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[Background] The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD., [Methods] We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities., [Results] 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity., [Conclusions] The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by this systematic international process should inform and motivate policymakers, funders, and researchers to support and conduct research to reduce the global burden of COPD., National Institute for Health Research (NIHR), Health Data Research UK.

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.

There is increasing focus on understanding the nature of chronic obstructive pulmonary disease (COPD) during the earlier stages. Mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 or the now-withdrawn GOLD stage 0) represents an early stage of COPD that may progress to more severe disease. This review summarises the disease burden of patients with mild COPD and discusses the evidence for treatment intervention in this subgroup. Overall, patients with mild COPD suffer a substantial disease burden that includes persistent or potentially debilitating symptoms, increased risk of exacerbations, increased healthcare utilisation, reduced exercise tolerance and physical activity, and a higher rate of lung function decline versus controls. However, the evidence for treatment efficacy in these patients is limited due to their frequent exclusion from clinical trials. Careful assessment of disease burden and the rate of disease progression in individual patients, rather than a reliance on spirometry data, may identify patients who could benefit from earlier treatment intervention. Electronic supplementary material The online version of this article (10.1186/s12931-019-1108-9) contains supplementary material, which is available to authorized users.

Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obs...

OBJECTIVE: To evaluate the proportion of patients with symptoms suggestive of asthma and normal lung function who exhibit airway hyperreactivity with methacholine challenge testing (MCT) in primary care. DESIGN: Retrospective chart review. SETTING: Primary care lung clinic in Toronto, Ont. PARTICIPANTS: A total of 69 patients presenting to the lung clinic who had symptoms compatible with asthma, normal spirometry test results, and were referred for MCT. MAIN OUTCOME MEASURES: Descriptive statistics, frequency counts, independent t tests, and [Image: see text] (2) tests were used to examine differences in the proportion of clinical and demographic variables identified in patients with or without a positive MCT result. Effect size was determined between MCT-positive and MCT-negative patients for both categorical ([Image: see text] coefficient) and continuous (Hedges g) data. RESULTS: Twenty-one patients (30.4%) had positive MCT results, and 48 patients (69.6%) had negative MCT results. Family history of asthma and reduced baseline and postbronchodilator forced expiratory volume in 1 second were associated with a positive MCT result. CONCLUSION: The findings of this study provide insight into the utility of simple spirometry for asthma diagnosis and the need to further clarify the role of MCT in the primary care setting.

Persistent ill health after acute COVID-19-referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition-has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID.

Several algorithms exist to facilitate spirometric interpretation in clinical practice, yet there is a lack of consensus on how spirometric criteria for asthma, COPD, and restrictive disorders should be incorporated into spirometry interpretation algorithms suitable for use in day-to-day primary care management. The purpose of this review was to identify and describe the variability that exists among spirometry interpretation algorithms and how this might be relevant to the interpretation of spirometric data of common conditions encountered in primary care. MEDLINE, Embase, and mainstream search engines were used to identify all English-language spirometry interpretation algorithm–related material between January 1990 and December 2018. Eight variations in spirometry interpretation algorithms were identified via specific a priori assumptions that each spirometry interpretation algorithm should contain content consistent with national and international guidelines related to spirometry interpretation. Of the 26 spirometry interpretation algorithms identified, 5 were deemed impractical for day-to-day use in primary care (19%), 23 lacked a logic string leading to the postbronchodilator FEV1/FVC (88%), 4 relied on postbronchodilator change in FEV1 to distinguish between asthma and COPD (15%), 24 lacked a prompt for bronchodilator challenge when FEV1/FVC was considered to be at a normal level (92%), 12 did not indicate whether the data represented a prebronchodilator or postbronchodilator scenario (46%), 7 did not include a logic string that considers mixed obstructive/restrictive defect (27%), 23 did not contain a prompt to refer for methacholine challenge testing when spirometry appeared normal (88%), and 2 spirometry interpretation algorithms did not include a logic string leading to restrictive disorder (8%). Our review suggests that there is considerable variability among spirometry interpretation algorithms available as diagnostic aids and that there is a need for standardization of spirometry interpretation algorithms in primary care.

Glycopyrronium is a once daily (o.d.) long-acting muscarinic antagonist that is approved for maintenance treatment of COPD. This post-hoc pooled analysis of two phase III studies, GLycopyrronium bromide in COPD airWays 1 and 2 (GLOW1 and GLOW2), evaluated the effects of glycopyrronium compared with placebo and tiotropium over 26-52 weeks in patients with moderate-to-severe COPD.Patients aged≥40 years were randomised to 26 weeks' treatment with glycopyrronium 50 μg o.d. or placebo (GLOW1) or 52 weeks' treatment with glycopyrronium 50 μg o.d., placebo, or open-label tiotropium 18 μg o.d. (GLOW2). The primary efficacy endpoint in both studies was trough forced expiratory volume in one second (FEV1) at Week 12. Other outcomes included additional spirometry endpoints, moderate or severe exacerbations, dyspnoea, health status, rescue medication use and safety. Serial spirometry over 24 hours was conducted in a subset of patients.Of 1888 subjects randomised, 98.2% were analysed (glycopyrronium 1059, tiotropium 267, placebo 528). Least squares mean (LSM) trough FEV1 was significantly higher with glycopyrronium versus placebo at Week 12 (treatment difference±standard error [SE]: 103±11.2 mL; p0.001), as well as at Day 1 and Weeks 26 and 52. More patients achieved≥100 mL increase in trough FEV1 from baseline with glycopyrronium versus placebo at all assessments (p0.001). Glycopyrronium significantly improved FEV1 immediately after the first dose on Day 1 versus placebo (90 mL at 5 minutes, 144 mL at 15 minutes; both p0.001) and versus tiotropium (43 mL at 5 minutes, 65 mL at 15 minutes; both p0.001). Glycopyrronium significantly improved other spirometry endpoints and provided clinically meaningful 24 hour bronchodilation versus placebo at most timepoints from Day 1 onwards (p0.05). Time to first moderate or severe exacerbation was significantly prolonged with glycopyrronium versus placebo over 26 and 52 weeks (36% and 33%, respectively; both p 0.001). Glycopyrronium provided significantly greater relief of dyspnoea, improved health status and reduced rescue medication use versus placebo. Glycopyrronium was safe and well tolerated.Glycopyrronium 50 μg o.d. provided early bronchodilation after the first dose that was sustained for 24 hours, and reduced the risk of exacerbations compared with placebo, with efficacy at least equivalent to tiotropium.NCT01005901 and NCT00929110.

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 β2-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.

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV1), ≥4 point increase in St George’s Respiratory Questionnaire score or a moderate-to-severe COPD exacerbation occurring after the first dose of study medication. A sustained CID was a CID occurring on ≥2 consecutive visits 4 weeks apart or for ≥50% of all available subsequent visits. Baseline characteristics for the overall population were similar. Patients had moderate (62%) or severe (38%) COPD. Mean post-bronchodilator FEV1 was approximately 55% predicted, and mean FEV1 reversibility was 16.7 and 18.6% in the glycopyrronium and tiotropium groups, respectively. Both glycopyrronium and tiotropium significantly reduced time to CID and sustained CID versus placebo (p, Chronic lung disease: Potential alternative treatment option A novel inhaled drug shows promise in treating moderate to severe chronic lung disease. Guidelines recommend long-term treatment of chronic obstructive pulmonary disease (COPD) with long-acting muscarinic antagonist (LAMA) inhalers. Tiotropium is a common COPD LAMA. Now, Anthony D’Urzo at the University of Toronto, Canada, together with an international research team, have carried out a pooled analysis of results from four clinical trials to compare the efficacy of a novel LAMA, glycopyrronium, with tiotropium. In these trials, 2936 patients were treated with either glycopyrronium or tiotropium, and the health status of patients using glycopyrronium was also compared with those given a placebo. Glycopyrronium was as effective as tiotropium in delaying or preventing clinically important deteriorations in patient health. The risk of deteriorations was significantly lower in the glycopyrronium group than the placebo group.

COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function, dyspnea, exacerbations, and health status. Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient’s adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician’s and patient’s experiences and preferences.

Rationale: Adults may exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD), a situation recently described as asthma–COPD overlap (ACO). There is a paucity of inf...

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting β2 agonist (LAMA/LABA) dual-bronchodilator maintenance therapy used to relieve symptoms and reduce future risk of exacerbations in adults with chronic obstructive pulmonary disease (COPD). To date, there have been several clinical studies and post hoc analyses of AB/FF, assessing treatment outcomes in patients with moderate-to-severe COPD. These studies have looked at a range of outcomes, including lung function parameters, patient-reported symptom scores, quality-of-life measures assessing impaired health and perceived well-being, and the frequency, duration, and severity of exacerbations. In light of the major 2017 revision to the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, and the subsequent updates, we present an update on the latest evidence supporting the efficacy and safety of AB/FF. This review discusses the clinical relevance of the improvements in lung function, symptoms, quality of life, and exacerbations in patients with COPD reported in the phase III and IV trials of AB/FF. Given the current concerns over unnecessary inhaled corticosteroid (ICS) use in COPD, we also touch briefly on the use of blood eosinophils as a biomarker for identifying those patients with COPD already using LAMA/LABA therapy for whom the addition of ICS might be of benefit.

Background ‘Clinically important deterioration’ (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 μg/formoterol fumarate (FF) 12 μg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 μg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD. Methods A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV1; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George’s Respiratory Questionnaire (SGRQ) total score (≥4 units). A ‘sustained’ CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18. Results AB/FF 400/12 μg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p

Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease. In some patients, inhaled corticosteroids can be prescribed in combination with bronchodilators. Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use (user vs. non-user), we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease. The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use. We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies. Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users, these data suggest that both groups achieve lung function improvements, which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids., Chronic lung disease: ‘Triple’ therapy could prove beneficial A dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease. Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease (COPD). While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD, little is known about combining the dual therapy with inhaled corticosteroids (ICSs). Anthony D’Urzo at the University of Toronto, Canada, and co-workers analysed data from 3394 patients with COPD undergoing dual therapy trials. Of these, 1180 were already taking ICSs. The team compared symptoms in the ICS group with those not taking ICSs. The dual therapy improved lung function across both groups regardless of ICS use, though patients gained different clinical benefits depending on ICS use and disease severity.

This was a 52-week, double-blind, extension study in which COPD patients previously treated with twice-daily (BID) aclidinium bromide 200 μg or 400 μg during a 12-week lead-in study (ACCORD COPD I) continued the same treatment, while patients previously receiving placebo were rerandomized (1:1) to aclidinium 200 μg or 400 μg BID. The primary objective of this study was to evaluate the long-term safety and tolerability of aclidinium treatment. Efficacy outcomes included bronchodilation, health status, and rescue medication use. A total of 467 patients completed the lead-in study and 291 patients consented to participate in the extension. At study end, the percentages of patients who reported a treatment-emergent adverse event (TEAE) were similar for both treatments (200 μg, 77.4%; 400 μg, 73.7%). Incidence of anticholinergic TEAEs was low and similar for both treatments, with dry mouth reported in only 1 patient (400 μg). Cardiac TEAEs were reported by a similarly low percentage of patients (

Introduction Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies (AUGMENT and ACLIFORM) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This Phase III, double-blind, placebo-controlled, 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg ( NCT01572792 ). Methods Patients were randomised in AUGMENT (1:1:1:1:1) to twice-daily AB/FF 400/12 μg, AB/FF 400/6 μg, AB 400 μg, FF 12 μg or placebo. Patients completing AUGMENT were invited to continue the same treatment in the extension. Adverse events (AEs), major adverse cardiovascular events (MACE), laboratory tests, electrocardiograms and vital signs were recorded. Efficacy was assessed. Results Of 1322 patients completing AUGMENT, 921 enrolled and 780 completed the extension. AE incidence was low and comparable across treatment groups; most common were nasopharyngitis (range 4.8%–9.3%), urinary tract infection (range 4.1%–8.8%) and upper respiratory tract infection (range 2.7%–5.5%). Serious AEs (SAEs) and MACE were low (ranges 6.8%–7.7% and 0.5%–1.5%, respectively). Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo. Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies. AB/FF combinations increased the time to first exacerbation by approximately 30% versus placebo (p Conclusion AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs, SAEs and MACE that were comparable across treatment groups. Improvements in bronchodilation, symptoms and health status were maintained across 52 weeks.

Identifying patients at risk of exacerbations and managing them appropriately to reduce this risk represents an important clinical challenge. Numerous treatments have been assessed for the prevention of exacerbations and their efficacy may differ by patient phenotype. Given their centrality in the treatment of COPD, there is strong rationale for maximizing bronchodilation as an initial strategy to reduce exacerbation risk irrespective of patient phenotype. Therefore, in patients assessed as frequent exacerbators (>1 exacerbation/year) we propose initial bronchodilator treatment with a long-acting muscarinic antagonist (LAMA)/ long-acting β2-agonist (LABA). For those patients who continue to experience >1 exacerbation/year despite maximal bronchodilation, we advocate treating according to patient phenotype. Based on currently available data on adding inhaled corticosteroids (ICS) to a LABA, ICS might be added to a LABA/LAMA combination in exacerbating patients who have an asthma-COPD overlap syndrome or high blood eosinophil counts, while in exacerbators with chronic bronchitis, consideration should be given to treating with a phosphodiesterase (PDE)-4 inhibitor (roflumilast) or high-dose mucolytic agents. For those patients who experience frequent bacterial exacerbations and/or bronchiectasis, addition of mucolytic agents or a macrolide antibiotic (e.g. azithromycin) should be considered. In all patients at risk of exacerbations, pulmonary rehabilitation should be included as part of a comprehensive management plan. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0425-5) contains supplementary material, which is available to authorized users.

Bronchodilators play a pivotal role in the management of symptomatic chronic obstructive pulmonary disease. Inhaled short-acting bronchodilators are used for all stages of chronic obstructive pulmonary disease, primarily for the immediate relief of symptoms; inhaled long-acting bronchodilators are recommended for maintenance therapy in patients with moderate-to-very severe disease and those with daily symptoms. When symptoms are not adequately controlled by a single bronchodilator, combining bronchodilators of different classes may prove effective. Several long-acting β(2)-agonists and long-acting muscarinic antagonists with 24-h duration of action and inhalers combining different classes of long-acting, once-daily bronchodilators are in development. The place of these agents in the treatment algorithm will be determined by their efficacy and safety profiles and their long-term impact on relevant clinical outcomes.

This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD.In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV₁ and peak FEV₁ at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed.A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV₁ of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV₁ compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV₁ by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%-1.6%; constipation: 0%-1.1%).Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo.This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as "Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)".

Results from two clinical trials of mometasone furoate administered via a dry powder inhaler (MF-DPI) were reviewed to evaluate the consistency of effects of MF-DPI administered once-daily in the evening (QD PM) or twice-daily (BID) on health-related quality of life (HRQOL) in adults with persistent asthma previously treated with inhaled corticosteroids. HRQOL data were collected from two 12-week, randomized, double-blind trials: in study 1 (n = 268), patients received MF-DPI 400 microg QD PM (1 inhalation), MF-DPI 200 microg BID, or placebo; in study 2 (n = 400), patients received MF-DPI 200 microg QD PM, MF-DPI 400 microg QD PM (1 inhalation), MF-DPI 200 microg BID, MF-DPI 400 microg QD PM (2 inhalations of 200 microg), or placebo. In both studies, HRQOL was assessed using the Medical Outcomes Survey 36-item Short Form (SF-36) and an asthma-specific module. MF-DPI was associated with consistent, statistically significant improvements in asthma-specific total scores, breathlessness, asthma concerns, and physical symptoms compared with placebo in both trials (p < 0.05 vs. placebo). MF-DPI improved SF-36 Physical Component Summary scores at all doses except 200 microg QD PM. In conclusion, the results from two placebo-controlled trials suggest that MF-DPI 400 microg/d, administered once or twice-daily, produces consistent, statistically, and clinically significant improvement in HRQOL measures in patients with persistent asthma.

Previous studies have raised concerns regarding the safety of regular use of beta2-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol.To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma.Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEVI], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 microg; 2 actuations of 45 microg; n = 496) or racemic albuterol HFA MDI (180 microg; 2 actuations of 90 microg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed.The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of beta-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV1 improved after dosing and was stable for both groups.In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.

Mometasone furoate dry-powder inhaler (MF-DPI) is an inhaled corticosteroid (ICS) used for the treatment of persistent asthma in patients agedor= 12 years. MF-DPI has low systemic bioavailability and high glucocorticoid receptor affinity compared with most other ICSs and modifies inflammatory mediators involved in the pathogenesis of asthma. MF-DPI, unlike other available ICSs, is approved for initiation as a once-daily in the afternoon (q.d. PM) regimen. Studies show that MF-DPI 200 or 400 microg q.d. PM treatment significantly improves lung function and symptom control in patients with mild, moderate or severe asthma. MF-DPI 400 microg q.d. PM is reported to be equivalent to fluticasone propionate 250 microg b.i.d. and beclometasone dipropionate 168 microg b.i.d. and more efficacious than budesonide 400 microg, b.i.d. or q.d. MF-DPI is generally well tolerated, with minimal effects on the hypothalamic-pituitary-adrenal axis.

Background The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT). Methods Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity

Introduction: Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects. Areas covered: Although the existence of asthma in patients with asthma–COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation. Expert opinion: For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.

Spirometry is recommended for the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) in international guidelines and may be useful for distinguishing asthma from COPD. Numerous spirometry interpretation algorithms (SIAs) are described in the literature, but no studies highlight how different SIAs may influence the interpretation of the same spirometric data. We examined how two different SIAs may influence decision making among primary-care physicians. Data for this initiative were gathered from 113 primary-care physicians attending accredited workshops in Canada between 2011 and 2013. Physicians were asked to interpret nine spirograms presented twice in random sequence using two different SIAs and touch pad technology for anonymous data recording. We observed differences in the interpretation of spirograms using two different SIAs. When the pre-bronchodilator FEV1/FVC (forced expiratory volume in one second/forced vital capacity) ratio was >0.70, algorithm 1 led to a ‘normal’ interpretation (78% of physicians), whereas algorithm 2 prompted a bronchodilator challenge revealing changes in FEV1 that were consistent with asthma, an interpretation selected by 94% of physicians. When the FEV1/FVC ratio was 12% and 200 ml, 76% suspected asthma and 10% suspected COPD using algorithm 1, whereas 74% suspected asthma versus COPD using algorithm 2 across five separate cases. The absence of a post-bronchodilator FEV1/FVC decision node in algorithm 1 did not permit consideration of possible COPD. This study suggests that differences in SIAs may influence decision making and lead clinicians to interpret the same spirometry data differently. Variations among algorithms used to interpret ‘blow’ tests for diagnosis of asthma and lung disease may be skewing test results. The researchers, led by Anthony D'Urzo from the University of Toronto in Canada, had 113 primary care physicians make diagnoses from nine sets of blow test or spirogram results using two different spirogram interpretation algorithms (SIAs). They found for a particular case with impaired blow test results, one SIA resulted in a ‘normal’ diagnosis by 78% of physicians, while the other resulted in a diagnosis of ‘consistent with asthma’ by 94% of doctors. The findings suggest a need to standardise the algorithms in order to minimise differences in interpreting data, and underscore the importance of educating physicians about the pitfalls of using spirograms in isolation.

Anthony D D’Urzo,1 Edward M Kerwin,2 Kenneth R Chapman,3 Marc Decramer,4 Robert DiGiovanni,5 Peter D’Andrea,6 Huilin Hu,6 Pankaj Goyal,5 Pablo Altman6 1Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; 2Clinical Research Institute of Southern Oregon, PC, Medford, USA; 3Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, ON, Canada; 4Respiratory Division, University of Leuven, Leuven, Belgium; 5Novartis Pharma AG, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Background: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. Methods: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50µg, placebo (both delivered via the Breezhaler® device), or tiotropium 18µg (delivered via the HandiHaler® device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA™. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated.Results: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data.Conclusion: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points. Keywords: COPD, drug safety, glycopyrronium, post-marketing surveillance

Once-daily dosing with an inhaled corticosteroid (ICS) may simplify asthma management and improve patient compliance. Since asthma is frequently worse at night, evening dosing appears to be a more obvious choice to accommodate the chronobiology of asthma than morning dosing.The primary study objective was to compare the efficacy and safety of mometasone furoate (MF) dry powder inhaler (MF-DPI) 400 microg qd PM (one 400 microg inhalation) with placebo for the treatment of asthma in patients previously dependent on twice a day (bid, bis in die) ICS therapy. We also compared different regimens of MF-DPI with each other and with placebo.This 12-week, multicenter, double-blind, placebo-controlled study evaluated lung function and asthma symptoms in 400 subjects with persistent asthma randomized to MF-DPI 200 microg qd (once a day, quaque die) PM, 400 microg qd PM as one inhalation from a 400 microg device, 400 microg qd PM as two inhalations from a 200 microg device, 200 microg twice daily (bid), or placebo. Evening doses were to be taken in the late afternoon or early evening, preferably before dinner time.Mean changes from baseline at endpoint in FEV1 (forced expiratory volume in 1 s) were similar for MF-DPI 400 microg qd PM (one inhalation; 0.41 L), MF-DPI 400 microg qd PM (2 inhalations; 0.49 L), MF-DPI 200 microg qd PM (0.41 L), and MF-DPI 200 microg bid (0.51 L); and all were significantly improved compared with placebo (0.16 L; p0.001). Secondary efficacy variables, including nocturnal awakenings and use of rescue albuterol, were also significantly improved with MF-DPI treatment compared with placebo. All treatments were generally safe and well tolerated, with adverse events of mild to moderate severity.Once-daily evening dosing of MF-DPI at doses of 400 and 200 microg restored lung function and improved nocturnal and daytime symptom control in subjects with asthma previously dependent on bid ICS therapy. Comparable effectiveness of a total daily dose of 400 microg was demonstrated between once daily in the evening and twice-daily administration. The results also confirm the effectiveness of MF-DPI 200 microg qd PM, the lowest dose studied.

Asthma represents one of the most common chronic conditions encountered in primary care and diagnosis should be confirmed objectively with the demonstration of variable airflow obstruction. As many asthmatics have normal lung function at the time of clinical presentation, objective confirmation of airflow limitation may be challenging. Fluctuations in airflow obstruction can be documented with simple office spirometry after bronchodilator challenge, home monitoring of peak expiratory flow and bronchoconstriction induced by spasmogens such as methacholine. We present a case highlighting the challenge of objective confirmation of asthma diagnosis in primary care and provide a critical review of the diagnostic approaches highlighted above. Our aim is to provide a pragmatic interpretation of the available literature with a view to assisting clinicians in selecting the diagnostic test best suited for individualised patient encounters.

Background Two once-daily long-acting muscarinic antagonists (LAMAs) are currently available for the treatment of chronic obstructive pulmonary disease (COPD) – tiotropium and glycopyrronium. Previous studies have compared glycopyrronium with open-label tiotropium. In the GLOW5 study, we compare glycopyrronium with blinded tiotropium. Methods In this blinded, double-dummy, parallel group, 12-week study, patients with moderate-to-severe COPD were randomized 1:1 to glycopyrronium 50 μg once daily or tiotropium 18 μg once daily. The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment (non-inferiority margin: –50 mL). Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes, breathlessness (Transition Dyspnea Index; TDI), health status (St George’s Respiratory Questionnaire; SGRQ), daily rescue medication use, COPD exacerbations and COPD symptoms over 12 weeks of treatment. Results 657 patients were randomized (glycopyrronium: 327; tiotropium: 330); 96% (630 patients) completed the study. Least squares mean trough FEV1 for both glycopyrronium and tiotropium was 1.405 L at Week 12, meeting the criterion for non-inferiority (mean treatment difference: 0 mL, 95% CI: –32, 31 mL). Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1, with significantly higher FEV1 at all time points from 0–4 h post-dose versus tiotropium (all p

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 μg, placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p

Is the family physician an accomplice in the development of the ‘primary care gap’? The importance of high quality real-life primary care respiratory research

Background This study investigated the efficacy and safety of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol; flutiform®), administered twice daily (b.i.d.) via a single aerosol inhaler, compared with its individual components administered separately and placebo, in patients with mild-to-moderate asthma. Methods Patients aged ≥ 12 years were evenly randomised to 12 weeks of treatment with fluticasone/formoterol (100/10 μg b.i.d.), fluticasone (100 μg b.i.d.), formoterol (10 μg b.i.d.), or placebo, in this double-blind, parallel group, multicentre study. The three co-primary endpoints were: a) change in forced expiratory volume in the first second (FEV1) from morning pre-dose at baseline to pre-dose at week 12 for the comparison with formoterol; b) change in FEV1 from morning pre-dose at baseline to 2 hours post-dose at week 12 for the comparison with fluticasone, and c) time to discontinuation due to lack of efficacy from baseline to week 12 for the comparison with placebo. Safety was assessed based on adverse events, clinical laboratory tests and vital sign evaluations. Results Statistically significant differences were demonstrated for all the three co-primary endpoints. Fluticasone/formoterol combination therapy showed significantly greater improvements from baseline to end of study in the change in pre-dose FEV1 compared with formoterol (Least Squares (LS) mean treatment difference: 0.101 L; 95% Confidence Interval (CI): 0.002, 0.199; p = 0.045) and the change in pre-dose compared with 2 hours post-dose FEV1 versus fluticasone (LS mean treatment difference: 0.200 L; 95% CI: 0.109, 0.292; p < 0.001). The time to discontinuation due to lack of efficacy was significantly longer for patients in the combination therapy group compared with those receiving placebo (p = 0.015). Overall, the results from multiple secondary endpoints assessing lung function, asthma symptoms, and rescue medication use supported the superior efficacy of the combination product compared with fluticasone, formoterol, and placebo. The fluticasone/formoterol combination therapy had a good safety and tolerability profile over the 12 week treatment period. Conclusions Fluticasone/formoterol had a good safety and tolerability profile and showed statistically superior efficacy for the three co-primary endpoints compared to fluticasone, formoterol, and placebo, in adolescents and adults with mild-to-moderate asthma. EudraCT number: 2007-002866-36; US NCT number: NCT00393991

Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting β(2) agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone.In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 μg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 μg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV(1)) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose ('trough') FEV(1) at week 12. Resting inspiratory capacity (IC) was measured in a subgroup.1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV(1) (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p0.001) and trough IC (by 130 and 100 ml, p0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (∼90%) of cough were mild. Other adverse events were similar for the treatment groups.Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action.NCT00846586 and NCT00877383.

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC

Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.

This 12-month dose-titration study assessed the effectiveness of budesonide/formoterol for maintenance plus relief with a control group using salmeterol/fluticasone for maintenance plus salbutamol for relief. Adolescents and adults (n = 2,143; mean forced expiratory volume in one second (FEV1) 73% predicted; mean inhaled corticosteroid (ICS) 884 microg.day(-1)) were randomised to budesonide/formoterol 160/4.5 microg two inhalations b.i.d. plus additional inhalations as needed, or salmeterol/fluticasone 50/250 microg b.i.d. plus salbutamol as needed. Treatment was prescribed open label; after 4 weeks, physicians could titrate maintenance doses in accordance with normal clinical practice. Maintenance plus as-needed budesonide/formoterol prolonged the time to first severe exacerbation versus salmeterol/fluticasone (25% risk reduction). The total number of severe exacerbations was significantly reduced in the budesonide/formoterol group (255 versus 329). Both regimens provided sustained improvements in symptoms, as-needed use, quality of life and FEV1, with differences in favour of the budesonide/formoterol group for as-needed use (0.58 versus 0.93 inhalations.day(-1)) and FEV1 (post-beta2-agonist values). Mean ICS dose during treatment was similar in both groups (653 microg budesonide.day(-1) (maintenance plus as-needed) versus 583 microg fluticasone.day(-1)). The simplified strategy using budesonide/formoterol for maintenance and reliever therapy is feasible, safe and at least as effective as salmeterol/fluticasone plus salbutamol.

Compliance with anti-asthma medication is essential in controlling symptoms and exacerbations in patients with asthma. Unfortunately, not all patients adhere to their treatment regimen, and it is difficult for clinicians to estimate a patient's compliance, since there is no simple and accurate method currently available to assist in its assessment. The objective of this study was to assess the validity and accuracy of utilizing clinical information regarding a patient's prescription refill frequency, inhaler emptying rate, reported forgetfulness, and short-acting bronchodilator usage to predict daily, anti-inflammatory intake. A questionnaire based on the clinical information described above was administered verbally to asthma patients with varying disease severities. Patient responses were compared to the patient's own pharmacy records. Questions that correlated significantly with pharmacy records were subsequently fit into a multiple regression model. Out of 147 eligible participants, 70 completed the questionnaire and had comprehensive pharmacy data available. There was a significant correlation between daily anti-inflammatory intake as estimated by pharmacy records and daily anti-inflammatory intake as determined by inhaler emptying rate (p

This double-blind, placebo-controlled, randomized, parallel-group, multicenter study was conducted in 302 children aged 6-11 years with asthma not optimally treated with inhaled corticosteroids alone. Patients continued with their existing dose of inhaled corticosteroids and in addition received placebo, formoterol 4.5 microg or formoterol 9 microg b.i.d., for 12 weeks (all delivered via Turbuhaler). Terbutaline was available as reliever medication. The primary efficacy variable was change from baseline in morning peak expiratory flow (PEF); secondary efficacy variables included forced expiratory volume in 1 sec (FEV(1)), serial PEF measured over 12 hr, evening PEF, asthma symptom score, and quality of life. Compared with placebo, formoterol 4.5 microg and 9 microg improved morning PEF by 8 l/min (P = 0.035) and 11 l/min (P = 0.0045), respectively. Evening PEF and FEV(1) were also significantly increased compared with placebo, with no statistically significant difference between formoterol doses. Lung-function improvements compared with placebo were greater in the middle of the day. Twelve-hour average serial PEF after 3 months increased by 24 l/min (95% CI, 9, 39 l/min) in the formoterol 9-microg group, and by 14 l/min (95% CI, 0, 29 l/min) in the formoterol 4.5-microg group. The incidence of severe exacerbations in both formoterol groups was numerically lower than in the placebo group, indicating that formoterol may have the potential to improve exacerbation control in children. Both formoterol doses were well-tolerated, and tolerance to the drug's bronchodilator effect was not observed. Formoterol provided sustained improvements in lung function and was well-tolerated in children with asthma suboptimally treated with inhaled corticosteroids alone.

OBJECTIVE: To describe an approach to diagnosis and treatment of patients with chronic cough. QUALIITY OF EVIDENCE: MEDLINE was search for reports of studies comducted between 1970 and 2000 on chronic cough and its epidemiology, natural history, diagnois, and theraphy. Articles were further selected based on clinical relevance and design. Most articles reviewed were epidemiology cohort and case studies and reviews. MAIN MESSAGE: Chronic cough, a commom ailment amoung adults, is often a diagnostic challenge. Most cases of chronic cough are associated with postnasal drip syndrome (PNDS), asthma, gastroesphageal reflux disease (GERD), or some combination of these. Initial investigation should include chest radiography to ruke out more ominous causes of chronic cough. Examinations and trials of treatment can diagnose PNDS, asthma, and GERD. Combination treatments are often necessary for managing chronic cough. CONCLUSION: The most common causes of chronic cough are PNDS, asthma, GERD, or some combination of these. A systematic approach to diagnosis and treatment is effective for most cases of chronic. cough.

Study objectives: To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings. Design: A randomized, double-blind, 6-month, parallel-group study involving 253 centers. Setting: Primarily nonspecialist practices (n 5 232). Patients: A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 mg; n 5 455) or matching placebo twice daily (n 5 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study. Measurements and results: The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p 5 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p 5 0.028). Conclusions: Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations. (CHEST 2001; 119:714‐719)

Mometasone furoate (MF) administered by dry powder inhaler (DPI) was composed with budesonide (BUD) Turbuhaler in the treatment of moderate persistent asthma. The patients were randomized to one of four treatment groups: MF DPI (100, 200, 400 microg b.i.d) or BUD Turbuhaler. 400 microg b.i.d in a 12-week, active-controlled, evaluator-blind, multicentre international trial. The primary efficacy variable was the mean change from baseline to endpoint (last treatment visit) in forced expiratory volume in one second (FEV1). Changes in FEV1 showed a statistically significant superiority (p

Objective measurement of lung function is considered essential in the management of patients with asthma and COPD. Many primary care practitioners lack the means necessary to obtain these measurements conveniently. To meet this need, electronic spirometers, offering portability, ease of operation, and timesaving readout options have been introduced. We compared the accuracy of a typical pneumotachograph-based device with a conventional volume displacement spirometer.We compared indexes of pulmonary function (FVC, FEV1, mean forced expiratory flow during the middle half of FVC, [FEF25-75%], and peak expiratory flow rate [PEFR]) measured by the handheld device with those measured by a conventional spirometer in 75 white subjects (33 men, 42 women) with a median age of 43 years (22 to 77 years) who were either healthy or were referred to the pulmonary function laboratory of a large tertiary care teaching hospital. The order of the instrument tested first was randomized and the patients were blinded to which instrument was being studied.There was a linear relationship between instruments for all indexes measured (r = 0.97, 0.98, 0.94, 0.94 for FVC, FEV1, FEF25-75%, and PEFR, respectively, for all p0.001). The random error (precision) was within 5% only for FEV1. The mean of the differences between the values obtained using both instruments (the bias) +/- limits of agreement (+/- 2 SD) were 0.06 +/- 0.56 L for FVC (p = NS), 0.2 +/- 0.44 L for FEV1 (p0.05), 0.61 +/- 1.26 L/s for FEF25-75% (p0.05), and 0.44 +/- 1.9 L/s for PEFR (p0.05).Our data suggest that measurements obtained using the pneumotachograph device are closely related to those obtained by volume displacement spirometry and that the handheld device may be useful in clinical practice. However, because the limits of agreement are wide and the difference between the two instrument measurements are significant for FEV1, FEF25-75%, and PEFR, the bias between them is not consistent nor is it insignificant. Therefore, the measurements made with the two types of machine cannot be used interchangeably.

The effect of oral caffeine on resting ventilation (VE), ventilatory responsiveness to progressive hyperoxic hypercapnia (HCVR), isocapnic hypoxia (HVR), and moderate exercise (EVR) below the anaerobic threshold (AT) was examined in seven healthy adults. Ventilatory responses were measured under three conditions: control (C) and after ingestion of either 650 mg caffeine (CF) or placebo (P) in a double-blind randomized manner. None of the physiological variables of interest differed significantly for C and P conditions (P greater than 0.05). Caffeine levels during HCVR, HVR, and EVR were 69.5 +/- 11.8, 67.8 +/- 10.8, and 67.8 +/- 10.9 (SD) mumol/l, respectively (P greater than 0.05). Metabolic rate at rest and during exercise was significantly elevated during CF compared with P. An increase in VE from 7.4 +/- 2.5 (P) to 10.5 +/- 2.1 l/min (CF) (P less than 0.05) was associated with a decrease in end-tidal PCO2 from 39.1 +/- 2.7 (P) to 35.1 +/- 1.3 Torr (CF) (P less than 0.05). Caffeine increased the HCVR, HVR, and EVR slopes (mean increase: 28 +/- 8, 135 +/- 28, 14 +/- 5%, respectively) compared with P; P less than 0.05 for each response. Increases in resting ventilation, HCVR, and HVR slopes were associated with increases in tidal volume (VT), whereas the increase in EVR slope was accompanied by increases in both VT and respiratory frequency. Our results indicate that caffeine increases VE and chemosensitivity to CO2 inhalation, hypoxia, and CO2 production during exercise below the AT.

Eight healthy volunteers performed gradational tests to exhaustion on a mechanically braked cycle ergometer, with and without the addition of an inspiratory resistive load. Mean slopes for linear ventilatory responses during loaded and unloaded exercise [change in minute ventilation per change in CO2 output (delta VE/delta VCO2)] measured below the anaerobic threshold were 24.1 +/- 1.3 (SE) = l/l of CO2 and 26.2 +/- 1.0 l/l of CO2, respectively (P greater than 0.10). During loaded exercise, decrements in VE, tidal volume, respiratory frequency, arterial O2 saturation, and increases in end-tidal CO2 tension were observed only when work loads exceeded 65% of the unloaded maximum. There was a significant correlation between the resting ventilatory response to hypercapnia delta VE/delta PCO2 and the ventilatory response to VCO2 during exercise (delta VE/delta VCO2; r = 0.88; P less than 0.05). The maximal inspiratory pressure generated during loading correlated with CO2 sensitivity at rest (r = 0.91; P less than 0.05) and with exercise ventilation (delta VE/delta VCO2; r = 0.83; P less than 0.05). Although resistive loading did not alter O2 uptake (VO2) or heart rate (HR) as a function of work load, maximal VO2, HR, and exercise tolerance were decreased to 90% of control values. We conclude that a modest inspiratory resistive load reduces maximum exercise capacity and that CO2 responsiveness may play a role in the control of breathing during exercise when airway resistance is artificially increased.

We wished to evaluate the role of hypoxia in the production of cardiovascular manifestations of acute airway obstruction. We monitored blood pressure, electrocardiogram, and radionuclide ejection fraction in 14 healthy volunteers on exposure to four experimental conditions: expiratory resistive loading while breathing room air (RAL), expiratory resistive loading while hypoxic (HL), hypoxia alone (H), and expiratory resistive loading while voluntarily hyperventilating in a pattern similar to HL trials (VL). Mean respiratory-related oscillation in systolic blood pressure (pulsus paradoxus) increased significantly under each experimental condition compared with those at baseline (2 +/- 2.3 mm Hg): for RAL, 21 +/- 8.4 mm Hg; for HL, 34 +/- 16.3 mm Hg; for H, 10 +/- 5.4 mm Hg; for VL 26 +/- 13.4 mm Hg. Pulsus paradoxus was significantly greater under conditions of moderate hypoxia (saturation, 80%) than of mild hypoxia (saturation, 90%). Electrocardiographic changes were more marked under HL and H conditions than under RAL and VL conditions. HL induced changes in blood pressure and frontal QRS axis that were qualitatively similar to those seen in naturally occurring asthma. Radionuclide ejection fraction showed no dramatic change with any experimental condition. We conclude that hypoxia magnifies the cardiovascular changes induced by acute expiratory resistive loads and may contribute to the degree of pulsus paradoxus seen in severe asthma.

Ear oximetry is widely used to detect arterial O2 desaturation during exercise in patients with cardiopulmonary disease. Although oximeters have been evaluated for accuracy, response time, and the influence of skin pigmentation, tests of their reliability have not been reported during strenuous exercise. Accordingly, we compared arterial O2 saturation (Sao2) measurements obtained by Hewlett-Packard (HP, model 47201A) and Biox II oximeters with those determined directly from arterial blood in six healthy volunteers during progressive exercise while rebreathing hypoxic gas mixtures. The relationship between the HP oximeter value and blood Sao2 was described by the equation: HP = 0.93 (Sao2) + 5.37 and for the Biox II: Biox = 0.55 (Sao2) + 38.97. With these equations, at a blood Sao2 value of 90%, the underestimation by both oximeters was less than 2%. At a blood value of 70%, the HP oximeter overestimated blood Sao2 by 0.7%, whereas the Biox II showed an overestimation of 10.7%. Below blood Sao2 of 83%, the Biox II tended to overestimate blood Sao2 by an amount greater than the error of the instrument, whereas the HP estimations were within the error of the instrument over all levels of blood Sao2 studied. We conclude that the HP oximeter provides valid estimates of Sao2 during exercise but that the Biox II oximeter, although reflecting qualitative changes in oxygenation that occur during exercise, does not provide accurate records of the degree of desaturation.

In the present study, we have undertaken a detailed analysis of the respiratory physiologic correlates of SaO2 during mild constant-load exercise in 38 patients with severe but stable COPD. Several respiratory physiologic variables that would be expected to influence exercise SaO2 were entered into a stepwise multiple linear regression analysis with mean exercise SaO2 as the dependent variable. Two variables (Dco and resting SaO2) were found to correlate strongly with mean exercise SaO2 (multiple r = 0.80; p less than 0.00001) and accounted for 65 percent of the variability among patients. The PaCO2 influenced resting SaO2 but had no independent influence on exercise SaO2. Subsequently, the model of mean exercise SaO2 derived in the present analysis was found to accurately predict mean exercise SaO2 in a group of 19 similar patients (r = 0.85; p less than 0.0001). While these findings do not establish a cause-and-effect relationship, they may provide clinicians with further insight as to which patients are likely to desaturate during exercise.