The clinical features of the overlap between COPD and asthma

Background

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.

Methods

We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.

Results

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.

Conclusion

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.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764     

Factors associated with change in exacerbation frequency in COPD

Background

Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined.

Methods

1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2.

Findings

Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV₁ and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE.

Conclusion

No parameter clearly predicts an imminent change in exacerbation frequency category.

Trial registration

SCO104960, clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00292552","term_id":"NCT00292552"}}NCT00292552     

Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD

Background

As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.

Methods

The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.

Results

The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).

Conclusions

This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.

Trials registration

ClinicalTrials.gov identifiers: {"type":"clinical-trial","attrs":{"text":"NCT00076089","term_id":"NCT00076089"}}NCT00076089 and {"type":"clinical-trial","attrs":{"text":"NCT00430729","term_id":"NCT00430729"}}NCT00430729.     

Fluticasone propionate/salmeterol 250/50?μg versus salmeterol 50?μg after chronic obstructive pulmonary disease exacerbation

Background

Inhaled long-acting beta₂ agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone.

Methods

Patients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 μg or SAL 50 μg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed.

Results

There was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV₁ change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort.

Conclusions

No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV₁ ≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment.

Trial registration

ClinicalTrials.gov (identifier NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0105-2) contains supplementary material, which is available to authorized users.     

The Salford Lung Study protocol: a pragmatic,randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease

Background

New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.

Methods

Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.

Conclusions

The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in COPD.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01551758","term_id":"NCT01551758"}}NCT01551758.     

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 {"type":"clinical-trial","attrs":{"text":"NCT00292552","term_id":"NCT00292552"}}NCT00292552     

Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study

Background

Development of adult respiratory disease is influenced by events in childhood. The impact of childhood pneumonia on chronic obstructive pulmonary disease (COPD) is not well defined. We hypothesize that childhood pneumonia is a risk factor for reduced lung function and COPD in adult smokers.

Methods

COPD cases and control smokers between 45–80 years old from the United States COPDGene Study were included. Childhood pneumonia was defined by self-report of pneumonia at <16 years. Subjects with lung disease other than COPD or asthma were excluded. Smokers with and without childhood pneumonia were compared on measures of respiratory disease, lung function, and quantitative analysis of chest CT scans.

Results

Of 10,192 adult smokers, 854 (8.4 %) reported pneumonia in childhood. Childhood pneumonia was associated with COPD (OR 1.40; 95 % CI 1.17-1.66), chronic bronchitis, increased COPD exacerbations, and lower lung function: post-bronchodilator FEV₁ (69.1 vs. 77.1 % predicted), FVC (82.7 vs. 87.4 % predicted), FEV₁/FVC ratio (0.63 vs. 0.67; p < 0.001 for all comparisons). Childhood pneumonia was associated with increased airway wall thickness on CT, without significant difference in emphysema. Having both pneumonia and asthma in childhood further increased the risk of developing COPD (OR 1.85; 95 % CI 1.10-3.18).

Conclusions

Children with pneumonia are at increased risk for future smoking-related lung disease including COPD and decreased lung function. This association is supported by airway changes on chest CT scans. Childhood pneumonia may be an important factor in the early origins of COPD, and the combination of pneumonia and asthma in childhood may pose the greatest risk.

Clinical trials registration

ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764 (Active since January 28, 2008).

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0273-8) contains supplementary material, which is available to authorized users.     

Epidemiology,radiology, and genetics of nicotine dependence in COPD

Background

Cigarette smoking is the principal environmental risk factor for developing COPD, and nicotine dependence strongly influences smoking behavior. This study was performed to elucidate the relationship between nicotine dependence, genetic susceptibility to nicotine dependence, and volumetric CT findings in smokers.

Methods

Current smokers with COPD (GOLD stage ≥ 2) or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND). Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung <-950 HU) and gas trapping on expiratory CT (% of lung <-856 HU) were obtained. Genotypes for two SNPs in the CHRNA3/5 region (rs8034191, rs1051730) previously associated with nicotine dependence and COPD were analyzed for association to COPD and nicotine dependence phenotypes.

Results

Among 842 currently smoking subjects (335 COPD cases and 507 controls), 329 subjects (39.1%) showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p < .0001) as well as in COPD cases (ρ = -0.18, p = 0.0008). Lower FTND score, male gender, lower body mass index, and lower FEV1 were independent risk factors for emphysema severity in COPD cases. Both CHRNA3/5 SNPs were associated with FTND in current smokers. An association of genetic variants in CHRNA3/5 with severity of emphysema was only found in former smokers, but not in current smokers.

Conclusions

Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes.

Trial registration

ClinicalTrials (NCT): {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764     

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis

Background

Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV₁) are correlated with changes in patient-reported outcomes.

Methods

Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George''s Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV₁. Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use.

Results

With increasing positive ΔFEV₁, TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV₁ was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV₁ and outcomes.

Conclusions

These results suggest that larger improvements in FEV₁ are likely to be associated with larger patient-reported benefits across a range of clinical outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00393458","term_id":"NCT00393458"}}NCT00393458, {"type":"clinical-trial","attrs":{"text":"NCT00463567","term_id":"NCT00463567"}}NCT00463567, and {"type":"clinical-trial","attrs":{"text":"NCT00624286","term_id":"NCT00624286"}}NCT00624286     

Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease

Background

Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.

Methods

We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.

Results

For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10^-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10^-7).

Conclusions

We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764, {"type":"clinical-trial","attrs":{"text":"NCT00292552","term_id":"NCT00292552"}}NCT00292552

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0113-2) contains supplementary material, which is available to authorized users.     

Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial

Background

Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations.

Methods

Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks'' follow-up.

Results

At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006).There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George''s Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%).

Conclusions

Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development.

Trial registration

ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00473460","term_id":"NCT00473460"}}NCT00473460 (ClincalTrials.gov).     

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Background

The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Methods

In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of ≤70% and FEV₁ <80% of the predicted value. The primary endpoint was trough FEV₁ at 12 and 28 weeks. Secondary endpoints were health status measured by St George''s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.

Results

At 12 and 28 weeks, aclidinium improved trough FEV₁ versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.

Conclusion

Aclidinium is effective and well tolerated in patients with moderate to severe COPD.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00363896","term_id":"NCT00363896"}}NCT00363896 (ACCLAIM/COPD I) and {"type":"clinical-trial","attrs":{"text":"NCT00358436","term_id":"NCT00358436"}}NCT00358436 (ACCLAIM/COPD II).     

Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial

Background

Macrolides reduce exacerbations in patients with COPD. Their effects on health status has not been assessed as primary outcome and is less clear. This study assessed the effects of prophylactic azithromycin on cough-specific health status in COPD-patients with chronic productive cough.

Methods

In this randomised controlled trial 84 patients met the eligibility criteria: age of ≥40 years, COPD GOLD stage ≥2 and chronic productive cough. The intervention-group (n = 42) received azithromycin 250 mg 3 times a week and the control-group (n = 42) received a placebo. Primary outcome was cough-specific health status at 12 weeks, measured with the Leicester Cough Questionnaire (LCQ). Secondary outcomes included generic and COPD-specific health status and exacerbations. Changes in adverse events and microbiology were monitored.

Results

Mean age of participants was 68 ± 10 years and mean FEV1 was 1.36 ± 0.47 L. The improvement in LCQ total score at 12 weeks was significantly greater with azithromycin (difference 1.3 ± 0.5, 95% CI 0.3;2.3, p = 0.01) and met the minimal clinically important difference. Similar results were found for the domain scores, and COPD-specific and generic health status questionnaires. Other secondary endpoints were non-significant. No imbalances in adverse events were found.

Conclusions

Prophylactic azithromycin improved cough-specific health status in COPD-patients with chronic productive cough to a clinically relevant degree.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01071161","term_id":"NCT01071161"}}NCT01071161     

Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week,randomized, double-blind,placebo-controlled study

Background

The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting β₂-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU. They are not indicated for the treatment of asthma.

Methods

In this 52-week, double-blind, placebo-controlled, parallel-group safety study (GSK study DB2113359; {"type":"clinical-trial","attrs":{"text":"NCT01316887","term_id":"NCT01316887"}}NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo. Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms. COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated.

Results

The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52–58%; SAEs: 6–7%; drug-related AEs: 12–13%). Headache was the most common AE in each treatment group (8–11%). AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups. No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo. The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were ≥2% greater than placebo. With active treatments, COPD exacerbations were fewer (13–15% of patients reporting ≥1 exacerbation) and on average less rescue medication was required (1.6–2.2 puffs/day) versus placebo (24% reporting ≥1 exacerbation, 2.6 puffs/day). Both active treatments improved lung function versus placebo.

Conclusion

UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD.     

Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD

Background

Cigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age.

Methods

All participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non-susceptible individuals, and by multiple regression analysis.

Results

Young susceptible individuals showed significantly higher increases in the expression of FcγRII (CD32) in its active forms (A17 and A27) on neutrophils after smoking (p = 0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients.

Conclusions

We show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00807469","term_id":"NCT00807469"}}NCT00807469

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0121-2) contains supplementary material, which is available to authorized users.     

The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: Patient Characterization Phase of a Randomized Clinical Trial

Background

To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls.

Methods

Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests.

Results

Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001).

Conclusions

Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01072396","term_id":"NCT01072396"}}NCT01072396     

Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral blood

Background

Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain.

Methods

We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants.

Results

Of 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations. No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased. During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased.

Conclusions

The decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues. GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD. These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00281216","term_id":"NCT00281216"}}NCT00281216, ClinicalTrials.gov.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0251-1) contains supplementary material, which is available to authorized users.     

Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease

Background

Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period. However, longer period follow-up studies are still lacking. Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.

Methods

A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV₁, 56% predicted) were included in the prospective study. We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years. Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.

Results

IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance. In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02]. CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.

Conclusions

The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.

Trial registration

No.:{"type":"clinical-trial","attrs":{"text":"NCT00605540","term_id":"NCT00605540"}}NCT00605540     

Adverse health consequences in COPD patients with rapid decline in FEV1 - evidence from the UPLIFT trial

Background

The rate of decline in forced expiratory volume in 1 second (FEV₁) is representative of the natural history of COPD. Sparse information exists regarding the associations between the magnitude of annualised loss of FEV₁ with other endpoints.

Methods

Retrospective analysis of UPLIFT^® trial (four-year, randomized, double-blind, placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [COPD], n = 5993). Decline of FEV₁ was analysed with random co-efficient regression. Patients were categorised according to quartiles based on the rate of decline (RoD) in post-bronchodilator FEV_1. The St George''s Respiratory Questionnaire (SGRQ) total score, exacerbations and mortality were assessed within each quartile.

Results

Mean (standard error [SE]) post-bronchodilator FEV₁ increased in the first quartile (Q1) by 37 (1) mL/year. The other quartiles showed annualised declines in FEV₁ (mL/year) as follows: Q2 = 24 (1), Q3 = 59 (1) and Q4 = 125 (2). Age, gender, respiratory medication use at baseline and SGRQ did not distinguish groups. The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers. The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD, but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 (Q1 = 19.5% [tiotropium], 26% [control]; Q4 = 33.8% [tiotropium] and 33.1% [control]). Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile. The group with the largest RoD had the highest mortality.

Conclusion

Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific (or more aggressive) approaches to management may be needed.

Trial Registration

ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00144339","term_id":"NCT00144339"}}NCT00144339