Pediatric Pulmonology 10:2-5 (1991)
Original Articles -
Effect of Inhaled Beclomethasone Dipropionate on Bronchial Hyperreactivity in Asthmatic Children During Maximal Allergen Exposure A. L. Boner, MD,’ G. L. Piacentini, MD,’ C. Bonizzato, M D , ~V. Dattoli, MD,’ and L. Sette, MD,’ Summary. In this double blind study we evaluated the effect of a 2 months long treatment with inhaled beclomethasone dipropionate (300 Fgiday) on methacholine responses in asthmatic children, during a period of maximal allergen exposure. Baseline values of methacholine PC-, FEV, were 0.66 2 0.22 mg/rnL (mean ? SEM) in 10 children treated with the active drug and 0.78 ? 0.21 mgimL in 10 children treated with placebo. After 1 month of treatment PC,,-FEV, was 1.91 2 0.64 and 0.80 0.33 mg/mL, respectively, in the groups treated with beclomethasone versus placebo. A statistically significant reduction in bronchial hyperreactivity (PC,,-FEV,, 5.49 5 1.86 mg/mL) but no systemic side effects were observed after 2 months of treatment with beclomethasone dipropionate. This is compared with a PC,,-FEV, of 1.38 2 0.52 mg/mL in the placebo group. The results confirm the effect of inhaled corticosteroids in reducing bronchial hyperreactivity, even during a period of maximal allergen exposure. Pediatr Pulmonol 1991; 10~2-5.
*
Key words: Grass pollen, parietaria; house dust mite allergies; methacholine challenge, PC,,-FEV, ; placebo-controlledseasonally arranged trial.
INTRODUCTION
The most characteristic feature of asthma is the increased bronchial reactivity to a large variety of environmental and physical agents. The severity of this bronchial hyperreactivity correlates strongly with that of asthma symptoms’ supporting its fundamental role in the pathophysiology of the disease. There is a growing awareness that inflammation plays a critical role in asthma and experimental studies have provided convincing evidence of a close association between the degree of inflammation in the airway wall and Althe degree of bronchial hyperrespon~iveness.~.~ though a number of studies suggest the therapeutic antiinflammatory effects of inhaled glucocorticoids in the control of relatively few studies were done in children.’-’ To our knowledge, none of them has evaluated the effectiveness of steroids during an allergy season. The purpose of our study was to investigate the effect of inhaled steroid beclomethasone dipropionate (BDP) on bronchial hyperreactivity in asthmatic children during a period of maximal allergen exposure. 0 1991 Wiley-Liss, Inc.
MATERIALS AND METHODS Patients
The study population consisted of 20 asthmatic patients, 17 male and 3 female, ranging in age from 6 to 12 years (mean, 9.2 k 1.9 SD) with documented asthma as defined by the American Thoracic Society. l o Patients were included if their baseline FEV, was greater than 70% of predicted values’ and improved by 15% or more after nebulized albuterol. All subjects were allergic either to seasonal allergens (grass pollen and parietaria; 13 patients) or to perennial allergen (house dust mite, Dermatophagoides pteronyssinus and farinae; 7 patients).
‘
From the Clinica Pediatrica, Universiti di Verona’, and lstituto Pi0 XI1 Misurina’, Italian Alps, Italy. Received April 1 I , 1990; (revision) accepted for publication August 4, 1990. Address correspondence and reprint requests to Dr. A. Boner, Clinica Pediatrica Universitg di Verona, Policlinico Borgo Roma, 37134 Verona, Italy.
Inhaled Beclomethasone Dipropionate in Asthmatic Children TABLE 1-Clinical
3
Data of the Study Population ~
BDP treated group Patient Age number Sex (yr)
1 4 5 9 12 16 17 18 19 20 Mean SD SEM
M
F M M M
M M M F M
9.2 12.0 9.0 9.0 8.0 6.0 6.0 11.0 8.0 10.0 8.8 1.9 0.6
Weight Height (kg) (cm)
25.0 60.0 26.0 30.0 25.0 34.6 27.0 32.0 29.0 36.5 32.5 10.4 3.3
131.0 159.0 129.0 130.0 126.0 127.0 122.0 142.0 124.0 145.0 133.5 11.6 3.7
Placebo treated group Treatrnent Treatment before Patient Age Weight Height before the trial number Sex (yr) (kg) (cm) the trial
IB IB IB IB IB B C B B+C C
2 3 6 7 8 10 11 13 14 15 Mean SD SEM
M
M M M F M M M M M
11.5 6.6 10.0 11.0 8.7 8.5 12.0 9.5 12.0 7.0 9.7 2.0 0.6
38.0 23.0 42.5 25.6 35.0 27.0 35.0 33.0 34.0 22.0 31.5 6.8 2.1
143.0 119.0 151.0 141.0 132.0 126.0 145.0 136.0 140.0 122.0 135.5 10.5 3.3
BfC B+C B IB IB C TB C T B
IB, intermittent P,-agonists; B, P,-agonists regularly; BDP, beclomethasone dipropionate; T, theophylline; C, cromolyn.
All patients were studied for 2 months during a period of maximal environmental exposure to specific allergens, namely in spring and in autumn-winter. Patient characteristics of the study population are given in Table 1. Treatment Patients were randomized in a double blind fashion and divided into two groups of 10 subjects each. One group of 10 patients received BDP (Becotide, Glaxo S.p.A.) using a metered-dose inhaler (MDI), each puff containing 50 pg. Two puffs of BDP were administered three times daily. The other group of 10 patients was treated with placebo. BDP or placebo was administered for 2 months during which time each patient was allowed to use inhaled albuterol when needed. The inhalation technique of each child was carefully evaluated at the beginning of the study and only those patients capable of using the MDI apparatus were included. All children had parental supervision in aerosol administration throughout the study period. Patient Evaluation Each patient was carefully evaluated clinically and tests of lung functions were performed using a Vitalograph Spirometer (Buckingham, England) every 15 days for a total of five observations. Patient compliance was checked by weighing each canister at the end of the study period. Bronchial Responsiveness The level of bronchial hyperreactivity was evaluated by methacholine challengeI2 at the initial visit and after 1 and 2 months (third and fifth visits) of treatment. Bron-
chial challenges were always performed at the same time of the day (8-9 A.M.). None of the children had respiratory infections within 2 months prior to the study and oral and inhaled steroids were not used during this period. Antihistamines and short acting theophylline preparations were discontinued 48 hr, long acting theophylline preparation and cromolyn 1 week before the first challenge. During the period of investigation no medication other than the study aerosol and albuterol aerosol, for symptomatic relief, was allowed. Albuterol was witheld for at least 12 hr before bronchial challenge, according to reccomended guidelines for bronchial challenges. l 3 Methacholine challenge was performed only if baseline FEV values were 2 70% of predicted. " Methacholine was delivered by a Me.Far dosimeter (Brescia, Italy)14 of which 0.01 mL could be nebulized with a De Vilbis 646 nebulizer in 1.2 sec, generating particles with diameters ranging from 0.5 to 3 pm. All inhalations were performed by slow inspiration, starting from functional residual capacity without reaching total lung capacity and followed by a 5 sec breath holding. Before methacholine provocation five inhalations of buffer solution were performed. One minute after the last inhalation FEV, was recorded again and the challenge proceeded only if FEV, changed less than 10%. Each patient received bronchoprovocation with five puffs of increasing concentrations of methacholine (0.075, 0.15, 0.31, 0.62, 1.25, 2.5, 5 , 10, and 25 mg/ mL) at 2 min intervals. After each dosing, FEV, was evaluated, the best of three efforts being considered for statistical analysis. The test was stopped when a decrease of 220% of FEV, occurred after buffer inhalation. Data were plotted with logarithmic concentrations of inhaled
4
Boner et al. TABLE 2-Changes in Methacholine PC,,-FEV, After 1 (Second Challenge) and 2 (Third Challenge) Months of Treatment With Beclomethasone Dipropionate (BDP) or Placebo BDP PCZO-FEV, Patient
Placebo PC,,-FEV,
Methacholine challenge
Patient number
1st
2nd
3rd
1 4 5 9 12 16 17 18 19 20
0.80 0.24 0.99 1.12 I .63 0.12 1.12 0.21 0.29 0.11
3.50 0.56 6.50 2. I3 4.00 0.87 0.68 0.24 0.27 0.40
0.56 15.50 7.00 3.50 4.50 0.60 0.14 7.50 15.00 0.59
Mean SEM
0.66 0.22 -NSh-
1.91 0.64 -NSP = 0.0069
5.49 1.86
number
NS
aData from patients number 7 and 13 in the placebo group were not considered in the statistical analysis. 'NS, no statistical difference
methacholine on the abscissa and arithmetic percentage decreases of FEV , compared with FEV, measured after buffer control nebulization, on the ordinate. The concentration of methacholine producing an exact 20% fall in FEV, (PC,,) was calculated as described by Rosenthal. The within-subject day to day variability of the method tested intervals of 1 to 2 weeks, is plus or minus one single 2-fold concentration, as commonly accepted. 1 3 3 1 s
,
Data Analysis Logarithmic transformation of the methacholine PC,, was used for statistical analysis. Values of FEV, and PC,,, for active treatment were compared with values obtained during placebo treatment, using Student's t test for unpaired data. ANOVA test of regression coefficient was used to analyze changes within each treatment group.
dicted) and placebo treated (87.8 -+ 10.7% of predicted) group at the entry of the study. Also, the baseline values, after 1 and 2 months of treatmcnt, did not differ significantly from the values observed at the first visit in the two groups and within the same group. Table 2 presents PC,,-FEV, values observed at the time of enrollment after 1 month and 2 months of treatment, respectively, with BDP or placebo together with the results of the ANOVA test. Baseline values of methacholine PC,,-FEV I in the active and placebo groups were not statistically different. A significant reduction in bronchial responsiveness to methacholine was observed in asthmatic children treated with BDP (mean regression coefficient: b = 0.832664 P = 0.0069), while no significant changes in bronchial reactivity occurred in patients receiving placebo (mean regression coefficient: b = 0.001336 P = 0.99) (Table 2, Fig. 1).
RESULTS
DISCUSSION
There was no difference in the study population for age, height, and weight (Table 1). Eighteen of the 20 patients admitted concluded the study according to the protocol. Two children (No. 7, 13) in the placebo group were dropped from the study because of acute worsening of bronchial symptoms. These two patients were not considered in the statistical analysis. There was good compliance with the use of aerosol medications as assessed by weighing the returned canisters. No difference existed in baseline values of FEV, between the active (mean t SD; 90.3 ? 7.63% of pre-
The ultimate goal of treatment of asthma is to reduce morbidity and mortality and to allow the patient to lead a life as normal as possible with minimum side effects or risks related to medications. Since a good correlation between severity of bronchial reactivity and asthma symptoms has been well documented,' drug treatment should also be targeted at reducing bronchial hyperreactivity . Previous studies in both adults6,'6,17and children with a ~ t h m a have ~ - ~ demonstrated a reduction in bronchial responsiveness after corticosteroid aerosol treatment.
Inhaled Beclomethasone Dipropionate in Asthmatic Children
0
Beclomethasone Dipropionate A Placebo
3 2
u2
\
34 5v
I
I
04
1 st
2nd 3rd rnethacholine challenges
Fig. 1. Changes in methacholine PC,,-FEV, (mean duced by 2 month treatments with BDP or placebo.
* SD) in-
The results of the present study confirm and further extend these observations. There was a progressive reduction in bronchial hyperreactivity which was observed 1 month after initial treatment and was statistically significant after two months. Although PC,,-FEV, increased in all but two (No. 1,17) patients receiving inhaled BDP, it increased in only two patients (No. 6,lO) receiving placebo. Furthermore, this report represents a study performed during a maximal exposure to environmental allergens responsible for the exacerbation of symptoms and bronchial hyperreactivity. For over a decade considerable clinical experience with the use of newer inhaled steroid preparations has been available. The most impressive results of inhaled steroids pertain to their impact on the reduced frequency of acute exacerbations, amounting to an almost 10-fold decrease during prolonged follow-up. ’*,” This effect is also evident in our study in which no patient in the BDP-treated group had an acute exacerbation during the period of study, while two of those in the placebo group completed the study prematurely because of asthma exacerbation. Elimination of these two patients from the biostatistical analysis, in fact, caused underestimation of the difference between the two treatments. Further, the reduction in bronchial hyperreactivity was obtained with a dose of BDP (300 pg/day) which is not usually associated with clinically apparent adverse systemic side effects .2”321 Our data support a more extensive role for the use of inhaled corticosteroids in the treatment of childhood asthma. REFERENCES 1. Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: Relationship to minimum treatment to central symptoms of asthma. Thorax 198 1; 36575 -579.
5
2. Chung KF. Role of inflammation in the hyperreactivity of the airways in asthma. Thorax 1986: 41:657-662. 3. Hargreave FE, Ramsdale EH, Kirby JG, O’Byrne PM. Asthma and the role of inflammation. Eur J Respir Dis 1986; 69 (suppl 147):16-2 1. 4. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990; 141:s70-s76. 5 . Kerrebijn KF. Use of topical corticosteroids in the treatment of childhood asthma. Am Rev Respir Dis 1990; 141:s77-s81. 6. Reed CE. Aerosol glucocorticoid treatment of asthma. Am Rev Respir Dis 1990; 141:s82-s88. 7. Kerrebijn KF, Van Essen-Zandvliet EEM, Neijens HJ. Effect of long term treatment with inhaled corticosteroids and beta agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 79:633-639. 8. Kerrebijn KF, Van Essen-Zandvliet EEM, Bosschaart A. The effect of inhaled glucocorticoids on bronchial responsiveness. In: Godfrey S , ed. Glucocorticoids in Childhood Asthma. Amsterdam: Excerpta Medica, 1987:37-41. 9. Kraemer R, Sennhauser F, Reinhardt M. Effect of regular inhalation of beclomethasone dipropionate and sodium cromoglycate on bronchial hyperreactivity in asthmatic children. Acta Pediatr Scand 1987: 76:119-123. 10. American Thoracic Society. Definition and classification of chronic bronchitis and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762-768. 1 1 . Polgar G, Promadhat V. Pulmonary Function Testing in Children: Technique and Standards. Philadelphia: WB Saunders, 1971. 12. Rosenthal RR. The emerging role of bronchoprovocation. J Allergy Clin Immunol 1979; 64564-568. 13. Townley RJ, Hopp RJ. lnhalation methods for the study of airway responsiveness. J Allergy Clin Immunol 1987; 80:111-124. 14. Balzano G, Schiavo M, Cocco G, D’Amato G, Melillo G. A new dosimeter Me.Far in bronchial provocation testing with phannacological agents. In: Proceedings of the 4th Congress of the International Society for Aerosols in Medicine, Brno, Czechoslovakia, June 1982. 15. Ryan G, Dolovich MB, Roberts RS, Frith PA, Juniper EF, Newhouse MT. Standardization of inhalation provocation tests: Two techniques of aerosol generation and inhalation comparison. Am Rev Respir Dis 1981; 123:195-199. 16. Ryan G, Latimer KM, Juniper EF, Roberts RS, Tech M, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonsteroid-dependent asthma. J Allergy Clin Immunol 1985; 75:25-30. 17. Woolcock AJ, Yan K , Salome CM. Effect of therapy on bronchial hyperresponsiveness in the long term management of asthma. Clin Allergy 198: 18:165-176. 18. Smith MJ, Hodson ME. High dose beclomethasone inhaler in the treatment of asthma. Lancet 1986; 1:265-269. 19. Smith MJ: Inhaled steroids in the management of childhood asthma. In: Hogg JC, Ellul Micallef R, Brattsand R Eds. Glucocorticoids Inflammation and Bronchial Hyperreactivity. Amsterdam: Excerpta Medica, 1985: 116-121. 20. Godfrey S , Balfour-Lynn L, Tooley M. A three to five years follow up of the use of the aerosol steroid beclomethasone dipropionate in childhood asthma. J Allergy Clin lmmunol 1978; 62: 335-339. 21. Toogod JH. Complications of topical steroid therapy for asthma. Am Rev Respir Dis 1990; 141:s89-s96.
Original Articles -
Effect of Inhaled Beclomethasone Dipropionate on Bronchial Hyperreactivity in Asthmatic Children During Maximal Allergen Exposure A. L. Boner, MD,’ G. L. Piacentini, MD,’ C. Bonizzato, M D , ~V. Dattoli, MD,’ and L. Sette, MD,’ Summary. In this double blind study we evaluated the effect of a 2 months long treatment with inhaled beclomethasone dipropionate (300 Fgiday) on methacholine responses in asthmatic children, during a period of maximal allergen exposure. Baseline values of methacholine PC-, FEV, were 0.66 2 0.22 mg/rnL (mean ? SEM) in 10 children treated with the active drug and 0.78 ? 0.21 mgimL in 10 children treated with placebo. After 1 month of treatment PC,,-FEV, was 1.91 2 0.64 and 0.80 0.33 mg/mL, respectively, in the groups treated with beclomethasone versus placebo. A statistically significant reduction in bronchial hyperreactivity (PC,,-FEV,, 5.49 5 1.86 mg/mL) but no systemic side effects were observed after 2 months of treatment with beclomethasone dipropionate. This is compared with a PC,,-FEV, of 1.38 2 0.52 mg/mL in the placebo group. The results confirm the effect of inhaled corticosteroids in reducing bronchial hyperreactivity, even during a period of maximal allergen exposure. Pediatr Pulmonol 1991; 10~2-5.
*
Key words: Grass pollen, parietaria; house dust mite allergies; methacholine challenge, PC,,-FEV, ; placebo-controlledseasonally arranged trial.
INTRODUCTION
The most characteristic feature of asthma is the increased bronchial reactivity to a large variety of environmental and physical agents. The severity of this bronchial hyperreactivity correlates strongly with that of asthma symptoms’ supporting its fundamental role in the pathophysiology of the disease. There is a growing awareness that inflammation plays a critical role in asthma and experimental studies have provided convincing evidence of a close association between the degree of inflammation in the airway wall and Althe degree of bronchial hyperrespon~iveness.~.~ though a number of studies suggest the therapeutic antiinflammatory effects of inhaled glucocorticoids in the control of relatively few studies were done in children.’-’ To our knowledge, none of them has evaluated the effectiveness of steroids during an allergy season. The purpose of our study was to investigate the effect of inhaled steroid beclomethasone dipropionate (BDP) on bronchial hyperreactivity in asthmatic children during a period of maximal allergen exposure. 0 1991 Wiley-Liss, Inc.
MATERIALS AND METHODS Patients
The study population consisted of 20 asthmatic patients, 17 male and 3 female, ranging in age from 6 to 12 years (mean, 9.2 k 1.9 SD) with documented asthma as defined by the American Thoracic Society. l o Patients were included if their baseline FEV, was greater than 70% of predicted values’ and improved by 15% or more after nebulized albuterol. All subjects were allergic either to seasonal allergens (grass pollen and parietaria; 13 patients) or to perennial allergen (house dust mite, Dermatophagoides pteronyssinus and farinae; 7 patients).
‘
From the Clinica Pediatrica, Universiti di Verona’, and lstituto Pi0 XI1 Misurina’, Italian Alps, Italy. Received April 1 I , 1990; (revision) accepted for publication August 4, 1990. Address correspondence and reprint requests to Dr. A. Boner, Clinica Pediatrica Universitg di Verona, Policlinico Borgo Roma, 37134 Verona, Italy.
Inhaled Beclomethasone Dipropionate in Asthmatic Children TABLE 1-Clinical
3
Data of the Study Population ~
BDP treated group Patient Age number Sex (yr)
1 4 5 9 12 16 17 18 19 20 Mean SD SEM
M
F M M M
M M M F M
9.2 12.0 9.0 9.0 8.0 6.0 6.0 11.0 8.0 10.0 8.8 1.9 0.6
Weight Height (kg) (cm)
25.0 60.0 26.0 30.0 25.0 34.6 27.0 32.0 29.0 36.5 32.5 10.4 3.3
131.0 159.0 129.0 130.0 126.0 127.0 122.0 142.0 124.0 145.0 133.5 11.6 3.7
Placebo treated group Treatrnent Treatment before Patient Age Weight Height before the trial number Sex (yr) (kg) (cm) the trial
IB IB IB IB IB B C B B+C C
2 3 6 7 8 10 11 13 14 15 Mean SD SEM
M
M M M F M M M M M
11.5 6.6 10.0 11.0 8.7 8.5 12.0 9.5 12.0 7.0 9.7 2.0 0.6
38.0 23.0 42.5 25.6 35.0 27.0 35.0 33.0 34.0 22.0 31.5 6.8 2.1
143.0 119.0 151.0 141.0 132.0 126.0 145.0 136.0 140.0 122.0 135.5 10.5 3.3
BfC B+C B IB IB C TB C T B
IB, intermittent P,-agonists; B, P,-agonists regularly; BDP, beclomethasone dipropionate; T, theophylline; C, cromolyn.
All patients were studied for 2 months during a period of maximal environmental exposure to specific allergens, namely in spring and in autumn-winter. Patient characteristics of the study population are given in Table 1. Treatment Patients were randomized in a double blind fashion and divided into two groups of 10 subjects each. One group of 10 patients received BDP (Becotide, Glaxo S.p.A.) using a metered-dose inhaler (MDI), each puff containing 50 pg. Two puffs of BDP were administered three times daily. The other group of 10 patients was treated with placebo. BDP or placebo was administered for 2 months during which time each patient was allowed to use inhaled albuterol when needed. The inhalation technique of each child was carefully evaluated at the beginning of the study and only those patients capable of using the MDI apparatus were included. All children had parental supervision in aerosol administration throughout the study period. Patient Evaluation Each patient was carefully evaluated clinically and tests of lung functions were performed using a Vitalograph Spirometer (Buckingham, England) every 15 days for a total of five observations. Patient compliance was checked by weighing each canister at the end of the study period. Bronchial Responsiveness The level of bronchial hyperreactivity was evaluated by methacholine challengeI2 at the initial visit and after 1 and 2 months (third and fifth visits) of treatment. Bron-
chial challenges were always performed at the same time of the day (8-9 A.M.). None of the children had respiratory infections within 2 months prior to the study and oral and inhaled steroids were not used during this period. Antihistamines and short acting theophylline preparations were discontinued 48 hr, long acting theophylline preparation and cromolyn 1 week before the first challenge. During the period of investigation no medication other than the study aerosol and albuterol aerosol, for symptomatic relief, was allowed. Albuterol was witheld for at least 12 hr before bronchial challenge, according to reccomended guidelines for bronchial challenges. l 3 Methacholine challenge was performed only if baseline FEV values were 2 70% of predicted. " Methacholine was delivered by a Me.Far dosimeter (Brescia, Italy)14 of which 0.01 mL could be nebulized with a De Vilbis 646 nebulizer in 1.2 sec, generating particles with diameters ranging from 0.5 to 3 pm. All inhalations were performed by slow inspiration, starting from functional residual capacity without reaching total lung capacity and followed by a 5 sec breath holding. Before methacholine provocation five inhalations of buffer solution were performed. One minute after the last inhalation FEV, was recorded again and the challenge proceeded only if FEV, changed less than 10%. Each patient received bronchoprovocation with five puffs of increasing concentrations of methacholine (0.075, 0.15, 0.31, 0.62, 1.25, 2.5, 5 , 10, and 25 mg/ mL) at 2 min intervals. After each dosing, FEV, was evaluated, the best of three efforts being considered for statistical analysis. The test was stopped when a decrease of 220% of FEV, occurred after buffer inhalation. Data were plotted with logarithmic concentrations of inhaled
4
Boner et al. TABLE 2-Changes in Methacholine PC,,-FEV, After 1 (Second Challenge) and 2 (Third Challenge) Months of Treatment With Beclomethasone Dipropionate (BDP) or Placebo BDP PCZO-FEV, Patient
Placebo PC,,-FEV,
Methacholine challenge
Patient number
1st
2nd
3rd
1 4 5 9 12 16 17 18 19 20
0.80 0.24 0.99 1.12 I .63 0.12 1.12 0.21 0.29 0.11
3.50 0.56 6.50 2. I3 4.00 0.87 0.68 0.24 0.27 0.40
0.56 15.50 7.00 3.50 4.50 0.60 0.14 7.50 15.00 0.59
Mean SEM
0.66 0.22 -NSh-
1.91 0.64 -NSP = 0.0069
5.49 1.86
number
NS
aData from patients number 7 and 13 in the placebo group were not considered in the statistical analysis. 'NS, no statistical difference
methacholine on the abscissa and arithmetic percentage decreases of FEV , compared with FEV, measured after buffer control nebulization, on the ordinate. The concentration of methacholine producing an exact 20% fall in FEV, (PC,,) was calculated as described by Rosenthal. The within-subject day to day variability of the method tested intervals of 1 to 2 weeks, is plus or minus one single 2-fold concentration, as commonly accepted. 1 3 3 1 s
,
Data Analysis Logarithmic transformation of the methacholine PC,, was used for statistical analysis. Values of FEV, and PC,,, for active treatment were compared with values obtained during placebo treatment, using Student's t test for unpaired data. ANOVA test of regression coefficient was used to analyze changes within each treatment group.
dicted) and placebo treated (87.8 -+ 10.7% of predicted) group at the entry of the study. Also, the baseline values, after 1 and 2 months of treatmcnt, did not differ significantly from the values observed at the first visit in the two groups and within the same group. Table 2 presents PC,,-FEV, values observed at the time of enrollment after 1 month and 2 months of treatment, respectively, with BDP or placebo together with the results of the ANOVA test. Baseline values of methacholine PC,,-FEV I in the active and placebo groups were not statistically different. A significant reduction in bronchial responsiveness to methacholine was observed in asthmatic children treated with BDP (mean regression coefficient: b = 0.832664 P = 0.0069), while no significant changes in bronchial reactivity occurred in patients receiving placebo (mean regression coefficient: b = 0.001336 P = 0.99) (Table 2, Fig. 1).
RESULTS
DISCUSSION
There was no difference in the study population for age, height, and weight (Table 1). Eighteen of the 20 patients admitted concluded the study according to the protocol. Two children (No. 7, 13) in the placebo group were dropped from the study because of acute worsening of bronchial symptoms. These two patients were not considered in the statistical analysis. There was good compliance with the use of aerosol medications as assessed by weighing the returned canisters. No difference existed in baseline values of FEV, between the active (mean t SD; 90.3 ? 7.63% of pre-
The ultimate goal of treatment of asthma is to reduce morbidity and mortality and to allow the patient to lead a life as normal as possible with minimum side effects or risks related to medications. Since a good correlation between severity of bronchial reactivity and asthma symptoms has been well documented,' drug treatment should also be targeted at reducing bronchial hyperreactivity . Previous studies in both adults6,'6,17and children with a ~ t h m a have ~ - ~ demonstrated a reduction in bronchial responsiveness after corticosteroid aerosol treatment.
Inhaled Beclomethasone Dipropionate in Asthmatic Children
0
Beclomethasone Dipropionate A Placebo
3 2
u2
\
34 5v
I
I
04
1 st
2nd 3rd rnethacholine challenges
Fig. 1. Changes in methacholine PC,,-FEV, (mean duced by 2 month treatments with BDP or placebo.
* SD) in-
The results of the present study confirm and further extend these observations. There was a progressive reduction in bronchial hyperreactivity which was observed 1 month after initial treatment and was statistically significant after two months. Although PC,,-FEV, increased in all but two (No. 1,17) patients receiving inhaled BDP, it increased in only two patients (No. 6,lO) receiving placebo. Furthermore, this report represents a study performed during a maximal exposure to environmental allergens responsible for the exacerbation of symptoms and bronchial hyperreactivity. For over a decade considerable clinical experience with the use of newer inhaled steroid preparations has been available. The most impressive results of inhaled steroids pertain to their impact on the reduced frequency of acute exacerbations, amounting to an almost 10-fold decrease during prolonged follow-up. ’*,” This effect is also evident in our study in which no patient in the BDP-treated group had an acute exacerbation during the period of study, while two of those in the placebo group completed the study prematurely because of asthma exacerbation. Elimination of these two patients from the biostatistical analysis, in fact, caused underestimation of the difference between the two treatments. Further, the reduction in bronchial hyperreactivity was obtained with a dose of BDP (300 pg/day) which is not usually associated with clinically apparent adverse systemic side effects .2”321 Our data support a more extensive role for the use of inhaled corticosteroids in the treatment of childhood asthma. REFERENCES 1. Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: Relationship to minimum treatment to central symptoms of asthma. Thorax 198 1; 36575 -579.
5
2. Chung KF. Role of inflammation in the hyperreactivity of the airways in asthma. Thorax 1986: 41:657-662. 3. Hargreave FE, Ramsdale EH, Kirby JG, O’Byrne PM. Asthma and the role of inflammation. Eur J Respir Dis 1986; 69 (suppl 147):16-2 1. 4. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990; 141:s70-s76. 5 . Kerrebijn KF. Use of topical corticosteroids in the treatment of childhood asthma. Am Rev Respir Dis 1990; 141:s77-s81. 6. Reed CE. Aerosol glucocorticoid treatment of asthma. Am Rev Respir Dis 1990; 141:s82-s88. 7. Kerrebijn KF, Van Essen-Zandvliet EEM, Neijens HJ. Effect of long term treatment with inhaled corticosteroids and beta agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987; 79:633-639. 8. Kerrebijn KF, Van Essen-Zandvliet EEM, Bosschaart A. The effect of inhaled glucocorticoids on bronchial responsiveness. In: Godfrey S , ed. Glucocorticoids in Childhood Asthma. Amsterdam: Excerpta Medica, 1987:37-41. 9. Kraemer R, Sennhauser F, Reinhardt M. Effect of regular inhalation of beclomethasone dipropionate and sodium cromoglycate on bronchial hyperreactivity in asthmatic children. Acta Pediatr Scand 1987: 76:119-123. 10. American Thoracic Society. Definition and classification of chronic bronchitis and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762-768. 1 1 . Polgar G, Promadhat V. Pulmonary Function Testing in Children: Technique and Standards. Philadelphia: WB Saunders, 1971. 12. Rosenthal RR. The emerging role of bronchoprovocation. J Allergy Clin Immunol 1979; 64564-568. 13. Townley RJ, Hopp RJ. lnhalation methods for the study of airway responsiveness. J Allergy Clin Immunol 1987; 80:111-124. 14. Balzano G, Schiavo M, Cocco G, D’Amato G, Melillo G. A new dosimeter Me.Far in bronchial provocation testing with phannacological agents. In: Proceedings of the 4th Congress of the International Society for Aerosols in Medicine, Brno, Czechoslovakia, June 1982. 15. Ryan G, Dolovich MB, Roberts RS, Frith PA, Juniper EF, Newhouse MT. Standardization of inhalation provocation tests: Two techniques of aerosol generation and inhalation comparison. Am Rev Respir Dis 1981; 123:195-199. 16. Ryan G, Latimer KM, Juniper EF, Roberts RS, Tech M, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonsteroid-dependent asthma. J Allergy Clin Immunol 1985; 75:25-30. 17. Woolcock AJ, Yan K , Salome CM. Effect of therapy on bronchial hyperresponsiveness in the long term management of asthma. Clin Allergy 198: 18:165-176. 18. Smith MJ, Hodson ME. High dose beclomethasone inhaler in the treatment of asthma. Lancet 1986; 1:265-269. 19. Smith MJ: Inhaled steroids in the management of childhood asthma. In: Hogg JC, Ellul Micallef R, Brattsand R Eds. Glucocorticoids Inflammation and Bronchial Hyperreactivity. Amsterdam: Excerpta Medica, 1985: 116-121. 20. Godfrey S , Balfour-Lynn L, Tooley M. A three to five years follow up of the use of the aerosol steroid beclomethasone dipropionate in childhood asthma. J Allergy Clin lmmunol 1978; 62: 335-339. 21. Toogod JH. Complications of topical steroid therapy for asthma. Am Rev Respir Dis 1990; 141:s89-s96.
