2013
Han MLK, Muellerova H, Curran-Everett D, Dransfield MT, Washko GR, Regan EA, Bowler RP, Beaty TH, Hokanson JE, Lynch DA, Jones PW, Anzueto A, Martinez FJ, Crapo JD, Silverman EK, Make BJ.
GOLD 2011 disease severity classification in COPDGene: a prospective cohort study. Lancet Respir Med 2013;1(1):43-50.
AbstractBACKGROUND: The 2011 GOLD (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease [COPD]) consensus report uses symptoms, exacerbation history, and forced expiratory volume (FEV1)% to categorise patients according to disease severity and guide treatment. We aimed to assess both the influence of symptom instrument choice on patient category assignment and prospective exacerbation risk by category.
METHODS: Patients were recruited from 21 centres in the USA, as part of the COPDGene study. Eligible patients were aged 45-80 years, had smoked for 10 pack-years or more, and had an FEV1/forced vital capacity (FVC) <0·7. Categories were defined with the modified Medical Research Council (mMRC) dyspnoea scale (score 0-1 vs ≥2) and the St George's Respiratory Questionnaire (SGRQ; ≥25 vs <25 as a surrogate for the COPD Assessment Test [CAT] ≥10 vs <10) in addition to COPD exacerbations in the previous year (<2 vs ≥ 2), and lung function (FEV1% predicted ≥50 vs <50). Statistical comparisons were done with k-sample permutation tests. This study cohort is registered with ClinicalTrials.gov, number NCT00608764.
FINDINGS: 4484 patients with COPD were included in this analysis. Category assignment using the mMRC scale versus SGRQ were similar but not identical. On the basis of the mMRC scale, 1507 (33·6%) patients were assigned to category A, 919 (20·5%) to category B, 355 (7·9%) to category C, and 1703 (38·0%) to category D; on the basis of the SGRQ, 1317 (29·4%) patients were assigned to category A, 1109 (24·7%) to category B, 221 (4·9%) to category C, and 1837 (41·0%) to category D (κ coefficient for agreement, 0·77). Significant heterogeneity in prospective exacerbation rates (exacerbations/person-years) were seen, especially in the D subcategories, depending on the risk factor that determined category assignment (lung function only [0·89, 95% CI 0·78-1·00]), previous exacerbation history only [1·34, 1·0-1·6], or both [1·86, 1·6-2·1; p<0·0001]).
INTERPRETATION: The GOLD classification emphasises the importance of symptoms and exacerbation risk when assessing COPD severity. The choice of symptom measure influences category assignment. The relative number of patients with low symptoms and high risk for exacerbations (category C) is low. Differences in exacerbation rates for patients in the highest risk category D were seen depending on whether risk was based on lung function, exacerbation history, or both.
FUNDING: National Heart, Lung, and Blood Institute, and the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor.
Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A, Sathirapongsasuti FJ, Cervo M, Yao H, Chung AL, Mizumura K, An CH, Shan B, Franks JM, Haley KJ, Owen CA, Tesfaigzi Y, Washko GR, Quackenbush J, Silverman EK, Rahman I, Kim HP, Mahmood A, Biswal SS, Ryter SW, Choi AMK.
Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J Clin Invest 2013;123(12):5212-30.
AbstractChronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/- or Map1lc3B-/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6-/Y) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1-/-, Map1lc3B-/-, and Hdac6-/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.
Freeman CM, Martinez FJ, Han MLK, Washko GR, McCubbrey AL, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL.
Lung CD8+ T cells in COPD have increased expression of bacterial TLRs. Respir Res 2013;14:13.
AbstractBACKGROUND: 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-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, 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-γ and TNF-α 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.
Hersh CP, Washko GR, San José Estépar R, Lutz S, Friedman PJ, Han MLK, Hokanson JE, Judy PF, Lynch DA, Make BJ, Marchetti N, Newell JD, Sciurba FC, Crapo JD, Silverman EK.
Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD. Respir Res 2013;14:42.
AbstractBACKGROUND: 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) RVC(856-950), 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 RVC(856-950) 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 RVC(856-950) 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.
Hansel NN, Washko GR, Foreman MG, Han MLK, Hoffman EA, DeMeo DL, Barr GR, van Beek EJR, Kazerooni EA, Wise RA, Brown RH, Black-Shinn J, Hokanson JE, Hanania NA, Make B, Silverman EK, Crapo JD, Dransfield MT.
Racial differences in CT phenotypes in COPD. COPD 2013;10(1):20-7.
AbstractBACKGROUND: 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.
Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O'Connor GT, Mittleman MA.
Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013;188(11):1351-7.
AbstractRATIONALE: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards.
OBJECTIVES: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study.
METHODS: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995-2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the "moderate" range of the EPA Air Quality Index to exposure in the "good" range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function.
MEASUREMENTS AND MAIN RESULTS: Exposure to pollutant concentrations in the "moderate" range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], -33.4, -6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, -60.9, -0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, -100.7, -10.8) compared with the "good" range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC.
CONCLUSIONS: Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.
Wassermann D, Ross J, Washko G, Westin CF, San Jose Estépar R.
Diffeomorphic point set registration using non-stationary mixture models. Biomedical Imaging (ISBI), 2013 IEEE 10th International Symposium onBiomedical Imaging (ISBI), 2013 IEEE 10th International Symposium on 2013;:1042-1045.
AbstractThis paper investigates a diffeomorphic point-set registration based on non-stationary mixture models. The goal is to improve the non-linear registration of anatomical structures by representing each point as a general non-stationary kernel that provides information about the shape of that point. Our framework generalizes work done by others that use stationary models. We achieve this by integrating the shape at each point when calculating the point-set similarity and transforming it according to the calculated deformation. We also restrict the non-rigid transform to the space of symmetric diffeomorphisms. Our algorithm is validated in synthetic and human datasets in two different applications: fiber bundle and lung airways registration. Our results shows that nonstationary mixture models are superior to Gaussian mixture models and methods that do not take into account the shape of each point. View full abstract
Castaldi P, San Jose Estépar R, Mendoza CS, Hersh CP, Laird N, Crapo J, Lynch DA, Silverman EK, Washko GR.
Distinct Quantitative CT Emphysema Patterns Are Associated With Physiology And Function In Smokers. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A3728-A3728.
Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle J, Nishino M, Kurugol S, Ross J, San Jose Estépar R, Murphy E, Steele MP, Loyd JE, Schwarz MI, Fingerlin T, Rosas IO, Washko GR, O'Connor G, Schwartz DA.
MUC5B Promoter Polymorphism (rs35705950) Is Predictive Of Interstitial Lung Abnormalities In The General Population. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A5980-A5980.
Nardelli P, San Jose Estépar R, Cantillon-Murphy P.
Semi-automated airway segmentation of lung CT using 3D slicer. International journal of computer assisted radiology and surgeryInternational journal of computer assisted radiology and surgery 2013;8:46-47.
Kinsey CM, San Jose Estépar R, Zhao Y, Yu X, Heist RS, Wain J, Washko GR, Christiani DC.
Adenocarcinoma Occurs Predominantly In The Upper Regions Of The Lung And Is Associated With Improved Survival Compared To Occurrence In Other Regions. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A3604-A3604.
Kurugol S, San Jose Estépar R, Ross JC, Kinney GL, Black-Shinn JL, Budoff M, Hokanson JE.
Automated Quantification Of Aorta Morphology And Mural Calcifications In Inspiratory Volumetric CTs Of COPD Patients. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A5453-A5453.
Kinney GL, San Jose Estépar R, Black-Shinn JL, Bowler RP, Han MLK, Come CE, Cho MH, Hersh CP, Reilly JP, Lynch DA, Dransfield MT, Hokanson J, Washko GR.
CT Measures Of Pulmonary Vascular Morphology Are Associated With 6 Minute Walk Distance And BODE Score. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A2874-A2874.
San Jose Estépar R, Kinney GL, Hokanson J, Washko GR.
Differences In Blood Volume Distribution In COPD: A Pilot Study. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A2374-A2374.
McDonald M-LN, Diaz AA, Ross JC, San Jose Estépar R, Regan EA, Eckbo E, Muralidhar N, Come CE, Cho MH, Hersh CP, Lange C, Celli BR, Kinney GL, Hokanson J, Silverman EK, Washko GR.
Pectoralis Muscle Area Is More Highly Associated Than BMI With COPD Severity. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A5454-A5454.
Soler X, Yen A, Black-Shinn JL, San Jose Estépar R, Hokanson JE, Ramsdell JW, Ries A, Malhotra A.
Upper Airway Dynamics In Patients With COPD And Concomitant Obstructive Sleep Apnea (OSA): A Pilot Study. In: American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013 p. A5705-A5705.
Mulshine JL, Avila R, Yankelevitz D, Baer TM, San Jose Estépar R, Fenton L, Aldige CR.
Application of High-Resolution CT Imaging Data to Lung Cancer Drug Development: Measuring Progress: Workshop IX. Journal of Thoracic OncologyJournal of Thoracic Oncology 2013;8:1352-1355.
AbstractBackground:Lung cancer is the leading cause of cancer death and a major public health challenge across the entire world. Computed tomography (CT) imaging of the lung is a rapidly improving medical imaging technique. Spiral CT has been reported to not only improve the early detection of lung cancer in screening high-risk tobacco-exposed populations but also to assist in the clinical assessment of new agents for therapy in lung cancer. Methods:The Prevent Cancer Foundation has sponsored a series of workshops to accelerate progress in using quantitative imaging to advance lung cancer research progress, of which this report summarizes the Ninth Workshop. The defining strategy of this forum to support innovation in quantitative research for early lung cancer management was to enable software validations by assembling collections of high-quality images for which long-term clinical follow-up is known. An additional approach was to define a process for high-quality and economical national implementation of lung cancer screening. Representatives from the Quantitative Imaging Biomarker Alliance, the International Association for the Study of Lung Cancer, the Lung Cancer Alliance, and other organizations outlined their efforts in this regard. A major opportunity exists to advance the dialogue on the use of quantitative imaging tools to cross-fertilize and accelerate image-processing research across lung cancer and chronic obstructive pulmonary disease (COPD). Conclusion:The use of high-resolution CT imaging provides a window into a much earlier stage of COPD as well as coronary artery disease, both being tobacco-induced diseases. Progress in this area was reviewed and opportunities for enhanced collaborative progress defined. Key sessions reviewed emerging developments with imaging technology and the infrastructure to support the storage and distribution of these high-content modalities. Cooperation among diverse collaborators is essential to enable the rapid organic evolution of this field, so that improved outcomes with lung cancer, artery disease, and COPD can be obtained.
Nava R, Marcos VJ, Escalante-Ramírez B, Cristobal G, Perrinet LU, San José Estépar R.
Advances in Texture Analysis for Emphysema Classification. In:
Ruiz-Shulcloper J, Sanniti di Baja G Lecture Notes in Computer Science. Berlin, Heidelberg: Springer Berlin Heidelberg; 2013 p. 214-221-221.
AbstractAbstract. In recent years, with the advent of High-resolution Com- puted Tomography (HRCT), there has been an increased interest for diagnosing Chronic Obstructive Pulmonary Disease (COPD), which is commonly presented as emphysema . Since low-attenuation ...
Paper Córdova H, San Jose Estépar R, Rodríguez-D'Jesús A, Martínez-Pallí G, Arguis P, Rodríguez de Miguel C, Navarro-Ripoll R, Perdomo JM, Cuatrecasas M, Llach J, Vosburgh KG, Fernandez-Esparrach G.
Comparative study of NOTES alone versus NOTES guided by a new image registration system for navigation in the mediastinum: a study in a porcine model. Gastrointestinal endoscopyGastrointestinal endoscopy 2013;77:102-107.
AbstractBACKGROUND:Natural orifice transluminal endoscopic surgery (NOTES) mediastinoscopy (MED) through the esophagus has proved to be feasible in the animal model. However, injury of the adjacent pleura and pneumothorax has been reported as a frequent adverse event when using a blind access.OBJECTIVE:To assess the utility and safety of a CT-based image registration system (IRS) for navigation in the mediastinum.DESIGN:Prospective, randomized, controlled trial in 30 Yorkshire pigs. Thirty-minute MEDs were performed: 15 MEDs were performed with IRS guidance (MED-IRS), and 15 MEDs were performed with a blind access.SETTING:Animal research laboratory.INTERVENTIONS:In both groups, the mediastinum was accessed through a 10-cm submucosal tunnel in the esophageal wall. Timed exploration was performed with identification of 8 mediastinal structures.MAIN OUTCOME MEASUREMENTS:Technical feasibility, adverse events, and the number of mediastinal structures identified.RESULTS:Thirty animals weighing 31.5 ± 3.5 kg were included in this study. MED was not possible in 2 animals in the "MED with blind access" group but was possible in all MEDs performed with IRS. The mean number of identified organs was slightly higher in "with IRS-MED" (6.13 ± 1.3) than with MED with blind access (4.7 ± 2.3; P = .066). Moreover, the right atrium and vena cava were identified in more cases with IRS-MED than in MED with blind access (13 vs 3 and 15 vs 11, P = .000 and P = .03, respectively). There were 3 (23%) adverse events with IRS-MED and 4 (27%) with "MED with blind access" (P = not significant), with pneumothorax being the most frequent (2 and 3, respectively).LIMITATIONS:Nonsurvival animal study.CONCLUSIONS:This study demonstrates that the IRS system appears feasible in natural orifice transluminal endoscopic surgery MED and suggests that IRS guidance might be useful for selected procedures.
San Jose Estépar R, Kinney GL, Black-Shinn JL, Bowler RP, Kindlmann GL, Ross JC, Kikinis R, Han MLK, Come CE, Diaz AA, Cho MH, Hersh CP, Schroeder JD, Reilly JJ, Lynch DA, Crapo JD, Wells MJ, Dransfield MT, Hokanson JE, Washko GR, Washko GR.
Computed Tomographic Measures of Pulmonary Vascular Morphology in Smokers and Their Clinical Implications. American journal of respiratory and critical care medicineAmerican journal of respiratory and critical care medicine 2013;188:231-239.
AbstractRationale: Angiographic investigation suggests that pulmonary vascular remodeling in smokers is characterized by distal pruning of the blood vessels. Objectives: Using volumetric computed tomography scans of the chest we sought to quantitatively evaluate this process and assess its clinical associations. Methods: Pulmonary vessels were automatically identified, segmented, and measured. Total blood vessel volume (TBV) and the aggregate vessel volume for vessels less than 5 mm(2) (BV5) were calculated for all lobes. The lobe-specific BV5 measures were normalized to the TBV of that lobe and the nonvascular tissue volume (BV5/T(issue)V) to calculate lobe-specific BV5/TBV and BV5/T(issue)V ratios. Densitometric measures of emphysema were obtained using a Hounsfield unit threshold of -950 (%LAA-950). Measures of chronic obstructive pulmonary disease severity included single breath measures of diffusing capacity of carbon monoxide, oxygen saturation, the 6-minute-walk distance, St George's Respiratory Questionnaire total score (SGRQ), and the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index. Measurements and Main Results: The %LAA-950 was inversely related to all calculated vascular ratios. In multivariate models including age, sex, and %LAA-950, lobe-specific measurements of BV5/TBV were directly related to resting oxygen saturation and inversely associated with both the SGRQ and BODE scores. In similar multivariate adjustment lobe-specific BV5/T(issue)V ratios were inversely related to resting oxygen saturation, diffusing capacity of carbon monoxide, 6-minute-walk distance, and directly related to the SGRQ and BODE. Conclusions: Smoking-related chronic obstructive pulmonary disease is characterized by distal pruning of the small blood vessels (<5 mm(2)) and loss of tissue in excess of the vasculature. The magnitude of these changes predicts the clinical severity of disease.