Search

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. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The fractional exhaled nitric oxide (FE NO ) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FE NO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FE NO . The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FE NO -based care. In patients with asthma in whom treatment is being considered, we suggest that FE NO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FE NO in patients with asthma in whom treatment is being considered based on current best available evidence.

Rationale: Asthma severity in children generally starts mild but may progress and stay severe for unknown reasons., Objectives: Identify factors in childhood that predict persistence of severe asthma in late adolescence and early adulthood., Methods: The Childhood Asthma Management Program is the largest and longest asthma trial in 1041 children aged 5-12 years with mild to moderate asthma. We evaluated 682 participants from the program with analyzable data in late adolescence (age 17-19) and early adulthood (age 21-23)., Measurements: Severe asthma was defined using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program to best capture severe asthma. Logistic regression with stepwise elimination was used to analyze clinical features, biomarkers, and lung function predictive of persistence of severe asthma., Main Results: In late adolescence and early adulthood 12% and 19% of the patents had severe asthma, respectively; only 6% were severe at both time periods. For every 5% decrease in post bronchodilator FEV1/FVC in childhood, the odds of persistence of severe asthma increased 2.36-fold (95% CI: 1.70-3.28; p <0.0001), for participants with maternal smoking during pregnancy odds of persistence of severe asthma increased 3.17-fold (95% CI: 1.18-8.53, p=0.02). Reduced growth lung function trajectory was significantly associated with persistence of severe asthma compared to normal growth., Conclusions: Lung function and maternal smoking during pregnancy were significant predictors of severe asthma from late adolescence to early adulthood. Interventions to preserve lung function early may prevent disease progression.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Children with asthma, even those with severe persistent disease, can have forced expiratory volume in 1 second (FEV 1 ) values ≥100% of predicted, while others have diminished FEV 1 ., Objective: We sought to characterize the lung mechanical properties underlying these two asthma phenotypes and the mechanisms explaining the paradox of severe asthmatic children, whom when clinically stable can have an FEV 1 >100% of predicted, but during an acute bronchospastic episode can experience a life-threatening asthma event., Methods: Lung mechanics were evaluated in three groups of children: asthmatics with FEV 1 ≥100% (HFEV 1 ; n = 13), asthmatics with FEV 1 ≤80% (LFEV 1 ; n = 14) and non-asthmatic controls (n = 10). A linear mixed model was used to examine the relationship between volume and static transpulmonary pressures obtained at total lung capacity (TLC); actual TLC %of predicted and flow; and static transpulmonary pressure and flow., Results: HFEV 1 asthmatics had larger airways (FEV 1 z-scores 1.12 vs -2.37; P < .05), greater lung volumes (mean % of predicted TLC 134.8% vs 109.6%; P < .05) and lower airway resistance (mean %of predicted Raw 101.9% vs 199.9%; P < .05) compared to the LFEV 1 group. Moreover, HFEV 1 asthmatics had significantly reduced elastic recoil pressure (pressure-volume curve shifted upward and to the left) and higher lung compliance (0.21 vs 00.9 L/cm H 2 O; P < .05) compared to the LFEV 1 group. The pressure-flow curves revealed the LFEV 1 group to have significantly increased resistance to flow in the upstream segment of the airways at all lung volumes studied compared to HFEV 1 ., Conclusion and Clinical Relevance: HFEV 1 asthmatic children display distinct lung mechanical proprieties compared to their LFEV 1 asthmatic peers. With loss of elastic recoil pressure, the HFEV 1 group could generate normal FEV 1 due to proportionally enlarged airways and reduced airway resistance, while airflow limitation in the LFEV 1 is due to increased airway resistance. Loss of elastic recoil and interdependence during acute bronchoconstriction episodes may predispose the HFEV 1 group to catastrophic reductions in airflow., (© 2020 John Wiley & Sons Ltd.)

Background: Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults., Objective: We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children., Methods: This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: ≥85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups., Results: Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P = .020) and exacerbations (1.4 vs 0.8, P = .009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0 days, P = .44; short-term ICS: 61.8 vs 52.9 days, P = .46; as-needed ICS: 53.3 vs 47.3 days, P = .53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P = .10; short-term ICS: 1.1 vs 0.8 days, P = .25; as-needed ICS: 1.0 vs 1.1, P = .72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P = .004) and exacerbations (1.4 vs 0.6, P = .006), while similar protective ICS effects were less apparent among NW., Conclusions: In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease., Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma., Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays., Measurements and Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10 -9 ; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene., Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

Background: Inhaled corticosteroids (ICSs) are the mainstay of daily controller treatment for persistent and uncontrolled asthma. However, many clinicians are wary of ICSs because of safety concerns. Clinicians need to know the underlying efficacy data that support the use of ICSs to weigh efficacy against safety., Objective: To discuss efficacy data from pivotal trials to aid clinicians in their decisions to use ICSs., Methods: Key efficacy studies were selected to augment discussion., Results: Clinical studies have revealed that ICSs are effective in reducing the risk of exacerbations in both children and adults. ICSs also reduce the risk of hospitalization and asthma-related death, improve asthma symptoms, and improve quality of life. In addition, ICSs improve lung function and airway responsiveness and reduce airway inflammation and remodeling. In young children, ICSs improve daytime and nighttime symptoms, improve lung function, reduce the risk of exacerbations, and reduce the need for rescue medications. To date, evidence is conflicting about whether intermittent ICS treatment is as effective as daily ICS treatment. The possibility of lower efficacy of intermittent therapy needs to be weighed against a reduced risk of slowed growth in children., Conclusion: ICSs effectively reduce the risk of exacerbations, hospitalizations, and asthma-related death and improve asthma symptoms, quality of life, lung function, and airway responsiveness. ICSs also reduce airway inflammation and remodeling. Intermittent therapy may not be as effective as daily therapy, and clinicians should weigh reduced efficacy against reduced risk of adverse effects, particularly slowed growth in children., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma., Study Design: This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated., Results: In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough., Conclusion: FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified., Trial Registration: ClinicalTrials.gov:NCT01563029., (Copyright © 2016 GlaxoSmithKline. Published by Elsevier Inc. All rights reserved.)

Background: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction., Methods: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma., Results: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001)., Conclusions: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

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 (FEV1) 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 FEV1 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).

Purpose of Review: This review describes the literature over the past 18 months that evaluated childhood asthma phenotypes, highlighting the key aspects of these studies, and comparing these studies to previous ones in this area., Recent Findings: Recent studies on asthma phenotypes have identified new phenotypes on the basis of statistical analyses (using cluster analysis and latent class analysis methodology) and have evaluated the outcomes and associated risk factors of previously established early childhood asthma phenotypes that are based on asthma onset and patterns of wheezing illness. There have also been investigations focusing on immunologic, physiologic, and genetic correlates of various phenotypes, as well as identification of subphenotypes of severe childhood asthma., Summary: Childhood asthma remains a heterogeneous condition, and investigations into these various presentations, risk factors, and outcomes are important since they can offer therapeutic and prognostic relevance. Further investigation into the immunopathology and genetic basis underlying childhood phenotypes is important so therapy can be tailored accordingly.

Background: Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response., Objective: Identify demographic, clinical, and atopic characteristics that may modify the inhaled corticosteroid treatment response among children enrolled in the Treating Children to Prevent Exacerbations of Asthma trial., Methods: Children aged 6 to 18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 μg of beclomethasone twice daily. Rescue treatment consisted of 40 μg of beclomethasone accompanying each symptom-driven albuterol actuation. Combined treatment consisted of both. Outcomes included time to first exacerbation and proportion of asthma control days. Fourteen baseline characteristics were selected for interaction testing on the basis of their clinical relevance., Results: Two hundred eighty-eight children were randomized. Seventy-five percent were white, and 55% were male. As measured by time to first exacerbation, 4 characteristics identified children who received greater benefit from treatment: non-Hispanic ethnicity, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and history of oral corticosteroid use in the year before enrollment. As measured by asthma control days, 4 characteristics identified children who received greater benefit from treatment: male sex, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and incomplete run-in asthma control., Conclusions: Children with mild persistent asthma who have markers of atopic asthma or who have greater asthma burden may obtain greater benefit from beclomethasone therapy. Additional study is needed to confirm whether these markers can guide individualized therapy., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum., Objective: To compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma., Methods: In this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels., Results: Compared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort., Conclusion: Severe persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the predictive factors of early childhood wheezing in children of low socioeconomic status., Study Design: The Childhood Asthma Prevention Study enrolled 177 low-income children (9-24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with ±CRPDA, ±BHR, and asthma. Baseline predictors for CRPDA, BHR, and asthma at 7 years of age were examined., Results: Maternal symptom report strongly differentiated children with +CRPDA (49%) despite comparable airflow measurements (P < .0001), and spirometric lung function measurements were different for +BHR (65%) versus -BHR (P < .005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity, and maternal psychological resources., Conclusions: This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in the determination of asthma status among low-income groups., (Copyright © 2013 Mosby, Inc. All rights reserved.)

The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.

This article covers the relationships between BHR and airway inflammation. Recent evidence suggests that various commonly used bronchoprovocation challenges (BPCs) differ in their potential to serve as inflammatory biomarkers. The response to direct stimuli depends on the smooth muscle's response to the chemical, whereas in indirect challenges, the reaction is caused by the smooth muscle's responsiveness to the mediators induced by the stimuli. The information obtained from studies with BPC has provided insights into the pathogenesis and pathophysiology of asthma, and the relationships between airway inflammation and bronchial hyper-responsiveness., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Interpretation: 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., Funding: National Heart, Lung and Blood Institute., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking., Methods: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%., Results: A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005)., Conclusions: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.), (2010 Massachusetts Medical Society)

Like obesity, the prevalence of asthma has increased over the past several decades. Accelerated patterns of infant growth have been associated with obesity and its co-morbidities. We aimed to determine if infant weight gain pattern is associated with asthma development later in childhood. Birth weight, growth, pulmonary function, and symptom data were collected in a trial of 2- to 3-yr-old children at-risk for asthma randomized to a 2-yr treatment with inhaled corticosteroids or placebo followed by a 1-yr observation period of study medication. Patterns of infant weight gain between birth and study enrollment were categorized as accelerated, average, or decelerated. Regression analyses were used to test the effects of infant weight gain pattern prior to study enrollment on outcomes during the observation year and at study conclusion while adjusting for demographics, baseline symptom severity, study treatment, and atopic indicators. Among the 197 study participants, early life weight gain pattern was not associated with daily asthma symptoms or lung function at the study's conclusion. However, both prednisone courses (p = 0.01) and urgent physician visits (p < 0.001) were significantly associated with weight gain pattern with fewer exacerbations occurring amongst those with a decelerated weight gain pattern. We conclude that early life patterns of weight change were associated with subsequent asthma exacerbations, but were not associated with asthma symptoms or pulmonary function during the pre-school years for these children at-risk for asthma., ((c) 2009 John Wiley & Sons A/S)

Background: The course of mild to moderate persistent asthma in children is not clearly established., Objective: To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence., Methods: The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by a 4-year observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent)., Results: Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all 3 asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting versus persistent asthma were lack of allergen sensitization and exposure to indoor allergens (odds ratio [OR], 3.23; P < .001), milder asthma (OR, 2.01; P = .03), older age (OR, 1.23; P = .01), less airway hyperresponsiveness (higher log methacholine FEV(1) PC(20) (OR, 1.39; P = .03), higher prebronchodilator FEV(1) percent predicted (OR, 1.05; P = .02), and lower forced vital capacity percent predicted (OR, 0.96; P = .04)., Conclusion: Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Asthma exacerbations are a common cause of critical illness in children., Objective: To determine factors associated with exacerbations in children with persistent asthma., Methods: Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study. Children age 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive either fluticasone propionate 100 microg twice daily (FP monotherapy), combination fluticasone 100 microg AM and salmeterol twice daily, or montelukast 5 mg once daily., Results: Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio [OR], 2.10; P < .001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast versus FP monotherapy (OR, 2.00; P = .005), season (spring, fall, or winter vs summer; P < or = .001), and average seasonal 5% reduction in AM peak expiratory flow (OR, 1.21; P = .01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low peak expiratory flow track together before an exacerbation, but have poor positive predictive value of exacerbation., Conclusion: Children with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers and diary card tracking are not reliable predictors of asthma exacerbations.

Objective: Systemic corticosteroids are known to induce osteoporosis and increase the risk for fractures in adults and children. Inhaled corticosteroids have been shown to increase the risk for osteoporosis and fractures in adults at risk; however, long-term prospective studies of children to assess risks of multiple short courses of oral corticosteroids and chronic inhaled corticosteroids have not been performed. Thus, we assessed the effects of multiple short courses of oral corticosteroids and long-term inhaled corticosteroids on bone mineral accretion over a period of years., Methods: This was a cohort follow-up study for a median of 7 years of children who had mild-to-moderate asthma and initially were randomly assigned into the Childhood Asthma Management Program trial. Serial dual-energy radiograph absorptiometry scans of the lumbar spine for bone mineral density were performed for all patients. Annual bone mineral accretion was calculated for 531 boys and 346 girls who had asthma and were aged 5 to 12 years at baseline (84% of the initial cohort)., Results: Oral corticosteroid bursts produced a dosage-dependent reduction in bone mineral accretion (0.052, 0.049, and 0.046 g/cm(2) per year) and an increase in risk for osteopenia (10%, 14%, and 21%) for 0, 1 to 4, and >or=5 courses, respectively, in boys but not girls. Cumulative inhaled corticosteroid use was associated with a small decrease in bone mineral accretion in boys but not girls but no increased risk for osteopenia., Conclusions: Multiple oral corticosteroid bursts over a period of years can produce a dosage-dependent reduction in bone mineral accretion and increased risk for osteopenia in children with asthma. Inhaled corticosteroid use has the potential for reducing bone mineral accretion in male children progressing through puberty, but this risk is likely to be outweighed by the ability to reduce the amount of oral corticosteroids used in these children.

Background: Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of nonoverlapping components., Objective: Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children 5 to 12 years old. Results were compared across time (baseline and 48-month visit) and treatment arms., Methods: Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n = 1041). Measurements of lung function, symptoms, and health care utilization from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyperresponsiveness were included. Data on fractional exhaled nitric oxide and sputum eosinophil cationic protein were included in a subgroup of patients., Results: In each of the study windows, factor analysis identified 5 factors that explained between 50% and 60% of the common variance. Factors identified included (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function, which subdivided into (4) FEV(1) and forced vital capacity, and (5) bronchodilator response and the FEV(1)/forced vital capacity ratio. Exploratory analyses suggest that fractional exhaled nitric oxide account for the atopy/inflammatory marker factor, and sputum measurements account for a sixth, separate factor., Conclusion: The consistent identification of a 5-factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.

Bronchial hyperresponsiveness (BHR) is an important feature of asthma and is useful in diagnosis, monitoring, and prognostication. It probably represents inherent elements of the disease process such as genetic predisposition, airway inflammation, and airway remodeling. Airway inflammation likely accounts for the variable component of BHR, whereas the persistent component of BHR correlates significantly with structural changes in the airway, such as basement membrane thickness and epithelial damage. It might be this component that is resistant or refractory to the effects of available interventions. A few trials of immunomodulatory therapy have shown considerable improvements in markers of airway inflammation, without significantly modifying airway reactivity. Interventions to impact the more permanent feature of BHR are needed.

Background: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children., Objective: The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control., Methods: A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) or= 80% predicted, confirming current guideline recommendations.

Background: Montelukast is a widely used controller agent in childhood asthma. It is modestly effective in reducing symptoms, decreasing the need for rescue albuterol, and improving forced expiratory volume in 1 second (FEV1)., Objective: To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes, air trapping, airway resistance (Raw), and specific conductance (Sgaw)., Methods: Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were randomized into a double-blind, placebo-controlled study to receive montelukast (5 or 10 mg) or matching placebo daily for 8 weeks. Symptoms and albuterol use were recorded twice daily, and exhaled nitric oxide measurement, forced oscillometry, spirometry, and body box plethysmography (before and after beta-agonist use) were performed at randomization and at 2, 4, 6, and 8 weeks. Circulating eosinophil counts and serum eosinophil cationic protein (ECP) levels were obtained at randomization and at 8 weeks., Results: Montelukast-treated patients had lower residual volume (P = .05), residual volume-total lung capacity ratio (P = .04), Raw (P = .02), Sgaw (P = .03), and serum ECP levels (P = .02) at 8 weeks compared with those treated with placebo. There was a trend toward reduced daytime and nighttime albuterol use, although the difference did not reach statistical significance. There were no significant differences in FEV1, FEV1-forced vital capacity ratio, exhaled nitric oxide levels, or daytime and nighttime symptom scores between the 2 groups., Conclusions: Montelukast therapy was associated with less air trapping, hyperinflation, and Raw and better Sgaw compared with placebo. Lower serum ECP levels, a surrogate measure of airway inflammation, were associated with improvements in lung function.

The aim of this study was to compare air-trapping as quantified by high-resolution computed tomography (HRCT) of the chest with measures of lung function and airway inflammation in children with mild to moderate asthma. Plethysmography indices, respiratory resistance, and reactance before and after bronchodilator with impulse oscillation (IOS), exhaled nitric oxide (eNO), total eosinophil count (TEC), and serum eosinophil cationic protein (ECP) levels were measured in 21 subjects. A single-cut HRCT image at end-expiration was obtained. Air-trapping was quantified and expressed in terms of the pixel index (PI) by determining the percentage of pixels in lung fields below -856 and -910 Hounsfeld units (HU). Pairwise linear correlations between PI and other parameters were evaluated. Subjects had only mild airflow limitation based on prebronchodilator forced expiratory volume in 1 sec (FEV(1)), but were hyperinflated and had air-trapping based on elevated total lung capacity (TLC) and residual volume (RV)/TLC ratio, respectively. The PI at -856 HU was positively correlated with % predicted TLC, total gas volume (TGV), and ECP level, and was inversely correlated with FEV(1)/forced vital capacity (FVC) and % predicted forced expiratory flow between 25-75% FVC (FEF(25-75)). The PI at -910 HU correlated similarly with these variables, and also correlated positively with IOS bronchodilator reversibility. This data suggest that quantitative HRCT may be a useful tool in the evaluation of peripheral airflow obstruction in children with asthma., (Copyright 2005 Wiley-Liss, Inc.)

In general, asthma runs a variable course. However, there are children with asthma who are at risk for progressive disease that can lead to failure to attain peak lung growth and eventually can result in clinical and functional impairment. We present a case of a 14-year-old girl who has demonstrated a deterioration in lung function at least in the past 6 years. This has been associated with increasing medication requirements, including chronic oral corticosteroid and a steroid-sparing medication, the presence of comorbidities, and the occurrence of frequent exacerbations. The patient has evidence of airway inflammation and remodeling based on biomarkers and biopsy findings. It remains a challenge to determine patients at risk for irreversible airflow obstruction, presumably a result of airway remodeling. Histopathologic studies from biopsy samples provide the best evidence for this. However, bronchoscopy and biopsy require technical expertise and cannot be routinely used. Clinically, once a patient increases medication requirements, this should serve as a marker of disease progression. Biomarkers of airway inflammation such as exhaled nitric oxide, exhaled breath condensates, and induced sputum analysis may have the potential to monitor disease progression. Additional efforts are necessary to understand the mechanisms involved in this phenomenon and to discover specific modalities of treatment to target the structural changes of airway remodeling.

Background: Asthma morbidity and mortality is increased in blacks., Objective: 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., Methods: 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% (log(10) IC(50)). Asthma medication history, atopic status, and spirometric lung function measures corrected for race were collected., Results: Black and white asthmatic subjects had similar FEV(1) 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) log(10) IC(50) 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 log(10) IC(50) values., Conclusion: 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.

Certain medications can generate asthma symptoms, with the potential to cause considerable morbidity. This article focuses on the common drugs that have the potential to cause distinct respiratory reactions in asthmatics: aspirin and other nonsteroidal anti-inflammatory drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. The means by which these medications can trigger asthma vary in terms of acuity of onset, severity, and the mechanisms involved. The general and most practical approach is avoidance and cautious use of these drugs in asthmatics. However, these classes of medications can exert a major role in the management of common and serious diseases. Fortunately, controller therapy for asthma and alternative or more selective medications for the treatment of these conditions are now available.

Background: The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers., Objective: At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils., Methods: Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol., Results: Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity., Conclusions: Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.

The management of infants and small children with asthma is a challenging task because of the many issues unique to this age group that deserve special consideration. The diagnosis of asthma is limited by inherent difficulties in obtaining objective measures of lung function and airway inflammation. In persistently symptomatic patients, the decision to initiate controller therapy is not as great an issue as it is in infants and young children with recurrent episodic wheeze in whom early intervention may allow a window of opportunity potentially to alter the course of the disease. The reality is that even if atopy has been consistently implicated in the development of persistent asthma, there is not a well-established set of criteria by which patients who are likely to benefit from early intervention controller therapy can be identified. Hence, large prospective studies need to be performed evaluating the impact of early pharmacologic intervention on the natural history of infantile asthma. Many areas needing investigation involve what medications to use, how best to deliver the medications, and how to monitor the response to treatment. Only a few medications have been approved for use in this population. Long-term studies evaluating available drugs such as inhaled glucocorticoids, LABAs, and the leukotriene-modifying agents in young children still need to be performed.

During the past dozen years, great strides have been made in the understanding of asthma. In addition, an excellent choice of effective and safe medications has become available for use in both the acute and chronic manifestations of this disease. Unfortunately, asthma continues to affect society adversely in terms of cost and morbidity. Following the NHLBI guidelines for the management of persistent asthma could substantially reduce the health care expenditures associated with asthma and, more importantly could significantly reduce asthma exacerbations, emergent care visits, hospitalizations, and even asthma deaths. All who care for children with asthma must continue to relay the message that asthma is a chronic condition that is best treated with controller agents. Inhaled glucocorticoids are considered first-line agents for all patients with persistent asthma. They have been shown to improve asthma control, improve lung function, and reduce morbidity and mortality. Whether the leukotriene-modifying agents will be shown to reduce morbidity and mortality significantly remains an important and unanswered question at present. Another important question is whether combination therapy and which combination (inhaled glucocorticoid plus LABA or inhaled glucocorticoid plus leukotriene-modifying agent) will provide even further improvement in asthma control and further reductions in hospitalizations and mortality than seen with the use of inhaled glucocorticoids alone.

Objective: Exhaled nitric oxide (FE(NO)) was evaluated in children with asthma after 4 to 6 years of treatment with budesonide, nedocromil, or albuterol as needed., Study Design: FE(NO), spirometry, total eosinophil count, and serum eosinophil cationic protein levels were obtained from 118 children at the Denver site of the Childhood Asthma Management Program upon completion of treatment and after a 2- to 4-month washout., Results: Budesonide-treated patients had significantly lower median (1st, 3rd quartile) FE(NO) (21.5 [13.2, 84.4] vs 62.5 [26.2, 115.0] ppb, P <.01) and eosinophil cationic protein levels (17.4 [10.1, 24.3] vs 24.0 [15.4, 33.9] mg/dL, P =.05) compared with placebo, whereas no differences were noted between nedocromil and placebo groups. After washout, FE(NO) levels were similar between the three treatments. FE(NO) levels significantly correlated with degree of bronchial hyperresponsiveness, bronchodilator reversibility, allergen skin prick tests, serum IgE, and total eosinophil count. FE(NO) levels were also higher in patients with nocturnal symptoms and in patients requiring beta-agonist use at least once weekly., Conclusions: Budesonide therapy was more effective than nedocromil in reducing FE(NO). Unfortunately, the effects of long-term budesonide were not sustained after its discontinuation. FE(NO) may be a complementary tool to current practice guidelines in assessing asthma control and medication response.

Background: Although high-dose inhaled glucocorticoids (GCs) with or without chronically administered oral GCs are often used in children with severe persistent asthma, the adverse effects associated with their use have not been well-described in this patient population., Objective: We sought to determine the GC-induced adverse effects profile of older children with severe persistent asthma., Methods: A chart review of 163 consecutive children 9 years of age or older admitted to National Jewish for difficult to control asthma was done., Results: The population studied consisted mostly of adolescents (mean +/- SD age, 14.4 +/- 2.1 years) with severe asthma receiving high-dose inhaled GC therapy (1675 +/- 94 microg/d) and averaging 6 systemic GC bursts per year. 50% required chronic oral GC therapy. GC-associated adverse effects were common and included hypertension (88%), cushingoid features (66%), adrenal suppression (56%), myopathy (50%), osteopenia (46%), growth suppression (39%), obesity and hypercholesterolemia (30%), and cataracts (14%). Height standard deviation scores of -0.44, -1.22, and -0.93 for those receiving intermittent, alternate day, and daily oral GCs, respectively, were smaller (less suppressed) than published values from the same institution before inhaled GC therapy (standard deviation scores of -1.26, -1.91, and -1.95, respectively). Osteopenia was strongly associated with growth suppression (odds ratio, 5.6; confidence interval, 2.7-11.8; P <.0001) and was found to be more common in female than male subjects, even after correcting for short stature (42% vs 18%, P <.006)., Conclusions: GC-associated adverse effects are still unacceptably common among children with severe asthma, even in those not receiving chronically administered oral GC therapy yet receiving high-dose inhaled GCs. Therefore close monitoring and proper intervention are warranted, especially in female subjects, who appear to be at greater risk for osteopenia. There is clearly a need to consider alternative therapy or earlier intervention. The magnitude of growth suppression, while still a problem, appeared to be less severe with the addition of inhaled GC therapy. This observation suggests that high-dose inhaled GC therapy, by affording better asthma control and allowing less use of systemic therapy, has attenuated the growth-suppressive effects of poorly controlled asthma.

The American Cancer Society recommends annual clinical breast examination (CBE) for women with average risk of breast cancer beginning at age 40. The purpose of the current chart review study was to determine the adequacy of CBE performed by house officers in a community teaching hospital. A chart audit of 92 women aged 50 or older who were consecutively admitted to the medical service was used as a baseline measure of CBE documentation. Two subsequent series of 100 women each were evaluated. The first series, which also involved women admitted to the medical service, followed increased emphasis on the importance of CBE during twice daily conferences with supervisor staff. The second series involved women admitted to the obstetrics/gynecology service. In that series, house staff used two history/physical examination forms: one with a slot dedicated to CBE and one without a dedicated slot. Results indicate that supervisors' stressing the importance of CBE resulted in only slight improvement in house officers' performance, even in the presence of risk factors for breast cancer. In the third chart audit, CBE was documented by 88% of house staff who used a form with a dedicated slot for CBE; there were no CBE documentations among staff who used a form without a dedicated slot. The dedicated form was more successful in increasing CBE performance and documentation than verbal emphasis about the importance of breast cancer screening.