Publications

2015
Wells MJ, Iyer AS, Rahaghi FN, Bhatt SP, Gupta H, Denney TS, Lloyd SG, Dell'Italia LJ, Nath H, Estepar RSJ, Washko GR, Dransfield MT. Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease. Circ Cardiovasc Imaging 2015;8(4)Abstract
BACKGROUND: Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function. METHODS AND RESULTS: A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance. CONCLUSIONS: The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.
2014
Kim V, Desai P, Newell JD, Make BJ, Washko GR, Silverman EK, Crapo JD, Bhatt SP, Criner GJ. Airway wall thickness is increased in COPD patients with bronchodilator responsiveness. Respir Res 2014;15:84.Abstract
RATIONALE: Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR. METHODS: We analyzed subjects with GOLD 1-4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated. RESULTS: 2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar. CONCLUSION: BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD.
Freeman CM, McCubbrey AL, Crudgington S, Nelson J, Martinez FJ, Han MLK, Washko GR, Chensue SW, Arenberg DA, Meldrum CA, McCloskey L, Curtis JL. Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent. PLoS One 2014;9(5):e96421.Abstract
UNLABELLED: Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically-indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-γ or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-γ production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-γ transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes. TRIAL REGISTRATION: ClinicalTrials.gov as NCT00281229.
Rahaghi FN, van Beek EJR, Washko GR. Cardiopulmonary coupling in chronic obstructive pulmonary disease: the role of imaging. J Thorac Imaging 2014;29(2):80-91.Abstract
Chronic obstructive pulmonary disorder (COPD) is a systemic disease that affects the cardiovascular system through multiple pathways. Pulmonary hypertension, ventricular dysfunction, and atherosclerosis are associated with smoking and COPD, causing significant morbidity and poor prognosis. Coupling between the pulmonary and cardiovascular system involves mechanical interdependence and inflammatory pathways that potentially affect the entire circulation. Although treatments specific for COPD-related cardiovascular and pulmonary vascular disease are limited, early diagnosis, study of pathophysiology, and monitoring the effects of treatment are enhanced with improved imaging techniques. In this article, we review recent advancements in the imaging of the vasculature and the heart in patients with COPD. We also explore the potential mechanism of coupling between the progression of COPD and vascular disease. Imaging methods reviewed include specific implementations of computed tomography, magnetic resonance imaging, dual-energy computed tomography, positron emission tomography, and echocardiography. Specific applications to the proximal and distal pulmonary vasculature, as well as to the heart and systemic circulation, are also discussed.
Diaz AA, Hardin ME, Come CE, San José Estépar R, Ross JC, Kurugol S, Okajima Y, Han MLK, Kim V, Ramsdell J, Silverman EK, Crapo JD, Lynch DA, Make B, Barr GR, Hersh CP, Washko GR. Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction. Ann Am Thorac Soc 2014;11(9):1371-8.Abstract
RATIONALE AND OBJECTIVES: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. METHODS: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. MEASUREMENTS AND MAIN RESULTS: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. CONCLUSION: In smokers with childhood-onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Castaldi PJ, Dy J, Ross J, Chang Y, Washko GR, Curran-Everett D, Williams A, Lynch DA, Make BJ, Crapo JD, Bowler RP, Regan EA, Hokanson JE, Kinney GL, Han MLK, Soler X, Ramsdell JW, Barr GR, Foreman M, van Beek E, Casaburi R, Criner GJ, Lutz SM, Rennard SI, Santorico S, Sciurba FC, DeMeo DL, Hersh CP, Silverman EK, Cho MH. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax 2014;69(5):415-22.Abstract
BACKGROUND: There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. METHODS: We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. FINDINGS: We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). INTERPRETATION: Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.
Rudyanto RD, Kerkstra S, van Rikxoort EM, Fetita C, Brillet P-Y, Lefevre C, Xue W, Zhu X, Liang J, Öksüz I, Ünay D, Kadipaşaoğlu K, San José Estépar R, Ross JC, Washko GR, Prieto J-C, Hoyos MH, Orkisz M, Meine H, Hüllebrand M, Stöcker C, Mir FL, Naranjo V, Villanueva E, Staring M, Xiao C, Stoel BC, Fabijanska A, Smistad E, Elster AC, Lindseth F, Foruzan AH, Kiros R, Popuri K, Cobzas D, Jimenez-Carretero D, Santos A, Ledesma-Carbayo MJ, Helmberger M, Urschler M, Pienn M, Bosboom DGH, Campo A, Prokop M, de Jong PA, Ortiz-de-Solorzano C, Muñoz-Barrutia A, van Ginneken B. Comparing algorithms for automated vessel segmentation in computed tomography scans of the lung: the VESSEL12 study. Med Image Anal 2014;18(7):1217-32.Abstract
The VESSEL12 (VESsel SEgmentation in the Lung) challenge objectively compares the performance of different algorithms to identify vessels in thoracic computed tomography (CT) scans. Vessel segmentation is fundamental in computer aided processing of data generated by 3D imaging modalities. As manual vessel segmentation is prohibitively time consuming, any real world application requires some form of automation. Several approaches exist for automated vessel segmentation, but judging their relative merits is difficult due to a lack of standardized evaluation. We present an annotated reference dataset containing 20 CT scans and propose nine categories to perform a comprehensive evaluation of vessel segmentation algorithms from both academia and industry. Twenty algorithms participated in the VESSEL12 challenge, held at International Symposium on Biomedical Imaging (ISBI) 2012. All results have been published at the VESSEL12 website http://vessel12.grand-challenge.org. The challenge remains ongoing and open to new participants. Our three contributions are: (1) an annotated reference dataset available online for evaluation of new algorithms; (2) a quantitative scoring system for objective comparison of algorithms; and (3) performance analysis of the strengths and weaknesses of the various vessel segmentation methods in the presence of various lung diseases.
Bhatt SP, Sieren JC, Dransfield MT, Washko GR, Newell JD, Stinson DS, Zamba GKD, Hoffman EA. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction. Thorax 2014;69(5):409-14.Abstract
BACKGROUND: Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity<0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard. METHODS: Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45-80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard. RESULTS: 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ=0.85; 95% CI 0.83 to 0.86, p<0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, p<0.001) and gas trapping (19.8% vs 7.5%, p<0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, p<0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls. CONCLUSIONS: Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.
Bhatt SP, Washko GR, Dransfield MT, Sieren JC, Newell JD, Hoffman EA. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction: authors' response. Thorax 2014;69(12):1147-8.
Doyle TJ, Dellaripa PF, Batra K, Frits ML, Iannaccone CK, Hatabu H, Nishino M, Weinblatt ME, Ascherman DP, Washko GR, Hunninghake GM, Choi AMK, Shadick NA, Rosas IO. Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest 2014;146(1):41-50.Abstract
BACKGROUND: Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. METHODS: All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. RESULTS: Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. CONCLUSIONS: We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.
Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JHM, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJM, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen MH, Rich SS, Barr GR. Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. Am J Respir Crit Care Med 2014;189(4):408-18.Abstract
RATIONALE: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering. OBJECTIVES: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States. METHODS: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity. MEASUREMENTS AND MAIN RESULTS: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema. CONCLUSIONS: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
Martinez CH, Okajima Y, Murray S, Washko GR, Martinez FJ, Silverman EK, Lee JH, Regan EA, Crapo JD, Curtis JL, Hatabu H, Han MLK. Impact of self-reported gastroesophageal reflux disease in subjects from COPDGene cohort. Respir Res 2014;15:62.Abstract
BACKGROUND: The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes. METHODS: Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score. RESULTS: GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George's Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association. CONCLUSIONS: In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.
Kinsey MC, Estepar RSJ, Zhao Y, Yu X, Diao N, Heist RS, Wain JC, Mark EJ, Washko G, Christiani DC. Invasive adenocarcinoma of the lung is associated with the upper lung regions. Lung Cancer 2014;84(2):145-50.Abstract
OBJECTIVES: We postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema. MATERIALS AND METHODS: One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema. RESULTS: The majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P = 0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P = 0.008, compared to lower region), whereas lobar location of tumor was not (P = 0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (P = 0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P = 0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P = 0.217). CONCLUSION: Invasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.
Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M, Kitada T, Glass K, Owen CA, Mahmood A, Washko GR, Hashimoto S, Ryter SW, Choi AMK. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 2014;124(9):3987-4003.Abstract
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.
Diaz AA, Come CE, Mannino DM, Pinto-Plata V, Divo MJ, Bigelow C, Celli B, Washko GR. Obstructive lung disease in Mexican Americans and non-Hispanic whites: an analysis of diagnosis and survival in the National Health and Nutritional Examination Survey III Follow-up Study. Chest 2014;145(2):282-289.Abstract
BACKGROUND: Although obstructive lung disease (OLD), which includes COPD, affects all the populations, Hispanics seem to be protected against COPD development and progression. Whether this advantage translates into a survival benefit for this population is unknown. We aimed to determine the risk for OLD in Mexican Americans, the largest US Hispanic subgroup, compared with non-Hispanic whites and to assess all-cause mortality in subjects with OLD. METHODS: We assessed the relationships between Mexican American ethnicity and spirometric OLD and risk of death among 6,456 US adults aged ≥ 40 years who participated in the Third National Health and Nutritional Examination Survey Follow-up Study. We used logistic and Cox regression analyses to estimate the OR for OLD among Mexican Americans and the hazard ratio (HR) for all-cause mortality among Mexican Americans with OLD, respectively. RESULTS: After adjustment for demographic factors, socioeconomic status, and COPD risk factors, Mexican Americans had decreased odds of OLD diagnosis compared with whites (OR, 0.72 [95% CI, 0.54-0.95]). Among the 1,734 participants with OLD, 1,054 (60.8%) died during median follow-up of 12 years. In an adjusted model, Mexican Americans had no advantage in mortality from all causes (HR, 0.88 [95% CI, 0.69-1.13]). After accounting for the fact that some Mexican Americans may have moved back to Mexico and died there (thus, had no US death certificate), there was still no difference in mortality between these groups. CONCLUSIONS: Although Mexican Americans appear to have lower risk for OLD, subjects of this ethnicity with OLD do not seem to have a survival advantage.
Hobbs BD, Foreman MG, Bowler R, Jacobson F, Make BJ, Castaldi PJ, San José Estépar R, Silverman EK, Hersh CP. Pneumothorax risk factors in smokers with and without chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014;11(9):1387-94.Abstract
RATIONALE: The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined. OBJECTIVES: We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema. METHODS: The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report. MEASUREMENTS AND MAIN RESULTS: Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33). CONCLUSIONS: Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Bowler RP, Kim V, Regan E, Williams AAA, Santorico SA, Make BJ, Lynch DA, Hokanson JE, Washko GR, Bercz P, Soler X, Marchetti N, Criner GJ, Ramsdell J, Han MLK, Demeo D, Anzueto A, Comellas A, Crapo JD, Dransfield M, Wells MJ, Hersh CP, MacIntyre N, Martinez F, Nath HP, Niewoehner D, Sciurba F, Sharafkhaneh A, Silverman EK, van Beek EJR, Wilson C, Wendt C, Wise RA. Prediction of acute respiratory disease in current and former smokers with and without COPD. Chest 2014;146(4):941-950.Abstract
BACKGROUND: The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown. METHODS: Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score. RESULTS: At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV1), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George's Respiratory Questionnaire score). Risks were similar for those with and without COPD. CONCLUSIONS: Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.
Rahaghi FN, Lazea D, Dihya S, San José Estépar R, Bueno R, Sugarbaker D, Frendl G, Washko GR. Preoperative pulmonary vascular morphology and its relationship to postpneumonectomy hemodynamics. Acad Radiol 2014;21(6):704-10.Abstract
RATIONALE AND OBJECTIVES: Pulmonary edema and pulmonary hypertension are postsurgical complications of pneumonectomy that may represent the remaining pulmonary vasculature's inability to accommodate the entirety of the cardiac output. Quantification of the aggregate pulmonary vascular cross-sectional area (CSA) has been used to study the development of pulmonary vascular disease in smokers. In this study, we applied this technique to demonstrate the potential utility of pulmonary vascular quantification in surgical risk assessment. Our hypothesis was that those subjects with the lowest aggregate vascular CSA in the nonoperative lung would be most likely to have elevated pulmonary vascular pressures in the postoperative period. MATERIALS AND METHODS: A total of 61 subjects with postoperative hemodynamics and adequate imaging were identified from 159 patients undergoing pneumonectomies for mesothelioma. The total CSA of blood vessels perpendicular to the plane of computed tomographic (CT) scan slices was computed for blood vessels <5 mm(2) (CSA 5 mm). This measurement expressed as a percentage of lung parenchyma area (CSA 5%) was compared to postoperative hemodynamic measurements obtained by right heart catheterization. RESULTS: In patients where a contrasted CT scan was used (n = 26), CSA 5% was correlated with postoperative day 0 minimum cardiac index (R = 0.37, P = .03) but not with the maximum pulmonary arterial pressures. In patients with noncontrast CT scans (n = 35), CSA 5% was inversely correlated with postoperative day 0 maximum pulmonary arterial pressures (R = 0.43, P = .03) but not with the minimum cardiac index. The preoperative perfusion fraction of the nonsurgical lung did not correlate with postoperative hemodynamics. CONCLUSIONS: CSA of pulmonary vasculature with an area ≤5 mm(2) has potential in estimating the ability of pulmonary vascular bed to accommodate postsurgical changes in pneumonectomy.
Díaz AA, Tringler MF. Prevalence of hypertension in rural populations from Ibero-America and the Caribbean. Rural Remote Health 2014;14:2591.Abstract
INTRODUCTION: Hypertension and cardiovascular risk factors are widespread in developing countries, but little is known about cardiovascular risk profiles in rural communities from Ibero-America and the Caribbean. The aim of the present study was to evaluate the peer-reviewed literature published from 1990 to 2012 relating to the prevalence of hypertension in rural populations from Ibero-America and the Caribbean. METHODS: A bibliographic search was conducted in MEDLINE, SCIELO and LILACS databases. Included were population-based studies in which prevalence of hypertension in adults was reported. RESULTS: A total of 30 peer-reviewed publications were identified that reported the prevalence of hypertension in 33 143 patients. The crude hypertension prevalence reported from rural Ibero-America was 32.6% (95% confidence interval: 31.4-32.5%; range: 1.8-52%). The prevalence of hypertension was lower in aboriginal populations than in other rural communities (19.5% vs 36%). Only nine studies assessed the awareness, treatment, and level of control of hypertension (means 54%, 57%, and 14% respectively). The most prevalent cardiovascular risk factors were abdominal obesity (39%) and overweight (39%). CONCLUSIONS: Hypertension is of public health importance in rural Ibero-America and the Caribbean, with evidence of considerable under-diagnosis, treatment, and control. There is an urgent need to develop strategies to prevent, detect, treat, and control hypertension effectively in this region.
McDonald M-LN, Diaz AA, Ross JC, Estepar RSJ, Zhou L, Regan EA, Eckbo E, Muralidhar N, Come CE, Cho MH, Hersh CP, Lange C, Wouters E, Casaburi RH, Coxson HO, MacNee W, Rennard SI, Lomas DA, Agusti A, Celli BR, Black-Shinn JL, Kinney GL, Lutz SM, Hokanson JE, Silverman EK, Washko GR. Quantitative computed tomography measures of pectoralis muscle area and disease severity in chronic obstructive pulmonary disease. A cross-sectional study. Ann Am Thorac Soc 2014;11(3):326-34.Abstract
RATIONALE: Muscle wasting in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis and is not readily assessed by measures of body mass index (BMI). BMI does not discriminate between relative proportions of adipose tissue and lean muscle and may be insensitive to early pathologic changes in body composition. Computed tomography (CT)-based assessments of the pectoralis muscles may provide insight into the clinical significance of skeletal muscles in smokers. OBJECTIVES: We hypothesized that objective assessment of the pectoralis muscle area on chest CT scans provides information that is clinically relevant and independent of BMI. METHODS: Data from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) Study (n = 73) were used to assess the relationship between pectoralis muscle area and fat-free mass. We then used data in a subset (n = 966) of a larger cohort, the COPDGene (COPD Genetic Epidemiology) Study, to explore the relationship between pectoralis muscle area and COPD-related traits. MEASUREMENTS AND MAIN RESULTS: We first investigated the correlation between pectoralis muscle area and fat-free mass, using data from a subset of participants in the ECLIPSE Study. We then further investigated pectoralis muscle area in COPDGene Study participants and found that higher pectoralis muscle area values were associated with greater height, male sex, and younger age. On subsequent clinical correlation, compared with BMI, pectoralis muscle area was more significantly associated with COPD-related traits, including spirometric measures, dyspnea, and 6-minute-walk distance (6MWD). For example, on average, each 10-cm(2) increase in pectoralis muscle area was associated with a 0.8-unit decrease in the BODE (Body mass index, Obstruction, Dyspnea, Exercise) index (95% confidence interval, -1.0 to -0.6; P < 0.001). Furthermore, statistically significant associations between pectoralis muscle area and COPD-related traits remained even after adjustment for BMI. CONCLUSIONS: CT-derived pectoralis muscle area provides relevant indices of COPD morbidity that may be more predictive of important COPD-related traits than BMI. However, the relationship with clinically relevant outcomes such as hospitalization and death requires additional investigation. Pectoralis muscle area is a convenient measure that can be collected in the clinical setting in addition to BMI.

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