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In patients with chronic obstructive pulmonary disease (COPD), lung function decreases rapidly. Analysis of data from a large observational study of COPD showed that the rate of such loss is highly variable, and current smoking was associated with a rapid loss. Since the seminal studY by Fletcher et al. in the 1970s, 1 , 2 it has been widely accepted that chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in forced expiratory volume in 1 second (FEV 1 ). However, surprisingly few longitudinal studies of patient cohorts have provided detailed data regarding the rate of decline in FEV 1 , 3 – 8 and none of these studies have related changes in FEV 1 to specific subgroups of patients with COPD or to levels of systemic biomarkers. We used data from a large, observational, 3-year study that included detailed assessments of patients . . .

Accurate prediction of mortality helps select patients for interventions aimed at improving outcome. 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. 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. 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. 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).

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.

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

Chronic obstructive pulmonary disease (COPD) seems to be a heterogeneous disease with a variable course. We wished to characterize the heterogeneity and variability of COPD longitudinally. 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. 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. 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).

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. To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations. 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). 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. 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.

Background Poor health status has been associated with morbidity and mortality in patients with COPD. To date, the impact of changes in health status on these outcomes remains unknown. Aims To explore the relationship of clinically relevant changes in health status with exacerbation, hospitalisation or death in patients with COPD. Methods Characteristics and health status (St George's Respiratory Questionnaire, SGRQ) were assessed over a period of 3 years in 2138 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study: a longitudinal, prospective, observational study. Associations between change in health status (=4 units in SGRQ score) during year 1 and time to first exacerbation, hospitalisation and death during 2-year follow-up were assessed using Kaplan–Meier plots and log-rank test. Results 1832 (85.7%) patients (age 63.4±7.0 years, 65.4% male, FEV1 48.7±15.6% predicted) underwent assessment at baseline and 1 year. Compared with those who deteriorated, patients with improved or stable health status in year 1 have a lower likelihood of exacerbation (HR 0.78 (95% CI 0.67 to 0.89), p<0.001 and 0.84 (0.73 to 0.97), p=0.016, respectively), hospitalisation (0.72 (0.58 to 0.90), p=0.004 and 0.77 (0.62 to 0.96), p=0.023, respectively) or dying (0.61 (0.39 to 0.95), p=0.027 and 0.58 (0.37 to 0.92), p=0.019, respectively) during 2-year follow-up. This effect persisted after stratification for age and the number of exacerbations and hospitalisations during the first year of the study. Conclusions Patients with stable or improved health status during year 1 of ECLIPSE had a lower likelihood of exacerbation, hospitalisation or dying during 2-year follow-up. Interventions that stabilise and improve health status may also improve outcomes in patients with COPD. Trial registration number NCT00292552, registered at ClinicalTrials.gov.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT. A post hoc analysis was performed to assess risk at baseline and follow-up at Week 12 in the TRIUMPH cohort (n = 148) and at Week 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort (n = 73). Overall survival, clinical worsening-free survival, and pulmonary arterial hypertension-related hospitalization-free survival were all assessed in the pooled TRIUMPH and inhaled treprostinil naïve placebo BEAT cohorts based on risk group/strata at Week 12/16 follow-up. Inhaled treprostinil improved REVEAL 2.0 risk stratum (OR: 2.38, 95% CI: 1.09–5.19, p = 0.0298) and REVEAL 2.0 score (p = 0.0008) compared to placebo in the TRIUMPH cohort at Week 12. REVEAL 2.0 risk stratum and the number of low-risk criteria by the French approach improved at Weeks 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort. Combining cohorts, REVEAL 2.0 risk stratification at follow-up was prognostic for clinical worsening-free, pulmonary arterial hypertension hospitalization-free, and overall survival, whereas the number of low-risk criteria was not. These post-hoc pooled analyses suggest inhaled treprostinil improves risk status and indicates that the REVEAL 2.0 calculator may be more suitable than the French noninvasive method for evaluating short-term clinical change in the New York Heart Association/World Health Organization functional class III/IV population.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 29 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan–Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322–991) days and 52% of patients were New York Heart Association/World Health Organization Functional Class III. For patients that cross-titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1–57) days. At 16- and 24-weeks post-transition, oral treprostinil persistence was 86 and 76%, respectively. Persistence was 59% at 52 weeks post-transition. Clinical stability for the majority of patients at first follow-up post-transition was suggested based on available New York Heart Association/World Health Organization Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil.

Outcomes other than spirometry are required to assess nonbronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the 6-minute-walk distance (6MWD) have been derived from narrow cohorts using nonblinded intervention. To determine minimum clinically important difference for change in 6MWD over 1 year as a function of mortality and first hospitalization in an observational cohort of patients with COPD. Data from the ECLIPSE cohort were used (n = 2,112). Death or first hospitalization were index events; we measured change in 6MWD in the 12-month period before the event and related change in 6MWD to lung function and St. George's Respiratory Questionnaire (health status). Of subjects with change in the 6MWD data, 94 died, and 323 were hospitalized. 6MWD fell by 29.7 m (SD, 82.9 m) more among those who died than among survivors (P < 0.001). A reduction in distance of more than 30 m conferred a hazard ratio of 1.93 (95% confidence interval, 1.29-2.90; P = 0.001) for death. No significant difference was observed for first hospitalization. Weak relationships only were observed with change in lung function or health status. A reduction in the 6MWD of 30 m or more is associated with increased risk of death but not hospitalization due to exacerbation in patients with chronic obstructive pulmonary disease and represents a clinically significant minimally important difference.