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Background: Some patients with asthma demonstrate normal spirometry and remain undiagnosed without further testing., Objective: To determine clinical predictors of asthma in symptomatic adults with normal spirometry, and to generate a tool to help clinicians decide who should undergo bronchial challenge testing (BCT)., Methods: Using random-digit dialling and population-based case-finding, we recruited adults from the community with respiratory symptoms and no previous history of diagnosed lung disease. Participants with normal pre- and post-bronchodilator spirometry subsequently underwent BCT. Asthma was diagnosed in those with symptoms and a methacholine provocative concentration (PC 20 ) of < 8 mg/ml. Sputum and blood eosinophils, and exhaled nitric oxide were measured. Univariate analyses identified potentially predictive variables, which were then used to construct a multivariable logistic regression model to predict asthma. Model sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated., Results: Of 132 symptomatic individuals with normal spirometry, 34 (26%) had asthma. Of those ultimately diagnosed with asthma, 33 (97%) answered 'yes' to a question asking whether they experienced cough, chest tightness or wheezing provoked by exercise or cold air. Other univariate predictors of asthma included female sex, pre-bronchodilator FEV1 percentage predicted, and percent positive change in FEV1 post bronchodilator. A multivariable model containing these predictive variables yielded an AUC of 0.82 (95% CI: 0.72-0.91), a sensitivity of 82%, and a specificity of 66%. The model was used to construct a nomogram to advise clinicians which patients should be prioritized for BCT., Conclusions: Four readily available patient characteristics demonstrated a high sensitivity and AUC for predicting undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry. These characteristics can potentially help clinicians to decide which individuals with normal spirometry should be investigated with bronchial challenge testing. However, further prospective validation of our decision tool is required., (© 2023. The Author(s).)

Background: In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT)., Research Question: We examined the proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis., Study Design and Methods: Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV 1 [PC 20 ] > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months., Results: Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist., Interpretation: In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objective: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler ® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma., Methods: In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV 1 ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler ® M2 or Turbuhaler ® M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV 1 (PC 20 ). Patients had a PC 20 methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV 1 at all visits (90-110% of enrolment value)., Results: 60 patients (mean age 31.1 years [range:18-64]; mean FEV 1 92.1% predicted normal [78.4-120.6%]) were randomised to treatment; all completed the study. There was a clear dose-response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler ® M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67-1.50, which was the pre-specified condition for equivalent effect., Conclusions: Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler ® to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence., Eudract Number: 2014-001457-16. CLINICALTRIALS., Gov Identifier: NCT02322788., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma., Methods: The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured., Results: Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo., Conclusions: ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.

Rationale: Current guidelines suggest that asthma should be controlled with the lowest dose of maintenance medication required., Objectives: To evaluate the effects of a low dose of inhaled corticosteroid compared to a placebo, on airway inflammation and responsiveness in patients with mild symptomatic asthma., Methods: In this randomized double-blind, placebo-controlled, parallel group study, we looked at the influence of inhaled fluticasone propionate 250 microg/day for 3 months followed by 100 microg/day for 9 months on airway inflammation and methacholine responsiveness in non-smoking subjects with mild allergic asthma. Subjects were evaluated at baseline and 3, 6, 9 and 12 months after treatments; a 2-week evaluation of respiratory symptoms and peak expiratory flow measurements was done before each visit., Results: Fifty-seven subjects completed the 3-month study period. Airway responsiveness, expressed as the PC20 methacholine, increased by 0.27 and 1.14 doubling concentrations, respectively, in placebo-treated (n=33) and in fluticasone-treated (n=24) asthmatic subjects (p=0.03). An additional improvement in PC20 up to 2.16 doubling concentrations was observed in the fluticasone-treated group during the 9-month lower-dose treatment (p=0.0004, end of low-dose period compared with placebo). Sputum eosinophil counts decreased after 3 months of fluticasone 250 microg/day compared with placebo (p<0.0001) and remained in the normal range during the 9-month lower-dose treatment. Respiratory symptoms and peak expiratory flows did not change significantly throughout the study in both groups., Conclusion: In mild asthma, keeping a regular minimal dose of ICS after asthma control has been achieved, may lead to a further reduction in airway responsiveness and keep sputum eosinophil count within the normal range.

Background: In patients with asthma, smoking has been associated with accelerated decline in pulmonary function, poor disease control and reduced responsiveness to corticosteroids., Objective: To assess the influence of current and former smoking on self-reported asthma control and health care use in a large population of asthma patients., Methods: The present analysis was conducted following a telephone survey of adult Canadians aged 18 to 54 years who had physician-diagnosed asthma and a smoking history of less than 20 pack-years., Results: Of 893 patients, 268 were former smokers and 108 were current smokers. Daytime and nighttime symptoms, absenteeism from work or school, emergency care use for asthma in the past year, and use of a short-acting bronchodilator without controller medication were reported more frequently by current smokers than nonsmokers and former smokers. Former smokers were not significantly different from nonsmokers with respect to most asthma outcomes., Conclusions: Current smokers with asthma show evidence of poorer asthma control and greater acute care needs than lifelong nonsmokers or former smokers. These observations stress the importance of smoking cessation to help achieve asthma control.

The aim of the present study was to compare the effectiveness, safety and health economics of budesonide/formoterol maintenance and a novel reliever therapy with conventional best practice in patients with persistent asthma in Canada. After 2 weeks of usual therapy, 1,538 patients were randomised for 6 months to open-label budesonide/formoterol maintenance and reliever therapy 160/4.5 microg twice daily and as needed, or to guideline-based conventional best practice. Severe asthma exacerbations, reliever medication use and total inhaled corticosteroid dose were analysed in all patients and airway inflammation was assessed in a sub-study of 115 patients. No differences were seen in time to first severe exacerbation and severe asthma exacerbation rate. There were numerically fewer emergency room visits or hospitalisations with budesonide/formoterol maintenance and reliever therapy (4.4 versus 7.5 events per 100 patients x yr(-1), 41% reduction); however, this did not reach statistical significance. Mean total inhaled corticosteroid dose, reliever use, asthma medication costs and total annual costs per patient were all significantly lower with budesonide/formoterol maintenance and reliever therapy. Mean sputum eosinophil cell counts remained in the range for controlled inflammation in both groups. In conclusion, budesonide/formoterol maintenance and reliever therapy achieved similar or improved clinical control compared with conventional best practice, with significantly lower total inhaled corticosteroid dose and lower cost, while maintaining similar control of eosinophilic inflammation.

Telephone surveys describing suboptimal asthma control may be biased by low response rates. In order to obtain an unbiased assessment of asthma control and assess its impact in primary care, primary care physicians used a 1-page control questionnaire in 50 consecutive asthma patients. Of the 10,428 patients assessed by 354 physicians, 59% were uncontrolled, 19% well-controlled and 23% totally controlled. Physicians overestimated control, regarding only 42% of patients as uncontrolled. Physicians were more likely to report plans to alter the regimens of uncontrolled patients than controlled patients (1.29 versus 0.20 medication changes per patient) doing so in a fashion consistent with guideline recommendations. Of the uncontrolled patients, 59% required one or more urgent care or specialist visits versus 26 and 15% of well-controlled or totally controlled patients, respectively. Patients were more likely to report short-term symptom control when they had not required urgent or specialist care (odds ratio 5.68; 95% confidence interval 4.91-6.58). The majority of asthma patients treated in general practice are uncontrolled. Lack of control can be recognised by physicians who are likely to consider appropriate changes to therapy. A lack of short-term symptom control of asthma is associated with excess healthcare utilisation.

The prevalence of obesity has noticeably increased worldwide. The clinician is now frequently facing the challenge of managing patients with concomitant chronic obstructive pulmonary disease (COPD) or asthma and obesity. Obesity is often associated with a poorer control of these chronic respiratory diseases and the optimal management of these conditions in the presence of obesity remains to be determined. Herein, the authors review the present understanding of the influence of obesity in the development, clinical manifestations and management of asthma and COPD. The influence of weight loss, response to present therapies as well as new targets for the treatment of COPD and asthma in obese subjects are also discussed, in addition to future directions for research.

Objective: To compare the effects of once-daily ciclesonide and twice-daily fluticasone propionate in patients with moderate persistent asthma., Methods: Patients aged 12-75 years with moderate bronchial asthma entered a 1-4 week run-in period. For inclusion into the 12-week, randomized, open-label treatment period, patients had to have a forced expiratory volume in 1s (FEV1) of either 60-80% of predicted or 80% of predicted and a defined use of rescue medication and asthma symptoms, depending on previous treatment. Patients received ciclesonide 320 microg once daily (ex-actuator) or fluticasone propionate 200 microg twice daily. Primary efficacy endpoint was change from baseline in FEV1., Results: In total, 474 patients were randomized. FEV1 increased significantly from baseline with ciclesonide and fluticasone propionate in the intention-to-treat (ITT) and per-protocol (PP) analyses (all p < 0.0001). Treatment difference was -31 mL (95% confidence interval [CI]: -121, 59) in the PP analysis, demonstrating non-inferiority of ciclesonide. Similar findings were seen for other measures of lung function. In the ITT population, asthma symptom scores and rescue medication use decreased with both treatments (all p < 0.0001). Improvement in health-related quality of life (HRQoL) from baseline was significantly greater with ciclesonide than fluticasone (p = 0.005; one-sided). There were no cases of oral candidiasis in patients receiving ciclesonide and nine cases (3.8%) in those receiving fluticasone propionate (p = 0.002; one-sided)., Conclusions: Treatment with once-daily ciclesonide and twice-daily fluticasone propionate resulted in similar improvements in lung function in patients with moderate persistent asthma. Ciclesonide showed significant improvements in oral candidiasis and HRQoL over fluticasone.

Background: Many patients with asthma require an inhaled long-acting beta(2)-agonist (LABA) in addition to an inhaled corticosteroid to adequately control their disease., Objective: The purpose of this study was to assess the long-term tolerability of a salmeterol xinafoate/ fluticasone propionate (SFC) hydrofluoroalkane metered-dose inhaler (MDI) at 3 different doses BID., Methods: This 52-week, open-label, stratified, parallel-group study assessed SFC in patients with persistent asthma. Patients, aged > or = 12 years, with a diagnosis of asthma for > or = 6 months, and a percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) between 40% and 90% were enrolled between January 1999 and June 1999. The last patient completed the 12-month study in June 2000. Patients were allowed to continue their current asthma treatment during run-in, with the exception that short-acting beta(2)-agonists (SABAs), LABAs, and oral bronchodilators were not to be used 6, 12, and 24 hours, respectively, prior to the randomization visit. During the open-label randomized treatment period, patients were instructed to discontinue all other asthma medications with the exception of the albuterol MDI to use on an as-needed basis. Patients were assigned to treatment based on their existing asthma regimen: SABA monotherapy or LABA with or without fluticasone propionate (FP) <250 microg/d or equivalent (group 1); FP 250 to 500 microg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 microg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 microg/actuation (group 1), 25/125 microg/actuation (group 2), or 25/250 pg/actuation (group 3). The primary end point was tolerability as assessed by adverse events (AEs). AEs were determined via diary cards and investigator inquiry at visits. Serious AEs were defined as death, any life-threatening event, hospitalization, disability, congenital anomaly in the patient's offspring, or other important medical events judged by the investigator to be serious. Other outcomes included clinical laboratory tests (hematology, chemistry, electrolytes), 24-hour urinary-free cortisol excretion, 12-lead electrocardiograms, oropharyngeal examinations, vital signs, clinic visit lung function tests (FEV(1) and PEF), daily diary card entries of morning PEF, and rescue medication usage., Results: Of the 372 patients assessed for eligibility, 325 from 22 centers across Canada were enrolled and randomized to treatment. Group 1 consisted of 98 patients (55% women; 86% white; mean age, 37 years; mean [SD] weight, 79 [20] kg). Group 2 consisted of 109 patients (46% women; 94% white; mean age, 44 years; mean [SD] weight, 80 [17] kg). Group 3 consisted of 118 patients (47% women; 90% white; mean age, 45 years; mean [SD] weight, 80 [18] kg). A total of 15 adolescents (aged 12-17 years) comprised 11%, 2%, and 2% of groups 1, 2, and 3, respectively. Treatments were well tolerated, and 274 (84%) of the 325 patients enrolled completed the study. Upper respiratory tract infection was the most common AE reported: 52%, 37%, and 49% of patients in groups 1, 2, and 3, respectively. Twenty (6%) patients withdrew because of an AE, with worsening asthma being the most frequent reason (n = 9). None of the serious AEs (11 [3 %]) were considered drug related by the investigators. Improvements in FEV(1) and PEF and re- duction in symptomatic albuterol use occurred during the first 4 weeks and were maintained in all groups throughout the 52-week study., Conclusions: BID doses of SFC hydrofluoroalkane 50/100 pg, 50/250 pg, and 50/500 pg administered via MDI for 52 weeks were well tolerated in this population of adolescents and adults with persistent asthma.

Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly.

Background: A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies., Objective: This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD)., Methods: This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits., Results: The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms., Conclusions: In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.

Objectives: This study evaluated the efficacy and safety of a novel asthma management strategy--budesonide/formoterol for both maintenance and symptom relief (Symbicort Single Inhaler Therapy)--compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma., Methods: This was a 12-month, randomised, double-blind, parallel-group study. Symptomatic patients with asthma (n = 1890; mean age 43 years [range 11 years-80 years], mean baseline forced expiratory volume in 1 s [FEV(1)] 70% of predicted, mean inhaled corticosteroid [ICS] dose 746 microg/day) received either budesonide (160 microg, 2 inhalations twice daily) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol (160/4.5 microg, 2 inhalations once daily) with additional inhalations of budesonide/formoterol 160/4.5 microg as needed. Time to first severe exacerbation (hospitalisation/emergency room [ER] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [PEF] to < or = 70% of baseline on 2 consecutive days) was the primary outcome variable., Results: A total of 1890 patients were randomised, of whom 1563 (83%) had severe asthma. The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy (p < 0.001) compared with a higher dose of budesonide. The risk of having a severe exacerbation was 39% lower with budesonide/formoterol single inhaler therapy compared with budesonide (p < 0.001). The number needed to treat to prevent one severe exacerbation per year with budesonide/formoterol compared with budesonide was 5. The budesonide/formoterol group had 45% fewer severe exacerbations requiring medical intervention per patient compared with the budesonide group (p < 0.001). Budesonide/formoterol patients had fewer hospitalisations/ER treatments (15 vs 25 events, respectively [descriptive statistics]) and fewer treatment days with systemic steroids (1776 days vs 3177 days, respectively [descriptive statistics]) compared with budesonide patients. Budesonide/formoterol single inhaler therapy patients used less as-needed medication compared with budesonide patients (0.90 vs 1.42 inhalations/day; p < 0.001). The mean daily ICS dose was lower in the budesonide/formoterol group than in the budesonide group (466 microg/day vs 640 microg/day). Over the 12-month study period, the budesonide/formoterol group achieved asthma control sufficient to not require any additional as-needed medication on 60% of days. Overall, budesonide/formoterol single inhaler therapy gave 31 more asthma control days (a night and day with no asthma symptoms and no as-needed medication use) per patient-year and 12 additional undisturbed nights per patient-year compared with a higher dose of budesonide. Both treatments were well tolerated., Conclusion: Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler, demonstrating a high level of efficacy in patients with moderate to severe asthma.

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.

Eosinophilic airway inflammation is one of the hallmarks of asthma. Sputum eosinophilia has been suggested as a predictor of the response to inhaled corticosteroids in asthma. This study sought to investigate the proportion of steroid-naive uncontrolled asthmatics without significant sputum eosinophilia (< or = 1%) and to examine whether sputum eosinophilia could predict the response to inhaled corticosteroids. A total of 51 mild uncontrolled steroid-naive asthmatics who had not been treated with oral or inhaled corticosteroids for at least 3 months were investigated. The evaluation included a spirometry, methacholine inhalation challenge and sputum induction on two occasions, one at baseline and the other after 1 month of treatment with 250 microg twice-daily fluticasone propionate. Of the 51 subjects, 15 had an eosinophil count < or = 1%, and 46 completed the two visits. Patients with baseline sputum eosinophils < or = 1% (n=14) were compared with those with sputum eosinophils > 1% (n=32). The baseline characteristics of these two groups were similar. After 1 month of treatment, respiratory symptoms, quality of life, forced expiratory volume in one second (FEV1) and provocative concentration causing a 20% fall in FEV1 improved in both groups. The absence of sputum eosinophilia does not seem to be an indicator of poor response to inhaled corticosteroid treatment in steroid-naive asthmatics. However, this finding needs to be investigated further in a double-blind, placebo-controlled study, entirely designed to answer this question.

A previous study suggested that the long-acting beta2-adrenergic agonist salmeterol (SM) had inhibitory effects on bronchial mucosal inflammation 6 hours after allergen exposure. To further evaluate the influence of SM on allergen-induced airway inflammation. We studied, in a randomized, double-blind, cross-over trial, 16 mild asthmatic patients who had a dual asthmatic response to allergen inhalation. Subjects received 50 microg of SM or placebo (P), twice daily for 1 week each, separated by a 2-week wash-out period. At the end of each treatment period, after withholding SM for 24 h, they had a methacholine inhalation test (medication was resumed after the test), followed 24 h later by an AC with the concentration of allergen that had induced a LAR at baseline. Airway inflammation was assessed 24 h after the AC by bronchoalveolar lavage (BAL) (n = 16) and bronchial biopsies (n = 13). As expected, SM improved baseline FEV1 and PC20 (P < or = 0.009) and decreased the allergen-induced early bronchoconstrictive response. There were no significant differences in BAL cell counts after the two treatments. On bronchial biopsies, numbers (median, mm2) of submucosal CD45 (P: 43 +/- 23; SM: 161 +/- 43, P = 0.031), CD45Ro (P: 37 +/- 19; SM: 126 +/- 41, P = 0.047) and AA1 positive cells (P: 38 +/- 6, SM: 65 +/- 17, P = 0.006) were significantly higher after SM than P treatment. The numbers of CD4 (P: 11 +/- 10; SM: 32 +/- 7, P = 0.085), HLA-DR (P: 65 +/- 30; SM: 116 +/- 36, P = 0.079) and EG2 positive cells (P: 25 +/- 15; SM: 38 +/- 26, P = 0.09) tended to increase with SM treatment. In summary, compared to placebo, 1 week of regular use of SM is associated with an increase in bronchial inflammatory cells 24 h after AC. This is in keeping with the recommendation that salmeterol should only be used with an anti-inflammatory agent, particularly in the context of significant allergen exposure.

Background: Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an "as required" basis (n=15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 microg; n=15) in addition to salbutamol to control their asthma., Methods: Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 microg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV1 (PS20) was evaluated on a modified Borg scale from 0 to 10., Results: Subjects using regular beclomethasone had a higher baseline PS20 than those using only salbutamol (means: 3.06 0.06 and 2.01+/-0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS20 compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS20 did not vary significantly throughout the study., Conclusion: These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.

Background: Leukotriene antagonists may inhibit bronchoconstrictive responses to a variety of stimuli., Objective: To evaluate the efficacy and safety of a new CYS LTI antagonist, BAY x 7195, given as a single oral dose of 500 mg, in prevention of allergen-induced asthmatic responses., Methods: This is a randomized, double-blind crossover, placebo-controlled study in mildly asthmatic non-smoking subjects (n = 10), aged 20 to 32 years (mean 24.8). Following an initial baseline allergen challenge, the subjects came back for two other challenges separated by at least a 2-week period, during which placebo or BAY x 7195 was administered two hours before allergen inhalation. Allergen challenges were preceded and followed by a methacholine inhalation test (24 hours before and 30 hours after)., Results: For each subject, the same allergen and doses were used throughout the study. In the randomized (intent-to-treat) population (n = 10), after BAY x 7195, the allergen induced % fall in FEV1 was less than after placebo, with mean between-treatment differences of 31.8 +/- 18.0% during the early asthmatic response, P = .03, and of 54.4 +/- 23.2% during the late asthmatic response (P = .04). The allergen-induced increase in methacholine responsiveness was reduced after BAY x 7195, with a change of -0.45 doubling concentrations of methacholine as compared with -1.77 after placebo; however, the change did not achieve statistical significance, P = .08., Conclusion: BAY x 7195 shows suppressive effects on allergen-induced responses, suggesting that it may be useful in the treatment of asthma.

Background: A long-acting inhaled bronchodilator that is both well tolerated and effective could allow for improved control of both daytime and nighttime symptoms in patients with asthma who use frequent as-needed short-acting bronchodilators despite antiinflammatory treatment., Objective and Methods: We compared the efficacy and safety of inhaled salmeterol, 50 micrograms twice daily, with inhaled salbutamol, 200 micrograms four times daily, delivered through a metered-dose inhaler for 3 months in a multicenter, randomized, double-blind, parallel-group study of 228 patients (aged 12 to 76 years) with mild-to-moderate asthma., Results: A single morning dose of salmeterol produced improvement in FEV1 that was significantly greater (p < or = 0.012) than that produced by two doses of salbutamol (taken 6 hours apart) when patients were assessed 3 to 6 hours and 10 to 12 hours after the dose. This greater bronchodilation was present on day 1 of the study and after 4, 8, and 12 weeks of regular treatment. Over the 12 weeks, compared with salbutamol, salmeterol treatment was associated with a greater mean improvement in morning peak expiratory flow (35 L/min vs -3 L/min, p < 0.001), a higher percentage of days with no symptoms (29% vs 15%; p = 0.012), and a higher percentage of nights with no awakenings (14% vs -1%; p < 0.001). Adverse events were similar for both treatments., Conclusions: In this study salmeterol, 50 micrograms twice daily, was well tolerated and more effective than salbutamol, 200 micrograms four times daily, in improving symptoms and lung function in patients with mild-to-moderate asthma.

Most clinical trials in asthma have focused on outcomes that are primarily of importance to the clinician. Very few have assessed whether patients feel better and can function better in day-to-day activities. The aim of this study was to compare the effects of salmeterol (50 micrograms twice daily), salbutamol (200 micrograms four times a day), and placebo on asthma-specific quality of life and to relate the findings to conventional clinical asthma outcomes. The study was a 12-wk multicenter, double blind, randomized, placebo-controlled crossover trial with each trial medication taken for 4 wk. The subjects were 140 adults with mild to moderate asthma enrolled from 14 respiratory clinics across Canada. Outcome measures were: (1) the Asthma Quality of Life Questionnaire and spirometry at the end of each treatment period; and (2) daily asthma symptoms, morning and evening peak expiratory flow rates (PEFRs), and rescue salbutamol use during the last 14 d of each treatment period. Asthma-specific quality of life, both overall and for the individual domains (activity limitation, symptoms, emotional function, and exposure to environmental stimuli) was better with salmeterol than with placebo (p < 0.0001), and better with salmeterol than with salbutamol (p < 0.001). In both comparisons, differences were not only statistically significant, but most were also clinically important. There were moderate correlations between change in quality of life and change in clinical outcomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Significant changes have occurred in aerosol therapy in the last few years. New devices have been developed to facilitate the administration of bronchodilator or anti-inflammatory drugs into the airways. Metered-dose inhaler with or without a spacer or powder devices are now considered the ideal mode of administration of aerosolized medications in the regular treatment of child or adult asthma as well as in COPD. In mild to moderate acute asthma, bronchodilators are ideally administered with a metered dose inhaler with a spacer device, nebulisation being required in only a minority of patients. Powder devices such as the Turbuhaler may also be useful in acute asthma but inspiratory flow should be sufficient, and their usefulness in this context remains to be better determined. In severe acute asthma or in patients unable to properly use the other inhalation devices, nebulisation can be used, with oxygen in the case of acute asthma. In patients requiring mechanical ventilation, administration of bronchodilators can be done with a metered-dose inhaler with a spacer device specifically designed for this purpose: it will replace nebulisation in most cases. In young children and infants unable to use spacer devices with a mouthpiece (< 5 years), wet nebulisation is still used during acute attacks of asthma. In these circumstances, the use of metered-dose inhalers with a spacer and mask are probably appropriate in some children but further studies are required to recommend their use.

Salmeterol is a new long acting bronchodilator which is specific for beta-2 adrenergic receptors. Its bronchodilator effects can persist for at least 12 hours after inhalation. This drug can inhibit the bronchoconstrictor effects of methacholine up to 12 hours after inhalation and this effect is proportional to the administered dose. Salmeterol improves daily expiratory flow rates and blocks exercise-induced bronchoconstriction. A 50 micrograms dose, inhaled before an antigenic bronchoprovocation, can markedly reduce for up to 24 hours the immediate and late bronchospastic responses to antigen. Moreover, salmeterol inhibits the increase in bronchial responsiveness induced by antigenic exposure. This latter effect does not seem to be related to a persisting bronchodilatation. The responsible mechanisms for this inhibition of allergic response or if its effects are only due to a functional antagonism remain to be explored. A particularly relevant point would be to determine of salmeterol diminishes or blocks the inflammatory bronchial asthmatic reaction.