Respiratory Medicine - Articles in Press

Airway obstruction lability helps distinguish levels of disease activity in asthma - Corrected Proof

2012-02-02

Summary: Classifying disease activity in asthma relies on clinical and physiological variables, but these variables do not capture all aspects of asthma that distinguish levels of disease activity.We used data from two pivotal trials of montelukast in asthma to classify disease activity as “high” or “low.” We performed a principal component analysis (PCA) of disease activity using 21 efficacy outcome variables, including several novel derived outcome variables reflecting clinical and airway obstruction lability. Then we performed discriminant analysis (DA) based on disease activity classification.PCA revealed 6 factors (daytime asthma control, nighttime-predominant asthma control, airway obstruction, exacerbations, clinical lability, airway obstruction lability) that explained 76% of the variance between outcome variables. Although airway obstruction lability (comprising both diurnal variability in peak expiratory flow and diurnal variability in β-agonist use) accounted for only 6% of the explained variance in PCA, in DA it was more accurate (canonical coefficient 0.75) than traditional measures of asthma severity such as obstruction (−0.54) and daytime control (−0.56) in distinguishing between high and low disease activity.We conclude that airway obstruction lability, a parameter not typically captured in clinical trials, may contribute to more complete assessment of asthma disease activity and may define an emerging clinical target of future therapy.

Ethnic and racial differences in the presence of idiopathic pulmonary fibrosis at death - Corrected Proof

2012-02-01

Summary: Background: In studies of idiopathic pulmonary fibrosis (IPF), whites makeup the vast majority of subjects. Whether ethnic/racial differences in idiopathic pulmonary fibrosis occur in the general population is unknown.Methods: To compare the presence of IPF between ethnic/racial groups of U.S. decedents from 1989 to 2007 by using the National Center for Health Statistics database.Results: There were 251,058 U.S. decedents with IPF; 87.2% were non-Hispanic whites (White), 5.1% were non-Hispanic African American (Black), 5.4% were Hispanic, and 2.2% were from other ethnic/racial groups (Other). Whites coded with IPF died older than those in the other groups (77.9 years vs. 72.1 years for Blacks, 75.3 years for Hispanics, and 75.6 years for Others; p < 0.0001 for all pairwise comparisons). When controlling for age and for sex, compared with Whites, both Hispanics and Others were more likely to be coded with IPF (OR = 1.47, 95% CI 1.44–1.49, p < 0.0001 and OR = 1.29, 95% CI 1.26–1.36, p < 0.0001 respectively), while Blacks were significantly less likely to be coded with IPF (OR = 0.48, 95% CI 0.47–0.49, p < 0.0001). Among decedents with IPF, Hispanics were more likely, and Blacks were less likely, than Whites to die from IPF (OR = 1.24, 95% CI 1.20–1.29, p < 0.0001 and OR = 0.91, 95% CI 0.87–0.94, p < 0.0001).Conclusion: From 1989 to 2007, Black decedents were less—and Hispanics were more—likely than Whites to die of/with IPF. Research is needed to determine if genetic differences between ethnic/racial groups explain these findings.

HIV and asthma, is there an association? - Corrected Proof

2012-01-30

Summary: Objective: To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.Methods: We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data.Results: HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported.Conclusion: The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.

Rituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome - Corrected Proof

I. Marie, S. Dominique, A. Janvresse, H. Levesque, J-F. Menard — 2012-01-27

Summary: Objective: To report our experience using rituximab as therapy for refractory antisynthetase syndrome (ASS)-associated interstitial lung disease.Methods: We retrospectively evaluated the medical records of 7 ASS patients with refractory interstitial lung disease, which had previously failed to respond to prednisone and/or other cytotoxic drugs. All 7 patients received rituximab therapy, i.e.: 1 g at days 0 and 14 and at 6-month follow-up. Data on pulmonary symptoms, pulmonary function tests and high resolution computed tomography (HRCT) scan of the lungs were collected: 1) before rituximab initiation; and 2) at 6-month and one-year follow-up after the first infusion of rituximab.Results: At one-year follow-up, ASS patients had resolution (n = 2) or improvement of pulmonary clinical manifestations. Patients also exhibited significant improvement of interstitial lung disease parameters: 1) on pulmonary function tests: FVC (p = 0.03) and DLCO (p = 2 × 10−5); 2) and HRCT-scan of the lungs. Due to clinical resolution/improvement of interstitial lung disease, the median daily dose of oral prednisone could be reduced in these 7 ASS patients at one-year follow-up, compared with baseline (20 mg/day vs. 9 mg/day; p = 0.015).Conclusion: Our findings suggest that rituximab may be a helpful therapy for refractory interstitial lung disease in patients with ASS.

Inhaler mishandling is very common in patients with chronic airflow obstruction and long-term home nebuliser use - Corrected Proof

2012-01-25

Summary: Inhalers and nebulisers are devices used for delivering aerosolised drugs in subjects with Chronic Airflow Obstruction (CAO).This multicentre, cross-sectional observational study was performed in a large population of outpatients with CAO regularly using home aerosol therapy and referring to chest clinics. The aims of the study were to compare the characteristics of the group of subjects with CAO who were using home nebulisers but also experienced with inhalers vs. those only using inhalers and to investigate whether the first group of subjects was particularly prone to inhaler misuse. Information was gained evaluating the responses to a standardised questionnaire on home aerosol therapy and the observations of inhaler technique.We enrolled 1527 patients (58% males; mean ± SE; aged 61.1 ± 0.4 years; FEV1% pred 69.9 ± 0.6; 51% and 44% respectively suffering from COPD and asthma) who were only inhaler users (OIU group) and 137 (85% males; aged 67.7 ± 1.3 years; FEV1% pred 62.3 ± 2.9; 60% and 23% respectively suffering from COPD and asthma) who were using both nebulisers and inhalers (NIU group).Nebuliser users were older, had more severe obstruction, related symptoms and health care resources utilisation. Nebulisers users performed more critical inhalers errors than those of the OIU group (49% vs. 36%; p = 0.009).We conclude that our patients with CAO and regular nebuliser treatment had advanced age, severe respiratory conditions and common inhaler misuse.

Impact of add-on pranlukast in stable asthma; the additive effect on peripheral airway inflammation - Corrected Proof

2012-01-24

Summary: Backgound: The importance of airway inflammation has been highlighted in the pathophysiology of asthma. Even in controlled asthmatics treated with inhaled corticosteroid (ICS), residual airway inflammation is reported. Systemic therapy with oral leukotriene receptor antagonist, pranlukast, may have additive effects to improve asthma control.Methods: Twenty-five controlled asthmatics treated with ICS or ICS plus long-acting β2-agonist (LABA) were enrolled for a randomized crossover trial evaluating the effect of additional oral pranlukast. The patients were assigned to two groups receiving ICS (+LABA) or ICS (+LABA) + pranlukast for 8 weeks. After washout period, two groups were switched over for another 8 weeks. Fraction of exhaled nitric oxide (FeNO), lung function tests, peak expiratory flow (PEF) and asthma control test (ACT) were evaluated at the beginning and end of each period. Central airway NO flux (J’awNO) and peripheral airway/alveolar NO concentration (CANO) were measured and adjusted for axial NO back-diffusion.Results: FEV1, % predicted, forced expired flow (FEF) 25–75, % predicted, morning PEF and ACT were significantly increased after the addition of pranlukast. Oral pranlukast administration significantly decreased both CANO and corrected CANO.Conclusions: The addition of oral pranlukast to ICS or ICS + LABA therapy may improve asthma control with reducing distal airway inflammation.Trial registration: UMIN 000003781.

Raised erythrocyte creatine in patients with pulmonary arterial hypertension – Evidence for subclinical hemolysis - Corrected Proof

2012-01-16

Summary: Background: Pulmonary arterial hypertension (PAH) has been associated with hemolytic conditions such as sickle cell disease but the possible role of hemolysis in the pathogenesis or pathophysiology of other forms of PAH has not been studied. Erythrocyte lifespan is the gold-standard test of hemolysis and may be measured by assaying erythrocyte creatine (EC) levels. EC decreases as the erythrocyte ages, so patients with hemolysis have high EC levels.Methods: We measured EC and other parameters of hemolysis in patients with idiopathic and connective tissue associated PAH and normal controls.Results: In patients with PAH (n = 40), EC levels were higher than in controls n = 30 (patients EC 1.72 mcmol/g HgB 95%CI[1.51, 1.96], controls EC 1.05 mcmol/g HgB [0.93, 1.19], p < 0.0001). High levels of EC correlated with worse 6 min walk (r = −0.42, p < 0.0001) and worse functional class (p = 0.002). Other indirect indices of hemolysis (total lactate dehydrogenase, red cell distribution width) were also increased in patients with PAH relative to controls.Conclusions: There is evidence of subclinical hemolysis in patients with PAH, and higher levels of hemolysis are associated with poorer exercise capacity.

Lung capillary blood volume and membrane diffusion in idiopathic interstitial pneumonia - Corrected Proof

2012-01-06

Summary: Rationale: Diffusing capacity of the lung for carbon monoxide (DLCO) is a good marker of disease severity in patients with idiopathic interstitial pneumonia (IIP). The combined diffusing capacity of nitric oxide (DLNO) and DLCO determines the two components of diffusion: membrane conductance (Dm, CO) and pulmonary capillary blood volume (Vc).Objectives: The aim of this study was to evaluate Vc and Dm, CO in patients with fibrosing IIP in order to determine the relative contribution of membrane resistance and vascular resistance to the loss of DLCO.Methods: 32 patients with IIP (IPF: n = 22, NSIP: n = 10) were evaluated using MRC dyspnea scale, plethysmography, combined DLNO/DLCO, 6-min walk test (6 MWT), echocardiography and chest computed tomography (chest CT).Results: DLCO (41.8 ± 11.9%pred), Dm, CO (40.5 ± 12.7%pred) and Vc (41.9 ± 18%pred) were severely and equally reduced. Dm, CO and Vc were related to MRC scale, FVC, maximal desaturation during 6 MWT, and systolic pulmonary artery pressure (sPAP). There was no correlation with the extent of fibrotic changes on chest CT.Conclusions: Our main results indicate that Dm, CO and Vc contribute almost equally to DLCO reduction in IIP. Dm, CO and Vc are related to functional indicators of disease severity and to sPAP in agreement with the concept of vascular involvement in IIP.

Chronic obstructive pulmonary disease and cancer risk: A Danish nationwide cohort study - Corrected Proof

2012-01-04

Summary: Introduction: Little is known about the risk of cancer in patients with chronic obstructive pulmonary disease (COPD), including which cancer sites are most affected. We examined the short- and long-term risk of lung and extrapulmonary cancer in a nationwide cohort of COPD patients.Methods: We linked the Danish National Registry of Patients and the nationwide cancer registry, and examined the incidence of various cancers in 236,494 individuals with a first incident hospital contact with COPD during 1980–2008. The observed cancer incidence in this cohort was compared with the expected incidence in the general population on the basis of national age-, sex-, and site-specific incidence rates.Results: Median follow-up was 3.5 years. During the first year of follow-up, 9434 cancers were diagnosed in COPD patients [standardized incidence ratio (SIR) = 3.1; 95% CI 3.0 to 3.2]. The 1-year SIR was 8.5 (8.2–8.9) for lung cancer, 5.1 (5.0–5.2) for all tobacco-related cancers, and 1.9 (1.9–2.0) for other cancers. In the following years, cancer incidence was increased 1.4-fold (1.4–1.5) in COPD patients. These patients had an increased risk of developing tobacco-related cancers (SIR = 2.1; 95% CI 2.0–2.1), including cancers of the lung, larynx, tongue, oral cavity, pharynx, esophagus, stomach, liver, pancreas, cervix uteri, and urinary tract (with SIRs ranging between 1.3 and 2.8).Conclusions: Patients with first-time hospital-diagnosed COPD are at considerably increased risk of developing both lung cancer and extrapulmonary cancers. Physicians should be aware of cancer in COPD patients.

S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis - Corrected Proof

2012-01-03

Summary: Background: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, and the prognosis remains poor. On the other hand, other fibrotic interstitial pneumonias such as idiopathic nonspecific interstitial pneumonia (I-NSIP) and collagen vascular disease-associated interstitial pneumonia (CVD-IP) resemble IPF, but they respond to therapy and the prognosis is better. We searched for biomarkers to distinguish IPF from other fibrotic interstitial pneumonias and investigated whether S100A9 could be useful for discriminating types of fibrotic interstitial pneumonia based on our preliminary proteomic findings.Methods: We measured S100A9 levels in serum and bronchoalveolar lavage fluid (BALF) from 28 patients with IPF, 15 with I-NSIP, 20 with cryptogenic organizing pneumonia (COP), 35 with CVD-IP and 23 healthy individuals (controls) using enzyme-linked immunosorbent assays. S100A9 in the lung was also immunohistochemically localized.Results: S100A9 levels in BALF, but not in serum, were significantly elevated in patients with IPF compared with I-NSIP, COP, CVD-IP and healthy individuals. S100A9 immunoreactivity was localized mainly in macrophages and neutrophils in lung specimens from patients with IPF. The results of receiver operating characteristic (ROC) curve analysis showed that BALF S100A9 levels had sufficient specificity and sensitivity to distinguish IPF from I-NSIP and CVD-IP.Conclusion: S100A9 in BALF might serve as a candidate biomarker to discriminate between IPF and other fibrotic interstitial pneumonias.

AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD - Corrected Proof

Piotr Kuna, Martin Jenkins, Christopher D. O’Brien, William A. Fahy — 2011-12-26

Summary: Background: Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60mg bid during Phase I/IIa development.Methods: This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George’s respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments.Results: Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: −0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo.Conclusions: Three months’ treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.

Have we underestimated the efficacy of pulmonary rehabilitation in improving mood? - Corrected Proof

2011-12-26

Summary: Background: Patients with COPD have a high prevalence of anxiety and depression. The efficacy of pulmonary rehabilitation (PR) in treating more severe anxiety and depression is unknown. The study aimed to explore the effectiveness of PR in reducing symptoms of anxiety and depression across a spectrum of severities.Methods: The study used principles of comparative effectiveness research. Data was analysed from 518 patients with COPD [57.5% male, mean (SD) age 69.2 years (±8.8 years)]. Patients were categorised into 3 groups based on their hospital anxiety and depression scale (HADS) scores pre PR (‘none’ 0–7, ‘probable’ 8–10 and ‘presence’ 11–21). A responder was defined as achieving a change of ≥48m on the incremental shuttle walk test (ISWT). Patients were categorised as ‘completers’ if they attended their discharge assessment for PR.Results: Anxiety and depression did not reduce following PR in patients with no symptoms (p > 0.05). Patients with a ‘probable’ or ‘presence’ of symptoms had significant reductions (both p 0.05). Responders and non-responders did not differ in their anxiety or depression levels (p > 0.05).Conclusion: PR is effective in reducing symptoms of anxiety and depression. Previous studies may have underestimated the effectiveness of the PR programme in improving mood.

A better response in exercise capacity after pulmonary rehabilitation in more severe COPD patients - Corrected Proof

Wytske A. Altenburg, Mathieu H.G. de Greef, Nick H.T. ten Hacken, Johan B. Wempe — 2011-12-08

Summary: Purpose: Pulmonary rehabilitation (PR) has positive effects on exercise capacity in Chronic Obstructive Pulmonary Disease (COPD). However, not all COPD patients benefit from PR to the same extent. We investigated whether there is a patient profile, which is associated with the improvement in endurance exercise capacity.Methods: In this observational study, we included 102 COPD patients who followed PR (age 60 ± 10 (mean ± SD) years, FEV1%predicted 44 ± 16%, 54 men). Lung function, maximal incremental cycle testing (Wpeak, VO2peak, Δlactate), quadriceps force and incremental and endurance shuttle walk test (ISWT/ESWT) were performed at the start of PR. The ESWT was repeated after 7 weeks of PR.Results: Mean change in ESWT (ΔESWT) was 100 ± 154%. Four variables showed a statistically significant negative correlation with ΔESWT: FEV1%pred. (ρ = −0.20), Wpeak (ρ = −0.24), Δlactate (ρ = −0.33) and incremental shuttle walk test (ISWT) (ρ = −0.31). A cluster analysis identified two patient profiles: A profile with high ΔESWT, TLC and RV and low FEV1, VO2peak, quadriceps force, Δlactate, HRpeak%pred. and ISWT distance and a profile with low ΔESWT, TLC and RV and high FEV1, VO2peak, quadriceps force, Δlactate, HRpeak%pred. and ISWT distance.Conclusions: Single variables from lung function or exercise testing at baseline have limited predictive value for response to exercise training.However, patients with worse disease status (i.e. a combination of lower FEV1, more hyperinflation, lower exercise capacity and worse quadriceps force) improve more in endurance exercise capacity.

Lymphangiogenesis in COPD: Another link in the pathogenesis of the disease - Corrected Proof

2011-12-08

Summary: Background: New lymphatic vessels are associated with tissue injury and repair. Recent studies have shown increased lymphatic follicles formation in the lungs of COPD patients. We hypothesized that lymphatic vascular remodeling could be part of COPD pathogenesis.Aim: To investigate the lymphangiogenetic process in COPD we measured the lymphatic microvessel density (LMVD), the lymphatic invasion (L.I), and their correlation with clinical and laboratory parameters.Methods: Lung tissue from 20 COPD patients and 20 non-COPD smokers was immunohistochemically stained for D2-40 (lymphatic endothelial cell marker), and LYVE-1 (lymphatic endothelial hyaluronan receptor 1). Both groups had similar age and smoking history.Results: D2-40 and LYVE-1 were expressed in all specimens. Lymphatic invasion was presented only in COPD specimens. Lymphatic microvessel density (LMVD) as revealed by D2-40 and LYVE-1 markers was statistically significantly higher in COPD patients when compared with non-COPD smokers. Both markers (D2-40, LYVE-1) were correlated with FEV1 (% pred) (R2 = 0.415, R2 = 0.605, respectively).Conclusions: We report for the first time high lymphatic microvessel density and lymphatic invasion in COPD patients, related to the degree of airway obstruction. Our findings could provide novel insights in the pathogenesis of the disease.

Influence of inspiration level on bronchial lumen measurements with computed tomography - Corrected Proof

M. Els Bakker, Jan Stolk, Johan H.C. Reiber, Berend C. Stoel — 2011-12-07

Summary: Background: Bronchial dimensions measured in CT images generally do not take inspiration level into consideration. However, some studies showed that the bronchial membrane is distensible with airway inflation. Therefore, re-examination of the elasticity of bronchi is needed.Purpose: To assess the influence of respiration on bronchial lumen area (defined as distensibility) in different segmental bronchi and to explore the correlations between distensibility and both lung function and emphysema severity.Material and methods: In 44 subjects with COPD related to alpha-1-antitrypsin deficiency (AATD), bronchial lumen area was measured in CT images, acquired at different inspiration levels. Measurements were done at matched locations in one apical and two basal segmental airways (RB1, RB10 and LB10). Airway distensibility was calculated as lumen area difference divided by lung volume difference.Results: Bronchial lumen area in the lower lobes (RB10 and LB10) correlated positively with FEV1%predicted (p=0.027 for RB10; and p=0.037 for LB10, respectively). Lumen area is influenced by respiration (p=0.006, p=0.045, and, p=0.005 for RB1, RB10 and LB10, respectively). Airway distensibility was different between upper and lower bronchi (p<0.001), but it was not correlated with lung function.Conclusion: Lumen area of third generation bronchi is dependent on inspiration level and this distensibility is different between bronchi in the upper and lower lobes. Therefore, changes in lumen area over time should be studied whilst accounting for the lung volume changes, in order to estimate the progression of bronchial disease while excluding the effects of hyperinflation.

Current and emerging medical treatments for non–small cell lung cancer: A primer for pulmonologists - Corrected Proof

Peter Mazzone, Tarek Mekhail — 2011-11-28

Summary: Pulmonary physicians commonly develop relationships with lung cancer patients through the evaluation and staging of the disease prior to the discussion of treatment options with oncologists. Given the relationship that develops, a pulmonologist is often asked about aspects of the treatment plan that may be slightly outside of their comfort zone. The aim of this overview of medical treatment of non–small cell lung cancer is to provide the pulmonologist with an overview of the evidence guiding current practice so that they can be more comfortable answering their patients’ questions while awaiting the expert opinion of the oncologist. We discuss standard chemotherapeutic agents, their common side effects, and their use in the adjuvant and neoadjuvant setting, as definitive therapy for locally advanced disease, as palliative therapy for advanced disease, and as maintenance therapy. We also discuss the mechanisms of action and side effects of targeted therapies (including inhibitors of vascular endothelial growth factor [VEGF], epidermal growth factor receptor [EGFR] signaling and the anaplastic lymphoma kinase [ALK] protein), their currently accepted uses, and upcoming phase III trials, the results of which may influence standard practice.

Physical activity monitoring in COPD: Compliance and associations with clinical characteristics in a multicenter study - Corrected Proof

2011-11-28

Summary: Background: Little is known about COPD patients’ compliance with physical activity monitoring and how activity relates to disease characteristics in a multi-center setting.Methods: In a prospective study at three Northern European sites physical activity and clinical disease characteristics were measured in 134 COPD patients (GOLD-stage II–IV; BODE index 0–9) and 46 controls. Wearing time, steps per day, and the physical activity level (PAL) were measured by a multisensory armband over a period of 6 consecutive days (in total, 144h). A valid measurement period was defined as ≥22 h wearing time a day on at least 5 days.Results: The median wearing time was 142 h:17 min (99%), 141 h:1min (98%), and 142 h:24 min (99%), respectively in the three centres. A valid measurement period was reached in 94%, 97%, and 94% of the patients and did not differ across sites (P = 0.53). The amount of physical activity did not differ across sites (mean steps per day, 4725 ± 3212, P = 0.58; mean PAL, 1.45 ± 0.20, P = 0.48). Multivariate linear regression analyses revealed significant associations of FEV1, 6-min walk distance, quadriceps strength, fibrinogen, health status, and dyspnoea with both steps per day and PAL. Previously unrecognized correlates of activity were grade of fatigue, degree of emphysema, and exacerbation rate.Conclusions: The excellent compliance with wearing a physical activity monitor irrespective of study site and consistent associations with relevant disease characteristics support the use of activity monitoring as a valid outcome in multi-center studies.

Strength training increases maximum working capacity in patients with COPD – Randomized clinical trial comparing three training modalities - Corrected Proof

2011-11-28

Summary: Background and objective: Skeletal muscle dysfunction contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). Strength training increases muscle strength and muscle mass, but there is an ongoing debate on the additional effect concerning the exercise capacity. The purpose of this study was to compare the effects of three different exercise modalities in patients with COPD including endurance training (ET), progressive strength training (ST) and the combination of strength training and endurance training (CT).Design: A prospective randomized trial.Methods: Thirty-six patients with COPD were randomly allocated either to ET, ST, or CT. Muscle strength, cardiopulmonary exercise testing, lung function testing and quality of life were assessed before and after a 12-week training period.Results: Exercise capacity (Wmax) increased significantly in all three training groups with increase of peak oxygen uptake (VO2peak) in all three groups, reaching statistical significance in the ET group and the CT group. Muscle strength (leg press, bench press, bench pull) improved in all three training groups, with a higher improvement in the ST (+39.3%, +20.9%, +20.3%) and the CT group (+43.3%, +18.1%, +21.6%) compared to the ET group (+20.4%, +6.4%, +12.1%).Conclusions: Progressive strength training alone increases not only muscle strength and quality of life, but also exercise capacity in patients with COPD, which may have implications in prescription of training modality.ClinicalTrials.gov Identifier: NCT01091623.

All Danish first-time COPD hospitalisations 2002–2008: Incidence, outcome, patients, and care - Corrected Proof

2011-11-24

Summary: Objective: This study aimed to investigate trends in first-time hospitalisations with chronic obstructive pulmonary disease (COPD) in a publicly financed healthcare system during the period from 2002 to 2008 with respect to incidence, outcome and characteristics of hospitalisations, departments, and patients.Methods: Using health administrative data from national registers, all first-time hospitalisations with COPD in Denmark (population 5.4 million) were identified. Data based on the individual hospitalisations and patients were retrieved and analysed.Results: During the period 2002 to 2008 the total rate of COPD hospitalisations decreased from 460 to 410 per 100 000 person years. Among persons above 45 years of age, the age- and sex-adjusted incidence rate of first-time COPD hospitalisations decreased by 8.2% (95% CI 5.0-11.2%). The inpatient mortality increased OR 1.16 (95% CI1.01-1.34) and the one-year mortality increased OR 1.12 (95% CI1.03-1.21). Concurrently, significant age- and sex-adjusted increases were found in use of intensive care, comorbidity, patient travel distance, bed occupancy rate of the receiving department, prior use of oral and inhaled corticosteroids, use of outpatient clinics and encounters in general practice, while length of stay and number of receiving hospitals decreased.Conclusion: Decreasing rate of first-time COPD hospitalisations combined with shorter lengths of stay and increasing severity of cases indicates that the use of hospital beds for COPD exacerbations has been gradually restricted. This may be causally related to both the centralisation into overcrowded departments and the improved outside hospital treatment of COPD, also demonstrated in this study.

Cause-specific mortality adjudication in the UPLIFT® COPD trial: Findings and recommendations - Corrected Proof

2011-11-21

Summary: Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a Mortality Adjudication Committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

Direct medical costs of COPD – An excess cost approach based on two population-based studies - Corrected Proof

2011-11-21

Summary: Aim: While it is known that severe COPD has substantial economic consequences, evidence on resource use and costs in mild disease is scarce. The objective of this study was to investigate excess costs of early stages of COPD.Methods: Using data from two population-based studies in Southern Germany, current GOLD criteria were applied to pre-bronchodilator spirometry for COPD diagnosis and staging in 2255 participants aged 41 to 89. Utilization of physician visits, hospital stays and medication was compared between participants with COPD stage I, stage II+ (II or higher) and controls. Costs per year were calculated by applying national unit costs. In controlling for confounders, two-part generalized regression analyses were used to account for the skewed distribution of costs and the high proportion of subjects without costs.Results: Utilization in all categories was significantly higher in COPD patients than in controls. After adjusting for confounders, these differences remained present in physician visits and medication, but not in hospital days. Adjusted annual costs did not differ between stage I (€ 1830) and controls (€ 1822), but increased by about 54% to € 2812 in stage II+.Conclusion: The finding that utilization and costs are considerably higher in moderate but not in mild COPD highlights the economic importance of prevention and of interventions aiming at early diagnosis and delayed disease progression.

Efficacy and safety of Flutiform compared with individual fluticasone and formoterol reference products - Corrected Proof

Alfredo García Arieta — 2011-06-23

The paper by Bodzenta-Lukaszyk et al. published recently in Respiratory Medicine investigated the two indications of Flutiform: substitution treatment in patients already controlled with the individual components and maintenance in patients whose symptoms are not adequately controlled with ICS plus “as needed” SABA.

WITHDRAWN: A case of acute pneumonitis associated with leflunomide treatment - Corrected Proof

Gareth Collier, P. Flood-Page — 2005-03-01

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: Endogenous lipoid pneumonia - Corrected Proof

D.G. Popov, N.I. Doncheva, V.I. Vlasov — 2005-02-02