Background Asthma guidelines emphasize both maintaining current control and reducing future risk, but the relationship between these 2 targets is not well understood. Objective This retrospective ...analysis of 5 budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Turbuhaler ) studies assessed the relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations. Methods The percentage of patients with Global Initiative for Asthma–defined controlled asthma over time was assessed for budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies; higher dose inhaled corticosteroid (ICS), same dose ICS/long-acting β2 -agonist (LABA), and higher dose ICS/LABA plus short-acting β2 -agonist. The relationship between baseline ACQ-5 and exacerbations was investigated. A Markov analysis examined the transitional probability of change in control status throughout the studies. Results The percentage of patients achieving asthma control increased with time, irrespective of treatment; the percentage Controlled/Partly Controlled at study end was at least similar to budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies: higher dose ICS (56% vs 45%), same dose ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%). Baseline ACQ-5 score correlated positively with exacerbation rates. A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (≥80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state and was lower with budesonide/formoterol maintenance and reliever therapy. Conclusions Current control predicts future risk of instability and exacerbations. Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control.
To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline ...in patients with asthma.
To determine whether severe asthma exacerbations are associated with a persistent decline in lung function.
The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function.
There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042).
Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.
Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids.
We evaluated the effect of an inhaled ...nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses.
Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6.
FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated.
Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).
The mechanisms underlying airway hyperresponsiveness remain unclear, although airway inflammation and remodeling likely play important roles. We have observed sustained airway hyperreactivity and ...airway remodeling occurring in mice after chronic allergen exposure and persisting beyond resolution of allergen-induced inflammation. The aim of this study was to delineate mechanisms involved in allergen-induced airway hyperreactivity and airway remodeling and to examine evidence for a causal association between airway remodeling and sustained airway hyperreactivity. Wild-type (WT) and interleukin (IL)-4-, IL-5-, and IL-13-deficient (-/-) mice were sensitized and studied 4 weeks after chronic allergen exposure. By measuring airway responsiveness and airway morphometry, we demonstrated that WT mice developed sustained airway hyperreactivity and aspects of airway remodeling after chronic allergen exposure. Both IL-4(-/-) and IL-13(-/-) mice were protected from developing sustained airway hyperreactivity and aspects of airway remodeling. In contrast, IL-5(-/-) mice developed sustained airway hyperreactivity and aspects of airway remodeling similar to that seen in WT mice. Our results confirm that IL-4 and IL-13, but not IL-5, are critical for the development of sustained airway hyperreactivity and airway remodeling after allergen exposure.
Background: Previous studies have suggested a reduced benefit from therapy with inhaled corticosteroids (ICSs) in asthmatic patients
who smoke. The objective of this post hoc study was to study the ...effects of low-dose inhaled budesonide on lung function in smokers and nonsmokers with mild persistent
asthma.
Methods: Adult patients (age, ⥠18 years) in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, a 3-year,
randomized, placebo-controlled, double-blind study, were stratified according to their smoking habits. The effects on lung
function of therapy with budesonide vs placebo were compared in 492 asthmatic patients who smoked habitually and 2,432 nonsmokers.
Results: When treated with placebo, newly diagnosed asthmatic patients who smoke had a greater 3-year decline in post-bronchodilator
therapy FEV 1 , the change being â263.9 mL (SE, 21.8), when compared with nonsmokers on placebo, which was â180.8 mL (SE, 10.6), the mean
difference being â83.1 mL (p < 0.001). Budesonide treatment was associated with a statistically significant 3-year increase
in post-bronchodilator therapy FEV 1 in both groups. The effect of budesonide vs placebo was 71.5 mL (p = 0.011) in smokers and 46.5 mL (p = 0.001) in nonsmokers.
The corresponding effect in pre-bronchodilator therapy FEV 1 was 118.1 mL (p = 0.002) in smokers and 72.9 mL (p < 0.001) in nonsmokers.
Conclusions: Asthmatic patients who smoke, and are not treated with ICSs, have a greater decline in lung function than asthmatic patients
who do not smoke. The benefits of therapy with inhaled budesonide on preventing lung function decline are similar in smokers
and nonsmokers with mild persistent asthma.
In some patients, asthma control is improved by combining inhaled corticosteroids with long-acting β2 -agonists. However, fluctuating asthma control and exacerbations can still occur. The STAY study ...evaluated whether, in patients with moderate to severe asthma, replacing a short-acting β2 -agonist reliever with the combination of budesonide/formoterol as reliever would both provide rapid symptom relief and reduce asthma exacerbations. The study evaluated 2760 patients with asthma (4-80 years) randomized to budesonide 400 μg twice daily (bid) and terbutaline as reliever, budesonide/formoterol 100/6 μg bid and terbutaline as reliever, or budesonide/formoterol 100/6 μg bid both as maintenance and reliever. Children (age 4-11 years) used a once-daily maintenance dose. Budesonide/formoterol as maintenance and reliever significantly reduced severe exacerbation risk by 45% to 47% compared with the other 2 treatments and improved symptoms, awakenings, and lung function. The benefit was seen in patients of all ages. Subsequent studies have revealed that this beneficial effect of budesonide/formoterol as maintenance and reliever requires both components of the combination.
Inhaled corticosteroid therapy improves exercise symptoms in asthmatic subjects.
We sought to evaluate exercise-induced bronchoconstriction (EIB) as a method of determining the dose and time ...responses of inhaled corticosteroid therapy.
In this double-blind, randomized, cross-over study with 2 parallel arms, 4 doses of inhaled ciclesonide (40 μg and 160 μg or 80 μg and 320 μg) were compared over 3 weeks of treatment. Twenty-six asthmatic subjects (age range, 14-27 years) with baseline FEV
1 values of greater than 70% of predicted value were enrolled. The primary outcome was the maximum percentage decrease in FEV
1 after standardized exercise challenge.
After 1 week of therapy, the mean ± SEM reduction in maximum decrease in FEV
1 in the ciclesonide 40-μg/80-μg dose group was 9% ± 2.6% (95% CI, 3.9% to 14%), with no additional reduction thereafter. In the ciclesonide 160-μg/320-μg dose group, there was an 8.7% ± 2.5% (95% CI, 3.7% to 13.7%) reduction in maximum decrease in FEV
1 after week 1, which continued in a linear fashion during subsequent weeks of treatment. No difference was found between the 2 treatment arms in the temporal response of EIB to ciclesonide treatment. The maximum percentage attenuation in EIB achieved was 51.1% ± 7.9%, which was achieved by using the 320-μg dose after 3 weeks of treatment.
A significant improvement in EIB was demonstrated for all doses of ciclesonide. Use of 160 μg/320 μg of ciclesonide resulted in a continuing improvement in FEV
1 with time, and no plateau was seen in protective effect during 3 weeks of treatment.
Attenuation in exercise-induced decrease can be seen as early as after 1 week of therapy with inhaled ciclesonide at doses greater than 40 μg. However, maximal attenuation in exercise response continues to increase at doses greater than or equal to 200 μg, even after 3 weeks of therapy.
Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control.
To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and ...physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma.
In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20+/-2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV1 of at least 15% or a decrease in PC20 of at least fourfold.
Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV1 and methacholine PC20 were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control.
In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.
IntroductionBehavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and ...whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and to explore whether there are differential effects among key subgroups.Methods and analysisSystematic searches of Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and trial registries for all ongoing and completed randomised controlled trials evaluating behavioural interventions for the prevention of early childhood obesity have been completed up to March 2021 and will be updated annually to include additional trials. Eligible trialists will be asked to share their IPD; if unavailable, aggregate data will be used where possible. An IPD meta-analysis and a nested prospective meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome will be body mass index z-score at age 24±6 months using WHO Growth Standards, and effect differences will be explored among prespecified individual and trial-level subgroups. Secondary outcomes include other child weight-related measures, infant feeding, dietary intake, physical activity, sedentary behaviours, sleep, parenting measures and adverse events.Ethics and disseminationApproved by The University of Sydney Human Research Ethics Committee (2020/273) and Flinders University Social and Behavioural Research Ethics Committee (HREC CIA2133-1). Results will be relevant to clinicians, child health services, researchers, policy-makers and families, and will be disseminated via publications, presentations and media releases.PROSPERO registration numberCRD42020177408.
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