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).

Background Individuals with COPD and asthma are an important but poorly characterized group. The genetic determinants of COPD-asthma overlap have not been studied. Objective Identify clinical features and genetic risk factors for COPD-asthma overlap. Methods Subjects were current or former smoking non-Hispanic whites (NHW) or African-Americans (AA) with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the NHW and AA populations, and combined these results in a meta-analysis. Results More women and African Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema, and greater airway wall thickness compared to subjects with COPD alone. The NHW GWAS identified SNPs in CSMD1 (rs11779254, P=1.57×10−6) and SOX5(rs59569785, P=1.61×10−6) and the meta-analysis identified SNPs in the gene GPR65 (rs6574978, P=1.18×10−7) associated with COPD-asthma overlap. Conclusions Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD-asthma overlap is an important syndrome and may require distinct clinical management.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown.Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up.Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results:In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline.Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

COPD is the third leading cause of death in the United States and is associated with signifi cant morbidity and health-care-related expenditures mostly due to acute exacerbations. 1,2 Patients with COPD may develop subclinical or overt pulmonary vascular disease, and the presence of pulmonary hypertension (PH) is an important predictor of both COPD and exacerbation-related morbidity and mortality, particularly in patients with severe disease. [3][4][5][6][7][8] Although PH can occur in patients with mild to moderate COPD because of pulmonary infl ammation and endothelial or cardiac dysfunction, it more commonly occurs and becomes clinically apparent when airfl ow limitation is severe and is believed to be primarily due to hypoxic vasoconstriction of small pulmonary arteries that result in intimal hyperplasia as well as smooth muscle hypertrophy and hyperplasia. [9][10][11] Right-sided heart catheterization (RHC) remains the gold standard for diagnosis of pulmonary vascular disease. 12 Although noninvasive strategies, such as Doppler echocardiography, allow the measurement of pulmonary artery systolic pressure (PASP), this modality is often problematic in patients with COPD because of lung hyperinfl ation and diffi culty in obtaining clear

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BackgroundPulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532).ResultsAmong NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10−11), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10−10); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 9 [DBH] (p-value = 9.69 × 10−9) and 19 [CYP2A6/7] (p-value = 3.49 × 10−8) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 4 [FAM13A] (p-value = 3.88 × 10−12), 11 [MMP3/12] (p-value = 3.29 × 10−10) and 14 [RIN3] (p-value = 5.64 × 10−9).ConclusionsIn a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0299-4) contains supplementary material, which is available to authorized users.

IMPORTANCE According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV 1 :FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial. OBJECTIVE To determine the discriminative accuracy of various FEV 1 :FVC fixed thresholds for predicting COPD-related hospitalization and mortality. DESIGN, SETTING, AND PARTICIPANTS The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016. EXPOSURES Presence of airflow obstruction, which was defined by a baseline FEV 1 :FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV 1 :FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach. RESULTS Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, −0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models. CONCLUSIONS AND RELEVANCE Defining airflow obstruction as FEV 1 :FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV 1 :FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

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