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Background: The purpose of this randomised double-blind double-dummy placebo-controlled trial was to investigate whether etanercept, a tumour necrosis factor α (TNFα) antagonist, would provide more effective anti-inflammatory treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) than prednisone.Methods: We enrolled 81 patients with acute exacerbations of COPD and randomly assigned them to treatment with either 40 mg oral prednisone given daily for 10 days or to 50 mg etanercept given subcutaneously at randomisation and 1 week later. Both groups received levofloxacin for 10 days plus inhaled bronchodilators. The primary endpoint was the change in the patient's forced expiratory volume in 1 s (FEV(1)) 14 days after randomisation. Secondary endpoints included 90-day treatment failure rates and dyspnoea and quality of life.Results: At 14 days the mean±SE change in FEV(1) from baseline was 20.1±5.0% and 15.2±5.7% for the prednisone and etanercept groups, respectively. The mean between-treatment difference was 4.9% (95% CI -10.3% to 20.2%), p=0.52. Rates of treatment failure at 90 days were similar in the prednisone and etanercept groups (32% vs 40%, p=0.44), as were measures of dyspnoea and quality of life. Subgroup analysis revealed that patients with serum eosinophils >2% at exacerbation tended to experience fewer treatment failures if treated with prednisone compared with etanercept (22% vs 50%, p=0.08).Conclusions: Etanercept was not more effective than prednisone for treatment of acute exacerbations of COPD. Efficacy of prednisone was most apparent in patients who presented with serum eosinophils >2%.Clinical Trials: gov number NCT 00789997. [ABSTRACT FROM AUTHOR]

Background: The economic impact of multimorbidity in severe or difficult-to-treat asthma has not been comprehensively investigated., Aims: To estimate the incremental healthcare costs of coexisting chronic conditions (comorbidities) in patients with severe asthma, compared with non-severe asthma and no asthma., Methods: Using health administrative data in British Columbia, Canada (1996-2016), we identified, based on the intensity of drug use and occurrence of exacerbations, individuals who experienced severe asthma in an incident year. We also constructed matched cohorts of individuals without an asthma diagnosis and those who had mild/dormant or moderate asthma (non-severe asthma) throughout their follow-up. Health service use records during follow-up were categorised into 16 major disease categories based on the International Classification of Diseases. Incremental costs (in 2016 Canadian Dollars, CAD$1=US$0.75=₤0.56=€0.68) were estimated as the adjusted difference in healthcare costs between individuals with severe asthma compared with those with non-severe asthma and non-asthma., Results: Relative to no asthma, incremental costs of severe asthma were $2779 per person-year (95% CI 2514 to 3045), with 54% ($1508) being attributed to comorbidities. Relative to non-severe asthma, severe asthma was associated with incremental costs of $1922 per person-year (95% CI 1670 to 2174), with 52% ($1003) being attributed to comorbidities. In both cases, the most costly comorbidity was respiratory conditions other than asthma ($468 (17%) and $451 (23%), respectively)., Conclusions: Comorbidities accounted for more than half of the incremental medical costs in patients with severe asthma. This highlights the importance of considering the burden of multimorbidity in evidence-informed decision making for patients with severe asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development., Methods: Using administrative health data, we retrospectively followed patients 14-55 years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors., Results: We followed 13,467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10 years. Sex was not associated with the clinical course., Conclusions: Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population., Aims: To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers., Method: We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for 'mild' and 'moderate-severe' COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA)., Results: The prevalence of COPD (FEV1/FVC

Rationale: Exacerbations of COPD are defined clinically by worsening of chronic respiratory symptoms. Chronic respiratory symptoms are common in the general population. There are no data on the frequency of exacerbation-like events in individuals without spirometric evidence of COPD., Aims: To determine the occurrence of 'exacerbation-like' events in individuals without airflow limitation, their associated risk factors, healthcare utilisation and social impacts., Method: We analysed the cross-sectional data from 5176 people aged 40 years and older who participated in a multisite, population-based study on lung health. The study cohort was stratified into spirometrically defined COPD (post-bronchodilator FEV1/FVC < 0.7) and non-COPD (post bronchodilator FEV1/FVC ≥ 0.7 and without self-reported doctor diagnosis of airway diseases) subgroups and then into those with and without respiratory 'exacerbation-like' events in the past year., Results: Individuals without COPD had half the frequency of 'exacerbation-like' events compared with those with COPD. In the non-COPD group, the independent associations with 'exacerbations' included female gender, presence of wheezing, the use of respiratory medications and self-perceived poor health. In the non-COPD group, those with exacerbations were more likely than those without exacerbations to have poorer health-related quality of life (12-item Short-Form Health Survey), miss social activities (58.5% vs 18.8%), miss work for income (41.5% vs 17.3%) and miss housework (55.6% vs 16.5%), p<0.01 to <0.0001., Conclusions: Events similar to exacerbations of COPD can occur in individuals without COPD or asthma and are associated with significant health and socioeconomic outcomes. They increase the respiratory burden in the community and may contribute to the false-positive diagnosis of asthma or COPD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The role of long-acting β-agonists (LABA) added to inhaled corticosteroids (ICS) in the management of asthma is extensively debated. We thought to assess the risk of asthma-related hospitalisation in individuals who regularly filled prescriptions for ICS+LABA compared to those who regularly filled prescriptions for ICS alone or LABA alone, and compared to those who did not regularly fill such medications., Methods: Using administrative health databases of the province of British Columbia (BC), Canada, from 1997 to 2012, we conducted a nested case-control analysis of a cohort of asthma patients. Cases were defined as those who experienced asthma-related hospitalisation after the first year of their entry into the cohort. For each case, up to 20 controls were matched based on age, sex, date of cohort entry, and several measures of asthma severity. We categorised individuals as regularly exposed, irregularly exposed, or non-exposed to ICS alone, LABA alone, or ICS+LABA based on dispensation records in the past 12 months. The primary outcome measures were the rate ratio (RR) of the asthma-related hospitalisation among categories of regular exposure., Results: 3319 cases were matched to 43 023 controls. The RR for regular dispensation of ICS+LABA was 1.14 (95% CI 0.93 to 1.41) compared with regular dispensation of ICS alone and 0.45 (95% CI 0.29 to 0.70) compared with regular dispensation of LABA alone. Those who regularly dispensed LABA had to dispense an ICS for at least three quarters of a year to reduce their risk to that of those who did not dispense LABA., Conclusions: Regular dispensation of ICS+LABA was not associated with an increased risk of asthma-related hospitalisation compared with regular dispensation of ICS alone. Adherence to ICS in patients who regularly receive ICS+LABA seems to be an important factor in the prevention of adverse asthma-related outcomes.

Background: Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD., Methods: This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 microg once daily + placebo twice daily (TP group); (2) T 18 microg once daily + S 25 microg/puff, 2 puffs twice daily (TS group); and (3) T 18 microg once daily + FS 250/25 microg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed., Results: The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243,180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP., Conclusions: TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

The use of anti-tumour necrosis factor (TNF) agents has expanded significantly over the past few years, particularly for rheumatological diseases and Crohn's disease. A number of associated opportunistic infections have been observed as a result of suppression of T cell-mediated immunity, the most frequent being tuberculosis. We report the first case of pulmonary actinomycosis in a patient receiving regular infusions of infliximab, an anti-TNF agent, for Crohn's disease.

Asthma exacerbations are common. They account for a significant morbidity and contribute a disproportionate amount to the cost of asthma management. The optimal strategies for the prevention of asthma exacerbations include the early introduction of anti-inflammatory treatment-most commonly, low dose inhaled corticosteroids. This should be coupled with a structured education programme which has a written action plan as an integral component. Where patients continue to be poorly controlled, the addition of a long acting beta agonist should be considered. The latter should not be used as monotherapy and should always be used with inhaled corticosteroids. Atopic patients with a history of repeated exacerbations, especially if they are steroid dependent and with a raised IgE, may be considered as potential candidates for omalizumab. In the early stages of an asthma exacerbation, doubling the dose of inhaled corticosteroids has been shown to be ineffective. The ideal strategy for the management of worsening asthma in patients on combination treatment, especially salmeterol and fluticasone, is uncertain. There is an emerging body of evidence for strategies on how to prevent progression to an exacerbation in patients taking a combination of budesonide and formoterol.

Background: Previous guidelines recommend doubling the daily dose of maintenance inhaled corticosteroid to treat or prevent progression of exacerbations of asthma., Methods: Over a 6 month period a cohort of patients were evaluated prospectively and randomised in a double blind controlled trial to treatment with either a continued maintenance dose (MD) of inhaled corticosteroid or doubling the dose (DD) at the time of an exacerbation., Results: A total of 290 patients were randomised (33% male) and 98 (DD, n = 46) experienced evaluable asthma exacerbations during the study period. Mean (SD) baseline characteristics at randomisation (age 33.5 (14.0) years; forced expiratory volume in 1 second (FEV(1)) 2.8 (0.7) l; peak expiratory flow (PEF) 422.9 (110.5) l/min) were similar in both groups. In the DD group 41% of patients were considered treatment failures because they either required systemic steroids (n = 12), had an unscheduled visit to a physician (n = 1), or their asthma did not return to baseline (n = 6). This did not differ from the MD group in which 40% were treatment failures (n = 9, 0, and 12, respectively; p = 0.94)., Conclusions: In patients who regularly take an inhaled corticosteroid, doubling the maintenance dose may not affect the pattern of the exacerbation.

Background: While smear positive patients with tuberculosis (TB) are considered more infectious than smear negative patients, the latter can also transmit TB., Methods: In a molecular epidemiology study of 791 patients in the Greater Vancouver regional district, the number of episodes of TB transmission from two groups of smear negative clustered patients by RFLP (assumed to be involved in recent transmission) was estimated after assessing for potential bias. Group 1 (n = 79) included patients with pulmonary TB or pulmonary + extrapulmonary disease (PTB or PTB+EPTB); group 2 (n = 129) included all patients in group 1 + extrapulmonary cases alone., Results: In the total sample the mean (SD) age was 51 (21) years, 54.3% were male, and 17.0% of patients were clustered. Compared with smear negative patients, smear positive patients were more likely to be in a cluster (OR = 2.0, 95% CI 1.1 to 3.6) and to have had a history of ethanol abuse (OR = 2.7, 95% CI 1.0 to 6.7), diabetes mellitus (OR = 2.8, 95% CI 1.1 to 7.0), injection drug use (OR = 3.1, 95% CI 1.1 to 8.3), and to have had a previous hospital admission (OR = 8.5, 95% CI 5.1 to 14.0). The proportion of episodes of transmission from smear negative clustered patients ranged from 17.3% to 22.2% in group 1 and from 25% to 41% in group 2., Conclusion: In Greater Vancouver, smear negative cases appear responsible for at least one sixth of culture positive episodes of TB transmission.

Background: The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin test results requires knowledge of the possible confounding factors such as previous BCG vaccination. Uncertainty about the effect of BCG vaccination on tuberculin skin testing and the strength with which recommendations are made to individual patients regarding treatment of LTBI have identified a need to analyse the available data on the effect of BCG on skin testing. A meta-analysis of the evidence for the effect of BCG vaccination on tuberculin skin testing in subjects without active tuberculosis was therefore performed., Methods: Medline was searched for English language articles published from 1966 to 1999 using the key words "BCG vaccine", "tuberculin test/PPD", and "skin testing". Bibliographies of relevant articles were reviewed for additional studies that may have been missed in the Medline search. Articles were considered for inclusion in the meta-analysis if they had recorded tuberculin skin test results in subjects who had received BCG vaccination more than 5 years previously and had a concurrent control group. Only prospective studies were considered. The geographical location, number of participants, type of BCG vaccine used, type of tuberculin skin test performed, and the results of the tuberculin skin test were extracted., Results: The abstracts and titles of 980 articles were identified, 370 full text articles were reviewed, and 26 articles were included in the final analysis. Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 2.65 [corrected] (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination., Conclusions: In subjects without active tuberculosis, immunisation with BCG significantly increases the likelihood of a positive tuberculin skin test. The interpretation of the skin test therefore needs to be made in the individual clinical context and with evaluation of other risk factors for infection. The size of the induration should also be considered when making recommendations for treatment of latent infection.

Background: Airway wall thickening has been observed in post mortem studies of patients with asthma. Assessment of airway wall thickening by high resolution computed tomographic (HRCT) scanning has been reported in experimental studies. We have used HRCT scanning to measure airway wall thickness at the segmental and subsegmental levels in 40 patients with asthma and 14 normal controls., Methods: The subjects were prospectively divided into four age and sex matched groups: 14 patients with a history of near fatal attack of asthma (NFA; group 1), 12 patients with moderate asthma (group 2), 13 patients with mild asthma (group 3), and 14 normal controls (group 4). All subjects were non-smokers. High resolution (1 mm collimation) CT scans of the chest were done at five different levels., Results: The mean (SD) forced expiratory volume in one second (FEV1) was 68 (20)% of predicted for group 1, 73 (12)% for group 2, 102 (12)% for group 3, and 103 (12)% for group 4. The ratio of airway wall thickness to outer diameter (T/D) and the percentage wall area (WA%) defined as (wall area/total airway area) x 100 were used to compare airway wall thickness between the groups. The mean (SD) T/D and WA% were 0.27 (0.05) and 78.0 (9.2)% for group 1, 0.27 (0.05) and 78.8 (9.2)% for group 2, 0.25 (0.04) and 74.2 (7.5)% for group 3, and 0.23 (0.04) and 70.9 (8.2)% for group 4. T/D and WA% were not significantly different between groups 1 and 2. However, both groups 1 and 2 had higher T/D and WA% than either group 3 or 4 (p < 0.001) and group 3 had a higher T/D and WA% than group 4 (p < 0.03). The differences (95% CI) between the groups in WA% were 7.1% (0 to 14.4) for groups 1 and 4, 3.8% (-3.4 to 10) for groups 1 and 3, and 3.3% (-4.4 to 10) for groups 3 and 4. The differences between the groups in T/D and WA% were noted both for those with airways with a luminal diameter of > 2 mm and those with a luminal diameter of < or = 2 mm., Conclusions: All the patient groups had greater airway wall thickening than the normal subjects as assessed by HRCT scanning, but patients with more severe asthma had greater airway wall thickening than those with mild asthma. The methodology described in this study may be useful in assessing airway calibre in early intervention studies with anti-inflammatory therapy.