Fluticasone Improves Pulmonary Function in Children under 2 Years Old with Risk Factors for Asthma
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美国呼吸和危急护理医学 2005年第3期
Respiratory Center, "Ricardo Gutierrez" Children's Hospital, Buenos Aires, Argentina
ABSTRACT
This study assessed the effects of treatment with fluticasone in children younger than 2 years old with recurrent wheezing and risk factors of developing asthma. This double-blind placebo-controlled study randomized children to receive fluticasone (125 e; n = 14) or placebo (n = 12) twice daily for 6 months. Pulmonary function was assessed at the beginning and end, and parents filled out a daily diary recording respiratory symptoms, need for rescue medication, and emergency care. The SD score of maximum flow at functional residual capacity was eC0.74 ± 0.6 at the beginning and 0.44 ± 1 at the end for the fluticasone group (p = 0.001), and eC0.79 ± 0.3 at the beginning and eC0.78 ± 1.4 at the end for the placebo group (p = 0.97). A statistically significant difference (p = 0.02) was observed between treatments. The percentage of symptom-free days was 91.3 ± 7% for fluticasone and 83.9 ± 10% for placebo (p = 0.05). The number of respiratory exacerbations was 2.1 ± 1.7 and 4.1 ± 3 (p = 0.04), and the percentage of days on albuterol was 8.6 ± 6% and 16.3 ± 9% (p = 0.028). Treatment with fluticasone twice daily for 6 months improves pulmonary function and clinical outcomes in children with asthma younger than 2 years.
Key Words: asthma infants inhaled corticosteroids pulmonary function
More than one third of children show signs of bronchial obstruction before they reach the age of 3 years (1). Many of these problems are associated with low pulmonary function at birth (2) or with bronchial hyperreactivity secondary to viral infections (3). For these limited, transient, and relatively benign episodes, antiinflammatory treatment is not required. Children who continue to experience wheezing at older ages (4) and have risk factors, such as familial history of asthma, eczema, high serum IgE, or eosinophilia, are considered to have asthma (5).
Symptoms of recurrent bronchial obstruction are difficult to manage in children younger than 2 years because of the following factors: difficulty in providing a certain diagnosis, the limited availability of objective evaluation variables, and the small number of efficacy and safety reports on antiinflammatory agents.
Inhaled corticosteroids are considered the most effective treatment for persistent asthma in children (6), and appropriate control of childhood asthma may prevent more serious asthma or irreversible obstruction in later years (7). There is no consensus, however, on when and how to treat infants and young children with symptoms of asthma.
Several studies have been published showing the clinical efficacy of inhaled corticosteroids in this age group (8eC11). Recently, two studies have assessed a beneficial effect of inhaled corticosteroids on tidal flow/volume curves (12) and on exhaled nitric oxide levels (13) in young children. Nevertheless, their effect on expiratory forced flows has not been fully addressed.
The primary objective of this study was to assess the effect of fluticasone propionate (FP) on pulmonary function in children younger than 2 years with recurrent wheeze and risk factors of developing asthma. The secondary objective was to study the clinical response to treatment. Some of the results of this study have been previously reported in the form of an abstract (14).
METHODS
This randomized, double-blind trial with a placebo-controlled parallel group was performed at the Hospital de Nios Ricardo Gutieerrez in Buenos Aires, Argentina, between March 2001 and September 2003. Patients were assessed at the beginning and end of a 6-month treatment with FP or placebo through a pulmonary function test and stadiometry, and during treatment by clinical assessment. Pulmonary function tests were obtained when children met eligibility criteria, had not suffered an acute exacerbation in the last 3 weeks, and had not received any corticosteroid (inhaled or systemic) over the last month. Pulmonary function tests were assessed by the rapid thoracic-abdominal compression technique (15eC17) with a SensorMedics 2600 system (Yorba Linda, CA) to obtain the maximal flow at the functional residual capacity (maxFRC).
The inclusion criteria were as follows: age 6 to 20 months; asthmatic symptoms, defined as three or more episodes of wheeze with clinical improvement after bronchodilators, as assessed by a physician, together with a familial history of asthma or any other clinical finding indicating atopy (e.g., allergic rhinitis or eczema) in one or both parents; and decreased pulmonary function, defined as an SD score (Z score) of maxFRC lower than eC1 according to the European Respiratory Society/American Thoracic Society Task Force on Standards for Infant Respiratory Function Testing (16). Patients were excluded if they had any other chronic pulmonary illness.
Each patient was given a metered dose inhaler that contained 125 e FP per puff (Flixotide) or placebo and albuterol (Ventolin), provided by GlaxoSmithKline (Buenos Aires, Argentina). Parents were instructed to administer a dose of the study drug in the morning and in the evening over 6 months, by means of a spacer (Aerochamber; Trudell, London, ON, Canada).
Parents recorded their child's day and night symptoms, use of rescue medication, and number of nonscheduled emergency care visits by filling in a daily card. The presence of symptoms and usage of rescue medication for 3 or more consecutive days were considered as a respiratory exacerbation.
The study was approved by the Education and Research Committee of the Hospital de Nios Ricardo Gutieerrez. The parents signed an informed written consent for their child.
Statistical Analysis
Obtained values of maxFRC were converted to their Z score according to sex and height (18). Comparisons within and between groups were done by using nested analysis of variance. Confidence intervals (p = 0.95) for the mean Z-score difference were calculated.
For the between-group comparisons of percentage of symptom-free days, number of respiratory exacerbations, and percentage of days on albuterol, each variable was tested by using the Shapiro-Wilk test and the F test. If normality and homoscedasticity were found for a variable, the Student's t test for the between-group comparison was applied. If not, the Mann-Whitney U test was used. To assess the children's growth with FP or placebo, height was analyzed in terms of their Z score and growth velocity.
A p value of less than 0.05 was considered significant. A type II error of 0.20 indicated that there was no difference between parameters.
RESULTS
A total of 102 children with a history of recurrent wheeze and risk factors of developing asthma were evaluated. Seventy-one patients presented a Z-score maxFRC higher than eC1 and were excluded. Of the 31 patients included in the study, 26 completed the trial. Of the five children not included in the analysis, two patients (one in each group) were excluded because their parent did not fill out the card properly, one from the placebo group required hospitalization, one from the FP group moved to a distant city, and the parent of one patient from the placebo group withdrew consent to continue in the trial. The demographic characteristics of the patients evaluated are shown in Table 1.
Pulmonary function was reported as Z-score maxFRC, consistent with recently published data (18). In our study, mean (± SD) Z-score maxFRC was eC0.74 ± 0.6 at the beginning and 0.44 ± 1 at the end (p = 0.001) for the FP group, and eC0.79 ± 0.3 at the beginning and eC0.78 ± 1.4 at the end (p = 0.97) for the placebo group. There was a statistically significant difference (p = 0.02) between FP and placebo. Figure 1 shows the individual changes of pulmonary function and variation in Z score.
During treatment, patients on FP had fewer episodes of bronchial obstruction and less need for albuterol as rescue medication. Table 2 shows results for symptom-free days, number of respiratory exacerbations, and percentage of days on albuterol.
The initial and final heights of patients on FP were 75.2 ± 5 cm (SD score: eC0.4 ± 1) and 82.5 ± 5 cm (SD score: 0.0 ± 1), with a mean growth velocity of 14.2 ± 4 cm/year. For patients on placebo, the initial and final heights were 76.7 ± 5 cm (SD score: eC0.1 ± 1) and 84.3 ± 4 cm (SD score: 0.1 ± 1), with a mean growth velocity of 12.1 ± 3 cm/year (p = 0.16).
DISCUSSION
This study found that infants and young children with recurrent wheeze, risk factors of developing asthma, and low maxFRC who received FP showed a significant improvement in pulmonary function. Patients who received placebo continued to have airflow obstruction. Children in the FP group demonstrated improved control of their illness through fewer days with symptoms, fewer respiratory exacerbations, and less need of bronchodilators.
It has been established that inhaled corticosteroids are a safe and effective alternative for the control of asthma (6) and normalization of pulmonary function in children older than 2 years (19eC23). So far, however, the safest and most effective treatment has not been proven for infants and young children with recurrent wheeze. Studies by Furfaro and colleagues (24) and Tasche and colleagues (25) demonstrated that sodium cromoglycate is not a useful treatment in these patients. Various authors have shown that inhaled corticosteroids, such as budesonide and FP, can help control asthma in young children (9eC11). Bisgaard and coworkers (8) demonstrated the efficacy of 50- and 100-e twice-daily doses of FP for 3 months delivered by metered dose inhaler (MDI) and spacer in children aged 1 to 3 years. They showed a dose-related effect, and the 200 e/day dose was the most effective. Patients treated with inhaled corticosteroids show clinical improvement because of a decrease in bronchial hyperreactivity and an increase in the diameter of airways. Some studies (26, 27) have shown that measurements of pulmonary function in young children with recurrent wheeze correlate well with overall health assessment by the study physician but not by the mother. This finding may imply that future studies aimed at evaluating therapeutic response in these patients should include pediatric respiratory physician examinations and lung function measurements.
We decided to evaluate only those children with low pulmonary function, because they can show more obvious improvement if the antiinflammatory treatment is effective. We found that 31 of 102 patients (30%) had persistent symptoms and low maxFRC. This finding is consistent with data (1) showing that the persistent wheezers represent one third of the children who wheezed and are those who showed a deterioration of the pulmonary function over time. Our study design used the European Respiratory Society/American Thoracic Society Task Force Standards for Infant Respiratory Function Testing (16) and considered a Z-score maxFRC lower than eC1 as an inclusion criterion. Following the latest recommendations, the results of this study use the more recently published reference values (18).
Stick and coworkers (28) performed a double-blind trial to evaluate the effect on pulmonary function and bronchial reactivity in wheezy infants of 200 e/day of bechlomethasone dipropionate for 2 months through a Volumatic spacer (GlaxoSmithKline, Middlesex, UK). Only bronchial reactivity was significantly modified in their study. The difference from ours in terms of pulmonary function may well be explained by the longer period of treatment in our study, our use of a more potent antiinflammatory drug, and perhaps our use of a spacer device specially designed for young children. Moeller and colleagues (13) found a beneficial effect of 4 weeks of FP treatment on exhaled nitric oxide but not on symptom score or pulmonary function in recurrently wheezy infants. The authors proposed that a normal baseline pulmonary function, a small sample, and a short period of treatment caused the relative lack of response. Recently, in an observational and prospective cohort study, Devulapalli and coworkers (12) found an improvement of the ratio of time to peak expiratory flow/total expiratory time obtained from tidal flow/volume curves in young children treated with inhaled corticosteroids.
Martinez and coworkers (1) have described a progressive deterioration of pulmonary function at age 6 years in a group of patients with persistent wheeze since an early age and risk factors for developing asthma. Studies by Agertoft and Pedersen (7) and Payne and colleagues (29) and the START (30) study in school-age children suggest that treatment with inhaled corticosteroids should begin early to avoid possible irreversible changes in pulmonary function. Our observations confirm that young children with recurrent wheeze and airflow limitation who do not receive antiinflammatory treatment continue to have these conditions. Those patients treated with FP early, however, can achieve normal pulmonary function. It has not been established if there is any relation between the persistence of diminished pulmonary function and airway remodeling in the first years of life.
Maternal smoking during pregnancy is associated with lower pulmonary function after birth (31). Also, exposure to environmental tobacco smoke and familial history of atopy have been shown to be related to bronchial hyperreactivity in young children (32). Other studies have found no differences in pulmonary function among infants exposed and unexposed to environmental tobacco smoke in the home after stratifying by prenatal exposure status (33). Although, in our patients, the incidence of environmental tobacco smoke exposure is high, with no difference between groups, our study design does not allow for determining the relevance of this issue to asthmatic symptoms.
FP doses lower than 250 e/day are safe in school-age children with asthma (34), and a recent study (9) found no adverse effects on growth, osteocalcic metabolism, or serum cortisol levels in children younger than 2 years who received FP at 100 and 250 mcg/day for 6 months. Our study found no significant differences in growth velocity between children treated with FP and those who received the placebo.
We conclude that treatment with FP at 125 e twice daily for 6 months in infants and young children with recurrent wheeze and risk factors of developing asthma increases pulmonary function and allows better control of the illness. Further studies should evaluate the role of inhaled corticosteroids in the first years of life to prevent irreversible bronchial obstruction.
Acknowledgments
The authors thank Dr. Sonia Buist for her helpful suggestions regarding the protocol design, Mrs. Martha Swain for assistance in the preparation of the article, GlaxoSmithKline, Argentina, for supplying the medication, and Trudell Medical International for supplying spacers.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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Teper AM, Szulman GA, Kofman CD, Navarra F, Zaragoza S, Fernandez S, Molise MC, Maffey AF, Vidaurreta SM. Does fluticasone propionate (FP) improve pulmonary function in asthmatic infants Eur Respir J 2003;22:A3108.
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ABSTRACT
This study assessed the effects of treatment with fluticasone in children younger than 2 years old with recurrent wheezing and risk factors of developing asthma. This double-blind placebo-controlled study randomized children to receive fluticasone (125 e; n = 14) or placebo (n = 12) twice daily for 6 months. Pulmonary function was assessed at the beginning and end, and parents filled out a daily diary recording respiratory symptoms, need for rescue medication, and emergency care. The SD score of maximum flow at functional residual capacity was eC0.74 ± 0.6 at the beginning and 0.44 ± 1 at the end for the fluticasone group (p = 0.001), and eC0.79 ± 0.3 at the beginning and eC0.78 ± 1.4 at the end for the placebo group (p = 0.97). A statistically significant difference (p = 0.02) was observed between treatments. The percentage of symptom-free days was 91.3 ± 7% for fluticasone and 83.9 ± 10% for placebo (p = 0.05). The number of respiratory exacerbations was 2.1 ± 1.7 and 4.1 ± 3 (p = 0.04), and the percentage of days on albuterol was 8.6 ± 6% and 16.3 ± 9% (p = 0.028). Treatment with fluticasone twice daily for 6 months improves pulmonary function and clinical outcomes in children with asthma younger than 2 years.
Key Words: asthma infants inhaled corticosteroids pulmonary function
More than one third of children show signs of bronchial obstruction before they reach the age of 3 years (1). Many of these problems are associated with low pulmonary function at birth (2) or with bronchial hyperreactivity secondary to viral infections (3). For these limited, transient, and relatively benign episodes, antiinflammatory treatment is not required. Children who continue to experience wheezing at older ages (4) and have risk factors, such as familial history of asthma, eczema, high serum IgE, or eosinophilia, are considered to have asthma (5).
Symptoms of recurrent bronchial obstruction are difficult to manage in children younger than 2 years because of the following factors: difficulty in providing a certain diagnosis, the limited availability of objective evaluation variables, and the small number of efficacy and safety reports on antiinflammatory agents.
Inhaled corticosteroids are considered the most effective treatment for persistent asthma in children (6), and appropriate control of childhood asthma may prevent more serious asthma or irreversible obstruction in later years (7). There is no consensus, however, on when and how to treat infants and young children with symptoms of asthma.
Several studies have been published showing the clinical efficacy of inhaled corticosteroids in this age group (8eC11). Recently, two studies have assessed a beneficial effect of inhaled corticosteroids on tidal flow/volume curves (12) and on exhaled nitric oxide levels (13) in young children. Nevertheless, their effect on expiratory forced flows has not been fully addressed.
The primary objective of this study was to assess the effect of fluticasone propionate (FP) on pulmonary function in children younger than 2 years with recurrent wheeze and risk factors of developing asthma. The secondary objective was to study the clinical response to treatment. Some of the results of this study have been previously reported in the form of an abstract (14).
METHODS
This randomized, double-blind trial with a placebo-controlled parallel group was performed at the Hospital de Nios Ricardo Gutieerrez in Buenos Aires, Argentina, between March 2001 and September 2003. Patients were assessed at the beginning and end of a 6-month treatment with FP or placebo through a pulmonary function test and stadiometry, and during treatment by clinical assessment. Pulmonary function tests were obtained when children met eligibility criteria, had not suffered an acute exacerbation in the last 3 weeks, and had not received any corticosteroid (inhaled or systemic) over the last month. Pulmonary function tests were assessed by the rapid thoracic-abdominal compression technique (15eC17) with a SensorMedics 2600 system (Yorba Linda, CA) to obtain the maximal flow at the functional residual capacity (maxFRC).
The inclusion criteria were as follows: age 6 to 20 months; asthmatic symptoms, defined as three or more episodes of wheeze with clinical improvement after bronchodilators, as assessed by a physician, together with a familial history of asthma or any other clinical finding indicating atopy (e.g., allergic rhinitis or eczema) in one or both parents; and decreased pulmonary function, defined as an SD score (Z score) of maxFRC lower than eC1 according to the European Respiratory Society/American Thoracic Society Task Force on Standards for Infant Respiratory Function Testing (16). Patients were excluded if they had any other chronic pulmonary illness.
Each patient was given a metered dose inhaler that contained 125 e FP per puff (Flixotide) or placebo and albuterol (Ventolin), provided by GlaxoSmithKline (Buenos Aires, Argentina). Parents were instructed to administer a dose of the study drug in the morning and in the evening over 6 months, by means of a spacer (Aerochamber; Trudell, London, ON, Canada).
Parents recorded their child's day and night symptoms, use of rescue medication, and number of nonscheduled emergency care visits by filling in a daily card. The presence of symptoms and usage of rescue medication for 3 or more consecutive days were considered as a respiratory exacerbation.
The study was approved by the Education and Research Committee of the Hospital de Nios Ricardo Gutieerrez. The parents signed an informed written consent for their child.
Statistical Analysis
Obtained values of maxFRC were converted to their Z score according to sex and height (18). Comparisons within and between groups were done by using nested analysis of variance. Confidence intervals (p = 0.95) for the mean Z-score difference were calculated.
For the between-group comparisons of percentage of symptom-free days, number of respiratory exacerbations, and percentage of days on albuterol, each variable was tested by using the Shapiro-Wilk test and the F test. If normality and homoscedasticity were found for a variable, the Student's t test for the between-group comparison was applied. If not, the Mann-Whitney U test was used. To assess the children's growth with FP or placebo, height was analyzed in terms of their Z score and growth velocity.
A p value of less than 0.05 was considered significant. A type II error of 0.20 indicated that there was no difference between parameters.
RESULTS
A total of 102 children with a history of recurrent wheeze and risk factors of developing asthma were evaluated. Seventy-one patients presented a Z-score maxFRC higher than eC1 and were excluded. Of the 31 patients included in the study, 26 completed the trial. Of the five children not included in the analysis, two patients (one in each group) were excluded because their parent did not fill out the card properly, one from the placebo group required hospitalization, one from the FP group moved to a distant city, and the parent of one patient from the placebo group withdrew consent to continue in the trial. The demographic characteristics of the patients evaluated are shown in Table 1.
Pulmonary function was reported as Z-score maxFRC, consistent with recently published data (18). In our study, mean (± SD) Z-score maxFRC was eC0.74 ± 0.6 at the beginning and 0.44 ± 1 at the end (p = 0.001) for the FP group, and eC0.79 ± 0.3 at the beginning and eC0.78 ± 1.4 at the end (p = 0.97) for the placebo group. There was a statistically significant difference (p = 0.02) between FP and placebo. Figure 1 shows the individual changes of pulmonary function and variation in Z score.
During treatment, patients on FP had fewer episodes of bronchial obstruction and less need for albuterol as rescue medication. Table 2 shows results for symptom-free days, number of respiratory exacerbations, and percentage of days on albuterol.
The initial and final heights of patients on FP were 75.2 ± 5 cm (SD score: eC0.4 ± 1) and 82.5 ± 5 cm (SD score: 0.0 ± 1), with a mean growth velocity of 14.2 ± 4 cm/year. For patients on placebo, the initial and final heights were 76.7 ± 5 cm (SD score: eC0.1 ± 1) and 84.3 ± 4 cm (SD score: 0.1 ± 1), with a mean growth velocity of 12.1 ± 3 cm/year (p = 0.16).
DISCUSSION
This study found that infants and young children with recurrent wheeze, risk factors of developing asthma, and low maxFRC who received FP showed a significant improvement in pulmonary function. Patients who received placebo continued to have airflow obstruction. Children in the FP group demonstrated improved control of their illness through fewer days with symptoms, fewer respiratory exacerbations, and less need of bronchodilators.
It has been established that inhaled corticosteroids are a safe and effective alternative for the control of asthma (6) and normalization of pulmonary function in children older than 2 years (19eC23). So far, however, the safest and most effective treatment has not been proven for infants and young children with recurrent wheeze. Studies by Furfaro and colleagues (24) and Tasche and colleagues (25) demonstrated that sodium cromoglycate is not a useful treatment in these patients. Various authors have shown that inhaled corticosteroids, such as budesonide and FP, can help control asthma in young children (9eC11). Bisgaard and coworkers (8) demonstrated the efficacy of 50- and 100-e twice-daily doses of FP for 3 months delivered by metered dose inhaler (MDI) and spacer in children aged 1 to 3 years. They showed a dose-related effect, and the 200 e/day dose was the most effective. Patients treated with inhaled corticosteroids show clinical improvement because of a decrease in bronchial hyperreactivity and an increase in the diameter of airways. Some studies (26, 27) have shown that measurements of pulmonary function in young children with recurrent wheeze correlate well with overall health assessment by the study physician but not by the mother. This finding may imply that future studies aimed at evaluating therapeutic response in these patients should include pediatric respiratory physician examinations and lung function measurements.
We decided to evaluate only those children with low pulmonary function, because they can show more obvious improvement if the antiinflammatory treatment is effective. We found that 31 of 102 patients (30%) had persistent symptoms and low maxFRC. This finding is consistent with data (1) showing that the persistent wheezers represent one third of the children who wheezed and are those who showed a deterioration of the pulmonary function over time. Our study design used the European Respiratory Society/American Thoracic Society Task Force Standards for Infant Respiratory Function Testing (16) and considered a Z-score maxFRC lower than eC1 as an inclusion criterion. Following the latest recommendations, the results of this study use the more recently published reference values (18).
Stick and coworkers (28) performed a double-blind trial to evaluate the effect on pulmonary function and bronchial reactivity in wheezy infants of 200 e/day of bechlomethasone dipropionate for 2 months through a Volumatic spacer (GlaxoSmithKline, Middlesex, UK). Only bronchial reactivity was significantly modified in their study. The difference from ours in terms of pulmonary function may well be explained by the longer period of treatment in our study, our use of a more potent antiinflammatory drug, and perhaps our use of a spacer device specially designed for young children. Moeller and colleagues (13) found a beneficial effect of 4 weeks of FP treatment on exhaled nitric oxide but not on symptom score or pulmonary function in recurrently wheezy infants. The authors proposed that a normal baseline pulmonary function, a small sample, and a short period of treatment caused the relative lack of response. Recently, in an observational and prospective cohort study, Devulapalli and coworkers (12) found an improvement of the ratio of time to peak expiratory flow/total expiratory time obtained from tidal flow/volume curves in young children treated with inhaled corticosteroids.
Martinez and coworkers (1) have described a progressive deterioration of pulmonary function at age 6 years in a group of patients with persistent wheeze since an early age and risk factors for developing asthma. Studies by Agertoft and Pedersen (7) and Payne and colleagues (29) and the START (30) study in school-age children suggest that treatment with inhaled corticosteroids should begin early to avoid possible irreversible changes in pulmonary function. Our observations confirm that young children with recurrent wheeze and airflow limitation who do not receive antiinflammatory treatment continue to have these conditions. Those patients treated with FP early, however, can achieve normal pulmonary function. It has not been established if there is any relation between the persistence of diminished pulmonary function and airway remodeling in the first years of life.
Maternal smoking during pregnancy is associated with lower pulmonary function after birth (31). Also, exposure to environmental tobacco smoke and familial history of atopy have been shown to be related to bronchial hyperreactivity in young children (32). Other studies have found no differences in pulmonary function among infants exposed and unexposed to environmental tobacco smoke in the home after stratifying by prenatal exposure status (33). Although, in our patients, the incidence of environmental tobacco smoke exposure is high, with no difference between groups, our study design does not allow for determining the relevance of this issue to asthmatic symptoms.
FP doses lower than 250 e/day are safe in school-age children with asthma (34), and a recent study (9) found no adverse effects on growth, osteocalcic metabolism, or serum cortisol levels in children younger than 2 years who received FP at 100 and 250 mcg/day for 6 months. Our study found no significant differences in growth velocity between children treated with FP and those who received the placebo.
We conclude that treatment with FP at 125 e twice daily for 6 months in infants and young children with recurrent wheeze and risk factors of developing asthma increases pulmonary function and allows better control of the illness. Further studies should evaluate the role of inhaled corticosteroids in the first years of life to prevent irreversible bronchial obstruction.
Acknowledgments
The authors thank Dr. Sonia Buist for her helpful suggestions regarding the protocol design, Mrs. Martha Swain for assistance in the preparation of the article, GlaxoSmithKline, Argentina, for supplying the medication, and Trudell Medical International for supplying spacers.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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