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It is 5 years since the development and first validation of the COPD Assessment Test (CAT) [1], so the review of papers concerning the CAT by Gupta et al. [2] in this issue of the European Respiratory Journal is very timely. The authors identified over 40 studies using a systematic approach to minimise biases, although they acknowledge that they introduced one bias by selecting papers published only in English, French and Spanish, so eight papers were excluded. That may not be too problematic, as the included papers report data on over 25 000 patients from 35 countries across five continents (none from Australasia or Antarctica). One of the strengths of a systematic review is that it can allow comparison of variability in outcomes across different studies. To this end, the data extracted for this review provide an indication of the reliability of the CAT in different settings, and it is generally very good. For example, the internal consistency measured using Cronbach’s alpha was in the range 0.85–0.98 across nine studies. This observation is important because the CAT was developed in English but these studies included Arabic-speaking countries, Brazil, Greece, Japan, South Korea and Turkey. This observation supports the finding by Kwon et al. [3], in a direct comparison, that the relationship …

Since the publication of the new Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposal for the assessment of chronic obstructive lung disease (COPD), four studies have used existing cohorts to explore the characteristics, temporal variability and/or relationship with outcomes of the four resulting patient categories (A, B, C and D). Here, we compare their results and address a number of frequently asked questions (FAQs) on the topic. The most salient findings were that: 1) the prevalence of these four groups depends on the specific population studied, C being the least prevalent; 2) comorbidities are particularly prevalent in the two “high-symptom” groups (B and D); 3) patients classifiedZ as A or D tend to remain in the same group over time, whereas those classified as B or C change substantially during follow-up; 4) mortality at 3 years was lowest in A and worst in D but surprisingly similar (and intermediate) in B and C; and 5) the incidence of exacerbations during follow-up increases progressively from A to D but that of hospitalisations behave similarly to mortality. These results identify several strengths and shortcomings of the new GOLD assessment proposal, particularly that group B is associated with more morbidity and high mortality.

The 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document recommends assessment of chronic obstructive pulmonary disease (COPD) using symptoms and future exacerbation risk, employing two score cut-points: COPD Assessment Test (CAT) score ≥ 10 or modified Medical Research Council dyspnoea scale (mMRC) grade ≥ 2. To explore the equivalence of these two symptom cut-points, the relationship between the CAT and the mMRC and St George's Respiratory Questionnaire (SGRQ), the Short-form Health Survey and the Functional Assessment of Chronic Illness Therapy Fatigue scores were retrospectively analysed using a primary care dataset. Data from 1817 patients (mean ± SD forced expiratory volume in 1 s 1.6 ± 0.6 L) showed a significant association between mMRC grades and all health status scores (ANOVA p

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.

Combination inhalers containing corticosteroids and long-acting β-agonists are used to reduce exacerbation rates in patients with severe chronic obstructive pulmonary disease (COPD). The FORWARD (Foster 48-week Trial to Reduce Exacerbations in COPD) clinical trial in severe COPD patients is a comparison of extrafine beclomethasone dipropionate and formoterol in a combination inhaler with extrafine formoterol; the co-primary end-points are exacerbation rates over 48 weeks and improvement in forced expiratory volume in 1 s over 12 weeks. The traditional physician diagnosis of exacerbations is a co-primary outcome, and the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) means of collecting patient-reported outcome data are also being used to enhance the detection of exacerbation events. EXACT data are being collected using a novel application of a digital platform technology. FORWARD is therefore expected to provide information on the ability of EXACT to detect and measure exacerbations in a large clinical trial setting. The study design of FORWARD is described in this article.

We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1))

In order to characterise the overall clinical picture of chronic obstructive pulmonary disease (COPD) a better understanding of all relevant comorbidities is required. It is increasingly recognised that COPD is a multi-component disease, but little attention has been paid to its effects on cognitive function. Cognitive dysfunction is associated with increased mortality and disability; however, it remains poorly understood in COPD. This review examines mechanisms of injury and dysfunction to the brain and considers the methods used to evaluate cognition, and assembles evidence concerning the nature and level of cognitive impairment in COPD. Our main findings are: 1) there may be a pattern of cognitive dysfunction specific to COPD; 2) cognitive function is only mildly impaired in patients without hypoxaemia; 3) the incidence of cognitive dysfunction is higher in hypoxaemia; 4) hypoxaemia, hypercapnia, smoking and comorbidities (such as vascular disease) are unlikely to account for all of the cognitive dysfunction seen in COPD; 5) there is weak or no association between cognitive function and mood, fatigue or health status; 6) cognitive dysfunction may be associated with increased mortality and disability; and 7) there is limited evidence for a significant effect of treatment on cognitive function.

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400–123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200–241,700) USD compared to 24,200 (15,200–56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

To the Editors: In his recent editorial, Suissa 1 has again expressed criticism of the TORCH (Toward a Revolution in Chronic Obstructive Pulmonary Disease (COPD) Health) trial 2. The focus this time is the analysis of rate of decline in lung function 3, and in particular he questions whether the reduction in rate of decline in forced expiratory volume in one second (FEV1) observed with the active treatments (salmeterol, fluticasone or the combination of both treatments) compared with placebo is due to “regression to the mean” caused by missing data. Missing data for lung function and exacerbations are unfortunately inevitable in any long-term trial in COPD. Suissa 1 states that “… measurements were missing so that the pure intent-to-treat analysis was not possible”. Such a “pure intent-to-treat” analysis of lung function or exacerbation data is not possible for any long-term COPD trial, as this would require complete data. In fact, the quantity of missing data for lung function in TORCH is similar to the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) 4 and OPTIMAL 5 trials quoted in the article by Suissa 1. In TORCH, 4,857 (79%) patients provided lung function data at 48 weeks, OPTIMAL had complete 1-yr lung function data for 322 (72%) patients and, …

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.

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.

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.

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p

This study was designed to identify a core set of items that may characterize impaired health in chronic respiratory failure (CRF) since none of the questionnaires commonly used to measure impaired health in patients with CRF were developed for use in such patients. Questionnaire items, identified from several sources, were administered to 92 patients with stable severe chronic hypoxia or hypercapnia, together with physiological measures of disease severity, the Sickness Impact Profile (SIP) and the St George's Respiratory Questionnaire (SGRQ). Of the 152 items identified, only 28 correlated with patients' perceptions of overall health and were also independent of age, sex, disease or type of treatment and did not show floor or ceiling effects. Principal components analysis identified three specific factors: "daily activities", "cognitive function", and "invalidity". The total score for the whole 28-item set correlated with other measures of disease activity, including SGRQ (r = 0.86) and SIP (r = 0.70), but not spirometry. The interquartile range of the 28-item set was wider than that of the SGRQ or the SIP. This study characterized two areas of health impairment in chronic respiratory failure that had not previously been identified: effects of impaired cognitive function on daily life, and a sense of invalidity. The measurements properties of this 28-item set suggest that it may be a more discriminative instrument for patients with chronic respiratory failure than existing questionnaires.

Patients with bronchiectasis have an active local and systemic inflammatory response during infective exacerbations. Systemic markers of inflammation were investigated during a stable phase of their illness, because continued inflammation could affect their general health and be involved in disease progression. The relationship between levels of various systemic markers of inflammation and extent of disease on computed tomographic scan, lung function, sputum bacteriology and health related quality of life (HRQoL) was investigated in 87 noncystic fibrosis bronchiectasis patients. Several markers were elevated and correlated with the extent of disease and poor lung function. The total white cell count, neutrophil count and erythrocyte sedimentation rate correlated with both disease measures. Sputum bacteriology did not correlate with inflammation markers and patients with positive and negative cultures were similar. C-reactive protein and total white cell count correlated with some components of a disease-specific HRQoL questionnaire. In conclusion, patients with bronchiectasis in a stable phase have raised systemic markers of inflammation. Some markers, particularly the neutrophil count, correlate with disease severity. This result is in keeping with the hypothesis that the level of inflammation determines disease progression and health status.

This study was designed to measure improvement in quality of life of patients with asthma, using a standardized disease-specific questionnaire, the St George's Respiratory Questionnaire, in a year long double-blind, placebo-controlled, group comparative study with nedocromil sodium. Two other questionnaires were used: the Sickness Impact Profile (a measure of general health) and the Hospital Anxiety and Depression Scale. Measurements were made at baseline and following 24 and 48 weeks of treatment. Response to therapy was also evaluated using daily diary card and peak flow measurements, clinic assessments and spirometry. Following a 4 week baseline, 719 adult asthmatics were randomized to treatment with 4 mg nedocromil sodium or placebo. Patients currently maintained on inhaled corticosteroids received treatments four times daily, those on bronchodilator alone received treatments twice daily. The Impacts component of the St George's Respiratory Questionnaire was significantly improved in patients receiving nedocromil sodium, as were night-time asthma, asthma severity at clinic, and daytime inhaled bronchodilator use. In patients receiving placebo, most of the traditional variables improved, and all three questionnaires recorded significant improvements in health. Patients and clinicians judged nedocromil sodium more effective than placebo. The improvement in St George's Questionnaire score in the nedocromil sodium treated patients was approximately double the change considered to be clinically significant. The study has shown that improvements in health with prophylactic therapy for asthma may be quantified by the use of a standardized disease-specific questionnaire.