Combined Analysis of Asthma Safety Trials of Long-Acting ß2-Agonists.

BACKGROUND: Safety concerns regarding long-acting ß2-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials. METHODS: As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone. The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations. RESULTS: Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001). CONCLUSIONS: Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

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).

Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.

BACKGROUND: Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). OBJECTIVE: We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. METHODS: We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts. RESULTS: We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. CONCLUSIONS: We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.

Effect of inhaled glucocorticoids in childhood on adult height.

BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS: We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 µg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial.

IMPORTANCE: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. OBJECTIVE: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. INTERVENTION: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. RESULTS: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed. CONCLUSIONS AND RELEVANCE: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01272635.

Daily or intermittent budesonide in preschool children with recurrent wheezing.

BACKGROUND: Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy. METHODS: We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy. RESULTS: The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen. CONCLUSIONS: A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).

Inhaled corticosteroids in lung diseases.

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD.

Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing?

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.

Asthma outcomes: composite scores of asthma control.

BACKGROUND: Current asthma guidelines recommend assessing the level of a patient's asthma control. Consequently, there is increasing use of asthma control as an outcome measure in clinical research studies. Several composite assessment instruments have been developed to measure asthma control. OBJECTIVE: National Institutes of Health institutes and federal agencies convened an expert group to propose the most appropriate standardized composite score of asthma control instruments to be used in future asthma studies. METHODS: We conducted a comprehensive search of PubMed using both the National Library of Medicine's Medical Subject Headings and key terms to identify studies that attempted to develop and/or test composite score instruments for asthma control. We classified instruments as core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. RESULTS: We identified 17 composite score instruments with published validation information; all had comparable content. Eight instruments demonstrated responsiveness over time; 3 demonstrated responsiveness to treatment. A minimal clinically important difference has been established for 3 instruments. The instruments have demographic limitations; some are proprietary, and their use could be limited by cost. CONCLUSION: Two asthma composite score instruments are sufficiently validated for use in adult populations, but additional research is necessary to validate their use in nonwhite populations. Gaps also exist in validating instruments for pediatric populations.

Corticosteroid use and bone mineral accretion in children with asthma: effect modification by vitamin D.

BACKGROUND: The adverse effects of corticosteroids on bone mineral accretion (BMA) have been well documented. Vitamin D insufficiency, a prevalent condition in the pediatric population, has also been associated with decreased bone mineral density (BMD). OBJECTIVE: We sought to determine whether children with asthma who have lower vitamin D levels are more susceptible to the negative effects of corticosteroids on BMD over time. METHODS: Children aged 5 to 12 years with mild-to-moderate asthma who participated in the Childhood Asthma Management Program were followed for a mean of 4.3 years. Total doses of inhaled corticosteroids and oral corticosteroids (OCSs) were recorded, serum 25-hydroxyvitamin D3 levels were measured at the beginning of the trial, and serial dual-energy x-ray absorptiometry scans of the lumbar spine were performed. Annual BMA rates were defined as follows: [(BMD at 4 years' follow-up - BMD at baseline)/4 years]. RESULTS: BMA was calculated for 780 subjects. In boys baseline vitamin D levels significantly modified the relationship between OCSs and BMA (vitamin D × OCS interaction, P= .023). Stratification by vitamin D levels showed a decrease in BMA with increased use of OCSs in vitamin D-insufficient boys only (P< .001). Compared with vitamin D-sufficient boys, vitamin D-insufficient boys exposed to more than 2 courses of OCSs per year had twice the decrease in BMA rate (relative to boys who were OCS unexposed). CONCLUSIONS: Vitamin D levels significantly modified the effect of OCSs on BMA in boys. Further research is needed to examine whether vitamin D supplementation in children with poorly controlled asthma might confer benefits to bone health.

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial.

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.

Inhaled corticosteroid dosing: double for nothing?

Two recent trials from the National Heart, Lung, and Blood Institute's asthma clinical trials networks raise a concern about using double the dose of an inhaled corticosteroid (ICS) as a positive control arm in clinical trials of add-on therapy. The literature evaluating the response to doubling the dose of an ICS is briefly reviewed. The vast majority of studies do not demonstrate a significant positive benefit from doubling the dose of an ICS but do show improvement with 4-fold increases that is equal to or greater than that of add-on long-acting bronchodilators. It is recommended that doubling the dose of an ICS no longer be considered a positive comparator arm in clinical trials, although it might be beneficial in individual patients.

Comparison of inhaled corticosteroids: an update.

OBJECTIVE: To review the basis for the estimated comparative daily dosages of inhaled corticosteroids for children and adults that are presented in the National Heart, Lung, and Blood Institute's Expert Panel Report 3; in addition, the pharmacodynamic and pharmacokinetic basis for potential clinical differences among inhaled corticosteroids is discussed. DATA SOURCES: A complete MEDLINE search was conducted of human studies of asthma pharmacotherapy published between January 1, 2001, and March 15, 2006, followed by a PubMed search up until August 2008, using ciclesonide, inhaled corticosteroids, and pharmacokinetics as key words. Product information on each inhaled corticosteroid was also included. STUDY SELECTION AND DATA EXTRACTION: Comparative clinical trials of inhaled corticosteroids and systematic reviews for efficacy comparisons were evaluated. Extensive literature reviews, meta-analyses, and selected clinical studies that illustrate or represent specific points of view were selected. Pharmacodynamic and pharmacokinetic data extracted from previously published reviews and specific studies were included. DATA SYNTHESIS: Pharmacodynamic characteristics (glucocorticoid receptor binding) and lung delivery determine the relative clinical efficacy and pharmacokinetic properties (oral bioavailability, lung retention, systemic clearance) and determine comparative therapeutic index of the inhaled corticosteroids. Secondary pharmacokinetic differences (intracellular fatty acid esterification, high serum protein binding) that have been posited to improve duration of action and/or therapeutic index are unproven, and current comparative clinical trials do not support the hypotheses that they provide an advantage. Ultrafine particle meter-dose inhalers (MDIs) have not demonstrated superior asthma control or improved safety over older MDIs. All of the inhaled corticosteroids demonstrate efficacy with once-daily dosing, and all are more effective when dosed twice daily. CONCLUSIONS: Current evidence suggests that all of the inhaled corticosteroids have sufficient therapeutic indexes to provide similar efficacy and safety in low to medium doses. Whether or not some of the newer inhaled corticosteroids offer any advantages at higher doses has yet to be determined.

Identification of a key gene module associated with glucocorticoid- induced derangement in bone mineral density in patients with asthma.

Derangement in bone mineral density (BMD) caused by glucocorticoid is well-known. The present study aimed to find key biological pathways associated with low BMD after glucocorticoid treatment in asthmatics using gene expression profiles of peripheral blood cells. We utilized immortalized B cells (IBCs) from 32 childhood asthmatics after multiple oral glucocorticoid bursts and peripheral blood mononuclear cells (PBMCs) from 17 adult asthmatics after a long-term use of oral glucocorticoid. We searched co-expressed gene modules significantly related with the BMD Z score in childhood asthmatics and tested if these gene modules were preserved and significantly associated with the BMD Z score in adult asthmatics as well. We identified a gene module composed of 199 genes significantly associated with low BMD in both childhood and adult asthmatics. The structure of this module was preserved across gene expression profiles. We found that the cellular metabolic pathway was significantly enriched in this module. Among 18 hub genes in this module, we postulated that 2 genes, CREBBP and EP300, contributed to low BMD following a literature review. A novel biologic pathway identified in this study highlighted a gene module and several genes as playing possible roles in the pathogenesis of glucocorticoid- induced derangement in BMD.

Pretreatment with albuterol versus montelukast for exercise-induced bronchospasm in children.

STUDY OBJECTIVES: To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise-induced bronchospasm in children with mild-to-moderate asthma, and to determine whether cysteinyl leukotriene (Cys-LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast. DESIGN: Prospective, randomized, double-blind, double-dummy, crossover study. SETTING: Asthma clinic at a university-affiliated medical center. PATIENTS: Eleven children aged 7-17 years with physician-diagnosed mild-to-moderate asthma for at least 6 months and with self-reported exercise-induced bronchospasm (defined as > or = 15% decrease in forced expiratory volume in 1 sec [FEV(1)] at screening and baseline visit). INTERVENTION: Patients were randomly assigned to receive 3-7 days of oral montelukast 5-10 mg/day or 2 puffs of an albuterol metered-dose inhaler just before an exercise challenge and then were crossed over to the alternate therapy for the last visit. MEASUREMENTS AND MAIN RESULTS: Serial spirometry was performed before and at 0, 5, 10, 15, 30, 45, and 60 minutes after the exercise challenge at each visit. Measurement of exhaled breath condensate was performed at the screening visit and study visits 1 and 2. The primary outcome was the maximum change in FEV(1) after exercise. Secondary outcomes were the area under the curve for FEV(1) (expressed as percentage decrease from baseline) during the first 60 minutes (AUC(0-60)) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV(1) after exercise challenge). The mean +/- SD maximum decrease in FEV(1) was 27.5 +/- 7.9% at baseline. Patients receiving montelukast had an 18.3 +/- 13.7% decrease in FEV(1) compared with 0.7 +/- 1.6% in patients receiving albuterol (p=0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p<0.05, McNemar's test). The AUC(0-60) was significantly smaller with albuterol compared with montelukast (p<0.001, Wilcoxon signed rank test). No correlations were found between Cys-LT concentration and the severity of exercise-induced bronchospasm or the response to montelukast. CONCLUSION: Pretreatment with albuterol is more effective than montelukast for prevention of exercise-induced bronchospasm in children with asthma.

Rationale for the major changes in the pharmacotherapy section of the National Asthma Education and Prevention Program guidelines.

Numerous changes have been incorporated into the new National Asthma Education and Prevention Program's Expert Panel Report 3. In the pharmacotherapy section of the report, many of these changes are minor in that they do not alter the basic philosophy of treatment recommendations from the previous Expert Panel Report but only add new formulations, change dosing or dosage forms, or add discussion of risks. However, 4 major changes have been identified, and the rationales for 3 are discussed in detail here. The treatment of childhood asthma is divided into 2 distinct age groups, infants less than 5 years of age and children 5 to 12 years of age, because of the availability of more data suggesting differences in response in these patients, as well as a relative paucity of quality data in the younger patients. Omalizumab, a humanized mAb to IgE, is the only new entity approved for the treatment of asthma since the previous guidelines, and its recommendations were reviewed. The indication for combination therapy with inhaled corticosteroids and long-acting inhaled beta(2)-agonists (LABAs) has been modified in lieu of the recent black box warning concerning the increased risk of severe asthma exacerbations and death associated with LABA use. However, the inhaled corticosteroids/LABAs are still recommended for patients with moderate-to-severe persistent asthma. The rationale for the continued recommendation is provided.