We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.
The Food and Drug Adminstration recently approved a diphtheria-conjugated pneumococcal polysaccharide vaccine for adults, although its long-term immunogenicity is unknown. We report that, in patients with moderate to severe chronic obstructive pulmonary disease, conjugate vaccination elicits a superior immune response to free-polysaccharide vaccine that persists for >2 years.
Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.
Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.
Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.
Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points.
Clinical Trials Registration: NCT00457977.
Information on the benefits of pulmonary rehabilitation (PR) in patients with idiopathic pulmonary fibrosis (IPF) is growing, but PR’s effects on certain important outcomes is lacking.
We conducted a pilot study of PR in IPF and analyzed changes in functional capacity, fatigue, anxiety, depression, sleep, and health status from baseline to after completion of a standard, 6-week PR program.
Six-min walk distance improved a mean ± standard error 202 ± 135 feet (P = .01) from baseline. Fatigue Severity Scale score also improved significantly, declining an average 1.5 ± 0.5 points from baseline. There were trends toward improvement in anxiety, depression, and health status.
PR improves functional capacity and fatigue in patients with IPF. (ClinicalTrials.gov registration NCT00692796.)
pulmonary rehabilitation; idiopathic pulmonary fibrosis; IPF; outcomes; functional capacity; fatigue
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
Imaging; COPD; emphysema
Rationale and Objectives
There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers.
Materials and Methods
We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions.
Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm2 for segmental bronchial lumen area, 10.4 vs 12.5 mm2 for subsegmental bronchi, 6.5 vs 7.7 mm2 for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness.
Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.
Airway dimensions; CT scan; Gender differences; Smoker
It can be challenging to maintain longitudinal follow-up of subjects in clinical studies. COPDGene is a multicenter, observational study designed to identify genetic factors associated with COPD and to characterize COPD-related phenotypes. To obtain follow-up data on patient's vital status and outcomes, the COPDGene Longitudinal Follow-up (LFU) Program was developed to supplement its parent study.
We used a telecommunication system that employed automated telephone contact or web-based questions to obtain longitudinal follow-up data in our subjects. A branching questionnaire asked about exacerbations, new therapies, smoking status, development of co-morbid conditions, and general health status. Study coordinators contacted subjects who did not respond to one of the automated methods. We enrolled 10,383 subjects in the COPDGene study. As of August 29, 2011, 7,959 subjects completed 19,955 surveys. On the first survey, 68.8% of subjects who completed their survey did so by electronic means, while 31.3% required coordinator phone follow-up. On each subsequent survey the number of subjects who completed their survey by electronic means increased, while the number of subjects who required coordinator follow-up decreased. Despite many of the patients in the cohort being chronically ill and elderly, there was broad acceptance of the system with over half the cohort using electronic response methods.
The COPDGene LFU Study demonstrated that telecommunications was an effective way to obtain longitudinal follow-up of subjects in a large multicenter study. Web-based and automated phone contacts are accepted by research subjects and could serve as a model for LFU in future studies.
COPD; COPDGene; Emphysema; Longitudinal data collection; Exacerbations; Follow-up studies; Elderly
The assessment of symptoms of chronic obstructive pulmonary disease (COPD) is important for monitoring and managing the disease and for evaluating outcomes of interventions. COPD patients experience symptoms during the day and night, and symptoms experienced at night often disturb sleep. The aim of this paper is to describe methods used to develop a patient-reported outcome (PRO) instrument for evaluating nighttime symptoms of COPD, and to document evidence for the content validity of the instrument.
Literature review and clinician interviews were conducted to inform discussion guides to explore patients’ nighttime COPD symptom experience. Data from focus groups with COPD patients was used to develop a conceptual framework and the content of a new PRO instrument. Patient understanding of the new instrument was assessed via cognitive interviews with COPD patients.
The literature review confirmed that there is no instrument with evidence of content validity currently available to assess nighttime symptoms of COPD. Additionally, the literature review and clinician interviews suggested the need to understand patients’ experience of specific symptoms in order to evaluate nighttime symptoms of COPD. Analyses of patient focus group data (N = 27) supported saturation of concepts and aided in development of a conceptual framework. Items were generated using patients’ terminology to collect data on concepts in the framework including the occurrence and severity of COPD symptoms, use of rescue medication at night, and nocturnal awakening. Response options were chosen to reflect concepts that were salient to patients. Subsequent cognitive interviewing with ten COPD patients demonstrated that the items, response options, recall period, and instructions were understandable, relevant, and interpreted as intended.
A new PRO instrument, the Nighttime Symptoms of COPD Instrument (NiSCI), was developed with documented evidence of content validity. The NiSCI is ready for empirical testing, including item reduction and evaluation of psychometric properties.
COPD; Symptoms; PRO; Nighttime; Awakening
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations.
We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation.
Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations.
Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.)
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that afflicts patients with relentlessly progressive shortness of breath [Joint Statement of the American Thoracic Society and the European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161:646–641]. Despite nearly 30 years of intense investigation, effective therapy for IPF remains elusive; median survival rates have stubbornly remained less than five years from the time of diagnosis [Bjoraker JA, Ryu JH, Edwin MK, Meyers J, Tazelaar H, Schroeder D, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199–2032, Flaherty KR, Thwaite E, Kazerooni EA, Gross B, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143–483], and no medical therapy has been proved to be in any way effective for the treatment of this disease. Without medications that help IPF patients live longer, an important question to ask is whether there are interventions that might allow these people to live better—to be more active; to experience less dyspnea, less depression, less anxiety; to possess a greater sense of control over their disease; and to have better quality of life. Pulmonary rehabilitation helps to accomplish many of these goals in patients with chronic obstructive pulmonary disease, and emerging data suggest that it may do the same for patients with IPF.
Pulmonary fibrosis; Pulmonary rehabilitation; Dyspnea
Although prior research indicates that religious and spiritual coping is associated with positive health outcomes, few studies have examined religious and spiritual coping among patients with emphysema.
To describe the utilization of religious and spiritual coping and its relationship to quality of life among patients with emphysema, in a 2-year longitudinal follow-up study.
Forty patients with emphysema (mean age 63.5 ± 6.0 y, 8 women) who participated in the National Emphysema Treatment Trial were matched on age, sex, race, and education with 40 healthy individuals recruited from the community. We conducted baseline assessment of overall coping strategies, psychological functioning, quality of life, pulmonary function, and exercise capacity, and we assessed overall coping strategies and religious and spiritual coping at 2-year follow-up.
Ninety percent of the patients with emphysema considered themselves at least slightly religious and spiritual. The patients reported using both negative religious coping (eg, questioning God) and positive religious coping (eg, prayer) more than the healthy control subjects at follow-up. However, greater use of religious and spiritual coping was associated with poorer illness-related quality of life.
Patients with emphysema appear to use various coping strategies in responding to their illness. Future research should investigate if patients using religious and spiritual coping would benefit from interventions to address emotional distress and reduced quality of life.
emphysema; pulmonary rehabilitations; coping; depression; anxiety; quality of life; religiosity; spirituality; National Emphysema Treatment Trial
Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.
Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.
In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.
Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
Emphysema; Chest CT scan; Small airways; Lung function tests; Smoking
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume.
In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O2 pulse=VO2/HR) at baseline and 6 months. Medical and surgical patients were divided into “deflators” and “non-deflators” based on change in RV/TLC from baseline (ΔRV/TLC). We defined deflation as the ΔRV/TLC experienced by 75% of surgical patients. We examined changes in O2 pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs.
In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O2 pulse (median ΔRV/TLC −18.0% vs. −9.3%, p=0.0003; median ΔO2 pulse 13.6% vs. 1.8%, p=0.12). Surgical deflators also improved iso-work O2 pulse (0.53 mL/beat, p=0.04 at 20 watts). In the validation cohort, surgical deflators experienced a greater improvement in peak O2 pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O2 pulse at rest and during unloaded pedaling (0.32 mL/beat, p<0.0001 and 0.47 mL/beat, p<0.0001, respectively) corresponded with significant reductions in HR and improvements in VO2. On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O2 pulse (OR 1.88, 95% CI 1.30–2.72, p=0.0008).
In COPD, decreased hyperinflation through lung volume reduction is associated with improved O2 pulse.
cardiac function; hyperinflation; lung volume reduction surgery; oxygen pulse
This study compared visuomotor speed and cognitive flexibility in emphysema patients treated either with standard multidisciplinary medical therapy (MT) or lung volume reduction surgery (LVRS), followed over a 2-year period.
MT patients (n=544) and 542 LVRS patients completed the Trail Making Test (TMT) Parts A and B prior to randomization (baseline). Testing was repeated at 1 and 2 years.
There were no differences on scores for TMT Part A and B between the LVRS and MT groups at baseline or at years 1 and 2. No significant difference between MT and LVRS was noted in terms of overall change in TMT Part A and B over 2 years. The MT group had a significant improvement on TMT-Part A at each followup time compared to baseline (P<.03) but the LVRS group did not. Both the MT and LVRS groups had a significant decline in performance (increase in time to completion) on TMT-Part B when comparing year 1 to baseline (P<.0001).
Emphysema patients who received LVRS or MT as treatment performed similarly on measures of visuomotor speed and flexibility at baseline and 1 and 2 year followup. Both groups showed improvement on visuomotor speed during the first year yet overall cognitive flexibility declined. By the second year neither group had any significant change from baseline. These findings suggest that improvement on visuomotor speed and flexibility, observed in a previous 6-month study of LVRS subjects, was not sustained at 1 and 2 year followup.
Lung volume reduction surgery; Medical therapy; Sequential skills
Rationale: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.
Methods: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV1 < 50% predicted).
Measurements and Main Results: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03).
Conclusions: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.
chronic obstructive pulmonary disease; female; African Americans
Severe hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD). Long term oxygen therapy is beneficial in hypoxemic COPD patients. However, the clinical and radiographic predictors of hypoxemia and the use of oxygen therapy are not well described. This study aimed to find the correlates of resting hypoxemia and the pattern of oxygen use in moderate to severe COPD patients.
Subjects with GOLD stage II or higher COPD from the first 2500 COPDGene subjects were included in this analysis. All subjects were current or ex-smokers between ages 45 and 80. Severe resting hypoxemia was defined as room air oxygen saturation (SpO2) ≤ 88%. Use of supplemental oxygen therapy was determined by questionnaire.
Eighty-two of 1060 COPD subjects (7.7%) had severe resting hypoxemia. Twenty-one of the 82 (25.6%) were not using continuous supplemental oxygen. Female sex, higher BMI, lower FEV1, and enrollment in Denver were independent risk factors for hypoxemia; emphysema severity on quantitative chest CT scan did not predict hypoxemia. 132 of 971(13.6%) subjects without severe resting hypoxemia were using continuous supplemental oxygen. In non-hypoxemic oxygen users, Denver recruitment, higher BMI, lower FEV1, and more severe dyspnea were associated with the use of continuous oxygen.
A large number of COPD patients without severe hypoxemia were using supplemental oxygen therapy and the pattern of oxygen use was affected by factors other than resting SpO2 and emphysema severity. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup.
Hypoxemia; long-term oxygen therapy; COPD; emphysema
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
chronic obstructive pulmonary disease genetics; chronic obstructive pulmonary disease epidemiology; chronic obstructive pulmonary disease metabolism; genome-wide association study
Rationale: A significant proportion of smokers have lung function impairment characterized by a reduced FEV1 with a preserved FEV1/FVC ratio. These smokers are a poorly characterized group due to their systematic exclusion from chronic obstructive pulmonary disease (COPD) studies.
Objectives: To characterize the clinical, functional, and radiographic features of Global Initiative for Chronic Obstructive Lung Disease (GOLD)-Unclassified (FEV1/FVC ≥ 0.7 and FEV1 < 80% predicted) and lower limits of normal (LLN)-unclassified (FEV1/FVC ≥ LLN and FEV1 < LLN) subjects compared to smokers with normal lung function and subjects with COPD.
Methods: Data from the first 2,500 subjects enrolled in the COPDGene study were analyzed. All subjects had 10 or more pack-years of smoking and were between the ages of 45 and 80 years. Multivariate regression models were constructed to determine the clinical and radiological variables associated with GOLD-Unclassified (GOLD-U) and LLN-Unclassified status. Separate multivariate regressions were performed in the subgroups of subjects with complete radiologic measurement variables available.
Measurements and Main Results: GOLD-U smokers account for 9% of smokers in COPDGene and have increased body mass index (BMI), a disproportionately reduced total lung capacity, and a higher proportion of nonwhite subjects and subjects with diabetes. GOLD-U subjects exhibit increased airway wall thickness compared to smoking control subjects and decreased gas trapping and bronchodilator responsiveness compared to subjects with COPD. When LLN criteria were used to define the “unclassified” group, African American subjects were no longer overrepresented. Both GOLD-U and LLN-Unclassified subjects demonstrated a wide range of lung function impairment, BMI, and percentage of total lung emphysema.
Conclusions: Subjects with reduced FEV1 and a preserved FEV1/FVC ratio are a heterogeneous group with significant symptoms and functional limitation who likely have a variety of underlying etiologies beyond increased BMI.
Clinical trial registered with www.clinicaltrials.gov (NCT000608764).
lung diseases, classification; lung diseases, diagnosis; lung diseases, epidemiology
Patients’ beliefs about the causes of their illness have been associated with emotional adjustment and behavioral outcomes in several medical conditions; however, few studies have examined illness attributions among patients with COPD. In the current study, patterns of patients’ causal attributions for COPD were identified and examined in relation to health behaviors and symptoms.
Three-hundred and ninety-four patients with COPD and ≥10 pack year history of smoking completed a self-report questionnaire that included the Illness Perception Questionnaire- Revised (IPQ-R).
A factor analysis of the IPQ-R cause items using principal axis factoring yielded four individual items (i.e., smoking, heredity, pollution, and personal behavior) and one large factor that was primarily driven by psychological attributions. Ninety-three percent of patients agreed or strongly agreed that smoking was a cause of their COPD. Higher scores on the large IPQ-R factor were associated with reduced quality of life (r=.25, p<.001) and symptoms of anxiety (r=.33, p<.001) and depression (r=.31, p<.001), indicating that patients who attributed their COPD to psychological factors were more likely to have poorer emotional adjustment and quality of life.
Our finding of one large factor with several stand-alone items is in contrast with previous research that has derived a multi-factor structure for the cause items of the IPQ-R in other chronic illness populations. This difference may be due to the importance of smoking, environmental exposures, and heredity in the development of COPD. Future research should expand upon these specific attributions in COPD‥
Chronic Obstructive Pulmonary Disease (COPD); Causal Attributions; Illness Perception Questionnaire- Revised (IPQ-R); Illness Beliefs
Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.
We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.
A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).
Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.)
We investigated a large population of patients with chronic obstructive pulmonary disease (COPD) to determine their frequency of medication use and patterns of pharmacotherapy.
Medical and pharmacy claims data were retrospectively analyzed from 19 health plans (>7.79 million members) across the US. Eligible patients were aged ≥40 years, continuously enrolled during July 2004 to June 2005, and had at least one inpatient or at least two outpatient claims coded for COPD. As a surrogate for severity of illness, COPD patients were stratified by complexity of illness using predefined International Classification of Diseases, Ninth Revision, Clinical Modification, Current Procedural Terminology, Fourth Edition, and Healthcare Common Procedure Coding System codes.
A total of 42,565 patients with commercial insurance and 8507 Medicare patients were identified. Their mean age was 54.7 years and 74.8 years, and 48.7% and 46.9% were male, respectively. In total, 66.3% of commercial patients (n = 28,206) were not prescribed any maintenance COPD pharmacotherapy (59.1% no medication; 7.2% inhaled short-acting β2-agonist only). In the Medicare population, 70.9% (n = 6031) were not prescribed any maintenance COPD pharmacotherapy (66.0% no medication; 4.9% short-acting β2-agonist only). A subset of patients classified as high-complexity were similarly undertreated, with 58.7% (5358/9121) of commercial and 68.8% (1616/2350) of Medicare patients not prescribed maintenance COPD pharmacotherapy. Only 18.0% and 9.8% of diagnosed smokers in the commercial and Medicare cohorts had a claim for a smoking cessation intervention and just 16.6% and 23.5%, respectively, had claims for an influenza vaccination.
This study highlights a high degree of undertreatment of COPD in both commercial and Medicare patients, with most patients receiving no maintenance pharmacotherapy or influenza vaccination.
managed care; chronic obstructive pulmonary disease; health care utilization; quality of care
The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.
We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.
119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.
Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.
Airway hyperresponsiveness; asthma; Chronic obstructive pulmonary disease; emphysema; Exacerbation; Gas-trapping
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
The objective of this study was to test three hypotheses in a sample of individuals with COPD: 1) unsupportive family relationships are associated with psychological distress; 2) psychological distress is associated with smoking status; and 3) unsupportive family relationships are indirectly associated with smoking status via psychological distress.
Cross-sectional data were collected via self-report questionnaires completed by 455 individuals with COPD who had at least a 10 pack-year smoking history. The hypotheses were tested with structural equation modeling.
All three hypotheses were supported. Unsupportive family relationships were associated with psychological distress (β = .67, p < .001), psychological distress was associated with smoking status (β = .40, p < .001), and unsupportive family relationships were indirectly associated with smoking status via psychological distress (β = .27, p < .001).
Results of this study suggest that family relationships are an important factor to include in future longitudinal research that attempts to elucidate social and psychological influences on smoking behavior.
depression; anxiety; smoking; chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a leading cause of death and 70% of the cost of COPD is due to hospitalizations. Self-reported daily physical activity and health status have been reported as predictors of a hospitalization in COPD but are not routinely assessed.
We tested the hypothesis that self-reported daily physical activity and health status assessed by a simple question were predictors of a hospitalization in a well-characterized cohort of patients with severe emphysema.
Investigators gathered daily physical activity and health status data assessed by a simple question in 597 patients with severe emphysema and tested the association of those patient-reported outcomes to the occurrence of a hospitalization in the following year. Multiple logistic regression analyses were used to determine predictors of hospitalization during the first 12 months after randomization.
The two variables tested in the hypothesis were significant predictors of a hospitalization after adjusting for all univariable significant predictors: >2 h of physical activity per week had a protective effect [odds ratio (OR) 0.60; 95% confidence interval (95% CI) 0.41–0.88] and self-reported health status as fair or poor had a deleterious effect (OR 1.57; 95% CI 1.10–2.23). In addition, two other variables became significant in the multivariate model: total lung capacity (every 10% increase) had a protective effect (OR 0.88; 95% CI 0.78–0.99) and self-reported anxiety had a deleterious effect (OR 1.75; 95% CI 1.13–2.70).
Self-reported daily physical activity and health status are independently associated with COPD hospitalizations. Our findings, assessed by simple questions, suggest the value of patient-reported outcomes in developing risk assessment tools that are easy to use.
Activity of daily living; Chronic obstructive pulmonary disease; Emphysema; Outcomes; Quality of life; Health status; Exercise