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PEDIATRICS Vol. 109 No. 5 May 2002, pp. 866-872

Nebulized Budesonide Inhalation Suspension Compared With Cromolyn Sodium Nebulizer Solution for Asthma in Young Children: Results of a Randomized Outcomes Trial

Jeffrey G. Leflein, MD*, Stanley J. Szefler, MD{ddagger}, Kevin R. Murphy, MD§, Sherahe Fitzpatrick, MDa, Mario Cruz-Rivera, PhD, MPH, Christopher J. Miller, MStat and Joseph A. Smith, MD

* Allergy & Immunology Associates of Ann Arbor, Ann Arbor, Michigan
{ddagger} Helen Wohlberg & Herman Lambert Chair in Pharmacokinetics, Division of Clinical Pharmacology and Allergy/Immunology, National Jewish Medical and Research Center and the Departments of Pediatrics and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado
§ Midwest Allergy & Asthma Clinic, Midwest Childrens Chest Physicians, Omaha, Nebraska
AstraZeneca LP, Wilmington, Delaware

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. The availability of antiinflammatory asthma medications for infants and young children has been limited. The objective of this study was to compare effects of nebulized budesonide inhalation suspension and cromolyn sodium nebulizer solution on asthma-related health outcomes in young children with asthma.

Methods. We conducted a randomized, parallel-group, 52-week, open-label study in 36 US clinical sites. Patients included 335 children who were 2 to 6 years of age and had persistent asthma that had been treated with at least 1 long-term control medication; 287 children (86%) completed the study. Patients received budesonide inhalation suspension, 0.5 mg daily (n = 168), or cromolyn sodium nebulizer solution, 20 mg 4 times daily (n = 167), for 8 weeks, followed by dose titration at the investigator’s discretion. The main outcome measure was the rate of asthma exacerbations over 52 weeks. Secondary measures included times to first asthma exacerbation and first use of additional asthma therapy, asthma symptom scores, rescue medication use, and health care resource use.

Results. The budesonide group had a mean (median) asthma exacerbation rate of 1.23 (0.99) per year compared with 2.41 (1.85) for the cromolyn group, significantly longer times to first exacerbation and first use of additional long-term asthma medication, greater improvements in asthma symptom scores, reduced use of rescue medication, and fewer urgent care visits. Both treatments were well tolerated.

Conclusions. Budesonide inhalation suspension was more effective than nebulized cromolyn sodium in young children with persistent asthma. Both treatments were well tolerated with similar adverse event profiles.

Key Words: budesonide inhalation suspension • Pulmicort Respules • cromolyn sodium • nebulizer therapy

Abbreviations: ICS, inhaled corticosteroid • ACTH, adrenocorticotropic hormone • ANOVA, analysis of variance


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Current asthma treatment guidelines state that inhaled corticosteroids (ICSs) are the most potent and effective long-term antiinflammatory medications for asthma and recommend their use in treating infants and young children with persistent asthma of any severity.1 However, until very recently, no ICSs that were designed to meet the special delivery needs of the pediatric asthma population were available or approved by the US Food and Drug Administration. Many children who are 4 years and younger lack the coordination for actuation and inhalation of metered-dose inhalers and cannot achieve the inspiratory flow rates required to use dry-powder inhalers effectively.2–4 Safety and efficacy data in young children for these formulations are lacking. Therefore, currently available metered-dose and dry-powder inhaler formulations of corticosteroids are approved in the United States only for children who are at least 4 years of age.5

Cromolyn sodium nebulizer solution (Intal Nebulizer Solution; Rhône-Poulenc Rorer, Collegeville, PA) is approved for long-term treatment of asthma in children who are as young as 2 years.6 Generally, cromolyn sodium has been shown to be more effective than placebo in the treatment of asthma in children who are 1 to 5 years of age7–9 but less effective than ICSs in children who are 4 to 16 years of age.10–14 Thus, current recommendations limit cromolyn sodium use to mild persistent asthma.1,2 However, cromolyn sodium has a well-established safety profile and was routinely used as first-line therapy for persistent asthma in the United States at the time of this study.15,16 Moreover, the lack of nebulizable corticosteroids has led to undertreatment with inhaled antiinflammatory medications, overtreatment with oral corticosteroids and inhaled ß 2-agonists, off-label use of metered-dose inhalers with a spacer and face mask, and off-label use of nasal or parenteral corticosteroids via nebulization.4

Budesonide inhalation suspension (Pulmicort Respules; AstraZeneca LP, Wilmington, DE) is the first nebulized corticosteroid developed and approved for pediatric asthma patients and is the first ICS developed for use in children who are younger than 4 years.17 Budesonide has been available worldwide for more than a decade in various dosage forms, including a nebulizable suspension and a dry-powder inhaler (Pulmicort Turbuhaler, AstraZeneca LP). Numerous studies have demonstrated the efficacy and safety of budesonide inhalation suspension.18 Three of these randomized, placebo-controlled trials were conducted in the United States with >1000 infants and young children (6 months to 8 years of age) who had mild to moderate persistent asthma and received budesonide inhalation suspension once or twice daily.19–21

The objective of the present study was to compare the effectiveness and safety of budesonide inhalation suspension with that of cromolyn sodium nebulizer solution for 52 weeks in pediatric patients with persistent asthma. The rate of asthma exacerbations was used as the primary outcome measure because it serves as a clinical measure of the ability of the 2 medications to control asthma in this population.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patient Population
Patients who were 2 to 6 years of age and had persistent asthma were eligible for enrollment. Children were required to have asthma symptoms more frequently than twice weekly within 6 months of study entry, nocturnal asthma symptoms more than twice monthly, and at least 1 asthma exacerbation requiring systemic corticosteroids within 6 months of enrollment or at least 2 such exacerbations within 9 months of enrollment. Patients were required to have used at least 1 long-term asthma medication (ICS, nedocromil sodium, cromolyn sodium, or an oral or inhaled bronchodilator) daily with periodic use of rescue medication within 3 months of study entry. Eligible patients could not have received long-term (>=14-day courses) or intermittent (<14-day courses) oral corticosteroid treatment within 12 weeks or 15 days of enrollment, respectively.

Patients were excluded if they were born prematurely (gestation <32 weeks), had a history of severe or unstable asthma or ventilatory assistance (except at birth), were hospitalized for treatment of airway obstruction within 30 days of study enrollment, had an upper respiratory tract infection and infectious sequelae of the lower respiratory tract within 14 days of study enrollment, or had concomitant lung disease or other significant medical conditions. The study was approved by each center’s institutional review board and followed the principles of the Declaration of Helsinki. Each patient’s legal guardian gave written informed consent before the patient’s enrollment.

Study Protocol
This 52-week, randomized, open-label study was conducted at 36 sites in the United States, including medical centers, clinical research centers, and community practices, between September 1997 and August 1999. After assessment during a 2- to 3-week baseline phase, patients were eligible for randomization if asthma symptom severity scores were >=2 (scale of 0–3; 0 = no symptoms and 3 = severe symptoms) on at least 7 of 14 days before randomization and if rescue medication use was reported on at least 5 of 14 days before randomization. On the basis of a computer-generated randomization schedule, patients were assigned in a 1:1 ratio in balanced blocks of 4 within each site to receive budesonide inhalation suspension 0.5 mg daily (administered either once daily or in divided doses twice daily per investigator judgment) or cromolyn sodium 20 mg 4 times daily, according to standard practice, for 8 weeks (both administered via standard compressor and nebulizer provided by the investigator). At the time of randomization, patients discontinued all previous long-term asthma medications. After 8 weeks and throughout the remainder of the trial, study drug doses could be adjusted at the discretion of the investigator. The maximum and minimum doses of budesonide were 1 mg twice daily and 0.25 mg once daily, respectively. The dose of cromolyn sodium could be reduced to 20 mg 3 times daily.6 Patients returned to the clinic 6 times during the treatment period (weeks 2, 8, 16, 28, 40, and 52) for evaluation and data collection.

Rescue (as needed) ß2-agonist use was allowed throughout the open-label treatment period, and use of systemic corticosteroids was allowed to treat asthma exacerbations at the investigator’s discretion. If >=3 asthma exacerbations that required treatment with oral or parenteral corticosteroids were recorded or if the patient required more than the maximum recommended dose of study drug to treat asthma symptoms, then long-term asthma medications other than systemic corticosteroids (eg, methylxanthines, oral or inhaled ß2-agonists, nedocromil sodium, other ICSs, or 5-lipoxygenase and leukotriene antagonists) could be added at the investigator’s discretion. Children who were randomized to either study medication could not receive the other as add-on treatment.

Outcome Measures
The primary outcome measure was the rate of asthma exacerbations defined by at least 1 of the following: use of systemic corticosteroids or additional long-term asthma maintenance therapy, an emergency department or urgent care visit, or hospitalization. Secondary outcome variables included times to first asthma exacerbation and first use of additional long-term asthma therapy, changes in nighttime and daytime asthma symptom scores, and use of rescue medications (ß2-agonist and number of oral corticosteroid courses). Both asthma symptom scores were based on a 4-point scale (0 = no symptoms of asthma; 1 = mild symptoms [easily tolerated]; 2 = moderate symptoms [causing some discomfort and interference with sleep or daily activities]; and 3 = severe symptoms [incapacitating or causing inability to sleep or perform daily activities]). Nighttime and daytime asthma symptom scores and daily rescue medication use were recorded in patient diaries by caregivers for at least 14 days before each clinic visit.

The effect of treatment on direct health care resource utilization was assessed by the likelihood of use and levels of use for asthma-related inpatient care, emergency department visits, urgent care visits, unscheduled physician visits, and asthma-related medication use. Parents called in weekly using an interactive voice recording system to report these data and were contacted by the research center if a weekly response was missing. These data and adverse event reports were compiled weekly.

Safety Evaluations
Safety was assessed by monitoring reported adverse events and changes from baseline in vital signs, laboratory tests, and body height and weight. Adverse events were assessed and a brief physical examination was performed at each clinic visit. Clinical chemistry, hematology tests, and stadiometry measurements using a wall-mounted stadiometer were performed before randomization and at week 52. At approximately one third of the study sites, blood specimens were obtained between 6:00 and 8:30 AM before Trandomization and at week 52 to determine basal plasma cortisol levels and again 60 minutes after intravenous administration of 0.25 mg of synthetic adrenocorticotropic hormone (ACTH; Cortrosyn, Organon, West Orange, NJ) to determine ACTH-stimulated plasma cortisol levels.

Statistical Analysis
All study endpoints, except for plasma cortisol levels and height changes, were analyzed using an all-patients-treated approach, including all patients who received at least 1 dose of study medication and had at least 1 observation while receiving a study drug. Only patients with 1 year (±4 weeks) of data collection were included in analyses of plasma cortisol levels and height changes.

The difference between groups in the rate of asthma exacerbations was assessed by an analysis of variance (ANOVA), using the response variable of natural log (exacerbation rate + 1) and terms for treatment, center, and length of time in the study as explanatory variables. The log transformation was applied to the response variable to reduce the effect of outliers and make the variances more homogeneous, thus making the data appropriate for parametric analysis.22 The results of this analysis were confirmed with the nonparametric Wilcoxon rank sum test.23 For patients who had been using additional long-term asthma medication, data that contributed to the rate of exacerbations were used up to and during the time of added medication. Because of the influence of added medication, data that contributed to the rate of exacerbations beyond this point were censored, and the rate of exacerbations was extrapolated to 1 year.

Life-table methods were used to analyze differences in times to first asthma exacerbation and first use of additional long-term asthma medication; P values associated with the log-rank test are reported.24 For asthma symptom scores and rescue medication use, changes from baseline (mean of the last 14 days before randomization) to the open-label treatment phase (mean over 52 weeks) were calculated and tested for treatment group differences using ANOVA. When a patient received long-term asthma therapy in addition to study drug, symptom score and rescue medication data were used only up to the time of added medication and were carried forward to subsequent time points thereafter. Logistic regression, adjusting for differences in duration of follow-up, was used to examine differences between treatment groups in the proportion of patients who used inpatient or outpatient services.25 The mean number of inpatient and outpatient services per patient was compared between treatment groups with Poisson regression, using duration of follow-up as an offset variable.26

Differences in cortisol response to ACTH stimulation from baseline to week 52 were assessed using ANOVA. For height data, standard deviation scores were calculated as the difference between observed height (centimeters) and standard median height (observed 50th percentile height) based on data from the National Center for Health Statistics.27 Changes from baseline to week 52 in standard deviation scores were compared between groups using ANOVA.

All statistical analyses were conducted as 2-sided tests. The planned sample size was based on an assumption that the exacerbation rate with cromolyn sodium nebulizer solution was 1.8 exacerbations per patient per year, that treatment with budesonide inhalation suspension would reduce that rate by 40%, and that the occurrence of exacerbations would follow a Poisson process. It was estimated that 119 patients per treatment group would be required to detect a true difference between groups with 90% power at a 5% level of significance.28 An attempt was made to randomize 150 patients per treatment group to allow for withdrawals during the 52-week study period.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Patient Population
Of 426 patients enrolled in the study, 335 were randomized to receive budesonide inhalation suspension (n = 168) or cromolyn sodium nebulizer solution (n = 167; Fig 1). Patient demographics; baseline asthma characteristics; and use of cromolyn sodium, ICSs, and ß2-agonists before study enrollment were similar between treatment groups (Table 1). A total of 287 patients completed the study; 154 (92%) received budesonide inhalation suspension, and 133 (80%) received cromolyn sodium nebulizer solution (P = .01).



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  		Fig 1. Flow chart of patient disposition throughout the study. *Other includes patients who were randomized in error or moved.

 

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  		TABLE 1. Patient Demographics and Baseline Asthma Characteristics

 
Interventions
After the 8-week fixed-dose phase of the trial, doses of study medications could be titrated at the investigator’s discretion and the product instructions. The mean daily dose of budesonide inhalation suspension ranged from 0.54 mg (weeks 0–8) to 0.61 mg (weeks 40–52). Initial doses were maintained in 53% of patients who were receiving budesonide inhalation suspension, doses were increased in 32% of patients, and doses were titrated up and down in a stepwise approach to maintain control in 15% of patients. The mean daily dose of cromolyn sodium nebulizer solution ranged from 76.3 mg (weeks 0–8) to 65.0 mg (weeks 40–52).

Outcome Measures
Treatment with budesonide inhalation suspension significantly (P <= .001) reduced the rate of asthma exacerbations per year compared with cromolyn sodium nebulizer solution (Table 2). From the ANOVA that included adjustments for independent, explanatory variables, the mean exacerbation rate for patients who were receiving cromolyn sodium was estimated to be 1.27 times (27%) greater than for those who were receiving budesonide inhalation suspension. Mean times to first asthma exacerbation and first use of additional long-term asthma medication were significantly (P < .001) longer in patients who were receiving budesonide than in patients who were receiving cromolyn sodium (Table 2).


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  		TABLE 2. Effectiveness Evaluations by Treatment Group

 
Patients in both treatment groups experienced by week 2 improvements in nighttime and daytime asthma symptom scores that were maintained throughout the 52-week study (Fig 2). Mean improvements in nighttime and daytime scores from baseline to study end for the budesonide inhalation suspension group were nearly double those of the nebulized cromolyn sodium group (P < .001). The mean number of days of rescue medication use per 2-week period before each clinic visit also decreased in both treatment groups by week 2 (Fig 3). Decreases in rescue medication use in both treatment groups were maintained throughout the open-label treatment period, but patients who were receiving budesonide inhalation suspension used consistently less rescue medication and had a significantly (P <= .001) greater change from baseline to study end compared with patients who were receiving cromolyn sodium nebulizer solution.



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  		Fig 2. Mean improvement in daytime and nighttime asthma symptom scores assessed over 2-week intervals before each clinic visit. *P < .001 versus nebulized cromolyn sodium. Mean change adjusted for center effect. All-patients-treated analysis, last value carried forward.

 


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  		Fig 3. Mean days of rescue medication use per 2 weeks before each clinic visit. *P < .001 versus nebulized cromolyn sodium. Mean change adjusted for center effect. All-patients-treated analysis, last value carried forward.

 
As shown in Table 3, patients who were treated with budesonide were significantly less likely to have an urgent care visit (P = .02) than those who were treated with cromolyn sodium. The mean number of services used generally followed a similar pattern (Table 3). Fewer patients who were receiving budesonide inhalation suspension used oral corticosteroids than those who were receiving cromolyn sodium nebulizer solution (47% vs 70%; P < .01); patients who were receiving budesonide also used oral corticosteroids for fewer days (6.3 vs 9.3 days; P < .01).


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  		TABLE 3. Health Care Resource Utilization by Treatment Group*

 
Safety
There were no clinically relevant differences in the incidence or type of adverse events reported between the treatment groups. The most frequently reported adverse events were respiratory infection, otitis media, and sinusitis (Table 4). Most adverse events were considered to be of mild or moderate intensity. One patient discontinued the study because of adverse events after cromolyn sodium treatment; no patient who was receiving budesonide inhalation suspension discontinued because of adverse events. The incidence of adverse effects commonly associated with the use of ICSs was similar among the budesonide and cromolyn sodium groups (dermatitis, 4% and 3%; moniliasis, 3% and 0%; conjunctivitis, 6% and 4%, respectively).


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  		TABLE 4. Adverse Events Reported by >= 10% of Patients in Either Study Group

 
Changes in vital signs, physical examinations, or laboratory test values showed no clinically relevant differences between groups. Basal and ACTH-stimulated plasma cortisol levels were similar between groups (Fig 4). Patients who completed 1 year of nebulized budesonide treatment (n = 153) had a mean increase in height from baseline to study end of 6.69 cm versus 7.55 cm in patients who completed 1 year of nebulized cromolyn sodium treatment (n = 129), a difference of 0.86 cm. This mean difference between groups was statistically significant (P < .001) when the data were expressed as changes in standard deviation scores for height, standardized by age and gender according to National Center for Health Statistics data.



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  		Fig 4. Basal and ACTH-stimulated cortisol levels at baseline and week 52. There were no significant differences between treatment groups (P = .424).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
This prospective 52-week US trial of nebulized cromolyn sodium and nebulized budesonide in children who were 2 to 6 years of age and had persistent asthma is particularly important given the increasing prevalence and severity of pediatric asthma and the limited therapeutic and Food and Drug Administration–approved choices available for these patients.29 Children who had persistent asthma and received nebulized budesonide had significantly lower rates of asthma exacerbations, longer times to first asthma exacerbation, and longer times to first use of additional asthma therapy compared with children who received nebulized cromolyn sodium. The mean and median rates of asthma exacerbations were nearly 2 times higher for patients who received cromolyn sodium than for those who received budesonide. Improvements in nighttime and daytime asthma symptom scores in children who were treated with budesonide were nearly double those with cromolyn sodium, and children who received budesonide used less rescue medication. These results are consistent with the significantly reduced use of rescue medications with inhaled budesonide versus placebo in 3 randomized, double-blind US trials.19–21

Previous studies comparing cromolyn sodium with ICSs in older children have consistently found ICSs to be more effective in controlling symptoms and improving lung function.10,11,13,14 In this study, asthma control was primarily assessed on the basis of the rate of asthma exacerbations because young children are unable to perform pulmonary function tests adequately and because standard reference values are not available for children who are younger than 5 years.1 Also, routine assessment of asthma exacerbations is an important measure of long-term asthma control.1,30 Asthma exacerbations cause substantial morbidity and mortality even in those with mild disease.31–33 The greater rate of asthma exacerbations in the cromolyn sodium group resulted in earlier and more frequent use of additional asthma medications, including oral corticosteroids, and more urgent care and unscheduled physician visits. A significantly (P < .003) reduced rate of asthma exacerbations with budesonide inhalation suspension versus nebulized cromolyn sodium was previously demonstrated in children who were aged 11.6 to 31.2 months.34

In childhood asthma, observations of early loss of pulmonary function suggest that there may be a critical "window of opportunity" for therapeutic intervention, after which treatment initiation may never produce optimal results because of irreversibility and remodeling. Improved outcomes in children who receive early antiinflammatory intervention35, 36 highlight the importance of defining the most effective antiinflammatory therapy for childhood asthma.37 The ability to titrate budesonide in the present study while maintaining symptom control suggests that a stepwise approach to dose titration can be used successfully to reduce the potential risks of ICSs.

Patients who were receiving ICSs or cromolyn sodium were eligible for study entry, and the 2 treatment groups were well balanced with respect to previous medication use. At study initiation, cromolyn sodium was the only nebulizable antiinflammatory drug approved for this age group; if patients who were receiving cromolyn sodium had been excluded, then trial recruitment and completion would have been difficult and prolonged and would not reflect current US practice.2

The open-label design of this effectiveness study was selected to reflect accurately "real-world" conditions. The results of an effectiveness study can be more readily generalized to actual practice than those of an efficacy study, in which inclusion and exclusion criteria and interventions are more strictly defined. However, the lack of blinding to treatment is a limitation of this type of study because of potential investigator bias attributable to, for example, comfort with an established therapy, previous knowledge, or experience.

Despite proven efficacy and safety of ICSs, physicians and parents remain concerned about their safety.38 In this trial, no statistically or clinically significant differences were observed between treatments in adverse events, vital signs, physical examinations (except for height), or laboratory tests over 1 year. There was no evidence of hypothalamic-pituitary-adrenal axis suppression in either treatment group.

Changes in standard deviation scores for height from baseline to study end were significantly different between the 2 groups, reflecting a greater mean change in height for patients who received cromolyn sodium versus budesonide (difference of 0.86 cm). Although the interpretation of these growth data are limited because this study was not designed as a prospective growth study, these results nevertheless are similar to those of other 52-week studies of ICSs.39 Results of the Childhood Asthma Management Program Research Study Group demonstrated that early decreases in growth velocity are not sustained over longer-term treatment (4–6 years).40 Although the mean increase in standing height with budesonide was 1.1 cm less than with placebo in the first year of treatment, final height projections based on bone age were similar for budesonide and placebo. In a second study, children reached their predicted adult height after an average of 9.2 years (range: 3–13 years) of treatment with inhaled budesonide.41 Notably, growth during the first year of treatment was not predictive of final height. These results support the long-term safety of budesonide in terms of growth. Any potential risk must be weighed against the potential benefit provided by improved asthma control.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Nebulized budesonide inhalation suspension was as well tolerated as nebulized cromolyn sodium and significantly more effective in reducing the risk for asthma exacerbations and associated medical care in children who were 2 to 6 years of age. This study supports the use of nebulized budesonide as first-line antiinflammatory therapy for prophylactic and maintenance therapy of persistent asthma in young children.


   ACKNOWLEDGMENTS
 
This work was supported in part by AstraZeneca LP. This study was conducted by the Budesonide Inhalation Nebulizer Suspension Study Group, which consisted of the following investigators: James W. Baker, MD (Portland, OR); Michael S. Blaiss, MD (Memphis, TN); David A. Brown, MD (Asheville, NC); Donald Bukstein, MD (Madison, WI); Bradley E. Chipps, MD (Sacramento, CA); Robert Cohen, MD (Lawrenceville, GA); Howard Eigen, MD (Indianapolis, IN); Mark Ellis, MD (Orange, CA); Stanley P. Galant, MD (Orange, CA); David Geller, MD (Orlando, FL); Pinkus Goldberg, MD (Indianapolis, IN); Evalyn N. Grant, MD (Chicago, IL); Anne-Marie Irani, MD (Richmond, VA); Charles G. Jackson, MD (Kirkland, WA); Robert L. Jacobs, MD (San Antonio, TX); Michael Kaplan, MD (Los Angeles, CA); Michael J. Kraemer, MD (Spokane, WA); Jeffrey G. Leflein, MD (Ann Arbor, MI); Bruce Martin, MD (San Antonio, TX); Michael Mellon, MD (San Diego, CA); Louis Mendelson, MD (West Hartford, CT); Gerald C. Moore, MD (Plano, TX); Kevin Murphy, MD (Omaha, NE); David Pearlman, MD (Aurora, CO); Andrew J. Pedinoff, MD (Princeton, NJ); Gary Rachelefsky, MD (Los Angeles, CA); Michael Ruff, MD (Dallas, TX); Barbara J. Sanders, MD (Littleton, CO); Gail Shapiro, MD (Seattle, WA); Jerry M. Shier, MD (Rockville, MD); Howard J. Silk, MD (Atlanta, GA); David P. Skoner, MD (Pittsburgh, PA); Joseph Sproviero, MD (Norwalk, CT); F. McDaniel Atkins, MD (Denver, CO); Melanie Gleason, PA (Denver, CO); Stanley J. Szefler, MD (Denver, CO); Michael Welch, MD (San Diego, CA); and Richard Wyatt, MD (Minneapolis, MN).

Drs Leflein, Szefler, and Murphy have received clinical research support from and serve on the speaker’s bureau for AstraZeneca LP.

We thank Michelle McDermott, PharmD, Amy Zannikos, PharmD, and Leslie Sell, PhD, of Scientific Connexions for editorial assistance.


   FOOTNOTES
 
Received for publication Oct 5, 2001; Accepted Jan 31, 2002.

Reprint requests to (J.G.L.) Allergy & Immunology Associates of Ann Arbor, Reichert Health Bldg, Ste R-1018, Ann Arbor, MI 48106. E-mail: mhurw78081{at}aol.com

a Formerly with AstraZeneca LP, Wayne, Pennsylvania. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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