Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.

Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team.

RATIONALE: Chronic obstructive pulmonary disease (COPD) seems to be a heterogeneous disease with a variable course. OBJECTIVES: We wished to characterize the heterogeneity and variability of COPD longitudinally. METHODS: In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study of 2,164 patients with clinically stable COPD, 337 smokers with normal lung function, and 245 never-smokers, we measured a large number of clinical parameters, lung function, exercise tolerance, biomarkers, and amount of emphysema by computed tomography. All three groups were followed for 3 years. MEASUREMENTS AND MAIN RESULTS: We found a striking heterogeneity among patients with COPD, with poor correlations between FEV1, symptoms, quality of life, functional outcomes, and biomarkers. Presence of systemic inflammation was found in only a limited proportion of patients, and did not relate to baseline characteristics or disease progression, but added prognostic value for predicting mortality. Exacerbations tracked over time and added to the concept of the "frequent exacerbator phenotype." Disease course was very variable, with close to a third of patients not progressing at all. Risk factors for 3-year change in both FEV1 and lung density were assessed. For FEV1 decline, continued smoking and presence of emphysema were the strongest predictors of progression; club cell protein was found to be a potential biomarker for disease activity. For progression of emphysema, the strongest predictors were continued smoking and female sex. CONCLUSIONS: By following a large, well characterized cohort of patients with COPD over 3 years, we have a clearer picture of a heterogeneous disease with clinically important subtypes ("phenotypes") and a variable and not inherently progressive course. Clinical trial registered with www.clinicaltrials.gov (NCT00292552).

Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality.

BACKGROUND: Coronary artery calcification is pathognomonic of coronary artery disease (CAD). Whether CAD in patients with COPD is linked to lung function, functional capacity and/or clinically relevant outcomes is unknown. The objective was to assess the association between CAD and disease severity, functional capacity and outcomes in patients with COPD. METHODS: Coronary artery calcium score (CACS; Agatston score) was measured using chest CT in patients with COPD, smokers with normal spirometry and non-smokers from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. RESULTS: CACS was measured in 942 subjects: 672 with COPD (mean age±SD, 63±7 years; FEV1 49±16% predicted), 199 smokers with normal spirometry (54±9 years; FEV1 110±12% predicted) and 71 non-smokers (55±9 years; FEV1 114±14% predicted). CACS was higher in patients with COPD than smokers or non-smokers (median (IQR), 128 (492) vs 0 (75) vs 0 (3) Agatston units (AU), p<0.001). In patients with COPD, CACS correlated with age, pack-years, 6 min walking distance, modified Medical Research Council Dyspnoea score and circulating levels of interleukin (IL)-6, IL-8, Clara Cell protein 16, surfactant protein D and peripheral blood neutrophil count, but not with emphysema, exacerbation frequency, % predicted FEV1 or decline in FEV1. CACS was higher in patients with COPD who died than in those who survived until 3-year follow-up (CACS 406 vs 103 AU, p<0.001), and was associated with mortality in a Cox proportional hazards model (p=0.036). CONCLUSIONS: Patients with COPD have more CAD than controls and this is associated with increased dyspnoea, reduced exercise capacity and increased mortality. These data indicate that the presence of CAD in patients with COPD is associated with poor clinical outcomes.

Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort.

Comorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically stable COPD subjects, 337 smokers and 245 non-smokers with normal lung function. COPD patients had a higher prevalence of osteoporosis, anxiety/panic attacks, heart trouble, heart attack, and heart failure, than smokers or nonsmokers. Heart failure (Hazard Ratio [HR] 1.9, 95% Confidence Interval [CI] 1.3-2.9), ischemic heart disease (HR 1.5, 95% CI 1.1-2.0), heart disease (HR 1.5, 95% CI 1.2-2.0), and diabetes (HR 1.7, 95% CI 1.2-2.4) had increased odds of mortality when coexistent with COPD. Multiple comorbidities had accumulative effect on mortality. COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores. Osteoporosis, hypertension and diabetes were associated with higher MRC dyspnea scores and reduced 6MWD. Higher blood concentrations of fibrinogen, IL-6 and IL-8 levels occurred in those with heart disease. Comorbidity is associated with poor clinical outcomes in COPD. The comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation.

Impact of emphysema and airway wall thickness on quality of life in smoking-related COPD.

BACKGROUND: Limited data are available as to the relationship between computed tomography (CT) derived data on emphysema and airway wall thickness, and quality of life in subjects with chronic obstructive pulmonary disease (COPD). Such data may work to clarify the clinical correlate of the CT findings. METHODS: We included 1778 COPD subjects aged 40-75 years with a smoking history of at least 10 pack-years. They were examined with St George's Respiratory Questionnaire (SGRQ-C) and high-resolution chest CT. Level of emphysema was assessed as percent low-attenuation areas less than -950 Hounsfield units (%LAA). Airway wall thickness was estimated by calculating the square root of wall area of an imaginary airway with an internal perimeter of 10 mm (Pi10). RESULTS: In both men and women, the mean total score and most of the subscores of SGRQ-C increased with increasing level of emphysema and increasing level of airway wall thickness, after adjusting for age, smoking status, pack years, body mass index and FEV1. The highest gradient was seen in the relationship between the activity score and the emphysema level. The activity score increased by 35% from the lowest to the highest emphysema tertile. The relationship between level of emphysema and the total SGRQ-C score became weaker with increasing GOLD (Global initiative for Chronic Obstructive Lung Disease) stages (p < 0.001), while the impact of gender was limited. CONCLUSION: In subjects with COPD, increasing levels of emphysema and airway wall thickness are independently related to impaired quality of life.

CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes.

Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 ± 49.5 Hounsfield units [HU] versus 183.8 ± 46.1 HU versus 212.1 ± 54.4 HU, p < 0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation correlated positively with forced expiratory volume in 1 second (FEV1, r = 0.062, p = 0.014), FEV1/forced vital capacity (FVC) ratio (r = 0.102, p < 0.001), body mass index (r = 0.243, p < 0.001), fat-free mass index (FFMI, r = 0.265, p < 0.001), and C-reactive protein (r = 0.104, p < 0.001), and correlated negatively with extent of emphysema (r = -0.090, p < 0.001), Agatston score (r = -0.177, p < 0.001), and interleukin-8 (r = -0.054, p = 0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation (r = -0.057, p = 0.022) and hospitalization (r = -0.078, p = 0.002) rates but was not associated with all-cause mortality. In conclusion, CT-measured bone attenuation was lower in COPD subjects compared with nonsmoker controls but not compared with smoker controls, after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition, and coronary artery calcification but was not associated with all-cause mortality.

The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study.

BACKGROUND: Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density. METHODS: We used a random coefficient model to assess predictors of both CT lung density and its longitudinal change over 3 years in 1928 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Lung density was measured for every voxel in the CT scan and after correcting for lung volume was expressed as the density at lowest 15th percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552. FINDINGS: Lung density at baseline was influenced by age, sex, body-mass index, current smoking status and smoking history, and severity of airflow limitation. The observed decline in lung density was variable (mean decline -1·13 g/L [SE 0·06] per year). The annual decline in lung density was more rapid in women (additional -0·41 [SE 0·14] g/L per year, p=0·003) than men and in current smokers (additional -0·29 [SE 0·14] g/L per year, p=0·047) than in former smokers. Circulating levels of the biomarkers surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung density and its decline over time. INTERPRETATION: This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender. We identified potential biochemical predictors of the presence and progression of emphysema. FUNDING: GlaxoSmithKline.

Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype.

BACKGROUND: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). METHODS AND FINDINGS: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. CONCLUSIONS: Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease.

RATIONALE: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome. OBJECTIVES: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy. METHODS: A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers. MEASUREMENTS AND MAIN RESULTS: At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers. CONCLUSIONS: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT00292552).

A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13.

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 FEV(1) (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.

COPD association and repeatability of blood biomarkers in the ECLIPSE cohort.

BACKGROUND: There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) cohort. METHODS: Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients. RESULTS: Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201) reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved. CONCLUSIONS: Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD). Further analysis of more promising biomarkers may reveal utility in subsets of patients. Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation. TRIAL REGISTRATION: SCO104960, clinicaltrials.gov identifier NCT00292552.

Respiratory system impedance with impulse oscillometry in healthy and COPD subjects: ECLIPSE baseline results.

RATIONALE: Current assessment of COPD relies extensively on the use of spirometry, an effort-dependent maneuver. Impulse oscillometry (IOS) is a non-volitional way to measure respiratory system mechanics, but its relationship to structural and functional measurements in large groups of patients with COPD is not clear. OBJECTIVES: We evaluated the ability of IOS to detect and stage COPD severity in the prospective ECLIPSE cohort of COPD patients defined spirometrically, and contrasted with smoking and non-smoking healthy subjects. Additionally, we assessed whether IOS relates to extent of CT-defined emphysema. METHODS: We measured lung impedance with IOS in healthy non-smokers (n = 233), healthy former smokers (n = 322) or patients with COPD (n = 2054) and related these parameters with spirometry and areas of low attenuation in lung CT. MEASUREMENTS AND MAIN RESULTS: In healthy control subjects, IOS demonstrated good repeatability over 3 months. In the COPD group, respiratory system impedance was worse compared with controls as was frequency dependence of resistance, which related to GOLD stage. However, 29-86% of the COPD subjects had values that fell within the 90% confidence interval of several parameters of the healthy non-smokers. Although mean values for impedance parameters and CT indices worsened as GOLD severity increased, actual correlations between them were poor (r ≤ 0.16). CONCLUSIONS: IOS can be reliably used in large cohorts of subjects to assess respiratory system impedance. Cross-sectional data suggest that it may have limited usefulness in evaluating the degree of pathologic disease, whereas its role in assessing disease progression in COPD currently remains undefined.

Evaluation of exhaled breath condensate pH as a biomarker for COPD.

INTRODUCTION: We assessed the utility of EBC pH as a biomarker in COPD in a large cohort of well-characterised individuals with COPD and control subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. We also determined short term reproducibility and the response of EBC to oral prednisolone. METHODS: EBC was collected with R-Tubes(TM), using techniques for sampling and measurement that have been shown to be reproducible. RESULTS: EBC pH was lower in COPD (n = 676, 7.29 ± SD 0.60) and in smoking controls (n = 31, 7.18 ± 0.85), compared with non-smoking controls (n = 50, 7.59 ± 0.44, p = 0.0008 and 0.0033 respectively), but was not different between COPD and smoking controls. There was no relationship between EBC pH and disease severity, as assessed by the percent predicted FEV(1), nor with airway inflammation as assessed by sputum leukocyte counts. Treatment with 20 mg.day-1 prednisolone for 4 weeks did not change EBC pH. CONCLUSION: EBC pH is lower in COPD than in healthy control non-smokers, but does not differentiate COPD from smokers without COPD, relate to disease severity or to airway inflammation, and does not respond to corticosteroids. EBC pH therefore does not appear to be a useful biomarker in COPD.

Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease.

RATIONALE: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. OBJECTIVES: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. METHODS: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. MEASUREMENTS AND MAIN RESULTS: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. CONCLUSIONS: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

Characterisation of COPD heterogeneity in the ECLIPSE cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE). METHODS: We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography. RESULTS: COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified. CONCLUSIONS: The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.

Montelukast added to fluticasone propionate does not alter inflammation or outcomes.

BACKGROUND: Airway inflammation is a key pathological feature of asthma which underlies its clinical presentation. OBJECTIVES: To examine whether adding a leukotriene modifier to an inhaled corticosteroid produces further clinical and/or anti-inflammatory benefits in patients symptomatic on short-acting beta(2)-agonists. METHODS: Patients uncontrolled on short-acting beta(2)-agonists were treated for 12 weeks with either fluticasone propionate (100mcg BD) or fluticasone propionate (100mcg BD) and montelukast (10mg QD) in a randomized, double-blind, parallel group study. Bronchoscopy with endobronchial biopsy and bronchoalveolar lavage (BAL) was performed before and after treatment to compare effects on airway inflammation. RESULTS: Of 103 subjects enrolled, 89 subjects completed treatment and 82 subjects had matched pair biopsy samples. Submucosal eosinophil counts, the primary endpoint, and asthma control improved to similar extents after both treatments (p

Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease.

RATIONALE: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood. OBJECTIVES: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations. METHODS: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN). MEASUREMENTS AND MAIN RESULTS: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10⁻4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10⁻4 and 4.8 × 10⁻5), and airflow obstruction (P = 0.004 and 1.8 × 10⁻5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10⁻4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function. CONCLUSIONS: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

Control of airway inflammation maintained at a lower steroid dose with 100/50 microg of fluticasone propionate/salmeterol.

BACKGROUND: Inhaled corticosteroids (ICSs) have been shown to reverse epithelial damage and decrease lamina reticularis thickness in patients with asthma. OBJECTIVE: This study investigated whether clinical asthma control and airway inflammation could be maintained after switching therapy from medium-dose fluticasone propionate (FP) to low-dose FP administered with the long-acting beta2-agonist (LABA) salmeterol. METHODS: Eighty-eight subjects (age, > or =18 years) who, during open-label screening, demonstrated improved asthma control after an increase from 100 microg of FP twice daily to 250 microg of FP twice daily were randomized to receive 100/50 microg of FP/salmeterol through a Diskus inhaler (GlaxoSmithKline, Research Triangle Park, NC) twice daily or continue 250 microg of FP twice daily through a Diskus inhaler for 24 weeks. Clinical outcomes were monitored, and bronchial biopsy specimens and bronchoalveolar lavage fluid were obtained before and after 24 weeks of treatment. RESULTS: There were no significant differences between treatments with respect to eosinophils in the bronchial mucosa and bronchoalveolar lavage fluid; mucosal mast cells, neutrophils, or CD3+, CD4+, CD8+, or CD25+ T lymphocytes; or concentration of mediators (GM-CSF, IL-8, and eosinophil cationic protein). The 2 treatments were not different with respect to lamina reticularis thickness. Consistent with the airway inflammatory measures, clinical and physiologic measures of asthma control were also similar. CONCLUSION: This study demonstrates that control of asthma and airway inflammation is maintained over the 24-week treatment period when patients requiring a medium-dose ICS are switched to a lower-dose ICS with a LABA. CLINICAL IMPLICATIONS: A lower-dose ICS with a LABA is effective in controlling inflammation and providing clinical asthma control, confirming current guideline recommendations.