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 FEV 1 decline.Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV 1 (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 FEV 1 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 FEV 1 decline (P , 0.001). In GOLD 1-4 participants, both PRM fSAD and PRM emph were associated with FEV 1 decline (P , 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV 1 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 FEV 1 decline, but the association with functional small airway disease has greatest importance in mildto-moderate stage chronic obstructive pulmonary disease where the rate of FEV 1 decline is the greatest.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

A reliable and valid Portuguese version of the Neck Disability Index and Neck Pain and DisabilityScale was developed, which will facilitate the examination of functional performance within a large patient population, as well as cross-cultural comparisons.

Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study. Methods We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

The mechanism by which chronic thromboembolic pulmonary hypertension (CTEPH) develops after acute pulmonary thromboembolism is unknown. We previously reported that fibrin from CTEPH patients is relatively resistant to fibrinolysis in vitro. In the present study, we performed proteomic, genomic, and functional studies on fibrin(ogen) to investigate whether abnormal fibrin(ogen) might contribute to the pathogenesis of CTEPH. Reduced and denatured fibrinogen from 33 CTEPH patients was subjected to liquid chromatography-mass spectrometry analysis. Fibrinogen from 21 healthy controls was used to distinguish atypical from commonly occurring mass peaks. Atypical peaks were further investigated by targeted genomic DNA sequencing. Five fibrinogen variants with corresponding heterozygous gene mutations (dysfibrinogenemias) were observed in 5 of 33 CTEPH patients: B␤ P235L/␥ R375W, B␤ P235L/␥ Y114H, B␤ P235L, A␣ L69H, and A␣ R554H (fibrinogens San Diego I-V ). B␤ P235L was found in 3 unrelated CTEPH patients. Functional analysis disclosed abnormalities in fibrin polymer structure and/or lysis with all CTEPH-associated mutations. These results suggest that, in some patients, differences in the molecular structure of fibrin may be implicated in the development of CTEPH after acute thromboembolism. (Blood. 2009;114: 1929-1936

Rationale: When obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) coexist in the so-called "overlap" syndrome, a high risk for mortality and morbidity has been reported. There is controversy about the prevalence of OSA in people affected by COPD.Objectives: The purpose of this study was to investigate objective meaures of sleep-disordered breathing in patients with moderate to severe COPD to test the hypothesis that COPD is associated with an increased prevalence of OSA.Methods: Fifty-four patients (54% men) with moderate to severe COPD were enrolled prospectively (mean 6 SD, FEV 1 = 42.8 6 19.8% predicted, and FEV 1 /FVC = 42.3 6 13.1). Twenty patients (37%) were on supplemental oxygen at baseline. Exercise tolerance; questionnaires related to symptoms, sleep, and quality of life; and home polysomnography were obtained.Measurements and Main Results: Forty-four patients had full polysomnography suitable for analysis. OSA (apnea-hypopnea index . 5/h) was present in 29 subjects (65.9%). Sleep efficiency was poor in 45% of subjects.Conclusions: OSA is highly prevalent in patients with moderate to severe COPD referred to pulmonary rehabilitation. Sleep quality is also poor among this selected group. These patients have greaterthan-expected sleep-disordered breathing, which could be an important contributory factor to morbidity and mortality. Pulmonary rehabilitation programs should consider including a sleep assessment in patients with moderate to severe COPD and interventions when indicated to help reduce the impact of OSA in COPD.

For personal use only. Permission required for all other uses.

Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

The importance of sleep on health has only been recently recognized, and the general public and the medical community are not yet fully knowledgeable about this issue. The great majority of sleep research has been performed in whites of European descent and to a lesser extent in African Americans, making generalization of the findings to other ethnic and racial groups difficult. Very little sleep research has been done in U.S. Hispanics. However, based on the available literature and the high prevalence of risk factors in Hispanics, such as obesity, diabetes, living in the inner city, and use of alcohol, the prevalence of such important sleep disorders such as obstructive sleep apnea and sleep habits such as poor sleep hygiene are suspected to be high. There is also some evidence that acculturation to the U.S. life style may lead to worse sleep habits in Hispanics, including fewer hours of sleep. Two current large NIH sponsored studies of sleep in U.S. Hispanics promise to significantly add to the literature on various sleep disorders such as sleep disordered breathing, insomnia, restless legs syndrome, periodic limb movement disorder, and sleep habits such as short sleep duration and sleep hygiene.