Chronic airflow obstruction and ambient particulate air pollution.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Helsinki by nature: The Nature Step to Respiratory Health.

BACKGROUND: The Nature Step to Respiratory Health was the overarching theme of the 12th General Meeting of the Global Alliance against Chronic Respiratory Diseases (GARD) in Helsinki, August 2018. New approaches are needed to improve respiratory health and reduce premature mortality of chronic diseases by 30% till 2030 (UN Sustainable Development Goals, SDGs). Planetary health is defined as the health of human civilization and the state of the natural systems on which it depends. Planetary health and human health are interconnected, and both need to be considered by individuals and governments while addressing several SDGs. RESULTS: The concept of the Nature Step has evolved from innovative research indicating, how changed lifestyle in urban surroundings reduces contact with biodiverse environments, impoverishes microbiota, affects immune regulation and increases risk of NCDs. The Nature Step calls for strengthening connections to nature. Physical activity in natural environments should be promoted, use of fresh vegetables, fruits and water increased, and consumption of sugary drinks, tobacco and alcohol restricted. Nature relatedness should be part of everyday life and especially emphasized in the care of children and the elderly. Taking "nature" to modern cities in a controlled way is possible but a challenge for urban planning, nature conservation, housing, traffic arrangements, energy production, and importantly for supplying and distributing food. Actions against the well-known respiratory risk factors, air pollution and smoking, should be taken simultaneously. CONCLUSIONS: In Finland and elsewhere in Europe, successful programmes have been implemented to reduce the burden of respiratory disorders and other NCDs. Unhealthy behaviour can be changed by well-coordinated actions involving all stakeholders. The growing public health concern caused by NCDs in urban surroundings cannot be solved by health care alone; a multidisciplinary approach is mandatory.

Prevalence and Characteristics of Asthma-Chronic Obstructive Pulmonary Disease Overlap in Routine Primary Care Practices.

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 information about ACO in primary care.Objectives: To estimate the prevalence and describe characteristics of individuals with ACO in primary care practices among patients currently diagnosed with asthma, COPD, or both; and to compare the prevalence and characteristics of ACO among the three source populations.Methods: The Respiratory Effectiveness Group conducted a cross-sectional study of individuals ≥40 years old and with ≥2 outpatient primary care visits over a 2-year period in the UK Optimum Patient Care Research Database. Patients were classified into one of three source populations based on diagnostic codes: 1) COPD only, 2) both asthma and COPD, or 3) asthma only. ACO was defined as the presence of all of the following 1) age ≥40 years, 2) current or former smoking, 3) post-bronchodilator airflow limitation (forced expiratory volume in 1 second/forced vital capacity <0.7), and 4) ≥12% and ≥200 ml reversibility in post-bronchodilator forced expiratory volume in 1 second.Results: Among 2,165 individuals (1,015 COPD only, 395 with both asthma and COPD, and 755 asthma only), the overall prevalence of ACO was 20% (95% confidence interval, 18-23%). Patients with ACO had a mean age of 70 years (standard deviation, 11 yr), 60% were men, 73% were former smokers (the rest were current smokers), and 66% were overweight or obese. Comorbid conditions were common in patients with ACO, including diabetes (53%), cardiovascular disease (36%), hypertension (30%), eczema (23%), and rhinitis (21%). The prevalence of ACO was higher in patients with a diagnosis of both asthma and COPD (32%) compared with a diagnosis of COPD only (20%; P < 0.001) or asthma only (14%; P < 0.001). Demographic and clinical characteristics of ACO varied across these three source populations.Conclusions: One in five individuals with a diagnosis of COPD, asthma, or both asthma and COPD in primary care settings have ACO based on the Respiratory Effectiveness Group ACO Working group criteria. The prevalence and characteristics of patients with ACO varies across the three source populations.

Overdiagnosis of COPD in Subjects With Unobstructed Spirometry: A BOLD Analysis.

BACKGROUND: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012. METHODS: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7). RESULTS: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication. CONCLUSIONS: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.

Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. OBJECTIVE: These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. METHODS: Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/µL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. RESULTS: Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. CONCLUSIONS: Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Effects of PACK guide training on the management of asthma and chronic obstructive pulmonary disease by primary care clinicians: a pragmatic cluster randomised controlled trial in Florianópolis, Brazil.

INTRODUCTION: The Practical Approach to Care Kit (PACK) guide was localised for Brazil, where primary care doctors and nurses were trained to use it. METHODS: Twenty-four municipal clinics in Florianópolis were randomly allocated to receive outreach training and the guide, and 24 were allocated to receive only the guide. 6666 adult patients with asthma or chronic obstructive pulmonary disease (COPD) were enrolled, and trial outcomes were measured over 12 months, using electronic medical records. The primary outcomes were composite scores of treatment changes and spirometry, and new asthma and COPD diagnosis rates. RESULTS: Asthma scores in 2437 intervention group participants were higher (74.8%, 20.4% and 4.8% with scores of 0, 1 and 2, respectively) than in 2633 control group participants (80.0%, 16.8% and 3.2%) (OR for higher score 1.32, 95% CI 1.08 to 1.61, p=0.006). Adjusted for asthma scores recorded in each clinic before training started, the OR was 1.24 (95% CI 1.03 to 1.50, p=0.022). COPD scores in 1371 intervention group participants (77.7%, 17.9% and 4.3% with scores of 0, 1 and 2) did not differ from those in 1181 control group participants (80.5%, 15.8% and 3.7%) (OR 1.21, 95% CI 0.94 to 1.55, p=0.142). Rates of new asthma and COPD diagnoses, and hospital admission, and indicators of investigation, diagnosis and treatment of comorbid cardiovascular disease, diabetes and depression, and tobacco cessation did not differ between trial arms. CONCLUSION: PACK training increased guideline-based treatment and spirometry for asthma but did not affect COPD or comorbid conditions, or diagnosis rates. TRIAL REGISTRATION: NCT02786030 (https://clinicaltrials.gov/).

Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort.

BACKGROUND: An association between chronic airflow limitation (CAL) and a history of pulmonary tuberculosis (PTB) has been confirmed in epidemiological studies, but the mechanisms responsible for this association are unclear. It is debated whether CAL in this context should be viewed as chronic obstructive pulmonary disease (COPD) or a separate phenotype. OBJECTIVE: To compare lung physiology and high-resolution computed tomography (HRCT) findings in subjects with CAL and evidence of previous (healed) PTB with those in subjects with smoking-related COPD without evidence of previous PTB. METHODS: Subjects with CAL identified during a Burden of Obstructive Lung Disease (BOLD) study performed in South Africa were studied. Investigations included questionnaires, lung physiology (spirometry, body plethysmography and diffusing capacity) and quantitative HRCT scans to assess bronchial anatomy and the presence of emphysema (<-950 HU), gas trapping (<-860 HU) and fibrosis (>-200 HU). Findings in subjects with a past history and/or HRCT evidence of PTB were compared with those in subjects without these features. RESULTS: One hundred and seven of 196 eligible subjects (54.6%) were enrolled, 104 performed physiology tests and 94 had an HRCT scan. Based on history and HRCT findings, subjects were categorised as no previous PTB (NPTB, n=31), probable previous PTB (n=33) or definite previous PTB (DPTB, n=39). Subjects with DPTB had a lower diffusing capacity (Δ=-17.7%; p=0.001) and inspiratory capacity (Δ=-21.5%; p=0.001) than NPTB subjects, and higher gas-trapping and fibrosis but not emphysema scores (Δ=+6.2% (p=0.021), +0.36% (p=0.017) and +3.5% (p=0.098), respectively). CONCLUSIONS: The mechanisms of CAL associated with previous PTB appear to differ from those in the more common smoking-related COPD and warrant further study.

Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

RATIONALE: Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. OBJECTIVES: To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. METHODS: We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups. CONCLUSIONS: Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

Consistent improvement in health-related quality of life with tiotropium in patients with chronic obstructive pulmonary disease: Novel and conventional responder analyses.

INTRODUCTION: Improving health-related quality of life (HRQoL) in COPD patients is an important pharmacotherapeutic objective. This study investigated the extent, consistency, and durability of tiotropium maintenance therapy impact on HRQoL in moderate-to-very severe COPD. METHODS: Patients received once-daily tiotropium 18 µg (n = 5244) or placebo (n = 4799) via HandiHaler® (10 trials), or once-daily tiotropium 5 µg (n = 2622) or placebo (n = 2618) via Respimat® inhaler (3 trials). St George's Respiratory Questionnaire (SGRQ) total scores were measured at baseline, and 6 months (13 trials) and 1 year (9 trials) from treatment start. Adjusted mean differences between treatments for change from baseline in total scores were calculated at each time-point for each trial. Responder and deteriorator rates (decrease or increase in score ≥4 units from baseline, respectively), net benefit (responder rate increase plus deteriorator rate decrease), and cumulative improvement and deterioration were determined. RESULTS: Adjusted mean total score differences between treatments for change from baseline were significant (p < 0.05) in favor of tiotropium in 10/13 trials at 6 months and in 8/9 trials at 1 year. In all trials, estimated differences in responder rates between treatments favored tiotropium (significant [p < 0.05]: 5/13 trials at 6 months; 8/9 trials at 1 year). Net benefit favored tiotropium and cumulative improvement rates were consistently greater and deterioration rates consistently lower for tiotropium versus placebo. CONCLUSIONS: Tiotropium maintenance therapy significantly and consistently improved HRQoL in moderate-to-very severe COPD patients in a durable manner. These results may provide a benchmark for assessing benefits on HRQoL of other COPD treatments.

Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status.

BACKGROUND: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting ß2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma. OBJECTIVE: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics. METHODS: Two randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat(®) 5 µg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics. RESULTS: 912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility. CONCLUSION: Once-daily tiotropium 5 µg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma. TRIAL REGISTRY: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov.

Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial.

BACKGROUND: Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid (ICS) maintenance therapy. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma. METHODS: In this 48-week, double-blind, placebo-controlled, parallel-group study, 398 patients aged 12 to 17 years were randomized to receive 5 µg (2 puffs of 2.5 µg) or 2.5 µg (2 puffs of 1.25 µg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to ICS background therapy, with or without a leukotriene receptor antagonist; long-acting ß2-agonist therapy was not permitted during the study. RESULTS: Improvement in peak FEV1 within 3 hours after dosing at 24 weeks (primary end point) was statistically significant with both tiotropium doses compared with placebo: 5 µg of tiotropium, 174 mL (95% CI, 76-272 mL); 2.5 µg of tiotropium, 134 mL (95% CI, 34-234 mL). Significant improvements in trough FEV1 at week 24 (a secondary end point) were observed with the 5-µg dose only. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed. CONCLUSIONS: Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma. Larger responses were observed with the 5-µg tiotropium dose.

Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma.

BACKGROUND: Roflumilast, a selective phosphodiesterase 4 inhibitor, has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma, but its efficacy in patients with moderate-to-severe asthma has not been assessed. We hypothesized that this drug might provide benefit if combined with montelukast, a leukotriene receptor antagonist, in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting ß-agonists. OBJECTIVE: We sought to examine the efficacy, safety, and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma. METHODS: In a phase 2, randomized, double-blind, placebo-controlled, multiple-dose, 2-sequence, crossover study, 64 patients were randomized to receive 500 µg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast (sequence AB) or placebo plus 10 mg of montelukast followed by 500 µg of roflumilast plus 10 mg of montelukast (sequence BA). All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting ß-agonist. RESULTS: The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinically meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast. Also, improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment. Adverse events were consistent with the known safety profile of roflumilast. CONCLUSION: The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication.

Indications for the use of bronchial thermoplasty in severe asthma.

Approximately 5% of the ~3 million asthmatics in South Africa have severe asthma that is associated with substantial morbidity, cost, absenteeism, preventable mortality, and the requirement for costly chronic medication that may be associated with significant adverse events. There is an unmet need for alternative safer and more effective interventions for severe asthma. A recently introduced option, bronchial thermoplasty (BT), imparts radiofrequency-generated heat energy to the airways to cause regression of airway smooth muscle. The effectiveness of this technique has been confirmed in randomised control trials and is now endorsed by several international guidelines, including the Global Initiative for Asthma (GINA) guideline, the British Asthma Guideline, and the UK National Institute of Clinical Excellence (NICE) guideline. We recommend BT as a potential therapeutic intervention for severe uncontrolled asthma, provided that it is performed by an experienced pulmonologist at an accredited centre and done within the broader context of appropriate management of the disease by doctors experienced in treating difficult-to-control asthma.

Tuberculosis associates with both airflow obstruction and low lung function: BOLD results.

In small studies and cases series, a history of tuberculosis has been associated with both airflow obstruction, which is characteristic of chronic obstructive pulmonary disease, and restrictive patterns on spirometry. The objective of the present study was to assess the association between a history of tuberculosis and airflow obstruction and spirometric abnormalities in adults.The study was performed in adults, aged 40 years and above, who took part in the multicentre, cross-sectional, general population-based Burden of Obstructive Lung Disease study, and had provided acceptable post-bronchodilator spirometry measurements and information on a history of tuberculosis. The associations between a history of tuberculosis and airflow obstruction and spirometric restriction were assessed within each participating centre, and estimates combined using meta-analysis. These estimates were stratified by high- and low/middle-income countries, according to gross national income.A self-reported history of tuberculosis was associated with airflow obstruction (adjusted odds ratio 2.51, 95% CI 1.83-3.42) and spirometric restriction (adjusted odds ratio 2.13, 95% CI 1.42-3.19).A history of tuberculosis was associated with both airflow obstruction and spirometric restriction, and should be considered as a potentially important cause of obstructive disease and low lung function, particularly where tuberculosis is common.

Development and validation of a novel risk score for asthma exacerbations: The risk score for exacerbations.

BACKGROUND: Identifying patients at risk of future severe asthma exacerbations, those whose asthma might be less treatment responsive, or both might guide treatment selection. OBJECTIVE: We sought to investigate predictors for failure to achieve Global Initiative for Asthma (GINA)-defined good current asthma control and severe exacerbations on treatment and to develop a simple risk score for exacerbations (RSE) for clinical use. METHODS: A large data set from 3 studies comparing budesonide/formoterol maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting ß2-agonist therapy was analyzed. Baseline patient characteristics were investigated to determine dominant predictors for uncontrolled asthma at 3 months and for severe asthma exacerbations within 12 months of commencing treatment. The RSE, right censored at 6 months to include all 3 studies, was based on the dominant predictors for exacerbations in two thirds of the data set and validated in one third. RESULTS: Patients (n = 7446) whose symptoms were not controlled on GINA treatment steps 3 and 4 and with 1 or more exacerbations (as judged by a clinician based on patient records, history, or both) in the previous year were included. On multivariate analysis, GINA step, reliever use, postbronchodilator FEV1, and 5-item Asthma Control Questionnaire score were dominant (all P < .001) predictors for both the risk of uncontrolled asthma and severe exacerbations. Additional dominant predictors for uncontrolled asthma were smoking status and asthma symptom scores and an additional predictor for severe exacerbation was body mass index. An exponential increase in risk was observed with increments in RSE based on 5 selected predictors for exacerbations. CONCLUSION: Risk of uncontrolled asthma at 3 months and a severe exacerbation within 12 months can be estimated from simple clinical assessments. Prospective validation of these predictive factors and the RSE is required. Use of these models might guide the management of asthmatic patients.

Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial.

IMPORTANCE: Behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit, but it is unclear whether combining nicotine replacement therapy (NRT) with varenicline to improve abstinence is effective and safe. OBJECTIVE: To evaluate the efficacy and safety of combining varenicline and a nicotine patch vs varenicline alone in smoking cessation. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, placebo-controlled clinical trial with a 12-week treatment period and a further 12-week follow-up conducted in 7 centers in South Africa from April 2011 to October 2012. Four hundred forty-six generally healthy smokers were randomized (1:1); 435 were included in the efficacy and safety analyses. INTERVENTIONS: Nicotine or placebo patch treatment began 2 weeks before a target quit date (TQD) and continued for a further 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. MAIN OUTCOMES AND MEASURES: Tobacco abstinence was established and confirmed by exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks. The primary end point was the 4-week exhaled carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 of treatment, ie, the proportion of participants able to maintain complete abstinence from smoking for the last 4 weeks of treatment, as assessed using multiple imputation analysis. Secondary end points included point prevalence abstinence at 6 months, continuous abstinence rate from weeks 9 through 24, and adverse events. Multiple imputation also was used to address loss to follow-up. RESULTS: The combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR], 1.85; 95% CI, 1.19-2.89; P = .007) and 24 weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) and point prevalence abstinence rate at 6 months (65.1% vs 46.7%; OR, 2.13; 95% CI, 1.32-3.43; P = .002). In the combination treatment group, there was a numerically greater incidence of nausea, sleep disturbance, skin reactions, constipation, and depression, with only skin reactions reaching statistical significance (14.4% vs 7.8%; P = .03); the varenicline-alone group experienced more abnormal dreams and headaches. CONCLUSIONS AND RELEVANCE: Varenicline in combination with NRT was more effective than varenicline alone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 months. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01444131.

Comparison of vilanterol, a novel long-acting beta2 agonist, with placebo and a salmeterol reference arm in asthma uncontrolled by inhaled corticosteroids.

BACKGROUND: Current maintenance therapies for asthma require twice-daily dosing. Vilanterol (VI) is a novel long-acting beta2 agonist, under development in combination with fluticasone furoate, a new inhaled corticosteroid (ICS). Findings from a previous 4-week study suggested that VI has inherent 24-hour activity and is therefore suitable for once-daily dosing. The study described here was a double-blind, double-dummy, randomised, placebo-controlled trial, the aim of which was to assess the efficacy of once-daily VI compared with placebo in patients with persistent asthma. The primary endpoint was change from baseline in 24-hour weighted mean forced expiratory volume in 1 second after 12 weeks of treatment vs. placebo. An active control arm received salmeterol (SAL) twice daily. All patients were maintained on a stable background dose of ICS. RESULTS: Patients (n = 347) received VI, placebo or SAL (1:1:1). For the primary endpoint, substantial improvements in lung function were seen with VI (359 ml), SAL (283 ml) and placebo (289 ml). There were no statistically significant treatment differences between either the VI (70 ml, P = 0.244) or SAL (-6 ml, P = 0.926) groups and placebo. Both active treatments were well tolerated, with similarly low rates of treatment-related adverse events compared with placebo. No treatment-related serious adverse events occurred. CONCLUSIONS: This study failed to show a treatment difference between VI and placebo for the primary endpoint, in the presence of a placebo response of unforeseen magnitude. Because the placebo response was so large, it is not possible to draw meaningful conclusions from the data. The reason for this magnitude of effect is unclear but it may reflect increased compliance with the anti-inflammatory therapy regimen during the treatment period. TRIAL REGISTRATION: NCT01181895 at ClinicalTrials.gov.

Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty--a BOLD analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a commonly reported cause of death and associated with smoking. However, COPD mortality is high in poor countries with low smoking rates. Spirometric restriction predicts mortality better than airflow obstruction, suggesting that the prevalence of restriction could explain mortality rates attributed to COPD. We have studied associations between mortality from COPD and low lung function, and between both lung function and death rates and cigarette consumption and gross national income per capita (GNI). METHODS: National COPD mortality rates were regressed against the prevalence of airflow obstruction and spirometric restriction in 22 Burden of Obstructive Lung Disease (BOLD) study sites and against GNI, and national smoking prevalence. The prevalence of airflow obstruction and spirometric restriction in the BOLD sites were regressed against GNI and mean pack years smoked. RESULTS: National COPD mortality rates were more strongly associated with spirometric restriction in the BOLD sites (<60 years: men rs=0.73, p=0.0001; women rs=0.90, p<0.0001; 60+ years: men rs=0.63, p=0.0022; women rs=0.37, p=0.1) than obstruction (<60 years: men rs=0.28, p=0.20; women rs=0.17, p<0.46; 60+ years: men rs=0.28, p=0.23; women rs=0.22, p=0.33). Obstruction increased with mean pack years smoked, but COPD mortality fell with increased cigarette consumption and rose rapidly as GNI fell below US$15 000. Prevalence of restriction was not associated with smoking but also increased rapidly as GNI fell below US$15 000. CONCLUSIONS: Smoking remains the single most important cause of obstruction but a high prevalence of restriction associated with poverty could explain the high 'COPD' mortality in poor countries.