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2.
Eur Respir J ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439683

RESUMO

The characteristics that predict progression to overt COPD in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post-hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the SPIROMICS cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC), CT-measured residual volume to total lung capacity ratio (RVCT/TLCCT) varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% [95%CI=0.06%-1.27%] faster rate of decline per year compared to those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current), or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (odds ratio=5.7 [95%CI=2.4-13.2] in upper versus lower RVCT/TLCCTtertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.

4.
Eur Respir J ; 54(3)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371443

RESUMO

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

5.
JAMA ; 322(6): 546-556, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408135

RESUMO

Importance: While air pollutants at historical levels have been associated with cardiovascular and respiratory diseases, it is not known whether exposure to contemporary air pollutant concentrations is associated with progression of emphysema. Objective: To assess the longitudinal association of ambient ozone (O3), fine particulate matter (PM2.5), oxides of nitrogen (NOx), and black carbon exposure with change in percent emphysema assessed via computed tomographic (CT) imaging and lung function. Design, Setting, and Participants: This cohort study included participants from the Multi-Ethnic Study of Atherosclerosis (MESA) Air and Lung Studies conducted in 6 metropolitan regions of the United States, which included 6814 adults aged 45 to 84 years recruited between July 2000 and August 2002, and an additional 257 participants recruited from February 2005 to May 2007, with follow-up through November 2018. Exposures: Residence-specific air pollutant concentrations (O3, PM2.5, NOx, and black carbon) were estimated by validated spatiotemporal models incorporating cohort-specific monitoring, determined from 1999 through the end of follow-up. Main Outcomes and Measures: Percent emphysema, defined as the percent of lung pixels less than -950 Hounsfield units, was assessed up to 5 times per participant via cardiac CT scan (2000-2007) and equivalent regions on lung CT scans (2010-2018). Spirometry was performed up to 3 times per participant (2004-2018). Results: Among 7071 study participants (mean [range] age at recruitment, 60 [45-84] years; 3330 [47.1%] were men), 5780 were assigned outdoor residential air pollution concentrations in the year of their baseline examination and during the follow-up period and had at least 1 follow-up CT scan, and 2772 had at least 1 follow-up spirometric assessment, over a median of 10 years. Median percent emphysema was 3% at baseline and increased a mean of 0.58 percentage points per 10 years. Mean ambient concentrations of PM2.5 and NOx, but not O3, decreased substantially during follow-up. Ambient concentrations of O3, PM2.5, NOx, and black carbon at study baseline were significantly associated with greater increases in percent emphysema per 10 years (O3: 0.13 per 3 parts per billion [95% CI, 0.03-0.24]; PM2.5: 0.11 per 2 µg/m3 [95% CI, 0.03-0.19]; NOx: 0.06 per 10 parts per billion [95% CI, 0.01-0.12]; black carbon: 0.10 per 0.2 µg/m3 [95% CI, 0.01-0.18]). Ambient O3 and NOx concentrations, but not PM2.5 concentrations, during follow-up were also significantly associated with greater increases in percent emphysema. Ambient O3 concentrations, but not other pollutants, at baseline and during follow-up were significantly associated with a greater decline in forced expiratory volume in 1 second per 10 years (baseline: 13.41 mL per 3 parts per billion [95% CI, 0.7-26.1]; follow-up: 18.15 mL per 3 parts per billion [95% CI, 1.59-34.71]). Conclusions and Relevance: In this cohort study conducted between 2000 and 2018 in 6 US metropolitan regions, long-term exposure to ambient air pollutants was significantly associated with increasing emphysema assessed quantitatively using CT imaging and lung function.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Pulmão/fisiologia , Enfisema Pulmonar , Idoso , Idoso de 80 Anos ou mais , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Carbono/efeitos adversos , Carbono/análise , Estudos de Coortes , Progressão da Doença , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/análise , Ozônio/efeitos adversos , Ozônio/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/fisiopatologia , Testes de Função Respiratória , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
6.
Sci Rep ; 9(1): 11367, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388056

RESUMO

Metabolomics is an emerging science that can inform pathogenic mechanisms behind clinical phenotypes in COPD. We aimed to understand disturbances in the serum metabolome associated with respiratory outcomes in ever-smokers from the SPIROMICS cohort. We measured 27 serum metabolites, mostly amino acids, by 1H-nuclear magnetic resonance spectroscopy in 157 white ever-smokers with and without COPD. We tested the association between log-transformed metabolite concentrations and one-year incidence of respiratory exacerbations after adjusting for age, sex, current smoking, body mass index, diabetes, inhaled or oral corticosteroid use, study site and clinical predictors of exacerbations, including FEV1% predicted and history of exacerbations. The mean age of participants was 53.7 years and 58% had COPD. Lower concentrations of serum amino acids were independently associated with 1-year incidence of respiratory exacerbations, including tryptophan (ß = -4.1, 95% CI [-7.0; -1.1], p = 0.007) and the branched-chain amino acids (leucine: ß = -6.0, 95% CI [-9.5; -2.4], p = 0.001; isoleucine: ß = -5.2, 95% CI [-8.6; -1.8], p = 0.003; valine: ß = -4.1, 95% CI [-6.9; -1.4], p = 0.003). Tryptophan concentration was inversely associated with the blood neutrophil-to-lymphocyte ratio (p = 0.03) and the BODE index (p = 0.03). Reduced serum amino acid concentrations in ever-smokers with and without COPD are associated with an increased incidence of respiratory exacerbations.

7.
Korean J Radiol ; 20(7): 1236-1245, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31270987

RESUMO

OBJECTIVE: Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites). MATERIALS AND METHODS: QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (Dh) and functional variables of air volume, total air volume change in the lung (ΔVair), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups. RESULTS: As compared with Whites, Koreans had smaller volume at inspiration, ΔVair between inspiration and expiration (p < 0.001), and Emph% at inspiration (p < 0.001). Especially, Korean females had a decrease of ΔVair in the lower lobes (p < 0.001), associated with fSAD% at the lower lobes (p < 0.05). In addition, Koreans had smaller Dh and WT of the trachea (both, p < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all p < 0.001) and forced vital capacity (R = 0.55, 0.45; all p < 0.001). CONCLUSION: Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.

8.
J Magn Reson Imaging ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276264

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality. Identification of imaging biomarkers for phenotyping is necessary for future treatment and therapy monitoring. However, translation of visual analytic pipelines into clinics or their use in large-scale studies is significantly slowed by time-consuming postprocessing steps. PURPOSE: To implement an automated tool chain for regional quantification of pulmonary microvascular blood flow in order to reduce analysis time and user variability. STUDY TYPE: Prospective. POPULATION: In all, 90 MRI scans of 63 patients, of which 31 had a COPD with a mean Global Initiative for Chronic Obstructive Lung Disease status of 1.9 ± 0.64 (µ ± σ). FIELD STRENGTH/SEQUENCE: 1.5T dynamic gadolinium-enhanced MRI measurement using 4D dynamic contrast material-enhanced (DCE) time-resolved angiography acquired in a single breath-hold in inspiration. [Correction added on August 20, 2019, after first online publication: The field strength in the preceding sentence was corrected.] ASSESSMENT: We built a 3D convolutional neural network for semantic segmentation using 29 manually segmented perfusion maps. All five lobes of the lung are denoted, including the middle lobe. Evaluation was performed on 61 independent cases from two sites of the Multi-Ethnic Study of Arteriosclerosis (MESA)-COPD study. We publish our implementation of a model-free deconvolution filter according to Sourbron et al for 4D DCE MRI scans as open source. STATISTICAL TEST: Cross-validation 29/61 (# training / # testing), intraclass correlation coefficient (ICC), Spearman ρ, Pearson r, Sørensen-Dice coefficient, and overlap. RESULTS: Segmentations and derived clinical parameters were processed in ~90 seconds per case on a Xeon E5-2637v4 workstation with Tesla P40 GPUs. Clinical parameters and predicted segmentations exhibit high concordance with the ground truth regarding median perfusion for all lobes with an ICC of 0.99 and a Sørensen-Dice coefficient of 93.4 ± 2.8 (µ ± σ). DATA CONCLUSION: We present a robust end-to-end pipeline that allows for the extraction of perfusion-based biomarkers for all lung lobes in 4D DCE MRI scans by combining model-free deconvolution with deep learning. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019.

9.
Radiology ; 292(3): 585-594, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31335282

RESUMO

BackgroundChronic obstructive pulmonary disease (COPD) is associated with hemodynamic changes in the pulmonary vasculature. However, cardiac effects are not fully understood and vary by phenotype of chronic lower respiratory disease.PurposeTo use four-dimensional (4D) flow MRI for comprehensive assessment of the right-sided cardiovascular system, assess its interrater and intraobserver reproducibility, and examine associations with venous return to the right heart in individuals with chronic COPD and emphysema.Materials and MethodsThe Multi-Ethnic Study of Atherosclerosis COPD substudy prospectively recruited participants who smoked and who had COPD and nested control participants from population-based samples. Electrocardiography and respiratory gated 4D flow 1.5-T MRI was performed at three sites with full volumetric coverage of the thoracic vessels in 2014-2017 with postbronchodilator spirometry and inspiratory chest CT to quantify percent emphysema. Net flow, peak velocity, retrograde flow, and retrograde fraction were measured on 14 analysis planes. Interrater reproducibility was assessed by two independent observers, and the principle of conservation of mass was employed to evaluate the internal consistency of flow measures. Partial correlation coefficients were adjusted for age, sex, race/ethnicity, height, weight, and smoking status.ResultsAmong 70 participants (29 participants with COPD [mean age, 73.5 years ± 8.1 {standard deviation}; 20 men] and 41 control participants [mean age, 71.0 years ± 6.1; 22 men]), the interrater reproducibility of the 4D flow MRI measures was good to excellent (intraclass correlation coefficient range, 0.73-0.98), as was the internal consistency. There were no statistically significant differences in venous flow parameters according to COPD severity (P > .05). Greater percent emphysema at CT was associated with greater regurgitant flow in the superior and inferior caval veins and tricuspid valve (adjusted r = 0.28-0.55; all P < .01), particularly in the superior vena cava.ConclusionFour-dimensional flow MRI had good-to-excellent observer variability and flow consistency. Percent emphysema at CT was associated with statistically significant differences in retrograde flow, greatest in the superior vena cava.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Choe in this issue.

10.
Chest ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31352035

RESUMO

BACKGROUND: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown. OBJECTIVE: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging. METHODS: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV1 ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders. RESULTS: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes). CONCLUSIONS: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.

11.
Respir Res ; 20(1): 153, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307479

RESUMO

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. RESULTS: We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. CONCLUSIONS: QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31339356

RESUMO

Rationale Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF; however, the extent to which there is additional overlap with IPF, or unique associations among those with ILA is not known. Objectives To perform a genome-wide association study (GWAS) of ILA. Methods: ILA and the subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27) and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, p=3.8x10-8) and FCF1P3 (rs73199442, p=4.8x10-8) with ILA, and HTRE1 (rs7744971, p=4.2x10-8) with subpleural-predominant ILA. These novel associations were not associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (p<0.05/12) with ILA. Conclusions In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common and suggest distinct genetically-driven biologic pathways between ILA and IPF.

13.
Eur Respir J ; 53(6)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31167881

RESUMO

BACKGROUND: Air pollution alters small pulmonary vessels in animal models. We hypothesised that long-term ambient air pollution exposure would be associated with differences in pulmonary vascular volumes in a population-based study. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited adults in six US cities. Personalised long-term exposures to ambient black carbon, nitrogen dioxide (NO2), oxides of nitrogen (NO x ), particulate matter with a 50% cut-off aerodynamic diameter of <2.5 µm (PM2.5) and ozone were estimated using spatiotemporal models. In 2010-2012, total pulmonary vascular volume was measured as the volume of detectable pulmonary arteries and veins, including vessel walls and luminal blood volume, on noncontrast chest computed tomography (TPVVCT). Peripheral TPVVCT was limited to the peripheral 2 cm to isolate smaller vessels. Linear regression adjusted for demographics, anthropometrics, smoking, second-hand smoke, renal function and scanner manufacturer. RESULTS: The mean±sd age of the 3023 participants was 69.3±9.3 years; 46% were never-smokers. Mean exposures were 0.80 µg·m-3 black carbon, 14.6 ppb NO2 and 11.0 µg·m-3 ambient PM2.5. Mean±sd peripheral TPVVCT was 79.2±18.2 cm3 and TPVVCT was 129.3±35.1 cm3. Greater black carbon exposure was associated with a larger peripheral TPVVCT, including after adjustment for city (mean difference 0.41 (95% CI 0.03-0.79) cm3 per interquartile range; p=0.036). Associations for peripheral TPVVCT with NO2 were similar but nonsignificant after city adjustment, while those for PM2.5 were of similar magnitude but nonsignificant after full adjustment. There were no associations for NO x or ozone, or between any pollutant and TPVVCT. CONCLUSIONS: Long-term black carbon exposure was associated with a larger peripheral TPVVCT, suggesting diesel exhaust may contribute to remodelling of small pulmonary vessels in the general population.

14.
Am J Epidemiol ; 188(9): 1655-1665, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145426

RESUMO

Rice accumulates arsenic, an established lung toxicant. Little is known about the association of rice consumption with arsenic-related health effects, particularly interstitial lung disease. Between 2000 and 2002, 6,814 white, black, Hispanic, and Chinese adults from 6 US cities were enrolled in the Multi-Ethnic Study of Atherosclerosis. We included 2,250 participants who had spirometry data, 2,557 with full-lung computed tomography (CT) scans, and 5,710 with cardiac CT scans. Rice consumption and 310 participants with urinary arsenic were assessed at baseline. Spirometry and full-lung CT-derived measures of total lung capacity and high attenuation area (HAA), and interstitial lung abnormalities were measured at examination 5. Cardiac CT-derived HAA was measured at 1-3 visits. Twelve percent of participants reported eating at least 1 serving of rice daily. Comparing data between that group with those who ate less than 1 serving weekly, the mean difference for forced vital capacity was -102 (95% confidence interval (CI): -198, -7) mL, and for forced expiratory volume in 1 second was -90 (95% CI: -170, -11) mL after adjustment for demographics, anthropometrics, dietary factors, and smoking. The cross-sectional adjusted percent difference for total lung capacity was -1.33% (95% CI: -4.29, 1.72) and for cardiac-based HAA was 3.66% (95% CI: 1.22, 6.15). Sensitivity analyses for urinary arsenic were consistent with rice findings. Daily rice consumption was associated with reduced lung function and greater cardiac-based HAA.

15.
Am J Respir Crit Care Med ; 200(6): 721-731, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30925230

RESUMO

Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown.Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT).Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general population-based cohort, and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). A weighted GRS was calculated from 83 SNPs that were previously associated with lung function. Lung density, spatially matched airway dimensions, and airway counts were assessed on full-lung CT. Generalized linear models were adjusted for age, age squared, sex, height, principal components of genetic ancestry, smoking status, pack-years, CT model, milliamperes, and total lung volume.Measurements and Main Results: MESA Lung and SPIROMICS contributed 2,517 and 2,339 participants, respectively. Higher GRS was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways, without effect modification by smoking. Adjustment for CT lung structure, particularly small airway measures, attenuated associations between the GRS and FEV1/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P < 0.0001), but not the GRS (P > 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone.Conclusions: A GRS associated with COPD susceptibility was associated with CT lung structure. Lung structure may be an important mediator of heritability and determinant of personalized COPD risk.

16.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
17.
Ann Am Thorac Soc ; 16(4): 439-446, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30653926

RESUMO

RATIONALE: There is an unmet need to investigate the lower airways in chronic obstructive pulmonary disease (COPD) to define pathogenesis and to identify potential markers to accelerate therapeutic development. Although bronchoscopy is well established to sample airways in various conditions, a comprehensive COPD research protocol has yet to be published. OBJECTIVES: To evaluate the safety and tolerability of a comprehensive research bronchoscopy procedure suitable for multicenter trials and to identify factors associated with adverse events. METHODS: We report the detailed methodology used to conduct the bronchoscopy used in SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study). The protocol entailed collection of tongue scrapings and oral rinses as well as bronchoscopy with airway inspection, bronchoalveolar lavage (BAL), protected brushings, and endobronchial biopsies. Visual airway characteristics were graded on a scale of 0 (normal appearance) to 3 (severe abnormality) in four domains: erythema, edema, secretions, and friability. Adverse events were defined as events requiring intervention. Logistic regression modeling assessed associations between adverse event occurrence and key variables. RESULTS: We enrolled 215 participants. They were 61 ± 9 years old, 71% were white, 53% were male, and post-bronchodilator forced expiratory volume in 1 second was 89 ± 19% predicted. Self-reported asthma was present in 22% of bronchoscopy participants. Oral samples were obtained in greater than or equal to 99% of participants. Airway characteristics were recorded in 99% and were most often characterized as free of edema (61.9%). Less than 50% reported secretions, friability, or erythema. BAL yielded 111 ± 57 ml (50%) of the 223 ± 65 ml of infusate, brushes were completed in 98%, and endobronchial biopsies were performed in 82% of procedures. Adverse events requiring intervention occurred in 14 (6.7%) of 208 bronchoscopies. In logistic regression models, female sex (risk ratio [RR], 1.10; 95% confidence interval [CI], 1.02-1.19), self-reported asthma (RR, 1.17; 95% CI, 1.02-1.34), bronchodilator reversibility (RR, 1.17; 95% CI, 1.04-1.32), COPD (RR, 1.10; 95% CI, 1.02-1.20), forced expiratory volume in 1 second (RR, 0.97; 95% CI, 0.95-0.99), and secretions (RR, 1.85; 1.08-3.16) or friability (RR, 1.64; 95% CI, 1.04-2.57) observed during bronchoscopy were associated with adverse events. CONCLUSIONS: A research bronchoscopy procedure that includes oral sampling, BAL, endobronchial biopsy, and brushing can be safely performed. Airway characteristics during bronchoscopy, demographics, asthma or COPD, and lung function may convey increased risk for procedure-related events necessitating intervention.

18.
Chest ; 155(5): 908-917, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30684474

RESUMO

BACKGROUND: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma. METHODS: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV1/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV1. RESULTS: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes. CONCLUSIONS: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.

19.
Chest ; 155(3): 519-527, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30593776

RESUMO

BACKGROUND: Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. METHODS: Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC < 70%). Acute exacerbations of COPD (AECOPD) were prospectively ascertained through quarterly structured telephone questionnaires up to 3 years and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring ED visit or hospitalization). Aspirin users were matched one-to-one with nonusers, based on propensity score. The association of aspirin use with total, moderate, and severe AECOPD was investigated using zero-inflated negative binomial models. Linear or logistic regression was used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance. RESULTS: Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (ß, -2.2; 95% CI, -4.1 to -0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (ß, -1.1; 95% CI, -1.9 to -0.2) but not 6-min walk distance (ß, 0.7 m; 95% CI, -14.3 to 15.6). CONCLUSIONS: Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov.

20.
Respir Res ; 19(1): 257, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563576

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. RESULTS: FEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. CONCLUSIONS: The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01969344 .


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/fisiopatologia , Enfisema Pulmonar/sangue , Enfisema Pulmonar/fisiopatologia , Calcificação Vascular/sangue , Calcificação Vascular/fisiopatologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde)/métodos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/diagnóstico , Fumar/sangue , Fumar/fisiopatologia , Calcificação Vascular/diagnóstico , Capacidade Vital/fisiologia
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