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Background: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts., Research Question: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables?, Study Design and Methods: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC)., Results: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV 1 , 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy., Interpretation: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oral corticosteroids are important components of pharmacotherapy in severe asthma. Our objective was to describe the extent, trends, and factors associated with exposure to oral corticosteroids (OCS) in a severe asthma cohort., Methods: We used administrative health databases of British Columbia, Canada (2000-2014) and validated algorithms to retrospectively create a cohort of severe asthma patients. Exposure to OCS within each year of follow-up was measured in two ways: maintenance use as receiving on average ≥ 2.5 mg/day (prednisone-equivalent) OCS, and episodic use as the number of distinct episodes of OCS exposure for up to 14 days. Trends and factors associated with exposure on three time axes (calendar year, age, and time since diagnosis) were evaluated using Poisson regression., Results: 21,144 patients (55.4% female; mean entry age 28.7) contributed 40,803 follow-up years, in 8.2% of which OCS was used as maintenance therapy. Maintenance OCS use declined by 3.8%/calendar year (p < 0.001). The average number of episodes of OCS use was 0.89/year, which increased by 1.1%/calendar year (p < 0.001). Trends remained significant for both exposure types in adjusted analyses. Both maintenance and episodic use increased by age and time since diagnosis., Conclusions: This population-based study documented a secular downward trend in maintenance OCS use in a period before widespread use of biologics. This might have been responsible for a higher rate of exacerbations that required episodic OCS therapy. Such trends in OCS use might be due to changes in the epidemiology of severe asthma, or changes in patient and provider preferences over time.

Background: As-needed budesonide/formoterol is effective in patients with mild asthma for whom low-dose inhaled corticosteroid (ICS) maintenance therapy is appropriate. We assessed the cost-effectiveness of this regimen versus maintenance low-dose ICS plus as-needed short-acting β2-agonist (SABA)., Methods: A probabilistic Markov cohort model was developed that simulated time within/outside severe asthma exacerbations, conducted from a UK NHS perspective with a 70-year time horizon. Clinical efficacy inputs were derived from the SYGMA 2 trial. Patients with mild asthma eligible for low-dose maintenance ICS therapy received as-needed budesonide/formoterol 200/6 μg or twice-daily budesonide 200 μg maintenance therapy plus as-needed terbutaline 0.5 mg. A severe exacerbation was defined as worsening asthma requiring systemic corticosteroid use alone/in combination with an emergency department visit, or hospitalisation for acute asthma. Utility values were derived from SYGMA 2 EQ-5D-5L data, and all-cause- and asthma-related mortality, reduction in utility of an exacerbation, and costs were based on published data. The base-case analysis discount rate was 3.5%. Model robustness was evaluated with one-way sensitivity, probabilistic sensitivity, and two scenario analyses., Results: On average, as-needed budesonide/formoterol was associated with a £292.99 cost saving and quality-adjusted life year (QALY) gains of 0.001 versus ICS + SABA. At a willingness-to-pay of £20,000/QALY, as-needed budesonide/formoterol had >85% probability of being cost-effective versus ICS + SABA. Key drivers were budesonide/formoterol and budesonide maintenance annual exacerbation rates, mean daily budesonide/formoterol inhalations, and costs and outcomes discount rates., Conclusions: From a UK healthcare payer perspective, as-needed budesonide/formoterol is a cost-effective option for the treatment of mild asthma versus regular ICS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The effects of inhaled corticosteroids (ICS) on fracture risk in older women with chronic respiratory diseases are not well established. Our results indicate long-term ICS use in this population does not increase the risk of major osteoporotic fracture. This finding further elucidates the long-term safety of ICS in older women., Introduction: Inhaled corticosteroids (ICS) are frequently used in older women with chronic respiratory diseases. There is insufficient evidence regarding the association between long-term ICS use and the risk of fragility fractures in this population., Methods: We used linked Manitoba health administrative databases and the provincial bone mineral density (BMD) registry (1996-2013) to identify women ≥ 40 years of age with asthma and/or chronic obstructive pulmonary disease (COPD) within 3 years preceding the baseline BMD test. We followed them until the first major osteoporotic fracture or end of study, whichever came first. ICS use, stratified by exposure tertiles, was measured within the 12-month period following the baseline BMD test (by total days and quantity, primary outcome), and over the entire follow-up period (by medication possession ratio (MPR) and average annual dose, secondary outcome). The hazard ratio of fracture with ICS use was estimated using a Cox proportional hazards model, controlling for baseline determinants of fracture., Results: Of 6880 older women with asthma (38%) or COPD (62%), 810 (12%) experienced a major osteoporotic fracture over a mean follow-up of 7.7 years (SD = 3.9). ICS use at any tertile was not associated with an increased risk of fracture (dispensed days, p = 0.90; dispensed quantity, p = 0.67). Similarly, ICS use at any tertile during the entire follow-up period was not associated with an increased risk of fracture (MPR, p = 0.62; average annual dose, p = 0.58)., Conclusion: Our findings do not support an increased risk of major osteoporotic fracture in older women with chronic respiratory diseases due to long-term ICS use.

Background: Oral corticosteroids (OCSs) are often used to achieve asthma control. OCS-related comorbidities increase the burden of disease for patients and healthcare providers. Most studies characterizing OCS use and risk of adverse events (AEs) are in non-asthma patients. We sought to systematically review the literature on the burden of OCS use among adults with asthma. Methods: We systematically reviewed the literature including MEDLINE (1946-May 2017), EMBASE (1974-May 2017), and the Cochrane Library (2005-May 2017) to identify studies that considered AEs due to OCS treatment of adults with asthma, their burden on healthcare utilization, and costs. Results: We retrieved 9,589 citations; and 15 studies were included. AEs were significantly higher among OCS-users compared with non-OCS users with pooled adjusted odds ratio (OR) 1.68 (95% CI 1.15-2.46) for diabetes mellitus and 1.34 (95% CI 1.23-1.46) for hypertension. Among high dose OCS-users (>10 mg) compared with non-OCS users, the pooled adjusted ORs for development of any complication was 3.35 (95% CI 2.94-3.82), and bone and muscle complications 2.30 (95% CI 2.18-2.42). The risk of any complication increased with higher doses of OCS, with pooled adjusted OR from 2 studies of 2.26 (95% CI 1.37-3.72), 2.94 (95% CI 2.62-3.29) and 3.35 (95% CI 2.94-3.82) for low dose (<6 mg), medium dose (5-12 mg) and high dose (>10 mg) respectively compared with no OCS use. Conclusions: The use of OCS in the management of asthma is associated with a higher risk of complications. This risk is higher as the OCS dose increases.

Inhaled corticosteroids (ICSs) are often prescribed in patients with chronic obstructive pulmonary disease (COPD). Their impact on the risk of lung cancer, a leading cause of mortality in COPD patients, remains uncertain.Population-based linked administrative data between the years 1997 and 2007 from the province of British Columbia, Canada, were used to evaluate the association between lung cancer risk and ICS use in COPD patients. COPD was defined on the basis of receipt of three COPD-related prescriptions in subjects ≥50 years of age. Exposure to ICS was incorporated into multivariable Cox regression models using several time-dependent methods ("ever" exposure, cumulative duration of use, cumulative dose, weighted cumulative duration of use and weighted cumulative dose).There were 39 676 patients who met the inclusion criteria. The mean±sd age of the cohort was 70.7±11.1 years and 53% were female. There were 994 (2.5%) cases of lung cancer during follow-up. In the reference case analysis (time-dependent "ever" exposure), ICS exposure was associated with a 30% reduced risk of lung cancer (HR 0.70 (95% CI 0.61-0.80)). ICS exposure was associated with a decrease in the risk of lung cancer diagnosis over all five methods of quantifying exposure.This population-based study suggests that ICS use reduces the risk of lung cancer in COPD patients., Competing Interests: Conflict of interest: A.J.N. Raymakers has nothing to disclose. Conflict of interest: M. Sadatsafavi has nothing to disclose. Conflict of interest: D.D. Sin reports grants and personal fees for advisory board work, speaking engagements and organising education from AstraZeneca, grants and personal fees for advisory board work and organising meetings from Boehringer Ingelheim, grants from Merck Frosst, and personal fees for advisory board work from Novartis, outside the submitted work. Conflict of interest: J.M. FitzGerald has nothing to disclose. Conflict of interest: C.A. Marra has nothing to disclose. Conflict of interest: L.D. Lynd reports grants from Canadian Institute for Health Research, during the conduct of the study; and grants from AstraZeneca, outside the submitted work., (Copyright ©ERS 2019.)

Introduction: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a heterogenous condition with clinical features shared by both asthma and COPD., Objectives: This online global survey of respiratory/allergy specialists and primary care practitioners (PCPs) was performed to understand current clinical approaches to the differential diagnosis and management of asthma, COPD and ACO., Methods: Respondents were recruited through: (a) a global online physician respondent community (49,980 PCPs and 7205 specialists); (b) market research agents; (c) experts; (d) professional societies; (e) colleague invitation. Respondents were presented with a survey including hypothetical clinical scenarios of diagnostic uncertainty to identify management approaches., Results: 891 responses (447 PCPs and 444 specialists) were collected across 13 countries. Reported features used for diagnosis of asthma and COPD were consistent with practice guidelines, but there was variability in those selected for ACO diagnosis. Features typically selected by specialists focused on spirometry/history, while PCPs focused on previous treatment/symptoms. Most respondents could correctly diagnose patients with features of ACO; however, features selected for theoretical diagnosis were often different to those selected in the case scenarios. Additionally, treatment selection was often inconsistent with guidelines, with over half of respondents not recommending inhaled corticosteroids in a patient with ACO and dominant features of asthma., Conclusion: While most PCPs and respiratory/allergy specialists can reach a working diagnosis of ACO, there remains uncertainty around which diagnostic features are most important and what constitutes optimal management. It is imperative that clinical studies including patients with ACO are initiated, allowing the generation of evidence-based management strategies., (© 2019 John Wiley & Sons Ltd.)

We assessed the association between long-term inhaled corticosteroid (ICS) use and bone mineral density (BMD) in older women with chronic respiratory disease. Women with > 50% adherence to ICS use had very slightly accelerated BMD loss at the total hip compared with those with lower or ICS use., Introduction: This study evaluated the impact of long-term ICS therapy on bone loss in older women with asthma or chronic obstructive pulmonary disease (COPD)., Methods: We used a population-based bone densitometry registry linked with administrative health data covering the province of Manitoba, Canada (1999-2013), to identify women aged > 40 years who had diagnosed asthma or COPD. ICS exposure was defined as cumulative dispensed days and medication possession ratio (MPR). Associations were examined both cross-sectionally and longitudinally, and results were covariate adjusted., Results: Among 6561 women with asthma and/or COPD (mean age 65 years [SD = 11]), compared to no ICS treatment, those in the highest tertile of prior ICS use (≥ 720 days) had lower BMD at the femoral neck (- 0.09 T-score, 95% CI - 0.16, - 0.02) and total hip (- 0.14 T-score, 95% CI - 0.22, - 0.05), but not at the lumbar spine. Over a mean of 5 years of follow-up, the highest tertile of ICS exposure (MPR > 0.5) was associated with a - 0.02 SD/year (95% CI - 0.04, - 0.01) greater decline in total hip BMD relative to non-users, with no significant effect at the femoral neck or lumbar spine. Middle and lower tertiles of ICS use were not associated with baseline or longitudinal change in BMD., Conclusions: The highest tertile of ICS use was associated with a slightly lower hip BMD at baseline and slightly greater reduction in total hip BMD over time in older women with asthma or COPD. No adverse effects on BMD were seen from low to moderate ICS exposure.

Additional management options, and better use of current options, are needed to help support a large proportion of patients with asthma whose symptoms remain uncontrolled on inhaled corticosteroids (ICS). Here, we aim to review the safety and efficacy of adding tiotropium to ICS compared with adding a long-acting β 2 -agonist (LABA) for adults whose asthma is not well controlled on ICS alone. Adding tiotropium to a background of ICS provides beneficial effects that are comparable with addition of a LABA in terms of lung function measures, exacerbations, asthma control and other endpoints. In addition, tiotropium and LABAs are both well tolerated. Some patients respond to either tiotropium or LABA treatment, but not both, suggesting that there are groups of patients that may respond better to one of these drugs. Currently, tiotropium is recommended as an add-on therapy in patients with severe asthma (Global Initiative for Asthma Steps 4 and 5) whose asthma is uncontrolled despite treatment with ICS/LABA. Tiotropium is also effective in patients with less severe disease and may benefit patients who experience adverse events from LABA treatment or where LABAs are ineffective. Tiotropium is therefore an important therapeutic option in asthma, not only as recommended as an add-on treatment with ICS/LABA, but also as an alternative to the addition of LABA to maintenance therapy with an ICS., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia., Methods: We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12-75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting β 2 -agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per μL and less than 300 cells per μL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV 1 ) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per μL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received. This study is registered with ClinicalTrials.gov, number NCT01928771., Findings: Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per μL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0·55, 95% CI 0·42-0·71; p<0·0001) or Q8W (0·49, 0·37-0·64; p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV 1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016-0·196; Q8W group 0·159 L, 0·068-0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference -0·25, 95% CI -0·45 to -0·06), but not the Q4W regimen (-0·08, -0·27 to 0·12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%])., Interpretation: These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population., Funding: AstraZeneca and Kyowa Hakko Kirin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Bronchial thermoplasty (BT) is a recently developed treatment for patients with moderate-to-severe asthma. A few studies have suggested the clinical efficacy of this intervention. However, no study has evaluated the cost-effectiveness of BT compared to other alternative treatments for moderate-to-severe allergic asthma, which currently include omalizumab and standard therapy., Objective: To evaluate the cost-effectiveness of standard therapy, BT, and omalizumab for moderate-to-severe allergic asthma in the USA., Methods: A probabilistic Markov model with weekly cycles was developed to reflect the course of asthma progression over a 5-year time horizon. The study population was adults with moderate-to-severe allergic asthma whose asthma remained uncontrolled despite using high-dose inhaled corticosteroids (ICS, with or without long-acting beta-agonists [LABA]). A perspective of the health-care system was adopted with asthma-related costs as well as quality-adjusted life years (QALYs) and exacerbations as the outcomes., Results: For standard therapy, BT, and omalizumab, the discounted 5-year costs and QALYs were $15,400 and 3.08, $28,100 and 3.24, and $117,000 and 3.26, respectively. The incremental cost-effectiveness ratio (ICER) of BT versus standard therapy and omalizumab versus BT was $78,700/QALY and $3.86 million/QALY, respectively. At the willingness-to-pay (WTP) of $50,000/QALY and $100,000/QALY, the probability of BT being cost-effective was 9%, and 67%, respectively. The corresponding expected value of perfect information (EVPI) was $155 and $1,530 per individual at these thresholds. In sensitivity analyses, increasing the costs of BT from $14,900 to $30,000 increased its ICER relative to standard therapy to $178,000/QALY, and decreased the ICER of omalizumab relative to BT to $3.06 million/QALY. Reducing the costs of omalizumab by 25% decreased its ICER relative to BT by 29%., Conclusions: Based on the available evidence, our study suggests that there is more than 60% chance that BT becomes cost-effective relative to omalizumab and standard therapy at the WTP of $100,000/QALY in patients with moderate-to-severe allergic asthma. However, there is a substantial uncertainty in the underlying evidence, indicating the need for future research towards reducing such uncertainty.

Background: The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) are widely used in asthma research; however, in studies of newer asthma treatments, mean improvements in these measures compared with placebo arms do not exceed the minimal important difference (MID), particularly when a new treatment is added to current treatment., Objective: We performed a systematic review and network meta-analysis to examine the magnitude of AQLQ and ACQ responses achieved with commonly used asthma drugs and factors influencing these end points in clinical trials., Methods: A systematic literature search was conducted to identify blinded randomized controlled trials reporting AQLQ or ACQ results. Mixed treatment comparisons, combined with meta-regression, were then performed., Results: Of the 64 randomized controlled trials (42,527 patients) identified, 54 included the AQLQ and 11 included the ACQ as end points. The presence of a run-in period, the nature of treatment during the run-in period, concurrent treatment during the treatment period, and instrument version significantly influenced the change in AQLQ score from baseline and whether it exceeded the MID. When compared with placebo, only inhaled corticosteroids (ICSs), with or without a long-acting β-agonist, achieved the MID. The ACQ results were comparable with those of the AQLQ: no differences from placebo exceeded the MID, and ICS-based treatments provided the greatest improvements., Conclusion: The established within-patient MID for the ACQ and AQLQ is not achievable as a group-wise efficacy threshold between treatment arms in clinical studies in which controllers are added to ICS treatment. Thus in addition to reporting mean changes of the instruments, other measurement criteria should be considered, including responder analyses., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Written action plans providing guidance in the early treatment of asthma exacerbations have traditionally advocated doubling of inhaled corticosteroids (ICS) as one of the first steps in treatment., Objectives: To compare the clinical effectiveness of increasing the dose of ICS versus keeping the usual maintenance dose as part of a patient-initiated action plan at the onset of asthma exacerbations., Search Strategy: We searched the Cochrane Airways Group Specialised Register (last search October 2009) which is derived from searches of CENTRAL, MEDLINE, EMBASE and CINAHL, as well as handsearched respiratory journals and meeting abstracts., Selection Criteria: Randomised controlled trials (RCTs) that compared the strategy of increasing the daily dose of ICS to continuing the same ICS dose in the home management of asthma exacerbations in children or adults with persistent asthma on daily maintenance ICS., Data Collection and Analysis: Two review authors independently selected trials, assessed quality and extracted data. We contacted authors of RCTs for additional information., Main Results: Five RCTs (four parallel-group and one cross-over) involving a total of 1250 patients (28 children and 1222 adults) with mild to moderate asthma were included. The mean daily baseline ICS dose was 555 mcg (range 200 mcg to 795 mcg) and the mean daily ICS dose achieved following increase was 1520 mcg (range 1000 mcg to 2075 mcg), in CFC beclomethasone dipropionate equivalents. Three parallel-group studies in adults (two doubling and one quadrupling; mean achieved daily dose of 1695 mcg with a range of 1420 to 2075 mcg), involving 1080 patients contributed data to the primary outcome. There was no significant reduction in the need for rescue oral corticosteroids when patients were randomised to the increased ICS compared to stable maintenance dose groups (OR 0.85, 95% CI 0.58 to 1.26). There was no significant difference in the overall risk of non-serious adverse events associated with the increased ICS dose strategy, but the wide confidence interval prevents a firm conclusion. No serious adverse events were reported., Authors' Conclusions: There is very little evidence from trials in children. In adults with asthma on daily maintenance ICS, a self-initiated ICS increase to 1000 to 2000 mcg/day at the onset of an exacerbation is not associated with a statistically significant reduction in the risk of exacerbations requiring rescue oral corticosteroids. More research is needed to assess the effectiveness of increased ICS doses at the onset of asthma exacerbations (particularly in children).

Background: Inhaled corticosteroids (ICS) are commonly prescribed medications for the management of asthma and chronic obstructive pulmonary disease. It is well established that long-term use of these drugs may lower bone mineral density. However, whether ICS increase the risk of fractures remains unknown. Recent studies that have attempted to explore this risk have had conflicting results. We sought to explore the risk of ICS and fractures among older adults by conducting a systematic review and meta-analysis of the literature., Methods: We systematically searched several databases, including MEDLINE, EMBASE and the Cochrane Library, to identify pertinent studies. Those studies that potentially met our inclusion criteria were identified by two reviewers. Relative risks (RRs) were pooled using the random effects model. We also explored dose-response by stratifying the analysis on high and low doses of ICS. Heterogeneity was assessed using the Q statistic and publication bias was assessed using the funnel plot., Results: Thirteen studies, including four randomized controlled trials, were included in the review. The pooled RRs for hip fractures and any fractures were 0.91 (95% CI 0.87, 0.96) and 1.02 (95% CI 0.96, 1.08), respectively. When we restricted the analysis to users of high-dose ICS, the pooled RRs for any fractures and hip fractures were 1.30 (95% CI 1.07, 1.58) and 1.32 (95% CI 0.90, 1.92), respectively. The funnel plot did not show evidence of publication bias., Conclusion: We found no association between the use of ICS and fractures in older adults. A slight increase in risk was seen in those using high-dose ICS. The significance of this association should be investigated further.

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: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler (Symbicort, AstraZeneca, Lund, Sweden) may provide a convenient means of maintaining asthma control with the minimum effective medication level., Objectives: To compare adjustable and fixed maintenance dosing regimens of budesonide/formoterol in asthma., Methods: This was an open-label, randomized, parallel-group, multicentre, Canadian study of asthma patients (aged 12 years or older, postbronchodilator forced expiratory volume in 1 s 70% or greater of predicted normal). Following a one-month run-in on budesonide/formoterol (100/6 µg or 200/6 µg metered doses, two inhalations twice daily), 995 patients were randomly assigned either to continue on this fixed dosing regimen or to receive budesonide/formoterol adjustable dosing (step down to one inhalation twice daily if symptoms were controlled or temporarily step up to four inhalations twice daily for seven or 14 days if asthma worsened). The primary efficacy variable was the occurrence of exacerbations (requiring oral or inhaled corticosteroids, emergency department treatment, serious adverse events or added maintenance therapy because of asthma)., Results: With adjustable dosing, significantly fewer patients experienced exacerbations compared with fixed dosing (4.0% versus 8.9%, P=0.002; number needed to treat=21 [95% CI 13 to 59]). Patients required 36% fewer overall doses of budesonide/formoterol (2.5 versus 3.9 inhalations/day, P<0.001), and total costs per patient were lower (difference over five months -141 Canadian dollars [95% CI -162 Canadian dollars to -116 Canadian dollars]). Asthma symptom severity (modified National Heart, Lung, and Blood Institute stage) was maintained or improved in 97% or greater of patients in both groups (pre-run-in to end of treatment). Both treatments were well tolerated., Conclusions: Budesonide/formoterol adjustable maintenance dosing provided more effective asthma control than fixed dosing, with a lower overall drug dose and reduced total cost.