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BACKGROUND: Small airways disease (SAD) is a major cause of airflow obstruction in COPD patients and has been identified as a precursor to emphysema. Although the amount of SAD in the lungs can be quantified using our Parametric Response Mapping (PRM) approach, the full breadth of this readout as a measure of emphysema and COPD progression has yet to be explored. We evaluated topological features of PRM-derived normal parenchyma and SAD as surrogates of emphysema and predictors of spirometric decline. METHODS: PRM metrics of normal lung (PRMNorm) and functional SAD (PRMfSAD) were generated from CT scans collected as part of the COPDGene study (n = 8956). Volume density (V) and Euler-Poincaré Characteristic (χ) image maps, measures of the extent and coalescence of pocket formations (i.e., topologies), respectively, were determined for both PRMNorm and PRMfSAD. Association with COPD severity, emphysema, and spirometric measures were assessed via multivariable regression models. Readouts were evaluated as inputs for predicting FEV1 decline using a machine learning model. RESULTS: Multivariable cross-sectional analysis of COPD subjects showed that V and χ measures for PRMfSAD and PRMNorm were independently associated with the amount of emphysema. Readouts χfSAD (ß of 0.106, p < 0.001) and VfSAD (ß of 0.065, p = 0.004) were also independently associated with FEV1% predicted. The machine learning model using PRM topologies as inputs predicted FEV1 decline over five years with an AUC of 0.69. CONCLUSIONS: We demonstrated that V and χ of fSAD and Norm have independent value when associated with lung function and emphysema. In addition, we demonstrated that these readouts are predictive of spirometric decline when used as inputs in a ML model. Our topological PRM approach using PRMfSAD and PRMNorm may show promise as an early indicator of emphysema onset and COPD progression.
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Enfisema , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Estudos Transversais , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Volume Expiratório Forçado/fisiologiaRESUMO
Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.
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Doença Pulmonar Obstrutiva Crônica , Produtos do Tabaco , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Expiratório Forçado , Pulmão , Qualidade de Vida , EspirometriaRESUMO
Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder with significant morbidity and mortality. Despite its prevalence, COPD is underdiagnosed, and many patients do not receive a diagnosis until the disease is clinically advanced. Recent basic science and clinical research have focused on the early physiologic and pathobiologic changes in COPD with the hopes of improving diagnosis, providing targets for disease-modifying therapy, and identifying patients most likely to benefit from early intervention. Available treatments for COPD have grown substantially in the past 20 years with the introduction of new oral and inhaled medications as well as novel surgical and bronchoscopic procedures. This article summarizes some of the recent advances in our understanding of disease pathogenesis and treatment paradigms.
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Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Saúde Global , Humanos , Morbidade/tendências , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória/métodos , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND: Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality. METHODS: In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography-mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini-Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst. RESULTS: We found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways. CONCLUSIONS: Metabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers.
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Enfisema , Niacina , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Fumantes , Pulmão , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/epidemiologia , Niacinamida , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/epidemiologiaRESUMO
Cigarette smoking is an established cause of chronic obstructive pulmonary disease (COPD). Numerous studies implicate acrolein, which occurs in relatively high concentrations in cigarette smoke and reacts readily with proteins, as one causative factor for COPD in smokers. Far less is known about the possible roles in COPD of the related α,ß-unsaturated carbonyl compounds of cigarette smoke crotonaldehyde, methacrolein, and methyl vinyl ketone. In the study reported here, we analyzed mercapturic acids of these α,ß-unsaturated compounds in the urine of 413 confirmed cigarette smokers in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)â202 with COPD and 211 without COPD. The mercapturic acids analyzed were 3-hydroxypropyl mercapturic acid (3-HPMA) from acrolein, 3-hydroxy-1-methylpropyl mercapturic acid (HMPMA-1) from crotonaldehyde, 3-hydroxy-2-methylpropyl mercapturic acid (HMPMA-2) from methacrolein, and 3-hydroxy-3-methylpropyl mercapturic acid (HMPMA-3) from methyl vinyl ketone. In models adjusting for age, sex, race, pack years of tobacco use, and BMI, all four mercapturic acids were increased in individuals with COPD but not significantly. Stratified by the GOLD status, there were increased levels of the metabolites associated with GOLD 3-4 compared to that with GOLD 0, with the methacrolein metabolite HMPMA-2 reaching statistical significance (adjusted odds ratio 1.23 [95% CI: 1.00-1.53]). These results highlight the possible role of methacrolein, which has previously received little attention in this regard, as a causative factor in COPD in cigarette smokers.
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BACKGROUND: In patients with acute respiratory distress syndrome undergoing mechanical ventilation, positive end-expiratory pressure (PEEP) can lead to recruitment or overdistension. Current strategies utilized for PEEP titration do not permit the distinction. Electric impedance tomography (EIT) detects and quantifies the presence of both collapse and overdistension. We investigated whether using EIT-guided PEEP titration leads to decreased mechanical power compared to high-PEEP/FiO2 tables. METHODS: A single-center, randomized crossover pilot trial comparing EIT-guided PEEP selection versus PEEP selection using the High-PEEP/FiO2 table in patients with moderate-severe acute respiratory distress syndrome. The primary outcome was the change in mechanical power after each PEEP selection strategy. Secondary outcomes included changes in the 4 × driving pressure + respiratory rate (4 ΔP, + RR index) index, driving pressure, plateau pressure, PaO2/FiO2 ratio, and static compliance. RESULTS: EIT was consistently associated with a decrease in mechanical power compared to PEEP/FiO2 tables (mean difference - 4.36 J/min, 95% CI - 6.7, - 1.95, p = 0.002) and led to lower values in the 4ΔP + RR index (- 11.42 J/min, 95% CI - 19.01, - 3.82, p = 0.007) mainly driven by a decrease in the elastic-dynamic power (- 1.61 J/min, - 2.99, - 0.22, p = 0.027). The elastic-static and resistive powers were unchanged. Similarly, EIT led to a statistically significant change in set PEEP (- 2 cmH2O, p = 0.046), driving pressure, (- 2.92 cmH2O, p = 0.003), peak pressure (- 6.25 cmH2O, p = 0.003), plateau pressure (- 4.53 cmH2O, p = 0.006), and static respiratory system compliance (+ 7.93 ml/cmH2O, p = 0.008). CONCLUSIONS: In patients with moderate-severe acute respiratory distress syndrome, EIT-guided PEEP titration reduces mechanical power mainly through a reduction in elastic-dynamic power. Trial registration This trial was prospectively registered on Clinicaltrials.gov (NCT03793842) on January 4th, 2019.
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Síndrome do Desconforto Respiratório , Humanos , Impedância Elétrica , Projetos Piloto , Síndrome do Desconforto Respiratório/terapia , Respiração com Pressão Positiva/métodos , Tomografia/métodosRESUMO
PURPOSE OF REVIEW: Risk assessment tools are essential in COPD care to help clinicians identify patients at higher risk of accelerated lung function decline, respiratory exacerbations, hospitalizations, and death. RECENT FINDINGS: Conventional methods of assessing risk have focused on spirometry, patient-reported symptoms, functional status, and a combination of these tools in composite indices. More recently, qualitatively and quantitatively assessed chest imaging findings, such as emphysema, large and small airways disease, and pulmonary vascular abnormalities have been associated with poor long-term outcomes in COPD patients. Although several blood and sputum biomarkers have been investigated for risk assessment in COPD, most still warrant further validation. Finally, novel remote digital monitoring technologies may be valuable to predict exacerbations but their large-scale performance, ease of implementation, and cost effectiveness remain to be determined. SUMMARY: Given the complex heterogeneity of COPD, any single metric is unlikely to fully capture the risk of poor long-term outcomes. Therefore, clinicians should review all available clinical data, including spirometry, symptom severity, functional status, chest imaging, and bloodwork, to guide personalized preventive care of COPD patients. The potential of machine learning tools and remote monitoring technologies to refine COPD risk assessment is promising but remains largely untapped pending further investigation.
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Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Pulmão , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Espirometria , EscarroRESUMO
OBJECTIVES: Muscle wasting is a recognised extra-pulmonary complication in chronic obstructive pulmonary disease and has been associated with increased risk of death. Acute respiratory exacerbations are associated with reduction of muscle function, but there is a paucity of data on their long-term effect. This study explores the relationship between acute respiratory exacerbations and long-term muscle loss using serial measurements of CT derived pectoralis muscle area (PMA). DESIGN AND SETTING: Participants were included from two prospective, longitudinal, observational, multicentre cohorts of ever-smokers with at least 10 pack-year history. PARTICIPANTS: The primary analysis included 1332 (of 2501) participants from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and 4384 (of 10 198) participants from Genetic Epidemiology of COPD (COPDGene) who had complete data from their baseline and follow-up visits. INTERVENTIONS: PMA was measured on chest CT scans at two timepoints. Self-reported exacerbation data were collected from participants in both studies through the use of periodic longitudinal surveys. MAIN OUTCOME MEASURES: Age-related and excess muscle loss over time. RESULTS: Age, sex, race and body mass index were associated with baseline PMA. Participants experienced age-related decline at the upper end of reported normal ranges. In ECLIPSE, the exacerbation rate over time was associated with an excess muscle area loss of 1.3% (95% CI 0.6 to 1.9, p<0.001) over 3 years and in COPDGene with an excess muscle area loss of 2.1% (95% CI 1.2 to 2.8, p<0.001) over 5 years. Excess muscle area decline was absent in 273 individuals who participated in pulmonary rehabilitation. CONCLUSIONS: Exacerbations are associated with accelerated skeletal muscle loss. Each annual exacerbation was associated with the equivalent of 6 months of age-expected decline in muscle mass. Ameliorating exacerbation-associated muscle loss represents an important therapeutic target.
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Atrofia Muscular/etiologia , Vigilância da População , Doença Pulmonar Obstrutiva Crônica/complicações , Qualidade de Vida , Fumar/efeitos adversos , Idoso , Progressão da Doença , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/fisiopatologia , Prognóstico , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01969344 (SPIROMICS).
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DNA Mitocondrial/genética , NADH Desidrogenase/genética , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , DNA Mitocondrial/sangue , Progressão da Doença , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , NADH Desidrogenase/sangue , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Fumantes , Fumar/efeitos adversos , Inquéritos e Questionários , Fatores de Tempo , Estados Unidos , Teste de CaminhadaRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and progressive airflow obstruction. Tobacco smoking is the leading cause but not the only one. A postbronchodilator FEV1-FVC ratio less than 0.70 is required for a diagnosis of COPD. Inhaler therapy is the backbone of treatment and should be complemented by a multifaceted management strategy that includes counseling and pharmacotherapy for smoking cessation, pulmonary rehabilitation, treatment of comorbidities, administration of influenza and pneumococcal immunizations, and prescription of long-term oxygen therapy in hypoxemic patients.
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Doença Pulmonar Obstrutiva Crônica/diagnóstico , Broncodilatadores/uso terapêutico , Humanos , Oxigenoterapia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/terapia , Testes de Função RespiratóriaRESUMO
Novel proteomics platforms, such as the aptamer-based SOMAscan platform, can quantify large numbers of proteins efficiently and cost-effectively and are rapidly growing in popularity. However, comparisons to conventional immunoassays remain underexplored, leaving investigators unsure when cross-assay comparisons are appropriate. The correlation of results from immunoassays with relative protein quantification is explored by SOMAscan. For 63 proteins assessed in two chronic obstructive pulmonary disease (COPD) cohorts, subpopulations and intermediate outcome measures in COPD Study (SPIROMICS), and COPDGene, using myriad rules based medicine multiplex immunoassays and SOMAscan, Spearman correlation coefficients range from -0.13 to 0.97, with a median correlation coefficient of ≈0.5 and consistent results across cohorts. A similar range is observed for immunoassays in the population-based Multi-Ethnic Study of Atherosclerosis and for other assays in COPDGene and SPIROMICS. Comparisons of relative quantification from the antibody-based Olink platform and SOMAscan in a small cohort of myocardial infarction patients also show a wide correlation range. Finally, cis pQTL data, mass spectrometry aptamer confirmation, and other publicly available data are integrated to assess relationships with observed correlations. Correlation between proteomics assays shows a wide range and should be carefully considered when comparing and meta-analyzing proteomics data across assays and studies.
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Infarto do Miocárdio/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumantes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Imunoensaio/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Doença Pulmonar Obstrutiva Crônica/sangueAssuntos
Doença Pulmonar Obstrutiva Crônica , Tomografia Computadorizada por Raios X , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Masculino , Doença Crônica , Feminino , Pessoa de Meia-Idade , Idoso , Múltiplas Afecções CrônicasRESUMO
Rationale: Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality.Objectives: To correlate ex vivo parametric response mapping (PRM) analysis to in vivo lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects.Methods: Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD (n = 11 subjects) and 22 control tissue samples (n = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema.Measurements and Main Results: PRM analysis was conducted to differentiate functional small airways disease (PRMfSAD) from emphysema (PRMEmph). In COPD lungs, TB numbers were reduced (P = 0.01); surviving TBs had increased wall area percentage (P < 0.001), decreased circularity (P < 0.001), reduced cross-sectional luminal area (P < 0.001), and greater airway obstruction (P = 0.008). COPD lungs had increased airspace size (P < 0.001) and decreased alveolar surface area (P < 0.001). Regression analyses demonstrated unique correlations between PRMfSAD and TBs, with decreased circularity (P < 0.001), decreased luminal area (P < 0.001), and complete obstruction (P = 0.008). PRMEmph correlated with increased airspace size (P < 0.001), decreased alveolar surface area (P = 0.003), and fewer alveolar attachments per TB (P = 0.01).Conclusions: PRMfSAD identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.
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Obstrução das Vias Respiratórias/diagnóstico por imagem , Biomarcadores , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Microtomografia por Raio-X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Rationale: Cor pulmonale (right ventricular [RV] dilation) and cor pulmonale parvus (RV shrinkage) are both described in chronic obstructive pulmonary disease (COPD). The identification of emphysema as a shared risk factor suggests that additional disease characterization is needed to understand these widely divergent cardiac processes.Objectives: To explore the relationship between computed tomography measures of emphysema and distal pulmonary arterial morphology with RV volume, and their association with exercise capacity and mortality in ever-smokers with COPD enrolled in the COPDGene Study.Methods: Epicardial (myocardium and chamber) RV volume (RVEV), distal pulmonary arterial blood vessel volume (arterial BV5: vessels <5 mm2 in cross-section), and objective measures of emphysema were extracted from 3,506 COPDGene computed tomography scans. Multivariable linear and Cox regression models and the log-rank test were used to explore the association between emphysema, arterial BV5, and RVEV with exercise capacity (6-min-walk distance) and all-cause mortality.Measurements and Main Results: The RVEV was approximately 10% smaller in Global Initiative for Chronic Obstructive Lung Disease stage 4 versus stage 1 COPD (P < 0.0001). In multivariable modeling, a 10-ml decrease in arterial BV5 (pruning) was associated with a 1-ml increase in RVEV. For a given amount of emphysema, relative preservation of the arterial BV5 was associated with a smaller RVEV. An increased RVEV was associated with reduced 6-minute-walk distance and in those with arterial pruning an increased mortality.Conclusions: Pulmonary arterial pruning is associated with clinically significant increases in RV volume in smokers with COPD and is related to exercise capacity and mortality in COPD.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
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Artéria Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Doença Cardiopulmonar/diagnóstico por imagem , Remodelação Vascular , Idoso , Tolerância ao Exercício , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Tamanho do Órgão , Modelos de Riscos Proporcionais , Artéria Pulmonar/patologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/complicações , Enfisema Pulmonar/fisiopatologia , Doença Cardiopulmonar/etiologia , Doença Cardiopulmonar/fisiopatologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Teste de CaminhadaRESUMO
Impaired single breath carbon monoxide diffusing capacity (DLCO) is associated with emphysema. Small airways disease (SAD) may be a precursor lesion to emphysema, but the relationship between SAD and DLCO is undescribed. We hypothesized that in mild COPD, functional SAD (fSAD) defined by computed tomography (CT) and Parametric Response Mapping methodology would correlate with impaired DLCO. Using data from ever-smokers in the COPDGene cohort, we established that fSAD correlated significantly with lower DLCO among both non-obstructed and GOLD 1-2 subjects. The relationship between DLCO with CT-defined emphysema was present in all GOLD stages, but most prominent in severe disease. TRIAL REGISTRATION: NCT00608764. Registry: COPDGene. Registered 06 February 2008, retrospectively registered.
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Obstrução das Vias Respiratórias/diagnóstico por imagem , Bronquíolos/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Idoso , Obstrução das Vias Respiratórias/patologia , Remodelação das Vias Aéreas/fisiologia , Bronquíolos/anormalidades , Monóxido de Carbono/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Capacidade de Difusão Pulmonar , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Análise de Regressão , Testes de Função Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. METHODS: Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. RESULTS: The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. CONCLUSIONS: In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS).
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Glicina/sangue , Prolina/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Espirometria/métodos , Escarro/metabolismo , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escarro/químicaRESUMO
BACKGROUND: Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity. METHODS: Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene). Cross-sectional associations of thrombocytosis (platelet count ≥350 × 109/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score ≥ 2), COPD Assessment Test (CAT) score ≥ 10, six-minute-walk distance (6MWD), and St. George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression. A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies. RESULTS: Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants. In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1-2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1-2.2), dyspnea (mMRC ≥ 2 aOR 1.4; 95% CI: 1.0-1.9), respiratory symptoms (CAT ≥ 10 aOR 1.6; 95% CI: 1.1-2.4), and higher SGRQ score (ß 2.7; 95% CI: 0.5, 5). Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2-2.4). CONCLUSIONS: Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms. Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment. Future longitudinal studies investigating the role of platelets in COPD progression may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).
Assuntos
Avaliação de Resultados em Cuidados de Saúde/tendências , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Trombocitose/epidemiologia , Trombocitose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Estudos Transversais , Tolerância ao Exercício/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Trombocitose/fisiopatologiaRESUMO
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 .