Abstract
Rationale. Topical antiinflammatory medications such as inhaled corticosteroids are recommended for therapy of asthma, but no formulation suitable for administration to infants and young children is available in the United States.
Methods. This was a 12-week, multicenter, double-blind, randomized, parallel-group study comparing the efficacy and safety of four dosing regimens of bude-sonide inhalation suspension (BIS) or placebo in 480 asthmatic infants and children (64% boys), ages 6 months to 8 years, with moderate persistent asthma. Approximately 30% of children were previously on inhaled corticosteroids that were discontinued before the study. Active treatments were comprised of BIS 0.25 mg once daily (QD), 0.25 mg twice a day (BID), 0.5 mg BID, or 1.0 mg QD. Efficacy was assessed by twice daily recording at home of asthma symptom scores and use of rescue medication, and discontinuation from the study because of worsening asthma and/or a requirement for systemic steroids. Peak flow measurements were recorded twice daily on diary and spirometry was recorded at clinic visits for those children able to perform these tests. Safety was assessed by reported adverse events and by cortisol testing (adrenocorticotropic hormone stimulation) in a subset of patients.
Results. Patients enrolled had an average duration of asthma of 34 months; the mean asthma symptom score was ∼1.3 (scale of 0–3). All dosing regimens with BIS produced statistically significant improvement in various clinical efficacy measures for asthma control compared with placebo. The lowest dose used, 0.25 mg QD, was efficacious but with fewer efficacy parameters than seen with the other doses administered. Separation between active treatment and placebo in daytime and nighttime symptom scores were observed by week 2 of treatment for all BIS treatment regimens. A significant increase in peak flow measurement was observed in most active treatment groups compared with placebo in the subset of children able to do pulmonary function testing. All treatment groups showed numerical improvement in forced expiratory volume in 1 second but only the 0.5-mg BID dose was significantly different from placebo. Adverse events for the entire group and response to adrenocorticotropic hormone in a subgroup of children who underwent cortisol testing before and at the end of the treatment period were no different in budesonide-treated patients in comparison to placebo.
Conclusion. Results of this study demonstrate that BIS is effective and safe for infants and young children with moderate persistent asthma in a multiple dose range, and that QD dosing is an important option to be considered by the prescribing physician.
Asthma is a common chronic disease of major public health importance in children.1 Recently, the efficacy and underutilization of antiinflammatory agents in the treatment of asthma have received widespread attention.2 Inhaled antiinflammatory medications, including glucocorticosteroids (GCS), are now recommended for use in all cases of persistent asthma regardless of severity.3 However, many pediatric patients, particularly infants and young children, are unable to use currently available formulations of inhaled GCS effectively because of delivery and technique problems.
Attempts to treat preschool infants and children with inhaled corticosteroids have used either a spacer with facial mask in conjunction with a standard metered dose inhaler (MDI), or jet nebulization of a corticosteroid solution not meant for nebulization. Limited studies using aerosolized GCS in an MDI delivered by a tube spacer or holding chamber with mask, have shown some success in controlling asthma symptoms in small children and infants as young as 6 months of age.4–6 However, this inhalation system can prove to be difficult to use by the caretaker as discovered by Noble et al5 who found that almost 20% of patients did not accept the spacer with mask, even when asleep, and had to be withdrawn from a clinical study of inhaled budesonide in infants and toddlers.
Early studies in the 1980s with nebulized GCS such as beclomethasone dipropionate (BDP) were disappointing,7–9probably as a result of the poor solubility of BDP precluding the ability to create a high enough concentration of BDP to deliver an adequate dose by nebulization. Budesonide is a GCS with a favorable ratio between topical antiinflammatory and systemic GCS effects over a wide dose range. The liquid suspension form of budesonide can be administered by nebulization at therapeutic concentrations, unlike other GCS, because of its better aqueous solubility. Godfrey et al10 in 1987 first reported the effectiveness of nebulized budesonide in an infant with severe, steroid-dependent asthma. Since then, there have been some reports demonstrating the value of budesonide inhalation suspension (BIS) in young children with asthma, but these studies were either uncontrolled, included primarily severely asthmatic infants many of whom were receiving long-term or frequent courses of oral steroids, or used one dose level that varied from study to study.11–17 Nebulized budesonide suspension has also been studied in older children 6 to 15 years of age18 and adults19 and found to be effective.
The purpose of this study was to evaluate the efficacy and safety of different doses and administration schedules of BIS in comparison with placebo for the treatment of moderate persistent asthma in a large number of infants and young children with well-defined disease criteria. The dose range included daily doses lower than previously investigated.
METHODS
Overall Study Design
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted at 38 study centers located throughout the United States. The study period was from May, 1995 to June, 1996. Institutional review board approval was obtained at each center.
The study design consisted of a 2- to 3-week baseline screening period followed by a 12-week, double-blind treatment period. At the first visit, informed consent was obtained from the legal guardian and the patient, if appropriate. A detailed medical history was obtained and a physical examination was performed. Blood and urine samples were obtained for laboratory studies. Pulmonary function tests were performed in those patients able to do them. Parents were provided with a diary card to record twice daily the child's daytime and nighttime asthma severity score during a 2- to 3-week baseline period. The symptom severity score used the following scale: 0 = none, no symptoms of asthma; 1 = mild symptoms; awareness of asthma symptoms and/or signs that are easily tolerated; 2 = moderate symptoms, asthma symptoms and/or signs with some discomfort, causing some interference of daily activities (or sleep); 3 = severe symptoms, incapacitating asthma symptoms and/or signs, with inability to perform daily activities (or sleep). The patient's daily chronic asthma medications were either withdrawn, reduced, or kept constant per the judgment of the investigator during the baseline period. Daily use of as-needed bronchodilator therapy was recorded, and in the subset of patients capable of performing peak flow measurements (PEFs), morning and evening PEFs were noted using a peak flow meter (Vitalograph, Inc, Lenexa, KS). At the end of the baseline phase (visit 2), eligible patients (see below) discontinued taking their chronic asthma medications and were randomized to receive one of the four active treatment regimens or placebo. Treatment was delivered by the nebulizer in the morning and evening and comprised one of the following: BIS, 0.25 mg am, placebo pm; BIS, 0.25 mg twice a day (BID); BIS, 0.5 mg BID; BIS, 1.0 mg am, placebopm; or placebo BID. Rescue medication (albuterol) continued to be available. Patients subsequently returned to the clinic for four additional visits (weeks 2, 4, 8, and 12). At every clinic visit, an interval history was obtained, a physical examination was conducted and daily diary records were checked. Spirometry was conducted in patients capable of performing the maneuver. A subset of patients had serum cortisol levels checked before and 60 minutes after adrenocorticotrophic hormone (ACTH) (Cortrosyn; Organon, West Orange, NJ) stimulation administered intravenously at visit 2 and at the end of the study (0.25 mg of ACTH dose was used except for young children, <2 years of age, who received 0.125 mg; intramuscular administration was allowed for infants). Plasma samples were analyzed for cortisol by BCO Medical Services BV (The Netherlands) using a high performance liquid chromatography assay. Laboratory assessments and oropharyngeal fungal cultures were performed at visit 2 and at the last visit.
The parent or legal guardian of the patients were asked at home on a daily basis to assess and record overall daytime and nighttime asthma severity scores (see scoring method above) and daytime and nighttime use of breakthrough medication. am and pm PEFs were also conducted and recorded in those children able to do this maneuver.
BIS was provided by Astra USA, Inc, (Westborough, MA) and was packaged in plastic ampules (Pulmicort Respules) with a volume of 2.0 mL; placebo ampules were identical in appearance. Medication or placebo were given by the Pari LC-Jet Plus nebulizer connected to a Pari Master compressor (Pari Respiratory Equipment, Inc, Richmond, VA) with use of a mouthpiece or face mask. Patients were instructed to receive study drug at approximately the same time each day and to operate the nebulizer until the cessation of audible sputtering, ie, no more drug was being nebulized. After nebulization, patients were asked to rinse their mouths; if using a face mask, parents were told to wipe the face clean with a towel. Compliance was checked by counting Respules at each visit. It needed to be 80% or greater, and if it was not, the parent was counseled, and if noncompliance continued, the patient was discontinued.
Patient Population
Boys and girls, ages 6 months to 8 years, with a diagnosis of asthma as defined by accepted criteria19 were eligible to participate in the study. The children needed to be using at least one asthma medication daily (eg, inhaled steroid, cromolyn, theophylline) and periodically using a rescue (bronchodilator) medication as needed for at least 3 months before visit 1. If the daily asthma medication was an inhaled corticosteroid, the patient must have been on the same corticosteroid at a stable dose for at least 2 months before visit 1; it was discontinued on entry to the study. Patients needed to have had exacerbations of cough and/or wheezing on a recurrent basis, including nocturnal asthma, with infrequent severe exacerbations, during the 6 months before visit 1. Based on the entry criteria, these children would be considered to have moderate persistent asthma using recent National Heart, Lung, and Blood Institute guidelines.3Patients with a history of severe and/or unstable asthma were excluded. Patients were also excluded if there had been long-term use of systemic steroids within 12 weeks of visit 1, or a history of intermittent use of systemic steroids within 30 days. To be eligible for randomization, patients were required at the end of the baseline period (visit 2) to have asthma symptoms (ie, a daytime or nighttime overall asthma severity score of 1, 2, or 3) on at least 5 of the last 7 days before visit 2, as recorded on the daily diary card. In addition, patients old enough to perform consistent pulmonary function tests had to demonstrate a basal forced expiratory volume in 1 second (FEV1) of ≥50% of the predicted value,21 and a 15% reversibility after a standard dose (2 puffs) of an inhaled bronchodilator (eg, albuterol).
Data Analysis
Changes in all efficacy variable scores from the baseline values (mean of the last 7 days before visit 2 for diary data [eg, symptoms, peak flow]) to the double-blind study phase (mean throughout weeks 0–12) were analyzed. An “All Patients Treated” analysis was conducted on the study population. It included all patients who received at least one dose of study drug after the baseline phase, and had at least one observation taken while receiving study drug. Data for patients who terminated early or who had missing data were carried forward and included in subsequent analysis. Analysis of variance techniques were used to compare differences between every active treatment group versus placebo for all efficacy variables with the exception of the proportion of patient discontinuations from the study that was analyzed using Fisher's exact test. Analysis of variance techniques were also used to analyze changes in the response to ACTH stimulation. Descriptive statistics were used to present all other data. Sample size was chosen to provide 80% power to detect a difference of 0.30 points in the efficacy variables of daytime and nighttime asthma symptoms scores between budesonide and placebo treatment groups for a two-sided test with a 5% level of significance. SAS statistical software package Version 6.11 (SAS Institute, Inc, Cary, NC) was used for statistical analyses.
RESULTS
A total of 481 patients were randomized into the double-blind treatment phase. One patient immediately refused to take the nebulization treatment and was dropped. Ten randomized patients who had no assessments made while on study drug were excluded from the efficacy analysis. Demographic and baseline disease characteristics for each of the five treatment groups are shown in Tables 1A and 1B. Demographic features and asthma history were similar for the five treatment groups. There were no significant differences between groups at baseline in the mean age of the patients, duration of asthma, and baseline asthma symptom scores. Treatment groups were similar with respect to the previous use of asthma drugs. Regular medication for asthma control was a requirement for participation in the study. The medications most frequently used were oral and inhaled albuterol (>99%), cromolyn sodium (72%), inhaled corticosteroids (31%), and theophylline (10%). Patients using inhaled corticosteroids at the time of entry into the study ranged from 25% to 38% of all patients in a given treatment group with the highest percentage being in the placebo group (38%). PEF and spirometry data at baseline in those capable of doing the maneuvers (34% of all patients) were similar among the treatment groups. Medication compliance with the BIS therapy was checked through the study period and was similar between treatment groups.
Patient Demographics and Asthma History
Baseline Pulmonary Function Data
The results of changes in the efficacy variables of daytime and nighttime asthma symptom scores during the 12-week treatment course, are presented in Table 2. The mean changes from baseline (adjusted for treatment center) for daytime and nighttime asthma symptom scores in patients in the 0.25-mg BID, 0.5-mg BID, and 1.0-mg every day (QD) BIS treatment groups were significantly greater compared with placebo (P ≤ .05); there was a numerical but not statistically significant improvement for the 0.25-mg QD treatment group compared with placebo. Results were stratified by age (0.5 to 4 years; >4 years) and improvements were noted to be statistically comparable between the two age groups.
Changes From Baseline to Double-blind Treatment in Efficacy Variables†
Changes from baseline in daytime and nighttime symptom scores during the study period with each treatment group are presented in Fig 1. Improvements in daytime and nighttime symptom scores were observed by the first visit after the start of treatment (week 2) for all budesonide treatment groups. Improvement in symptom scores began to plateau around 2 to 6 weeks after starting therapy, and was sustained until the study ended at 12 weeks. When symptom scores for all active treatment groups were combined, a statistically significant difference between active treatment compared with placebo was seen as early as day 2 for nighttime asthma symptoms, and day 5 for daytime asthma symptoms (not shown, P ≤ .05).
Changes from baseline in daytime and nighttime symptom scores during the study period with each treatment group.
Approximately one-third of patients in each treatment group were able to perform PEF and pulmonary function test maneuvers. The data obtained for pulmonary function measures are summarized in Table 2. There were statistically significant improvements in morning PEFs in the 0.25-mg BID, 0.5-mg BID, and 1.0-mg QD BIS treatment groups compared with placebo (P < .030) and in evening PEF for each active treatment (P = .034) except BIS 1.0 mg QD. All treatment groups showed numerical improvement in FEV1 but the only improvement that was statistically significant for FEV1 compared with placebo was for the 0.5-mg BID group (P = .031).
Patients in all active BIS treatment groups showed a significantly reduced number of days needing rescue asthma medication from the baseline period to weeks 0 to 12 of the double-blind study as compared with placebo. (The treatment period data were normalized to 2 weeks to be able to compare with the 2-week baseline.) The average reduction in the number of days that rescue medication was used was 4.4, 5.2, 4.9, and 4.4 days for the 0.25-mg QD, 0.25-mg BID, 0.5-mg BID, and 1.0-mg QD treatment groups, respectively, as compared with 2.4 days for patients on placebo. The differences between each BIS regimen and placebo were statistically significant (P < .014).
A total of 126 of the 470 patients eligible for efficacy analysis (27%) were discontinued from the treatment phase of the study; ∼70% of these discontinuations were because of a lack of therapeutic effect or disease deterioration, usually requiring oral steroid therapy. The proportion of patients who were discontinued from the placebo group (39%) was greater than that for the BIS groups (21%, 21%, 19%, and 31% for the 0.25-mg QD, 0.25-mg BID, 0.5-mg BID, and 1.0-mg QD groups, respectively). The difference between the placebo and the 0.25-mg QD, 0.25-mg BID, and 0.5-mg BID BIS groups was statistically significant (P ≤ .011) but there was no significant difference between the BIS 1.0-mg QD and placebo groups.
A dose-related trend was seen with a stepwise increase in efficacy noted in many variables between placebo, 0.25-mg QD, and 0.25-mg BID doses, but this upward trend reached a plateau with the 0.5-mg BID dose. The 1.0-mg QD treatment group actually showed a numerically higher discontinuation rate than the 0.5-mg BID group, and a numerically smaller improvement from baseline than the 0.5-mg BID group for every efficacy variable examined (Table 2), including the number of rescue medication days (see above), suggesting a difference between the two dosing regimens.
The incidence of adverse events considered to be possibly or probably related to treatment was similar between the placebo and the BIS treatment groups. Fifteen serious adverse events (eg, bronchospasm, pneumonia, otitis media) in 13 patients were reported during the double-blind treatment phase (4 serious adverse events in 4 placebo group patients, 4 events in 3 0.25-mg QD patients, 2 events in 1 0.25-mg BID patient, 1 event in 1 0.5-mg BID patient, and 4 events in 4 1.0-mg QD patients.) All events resolved without sequelae. Only 6 patients were discontinued from the treatment phase because of adverse events (2, 1, 1, and 2 patients in the placebo, 0.25-mg BID, 0.5-mg BID, and 1.0-mg QD BIS treatment groups, respectively). Monilia was reported by or discovered in 18 patients (4%) in the BIS treatment groups, and by 2 patients (2%) in the placebo group. The distribution of monilia between treatment groups was similar and did not show a dose effect. Mean changes in height and weight during the 12-week study period were calculated and found to be similar between the different treatment groups.
One hundred thirty-four patients (28%) underwent basal and post-ACTH cortisol determinators to assess hypothalamic pituitary axis function before and at the end of BIS treatment. No clinically relevant changes in basal cortisol levels were found during the double-blind treatment period for any treatment group. The adjusted mean changes in ACTH-stimulated cortisol levels from baseline to week 12 were similar between active treatment and placebo groups. There were no apparent differences from baseline to week 12 among treatment groups in the number of individual patients showing a change in responsiveness to ACTH stimulation (see Table 3). There were also no clinically significant changes between baseline and the end of the study in other laboratory tests performed for safety purposes.
Shifts in ACTH Stimulation Test From Baseline to Double-blind Treatment Phase (Week 12)*
DISCUSSION
The results of this study demonstrate that BIS given to young children with moderate persistent asthma at a dose of 0.5 mg to 1.0 mg daily given QD or BID significantly improved asthma symptoms, and decreased use of short acting rescue medication during a 12-week treatment period as compared with placebo. A dose of BIS 0.25 mg QD was efficacious but with fewer efficacy parameters than that seen with the other doses administered in this study. A subset (approximately one-third) of these children were able to carry out home peak flow monitoring and office pulmonary function testing. In this smaller group, significant improvements in am and pmPEFs were observed in most active treatment groups relative to placebo. Analysis of changes in FEV1 showed only the 0.5-mg BID dose regimen to be efficacious. Although the improvements in FEV1 for the other active treatment groups were numerically greater than those seen in the placebo group they did not reach statistical significance. The lower degree of sensitivity of FEV1 measurement relative to symptom scores in detecting a treatment effect may have been because of a high degree of variability in the quality of performing spirometry in this young population.
These positive results are similar to the findings of other studies that evaluated the efficacy of BIS in young children with asthma.10–18 However, many of these previous investigations were conducted in young infants with severe asthma, and lacked a placebo control arm, unlike the present placebo-controlled study in which patients ranged in age from infants to school-age, and had more stable, less severe asthma. The one study by Van Bever et al17 that did include children with mild asthma and a placebo group found a trend toward improvement with BIS treatment of 1-month duration in 23 infants, but it was not statistically significant. This may have been because of the small sample size, the relatively short treatment period, and the milder disease of their patients that did not allow for much clinical improvement.
Three different daily total doses of BIS (0.25 mg, 0.5 mg, 1.0 mg) were compared with placebo, and based on subjective asthma symptom scores and use of rescue medications, as well as am andpm PEFs, the two higher doses showed statistically significant effects. For unexplained reasons, this was not true when the percent of early patient discontinuations was analyzed (the 1.0-mg QD dose looked similar to the placebo group and worse than the three other treatment doses). Therefore, in general, the results suggest that the minimal effective daily dose of BIS is 0.5 mg. However, some of the efficacy parameters (patient discontinuations because of lack of efficacy, evening PEF, use of rescue medications) did show that the 0.25-mg QD treatment group improved significantly more than patients on placebo, suggesting that even the lowest dose used in this study (0.25 mg/d) offered some clinical benefit. Other studies with BIS in children10–18 have not directly addressed the issue of minimal effective dose because they either lacked a placebo-control group, or used a single dose (usually 1.0 mg QD or greater). Vikre-Jorgensen et al22 using a gradual dose reduction study design but no placebo group, and starting with 2.0 mg/day of BIS, found that the minimal effective dose of BIS varied from 0.5 mg to 2.0 mg daily in 30 young children (<age 4 years) with chronic asthma. Nearly one-third of all patients could be controlled by a dose of 0.5 mg/day (the lowest dose used) given on a BID basis. Our findings regarding minimal effective dose are similar.
Although a dose-related trend was seen with some of the efficacy variables, overall there was not a large degree of difference in improvement seen between all the different active treatment regimens. This observation is similar to the findings in other studies of BIS in children,15,,18 in which more than one dose of BIS was studied. Grimfeld et al 199414 assessed dose-response with BIS in young children with moderate to severe asthma and did find 0.5 mg/day to be less effective in protecting against acute exacerbations than the 2.0-mg/day dose, but only in terms of wheezing episodes and not in terms of need for systemic steroid therapy. Differences between patients, especially infants and small children, with regards to asthma severity, cooperation, and inhalation technique, along with differences in nebulizer/compressor systems, make it difficult to predict the dose requirement of individual patients. Information available now, including results from this study, suggests that daily doses of 1.0 to 2.0 mg may be necessary in young children with severe oral steroid-dependent asthma, and lower daily doses in the range of 0.5 to 1.0 mg for children with moderately severe asthma, and 0.25 mg for children with mild asthma, may be appropriate.
The effect of the frequency of administration of BIS was also explored in this study. Two of the treatment groups received the same daily dose, 1.0 mg, one group in a single treatment and one group as 0.5 mg BID. Although the QD dosing frequency was efficacious relative to placebo, for certain efficacy parameters improvement was somewhat less than that obtained with the BID dosing. Enhanced efficacy with more frequent dosing has been reported in other studies.23–26 It is also possible that the more consistent benefits observed in the 0.5-mg BID group, more than the 1.0-mg QD group, is related to giving a dose in the pmbecause there is evidence in the literature that suggests late afternoon and evening dosing may be more effective than a morning dose.27 Nevertheless, our results do show that once-a-day dosing with BIS would be appropriate therapy for many children with chronic asthma. This is consistent with recent studies in adults using budesonide that have shown QD dosing to be effective in maintaining asthma control in patients with mild to moderate asthma.28–30 Many patients and parents find the need for twice daily nebulization to be time-consuming, and therefore the ability to use just once-a-day treatment with BIS should simplify their therapy program and thereby improve compliance.
Marked improvement in symptom scores was seen at the time of the first posttreatment evaluation at 2 weeks for all budesonide treatment groups by comparison with placebo. In fact, pooled active-treatment symptoms score data from daily diaries showed statistically significant separation between budesonide-treated patients and those receiving placebo as early as 2 to 5 days after baseline. Moreover, the overall time course of activity during the 12 weeks of the study suggests that improvement in asthma symptoms in certain treatment groups continued to occur up to 4 to 6 weeks after drug initiation, and then reached a plateau. Results of other studies of budesonide, given by MDI in children do show, as with this study, a continued improvement in asthma parameters for a number of weeks, even months, before reaching a plateau.31–33
The safety data from this 12-week study is more extensive than any previously published data on the safety of inhaled GCS in infants and young children below the age of 8 years. Reported adverse effects in the BIS-treated patients were not significantly different when compared with placebo-treated patients. Furthermore, hypothalamic-pituitary axis function was not affected by any BIS dose as determined by am basal cortisol levels and post-ACTH stimulation cortisol levels before and after the 12-week study treatment. No differences were found between active treatment and placebo groups in individuals showing a change in responsiveness to ACTH stimulation. The observed safety of BIS in this study is similar to safety findings of other investigations of BIS therapy in children.5,,13,15,16,17,31 It should be noted that this study's duration was 12 weeks only, and that long-term safety still needs to be examined.
Recognition of the importance of chronic inflammation in asthma has led to the general view that antiinflammatory therapy should be used at an earlier stage than previously recommended.34Many infants and young children are unable to be successfully treated with inhaled antiinflammatory agents using the standard MDI with spacer devices, and therefore, have been treated with nebulized cromolyn, a nonsteroidal antiinflammatory medication. However, asthma therapy with cromolyn in older children and adults has generally not been as efficacious as inhaled corticosteroid therapy,35,,36 and has the drawback of requiring three to four times a day dosing. Furthermore, Tasche et al37 recently found cromolyn delivered by an MDI with spacer to be ineffective for children below 2 to 3 years of age. BIS represents the first nebulizable corticosteroid formulation that has the potential, as a potent antiinflammatory agent, to control asthma in infants and young children. Results of this study demonstrate that BIS is effective and safe for children with moderate persistent asthma in a multiple dose range, and that QD dosing is an important option to be considered by the prescribing physician.
ACKNOWLEDGMENTS
This work was supported in part by Astra USA, Inc.
This study was conducted by the Budesonide Inhalation Nebulizer Suspension Study Group consisting of the following investigators: James W. Baker, MD; William Berger, MD; Kathryn Blake, MD; David Brown, MD; Don Bukstein, MD; Paul Chervinsky, MD; Jim Christensen, MD; Robert Cohen, MD; David Cook, MD; Alan Goldsobel, MD; Marc Goldstein, MD; Jim Haltom, MD; Mary Pat Hemstreet, MD; Ann-Marie Irani, MD; Charles Jackson, MD; Robert Jones, MD; Paul Kubic, MD; Jeffrey Leflein, MD; Philip Marcus, MD; Michael Mellon, MD; Louis Mendelson, MD; William Morgan, MD; Anjuli Nayak, MD; Lawrence Newman, MD; Gary Rachelefsky, MD; Eric Schenkel, MD; Lynda Schneider, MD; Bernard Silverman, MD; Thomas Smith, MD; William Storms, MD; James Sublett, MD; Mark Vandewalker, MD; Jeffrey Wald, MD; Richard Wasserman, MD; Lawrence Weiner, MD; Martha White, MD; John Yarbrough, MD; and John Yunginger, MD.
We are indebted to the children who participated in this study, to their parents (and guardians), and to the excellent nurses and respiratory technicians involved in patient care. We also extend our appreciation to H. Alice Orgel, MD, PhD, Allergy and Asthma Medical Group and Research Center (San Diego), for her technical and editorial assistance.
Footnotes
- Received February 23, 1998.
- Accepted August 3, 1998.
Reprint requests to (J.W.B.) 545 NE 47th, Suite 310, Portland, OR 97213.
- GCS =
- glucocorticosteroids •
- MDI =
- metered dose inhaler •
- BDP =
- beclomethasone dipropionate •
- BIS =
- budesonide inhalation suspension •
- PEF =
- peak flow measurement •
- BID =
- twice a day •
- ACTH =
- adrenocorticotropic hormone •
- FEV1 =
- forced expiratory volume in 1 second •
- QD =
- once daily
REFERENCES
- Copyright © 1999 American Academy of Pediatrics
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