2.6% per 1-unit increase in WA%, respectively; P < .05 for most bronchial paths). After adjusting for emphysema, the association between subsegmental WA% and FEV1 % predicted was weakened in two bronchial paths. Increases in WA% between bronchial segments correlated directly with emphysema in all bronchial paths (P < .05). In multivariate regression models, emphysema was directly related to subsegmental WA% in most bronchial paths and inversely related to subsegmental TBA in all bronchial paths.
The greater effect of subsegmental WA% on airflow obstruction is mitigated by emphysema. Part of the emphysema effect might be due to loss of airway tethering, leading to a reduction in TBA and an increase in WA%.
ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
Chest 03/2013; 143(3):687-93. · 5.25 Impact Factor
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Nadia N Hansel,
George R Washko,
Marilyn G Foreman, Meilan K Han,
Eric A Hoffman,
Dawn L Demeo,
R Graham Barr,
Edwin J R Van Beek,
Ella A Kazerooni,
Robert A Wise,
Robert H Brown,
Jennifer Black-Shinn,
John E Hokanson,
Nicola A Hanania,
Barry Make,
Edwin K Silverman,
James D Crapo,
Mark T Dransfield For The Copdgene Investigators
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ABSTRACT: Abstract Background: Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD. Methods: First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of% emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment. Results: Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean% emphysema (13.1% vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs. Conclusions: AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs.
COPD Journal of Chronic Obstructive Pulmonary Disease 02/2013; 10(1):20-7. · 1.79 Impact Factor
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ABSTRACT: BACKGROUND: Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. METHODS: Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3epsilon without or with various TLR ligands. We measured protein expression of IFN-gamma, TNF-alpha, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. RESULTS: All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-gamma and TNF-alpha by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. CONCLUSIONS: These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1.
Respiratory research 02/2013; 14(1):13. · 3.36 Impact Factor
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ABSTRACT: ABSTRACT BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with pulmonary vasculopathy. OBJECTIVE: To determine whether sildenafil improves six minute walk distance (6MWD) in subjects with right ventricular dysfunction. MEASUREMENTS: The IPFnet conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by DLCO <35% predicted. A substudy examined 119/180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD) and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment and changes in 6MWD, St. George's Respiratory Score (SGRQ), EuroQol and SF36 from enrollment to 12 weeks. RESULTS: The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71/119 subjects, 60%; mean RVSP was 42.5 mmHg. In the subgroup of subjects with RVSD, sildenafil-treated subjects experienced less decrement in 6MWD (99.3 meters, p=0.01) and greater improvement in SGRQ (13.4 points, p=0.005) and EuroQol visual analog scores (17.9 points, p=0.04) than placebo-treated subjects. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (p=0.13), but was associated with greater relative improvement in SGRQ (14.8 points, p=0.02) versus placebo-treated subjects. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF36. CONCLUSIONS: Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared to placebo; sildenafil also improves quality of life in subjects with RVH and RVSD.
Chest 01/2013; · 5.25 Impact Factor
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Carlos H Martinez,
Swetha Raparla,
Craig A Plauschinat,
Nicholas D Giardino,
Barbara Rogers,
Julien Beresford,
Judith D Bentkover,
Amy Schachtner-Appel,
Jeffrey L Curtis,
Fernando J Martinez, Meilan K Han
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ABSTRACT: Abstract Background: Morbidity and mortality for women with chronic obstructive pulmonary disease (COPD) are increasing, and little is known about gender differences in perception of COPD care. Methods: Surveys were administered to a convenience sample of COPD patients to evaluate perceptions about symptoms, barriers to care, and sources of information about COPD. Results: Data on 295 female and 273 male participants were analyzed. With similar frequencies, women and men reported dyspnea and rated their health as poor/very poor. Although more women than men reported annual household income <$30,000, no significant gender differences in frequency of health insurance, physician visits, or ever having had spirometry were detected. In adjusted models (1) women were more likely to report COPD diagnostic delay (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.13-2.45, p=0.01), although anxiety (OR 1.83, 95% CI 1.10-3.06, p=0.02) and history of exacerbations (OR 1.60, 95% CI 1.08-2.37, p=0.01) were also significant predictors, (2) female gender was associated with difficulty reaching one's physician (OR 2.54, 95% CI 1.33-4.86, p=0.004), as was prior history of exacerbations (OR 2.25, 95% CI 1.21-4.20, p=0.01), and (3) female gender (OR 2.15, 95% CI 1.10-4.21, p=0.02) was the only significant predictor for finding time spent with their physician as insufficient. Conclusions: Significant gender-related differences in the perception of COPD healthcare delivery exist, revealing an opportunity to better understand what influences these attitudes and to improve care for both men and women.
Journal of Women s Health 12/2012; 21(12):1267-74. · 1.57 Impact Factor
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J Michael Wells,
George R Washko, MeiLan K Han,
Naseer Abbas,
Hrudaya Nath,
A James Mamary,
Elizabeth Regan,
William C Bailey,
Fernando J Martinez,
Elizabeth Westfall,
Terri H Beaty,
Douglas Curran-Everett,
Jeffrey L Curtis,
John E Hokanson,
David A Lynch,
Barry J Make,
James D Crapo,
Edwin K Silverman,
Russell P Bowler,
Mark T Dransfield
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ABSTRACT: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations.
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.).
New England Journal of Medicine 09/2012; 367(10):913-21. · 53.30 Impact Factor
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Jordan Alexander Zach,
John D Newell,
Joyce Schroeder,
James R Murphy,
Douglas Curran-Everett,
Eric A Hoffman,
Philip M Westgate, Meilan K Han,
Edwin K Silverman,
James D Crapo,
David A Lynch
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ABSTRACT: OBJECTIVES: The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them. MATERIALS AND METHODS: Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAAI-950). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAAE-856). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLCCT and FRCCT), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10). RESULTS: Mean (SD) %LAAI-950 was 2.0% (2.7%), and mean (SD) %LAAE-856 was 9.2% (6.8%). Mean (SD) %LAAI-950 was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P < 0.001). The %LAAI-950 did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAAE-856 did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAAI-950 showed a direct relationship to TLCCT (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAAE-856 was related to age (P = 0.001), FRCCT (P = 0.007), and scanner type (P < 0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLCCT (P < 0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P < 0.001). CONCLUSIONS: Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution.
Investigative radiology 07/2012; 47(10):596-602. · 4.85 Impact Factor
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ABSTRACT: * COPD is a heterogeneous disease, modified by environmental and intrinsic host factors. The interaction between COPD and its comorbidities is complex and bidirectional. * It has been estimated that the proportion of patients with COPD caused by cigarette smoking is between 80% and 90%. Risk factors associated with COPD in nonsmokers are numerous and incompletely understood, but a history of asthma or tuberculosis, exposure to traffic and outdoor pollution, and exposure to biomass smoke show the strongest associations. Other factors that may contribute to COPD phenotypes include gender, genetics, and the lung microbiome. * Certain comorbid conditions, such as cardiovascular disease and osteoporosis, are more common in the COPD patient population. Other comorbidities, such as overlap syndrome, the coexistence of COPD, and obstructive sleep apnea may not be as prevalent in COPD but are important because they may modify disease course. * Systemic inflammation may be pathogenically related to many comorbidities seen in COPD including cardiovascular disease, osteoporosis, metabolic syndrome, and depression. * Based on the data presented here, two general patterns of clinical features and comorbidities that share some associations are (1) emphysema, low BMI and osteoporosis and (2) chronic bronchitis, airway disease, high BMI, OSA, and diabetes. * The classification of patients with COPD into subgroups with shared characteristics and outcomes offers the potential for specific interventions. New research tools from the fields of epidemiology, immunology, imaging, and data analysis will be helpful in accomplishing this goal.
The Medical clinics of North America 07/2012; 96(4):713-27. · 2.18 Impact Factor
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Mark T Dransfield,
Sarah Harnden,
Robert L Burton,
Richard K Albert,
William C Bailey,
Richard Casaburi,
John Connett,
J Allen D Cooper,
Gerard J Criner,
Jeffrey L Curtis, [......],
Moon H Nahm,
Dennis E Niewoehner,
Janos Porszasz,
John Reilly,
Paul D Scanlon,
Steven M Scharf,
Frank C Sciurba,
George R Washko,
Prescott G Woodruff,
Stephen C Lazarus
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ABSTRACT: Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.
One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.
Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.
PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points. Clinical Trials Registration: NCT00457977.
Clinical Infectious Diseases 05/2012; 55(5):e35-44. · 9.15 Impact Factor
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ABSTRACT: Background
Health-related quality of life (HRQL) measures have been correlated with lung function in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). However, different pathophysiologic mechanisms may influence how these distinct diseases affect HRQL, resulting in differing HRQL by pulmonary diagnosis among patients with similar severity of ventilatory impairment.Methods
The NHLBI Lung Tissue Research Consortium provided data on well-characterized participants with COPD (n=576) and ILD (n=405) at four clinical sites. Using multiple linear regression, we examined the effects of FEV(1) (% predicted) and diagnosis (ILD versus COPD) on HRQL scores, including total St. George's Respiratory Questionnaire (SGRQ) scores and Short Form-12 physical component summary (PCS) and mental component summary (MCS) scores.ResultsParticipants with ILD had on average higher SGRQ scores (15.33 points; 95% CI 12.46, 18.19; p<0.001) and lower SF-12 PCS scores (-4.73 points; 95% CI -6.31,-3.14; p<0.001) compared to COPD patients with similar FEV(1) % predicted values, indicating worse HRQL. The specific diagnosis also modified the effect of FEV(1) on the total SGRQ score (p=0.003) and the SF-12 PCS score (p=0.03). There was no relationship between lung function and SF-12 MCS scores.ConclusionHRQL scores were worse for ILD patients compared to COPD patients with similar degrees of ventilatory impairment. Differences in dyspnea mechanism or in the rate of disease progression may account for these differences in HRQL.
Chest 05/2012; · 5.25 Impact Factor
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Carlos H Martinez,
Ya-Hong Chen,
Phillip M Westgate,
Lyrica X Liu,
Susan Murray,
Jeffrey L Curtis,
Barry J Make,
Ella A Kazerooni,
David A Lynch,
Nathaniel Marchetti,
George R Washko,
Fernando J Martinez, Meilan K Han
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ABSTRACT: The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE).
1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a -950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20-fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26-fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
Thorax 05/2012; 67(5):399-406. · 6.84 Impact Factor
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R Graham Barr,
Eugene A Berkowitz,
Francesca Bigazzi,
Frederick Bode,
Jessica Bon,
Russell P Bowler,
Caroline Chiles,
James D Crapo,
Gerard J Criner,
Jeffrey L Curtis, [......],
Robert M Steiner,
Charlton Strange,
Nicola Sverzellati,
Joseph H Tashjian,
Edwin J R van Beek,
Lacey Washington,
George R Washko,
Gloria Westney,
Susan A Wood,
Prescott G Woodruff
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ABSTRACT: The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring.
Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9-11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements.
Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively.
Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.
COPD Journal of Chronic Obstructive Pulmonary Disease 03/2012; 9(2):151-9. · 1.79 Impact Factor
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Radiology 03/2012; 262(3):1042; author reply 1043. · 5.73 Impact Factor
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Jin-Fu Xu,
George R Washko,
Kiichi Nakahira,
Hiroto Hatabu,
Avignat S Patel,
Isis E Fernandez,
Mizuki Nishino,
Yuka Okajima,
Tsuneo Yamashiro,
James C Ross, [......],
Fernando J Martinez, MeiLan K Han,
David A Lynch,
James D Crapo,
Danielle Morse,
Stefan W Ryter,
Edwin K Silverman,
Ivan O Rosas,
Augustine M K Choi,
Gary M Hunninghake
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ABSTRACT: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.
To evaluate the association between statin use and ILD.
We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro.
In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03-2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3(-/-) and Casp1(-/-) mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages.
Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
American Journal of Respiratory and Critical Care Medicine 03/2012; 185(5):547-56. · 11.08 Impact Factor
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Meilan K Han,
Yvonne J Huang,
John J Lipuma,
Homer A Boushey,
Richard C Boucher,
William O Cookson,
Jeffrey L Curtis,
John Erb-Downward,
Susan V Lynch,
Sanjay Sethi,
Galen B Toews,
Vincent B Young,
Matthew C Wolfgang,
Gary B Huffnagle,
Fernando J Martinez
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ABSTRACT: The composition of the lung microbiome contributes to both health and disease, including obstructive lung disease. Because it has been estimated that over 70% of the bacterial species on body surfaces cannot be cultured by currently available techniques, traditional culture techniques are no longer the gold standard for microbial investigation. Advanced techniques that identify bacterial sequences, including the 16S ribosomal RNA gene, have provided new insights into the depth and breadth of microbiota present both in the diseased and normal lung. In asthma, the composition of the microbiome of the lung and gut during early childhood development may play a key role in the development of asthma, while specific airway microbiota are associated with chronic asthma in adults. Early bacterial stimulation appears to reduce asthma susceptibility by helping the immune system develop lifelong tolerance to innocuous antigens. By contrast, perturbations in the microbiome from antibiotic use may increase the risk for asthma development. In chronic obstructive pulmonary disease, bacterial colonisation has been associated with a chronic bronchitic phenotype, increased risk of exacerbations, and accelerated loss of lung function. In cystic fibrosis, studies utilising culture-independent methods have identified associations between decreased bacterial community diversity and reduced lung function; colonisation with Pseudomonas aeruginosa has been associated with the presence of certain CFTR mutations. Genomic analysis of the lung microbiome is a young field, but has the potential to define the relationship between lung microbiome composition and disease course. Whether we can manipulate bacterial communities to improve clinical outcomes remains to be seen.
Thorax 02/2012; 67(5):456-63. · 6.84 Impact Factor
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ABSTRACT: Mannose-binding lectin is a collectin involved in host defense against infection. Whether mannose-binding lectin deficiency is associated with acute exacerbations of chronic obstructive pulmonary disease is debated.
Participants in a study designed to determine if azithromycin taken daily for one year decreased acute exacerbations had serum mannose-binding lectin concentrations measured at the time of enrollment.
Samples were obtained from 1037 subjects (91%) in the trial. The prevalence of mannose-binding lectin deficiency ranged from 0.5% to 52.2%, depending on how deficiency was defined. No differences in the prevalence of deficiency were observed with respect to any demographic variable assessed, and no differences were observed in time to first exacerbation, rate of exacerbations, or percentage of subjects requiring hospitalization for exacerbations in those with deficiency versus those without, regardless of how deficiency was defined.
In a large sample of subjects with chronic obstructive pulmonary disease selected for having an increased risk of experiencing an acute exacerbation of chronic obstructive pulmonary disease, only 1.9% had mannose-binding lectin concentrations below the normal range and we found no association between mannose-binding lectin concentrations and time to first acute exacerbation or frequency of acute exacerbations during one year of prospective follow-up.
International Journal of COPD 01/2012; 7:767-77.
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ABSTRACT: An increase in airway caliber (airway distensibility) with lung inflation is attenuated in COPD. Furthermore, some subjects have a decrease in airway caliber with lung inflation. We aimed to test the hypothesis that airway caliber increases are lower in subjects with emphysema-predominant (EP) compared with airway-predominant (AP) CT scan subtypes. Additionally, we compared clinical and CT scan features of subjects with (airway constrictors) and without a decrease in airway caliber.
Based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages and CT scan subtypes, we created a control group (n = 46) and the following matched COPD groups (n = 23 each): GOLD-2-AP, GOLD-2-EP, GOLD-4-AP, and GOLD-4-EP. From the CT scans of all 138 subjects, we measured emphysema, lung volumes, and caliber changes in the third and fourth airway generations of two bronchi. We expressed airway distensibility (ratio of airway lumen diameter change to lung volume change from end tidal breathing to full inspiration) as a global or lobar measure based on normalization by whole-lung or lobar volume changes.
Global distensibility in the third and fourth airway generations was significantly lower in the GOLD-2-EP and GOLD-4-EP groups than in control subjects. In GOLD-2 subjects, lobar distensibility of the right-upper-lobe fourth airway generation was significantly lower in those with EP than in those with AP. In multivariate analysis, emphysema was an independent determinant of global and lobar airway distensibility. Compared with nonconstrictors, airway constrictors experienced more dyspnea, were more hyperinflated, and had a higher percentage of emphysema.
Distensibility of large- to medium-sized airways is reduced in subjects with an EP CT scan subtype. Emphysema seems to alter airway-parenchyma interdependence. Trial registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
Chest 09/2011; 141(3):736-44. · 5.25 Impact Factor
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Richard K Albert,
John Connett,
William C Bailey,
Richard Casaburi,
J Allen D Cooper,
Gerard J Criner,
Jeffrey L Curtis,
Mark T Dransfield, Meilan K Han,
Stephen C Lazarus, [......],
Dennis E Niewoehner,
Janos Porsasz,
Connie S Price,
John Reilly,
Paul D Scanlon,
Frank C Sciurba,
Steven M Scharf,
George R Washko,
Prescott G Woodruff,
Nicholas R Anthonisen
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ABSTRACT: Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.
We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.
A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).
Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).
New England Journal of Medicine 08/2011; 365(8):689-98. · 53.30 Impact Factor
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Carolyn E Come,
Miguel J Divo,
Raúl San José Estépar,
Frank C Sciurba,
Gerard J Criner,
Nathaniel Marchetti,
Steven M Scharf,
Zab Mosenifar,
Barry J Make,
Cesar A Keller,
Omar A Minai,
Fernando J Martinez, MeiLan K Han,
John J Reilly,
Bartolome R Celli,
George R Washko
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ABSTRACT: In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume.
In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O(2) pulse=VO(2)/HR) at baseline and 6 months. Medical and surgical patients were divided into "deflators" and "non-deflators" based on change in RV/TLC from baseline (∆RV/TLC). We defined deflation as the ∆RV/TLC experienced by 75% of surgical patients. We examined changes in O(2) pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs.
In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O(2) pulse (median ∆RV/TLC -18.0% vs. -9.3%, p=0.0003; median ∆O(2) pulse 13.6% vs. 1.8%, p=0.12). Surgical deflators also improved iso-work O(2) pulse (0.53 mL/beat, p=0.04 at 20 W). In the validation cohort, surgical deflators experienced a greater improvement in peak O(2) pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O(2) pulse at rest and during unloaded pedaling (0.32 mL/beat, p<0.0001 and 0.47 mL/beat, p<0.0001, respectively) corresponded with significant reductions in HR and improvements in VO(2). On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O(2) pulse (OR 1.88, 95% CI 1.30-2.72, p=0.0008).
In COPD, decreased hyperinflation through lung volume reduction is associated with improved O(2) pulse.
Respiratory medicine 08/2011; 106(1):109-19. · 2.33 Impact Factor
