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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.

Novel asthma pharmacotherapy has changed the management of severe childhood asthma. This study determined whether the introduction and use of second-generation inhaled glucocorticoids (GCs), long-acting beta-agonists (LABAs), and combination inhaled GC/LABA (iGC/LABA) products and leukotriene receptor antagonists (LTRAs) have impacted children with severe asthma. A retrospective review of children (aged 6-18 years) referred to National Jewish Health for severe asthma between 2003 and 2007 (current cohort) was performed (n = 65); the results were compared with a published cohort from 1993 to 1997 (historic cohort; n = 164). When comparing the current cohort to the historic cohort, the percentage requiring chronic oral GC therapy (28% versus 51%; p = 0.001), average dose (3.7 ± 2.4 mg/dose versus 16.7 ± 1.4 mg/dose; p < 0.0001), and duration of oral GC use (17.8 ± 8.6 months versus 33.7 ± 3.5 months; p = 0.09) were less. Ninety-seven percent of the current cohort was on a second-generation iGC either alone or in combination with an LABA, 76% were on an LTRA, and 66% were on combination iGC/LABA product, while none of the historic cohort received these medications. In addition, the current cohort had a higher forced expiratory volume in 1 second (84 ± 2.5% versus 76 ± 2% of predicted; p = 0.008), required less albuterol (33 ± 9 inhalations/week versus 71 ± 7 inhalations/week; p = 0.0007), had fewer intubations in the past (13% versus 21%; p = 0.13) and had fewer GC-induced adverse effects compared with the historic cohort. The current cohort required less chronic oral GCs, had better asthma control, and had fewer GC-induced adverse effects compared with the historic cohort studied 10 years ago. This is most likely because of the use of more effective medications for childhood asthma.

Background Selected macrolide antibiotics have steroid-sparing effects in patients with steroid-dependent asthma. In addition to inhibiting methylprednisolone clearance, macrolides may also display anti-inflammatory effects. Objective To determine whether clarithromycin, by virtue of its anti-inflammatory effects, enhances glucocorticoid sensitivity. Design Open-label, pilot study in a paired design (pre- and posttreatment). Participants Seven patients, mean age 27 (range 15 to 42 years), with mild to moderate asthma under good control. Methods Clarithromycin (500 mg) was administered twice daily for 10 days with blood drawn for lymphocyte stimulation assays at baseline, and again upon completion of therapy. Lymphocytes were stimulated with phytohemagglutinin in the presence and absence of increasing concentrations of clarithromycin and dexamethasone (DEX). Results At baseline, clarithromycin alone did not cause a significant degree of suppression of T-lymphocyte activation, yet clarithromycin significantly enhanced the sensitivity of lymphocytes to suppression by DEX as measured by a shift in the DEX dose-response curve by at least 6-fold ( P = 0.04). In addition, a 10-day course of clarithromycin resulted in: 1) a significant decrease in the inhibitory concentration which results in a 50% reduction in proliferation for DEX alone, thereby increasing glucocorticoid sensitivity ( P = 0.04); 2) heightened inhibitory effect of clarithromycin alone ( P = 0.03); and 3) a sustained suppressive effect with the combination of clarithromycin and DEX on the inhibition of lymphocyte stimulation ( P = 0.01). Conclusions Clarithromycin acts synergistically with DEX in suppressing lymphocyte activation. In addition, a 10-day course resulted in a significant treatment effect as evidenced by lower inhibitory concentration which results in a 50% reduction in proliferation value for DEX, a heightened response to clarithromycin alone, and a consistent degree of suppression of lymphocyte stimulation when clarithromycin and DEX were used together.

Asthma is a chronic respiratory disease characterized by reversible airflow limitation and airway hyper-responsiveness to a variety of stimuli. The understanding of the pathogenesis of asthma has evolved from that of a purely bronchospastic disease to one in which airway inflammation plays a central role. 16,55 Consequently, there has been a shift from routinely administered bronchodilator therapy to using anti-inflammatory medications earlier in the course of the disease and for patients with less severe asthma. All of the guidelines now recommend an anti-inflammatory agent for all asthmatics except those with mild intermittent asthma. 24,27 Given that glucocorticoids (GC) have potent anti-inflammatory effects, they constitute the pharmacologic cornerstone of asthma therapy. 64 Inhaled GCs are among the most effective controller therapies for the management of persistent asthma, and systemic GCs are used primarily as rescue therapy for moderate and severe acute manifestations of asthma. Although the majority of asthmatics respond favorably to GC therapy, a subset of individuals do not. These asthmatics are termed steroid resistant (SR).

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 μg/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. (J Allergy Clin Immunol 2000;106:651-9.)

Background Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. Objective We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy. Methods A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting β 2 -agonist (LABA step-up therapy). Results In multivariate analyses higher impulse oscillometry reactance area was associated ( P = .048) with a differential FEV 1 response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E 4 levels were marginally ( P = .053) related to a differential FEV 1 response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV 1 and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses. Conclusion Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E 4 levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.

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 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.

More than half of preschool-aged children are enrolled in child care in the United States. Roughly 8% of children between 3 and 5 years of age have a food allergy. Child care center workers (CCCWs) are important caregivers who frequently encounter food allergies, but little is known about their education and understanding of food allergy and anaphylaxis.To perform a food allergy and anaphylaxis educational needs assessment, provide a training curriculum for CCCWs, and assess the effectiveness of the training curriculum.An online educational needs assessment and live training curriculum addressing food allergy recognition, treatment, and food labeling with pretests and posttests were created, and content and face validity were obtained. A needs assessment survey was sent to centers in Dallas and Tarrant counties. The training curriculum was performed at continuing education conferences.Seventy-three workers responded to the needs assessment, with 46% reporting prior food allergy training. They reported information sources as parents (73%), self (54%), educational curricula (21%), and conferences (19%). Most believed they have a high or moderately high proficiency in food allergy management. Forty-five workers participated in the training curriculum. Total scores improved from 54% correct on the pretest to 83% correct on the posttest (P.001). Categorical subanalysis reveals similar results, with statistically significant improvement in all areas.CCCWs have diverse educational backgrounds and infrequently experience standardized training about food allergies. There is a significant lack of knowledge regarding food allergies and anaphylaxis. The curriculum was successful at increasing food allergy knowledge among CCCWs.

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.

Background Outcomes of pulmonary physiology have a central place in asthma clinical research. Objective At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons. Methods Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV 1 , forced vital capacity, and FEV 1 /forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV 1 also are core outcomes for study population characterization and observational studies. Conclusions The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.

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 (p0·0001), 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.

Background Clinical trials in children with moderate-to-severe persistent asthma are limited. Objective We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. Methods The budesonide dose (with salmeterol [50 μg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 μg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. Results Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. Conclusion Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid–sparing alternative in children with moderate-to-severe persistent asthma.

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 utilizations 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.

Glucocorticoids (GCs) are the most effective therapy we have for the treatment of asthma. Systemically administered GCs are first-line agents for acute severe asthma, whereas topical (i.e., inhaled) GCs are first line agents for the long-term management of all patients with persistent asthma. In the treatment of acute asthma exacerbations, early institution of systemic GCs can prevent further worsening of symptoms, reduce emergency room visits, and hospitalizations. Inhaled GCs are the recommended controller class of medications for all patients with persistent asthma, including children. They are the most effective class of agents in reducing symptoms, improving lung function, and decreasing bronchial hyperresponsiveness, in addition to reducing asthma morbidity and mortality. Long-term administration of oral GCs is associated with multiple adverse effects including adrenal insufficiency, weight gain, increased skin fragility, myopathy, osteoporosis, cataracts, and mood changes. Thus, in patients with chronic severe asthma who require regular systemic GC therapy, all other treatments should be maximized, and the lowest dose sufficient for control should be established through regular monitoring visits. As with oral GC therapy, high-dose inhaled GC therapy can result in systemic adverse effects. Several studies have shown that low-dose inhaled GC therapy, even when administered long term, is unlikely to result in any clinically meaningful adverse effects. By using the lowest possible effective GC dose, as well as maximizing other therapeutic modalities, adverse systemic effects from GCs can be greatly minimized.

Environmental exposures during the early years and airway obstruction that develops during this time, in conjunction with genetic susceptibility, are important factors in the development of persistent asthma in childhood. Established risk factors for childhood asthma include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia, as well as allergic sensitization to aeroallergens and certain foods. Risk factors for the development of asthma in adulthood remain ill defined. Moreover, reasons for variability in the clinical course of asthma--persistence in some individuals and progression in others--remain an enigma. The distinction between disease persistence and disease progression suggests that these are different entities or phenotypes. There is currently no consensus on whether disease progression requires either airway inflammation or airway remodeling or the combination of the two. For patients with irreversible airway obstruction, inflammation might, in part, be necessary but perhaps not entirely sufficient to induce the irreversible component, some of which could be attributed to alterations in the structure of the bronchial wall. Intervening with intermittent or daily inhaled corticosteroids in high-risk infants and children does not prevent disease progression or impaired lung growth. These findings, however, might not apply to adults, and further study in adults is needed to determine the effect of inhaled corticosteroid therapy on disease progression.

Asthma, an enormously common illness, has been a focus of research studies, many published in the journals of the American Thoracic Society and/or American Lung Association for more than 100 yr (1). In 2005, ongoing research focused on several emerging areas, including studies on the use of biomarkers to understand the clinical phenotypes and activity of the asthma, a renewed interest in the role infections play in both acute and chronic phases of asthma, an increased appreciation of the role that structural cells play in the pathogenesis of asthma, as well as studies focusing on treatment of both pediatric and adult patients.

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.

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.

Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4–18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999–2002. In total, 2,728 children performed 24,388 measures. The mean ± SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV1), FEV1/FVC ratio, and forced expiratory flow (FEF)25–75 were 92.7 ± 16.2, 92.2 ± 18.0, 85.3 ± 9.3, and 78.0 ± 36.5 percent predicted, respectively. Seventy-seven percent of FEV1 values were ≥ 80%, 18.6% were between 60–80%, and 3.1% were

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] FEV(1), 74.0 +/- 2.1% predicted vs 57.1 +/- 1.8% predicted, respectively; p0.0001), less resistance to airflow (mean airway resistance, 140.3 +/- 8.5% predicted vs 311 +/- 18% predicted, respectively; p0.0001), and larger lung volumes (mean total lung capacity, 116.4 +/- 1.6% predicted vs 105.3 +/- 1.8% predicted, respectively; p0.0001) 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.

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.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.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.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 Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses. Objective We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze. Methods We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates. We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes. Results Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs ( P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings ( P = .46 for AUC of total symptoms score comparison). Conclusion In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.

Rationale The primary objective of this study was to determine if blacks, asthmatic or non-asthmatic, displayed diminished T lymphocyte response to glucocorticoid (GC) in vitro compared to their white counterparts. If differences were noted, this would suggest a racial predisposition to decreased GC responsiveness among blacks. Methods Asthmatic (n=395, 27% blacks) and control (n=202, 52% blacks) subjects recruited from National Jewish and from the surrounding community participated in the study. In vitro GC responsiveness of peripheral blood T lymphocytes was determined using log 10 IC 50 values (i.e. dexamethasone concentration required to suppress phytohemagglutinin-stimulated T lymphocytes by 50%). Asthma medication history, atopic status, and spirometric lung function measures corrected for race were collected. Results Black and white asthmatics had similar FEV 1 % predicted and inhaled and oral GC requirements. Black asthmatics displayed significantly diminished GC responsiveness compared to whites (log 10 IC 50 values of 1.20 ± 1.06 vs. 0.92 ± 1.05, P P 10 IC 50 values. Conclusion Our observation that black asthmatics and non-asthmatic controls require greater concentrations of GC in vitro to suppress T lymphocyte activation suggests blacks to have a racial predisposition to diminished GC responsiveness which may contribute to their heightened asthma morbidity.

Background Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. Objectives We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. Methods In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. Results The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. Conclusions In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.