Background Antiinflammatory therapies, such as inhaled corticosteroidsor nedocromil, are recommended for children with asthma, althoughthere is limited information on their long-term use.
Methods We randomly assigned 1041 children from 5 through 12years of age with mild-to-moderate asthma to receive 200 µgof budesonide (311 children), 8 mg of nedocromil (312 children),or placebo (418 children) twice daily. We treated the participantsfor four to six years. All children used albuterol for asthmasymptoms.
Results There was no significant difference between either treatmentand placebo in the primary outcome, the degree of change inthe forced expiratory volume in one second (FEV1, expressedas a percentage of the predicted value) after the administrationof a bronchodilator. As compared with the children assignedto placebo, the children assigned to receive budesonide hada significantly smaller decline in the ratio of FEV1 to forcedvital capacity (FVC, expressed as a percentage) before the administrationof a bronchodilator (decline in FEV1:FVC, 0.2 percent vs. 1.8percent). The children given budesonide also had lower airwayresponsiveness to methacholine, fewer hospitalizations (2.5vs. 4.4 per 100 person-years), fewer urgent visits to a caregiver(12 vs. 22 per 100 person-years), greater reduction in the needfor albuterol for symptoms, fewer courses of prednisone, anda smaller percentage of days on which additional asthma medicationswere needed. As compared with placebo, nedocromil significantlyreduced urgent care visits (16 vs. 22 per 100 person-years)and courses of prednisone. The mean increase in height in thebudesonide group was 1.1 cm less than in the placebo group (22.7vs. 23.8 cm, P=0.005); this difference was evident mostly withinthe first year. The height increase was similar in the nedocromiland placebo groups.
Conclusions In children with mild-to-moderate asthma, neitherbudesonide nor nedocromil is better than placebo in terms oflung function, but inhaled budesonide improves airway responsivenessand provides better control of asthma than placebo or nedocromil.The side effects of budesonide are limited to a small, transientreduction in growth velocity.
Asthma is a disease of chronic airway inflammation characterizedby reversible airway obstruction and increased airway responsiveness.1,2,3Recent studies have demonstrated that asthma can be associatedwith impaired lung growth during childhood and with a progressivedecline in pulmonary function in adulthood.4,5,6,7,8,9,10,11Clinical practice guidelines recommend antiinflammatory medicationfor the long-term control of persistent asthma; treatment withinhaled corticosteroids or nedocromil is recommended for children.1,2
The Childhood Asthma Management Program was designed to evaluatewhether continuous, long-term treatment (over a period of fourto six years) with either an inhaled corticosteroid (budesonide)or an inhaled noncorticosteroid drug (nedocromil) safely producesan improvement in lung growth as compared with treatment forsymptoms only (with albuterol and, if necessary, prednisone,administered as needed).12 The primary outcome in the studywas lung growth, as assessed by the change in forced expiratoryvolume in one second (FEV1,expressed as a percentage of thepredicted value) after the administration of a bronchodilator.Secondary outcomes included the degree of airway responsiveness,morbidity, physical growth, and psychological development.
Methods
The design and methods of the research program have been describedpreviously.7,12,13,14,15
Screening and Schedule of Visits
Between December 1993 and September 1995, we enrolled 1041 childrenfrom 5 through 12 years of age at eight clinical centers. Thechildren had mild-to-moderate asthma, as defined by the presenceof symptoms or by the use of an inhaled bronchodilator at leasttwice weekly or the use of daily medication for asthma. Thechildren's airway responsiveness to methacholine, as indicatedby the concentration of the drug that caused a 20 percent decreasein the FEV1, was 12.5 mg per milliliter or less. They had noother clinically significant conditions.12 The children's parentsor guardians signed an informed-consent form approved by thelocal institutional review board. Follow-up visits occurredtwo and four months after randomization and at four-month intervalsthereafter. From March through June 1999 (the end of the treatmentperiod), the children discontinued the study medication andreturned two to four months later for spirometry and methacholinechallenge. Children who had been using additional medicationsbecause of inadequate control of asthma continued to use thosemedications.
Treatment
Three hundred eleven children were randomly assigned to receivebudesonide (Pulmicort, AstraZeneca, Westborough, Mass.) (200µg twice daily, delivered by two 100-µg actuationsof a breath-actuated metered-dose inhaler [Turbuhaler, AstraZeneca]),and 208 were assigned to receive a matching placebo. Three hundredtwelve children were assigned to receive nedocromil sodium (8mg twice daily, delivered by four 2-mg actuations of a pressurizedmetered-dose inhaler [Tilade, Rhone–Poulenc Rorer, Collegeville,Pa.]), and 210 were assigned to receive a matching placebo.Assignments were made by permuted-blocks randomization withstratification according to clinic.16 The total daily dosesof budesonide (400 µg) and nedocromil (16 mg) were administeredas two equal daily doses to maximize adherence to the treatmentregimen,17,18,19,20 and adherence was also promoted by an educationalprogram.15 Albuterol (Ventolin, Glaxo Wellcome, Research TrianglePark, N.C.), delivered by two 90-µg actuations of a pressurizedmetered-dose inhaler, was used as needed for symptoms of asthmaor to prevent exercise-induced bronchospasm.12 A written actionplan guided rescue treatment.12,15 Short courses of oral prednisonewere prescribed for exacerbations of asthma.12 The additionof beclomethasone dipropionate (168 µg twice daily; Vanceril,Schering-Plough, Kenilworth, N.J.) to the study medication wasallowed if the control of asthma was inadequate. If controlremained unsatisfactory, replacement or addition of medicationswas allowed. To account for remission, it was permissible totaper the study medication to a dose of zero (by stepwise reductionsfrom 100 percent to 50 percent to zero), according to definedprocedures.12 Algorithms guided the resumption of the full doseof the study medication.12
Outcome Measures
Spirometry was performed twice yearly, with measurements obtainedboth before and after the administration of a bronchodilator.7,12A methacholine challenge was performed annually.12 Methacholinechallenge was not performed within 28 days of an upper respiratorytract infection or the use of prednisone for exacerbations ofasthma.
The children (or their parents or guardians) completed a diarycard each day that recorded night awakenings due to asthma,morning and evening peak flows as measured by a peak-flow meter(Assess, HealthScan Products, Cedar Grove, N.J.), use of studymedication, use of albuterol for symptoms and to prevent exercise-inducedbronchospasm, use of prednisone, absences from school due toasthma, visits to a physician's office or hospital because ofasthma, and severity of symptoms.12
The children's height (measured by Harpenden stadiometer) andweight were recorded at every visit; the total bone mineraldensity of the spine from L1 to L4 and the Tanner stage of sexualdevelopment (assessed on the basis of the development of pubichair, genitals [in boys] or breasts [in girls], and testicularvolume, each scored from 1 [preadolescent characteristics] to5 [adult characteristics]) were assessed annually.12 Skeletalmaturation (bone age) during the last eight months of follow-upwas determined at a central reading center by evaluation ofa radiograph of the left wrist and hand by the method of Greulichand Pyle21 and was used to estimate the projected final height.22Psychological development was assessed with four neurocognitivetests administered at base line and three years later, and byeight psychosocial questionnaires completed at base line andduring annual visits.12 Psychosocial questionnaires includedthe Children's Depression Inventory,23 a 27-item questionnairecompleted by the child with regard to the symptoms of depression.The total score for this scale ranges from 0 to 54, with higherscores indicating greater depression. Skin-prick testing, witha core battery of 10 allergens and several locally relevantallergens, was performed at base line and four years later.12,14
Anterior and posterior images of the lens of the eye, takenwith a digital retroluminescent camera (Neitz Cataract ScreenerCT-S, Neitz Instruments, Tokyo) during the last eight monthsof follow-up, were examined for posterior subcapsular cataractsat a central reading center.24
Statistical Analysis
Our study had 90 percent power to detect a difference of 3.5percent between either treatment group and the placebo groupin the mean change in the FEV1, expressed as a percentage ofthe predicted value, after the administration of a bronchodilator,after four to six years of treatment.12 Data from the two placebogroups were pooled after we determined that the children inthe two groups were similar with respect to base-line characteristicsand outcomes. Each participant was included in his or her assignedstudy group, regardless of any adjustments of treatment (intention-to-treatanalysis). The degree of change in an outcome measure was determinedby subtracting the base-line measurement from the measurementobtained at the last follow-up visit during the treatment period.The difference between each treatment group and the placebogroup in each measure of change was determined with use of multipleregression,25 with the change in the measure as the responsevariable, two indicator variables for the treatment groups,and the following eight covariates: the base-line value of theoutcome measure, the child's age at randomization, race (twoindicator variables), sex, clinic (seven indicator variables),duration of asthma at base line, severity of asthma at baseline, and skin-test reactivity at base line (any reactivityvs. none). The adjusted mean change in each outcome measurein each study group was computed from the regression model bythe use of mean values for all covariates.26 Kaplan–Meierestimates of cumulative probability and log-rank tests27 wereused to evaluate the time to the first course of prednisoneand the time to the initiation of therapy with beclomethasoneor any other nonassigned medication for asthma in each treatmentgroup. All analyses were performed with SAS software (version6.12, SAS Institute, Cary, N.C.). The P values presented aretwo-sided and have not been adjusted for multiple comparisons.Interim monitoring of results by a data and safety monitoringboard took place semiannually; statistical guidelines for stoppingthe study were not used. In the comparisons among the studygroups we used regression models to adjust for small imbalancesin base-line measures; however, unadjusted analyses for alloutcome measures yielded qualitatively similar results.
Results
Study Population
The three study groups were similar at base line, except fora slightly higher proportion of boys in the nedocromil group(Table 1). The duration of follow-up was similar in all thestudy groups, with a mean of 4.3 years (Table 2).
Table 2. Follow-up, Asthma Treatment, and Morbidity during the Trial.
Measures of Pulmonary Function
Budesonide treatment improved the FEV1 after the administrationof a bronchodilator from a mean of 103.2 percent of the predictedvalue to a mean of 106.8 percent within two months, but thismeasurement gradually diminished to 103.8 percent by the endof the treatment period, at which point the change in the FEV1after bronchodilator use in the budesonide group was not significantlydifferent from that in the placebo group (Table 3 and Figure 1).The nedocromil group was similar to the placebo group inthis measure throughout the treatment period (Table 3 and Figure 1).The ratio of the FEV1 to the forced vital capacity (FVC,expressed as a percentage of the predicted value) after bronchodilatoruse was smaller at the end of the treatment period than at thestart in all study groups; the decline in the budesonide groupwas less than that in the placebo group (1.0 percent vs. 1.7percent, P=0.08) (Table 3 and Figure 1).
Figure 1. Mean Values for Spirometric Measures before and after the Use of a Bronchodilator, Airway Responsiveness, Standing Height, and Standing-Height Velocity during Four Years of Follow-up in the Budesonide (Bud), Nedocromil (Ned), and Placebo (Plbo) Groups.
The numbers of observations used to calculate means at annual intervals are shown below each panel. When comparisons were made over the total follow-up time, the budesonide group differed significantly (P<0.001) from the placebo group in all measures, even though these differences may not be apparent in every panel, and there were no significant differences between the nedocromil group and the placebo group in any measure. FEV1 denotes forced expiratory volume in one second, FVC forced vital capacity, and FEV1 PC20 airway responsiveness measured by the concentration of methacholine that caused a 20 percent decrease in FEV1. For FEV1 PC20 , values were obtained at 0, 8, 20, 32, and 44 months. P values for the comparisons between study groups of the changes from base line to last follow-up are shown in Table 3.
In patients treated with budesonide, FEV1 before the administrationof a bronchodilator increased within two months and was significantlyhigher at the end of the treatment period than it was in thosereceiving placebo (P=0.02); the nedocromil group was similarto the placebo group with respect to this measure throughoutthe treatment period (Table 3 and Figure 1). The FVC (expressedas a percentage of the predicted value) before bronchodilatoruse increased in all study groups. The increase in the nedocromilgroup was less than that in the placebo group (P=0.02), whereasthe increase in the budesonide group was similar to that inthe placebo group (Table 3). The FEV1:FVC ratio before bronchodilatoruse was smaller at the end of the treatment period than at thestart in all three groups; the decline in the budesonide groupwas less than that in the placebo group (0.2 percent vs. 1.8percent, P=0.001) (Table 3 and Figure 1).
Airway responsiveness to methacholine, expressed as the concentrationthat caused a 20 percent decrease in FEV1, improved throughoutthe treatment period in all three groups (Figure 1), with thegreatest improvement occurring in the budesonide group. At theend of the treatment period, airway responsiveness to methacholinewas significantly improved in the budesonide group as comparedwith the placebo group (P<0.001), whereas the change in thenedocromil group was similar to that in the placebo group (Table 3and Figure 1).
Health Outcomes
As compared with the placebo group, the budesonide group hada 43 percent lower rate of hospitalization (P=0.04), a 45 percentlower rate of visits for urgent care (P<0.001), and a 43percent lower rate of use of courses of prednisone (P<0.001)over the treatment period (Table 2). The nedocromil group hada 27 percent lower rate of urgent care visits (P= 0.02) anda 16 percent lower rate of use of courses of prednisone (P=0.01)than the placebo group, but there was no significant differencein the rate of hospitalization. One death from asthma occurredin the nedocromil group; the child had been receiving supplementaltreatment, including inhaled corticosteroids, for several monthsbefore her death. One child in the placebo group required intubationfor an exacerbation of asthma.
Control of asthma was best in the budesonide group, as indicatedby significantly fewer symptoms (P=0.005), less use of albuterolfor symptoms (P< 0.001), and more episode-free days (P=0.01)(Table 3). Changes in morning peak flow and the number of nightawakenings per month were similar in all groups (Table 3). Thetimes to the first course of prednisone and to the initiationof treatment with beclomethasone or other nonassigned asthmamedications were significantly longer in the budesonide groupthan in the placebo group (P<0.001) (Figure 2).
Figure 2. Kaplan–Meier Estimates of the Cumulative Probability of a First Course of Prednisone and Initiation of Additional Therapy (Beclomethasone or Other Nonassigned Asthma Medications) during Four Years of Follow-up in the Budesonide (Bud), Nedocromil (Ned), and Placebo (Plbo) Groups.
The numbers of children at risk at annual intervals are shown below each graph.
During the treatment period, the percentage of days on whichbeclomethasone or another asthma medication was prescribed inaddition to or instead of the originally assigned treatmentwas significantly lower (P<0.001) for children assigned tobudesonide (6.6 percent) than for those assigned to placebo(18.7 percent); there was no significant difference in the measurebetween the nedocromil group (17.1 percent) and the placebogroup (Table 2). Compliance with treatment, defined as the percentageof days on which a child was reported to have taken the prescribeddose of study medication, was similar in children assigned tobudesonide and those assigned to placebo (73.7 percent and 76.2percent, respectively), but it was lower in children assignedto nedocromil (70.2 percent) (P=0.01 for the comparison withplacebo) (Table 2).
Measures of Growth and Assessment for Cataracts
At the end of the treatment period, the mean increase in heightin the budesonide group was 1.1 cm less than the mean increasein the placebo group (22.7 vs. 23.8 cm, P=0.005); the heightincrease was similar in the nedocromil and the placebo groups(Table 3). The difference between the budesonide and placebogroups in the rate of growth was evident primarily within thefirst year of treatment and did not increase later: all groupshad similar growth velocity by the end of the treatment period(Figure 1), as well as similar changes in bone density (Table 3).At the end of treatment, the bone age, projected final height,and Tanner stage in the budesonide and nedocromil groups weresimilar to those in the placebo group (Table 3). The only differencewith respect to changes in any of the psychosocial measureswas a greater improvement in the total score on the Children'sDepression Inventory,23 indicating less depression, in the budesonidegroup as compared with the placebo group (a decline of 3.2 vs.2.2, P=0.01) (Table 3). None of the children had posterior subcapsularcataracts according to lens-photography criteria (Table 2).However, one child in the budesonide group was classified ashaving a questionable posterior subcapsular cataract. A barelymeasurable (<0.5 mm) posterior subcapsular cataract was foundin this child on slit-lamp examination by an ophthalmologistfive months after the photographs were taken. The uncorrectedSnellen visual acuity in the eye was 20/25. This child receivedbudesonide as study medication, beclomethasone (for 13 months),and oral prednisone (for 38 days) during the study, as wellas an intranasal corticosteroid.
Discontinuation of Study Medication
Four months after discontinuation of the study medication, thechildren assigned to nedocromil had a smaller reduction frombase line in the FEV1:FVC ratio after bronchodilator use thandid those assigned to placebo (a decline of 1.2 percent vs.2.2 percent, P=0.03). Also at this time, children assigned tobudesonide or nedocromil had a smaller reduction in FEV1:FVCbefore bronchodilator use than did those assigned to placebo(budesonide vs. placebo: a decline of 0.9 percent vs. 2.5 percent,P=0.005; nedocromil vs. placebo: a decline of 1.1 percent vs.2.5 percent, P=0.01). The groups were similar in all other measures,including airway responsiveness, which worsened in the budesonidegroup during the four-month period after discontinuation ofbudesonide and became similar to that in the placebo group (dataare available elsewhere, ).
Discussion
The finding that neither budesonide nor nedocromil improvedlung function, as measured by the percentage of the predictedvalue for FEV1 after the administration of a bronchodilator,was unexpected. FEV1 was chosen as the primary outcome measurebecause it is widely accepted as the most clinically usefuland predictive measure of lung function. It is highly reproducibleand correlates well with the progression of disease,28,29 useof health care,30 and severity of asthma1,2,3,31 and accuratelydescribes the natural history of childhood asthma. The valueafter bronchodilator use was chosen as the outcome measure becauseit minimizes the effects of airway constriction and has lessvariability over time in individual patients than the valuebefore bronchodilator use.
The use of budesonide was associated with improvement in theFEV1 before bronchodilator use, when measured as a percentageof the predicted value, but not when measured in liters (Table 3).The use of nedocromil was not associated with improvementin either measure of FEV1. Since predicted values depend onheight,32,33 the statistical significance of the change in theFEV1 as a percentage of the predicted value is mostly attributableto the slightly smaller stature of the children in the budesonidegroup.
As a consequence of normal lung growth,34 the FEV1:FVC ratiobefore bronchodilator use decreased over time in all three groups(Figure 1). The decrease was minimized by budesonide (beforebronchodilator use, P=0.001; after bronchodilator use, P=0.08).The minimization of the decrease was not due to improvementin FEV1 and might have been due to lower FVC or improved bronchodilationin the budesonide group.
During the trial, there was a lack of decline in the FEV1 beforeand after bronchodilator use in the placebo group and a lackof long-term improvement in the budesonide and nedocromil groupsas compared with the placebo group. An irreversible deteriorationin lung function might have occurred in the patients beforetheir enrollment, and the treatment might therefore have beentoo late to effect a change. Eighty percent of all childhoodasthma is diagnosed by the age of six years,35 and normal proliferationof the alveoli and airway development occur predominantly beforethe age of five years.36 We enrolled children from 5 through12 years of age, who had had asthma for a mean of five years.Some studies recommend initiating treatment within two to threeyears after the onset of disease.9
In contrast to the results of lung-function measurements, ourfindings on airway responsiveness and health outcomes clearlyfavor budesonide. As expected,37 improvement in airway responsivenessto methacholine occurred during the treatment period in allthree study groups (Figure 1) but was substantially and significantlygreater in the budesonide group (Table 3); this finding is consistentwith the results of shorter trials in children.38,39 The relativeimprovement in the budesonide group suggests additional improvementas a consequence of lower bronchomotor tone or diminished airwayinflammation.
The rates of hospitalization and of urgent care visits and theneed for additional therapy and oral prednisone were lowestin the budesonide group (Table 2). Budesonide was also associatedwith a greater reduction in symptoms and in the use of albuterolfor symptoms and with an increase in the number of episode-freedays as compared with placebo (Table 3).
We also evaluated the long-term effects of inhaled nedocromilin children. Overall, the results in the nedocromil group weresimilar to those in the placebo group, except that nedocromilwas associated with fewer exacerbations, as evidenced by a lowerrate of prednisone use and a lower rate of urgent care visits.
The current literature indicates that treatment of childrenwith inhaled or nasal corticosteroids, specifically beclomethasonedipropionate, results in a loss of 0.7 to 1.4 cm in linear growthover a one-year period.38,39,40,41,42,43,44,45,46 Our four-to-six-yeartrial provides evidence that the effect of budesonide on growthvelocity is not sustained and that extrapolations from one-yearstudies to projected loss in subsequent years are not appropriate.Calculations of projected final height22 suggest that the childrenin the study groups will achieve similar final heights.
There were no significant differences among the three groupsin the change in bone density. Several recent studies have suggestedthat the use of high doses of inhaled corticosteroids in adultscan lead to the development of cataracts.47,48 In one childin the budesonide group, an area of one eye was classified asa questionable posterior subcapsular cataract on photographicassessment. However, interpretation of this finding was complicatedby the child's use of oral corticosteroids and the lack of base-linephotographic assessment.
After discontinuation of the study medication, no differenceswere observed among the study groups in lung function or growthfrom base line (the beginning of the study) to the final measurement,except for the FEV1:FVC ratio before bronchodilator use. Theincrease in responsiveness to methacholine seen in the budesonidegroup after discontinuation of the study medication suggeststhat the beneficial effect of budesonide on airway responsivenessto methacholine is due to changes in bronchomotor tone or airwayinflammation, and not to the prevention or resolution of remodelingof the airway wall.
The percentage of days on which only the full dose of the assignedstudy medication was prescribed was greater in the budesonidegroup than in the placebo group (88.9 percent vs. 78.4 percent,P<0.001) (Table 2). However, it is unlikely that this differencesubstantially influenced the findings. Four post hoc analysesconfirmed the results of the intention-to-treat analysis. Theseanalyses excluded any outcome measures obtained after departurefrom full-dose study medication, were restricted to childrenwho used only full-dose study medication throughout the follow-up,included only children who had reported compliance with full-dosestudy medication on at least 80 percent of days, and categorizedchildren according to their prescribed treatment at the endof the treatment period (data are available elsewhere, ).
Our study demonstrates the importance of long-term, controlledtrials of treatment for asthma. A benefit of budesonide in termsof lung function, as measured by the FEV1 after bronchodilatoruse, was evident at one year, but not at four years; a reductionin linear growth velocity in children treated with budesonidewas evident at one year but was absent by the second year. Airwayresponsiveness to methacholine improved in all study groupsover the four to six years of treatment. The improvement wassubstantially and significantly greater with budesonide thanwith placebo, but this advantage disappeared after the discontinuationof treatment with budesonide.
In summary, we found that in children five or more years ofage with mild-to-moderate asthma, continuous daily treatmentwith inhaled budesonide or nedocromil had no therapeutic benefitin terms of lung function, as measured by the FEV1 after bronchodilatoruse, as compared with therapy given as needed for the controlof symptoms (as in the placebo group). Intervention with antiinflammatorymedications earlier in childhood, earlier after the onset ofdisease, or in patients selected because of a decline in pulmonaryfunction might still be beneficial and should be evaluated.Continuous daily treatment with inhaled budesonide leads tobetter control of asthma than symptomatic treatment (as in ourplacebo group) or treatment with nedocromil, and its side effectsare limited to a small, transient reduction in growth velocity.Inhaled corticosteroids are safe and effective for long-termuse in children with asthma.
Supported by contracts with the National Heart, Lung, and BloodInstitute (NO1-HR-16044, NO1-HR-16045, NO1-HR-16046, NO1-HR-16047,NO1-HR-16048, NO1-HR-16049, NO1-HR-16050, NO1-HR-16051, andNO1-HR-16052) and by General Clinical Research Center grantsfrom the National Center for Research Resources (M01RR00051,M01RR0099718-24, M01RR02719-14, and RR00036).
Pharmaceuticals were supplied by AstraZeneca, Westborough, Mass.;Glaxo Research Institute, Research Triangle Park, N.C.; Rhone–PoulencRorer, Collegeville, Pa.; and Schering-Plough, Kenilworth, N.J.
* The members of the research group are listed in the Appendix.
See NAPS document no. 05569 for 16 pages of supplementary material.To order, contact NAPS c/o Microfiche Publications, 248 HempsteadTpk., West Hempstead, NY 11552.
Source Information
Stanley Szefler, M.D., Scott Weiss, M.D., and James Tonascia, Ph.D., take responsibility for the content of this article. The other members of the writing committee were N. Franklin Adkinson, M.D., Bruce Bender, Ph.D., Reuben Cherniack, M.D., Michele Donithan, M.H.S., H. William Kelly, Pharm.D., Joseph Reisman, M.D., M.B.A., Gail G. Shapiro, M.D., Alice L. Sternberg, Sc.M., Robert Strunk, M.D., Virginia Taggart, M.P.H., Mark Van Natta, M.H.S., Robert Wise, M.D., Margaret Wu, Ph.D., and Robert Zeiger, M.D., Ph.D. Dr. Szefler has served as a consultant or advisory panel member for Astra USA, Glaxo Wellcome, Merck, 3M Pharmaceuticals, and Sepracor.
Address reprint requests to Dr. Tonascia at the CAMP Coordinating Center, Johns Hopkins University, 615 N. Wolfe St., Rm. 5010, Baltimore, MD 21205.
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Appendix
The members of the Childhood Asthma Management Program (CAMP)Research Group are as follows: Asthma, Inc., Seattle: G.G. Shapiro,L.C. Altman, J.W. Becker, C.W. Bierman, T. Chinn, D. Crawford,T.R. DuHamel, H. Eliassen, C.T. Furukawa, B. Hammond, M.S. Kennedy,M.V. Lasley, D.A. Minotti, C. Reagan, M. Sharpe, F.S. Virant,G. White, T.G. Wighton, and P.V. Williams; Brigham and Women'sHospital, Boston: S. Weiss, S. Babigian, P. Barrant, L. Benson,J. Caicedo, T. Calder, A. DeFilippo, C. Dorsainvil, J. Erickson,P. Fulton, J. Gilbert, M. Grace, D. Greineder, S. Haynes, M.Higham, D. Jakubowski, S. Kelleher, J. Koslof, N. Madden, D.Mandel, A. Martinez, J. McAuliffe, P. Pacella, P. Parks, A.Plunkett, J. Sagarin, K. Seligsohn, M. Syring, M. Tata, W. Torda,J. Traylor, M. Van Horn, C. Wells, and A. Whitman; Hospitalfor Sick Children, Toronto: J. Reisman, Y. Benedet, S. Carpenter,J. Chay, M. Collinson, J. Finlayson-Kulchin, K. Gore, A. Hall,N. Holmes, S. Klassen, H. Levison, I. MacLusky, M. Miki, J.Quenneville, R. Sananes, and C. Wasson; Johns Hopkins Asthmaand Allergy Center, Baltimore: N.F. Adkinson, Jr., N. Bollers,P. Eggleston, K. Huss, K. Hyatt, B. Leritz, M. Pessaro, S. Philips,L. Plotnick, M. Pulsifer, C. Rand, and B. Wheeler; NationalJewish Medical and Research Center, Denver: S. Szefler, B. Bender,K. Brelsford, J. Bridges, J. Ciacco, R. Covar, M. Eltz, M. Flynn,M. Gleason, J. Hassell, M. Hefner, C. Hendrickson, D. Hettleman,C.G. Irvin, J. Jacobs, T. Junk-Blanchard, A. Kamada, A. Liu,H.S. Nelson, S. Nimmagadda, K. Sandoval, J. Sheridan, J. Spahn,D. Sundström, T. Washington, M.P. White, and E. Willcutt;University of California, San Diego, and Kaiser Permanente SouthernCalifornia Region, San Diego: R. Zeiger, J.G. Easton, N. Friedman,L.L. Galbreath, E. Hanson, K. Harden, A. Horner, A. Jalowayski,E.M. Jenson, S. King, A. Lincoln, B. Lopez, M. Magiari, M.H.Mellon, A. Moscona, K. Mostafa, C.A. Nelle, S. Pizzo, E. Rodriquez,K. Sandoval, M. Schatz, and N.W. Wilson; University of New Mexico,Albuquerque: H.W. Kelly, R. Annett, T. Archibeque, N. Bashir,H.S. Bereket, M. Braun, S. Bush, M. Clayton, A. Colon-Semidey,S. Devault, R. Grad, D. Hunt, J. Larsson, S. McClelland, B.McWilliams, E. Montoya, M. Moreshead, S. Murphy, B. Ortega,H.H. Raissey, M. Spicher, D. Weers, and J. Zayas; WashingtonUniversity, St. Louis: R.C. Strunk, E. Albers, L. Bacharier,G. Belle, G.R. Bloomberg, W.P. Buchanan, M. Caesar, J.M. Corry,M. Dolinsky, E.B. Fisher, S.J. Gaioni, E. Glynn, B.D. Heckman,C. Hermann, D. Kemp, C. Lawhon, C. Moseid, T. Oliver-Welker,D.S. Richardson, D. Rodgers, E. Ryan, S. Sagel, T.F. Smith,S.C. Sylvia, C. Turner, and D.K. White; Bone Age Reading Center,Washington University, St. Louis: W. McAlister, K. Kronemer,and P. Suntrup; Chair's Office, National Jewish Medical andResearch Center, Denver: R. Cherniack; Coordinating Center,Johns Hopkins University, Baltimore: J. Tonascia, D. Amend-Libercci,M. Bacsafra, P. Belt, K. Collins, B. Collison, C. Dawson, D.Dawson, J. Dodge, M. Donithan, V. Edmonds, C. Ewing, J. Harle,R. Huffman, R. Jackson, K.-Y. Liang, C. Meinert, J. Meinert,J. Meyers, D. Nowakowski, L. Oelberg, B. Piantadosi, M. Smith,A. Sternberg, M. Van Natta, and R. Wise; Dermatology, Allergy,and Clinical Immunology Reference Laboratory, Johns HopkinsAsthma and Allergy Center, Baltimore: R.G. Hamilton, C. Schatz,and J. Wisenauer; Drug Distribution Center, McKesson BioServicesCorporation, Rockville, Md.: R. Rice, K. Farris, B. Hughes,J. Lee, and T. Lynch; Fundus Photography Reading Center, Universityof Wisconsin, Madison: B. Klein, L. Hubbard, M. Neider, K. Osterby,N. Robinson, and H. Wabers; Immunology and Complement Laboratory,National Jewish Medical and Research Center, Denver: R.J. Harbeck,R. Emerick, and B. Watson; Patient Education Center, NationalJewish Medical and Research Center, Denver: S. Szefler, B. Bender,C. Culkin, J. Feeley, C. Lumlung, A. Mullen, H. Nelson, S. Oliver,C. Szefler, and A. Walker; PDS Instrumentation, Louisville,Colo.: A. Lehman; Project Office, National Heart, Lung, andBlood Institute, Bethesda, Md.: V. Taggart, P. Albert, S. Hurd,J. Kiley, P. Lew, S. Parker, and M. Wu; University of Iowa,College of Pharmacy, Division of Pharmaceutical Services, IowaCity: R. Poust, D. Elbert, and D. Herold; Data and Safety MonitoringBoard: H. Eigen, M. Cloutier, J. Connett, L. Cuttler, C.E. Davis,D. Evans, M. Kattan, S. Leikin, R. Menendez, and F.E.R. Simons.
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). 
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