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Data from a controlled trial of asthma treatment that enrolled patients in the first decade of life were combined with follow-up data to provide novel information on the growth and decline in lung function in the first three decades of life in patients with asthma. In persons without lung disease, forced expiratory volume in 1 second (FEV 1 ) reaches its maximal level in late adolescence or early adulthood and remains stable for several years, a period known as the plateau of lung function, before gradually declining thereafter (Figure 1). 1 Under the construct described by Speizer and Tager, 1 the pattern of FEV 1 growth and decline in childhood and early adulthood is an important determinant of lung function in later adulthood; both reduced growth resulting in a low maximal level of lung function and early decline are associated with the subsequent development of chronic airflow . . .

The airway microbiome has an important role in asthma pathophysiology. However, little is known on the relationships between the airway microbiome of asthmatic children, loss of asthma control, and severe exacerbations. Here we report that the microbiota’s dynamic patterns and compositions are related to asthma exacerbations. We collected nasal blow samples (n = 319) longitudinally during a clinical trial at 2 time-points within one year: randomization when asthma is under control, and at time of early loss of asthma control (yellow zone (YZ)). We report that participants whose microbiota was dominated by the commensal Corynebacterium   +   Dolosigranulum cluster at RD experience the lowest rates of YZs (p = 0.005) and have longer time to develop at least 2 episodes of YZ (p = 0.03). The airway microbiota have changed from randomization to YZ. A switch from the Corynebacterium   +   Dolosigranulum cluster at randomization to the Moraxella- cluster at YZ poses the highest risk of severe asthma exacerbation (p = 0.04). Corynebacterium’s relative abundance at YZ is inversely associated with severe exacerbation (p = 0.002). How the airway microbiome influences asthma pathophysiology remains unclear. Here, the authors analyse nasal samples of cohort of school-age children with persistent asthma and find that the microbiota’s patterns and composition at time of early loss of asthma control associate with severe asthma exacerbations.

Many children have uncontrolled asthma symptoms when treated with low-dose inhaled corticosteroids (ICS). In this three-way crossover trial, the investigators asked whether doubling the dose of ICS, adding a leukotriene-receptor antagonist to the ICS, or adding a long-acting beta-agonist to the ICS would result in better asthma control. Most children had a best response to the long-acting beta-agonist, but some children had a best response to an increased dose of ICS or a leukotriene-receptor antagonist. In this crossover trial comparing three step-up treatments, most children had a best response to the long-acting beta-agonist, but some children had a best response to an increased dose of inhaled corticosteroids or a leukotriene-receptor antagonist. Uncontrolled asthma occurs in many children who receive treatment with low-dose inhaled corticosteroids. In the Pediatric Asthma Controller Trial (PACT), 1 administration of 100 μg of fluticasone twice daily was the most effective therapy, but uncontrolled asthma occurred in more than 50% of the children, and 39% of the children had at least one asthma exacerbation that was treated with oral corticosteroids during a 48-week period. The few data that are available to guide practitioners about how to treat children whose asthma is poorly controlled while they are receiving low-dose inhaled corticosteroids 2 – 8 are inconsistent. The discrepancies may be related to . . .

Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5–18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)—555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37–61), the frequency of exacerbations was lower in the daily (28%, 18–40, p=0·03), combined (31%, 21–43, p=0·07), and rescue (35%, 24–47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14–43) in the placebo group, compared with 5·6% (1·6–14) in the combined (p=0·012), 2·8% (0–10) in the daily (p=0·009), and 8·5% (2–15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. National Heart, Lung and Blood Institute.

Guidelines suggest daily inhaled glucocorticoids in young children at high risk for asthma exacerbation. These investigators found that such treatment was not superior to the intermittent use of budesonide initiated when signs and symptoms indicated an impending asthma exacerbation. Recurrent wheezing episodes in preschool-age children are usually triggered by respiratory tract infections, 1 , 2 which often progress to severe exacerbations requiring systemic glucocorticoids 3 and frequent use of health care services. 4 , 5 In children under the age of 5 years who had at least four wheezing episodes during the previous year and positive values on the modified asthma predictive index (API) (indicating an increased likelihood of persistent asthma in the future), 6 , 7 the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) recommends the initiation of long-term daily inhaled glucocorticoid therapy 8 on the basis of the results of the . . .

From the Childhood Asthma Management Program cohort, which was randomly assigned to receive budesonide, nedocromil, or placebo for 4-6 years, we determined the prevalence of and factors associated with at least 1% per year loss in postbronchodilator FEV(1)% predicted. Participants who had a significant reduction in postbronchodilator FEV(1)% predicted (SRP), comprised 25.7% of the cohort (n = 990). Using logistic regression, predictors of SRP at baseline were younger age (p = 0.0005), male sex (p < 0.0001), clinic (p = 0.02), and higher postbronchodilator FEV(1)% predicted (p = 0.02). Examination of the SRPs indicated that the effect of baseline lung function was such that the higher the lung function, the less steep the reduction in postbronchodilator FEV(1)% predicted (p < 0.0001). A similar proportion of SRPs was found in each treatment group. Among the SRPs, the rate of reduction in postbronchodilator FEV(1)% predicted was similar in all treatment groups. At a single site where biomarker assessment was performed, SRPs also had more prominent eosinophilic inflammation during the washout period. The course and mechanisms of lung function reduction or slow lung growth velocity in children with asthma must be defined.

Background Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose–response, efficacy, and safety of once-daily VI (6.25 μg, 12.5 μg and 25 μg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. Methods This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5–11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 μg twice daily. Children were randomised to receive placebo, VI 6.25 μg, VI 12.5 μg or VI 25 μg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV 1 ) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. Results In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant ( p  = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV 1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28–33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period. Conclusion VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed. Trial registration NCT01573767 (ClinicalTrials.gov).

This study sought to better define the clinical characteristics of severe asthma in both children and adults, and to evaluate the effect of asthma duration on multiple parameters of disease severity. Retrospective analysis of prospectively collected data on 275 patients (125 children) with severe asthma who were admitted to a tertiary asthma referral center. Demographics, lung function (ie, spirometry and body box plethysmography), glucocorticoid (GC) pharmacokinetic studies, and lymphocyte stimulation assays were performed on all patients. Children were as likely to require therapy with high-dose inhaled GCs and long-term therapy with oral GCs, and to have had a prior intubation, yet they had significantly less airflow limitation (mean [± SEM] FEV1, 74.0 ± 2.1% predicted vs 57.1 ± 1.8% predicted, respectively; p < 0.0001), less resistance to airflow (mean airway resistance, 140.3 ± 8.5% predicted vs 311 ± 18% predicted, respectively; p < 0.0001), and larger lung volumes (mean total lung capacity, 116.4 ± 1.6% predicted vs 105.3 ± 1.8% predicted, respectively; p < 0.0001) compared to adults. Children were more likely to be male and to display greater responsiveness to GCs in vitro. Lung function impairment was associated with asthma duration in children and in adults with onset of asthma in childhood, while there was no relationship between disease severity and asthma duration among those with adult-onset asthma. Despite significant differences in disease duration, patients with adult-onset asthma had equally compromised lung function compared to adults with long-standing asthma. Children with severe asthma tended to be male, to have less severe airflow obstruction, and to display greater responsiveness to GCs in vitro compared to adults. Symptoms and episodic acute declines in lung function may precede chronic airflow limitation in this group of children. As such, it may be more relevant to follow the deterioration in lung function over time in children. Finally, disease severity in children and adults whose onset of asthma occurred in childhood was related to disease duration, but not in patients with onset of asthma in adulthood.

Asthma morbidity and mortality is increased in blacks. The primary objective of this cross-sectional study was to determine if blacks, asthmatic or nonasthmatic, displayed diminished T-lymphocyte response to glucocorticoids in vitro compared to their white counterparts. If differences were noted, this would suggest a racial predisposition to decreased glucocorticoid responsiveness among blacks. Asthmatic (n = 395, 27% blacks) and control (n = 202, 52% blacks) subjects recruited from National Jewish Medical and Research Center and from the surrounding community participated in the study. In vitro glucocorticoid responsiveness was determined by assessing the log-transformed concentration of dexamethasone required to suppress phytohemagglutinin-induced T-lymphocyte proliferation by 50% (log10 IC50). Asthma medication history, atopic status, and spirometric lung function measures corrected for race were collected. Black and white asthmatic subjects had similar FEV1 percentage of predicted values and inhaled and oral glucocorticoid requirements. Black asthmatic subjects displayed significantly diminished glucocorticoid responsiveness compared to white asthmatic subjects, as follows: median (first, third quartile) log10 IC50 values of 1.00 nmol (0.48, 1.83) vs 0.78 nmol (0.29, 1.45) [p = 0.028]. Similar results were found between black and white control subjects, as follows: median, 1.26 nmol (0.70, 2.14) vs 0.95 nmol (0.55, 1.48) [p = 0.01]. Age, race, and basal T-lymphocyte activity were significantly positively correlated to the log10 IC50 values. Our observation that black asthmatic subjects and non-asthmatic control subjects require greater concentrations of glucocorticoid in vitro to suppress T-lymphocyte activation suggests that blacks have a racial predisposition to diminished glucocorticoid responsiveness, which may contribute to their heightened asthma morbidity.

In this trial involving patients with mild, persistent asthma, there was no significant difference in therapeutic effect between an inhaled glucocorticoid (mometasone) and placebo in patients with a low sputum eosinophil level (<2%), which was reported in nearly three quarters of the patients.