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Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index

The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) is a patient-reported outcome measure to standardize the symptomatic assessment of chronic obstructive pulmonary disease exacerbations, including reported and unreported events. The instrument has been validated in a short-term study of patients with acute exacerbation and stable disease; its performance in longer-term studies has not been assessed.To test the EXACT's performance in three randomized controlled trials and describe the relationship between resource-defined medically treated exacerbations (MTEs) and symptom (EXACT)-defined events.Prespecified secondary analyses of data from phase II randomized controlled trials testing new drugs for the management of chronic obstructive pulmonary disease: one 6-month trial (United States) (n = 235) and two 3-month, multinational trials (AZ 1 [n = 749], AZ 2 [n = 597]). In each case, the experimental drugs were found to be ineffective, permitting assessment of the EXACT's performance in three independent studies of moderate to severe high-risk patients on maintenance therapies.The mean age of subjects was 62 to 64 years; 48 to 76% were male. Mean FEV1 % predicted was 42 to 59%. EXACT scores exhibited internal consistency (Cronbach's α ≥ 0.90), reproducibility (intraclass correlation ≥ 0.70), correlation with St. George's Respiratory Questionnaire (Spearman rho [rs] = 0.62, 0.46, 0.46 in the three trials; P0.001), and Breathlessness Cough and Sputum Scale (AZ 1, rs = 0.83; AZ 2, rs = 0.83; P0.001). EXACT-defined events had a high correspondence with alternative indicators of worsening (94, 88, and 93%). In each trial, unreported events were similar in severity (mean EXACT score, 56, 57, 61 vs. 53, 54 [P0.05], 57 [P0.05], respectively; 100-point scale) and longer (median, 9, 8, 7 vs. 8, 7 [P0.01], 6 days, respectively) than moderate MTEs.Data generated through the EXACT offers insight into the symptomatic nature of MTEs and the frequency, severity, and duration of unreported symptom-defined events. Clinical trials registered with www.clinicaltrials.gov (MPEX: NCT00739648; AZ 1: NCT00949975; AZ 2: NCT01023516).

Brain pathology is a poorly understood systemic manifestation of chronic obstructive pulmonary disease (COPD). Imaging techniques using magnetic resonance (MR) diffusion tensor imaging (DTI) and resting state functional MR imaging (rfMRI) provide measures of white matter microstructure and gray functional activation, respectively.We hypothesized that patients with COPD would have reduced white matter integrity and that functional communication between gray matter resting-state networks would be significantly different to control subjects. In addition, we tested whether observed differences related to disease severity, cerebrovascular comorbidity, and cognitive dysfunction.DTI and rfMRI were acquired in stable nonhypoxemic patients with COPD (n = 25) and compared with age-matched control subjects (n = 25). Demographic, disease severity, stroke risk, and neuropsychologic assessments were made.Patients with COPD (mean age, 68; FEV(1) 53 ± 21% predicted) had widespread reduction in white matter integrity (46% of white matter tracts; P0.01). Six of the seven resting-state networks showed increased functional gray matter activation in COPD (P0.01). Differences in DTI, but not rfMRI, remained significant after controlling for stroke risk and smoking (P0.05). White matter integrity and gray matter activation seemed to account for difference in cognitive performance between patients with COPD and control subjects.In stable nonhypoxemic COPD there is reduced white matter integrity throughout the brain and widespread disturbance in functional activation of gray matter, which may contribute to cognitive dysfunction. White matter microstructural integrity but not gray matter functional activation is independent of smoking and cerebrovascular comorbidity. The mechanisms remain unclear, but may include cerebral small vessel disease caused by COPD.

Exacerbations of chronic obstructive pulmonary disease (COPD) offer a considerable clinical challenge for clinical practice and drug development. The underlying pathobiology of these characteristic events is unclear. We are far behind other disease areas, such as cardiology, where there are effective approaches for diagnosing and managing acute and potentially fatal events. A joint initiative has begun between the pharmaceutical industry, academia, and the Food and Drug Administration to produce a valid diary card measure of exacerbation severity: the EXAcerbations of Chronic pulmonary disease Test-Patient-Reported Outcome (EXACT-PRO). This article describes the background to this initiative, using the consensus definition of a COPD exacerbation as the starting point from which to propose a new method for quantifying the severity of the event. This approach takes into account the relationships between the symptoms that make up an exacerbation and shows that they can be used in a single continuous severity scale. Methods for defining exacerbation onset and cessation are also proposed.

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition (1). The identification of COPD phenotypes may allow stratified treatment approaches that modulate discrete disease mechanisms. Peripheral blood eosinophilia is both a common and repeatable finding in COPD (2). In addition, the presence of a blood/sputum eosinophilia is associated with a significant proportion of COPD exacerbations (3, 4) and a favorable response to systemic steroids (5). However, the role of blood eosinophils in stratifying treatment response to inhaled corticosteroid/long-acting β-agonist combinations is poorly understood. The FORWARD (Foster 48-Week Trial to Reduce Exacerbations in COPD) study was a randomized, double-blind, parallel group trial that compared 48 weeks of treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP/FF), 100/6 μg pressurized metered-dose inhaler, two inhalations twice a day, versus FF 12 μg pressurized metered-dose inhaler, one inhalation twice a day, in patients with severe COPD with a history of exacerbations (clinical trial registered with www.clinicaltrials.gov [NCT 00929851]). The results of the study have been reported (6) and showed a significant reduction in exacerbation rate (28%) and improvement in lung function with BDP/FF compared with FF treatment. Here we evaluate the hypothesis that these treatment differences differ according to the baseline blood eosinophil count by performing a post hoc analysis on the FORWARD study data. Methods The median (quartile 1; quartile 3) baseline blood eosinophil count was 181.6 (110.4; 279.8), and the distribution of counts is shown in Figure E1 in the online supplement. The patients (n = 1,184) were stratified into quartile groups on the basis of the baseline eosinophil count. The clinical characteristics of the study population across the quartiles of baseline blood eosinophils are reported in Table E1. The following endpoints were analyzed: COPD exacerbation rate over the course of 48 weeks, using a negative binomial model for adjusted exacerbation rates, Kaplan-Meier analysis, and Cox proportional hazard model for time to first exacerbation event; change from baseline in predose morning FEV1 at 48 weeks, using a linear mixed model for repeated measurements; and change from baseline in St. George’s Respiratory Questionnaire total score at 48 weeks, using an analysis of covariance model. Further details of the models are provided in the online supplement. Additional analyses using percentage eosinophil count thresholds and considering absolute counts as a continuous variable were also performed. A predictive model (see online supplement for details) for future COPD exacerbation rate was estimated, accounting for a variety of baseline factors that may influence exacerbations (7). The effect of baseline blood eosinophil count on adverse events, and in particular pneumonia, was also evaluated.

Disturbances to health can be divided broadly into limitations of basic activities of daily living (washing, dressing, etc.) that are common to all patients and other limitations that depend on individual circumstances. A distinction should be drawn between health status and health-related quality of life. Health status questionnaires are standardized for "typical patients," and this should be borne in mind when interpreting such scores from studies that give an average result using population-based measurements. Such studies give a good indication to payers of the average effects of a treatment, but provide no indication other than probability of benefit to individuals. This applies even more with health improvements that manifest uniquely in each patient. Two widely used disease-specific questionnaires in chronic obstructive pulmonary disease-the Chronic Respiratory Questionnaire and the St. George's Respiratory Questionnaire-are health status, rather than quality of life, instruments. Health status scores from questionnaires provide measures of the effects of disease, not measures of the disease itself. The relationship between high health status score and increased risk of dying is due to the fact that both reflect underlying disease activity. In therapeutic studies, health status improves because the underlying disease activity has been moderated by therapy. Improved health does not improve mortality or morbidity per se. It is also important to appreciate that the impact of any measured change in health may also be determined by the patient's baseline state.

Chronic obstructive pulmonary disease (COPD) has multiple pathophysiologic effects that are not confined to the lungs. Similarly, treatment for COPD may have a number of different beneficial effects, and although each of these may be small, their cumulative effect may add up to a worthwhile overall outcome. Many of the effects of COPD are only weakly related to FEV(1), and there is good evidence that health status questionnaires are the best overall measures of disease severity. Recently it has been shown, using such instruments, that health status in patients with COPD deteriorates progressively and at a measurable rate. Fluticasone reduces that decline, an effect that may take months to be detectable but continues to develop over 3 years. The effect of fluticasone on health appears to be due to a reduction in exacerbations coupled with its small effect on FEV(1).

This study examined health status decline in patients with chronic obstructive pulmonary disease (COPD). Data are from the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. After an 8-wk run-in, 751 patients (566 male), mean age 64 yr, were randomized to receive fluticasone propionate (FP) 500 microg twice daily (376 patients) or placebo (375 patients). Mean baseline postbronchodilator FEV1 was 50 +/- 15% predicted. Patients completed the St George's Respiratory Questionnaire (SGRQ) and the Short-Form 36 (SF-36) at baseline and every 6 mo for 3 yr. FEV1 and smoking status were assessed at baseline and at 3-mo intervals. A total of 387 (212 FP) patients completed the trial. All SGRQ components (p = 0.03 to 0.004) and Physical Function, Mental Health, Energy/ Vitality, and Physical Role Limitation scales of the SF-36 (p = 0.05 to 0.005) deteriorated faster in the placebo group. FEV1 and SGRQ scores correlated at baseline values (r = -0.25, p < 0.0001), as did change in FEV1 and change in SGRQ (Delta r = -0.24, p < 0.0001). At baseline values smokers had worse SGRQ Total, Symptoms, and Impacts scores than ex-smokers. This difference was maintained throughout the study. Smoking status did not influence the rate of decline in health status. The SGRQ Total scores of FP-treated patients took 59% longer than placebo to deteriorate by a clinically significant amount. We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone.

There is no disease-specific instrument available for health status assessment in bronchiectasis. We examined the stability, validity and responsiveness of a measure designed for asthma and COPD, the St. George's Respiratory Questionnaire (SGRQ), in this condition. One hundred and eleven patients were studied on 2 separate d 6 mo apart. On both days each patient completed the SGRQ and measures of general and disease-specific health, mood, and fatigue. They also performed a shuttle walking test and comprehensive lung function tests. Repeatability was tested over 2 wk in 23 patients. The intraclass correlation (ri) for the SGRQ Total score was 0.97. The SGRQ component scores correlated well with relevant markers of disease activity. Examples include: SGRQ Symptoms score versus MRC Wheeze score, r = 0.634, p < 0.0001; Activity score versus shuttle walking test, r = -0.659, p < 0.0001; and impacts score versus physical fatigue, r = 0.610, p < 0.0001. Changes in the SGRQ Total score from entry to follow-up also correlated with changes in other measures of the patients' health. There were significant differences in the SGRQ total score between patients who improved and those who deteriorated over the 6 mo in respect to wheeze (F = 5.6, p < 0.01) and breathlessness (F = 6.05, p < 0.01). We conclude that the SGRQ reflects impaired health in bronchiectasis patients.

Non-invasive ventilation has been used in chronic respiratory failure due to chronic obstructive pulmonary disease (COPD), but the effect of the addition of nasal positive-pressure ventilation to long-term oxygen therapy (LTOT) has not been determined. We report a randomized crossover study of the effect of the combination of nasal pressure support ventilation (NPSV) and domiciliary LTOT as compared with LTOT alone in stable hypercapnic COPD. Fourteen patients were studied, with values (mean +/- SD) of Pao2 of 45.3 +/- 5.7 mm Hg, PaCO2 of 55.8 +/- 3.6 mm Hg, and FEV1 of 0.86 +/- 0.32 L. A 4 wk run-in period (on usual therapy) was followed by consecutive 3-mo periods of: (1) oxygen therapy alone, and (2) oxygen plus NPSV in randomized order. Assessments were made during run-in and at the end of each study period. There were significant improvements in daytime arterial PaO2 and PaCO2, total sleep time, sleep efficiency, and overnight PaCO2 following 3 mo of oxygen plus NPSV as compared with run-in and oxygen alone. Quality of life with oxygen plus NPSV was significantly better than with oxygen alone. The degree of improvement in daytime PaCO2 was correlated with the improvement in mean overnight PaCO2. Nasal positive-pressure ventilation may be a useful addition to LTOT in stable hypercapnic COPD.

Background The COPD (chronic obstructive pulmonary disease) assessment test (CAT) is a recently introduced, simple to use patient-completed quality of life instrument that contains eight questions covering the impact of symptoms in COPD. It is not known how the CAT score performs in the context of clinical pulmonary rehabilitation (PR) programmes or what the minimum clinically important difference is. Methods The introduction of the CAT score as an outcome measure was prospectively studied by PR programmes across London. It was used alongside other measures including the St George9s Respiratory Questionnaire, the Chronic Respiratory Disease Questionnaire, the Clinical COPD Questionnaire, the Hospital Anxiety and Depression score, the Medical Research Council (MRC) dyspnoea score and a range of different walking tests. Patients completed a 5-point anchor question used to assess overall response to PR from ‘I feel much better’ to ‘I feel much worse’. Results Data were available for 261 patients with COPD participating in seven programmes: mean (SD) age 69.0 (9.0) years, forced expiratory volume in 1 s (FEV 1 ) 51.1 (18.7) % predicted, MRC score 3.2 (1.0). Mean change in CAT score after PR was 2.9 (5.6) points, improving by 3.8 (6.1) points in those scoring ‘much better’ (n=162), and by 1.3(4.5) in those who felt ‘a little better’ (n=88) (p=0.002). Only eight individuals reported no difference after PR and three reported feeling ‘a little worse’, so comparison with these smaller groups was not possible. Conclusion The CAT score is simple to implement as an outcome measure, it improves in response to PR and can distinguish categories of response.

A need was identified for a fixed-format self-complete questionnaire for measuring health in chronic airflow limitation. A 76-item questionnaire was developed, the St. George's Respiratory Questionnaire (SGRQ). Three component scores were calculated: symptoms, activity, and impacts (on daily life), and a total score. Three studies were performed. (1) Repeatability was tested over 2 wk in 40 stable asthmatic patients and 20 patients with stable COPD. The coefficient of variation for the SGRQ total score was 19%. (2) SGRQ scores were compared with spirometry, 6-min walking distance (6-MWD), MRC respiratory symptoms questionnaire, anxiety, depression, and general health measured using the Sickness Impact Profile score. A total of 141 patients were studied, mean age 63 yr (range 31 to 75) and prebronchodilator FEV1, 47% (range 11 to 114%). SGRQ scores correlated with appropriate comparison measures. For example, symptom score versus frequency of wheeze, r2 = 0.32, p less than 0.0001; activity versus 6-MWD, r2 = 0.50, p less than 0.0001; impact versus anxiety, r2 = 0.38, p less than 0.0001. Multivariate analysis demonstrated that SGRQ scores summed a number of areas of disease activity. (3) Changes in SGRQ scores and other measures were studied over 1 yr in 133 patients. Significant correlations were found between changes in SGRQ scores and the comparison measures (minimum r2 greater than 0.05, p less than 0.01). Multivariate analysis showed that change in total SGRQ score summed changes in a number of aspects of disease activity. We conclude that the SGRQ is a valid measure of impaired health in diseases of chronic airflow limitation that is repeatable and sensitive.