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As a result of recent technological advances, a significant (and increasing) number of the images in a typical radiology department are represented in digital form. This includes images that have been captured using digital imaging modalities such as computed tomography and magnetic resonance imaging as well as images that have been digitally converted from film originals as in computed radiography. To provide economical storage of such images and to allow for their efficient transmission over various networks, it becomes necessary to consider digital image compression techniques. In this article, the fundamental concepts of several popular reversible and nonreversible image compression schemes are reviewed. In addition, the performance of the schemes in terms of compression ratio and reconstructed image quality as applied to medical diagnostic images is investigated.

Pulmonary rehabilitation confers significant benefit to patients with COPD. The beneficial effects are seen in dyspnea and health-related quality of life. These measures are often considered in clinical trials as study endpoints. Pulmonary rehabilitation may affect the study population and study enrollment in clinical trials of other therapies in COPD, so it is important to anticipate the effects of pulmonary rehabilitation when designing and performing clinical trials. We review pulmonary rehabilitation and clinical trial design in patients with severe COPD. No publications were found that specifically address the impact of pulmonary rehabilitation on study design. No consensus statements, guidelines, or pharmaceutical studies in COPD were found that addressed pulmonary rehabilitation and study design. Pre-operative pulmonary rehabilitation is almost universal with lung transplantation and lung volume reduction surgery (LVRS). The National Emphysema Treatment Trial (NETT) included a mandatory pre-operative pulmonary rehabilitation program. The NETT reported that the mandatory pre-operative program reduced their study population by 32%. The NETT pre-operative program is required for Medicare reimbursement for LVRS, restricting the surgery to the subgroup of patients completing the program. Pulmonary rehabilitation can affect selection of the study population, study enrollment, outcome measures, and influence whether the results can be generalized to other patients. Clinical trials with medications, devices, or surgery for severe COPD should consider study designs that anticipate the significant effects of pulmonary rehabilitation.

Introduction: CRT-D improves cardiac function and quality of life, and decreases HF hospitalization and death for many patients. However, impact on therapy delivered for ventricular arrhythmias is less clear. Methods: Device-determined VT and VF episodes with therapy (n = 1835) from CRT-D patients in two trials (CRT RENEWAL & REFLEX; n = 1698) were analyzed in a post hoc fashion. Patients were divided into lifetime biventricular (BiV) pacing percentage quartiles. Zero-inflated Poisson regression models were used to evaluate impact of pacing on VT/VF incidence and frequency, adjusting for baseline covariates including lifetime ATR mode switch percentage. Results: Patient characteristics: 69 ± 11 years, 73% male, 68% CAD. Dividing patients in quartiles resulted in the following pacing breakdown: 0–92% (n = 445), 93–97% (n = 445), 98–99% (n = 482), and 100% (n = 326). There were no differences in gender, NYHA, or history of diabetes, MI, CAD or hypertension among the groups. Patients paced 0–92% and 93–97% had similar VT/VF therapy incidence (24.72% vs. 24.27%) and frequency (17.05% vs. 16.00%). Patients paced 98–99% had lower VT/VF therapy incidence (15.15%) than patients paced ≤ 97% (p < 0.001) but similar frequency after adjusting for incidence. Patients paced 100% had similar VT/VF therapy incidence (13.80%) and frequency (6.45%) to patients paced 98–99%. The figure shows the time to first therapy for VT/VF. Conclusions: For CRT-D patients in this analysis, incidence and frequency of therapy delivered for VT/VF is significantly decreased when lifetime BiV pacing percentage is above 97%.

Background: Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD. Methods: This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 µg once daily + placebo twice daily (TP group); (2) T 18 µg once daily + S 25 µg/puff, 2 puffs twice daily (TS group); and (3) T 18 µg once daily + FS 250/25 µg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed. Results: The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243 180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP. Conclusions: TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

The goal of this analysis was to determine the appropriate biventricular pacing target in patients with heart failure (HF).Cardiac resynchronization therapy (CRT) decreases the risk of death and HF hospitalization. However, the appropriate amount of biventricular pacing is ill-defined.Mortality and HF hospitalization data from patients undergoing CRT in 2 trials (CRT RENEWAL [Cardiac Resynchronization Therapy Registry Evaluating Patient Response with RENEWAL Family Devices] and REFLEx [ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance Study]; n = 1,812) were analyzed in a post-hoc fashion. Subjects were grouped based on percent biventricular pacing quartiles with the use of Kaplan-Meier survival analysis.Subjects were age 72 +/- 11 years; 72% were men and 67% had coronary artery disease. Subjects paced 93% to 100% (quartiles 2 to 4) had a 44% reduction in hazard of an event compared with subjects paced 0% to 92% (quartile 1; hazard ratio [HR]: 0.56, p0.00001). Subjects paced 98% to 99% (quartile 3) had similar outcomes as subjects paced 93% to 97% (quartile 2; HR: 0.97, p = 0.82). Subjects paced 100% (quartile 4) had similar outcomes as subjects paced 98% to 99% (HR: 0.78, p = 0.17). There was a significant interaction between a history of atrial arrhythmia and percent pacing. Subjects with a history of atrial arrhythmia were more likely to be pacedor =92% (p0.001).For CRT patients in this retrospective analysis, the greatest magnitude of benefit was observed with92% biventricular pacing.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. Objectives :I n apost hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 mg plus fluticasone propionate 500 mg, either component alone or placebo, on the rate of post-bronchodilator FEV1 decline in patients with moderate or severe COPD. Methods: A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. Measurements and Main Results: Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV1 was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV1 decline by 16 ml/ year compared with placebo (95% confidence interval [CI], 7–25;P , 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5–22; P 5 0.003). Rates of decline were similar among the active treatment arms. FEV1 declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV1 decline. Conclusions: Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV1 in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www. clinicaltrials.gov (NCT00268216).

Summary The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

Limitation of activity and impaired quality of life are important outcomes of COPD. There is an association between measures of self-reported physical activity and overall health status, and they appear to change together spontaneously over time and in response to treatment. The relationship between symptoms and activity limitation is complex, because activity can be limited entirely by symptoms, or impaired by symptoms so that it requires greater effort or causes discomfort. The patient has the choice of whether to restrict their activity or maintain it at the cost of having symptoms. In theory, this may make it difficult to produce reliable standardized assessments of activity limitation because it may not be clear exactly what is being measured. Analysis of items in the St George's Respiratory Questionnaire (SGRQ) concerned with activities that are either not possible due to breathlessness, or are a cause of breathlessness, show that they contribute to a unidimensional model of activity limitation in daily life and a unidimensional model of overall COPD-related health status. The items lie distributed evenly along the same severity continuum, from very mild to very severe, along with other items concerned with symptoms and the psycho-social impact of the disease. This suggests that self-reported limitation of activity may form a reliable construct, and may also provide a good surrogate marker of health status in COPD.

OBJECTIVE: To produce an improved, COPD-specific version of the St. George respiratory questionnaire (SGRQ-C). METHODS: Five different steps were required: (1) Rasch analysis of the responses of 893 COPD patients to the St. George respiratory questionnaire (SGRQ) identified weaker items to be removed; (2) a scoring algorithm was produced using data from 1,036 patients; (3) validity of the new and original SGRQ was tested using data from the original validation study; (4) responsiveness was tested using data from a previously published trial; and (5) a reworded version (SGRQ-C) that no longer specified the recall period was administered to 63 pulmonary rehabilitation participants. RESULTS: Items were removed due to lack of response (n = 1), misfit to the Rasch model (n = 8), and disordered responses (n = 1). Another six items had disordered responses; this was corrected. Scores from the two versions differed slightly, so the scoring algorithm was revised to produce scores equivalent to the original. Intraclass correlation coefficient (ICCC) for the scores for original and new versions was 0.99. Correlations with other measures of disease were very similar to those obtained with the original. New and original scores for treatment effects were similar: difference, 0.1 +/- 2.7 U (+/- SD). Baseline SGRQ and SGRQ-C scores were similar (ICCC, 0.95; 95% confidence interval, 0.92 to 0.97; mean difference, 0.9 +/- 5.8 U). Change scores were similar (difference, 1.0 +/- 7.3 U). CONCLUSIONS: The SGRQ-C contains the best of the original items, no longer specifies a recall period, and produces scores equivalent to the original.

Chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation. Tiotropium has been shown to reduce exacerbation frequency, but its effect on airway inflammation is unknown. The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency. Patients (n = 142) were randomised to receive tiotropium or placebo in addition to their usual medication for 1 yr. Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary. There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups, but sputum IL-8 level was increased in the tiotropium arm. There was no difference between start and end of study in serum IL-6 or C-reactive protein level. Tiotropium was associated with a 52% reduction in exacerbation frequency (1.17 versus 2.46 exacerbations·yr −1 ). Of patients on tiotropium, 43% experienced at least one exacerbation, compared with 64% on placebo. The total number of exacerbation days was reduced compared with placebo (17.3 versus 34.5 days). Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease, but this effect does not appear to be due to a reduction in airway or systemic inflammation.

Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown.We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed.Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P0.001 for comparisons between these treatments and placebo).The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).

Introduction Prevalence of coronary artery disease (CAD) in chronic obstructive pulmonary disease (COPD) is 16–53% (Smith and Wrobel. Int J Chron Obstruct Pulmon Dis. 2014;9:871–888), with ~25% COPD patients dying from cardiovascular disease. Diverse studies demonstrate ~2-fold increased risk of CAD in COPD after adjustment for known cardiovascular risk factors. By contrast, in asthma increased CAD risk appears to be restricted to smokers (Colak et al . Am J Respir Crit Care Med. 2015 Apr 27). Our objectives were to investigate the association between airflow limitation and severity of coronary artery atheroma in patients undergoing coronary angiography and to determine the effect of smoking on this relationship. Methods Patients attending for elective coronary angiography March–July 2015 underwent clinical assessment and spirometry prior to the procedure. Coronary artery disease burden was quantified from angiograms using the Gensini score (Needland et al. Am Heart J 164:547–552). A single rater (Professor of Interventional Cardiology), blinded to clinical diagnosis, determined number and severity of lesions. Blinded repeats were performed and ratings compared to clinical reports to ensure reliability. A nonlinear score was assigned to each lesion based on the severity of stenosis and a multiplier applied depending on lesion location in the coronary tree. Lesion scores were summed to derive total score, which was log-transformed for analysis. Results 233 people (age 66 ± 10 years (mean±SD), 69% male) had FEV 1 82 ± 21% predicted, FVC 89 ± 21% predicted, FEV 1 :FVC ratio 73 ± 10%, Gensini median score 14 (IQR 6–33). On univariate analysis (Table 1), FEV 1 and FEV 1 :FVC were significantly and inversely correlated with Gensini score, but Gensini was not significantly associated with smoking status or pack year load. On multivariate analysis, neither airflow limitation nor smoking were significant determinants of Gensini. Conclusions People with more severe airflow limitation have more coronary atheroma, but smoking does not appear to be a direct determinant of this relationship. Shared comorbid disease (e.g. dyslipidaemia) between COPD and CAD may be more important than smoking in determining the association, supporting the hypothesis that COPD and CAD are part of a multi-morbid disease complex. References 1 Smith MC, Wrobel JP. Epidemiology and clinical impact of major comorbidities in patients with COPD. Int J Chron Obstruct Pulmon Dis . 2014; 9 :871–88 2 Colak Y, Afzal S, Nordestgaard BG, et al. Characteristics and prognosis of never-smokers and smokers with asthma in the copenhagen general population study. a prospective cohort study. Am J Respir Crit Care Med . 2015; 192 :172–81 3 Neeland IJ, Patel RS, Eshtehardi P, et al. Coronary angiographic scoring systems: an evaluation of their equivalence and validity. Am Heart J 2012; 164 :547–552.e1

Background COPD is a progressive disease leading to adverse outcomes such as exacerbations and death. Numerous predictors of these outcomes have been identified, based on observations at single time points, but little is known about disease trajectory as a predictor of long-term outcome. We hypothesised that the occurrence of a composite measure of clinically important deterioration (CID) made up of moderate/severe exacerbations, worsening of FEV 1 or St George’s Respiratory Questionnaire (SGRQ) total score measured over 6 months may predict future long-term adverse outcomes. Method A post hoc analysis of the TORCH data, in all four treatment arms, was performed in 5292 (86.5%) of the 6112 COPD patients in the study at 6-months (day 182). CID was defined as: decrease of ≥100 mL in post-bronchodilator FEV 1 , or increase of ≥4 units in the SGRQ, or a moderate/severe exacerbation. Using day 182 status, we tested the association between the occurrence of any CID type at or before 6 months and outcomes over the next 30 months including: sustained deterioration in FEV 1 and SGRQ scores, moderate/severe exacerbations and mortality. A Cox’s proportional hazards model used day 182 deterioration status with covariates collected at day 182, smoking status and geographical region to estimate future risk. Results By day 182, 2870 [54%] patients had experienced a CID (CID+) and 2422 [46%] had not (CID-). 30 months later, the CID- group had a LS mean post-bronchodilator FEV 1 117 ml (95% CL 100,134; p Conclusion Patients experiencing a clinically important deterioration early in the TORCH trial appeared to be set on a clinical path of sustained deterioration in both health status and FEV 1 with an increased medium/long-term future risk of exacerbations and all-cause death.

Background Widespread white matter damage and cognitive impairment have been demonstrated in COPD. However, it remains unclear if regional atrophy is present. We used a simple clinical visual rating scale to measure regional atrophy in a well-characterised population with COPD and compared age-matched controls. We explored correlations with demographics, disease factors and cognitive measures. Objectives a) To determine if there are significant differences in regional atrophy between COPD patients and age-matched control subjects. b) To investigate whether patient characteristics or measures of disease severity account for group differences in atrophy severity. c) To seek correlations with regional atrophy. Methods A validated visual analogue MRI grading technique was used to assess the degree of atrophy in multiple brain regions in stable non-hypoxaemic COPD patients (n = 25) and age-matched control subjects (n = 25). This study is a further analysis of a previous case-control multi modal cranial MRI study. 1 Main results COPD patients had significantly greater frontal atrophy than control subjects (p = 0.01), this was independent of smoking history, comorbidities and hospital anxiety and depression scores. Cognitive function was significantly worse in the COPD group for executive function, working memory, verbal memory and processing speed. Group differences in atrophy did not seem to account for differences in cognitive function. We were unable to identify meaningful correlations between regional atrophy and disease severity or cognitive function. Conclusions There is significant frontal brain atrophy in stable non-hypoxaemic COPD patients. This regional atrophy does not appear to be related to disease severity or cognitive function. Further work is needed to identify causative mechanisms behind this structural change. Reference 1 Dodd JW, Chung AW, van den Broek MD, Barrick TR, Charlton RA, Jones PW. Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. Am J Respir Crit Care Med . 2012; 186 :240–245

Introduction Coronary artery disease (CAD) affects 16–53% people with chronic obstructive pulmonary disease (COPD) and is the cause of death in ~25% (Smith and Wrobel. Int J COPD. 2014;9:871–888). People with COPD have both high prevalence of cardiovascular risk factors and increased systemic inflammation and oxidative stress that can drive atherosclerosis. We therefore tested the hypothesis that patients with COPD have more extensive coronary artery disease compared to those without. Methods All patients attending for elective coronary angiography March–July 2015 were invited to take part in a cross-sectional, observational study. Participants who gave consent underwent clinical assessment and spirometry prior to the procedure. COPD was defined as FEV 1 /FVC 10 pack-year smoking history. CAD burden was quantified from the angiogram using the Gensini score (Neeland et al . Am Heart J 2012;164:547–552). A single rater (Professor of Interventional Cardiology), blinded to clinical diagnosis, determined number and severity of lesions. Blinded repeats were performed and ratings compared to clinical reports to ensure reliability. A nonlinear score was assigned to each lesion based on severity of stenosis and a multiplier applied depending on lesion location in the coronary tree. Lesion scores were summed to derive Gensini score which was log-transformed for analysis. Results 249 of 294 (85%) people approached took part, 46 (19%) had COPD. The Table 1 compares demographic, respiratory disease-related and cardiovascular risk factors between people with and without COPD. Gensini score was higher in COPD patients (22.5 (8.5–46.0)) than in those without (12.5 (6.0–26.8), p = 0.04), indicating greater burden of coronary atheroma. COPD patients had more circumflex lesions and tended to have more lesions in the right coronary artery and in total than those without. Conclusions People with COPD have more severe coronary artery disease than those without. This analysis cannot determine whether this was due to the presence of COPD or the fact that patients with CAD and COPD had much greater cigarette smoke exposure than CAD patients without COPD.

Source Citation Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;9:CD001288. 25178099

Source Citation Walters JA, Tan DJ, White CJ, Wood-Baker R. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 201...

Three long-acting muscarinic antagonists (LAMAs) are now available in Europe, providing clinicians and patients with a choice of interventions, which is important in COPD, which is clinically a heterogeneous disease. The first LAMA, tiotropium, has been widely used over the last decade as a once-daily maintenance therapy in stable COPD to improve patients' health-related quality of life and to reduce the risk of exacerbations. Administered via the HandiHaler(®) device, it is safe and well tolerated. Another new once-daily LAMA, glycopyrronium, has also been shown to improve health status and reduce exacerbations, and is well tolerated. The subject of this review is a third LAMA, aclidinium bromide, which was approved as a twice-daily maintenance bronchodilator treatment. In the pivotal Phase III clinical trials, patients receiving aclidinium achieved significantly greater improvements in lung function, reductions in breathlessness, and improvements in health status compared with placebo, for up to 24 weeks. In continuation studies, these improvements were sustained for up to 52 weeks. Pooled data showed exacerbation frequency was significantly reduced with aclidinium versus placebo. Preclinical and pharmacological studies demonstrating low systemic bioavailability and a low propensity to induce cardiac arrhythmias were translated into a favorable tolerability profile in the clinical trial program - the adverse event profile of aclidinium was similar to placebo, with a low incidence of anticholinergic and cardiac adverse events. While additional studies are needed to evaluate its full clinical potential, aclidinium is an important part of this recent expansion of LAMA therapeutic options, providing clinicians and patients with an effective and well-tolerated COPD treatment.

The clinical presentation of chronic obstructive pulmonary disease (COPD) is highly variable, reflecting the interaction of a complex range of pathological changes including both pulmonary and systemic effects. The consequences of COPD experienced by the patient (i.e. its outcomes) include: symptoms, weight loss, exercise intolerance, exacerbations, health-related quality of life, health resource use and death. No single measure can reflect the variety of pathological effects or adequately describe the nature or severity of COPD. Currently, there are few validated markers for assessing COPD and evaluating the effectiveness of treatment. The forced expiratory volume in one second has been used as a global marker of COPD, but it does not fully reflect the burden of COPD on patients. New markers are needed to better characterise the full clinical spectrum of the disease and to guide the development and assessment of new and more effective therapies. This article considers the distinction between outcomes and markers, the various ways in which markers are used and the need for new markers in the management of chronic obstructive pulmonary disease. The process of marker selection and validation is reviewed and potential new biological, physiological and symptomatic markers for chronic obstructive pulmonary disease are assessed.

The MOSAIC study compared moxifloxacin with three standard antibiotic regimens in patients with Anthonisen type 1 acute exacerbations of chronic bronchitis (AECB). Further exploratory analyses were performed to identify prognostic factors of short and long term clinical outcomes and their value for clinical research.Outpatients agedor =45 years were screened between AECB episodes, randomised to treatment upon presenting with an AECB, assessed 7-10 days after study treatment, and followed monthly until a new AECB or for up to 9 months. Logistic regression assessed the predictive factors for clinical cure (return to pre-AECB status) and clinical success (cure or improvement), and a stepwise Cox regression model time to a composite event (failure of study treatment, new AECB, or further antibiotic treatment for AECB).In multivariate analyses, clinical cure was positively influenced by treatment with moxifloxacin (odds ratio (OR) 1.49; 95% CI 1.08 to 2.04) while cardiopulmonary disease (OR 0.59; 95% CI 0.38 to 0.90), forced expiratory volume in 1 second (FEV1)50% predicted (OR 0.48; 95% CI 0.35 to 0.67), andor =4 AECBs in the previous year (OR 0.68; 95% CI 0.48 to 0.97) predicted a poorer outcome. For clinical success, treatment with moxifloxacin had a positive influence (OR 1.57; 95% CI 1.03 to 2.41) while cardiopulmonary disease (OR 0.41; 95% CI 0.25 to 0.68) and use of acute bronchodilators (OR 0.50; 95% CI 0.30 to 0.84) predicted a poorer outcome. The occurrence of the composite event was influenced by antibiotic treatment (hazard ratio (HR) 0.82; 95% CI 0.68 to 0.98), ageor =65 years (HR 1.22; 95% CI 1.01 to 1.47), FEV150% predicted (HR 1.27; 95% CI 1.05 to 1.53),or =4 AECBs in previous year (HR 1.63; 95% CI 1.34 to 1.99), and acute bronchodilator use (HR 1.48; 95% CI 1.17 to 1.87). For the composite event the beneficial effect of moxifloxacin was primarily seen in patients agedor =65 years.Despite selection of a homogeneous population of patients with chronic bronchitis, between group differences relating to antibiotic treatment could still be confounded by factors related to medical history, severity of disease, and use of concomitant medications. The design of future clinical trials should take these factors into account.

Breathing supplemental oxygen reduces breathlessness during exercise in patients with chronic obstructive pulmonary disease (COPD). Replacing nitrogen with helium reduces expiratory flow resistance and may improve lung emptying. Combining these treatments should be independently effective.Study the effect of changing oxygen or helium concentration in inspired gas during exercise in patients with stable COPD.In 82 patients (mean age, 69.7 yr; mean FEV(1), 42.6% predicted), we measured endurance shuttle walking distance, resting and exercise oxygen saturation, and end-exercise dyspnea (Borg scale) while patients breathed Heliox28 (72% He/28% O(2)), Heliox21 (79% He/21% O(2)), Oxygen28 (72% N(2)/28% O(2)), or medical air (79% N(2)/21% O(2)). Gases were administered using a randomized, blinded, crossover design via a face mask and an inspiratory demand valve.Breathing Heliox28 increased walking distance (mean+/-SD, 147+/-150 m) and reduced Borg score (-1.28+/-1.30) more than any other gas mixture. Heliox21 significantly increased walking distance (99+/-101 m) and reduced dyspnea (Borg score, -0.76+/-0.77) compared with medical air. These changes were similar to those breathing Oxygen28. The effects of helium and oxygen in Heliox28 were independent. The increase in walking distance while breathing Heliox28 was inversely related to baseline FEV(1) breathing air.Reducing inspired gas density can improve exercise performance in COPD as much as increasing inspired oxygen. These effects can be combined as Heliox28 and are most evident in patients with more severe airflow obstruction.

SummaryInhaled corticosteroids form the cornerstone of treatment for most patients with asthma. A range of compounds are available with a wide range of prescribable doses. In this overview, we summarize the findings from a number of Cochrane systematic reviews that have examined the relative benefits of different doses of beclometasone dipropionate, budesonide and fluticasone propionate when used to treat children and adults. The key findings are that all inhaled corticosteroids demonstrate a dose–response relationship for efficacy measures, but most of the benefit in mild-to-moderate severity disease is gained in the low-to-moderate dose range of each drug. In this group, high doses of fluticasone lead to small improvements in measures of control at the expense of a steep increase in the incidence of oral side-effects. In patients with severe disease who are dependent on oral steroids, there may be appreciable benefit in reducing oral steroids from very high compared with high doses of fluticasone.

Rasch analysis is now used widely to assess the measurement properties of health status questionnaires. This study tested the stability of the AQ20 - a dichotomous-response measure of health status in asthma, using parameters estimated by a Rasch model. One hundred forty-four asthma patients completed the AQ20 on five occasions over 3 months. At visit 1, two items showed significant misfit and were deleted. At each visit, the overall mean item-person and item-trait interaction statistics from the remaining 18 items (AQ18) were very similar. The repeatability of the item calibrations was excellent (intraclass correlation coefficient 0.95), despite the patients' health having changed (repeated-measures ANOVA: FEV(1) and AQ18 score p0.0001). Tests of differential item functioning (DIF) over time showed that one item increased in severity. This item refers to ability to garden, and changes in response patterns could be related to seasonal changes over the study period. We conclude that this study has highlighted the usefulness of multiple repeat assessments which allow items to be tested for DIF over time. This is important as inclusion of 'time-dependent' items in a questionnaire may reduce the reliability of the instrument.

Background Inhaled fluticasone propionate (FP) is a relatively new inhaled corticosteroid for the treatment of asthma. Objectives 1. To assess efficacy and safety outcomes in studies that compared FP to placebo for treatment of chronic asthma.2. To explore the presence of a dose-response effect. Search strategy We searched the Cochrane Airways Group Trial Register (January 2004), reference lists of articles, contacted trialists and searched abstracts of major respiratory society meetings (1997-2004). Selection criteria Randomised trials in children and adults comparing FP to placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. Data collection and analysis Two reviewers extracted data. Quantitative analyses where undertaken using RevMan Analyses 4.2.7. Main results Sixty eight studies met the inclusion criteria (11, 104 participants). Methodological quality was high. In non-oral steroid treated asthmatics with mild and moderate disease FP resulted in improvements from baseline compared with placebo across all dose ranges (100 to 1000 mcg/d) in FEV1 (between 0.13 to 0.45 litres); morning PEF (between 27 and 47 L/min); symptom scores (based on a standardised scale, between 0.5 and 0.85); reduction in rescue beta-2 agonist use (between 1.2 and 2.2 puffs/d). High dose FP reduced the number of patients dependent on prednisolone: FP 1000-1500 mcg/d Peto Odds Ratio 0.07 (95% CI 0.05 to 0.10). FP at all doses led to a greater likelihood of sore throat, hoarseness and oral Candidiasis, but 21 patients would need to be treated for one extra to develop Candidiasis (FP 500 mcg/day), whilst only three or four patients need to be treated to avoid one extra patient being withdrawn due to lack of efficacy at all doses of FP. Authors' conclusions Doses of FP in the range 100-1000 mcg/d are effective. In most patients with mild-moderate asthma improvements with low dose FP are only a little less than those associated with high doses when compared with placebo. High dose FP appears to have worthwhile oral-corticosteroid reducing properties. FP use is accompanied by an increased likelihood of oropharyngeal side effects.

Background Beclomethasone dipropionate (BDP) and budesonide (BUD) are commonly prescribed inhaled corticosteroids for the treatment of asthma. Fluticasone propionate (FP) is newer agent with greater potency in in-vitro assays. Objectives To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma. Search strategy We searched the Cochrane Airways Group trial register (January 2004) and reference lists of articles. We contacted trialists and pharmaceutical companies for additional studies and searched abstracts of major respiratory society meetings (1997 to 2003). Selection criteria Randomised trials in children and adults comparing Fluticasone to either Beclomethasone or Budesonide in the treatment of chronic asthma. Data collection and analysis Two reviewers independently assessed articles for inclusion and methodological quality. One reviewer extracted data. Quantitative analyses were undertaken using RevMan analyses 1.0.1. Main results Fifty six studies (12, 119 participants) met the inclusion criteria. Methodological quality was variable. Dose ratio 1:2: FP produced a significantly greater FEV1 (0.14 litres, 95% Confidence Interval (CI) 0.06 to 0.22), morning PEF (11.10 L/min, 95%CI 3.12 to 19.09 L/min) and evening PEF (9.31 L/min, 95%CI 5.12 to 13.5 L/min). This applied to all drug doses, age groups, and delivery devices. No difference between FP and BDP/BUD were seen for trial withdrawals. Symptoms and rescue medication use were widely reported but few trials provided sufficient data for analysis. When given at half the dose of BDP/BUD, FP led to a greater likelihood of pharyngitis. There was no difference in the likelihood of oral candidiasis. Plasma cortisol and 24 hour urinary cortisol was measured frequently but data presentation was limited. Dose ratio 1:1: FP produced a statistically significant difference in am PEF (9.58 L/min (95% CI 5.20 to 13.97)), pm PEF (7.41 L/min (95% CI 2.61 to 12.22)), and FEV1 (0.09 L (0.02 to 0.17)). The effects on exacerbations were mixed. There was an increase in the incidence of hoarseness, but no significant difference in pharyngitis, candidiasis, or cough. Authors' conclusions Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing hoarseness when given at the same daily dose. Future studies should attempt to establish the relative efficacy of inhaled steroids delivered with CFC-free propellants.

Summary Study objectives This study was aimed at assessing health-related quality of life (HRQL) in patients with chronic respiratory failure (CRF) and long-term survival following prolonged intensive care mechanical ventilation. Design Observational cohort study. Setting Patients with CRF who had been transferred to our specialized weaning centre due to prolonged mechanical ventilation (>14 days) and weaning failure. Patients and participants Out of 87 long-term survivors (>6 months), 73 patients (mean age: 60.3±13.6 years, chronic obstructive pulmonary disease (COPD, 43%), thoraco-restrictive (21%) or neuromuscular disorders (15%), various chronic diseases (22%)) returned the MOS 36-Item Short-Form Health Status Survey (SF-36) and the St. George's respiratory questionnaire (SGRQ). Measurements and results The total ventilation time was 38.7±45.9 days. The time between discharge from ICU and HRQL assessment was 31.0±22.2 months. Physical health was markedly reduced compared to general population norm, but mental health was mildly impaired. HRQL was comparable to patients with stable CRF receiving non-invasive ventilation who did not need prolonged invasive MV. In addition, general HRQL was better in patients with restrictive respiratory disease compared to patients with neuromuscular diseases ( P 0.0 5 ). Physiological parameters such as blood gases or lung function parameters were not correlated to any HRQL measurements. Conclusions In patients with CRF surviving prolonged ventilation on ICU, the presence of CRF itself is the major determinant of HRQL. Here, the underlying cause of CRF is the major factor which determines the degree of HRQL impairment with patients suffering from restrictive ventilatory disorders reporting the best HRQL when compared to patients with COPD or neuromuscular diseases. Despite severe physical handicaps due to CRF mental health is only mildly compromised.

Background Inhaled beclomethasone dipropionate (BDP) has been, together with inhaled budesonide, the mainstay of anti-inflammatory therapy for asthma for many years. A range of new prophylactic therapies for asthma is becoming available and BDP has been reformulated using a hydrofluoroalkane-134a (HFA) propellant which is free from chlorofluorocarbon (CFC). Objectives The objectives of this review were to: (1) Compare the efficacy of BDP with placebo with both CFC and HFA propellants in the treatment of chronic asthma. (2) Explore the possibility that a dose response relationship exists for BDP in the treatment of chronic asthma. (3) To provide the best estimate of the efficacy of BDP as a benchmark for evaluation of newer asthma therapies. Search methods Electronic searches were current as of January 2003. Selection criteria Randomised parallel group design trials for a minimum period of four weeks, in children and adults comparing CFC-BDP or HFA-BDP with placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. Data collection and analysis One reviewer extracted data; authors were contacted to clarify missing information. We analysed data with RevMan Analyses 1.0.2. Main results 60 studies recruiting 6542 participants met the inclusion criteria. CFC-BDP (57 studies): In non-oral steroid treated patients, at doses of 400mcg/day or less CFC-BDP produced significant improvements from baseline in a number of efficacy measures compared with placebo, including forced expiratory volume in one second (FEV1) 360 ml (95% CI 260 to 460); FEV1 (% predicted) WMD 12.41% (95% CI 8.18 to 16.64) and morning peak expiratory flow rate (am PEF) WMD 35.95 L/min (95% CI 27.85 to 44.04). BDP also led to reductions in rescue beta-2 agonist use compared with placebo of -2.32 puffs/d (95% CI -2.55 to -2.09) and reduced the relative risk (RR) of trial withdrawal due to an asthma exacerbation 0.25 (95% CI 0.12 to 0.51). Subgroup analyses based on treatment duration provide support to the proposal that a treatment period of greater than four weeks is required to realise a fuller treatment effect. In oral steroid treated patients BDP led to significantly greater reductions in oral prednisolone use WMD -4.91 mg/d (95% CI -5.88 to -3.94 mg/d) and greater likelihood of withdrawing oral steroid treatment RR 8.02 (95% CI 3.23 to 19.92). HFA-BDP (3 studies): In non-oral steroid-treated patients, HFA-BDP was significantly more effective than placebo in improving FEV1, morning and evening PEF, FEF25 to 75%, reduced asthma symptoms and beta2-agonists daily consumption. Significant effects for such outcomes were apparent after six weeks of treatment. In oral steroid treated patients, HFA-BDP improved significantly FEV1 and am PEF. The summary estimates for these outcomes suggested a high level of heterogeneity, and divergent aims of the studies may contribute to the variation we observed. Limited data on adverse events were reported. Authors' conclusions This review has quantified the efficacy of CFC-BDP and HFA-BDP in the treatment of chronic asthma and strongly supports its use. Current asthma guidelines recommend titration of dose to individual patient response, but the published data provide little support for dose titration above 400 mcg/d in patients with mild to moderate asthma. There are insufficient data to draw any conclusions concerning dose-response in people with severe asthma.

The severity of chronic obstructive pulmonary disease (COPD) is currently assessed using a single physiological measurement, the forced expiratory volume in 1s (FEV1). COPD, however, has complex effects on other aspects of respiratory function, and in many patients is associated with important systemic changes. We hypothesized that a multidimensional staging system for COPD could provide a more complete assessment of the disease's impact. We considered over 40 potential staging variables, evaluating them according to sensitivity to change, measured reproducibly, independence of the information they provide and prognostic value. We finally selected three: FEV1 (including arterial blood gas measurements when FEV1 falls below 35% predicted), Medical Research Council dyspnea scale and body mass index (BMI). Each measure correlates independently with prognosis in COPD, is supported by a significant body of literature and serves as a surrogate for other potentially important variables. We then used principal components analysis (PCA) to determine the degree of association between 30 of the potential variables measured in 813 stable COPD patients. Using PCA, six groups of measurements defined independent categories of patient information: pulmonary function (including FEV1), symptoms of cough and sputum, dyspnea, health status, bronchodilator reversibility and BMI. These include the three principal variables selected for the staging system. Although the staging boundaries were based on existing literature, they have proven useful in predicting survival. We conclude that a multidimensional grading system is useful to assess the impact of COPD.

Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (1.65 exacerbations x yr(-1)) and frequent (1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.

To compare the effectiveness of oral moxifloxacin with standard antibiotic therapy in acute exacerbation of chronic bronchitis (AECB).Multicenter, multinational, randomized, double-blind study of two parallel treatment arms.Outpatientsor= 45 years old with stable chronic bronchitis, smoking history ofor= 20 pack-years, two or more AECBs in the previous year, and FEV(1)85% of predicted value. Patients were enrolled when in a stable condition, and patients with exacerbations within 12 months of enrollment were randomized.Randomization (stratified on steroid use) between moxifloxacin (400 mg qd for 5 days) and standard therapy (amoxicillin [500 mg tid for 7 days], clarithromycin [500 mg bid for 7 days], or cefuroxime-axetil [250 mg bid for 7 days]).Assessment at enrollment, randomization (Anthonisen type 1 exacerbation), 7 to 10 days after treatment, and monthly until next AECB or up to 9 months. The primary efficacy variable was clinical success (sufficient improvement, no alternative antimicrobial therapy required) 7 to 10 days after therapy. Secondary predefined end points were clinical cure (return to pre-exacerbation status), further antimicrobial use, time to next AECB, and bacteriologic success.Three hundred fifty-four patients received moxifloxacin, and 376 patients received standard therapy. At 7 to 10 days after therapy, clinical success rates were similar in intention-to-treat (ITT) patients (95% confidence interval [CI], - 0.7 to 9.5) and per-protocol (PP) patients (95% CI, - 3.0 to 8.5). Moxifloxacin showed superior clinical cure rates over standard therapy in both ITT patients (95% CI, 1.4 to 14.9) and PP patients (95% CI, 0.3 to 15.6), and higher bacteriologic success in microbiologically valid patients (95% CI, 0.4 to 22.1). Fewer ITT patients required antimicrobials after treatment with moxifloxacin than standard therapy (p0.01). Time to next exacerbation was longer with moxifloxacin; median and mean times to new AECBs in ITT patients who did not require any further antibiotics were 131.0 days and 132.8 days in moxifloxacin, and 103.5 days and 118.0 days in standard therapy, respectively (p = 0.03). The occurrence of failure, new exacerbation, or any further antibiotic was less frequent in moxifloxacin-treated patients for up to 5 months of follow-up (p = 0.03).Moxifloxacin was equivalent to standard therapy for clinical success and showed superiority over standard therapy in clinical cure, bacteriologic eradication, and long-term outcomes.

This study describes the correlations and reproducibility of AQ20, a simple health status questionnaire with 20 questions, which was designed to be useful especially in time sparing situations. A formal language validation process was done, in order to validate the AQ20 before studying its reproducibility. Thirty stable COPD patients answered the final version twice within 15 days. To test the reproducibility of AQ20, the interclass correlation coefficient and Bland-Altman display were used. Results were correlated with FEV1, SpO2, BMI, Mahler BDI, and the Saint George Respiratory Questionnaire (SGRQ). Twenty-five patients (83.3%) were male, with a mean age of 68.6 years. The mean predicted FEV1 (%) was 56.8%. The interclass correlation ratio for the total score was alpha=0.90 for the intraobserver variability and alpha=0.93 for the interobserver variability. The correlation with total SGRQ score was 0.76, with P

A 1-day meeting, attended by invited respiratory and primary-care specialists all of whom had an international profile and a specific interest in Chronic Obstructive Pulmonary Disease (COPD), considered specific research recommendations from the Global Initiative in Obstructive Lung Disease (GOLD) workshop report. Attendees discussed developing a tool to complement spirometry and help primary-care physicians assess treatment success in patients with chronic obstructive pulmonary disease. Discussion focused on the requirement of such a tool, and the limitations of existing tools. Proposals followed for a simple, cost-effective checklist for primary-care. This paper is a consensus report of the discussions from the meeting. Decisions reached on the proposed questionnaire were unanimous.

A series of wound fluid and blood plasma samples from 20 patients with breast cancer were analysed by Potentiometric Stripping Analysis and computer-aided chemical speciation to quantify the concentrations of the trace elements of copper and zinc in the samples and to investigate the individual species of copper and zinc present. Comparisons were made between total concentrations of copper and zinc in wound fluid, pre-operative blood plasma levels and reference values. A wound fluid model constructed using JESS identified the main copper and zinc species present. It was also used to investigate the effects of a change in pH and changes in the total concentrations of certain components on their predominance. The clinical significance of the research is discussed, together with suggestions for a continuation in the research.

Background: The magnitude and time course of effect of an acute exacerbation of chronic bronchitis (AECB) on health status are not known. Data from the GLOBE study, a randomised double blind trial of antibiotic therapy, were used to investigate these effects. Methods: 438 patients with AECB received either gemifloxacin 320 mg once daily for 5 days (214 patients) or clarithromycin 500 mg twice daily for 7 days (224 patients) and were followed up for 26 weeks. St George's Respiratory Questionnaire (SGRQ) scores were obtained at baseline and after 4, 12, and 26 weeks. Results: At presentation during an exacerbation SGRQ scores were worse (Total score difference 5.4 units, 95% CI 1.9 to 8.8, p=0.002) in patients who had a subsequent exacerbation during follow up. The greatest improvement in SGRQ score occurred within the first 4 weeks (mean 8.9 units, 95% CI 6.5 to 11.5, p

Breathing retraining is used increasingly throughout the world by many patients with asthma in addition to their usual medical care. We undertook a systematic review of the literature in order to determine the effectiveness of breathing retraining in the management of asthma. Six randomised-controlled trials were identified that involved breathing retraining in asthma. Due to the variation in reported trial outcomes, limited reporting of study data and small number of included trials it was not possible to draw any firm conclusions as to its effectiveness. However, outcomes that were reported from individual trials do show that breathing retraining may have a role in the treatment and management of asthma. Further large-scale trials using breathing retraining techniques in asthma are required to address this important issue.

Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone.1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol.All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p0.0001), salmeterol (73 mL, 46-101, p0.0001), or fluticasone alone (95 mL, 67-122, p0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration.Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD.