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.
To investigate whether interstitial lung abnormalities are associated with increased mortality.
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).
Interstitial lung abnormality status as determined by chest CT evaluation.
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.
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.
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.
The Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, which began in 2007, is an ongoing multicenter observational cohort study of more than 10,000 current and former ...smokers. The study is aimed at understanding the etiology, progression, and heterogeneity of chronic obstructive pulmonary disease (COPD). In addition to genetic analysis, the participants have been extensively characterized by clinical questionnaires, spirometry, volumetric inspiratory and expiratory computed tomography, and longitudinal follow-up, including follow-up computed tomography at 5 years after enrollment. The purpose of this state-of-the-art review is to summarize the major advances in our understanding of COPD resulting from the imaging findings in the COPDGene study. Imaging features that are associated with adverse clinical outcomes include early interstitial lung abnormalities, visual presence and pattern of emphysema, the ratio of pulmonary artery to ascending aortic diameter, quantitative evaluation of emphysema, airway wall thickness, and expiratory gas trapping. COPD is characterized by the early involvement of the small conducting airways, and the addition of expiratory scans has enabled measurement of small airway disease. Computational advances have enabled indirect measurement of nonemphysematous gas trapping. These metrics have provided insights into the pathogenesis and prognosis of COPD and have aided early identification of disease. Important quantifiable extrapulmonary findings include coronary artery calcification, cardiac morphology, intrathoracic and extrathoracic fat, and osteoporosis. Current active research includes identification of novel quantitative measures for emphysema and airway disease, evaluation of dose reduction techniques, and use of deep learning for phenotyping COPD.
Summary Objectives We aimed to explore physiological responses to the six-minute walk test (6MWT) and assess computed tomographic (CT) features of the lungs and thigh muscle in order to determine ...contributors to dyspnea intensity and exercise limitation in dyspneic and non-dyspneic subjects with GOLD-1 COPD and controls. Methods We compared Borg dyspnea ratings, ventilatory responses to 6MWT, and CT-measures of emphysema, airway lumen caliber, and cross-sectional area of the thigh muscle (RTMCT-CSA ) in 19 dyspneic, 22 non-dyspneic, and 30 control subjects. Results Dyspneic subjects walked less and experienced greater exertional breathlessness than non-dyspneic (105 m less and 2.4 Borg points more, respectively) and control subjects (94 m less and 2.6 Borg points more, respectively ( P < 005 for all comparisons). At rest, dyspneic subjects had significant greater expiratory airflow obstruction, air trapping, ventilation/perfusion mismatch, burden of emphysema, narrower airway lumen, and lower RTMCT-CSA than comparison subjects. During walking dyspneic subjects had a decreased inspiratory capacity (IC) along with high ventilatory demand. Dyspneic subjects exhibited higher end-exercise tidal expiratory flow limitation and oxygen saturation drop than comparison subjects. In regression analysis, dyspnea intensity was best explained by ΔIC and forced expiratory volume in 1 s %predicted. RTMCT-CSA and ΔIC were independent determinants of distance walked. Conclusions Among subjects with mild COPD, those with daily-life dyspnea have worse exercise outcomes; distinct lung and thigh muscle morphologic features; and different pulmonary physiologic characteristics at rest and exercise. ΔIC was the main contributor to dyspnea intensity and ΔIC and thigh muscle wasting were determinants of exercise capacity.
The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.
We hypothesized a novel computed tomography (CT) ...biomarker of small airway disease predicts FEV1 decline.
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.
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.
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).
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.
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.
Epicardial (myocardium and chamber) RV volume (RV
), distal pulmonary arterial blood vessel volume (arterial BV5: vessels <5 mm
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 RV
with exercise capacity (6-min-walk distance) and all-cause mortality.
The RV
was approximately 10% smaller in Global Initiative for Chronic Obstructive Lung Disease stage 4 versus stage 1 COPD (
< 0.0001). In multivariable modeling, a 10-ml decrease in arterial BV5 (pruning) was associated with a 1-ml increase in RV
. For a given amount of emphysema, relative preservation of the arterial BV5 was associated with a smaller RV
. An increased RV
was associated with reduced 6-minute-walk distance and in those with arterial pruning an increased mortality.
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).
Alpha-1 antitrypsin deficiency (AATD) is characterized by low serum levels of or dysfunctional alpha-1 proteinase inhibitor. In the lung parenchyma, this results in a loss of protection against the ...activity of serine proteases, particularly neutrophil elastase. The resultant imbalance in protease and antiprotease activity leads to an increased risk for the development of early-onset emphysema and COPD. As in traditional smoke-related COPD, the assessment of the severity and disease progression of lung disease in AATD is conventionally based on lung function; however, pulmonary function tests are unable to discriminate between emphysema and airways disease, the two hallmark pathologic features of COPD. CT imaging has been used as a tool to further characterize lung structure and evaluate therapeutic interventions in AATD-related COPD. Moreover, recent advances in quantitative CT have significantly improved our assessment of the lung architecture, which has provided investigators and clinicians with a more detailed evaluation of the extent and severity of emphysema and airways disease in AATD. In addition, serial CT imaging measures are becoming increasingly important, as they provide a tool to monitor emphysema progression. This review describes the principles of CT technology and the role of CT imaging in assessing pulmonary disease progression in AATD, including the effect of therapeutic interventions.
It is well known that the central nervous system (CNS) has a limited regenerative capacity and that many therapeutic molecules cannot cross the blood brain barrier (BBB). The use of biomaterials has ...emerged as an alternative to overcome these limitations. For many years, biomedical applications of chitosan have been studied due to its remarkable biological properties, biocompatibility, and high versatility. Moreover, the interest in this biomaterial for CNS biomedical implementation has increased because of its ability to cross the BBB, mucoadhesiveness, and hydrogel formation capacity. Several chitosan-based biomaterials have been applied with promising results as drug, cell and gene delivery vehicles. Moreover, their capacity to form porous scaffolds and to bear cells and biomolecules has offered a way to achieve neural regeneration. Therefore, this review aims to bring together recent works that highlight the potential of chitosan and its derivatives as adequate biomaterials for applications directed toward the CNS. First, an overview of chitosan and its derivatives is provided with an emphasis on the properties that favor different applications. Second, a compilation of works that employ chitosan-based biomaterials for drug delivery, gene therapy, tissue engineering, and regenerative medicine in the CNS is presented. Finally, the most interesting trends and future perspectives of chitosan and its derivatives applications in the CNS are shown.
PDF
