Primary Care Severe Asthma Registry and Education Project (PCSAR-EDU): Phase 1 - an e-Delphi for registry definitions and indices of clinician behaviour.

INTRODUCTION: Although most asthma is mild to moderate, severe asthma accounts for disproportionate personal and societal costs. Poor co-ordination of care between primary care and specialist settings is recognised as a barrier to achieving optimal outcomes. The Primary Care Severe Asthma Registry and Education (PCSAR-EDU) project aims to address these gaps through the interdisciplinary development and evaluation of both a 'real-world' severe asthma registry and an educational programme for primary care providers. This manuscript describes phase 1 of PCSAR-EDU which involves establishing interdisciplinary consensus on criteria for the: (1) definition of severe asthma; (2) generation of a severe asthma registry and (3) definition of an electronic-medical record data-based Clinician Behaviour Index (CBI). METHODS AND ANALYSIS: In phase 1, a modified e-Delphi activity will be conducted. Delphi panellists (n≥13) will be invited to complete a 30 min online survey on three separate occasions (i.e., three separate e-Delphi 'rounds') over a 3-month period. Expert opinion will be collected via an open-ended survey ('Open' round 1) and 5-point Likert scale and ranking surveys ('Closed' round 2 and 3). A fourth and final Delphi round will occur via synchronous meeting, whereby panellists approve a finalised ideal 'core criteria list', CBI and corresponding item weighting. ETHICS AND DISSEMINATION: Ethical approval has been obtained for the activities involved in phase 1 from the University of Toronto's Human Research Ethics Programme (approval number 39695). Future ethics approvals will depend on information gathered in the proceeding phase; thus, ethical approval for phase 2 and 3 of this study will be sought sequentially. Findings will be disseminated through conference presentations, peer-reviewed publications and knowledge translation tools.

Importance of distinguishing between asthma and chronic obstructive pulmonary disease in primary care.

OBJECTIVE: To facilitate distinction between asthma and chronic obstructive pulmonary disease (COPD) in day-to-day primary care practice, and provide practical treatment strategies using spirometric cases to outline how to recognize the clinical and spirometric overlap between asthma and COPD. SOURCES OF INFORMATION: The approaches described here were developed using evidence-based guidelines and the expertise of the authors, including research findings by the authors in the areas of asthma, COPD management, and spirometric testing in primary care. MAIN MESSAGE: There are patients with clinical or spirometric features of both asthma and COPD. Both asthma and COPD are associated with some degree of inflammation of the respiratory tract, mediated by the increased expression of inflammatory proteins. However, there are clear differences between asthma and COPD in the pattern of inflammation that occurs in the lungs. Diagnostic confusion between COPD and asthma is most likely to arise in older patients with respiratory complaints, particularly against a background that includes cigarette smoke or workplace exposure. Both asthma and COPD are clinical diagnoses based on patient history, symptoms, physical examination findings, and objective measures of lung function. Postbronchodilator spirometry is always needed to confirm a new diagnosis of COPD and should also be performed prebronchodilator for the diagnosis of asthma. However, in many cases, the interpretation of spirometry results is not straightforward. CONCLUSION: Understanding the nature and extent of the spirometric overlap between asthma and COPD is critical for tailoring a therapeutic strategy that is based on factors that include medical and family history, signs and symptoms, and a clear interpretation of spirometry data. This information will be leveraged differently for individual patients to arrive at the correct clinical diagnosis and to select the most appropriate therapy.

Importance de distinguer l'asthme de la maladie pulmonaire obstructive chronique en première ligne.

OBJECTIF: Faciliter la distinction entre l'asthme et la maladie pulmonaire obstructive chronique (MPOC) en pratique de première ligne de tous les jours, et fournir des stratégies thérapeutiques pratiques à l'aide de cas de spirométrie pour illustrer comment reconnaître le chevauchement clinique et spirométrique entre l'asthme et la MPOC. SOURCES D'INFORMATION: Les approches décrites ici s'appuient sur les lignes directrices factuelles et sur l'expertise des auteurs, y compris des observations de recherches menées par les auteurs dans les domaines de l'asthme, de la prise en charge de la MPOC et des examens de spirométrie en première ligne. MESSAGE PRINCIPAL: Certains patients présentent des caractéristiques cliniques communes à l'asthme et à la MPOC. Ces deux maladies sont associées à un certain degré d'inflammation des voies respiratoires, médiée par l'expression accrue de protéines inflammatoires. Il existe toutefois des différences évidentes entre l'asthme et la MPOC pour ce qui est de l'inflammation présente dans les poumons. La confusion diagnostique entre la MPOC et l'asthme survient le plus souvent chez les patients âgés qui se plaignent de symptômes respiratoires, surtout en contexte de tabagisme ou d'exposition professionnelle. Les diagnostics cliniques d'asthme et de MPOC sont fondés sur les antécédents du patient, les symptômes, l'examen physique et les mesures objectives de la fonction respiratoire. La spirométrie après bronchodilatation est toujours nécessaire pour confirmer un nouveau diagnostic de MPOC et elle doit également être réalisée avant la bronchodilatation pour poser un diagnostic d'asthme. Dans de nombreux cas, toutefois, il n'est pas évident d'interpréter les résultats de la spirométrie. CONCLUSION: Il est essentiel de bien comprendre la nature et la portée du chevauchement spirométrique entre l'asthme et la MPOC afin de concevoir une stratégie thérapeutique qui s'appuie sur des facteurs qui incluent les antécédents médicaux et familiaux, les signes et les symptômes, et l'interprétation claire des données de spirométrie. Cette information sera utilisée différemment auprès de chaque patient pour arriver au bon diagnostic clinique et sélectionner le traitement le plus approprié.

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

INTRODUCTION: During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 µg, and compare it with the dose response of olodaterol monotherapy. METHODS: In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 µg or a fixed-dose combination of tiotropium 5 µg with olodaterol 2 µg, 5 µg, or 10 µg, delivered once daily via the Respimat® for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥ 30 and < 80% of predicted normal. The primary endpoint was trough FEV1 response (change from baseline) after 4 weeks. Secondary endpoints included FEV1 and forced vital capacity (FVC) over 6 h after dosing. RESULTS: Compared with tiotropium 5 µg, mean (standard error) trough FEV1 increased with the addition of olodaterol 2 µg by 0.024 L (0.027), olodaterol 5 µg by 0.033 L (0.027), and olodaterol 10 µg by 0.057 L (0.027). Statistically significant improvements in FEV1 versus tiotropium were seen across all timepoints up to 6 h with all doses of tiotropium/olodaterol. Similar results were observed for FVC. CONCLUSION: There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV1 and FVC. There was a dose-response relationship for olodaterol on top of tiotropium for FEV1 and FVC similar to the dose response previously seen for olodaterol monotherapy. These results, together with the results of a study investigating the dose response of tiotropium on top of olodaterol, helped to inform the dose selection for the phase III studies. FUNDING: Boehringer Ingelheim International GmbH.

Inhaler Devices for Delivery of LABA/LAMA Fixed-Dose Combinations in Patients with COPD.

Inhaled fixed-dose combinations (FDCs) of a long-acting ß-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) have become the cornerstone for the maintenance treatment of symptomatic COPD patients. In this regard, global COPD treatment guidelines have recognized the importance of inhaler devices as integral contributors to the effectiveness of LABA/LAMA FDCs and recommend regular assessment of inhaler device use by the patients in order to improve long-term clinical outcomes. Optimal disease control is also highly dependent upon patient preferences and adherence to inhaler devices. This review objectively examines and compares the major inhaler devices used to deliver different LABA/LAMA FDCs, discusses the inhaler device characteristics that determine drug deposition in the airways, real-life preference for inhaler devices, and handling of inhaler devices that impact the results of the long-term management of COPD. The introduction of new LABA/LAMA FDCs, new inhaler devices, and more clinical studies have created confusion among physicians in choosing the optimal inhaled therapy for COPD patients; in this context, this review attempts to provide an evidence-based framework for informed decision-making with a particular focus on the inhaler devices.Funding. The preparation of this manuscript was funded by Novartis Pharma AG.

New developments in optimizing bronchodilator treatment of COPD: a focus on glycopyrrolate/formoterol combination formulated by co-suspension delivery technology.

COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes.

Comprehensive assessment of the safety of olodaterol 5 µg in the Respimat® device for maintenance treatment of COPD: comparison with the long-acting ß2-agonist formoterol.

This analysis provides a comprehensive clinical assessment of the long-term safety of the licensed dose of olodaterol (5 µg once daily [QD] via Respimat® inhaler) in patients with chronic obstructive pulmonary disease by exploring the occurrence of acknowledged side effects of long-acting ß2-agonists as well as those included in the olodaterol and formoterol labels. We analysed pooled data from two replicate, double-blind studies of olodaterol (5 µg QD via Respimat®) compared to formoterol (12 µg twice daily [BID]) or placebo over 48 weeks (1222.13, NCT00793624; 1222.14, NCT00796653). Patients could continue their background treatment. The analysis considered adverse events (AEs) typically associated with ß2-agonists, including cardiovascular events, as well as administration-related events. Descriptive statistics were provided for the incidence of AEs and aggregated AEs. The analysis included 1379 patients: 460 placebo, 459 olodaterol and 460 formoterol; AEs were reported by 70.9, 71.7 and 69.1% of patients, respectively. Exposure-adjusted incidence rates of cardiac AEs (arrhythmia and myocardial ischaemia) and cough were numerically lower in the olodaterol group than the formoterol group, while nasopharyngitis, throat irritation, metabolism and psychiatric disorders were numerically higher in the olodaterol group. The most frequent event in the olodaterol group was nasopharyngitis (placebo 8.0%; olodaterol 12.9%; formoterol 10.0%). Except for cough (incidence rate ratio of 0.46 [95% confidence interval 0.24, 0.89] in favour of olodaterol), there were no significant differences between active groups. In conclusion, olodaterol 5 µg QD was well tolerated over 48 weeks with a typical ß2-agonist safety profile comparable to formoterol 12 µg BID.

Assessing Short-term Deterioration in Maintenance-naïve Patients with COPD Receiving Umeclidinium/Vilanterol and Tiotropium: A Pooled Analysis of Three Randomized Trials.

INTRODUCTION: Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status versus monotherapy. The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD. METHODS: This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (n = 1747). Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis. The primary endpoint was trough forced expiratory volume in 1 s (FEV1). St George's Respiratory Questionnaire (SGRQ) score, rescue medication use, and a novel composite endpoint of short-term clinically important deterioration (CID; ≥100 ml decrease in trough FEV1, ≥4-unit increase in SGRQ score, or a COPD exacerbation) were also assessed. RESULTS: UMEC/VI improved trough FEV1 versus TIO at day 169 [least squares mean (95% confidence interval): MN: 146 ml (102-189) and ITT: 95 ml (71-118); both P < 0.001]. Both UMEC/VI and TIO improved SGRQ and rescue use in the two populations, with greater improvements in rescue use with UMEC/VI versus TIO. UMEC/VI reduced the risk of short-term clinically important deterioration versus TIO [hazard ratio; 95% confidence interval: MN: 0.66 (0.51-0.85); ITT: 0.62 (0.54-0.71), both P ≤ 0.001]. Adverse events were similar across both populations and treatments. CONCLUSIONS: Early use of dual-bronchodilator therapy has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to monotherapy in symptomatic patients with COPD. CLINICAL TRIAL REGISTRATION: GSK analysis 202066 (NCT01316900/DB2113360, NCT01316913/DB2113374, NCT01777334/ZEP117115). FUNDING: This study was funded by GSK.

Prevention of clinically important deteriorations in COPD with umeclidinium/vilanterol.

BACKGROUND: Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. METHODS: This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. RESULTS: In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). CONCLUSION: This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.

Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat® Inhaler in Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Combining long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat(®) inhaler. METHODS: This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks. RESULTS: Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments. CONCLUSIONS: Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased. FUNDING: Boehringer Ingelheim. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01040403.

A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting ß2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease.

BACKGROUND: Olodaterol is a novel long-acting ß2-agonist (LABA) with ≥24-h duration of action in preclinical and clinical studies. OBJECTIVE: This Phase II, multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study evaluated four doses of once-daily olodaterol over 4 weeks in patients with chronic obstructive pulmonary disease (COPD), based on efficacy, safety and pharmacokinetic parameters. METHODS: Patients received olodaterol inhalation solution or placebo via Respimat® Soft Mist™ inhaler once daily for 4 weeks. Pulmonary function testing was performed pre-dose (trough) and up to 3 or 6 h post-dose, depending on visit. Primary end point was change from baseline in trough forced expiratory volume in 1 s (FEV1) after 4 weeks' treatment. Secondary end points included change from baseline in peak FEV1 and FEV1 area under the curve from 0 to 6 h. RESULTS: 405 patients with COPD were randomised and assigned to treatment. Mean baseline post-bronchodilator FEV1 was 1.50 L (54% predicted). All olodaterol doses provided statistically significant increases in trough FEV1 compared to placebo (2 µg: 0.061 L [p = 0.0233]; 5 µg: 0.097 L [p = 0.0003]; 10 µg: 0.123 L [p < 0.0001]; 20 µg: 0.132 L [p < 0.0001]). A clear dose-response relationship was demonstrated regarding pulmonary function; the two highest olodaterol doses (10 and 20 µg) formed the plateau of the dose-response curve. All olodaterol doses were well tolerated, with no dose-dependent safety effects. CONCLUSION: Once-daily olodaterol demonstrated 24-h bronchodilator efficacy, confirming its potential as a once-daily LABA for the management of COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00452400.

Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.

BACKGROUND: Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and ß2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease (COPD). METHODS: This study was a 24-week, Phase III, multicenter, randomized, blinded, double-dummy, parallel-group study of the once-daily, inhaled, fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting ß2-agonist vilanterol (UMEC/VI 62.5/25 mcg) versus tiotropium (TIO, 18 mcg). The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169. The secondary endpoint was weighted mean FEV1 over 0­6 h post-dose at Day 168. For key endpoints, a step-down closed testing hierarchy was applied to account for multiplicity. Other efficacy and safety endpoints were assessed. RESULTS: Statistically significant improvements in trough FEV1 at Day 169 (0.112 L, 95% confidence interval [CI]: 0.081, 0.144; p < 0.001) and weighted mean FEV1 over 0­6 h post-dose at Day 168 (0.105 L, 95% CI: 0.071, 0.140; p < 0.001) were observed for UMEC/VI versus TIO. In addition UMEC/VI improved health-related quality of life, and reduced requirement for the use of rescue medication compared with TIO. The incidence of adverse events was similar between treatment groups. CONCLUSIONS: UMEC/VI was associated with statistically significant and clinically meaningful improvements in lung function versus TIO. UMEC/VI was well tolerated. UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD.

The burden of illness in patients with moderate to severe chronic obstructive pulmonary disease in Canada.

INTRODUCTION: No recent Canadian studies with physician- and spirometry-confirmed diagnosis of chronic obstructive pulmonary disease (COPD) that assessed the burden of COPD have been published. OBJECTIVE: To assess the costs associated with maintenance therapy and treatment for acute exacerbations of COPD (AECOPD) over a one-year period. METHODS: Respirologists, internists and family practitioners from across Canada enrolled patients with an established diagnosis of moderate to severe COPD (Global initiative for chonic Obstructive Lung Disease stages 2 and 3) confirmed by postbronchodilator spirometry. Patient information and health care resources related to COPD maintenance and physician-documented AECOPD over the previous year were obtained by chart review and patient survey. RESULTS: A total of 285 patients (59.3% male; mean age 70.4 years; mean pack years smoked 45.6; mean duration of COPD 8.2 years; mean postbronchodilator forced expiratory volume in 1 s 58.0% predicted) were enrolled at 23 sites across Canada. The average annual COPD-related cost per patient was $4,147. Across all 285 patients, maintenance costs were $2,475 per patient, of which medications accounted for 71%. AECOPD treatment costs were $1,673 per patient, of which hospitalizations accounted for 82%. Ninety-eight patients (34%) experienced a total of 157 AECOPD. Treatment of these AECOPD included medications and outpatient care, 19 emergency room visits and 40 hospitalizations (mean length of stay 8.9 days). The mean cost per AECOPD was $3,036. DISCUSSION: The current costs associated with moderate and severe COPD are considerable and will increase in the future. Appropriate use of medications and strategies to prevent hospitalizations for AECOPD may reduce COPD-related costs because these were the major cost drivers.

Early detection and impaired quality of life in COPD GOLD stage 0: a pilot study.

This pilot study aimed to identify early stages of chronic obstructive pulmonary disease (COPD) in an urban population of smokers and ex-smokers using the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2001, 2003) classification guidelines and to assess the impact of early disease on quality of life. Smokers and ex-smokers of >or= 10 pack years and age >or= 50 years were recruited. After an initial telephone interview, eligible subjects completed a clinical assessment, spirometry tests, and the St. George's Respiratory Questionnaire (SGRQ). A total of 244 subjects completed the study; 91 subjects (37%) were normal, 153 subjects (63%) met the criteria for GOLD stages 0 to III: 65 stage 0 (27%), 43 stage I (18%), 38 stage II (16%), 7 stage III (3%) and 0 in stage IV. The stage 0 patients were younger than any other COPD groups (p<0.0005), including normal subjects (55.5+/-5.4 years vs. 59.6+/-7.2 years; p=0.0005). The frequency of current smoking in stage 0 patients was greater than those in the normal category (80% vs. 33%; p<0.0001). There were significant impairments in quality of life measures between normal subjects and all GOLD stages (SGRQ total scores; p<0.0001) except for stage I (SGRQ total scores; p=0.1409). Subjects with COPD at GOLD stage 0 were markedly under-diagnosed. These subjects had a significant impairment in their health-related quality of life measures, were younger than other categories, and were mostly current smokers. Thus, detection of COPD at GOLD stage 0 may provide a unique opportunity for early intervention and smoking cessation and the removal of GOLD stage 0 from the 2006 update should be re-assessed.