Publications by Year: 2016

2016
Bhatt SP, Terry NLJ, Nath H, Zach JA, Tschirren J, Bolding MS, Stinson DS, Wilson CG, Curran-Everett D, Lynch DA, Putcha N, Soler X, Wise RA, Washko GR, Hoffman EA, Foreman MG, Dransfield MT. Association Between Expiratory Central Airway Collapse and Respiratory Outcomes Among Smokers. JAMA 2016;315(5):498-505.Abstract
IMPORTANCE: Central airway collapse greater than 50% of luminal area during exhalation (expiratory central airway collapse [ECAC]) is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, its prevalence and clinical significance are unknown. OBJECTIVE: To determine whether ECAC is associated with respiratory morbidity in smokers independent of underlying lung disease. DESIGN, SETTING, AND PARTICIPANTS: Analysis of paired inspiratory-expiratory computed tomography images from a large multicenter study (COPDGene) of current and former smokers from 21 clinical centers across the United States. Participants were enrolled from January 2008 to June 2011 and followed up longitudinally until October 2014. Images were initially screened using a quantitative method to detect at least a 30% reduction in minor axis tracheal diameter from inspiration to end-expiration. From this sample of screen-positive scans, cross-sectional area of the trachea was measured manually at 3 predetermined levels (aortic arch, carina, and bronchus intermedius) to confirm ECAC (>50% reduction in cross-sectional area). EXPOSURES: Expiratory central airway collapse. MAIN OUTCOMES AND MEASURES: The primary outcome was baseline respiratory quality of life (St George's Respiratory Questionnaire [SGRQ] scale 0 to 100; 100 represents worst health status; minimum clinically important difference [MCID], 4 units). Secondary outcomes were baseline measures of dyspnea (modified Medical Research Council [mMRC] scale 0 to 4; 4 represents worse dyspnea; MCID, 0.7 units), baseline 6-minute walk distance (MCID, 30 m), and exacerbation frequency (events per 100 person-years) on longitudinal follow-up. RESULTS: The study included 8820 participants with and without COPD (mean age, 59.7 [SD, 6.9] years; 4667 [56.7%] men; 4559 [51.7%] active smokers). The prevalence of ECAC was 5% (443 cases). Patients with ECAC compared with those without ECAC had worse SGRQ scores (30.9 vs 26.5 units; P < .001; absolute difference, 4.4 [95% CI, 2.2-6.6]) and mMRC scale scores (median, 2 [interquartile range [IQR], 0-3]) vs 1 [IQR, 0-3]; P < .001]), but no significant difference in 6-minute walk distance (399 vs 417 m; absolute difference, 18 m [95% CI, 6-30]; P = .30), after adjustment for age, sex, race, body mass index, forced expiratory volume in the first second, pack-years of smoking, and emphysema. On follow-up (median, 4.3 [IQR, 3.2-4.9] years), participants with ECAC had increased frequency of total exacerbations (58 vs 35 events per 100 person-years; incidence rate ratio [IRR], 1.49 [95% CI, 1.29-1.72]; P < .001) and severe exacerbations requiring hospitalization (17 vs 10 events per 100 person-years; IRR, 1.83 [95% CI, 1.51-2.21]; P < .001). CONCLUSIONS AND RELEVANCE: In a cross-sectional analysis of current and former smokers, the presence of ECAC was associated with worse respiratory quality of life. Further studies are needed to assess long-term associations with clinical outcomes.
Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, Okajima Y, Dupuis J, Latourelle JC, Cho MH, El-Chemaly S, Coxson HO, Celli BR, Fernandez IE, Zazueta OE, Ross JC, Harmouche R, San José Estépar R, Diaz AA, Sigurdsson S, Gudmundsson EF, Eiríksdottír G, Aspelund T, Budoff MJ, Kinney GL, Hokanson JE, Williams MC, Murchison JT, MacNee W, Hoffmann U, O'Donnell CJ, Launer LJ, Harrris TB, Gudnason V, Silverman EK, O'Connor GT, Washko GR, Rosas IO, Hunninghake GM. Association Between Interstitial Lung Abnormalities and All-Cause Mortality. JAMA 2016;315(7):672-81.Abstract
IMPORTANCE: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE: To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES: Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.
González G, Washko GR, San José Estépar R. AUTOMATED AGATSTON SCORE COMPUTATION IN A LARGE DATASET OF NON ECG-GATED CHEST COMPUTED TOMOGRAPHY. Proc IEEE Int Symp Biomed Imaging 2016;2016:53-57.Abstract
The Agatston score, computed from ECG-gated computed tomography (CT), is a well established metric of coronary artery disease. It has been recently shown that the Agatston score computed from chest CT (non ECG-gated) studies is highly correlated with the Agatston score computed from cardiac CT scans. In this work we present an automated method to compute the Agatston score from chest CT images. Coronary arteries calcifications (CACs) are defined as voxels contained within the coronary arteries with a value greater or equal to 130 Hounsfield Units (HU). CACs are automatically detected in chest CT studies by locating the heart, generating a region of interest around it, thresholding the image in such region and applying a set of rules to discriminate CACs from calcifications in the main vessels or from metallic implants. We evaluate the methodology in a large cohort of 1500 patients for whom manual reference standard is available. Our results show that the Pearson correlation coefficient between manual and automated Agatston score is ρ = 0.86 ( < 0.0001).
Jimenez-Carretero D, Estepar RSJ, Diaz Cacio M, Ledesma-Carbayo MJ. Automatic Synthesis of Anthropomorphic Pulmonary CT Phantoms. PLoS One 2016;11(1):e0146060.Abstract
The great density and structural complexity of pulmonary vessels and airways impose limitations on the generation of accurate reference standards, which are critical in training and in the validation of image processing methods for features such as pulmonary vessel segmentation or artery-vein (AV) separations. The design of synthetic computed tomography (CT) images of the lung could overcome these difficulties by providing a database of pseudorealistic cases in a constrained and controlled scenario where each part of the image is differentiated unequivocally. This work demonstrates a complete framework to generate computational anthropomorphic CT phantoms of the human lung automatically. Starting from biological and image-based knowledge about the topology and relationships between structures, the system is able to generate synthetic pulmonary arteries, veins, and airways using iterative growth methods that can be merged into a final simulated lung with realistic features. A dataset of 24 labeled anthropomorphic pulmonary CT phantoms were synthesized with the proposed system. Visual examination and quantitative measurements of intensity distributions, dispersion of structures and relationships between pulmonary air and blood flow systems show good correspondence between real and synthetic lungs (p > 0.05 with low Cohen's d effect size and AUC values), supporting the potentiality of the tool and the usefulness of the generated phantoms in the biomedical image processing field.
Diaz AA, San José Estépar R, Washko GR. Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy?. Ann Am Thorac Soc 2016;13(1):4-9.Abstract
Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.
Washko GR, Parraga G. Imaging Biomarkers in Lymphangioleiomyomatosis Clinical Trials. A Wolf in Sheep's Clothing?. Ann Am Thorac Soc 2016;13(3):307-8.
Torrado-Carvajal A, Herraiz JL, Hernandez-Tamames JA, San Jose-Estepar R, Eryaman Y, Rozenholc Y, Adalsteinsson E, Wald LL, Malpica N. Multi-atlas and label fusion approach for patient-specific MRI based skull estimation. Magn Reson Med 2016;75(4):1797-807.Abstract
PURPOSE: MRI-based skull segmentation is a useful procedure for many imaging applications. This study describes a methodology for automatic segmentation of the complete skull from a single T1-weighted volume. METHODS: The skull is estimated using a multi-atlas segmentation approach. Using a whole head computed tomography (CT) scan database, the skull in a new MRI volume is detected by nonrigid image registration of the volume to every CT, and combination of the individual segmentations by label-fusion. We have compared Majority Voting, Simultaneous Truth and Performance Level Estimation (STAPLE), Shape Based Averaging (SBA), and the Selective and Iterative Method for Performance Level Estimation (SIMPLE) algorithms. RESULTS: The pipeline has been evaluated quantitatively using images from the Retrospective Image Registration Evaluation database (reaching an overlap of 72.46 ± 6.99%), a clinical CT-MR dataset (maximum overlap of 78.31 ± 6.97%), and a whole head CT-MRI pair (maximum overlap 78.68%). A qualitative evaluation has also been performed on MRI acquisition of volunteers. CONCLUSION: It is possible to automatically segment the complete skull from MRI data using a multi-atlas and label fusion approach. This will allow the creation of complete MRI-based tissue models that can be used in electromagnetic dosimetry applications and attenuation correction in PET/MR.
Araki T, Nishino M, Gao W, Dupuis J, Hunninghake GM, Murakami T, Washko GR, O'Connor GT, Hatabu H. Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. Eur Radiol 2016;26(1):15-24.Abstract
OBJECTIVE: To investigate CT appearance and size of the thymus in association with participant characteristics. MATERIALS AND METHODS: 2540 supposedly healthy participants (mean age 58.9 years, 51 % female) were evaluated for the CT appearance of thymic glands with four-point scores (according to the ratio of fat and soft tissue), size and morphology. These were correlated with participants' age, sex, BMI and smoking history. RESULTS: Of 2540 participants, 1869 (74 %) showed complete fatty replacement of the thymus (Score 0), 463 (18 %) predominantly fatty attenuation (Score 1), 172 (7 %) half fatty and half soft-tissue attenuation (Score 2) and 36 (1 %) solid thymic gland with predominantly soft-tissue attenuation (Score 3). Female participants showed less fatty degeneration of the thymus with higher thymic scores within age 40-69 years (P < 0.001). Participants with lower thymic scores showed higher BMI (P < 0.001) and were more likely to be former smokers (P < 0.001) with higher pack-years (P = 0.04). CONCLUSIONS: Visual assessment with four-point thymic scores revealed a sex difference in the fatty degeneration of the thymus with age. Women show significantly higher thymic scores, suggesting less fat content of the thymus, during age 40-69 years. Cigarette smoking and high BMI are associated with advanced fatty replacement of the thymus. KEY POINTS: 74% of participants (mean age 58.9 years) demonstrated complete fatty thymus. Women show less fatty thymus compared to men at ages 40-69 years. Smoking and high BMI are associated with advanced fatty degeneration in thymus.
Kinney GL, Baker EH, Klein OL, Black-Shinn JL, Wan ES, Make B, Regan E, Bowler RP, Lutz SM, Young KA, Duca LM, Washko GR, Silverman EK, Crapo JD, Hokanson JE. Pulmonary Predictors of Incident Diabetes in Smokers. Chronic Obstr Pulm Dis 2016;3(4):739-747.Abstract
BACKGROUND: Diabetes mellitus and its complications are a large and increasing burden for health care worldwide. Reduced pulmonary function has been observed in diabetes (both type 1 and type 2), and this reduction is thought to occur prior to diagnosis. Other measures of pulmonary health are associated with diabetes, including lower exercise tolerance, greater dyspnea, lower quality of life (as measured by the St. George's Respiratory Questionaire [SGRQ]) and susceptibility to lung infection and these measures may also predate diabetes diagnosis. METHODS: We examined 7080 participants in the COPD Genetic Epidemiology (COPDGene) study who did not report diabetes at their baseline visit and who provided health status updates during 4.2 years of longitudinal follow-up (LFU). We used Cox proportional hazards modeling, censoring participants at final LFU contact, reported mortality or report of incident diabetes to model predictors of diabetes. These models were constructed using known risk factors as well as proposed markers related to pulmonary health, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV/FVC, respiratory exacerbations (RE), 6-minute walk distance (6MWD), pulmonary associated quality of life (as measured by the SGRQ), corticosteroid use, chronic bronchitis and dyspnea. RESULTS: Over 21,519 person years of follow-up, 392 of 7080 participants reported incident diabetes which was associated with expected predictors; increased body mass index (BMI), high blood pressure, high cholesterol and current smoking status. Age, gender and accumulated smoking exposure were not associated with incident diabetes. Additionally, preserved ratio with impaired spirometry (PRISm) pattern pulmonary function, reduced 6MWD and any report of serious pulmonary events were associated with incident diabetes. CONCLUSIONS: This cluster of pulmonary indicators may aid clinicians in identifying and treating patients with pre- or undiagnosed diabetes.
Bersvendsen J, Toews M, Danudibroto A, Wells WM, Urheim S, San José Estépar R, Samset E. Robust Spatio-Temporal Registration of 4D Cardiac Ultrasound Sequences. Proc SPIE Int Soc Opt Eng 2016;9790Abstract
Registration of multiple 3D ultrasound sectors in order to provide an extended field of view is important for the appreciation of larger anatomical structures at high spatial and temporal resolution. In this paper, we present a method for fully automatic spatio-temporal registration between two partially overlapping 3D ultrasound sequences. The temporal alignment is solved by aligning the normalized cross correlation-over-time curves of the sequences. For the spatial alignment, corresponding 3D Scale Invariant Feature Transform (SIFT) features are extracted from all frames of both sequences independently of the temporal alignment. A rigid transform is then calculated by least squares minimization in combination with random sample consensus. The method is applied to 16 echocardiographic sequences of the left and right ventricles and evaluated against manually annotated temporal events and spatial anatomical landmarks. The mean distances between manually identified landmarks in the left and right ventricles after automatic registration were (mean ± SD) 4.3 ± 1.2 mm compared to a reference error of 2.8 ± 0.6 mm with manual registration. For the temporal alignment, the absolute errors in valvular event times were 14.4 ± 11.6 ms for Aortic Valve (AV) opening, 18.6 ± 16.0 ms for AV closing, and 34.6 ± 26.4 ms for mitral valve opening, compared to a mean inter-frame time of 29 ms.
Bhatt SP, Wells JM, Kinney GL, Washko GR, Budoff M, Kim Y-I, Bailey WC, Nath H, Hokanson JE, Silverman EK, Crapo J, Dransfield MT. β-Blockers are associated with a reduction in COPD exacerbations. Thorax 2016;71(1):8-14.Abstract
BACKGROUND: While some retrospective studies have suggested that β-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful. METHODS: Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers. RESULTS: 3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use. CONCLUSIONS: β-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial. TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT00608764).
Martinez CH, Diaz AA, Parulekar AD, Rennard SI, Kanner RE, Hansel NN, Couper D, Holm KE, Hoth KF, Curtis JL, Martinez FJ, Hanania NA, Regan EA, Paine R, Cigolle CT, Han MLK. Age-Related Differences in Health-Related Quality of Life in COPD: An Analysis of the COPDGene and SPIROMICS Cohorts. Chest 2016;149(4):927-35.Abstract
OBJECTIVE: Younger persons with COPD report worse health-related quality of life (HRQL) than do older individuals. The factors explaining these differences remain unclear. The objective of this article was to explore factors associated with age-related differences in HRQL in COPD. METHODS: Cross-sectional analysis of participants with COPD, any Global Initiative for Chronic Obstructive Lung Disease grade of airflow limitation, and ≥ 50 years old in two cohorts: the Genetic Epidemiology of COPD (COPDGene) study and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). We compared St. George's Respiratory Questionnaire (SGRQ) scores by age group: middle-aged (age, 50-64) vs older (age, 65-80) adults. We used multivariate linear modeling to test associations of age with HRQL, adjusting for demographic and clinical characteristics and comorbidities. RESULTS: Among 4,097 participants in the COPDGene study (2,170 middle-aged and 1,927 older adults) SGRQ total scores were higher (worse) among middle-aged (mean difference, -4.2 points; 95% CI, -5.7 to -2.6; P < .001) than older adults. Age had a statistically significant interaction with dyspnea (P < .001). Greater dyspnea severity (modified Medical Research Council ≥ 2, compared with 0-1) had a stronger association with SGRQ score among middle-aged (β, 24.6; 95% CI, 23.2-25.9) than older-adult (β, 21.0; 95% CI, 19.6-22.3) participants. In analyses using SGRQ as outcome in 1,522 participants in SPIROMICS (598 middle-aged and 924 older adults), we found similar associations, confirming that for the same severity of dyspnea there is a stronger association with HRQL among younger individuals. CONCLUSIONS: Age-related differences in HRQL may be explained by a higher impact of dyspnea among younger subjects with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764 and No.: NCT01969344; URL: www.clinicaltrials.gov.
Rahaghi FN, Wells MJ, Come CE, De La Bruere IA, Bhatt SP, Ross JC, Vegas-Sánchez-Ferrero G, Diaz AA, Minhas J, Dransfield MT, San José Estépar R, Washko GR. Arterial and Venous Pulmonary Vascular Morphology and Their Relationship to Findings in Cardiac Magnetic Resonance Imaging in Smokers. J Comput Assist Tomogr 2016;40(6):948-952.Abstract
OBJECTIVE: Prior work has described the relationship between pulmonary vascular pruning on computed tomography (CT) scans and metrics of right-sided heart dysfunction in smokers. In this analysis, we sought to look at pruning on a lobar level, as well as examine the effect of the arterial and venous circulation on this association. METHODS: Automated vessel segmentation applied to noncontrast CT scans from the COPDGene Study in 24 subjects with cardiac magnetic resonance imaging scans was used to create a blood volume distribution profile. These vessels were then manually tracked to their origin and characterized as artery or vein. RESULTS: Assessment of pruning on a lobar level revealed associations between pruning and right ventricular function previously not observed on a global level. The right ventricular mass index, the right ventricular end-systolic volume index, and pulmonary arterial-to-aorta ratio were associated with both arterial and venous pruning, whereas right ventricular ejection fraction was associated with only arterial pruning. CONCLUSIONS: Lobar assessment and segmentation of the parenchymal vasculature into arterial and venous components provide additional information about the relationship between loss of vasculature on CT scans and right ventricular dysfunction.
Bhatt SP, Soler X, Wang X, Murray S, Anzueto AR, Beaty TH, Boriek AM, Casaburi R, Criner GJ, Diaz AA, Dransfield MT, Curran-Everett D, Galbán CJ, Hoffman EA, Hogg JC, Kazerooni EA, Kim V, Kinney GL, Lagstein A, Lynch DA, Make BJ, Martinez FJ, Ramsdell JW, Reddy R, Ross BD, Rossiter HB, Steiner RM, Strand MJ, van Beek EJR, Wan ES, Washko GR, Wells MJ, Wendt CH, Wise RA, Silverman EK, Crapo JD, Bowler RP, Han MLK. Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2016;194(2):178-84.Abstract
RATIONALE: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Wells MJ, Estepar RSJ, McDonald M-LN, Bhatt SP, Diaz AA, Bailey WC, Jacobson FL, Dransfield MT, Washko GR, Make BJ, Casaburi R, van Beek EJR, Hoffman EA, Sciurba FC, Crapo JD, Silverman EK, Hersh CP. Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study. BMC Pulm Med 2016;16(1):169.Abstract
BACKGROUND: Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD METHODS: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia. RESULTS: Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05-22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58-0.85), self-reported heart failure (OR 6.92, 95%CI 1.56-30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17-6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38-7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up. CONCLUSIONS: Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia. TRIAL REGISTRATION: COPDGene is registered at ClinicalTrials.gov: NCT00608764 (Registration Date: January 28, 2008).
Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, Nishino M, Zazueta OE, Kurugol S, Ross JC, San José Estépar R, Schwartz DA, Rosas IO, Washko GR, O'Connor GT, Hunninghake GM. Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 2016;194(12):1514-1522.Abstract
RATIONALE: The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated. OBJECTIVES: To determine the risk factors for, and the clinical consequences of, having ILA progression in participants from the Framingham Heart Study. METHODS: ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart. Mixed effect regression (and Cox) models were used to assess the association between ILA progression and pulmonary function decline (and mortality). MEASUREMENTS AND MAIN RESULTS: During the follow-up period 660 (35%) participants did not have ILA on either CT scan, 37 (2%) had stable to improving ILA, and 118 (6%) had ILA with progression (the remaining participants without ILA were noted to be indeterminate on at least one CT scan). Increasing age and increasing copies of the MUC5B promoter polymorphism were associated with ILA progression. After adjustment for covariates, ILA progression was associated with a greater FVC decline when compared with participants without ILA (20 ml; SE, ±6 ml; P = 0.0005) and with those with ILA without progression (25 ml; SE, ±11 ml; P = 0.03). Over a median follow-up time of approximately 4 years, after adjustment, ILA progression was associated with an increase in the risk of death (hazard ratio, 3.9; 95% confidence interval, 1.3-10.9; P = 0.01) when compared with those without ILA. CONCLUSIONS: These findings demonstrate that ILA progression in the Framingham Heart Study is associated with an increased rate of pulmonary function decline and increased risk of death.
Diaz AA, Petersen H, Meek P, Sood A, Celli B, Tesfaigzi Y. Differences in Health-Related Quality of Life Between New Mexican Hispanic and Non-Hispanic White Smokers. Chest 2016;150(4):869-876.Abstract
BACKGROUND: Smoking is associated with impaired health-related quality of life (HRQL) across all populations. Because decline in lung function and risk for COPD are lower in New Mexican Hispanic smokers compared with their non-Hispanic white (NHW) counterparts, the goal of this study was to ascertain whether HRQL differs between these two racial/ethnic groups and determine the factors that contribute to this difference. METHODS: We compared the score results of the Medical Outcomes Short-Form 36 Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) in 378 Hispanic subjects and 1,597 NHW subjects enrolled in the Lovelace Smokers' Cohort (LSC) from New Mexico. The associations of race/ethnicity with SGRQ and SF-36 were assessed by using multivariable regression. RESULTS: Physical functioning (difference, -4.5; P = .0008) but not mental health or role emotional domains of the SF-36 was worse in Hispanic smokers than in their NWH counterparts in multivariable analysis. SGRQ total score and its activity and impact subscores were worse in Hispanic (vs NHW) smokers after adjustment for education level, current smoking, pack-years smoked, BMI, number of comorbidities, and FEV % predicted (difference range, 2.9-5.0; all comparisons, P ≤ .001). Although the difference in the SGRQ activity domain was above the clinically important difference of four units, the total score was not. CONCLUSIONS: New Mexican Hispanic smokers have clinically relevant, lower HRQL than their NHW counterparts. A perception of diminished physical functioning and impairment in daily life activities contribute to the poorer HRQL among Hispanic subjects.
Ostridge K, Williams N, Kim V, Harden S, Bourne S, Coombs NA, Elkington PT, Estepar RSJ, Washko G, Staples KJ, Wilkinson TMA. Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases. Respir Res 2016;17(1):92.Abstract
BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Trial registration number NCT01701869 .
Ho JE, Gao W, Levy D, Santhanakrishnan R, Araki T, Rosas IO, Hatabu H, Latourelle JC, Nishino M, Dupuis J, Washko GR, O'Connor GT, Hunninghake GM. Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities. Am J Respir Crit Care Med 2016;194(1):77-83.Abstract
RATIONALE: Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis. OBJECTIVES: We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis. METHODS: We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography. MEASUREMENTS AND MAIN RESULTS: Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P ≤ 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable-adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001). CONCLUSIONS: Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis.
Lai PS, Hang J-Q, Zhang F-Y, Sun J, Zheng B-Y, Su L, Washko GR, Christiani DC. Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline. Environ Health Perspect 2016;124(9):1436-42.Abstract
BACKGROUND: Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined. OBJECTIVE: We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT). METHODS: The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis. RESULTS: Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (-1.3%) in percent emphysema (LAAI-950), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAAI-950 were highly correlated with 15th percentile density (correlation -1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (-6.1 mL) of FEV1 (p = 0.001) between 1981 and 2011. CONCLUSIONS: There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAAI-950 may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline. CITATION: Lai PS, Hang J, Zhang F, Sun J, Zheng BY, Su L, Washko GR, Christiani DC. 2016. Imaging phenotype of occupational endotoxin-related lung function decline. Environ Health Perspect 124:1436-1442; http://dx.doi.org/10.1289/EHP195.

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