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9811024

The Effect of Inhaled Fluticasone Propionate in
the Treatment of Young Asthmatic Children
A Dose Comparison Study
HANS BISGAARD, JOHN GILLIES, MARCELLE GROENEWALD, and CLAIRE MADEN
on behalf of an International Study Group
Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Hamilton, New Zealand; Pretoria, South Africa;and Glaxo Wellcome Research and Development, Greenford, United Kingdom The response in asthmatic young children to inhaled steroids within the usual pediatric dose range is
unknown. We therefore evaluated the dose-related response in young children with moderate
asthma to inhaled fluticasone propionate (FP) (delivered via the Babyhaler spacer device) within the
pediatric dose range. A total of 237 children (mean age 28 mo, range 12 to 47) with moderate asth-
matic symptoms were studied in this multicenter, randomized, double-blind, parallel group, placebo-
controlled study of 12 wk treatment following a 4-wk run-in period. The median use of rescue medi-
cation was 1 dose in 2 d during the run-in period. FP 50 mg twice daily (FP100) and 100 mg twice daily
(FP200) was compared with placebo inhaled from a pressurized metered-dose inhaler (pMDI) and
the Babyhaler spacer device. With FP200 there was a statistically significant improvement from base-
line, as compared with the placebo group, in 8 of 10 diary card parameters, including the three symp-
tom domains of wheeze, cough, and breathlessness, and use of rescue medication. FP100 produced a
significant reduction in 5 of these 10 parameters, whereas no significant differences were found be-
tween the FP200 and FP100. The numbers of patients with at least one exacerbation during treat-
ment with placebo, FP100, and FP200 were 37%, 26%, and 20%, respectively. This difference be-
tween placebo and FP200, as well as the dose-related order was significant (p , 0.05). Both FP doses
were as well tolerated as placebo over the 12 wk treatment with a similar incidence of adverse ef-
fects. Asthmatic symptoms in 1- to 3-yr-old children responded in a significant and dose-related man-
ner to treatment with FP within a pediatric dose range. Bisgaard H, Gillies J, Groenewald M,
Maden C on behalf of an International Study Group. The effect of inhaled fluticasone propi-
onate in the treatment of young asthmatic children: a dose comparison study.
AM J RESPIR CRIT CARE MED 1999;160:126–131.
Cough and wheezing are very common in children younger not have reduced lung function as a predisposing factor, their than 4 yr of age and are a major cause of illness and admis- lung function is diminished by 6 yr of age. Diagnosis of asthma sions to hospital. Up to 40% of all children are reported to is ambiguous, and objective supportive evidence for the diag- have wheezing disorders during the first 3 yr of life (1). Recent nosis is missing. At present the diagnosis of asthma in young longitudinal studies indicate that approximtely 60% of wheeze children can only be delineated empirically, and carries no im- occurring in the first 3 yr of life is transient and benign, and plication for prognosis or underlying pathology.
may disappear by the age of 6 yr (2, 3). It is suggested that this Children younger than 4 yr of age with wheeze or asthma group of children have congenitally narrow airways, which are a difficult population in which to conduct clinical studies predisposes them to wheezing in association with viral infec- because of the variable nature of the symptoms and the lim- tions in early life (4). Most children who develop chronic ited outcome measures. Since the first placebo-controlled asthma in later childhood will have had their first symptoms study of inhaled corticosteroid in young asthmatic children un- during the first 3 yr of life (5). These infants have most of the der 4 yr of age (6), a number of clinical trials with inhaled cor- risk factors associated with asthma (high serum IgE levels, ticosteroids have been performed in these age groups. Effi- positive skin test reactivity to allergens, bronchial hyperre- cacy of inhaled corticosteroids has been documented in sponsiveness, family history of asthma) and, although they do asthmatic children younger than 4 yr of age with moderate tosevere persistent asthma symptoms (6–8). Sodium cromogly-cate was recently reported to be ineffective in a large parallel (Received in original form November 5, 1998 and in revised form January 25, 1999) study of 167 young children with moderate persistent asth- Sponsored by Glaxo Wellcome.
matic symptoms, very similar to the present design (9). In the Correspondence and requests for reprints should be addressed to Hans Bisgaard, case of episodic viral wheeze in preschool children, modest Professor of Paediatrics, Dept. of Paediatrics, Rigshospitalet, Copenhagen Univer- improvements have been shown with intermittent high-dose sity Hospital, DK-2100 Copenhagen, Denmark. E-mail: [email protected] Am J Respir Crit Care Med
Vol 160. pp 126–131, 1999
inhaled corticosteroids (10, 11), but continuous prophylactic Internet address: www.atsjournals.org
treatment showed no effect (12).
Bisgaard, Gillies, Groenewald, et al.: Fluticasone Propionate in Young Asthmatic Children Daily doses of 800 mg budesonide from a pressurized me- the study. A parent or guardian of every patient provided written in- tered dose inhaler (pMDI) and spacer or 2,000 mg from a neb- formed consent.
ulizer were used in the studies documenting the effect of in- Assessments were performed in the clinic at the beginning and end haled corticosteroids in asthmatics younger than 4 yr of age.
of the placebo run-in period and thereafter every 3 wk for a totaltreatment period of 12 wk. At the first clinic visit, demographic details The high doses used in the treatment of persistent young asth- and a full clinical history were recorded, and a physical examination matics were justified in such pioneering studies aiming to es- was performed. On randomization, pulmonary auscultation was con- tablish a new treatment modality, but should not be used as ducted, and parents were given a questionnaire about the child's guideline for the dose range required to control asthma in asthma symptoms, the impact of the child's asthma symptoms on the young children.
parents' activities in and around the house, leisure activities, work ac- No formal dose response studies of inhaled steroids have tivities, the need for alternative childcare arrangements, and the over- been performed in preschool children, so the optimal dose in all control of asthmatic symptoms. This questionnaire was repeated at these age groups is not known. In the present study we have the end of treatment. At every clinic visit throughout the study, ad- sought to elucidate the dose response to inhaled corticoster- verse events, asthma exacerbations, and compliance with the study oids within a pediatric dose range for the treatment of young protocol, including inhalation technique, were checked and the oro-pharynx was examined, with a swab taken if there was visual evidence children with asthmatic symptoms. We have compared the ef- of fungal infection, to determine the presence of candida.
fect of fluticasone propionate (FP) (Glaxo Wellcome, UK) in- Throughout the study, parents kept daily record cards of their haled from a Babyhaler spacer device (Glaxo Wellcome, UK) child's symptoms, recording daytime and nighttime scores for wheeze, in a daily dose of 100 mg (FP100) with that of 200 mg (FP200) cough, and shortness of breath on a scale of 0 to 3. Parents were asked and with placebo in parallel groups of young children age 1 to to record the number of occasions during the night that they were 3 yr with a history of moderate asthmatic symptoms.
awoken because of the child's asthma symptoms. The number of occa-sions on which rescue salbutamol was used to relieve asthma symp-toms during each day and night was also recorded.
Exacerbation of asthma was defined as a worsening of the child's asthmatic symptoms that required either a change in medication Pediatric outpatients age 12 to 47 mo with a documented history of re- (other than relief salbutamol) and/or required the parents to contact current wheeze or asthma symptoms were recruited for the study. Pa- their general practitioner or the investigator. Treatment of the exacer- tients were randomized to the study if, on at least 7 d out of the last 14 bation was at the discretion of the investigator, and could include a d of the run-in period, they had any asthmatic symptoms, as recorded short course of inhaled or oral corticosteroids if needed. Patients were in three symptom domains (wheeze, cough, and shortness of breath) withdrawn from the study if more than one exacerbation occurred for daytime and nighttime separately, or had required relief salbuta- that required extra oral or inhaled corticosteroids, or if symptoms be- mol. Patients were excluded if, in the 2 wk before entering the run-in came unacceptable or poorly controlled despite backup medication.
period, they received inhaled or systemic corticosteroids or methyl- All analyses were performed on the intention-to-treat population, xanthine therapy, had been hospitalized for asthma, had any changes which consisted of all randomized patients who took at least one dose in asthma medication, or if they had received antibiotics for a chest in- of study medication. The primary measures of efficacy were the per- fection. Patients were also excluded if, after practicing inhalation tech- centages of cough-free and wheeze-free days, derived from the daily nique during the run-in period, they were unable to use the Babyhaler diary card data, over treatment wk 1 to 12. Secondary measures of ef- device correctly.
ficacy included percentage of nights without cough or wheeze, per- This was a randomized, double blind, placebo-controlled parallel centage of days/nights without relief salbutamol medication, percent- group study, with patients recruited from 33 centers in nine countries age of overall symptom-free days and nights, and percentage of nights (as listed in the ACKNOWLEDGMENT). Patients who fulfilled the inclu- without parental sleep disturbance, as well as the incidence of exacer- sion and exclusion criteria entered a 4-wk run-in period, during which bations and data from the parental questionnaires. All daily diary they received two puffs twice daily of placebo from a pMDI, via the card variables were analyzed as change from baseline. Baseline was Babyhaler spacer, and salbutamol as required to relieve symptoms. At taken as the last 2 wk of the run-in period, which was also the period the end of the run-in period, patients who fulfilled the eligibility crite- evaluated before randomization to determine if the child was eligible ria were randomly assigned to receive either two puffs of FP 25 mg twice for the study.
daily (total daily dose of 100 mg [FP100]), or two puffs of FP 50 mg A nonparametric method (the Van Elteren extension to the Wil- twice daily (total daily dose of 200 mg [FP200]), or two puffs of placebo coxon rank sum test) was used for each variable to assess pairwise dif- twice daily via identical CFC-formulated pMDIs delivered through a ferences between the treatment groups over the treatment period.
Babyhaler spacer device. Parents were taught to actuate the trial in- Mann-Whitney rank sum test was used to compare exacerbation rates haler once the spacer was in position, with the face mask over the in the three treatment groups. Kaplan-Meier estimates of survival child's nose and mouth, and then to allow at least five tidal breaths (or times were used to compare times to first exacerbation. Treatment 15 s) for inhalation. This procedure was then repeated for the second differences were assessed using two-sided significance tests, based at puff. No instructions were given on priming of the Babyhaler before the 5% level of significance. The sample size for this study was based use, although during use, parents were instructed to wash it once a on the nonparametric analysis of the percentage of asthma symptom- week in mild soapy water, followed by rinsing and leaving it to dry.
free days during treatment. Based on a standard deviation of 29% Patient compliance was carefully checked at the clinic visits every 3 wk, (shown in a previous pilot study), it was calculated that 70 children though not quantitated.
per treatment group were needed to detect a treatment difference of Salbutamol was used throughout the study as relief medication in a 15% between groups, with 80% power at the 5% level of significance.
formulation appropriate to each child: either inhaled from a pMDI(100 mg salbutamol per actuation) via the Babyhaler; or as dry powder (200 mg salbutamol per blister) inhaled using a Diskhaler; or nebu-lized using Ventolin Nebules (2.5 mg/2.5 ml salbutamol); or orally as A total of 314 patients were recruited to the study of which Ventolin Syrup (2.0 mg/5 ml salbutamol). Patients continued with any 237 were randomized to treatment and comprised the inten- regular medication, including sodium cromoglycate, ketotifen, and an- tion-to-treat population (Figure 1). The majority of the 77 tihistamines, for asthma or other conditions providing the dose re- patients withdrawn prior to randomization were withdrawn mained constant. Inhaled or systemic corticosteroids, anticholinergic because they had insufficient asthma symptoms, others for agents, nedocromil sodium, b2-agonists (other than salbutamol sup- reason of asthma exacerbations. Thirty-seven randomized plied for rescue medication), and methylxanthine derivatives were notpermitted, unless for treatment of an exacerbation. Regulatory ap- children violated the protocol, equally distributed among proval was obtained in those countries where it was required, and eth- treatment groups (12 placebo, 12 FP100, 13 FP200). Reasons ics committee approval was obtained for each site before the start of for classification as a protocol violator included age violation AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (four patients), insufficient symptoms or insufficient salbuta- mol usage during run-in (18 patients), respiratory tract infec- tions requiring antibiotics, asthma medication changes or hos-pitalization during run-in (four patients), failing to have diary card data from at least 50% of the treatment period (11 pa- tients), and taking disallowed concurrent medications during the treatment period (four patients). Two patients were with- drawn during the study by the investigator for reason of non- compliance. However, the analysis was done on the intention- to-treat group of children including all protocol violators.
Family history of asthma The mean age across all three groups was 28 mo (range 12 History of eczema to 47 mo). Pretreatment characteristics (Table 1), including Exacerbation upon exercise weight, height, asthma history, current medical condition, and Never hospitalized for current medications, were all generally comparable among the asthmatic symptoms No excerbations in the last year groups. The study group of children appeared to have moder- Use of one or more asthma ately severe recurrent asthmatic symptoms. During the run-in medications in the month period, the children had symptoms on a median of 81% of prior to randomization days, and salbutamol was used on a median of 48% of days.
*Values are mean 6 SD.
Forty-six percent had had 1 to 3 exacerbations, and 38% morethan 3 exacerbations during the previous year. Sixty-eight per-cent had not been hospitalized for asthma-related symptoms, Figure 2 illustrates the median differences in the changes 17% only once, and 15% more than once during the previous from baseline, and the 95% confidence limits (CL), between year. Fifty-three percent of the study group had had asthmatic active and placebo treatments for the various diary card pa- symptoms for more than 12 mo. A total of 57 patients (24%) rameters. FP200 produced a significant reduction in 8 of 10 di- were receiving sodium cromoglycate on entry to the study and18 patients (7%) were receiving ketotifen, and these patientsall continued on these medications during the treatment pe-riod. Over all patients, current asthma control on entry intothe study was rated as 7 by the parents on a scale from 1(poorly controlled) to 10 (well controlled). The groups dif-fered at baseline. The percentages of days with no cough dur-ing the run-in period were 41%, 31%, and 29% in the placebo,FP100, and FP200 groups, respectively. The correspondingpercentages of days with no symptoms of any type were 21%,14%, and 7%. The placebo group used salbutamol on 43% ofthe days, whereas the FP200 group used salbutamol on 64% ofthe days during run-in. A similar trend was consistent through-out the secondary efficacy variables, and indicated that theplacebo group had fewer and milder symptoms at baseline.
Figure 2. Changes from baseline. Differences between the FP
group and the placebo group. Median (95% CL). Eight of 10 diary
card parameters showed significant improvement from FP200
compared with placebo, and 5 of 10 showed significant improve-
Figure 1. Patient flow through the study.
ment from FP100 compared with placebo.
Bisgaard, Gillies, Groenewald, et al.: Fluticasone Propionate in Young Asthmatic Children Figure 3. Percentage of symptom-free days (median change from baseline).
ary card parameters compared with placebo, whereas FP100 significant differences between the FP100 group and placebo produced a significant reduction in 5 of 10 parameters com- or between the two FP groups.
pared with placebo. No significant differences were found be- The parents rated the current asthma symptoms on a scale tween FP200 and FP100. The treatment effect was most control from 1 (poorly controlled) to 10 (well controlled). In clearly revealed by reduction in cough and use of salbutamol.
all three treatment groups, the median score on entrance into Wheeze and shortness of breath also exhibited significant im- the study was 7 and improvements were seen in all three treat- provement in the actively treated children compared with pla- ment groups at completion of the treatment, with a median cebo treatment, although the numbers of patients recording score of 9. In the placebo group there was a 12% increase in these particular symptoms at baseline were relatively low. The the number of parents reporting current asthma symptoms as development in symptom-free days is illustrated in Figure 3.
"well controlled," with 18% and 22% increase in the FP100 The number of patients with at least one exacerbation dur- and FP200, groups, respectively. However, there were no sta- ing the treatment period was found to be significantly lower in tistically significant differences (placebo versus FP200, p 5 the FP200 treatment group (15 of 76 patients; 20%) compared 0.06). Impact on parents' activities in and around the house, with the placebo group (30 of 82 patients; 37%), p 5 0.03, 95% leisure activities, work activities, the need for alternative CL for the difference 2 to 32% (Figure 4). Using Kaplan-Meier childcare arrangements, and the overall control of asthma estimates of survival times, there was a significant difference symptoms consistently showed trends of increased improve- in the distribution of times to first exacerbation between the ment in the active treatment groups, but there were no statisti- FP200 group and the placebo group (p 5 0.022), indicating a cally significant differences.
smaller likelihood of exacerbation in the FP200 group.
A total of 68 patients treated with placebo, 63 patients The number of children in the FP100 group who experi- treated with FP100, and 64 patients treated with FP200 re- enced exacerbations (21 of 80 patients; 26%) was also lower ported adverse events during treatment. The adverse event than in the placebo-treated group. The dose-related effect on profile did not differ markedly among the three treatment exacerbation rate was significant (p , 0.05). This difference in groups. Asthma was the most commonly reported adverse exacerbation rate became apparent early during the study, event, being reported by 21 patients (26%), 18 patients (23%), with 10 (12%) of the placebo patients exacerbating during the and 13 patients (17%) in the placebo, FP100, and FP200 treat- first 2 wk of treatment compared with 7 (9%) in the FP100group and 3 (4%) in the FP200 group. Rescue treatment withcorticosteroids was required in 16% of the patients in the pla-cebo group compared with 5% in the FP100 group, and 5% inthe FP200 group, and these differences were statistically sig-nificant. (FP200 versus placebo: p 5 0.039; FP100 versus pla-cebo: p 5 0.038).
The number of patient withdrawals did not differ signifi- cantly among the three treatment groups, with 8, 7, and 10withdrawals from the treatment groups of placebo, FP100, andFP200 respectively (Figure 1). On randomization into thestudy, parents were asked to rate their child's asthma symp-toms as either "much better," somewhat better," "about thesame," "somewhat worse," or "much worse" than 3 mo ago.
The findings revealed a median score of "somewhat better"compared with 3 mo ago. Asked the same question at the endof the 12-wk treatment period, there was a 20%, 43%, and37% increase in the rating of asthma as "much better" in theplacebo, FP100, and FP200 groups, respectively. The scoresfor the parental rating of symptom control were statisticallysignificantly more favorable for the FP200 group comparedwith the placebo group (p 5 0.03). There were no statistically Figure 4. Exacerbation rate. Dose relation is significant, p , 0.05.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE ment groups, respectively. Fever and upper respiratory tract present unable to predict who will respond to treatment. The infections were also commonly reported.
clinical implication of the present data is therefore that chil- Of the events considered predictable, skin rashes were re- dren with moderate asthmatic symptoms may respond to ported in two patients (2%) on placebo, two (3%) on FP100, treatment with inhaled FP 100 mg twice daily. A therapeutic and four (5%) on FP200. Throat irritation was reported in two trial of 1 to 2 mo may be a feasible approach to help determine patients (2%) on placebo, two (3%) on FP100, and four (5%) the optimal treatment of the individual child. Scheduled fol- on FP200. Hoarseness/dysphonia was reported in only two pa- low-up visits should ascertain if control is obtained. If convinc- tients, both on FP100, and candidiasis of the mouth/throat was ing control is not obtained, treatment should obviously not be reported as an adverse event in only one patient, who was re- maintained. If control of symptoms does occur, withdrawal or ceiving placebo.
dose reduction should be attempted to ascertain the continued Visual evidence of oral candida was observed during the need for treatment at the minimal dose level. This would en- treatment period in 6% of children on placebo, 10% of chil- sure that treatment with inhaled corticosteroids is only pro- dren on FP100, and 4% of children on FP200. Fourteen pa- vided to those deriving benefit. Further, a determined attempt tients experienced serious adverse events during the treatment to down-titrate the dose toward no treatment or to the mini- period, seven (9%) receiving placebo, two (3%) receiving mal effective dose assures that no child is kept on inhaled cor- FP100, and five (7%) receiving FP200. The most common seri- ticosteroids longer than needed. A similar approach is re- ous adverse event was asthma reported in four patients (5%) flected in the recent guidelines from the British Thoracic in placebo, two (3%) on FP100, and two (3%) on FP200. Of Society (13).
the three serious adverse events on FP200 not related to In the present study, FP200 was as well tolerated as placebo asthma, one was a case of gastritis, one presented with fever, and no unexpected side effects became apparent over this 12-wk and one had diarrhea.
observation period. A knemometry study in 1 to 3-yr-old tod-dlers has demonstrated systemic activity with inhaled FP 400 mg daily (twice the daily dosage of the present study) as well asfrom inhaled budesonide 400 mg daily (14). Budesonide was Toddlers 1 to 3 yr of age with moderate asthmatic symptoms without systemic activity in a daily dose of 200 mg in a previous improved significantly from 12 wk treatment with FP 100 mg knemometry study (15), but clinical efficacy at such a dose of twice daily inhaled from the Babyhaler spacer device. A clini- budesonide remains to be documented. The present study cal effect became apparent within 2 wk of starting treatment, documents clinical efficacy from 200 mg daily dose of FP, but as indicated by differences in exacerbation rate and days with- lack of systemic activity at this dose remains to be docu- out symptoms. The treatment was dose-related and well toler- mented. The use of inhaled corticosteroids in young children ated in the usual pediatric dose range of 100 to 200 mg daily should be restricted to experienced doctors until more evi- dence of the safety of this treatment is obtained.
The present study group comprised young children of 1 to 3 yr Dedicated spacer devices for drug delivery to young chil- of age with a documented history of recurrent wheeze and dren have recently become available, and have facilitated the other asthma symptoms. Because there is no consensus on the treatment of this poorly compliant patient group (16). This definition of asthma in young children, there is no recognized study confirmed spacer with pMDI as a convenient device grading of the disease severity either. If the grading of inten- able to deliver a clinically efficacious dose of aerosol to young sity of symptoms and use of rescue medication in schoolchil- dren is applied, these children had moderate asthma. During In conclusion, this study showed a significant clinical effect the run-in period, rescue salbutamol medication was used on from both FP200 and FP100 delivered via the Babyhaler approximately 1 of 2 d, and the children were symptomatic on spacer device in the treatment of asthmatic symptoms in 1- to 4 of 5 d. The history attested to the persistence of symptoms with, 3-yr-old children, with a dose-related effect and with FP200 as on average, 3 exacerbations during the previous year and one- the most effective dose. Symptom control was obtained in some third of the children having been hospitalized for this reason.
children even in the low dose, and the dose-related response FP200 resulted in significant improvement in 8 of 10 diary indicates that dose requirement should be titrated individu- card parameters, including all three symptom domains of ally. These findings support the option of inhaled corticoste- cough, wheeze, shortness of breath, and in the use of salbuta- roid treatment for asthmatic symptoms in young children.
mol and parental sleep disturbance. FP100 produced signifi- Acknowledgment : Thanks are due to the following physicians who partici-
cant improvement in 5 of the 10 diary card parameters. A sig- pated in and randomized patients into this study: Belgium: Dr. A. Malfroot, nificant dose-related effect was observed in the number of Dr. H. Van Bever, Dr. C. de Boeck. Canada: Dr. S. Feanny, Dr. M. Gold, Dr.
exacerbations, which is a key outcome measure. It cannot be S. Lavi, Dr. M. Montgomery, Dr. B. Lyttle, Dr. D. Berube. Denmark: Dr. H.
known if higher doses would lead to further improvement.
Bisgaard, Dr. K. Ibsen. Ireland: Dr. D. Lillis, Dr. M. Taylor, Dr. P. Greally.
Disease control, evaluated from percentage of days and New Zealand: Dr. J. Gillies, Dr. J. Brown. Poland: Prof. D. Chmielewska, Prof.
R. Kurzawa, Prof. J. Alkiewicz. South Africa: Dr. C. Bester, Dr. D. Luyt, Dr. A.
nights with no symptoms, was significantly higher in the FP200 I. Manjra, Dr. M. Groenewald. Spain: Dr. G. Ferres, Dr. A. Escribano, Dr. M.
treatment group than in the placebo group (median difference Navarro, Dr. J. Botey, Dr. E. Gonzalez Perez-Yarza. United Kingom: Dr. J. Ca- in change from baseline 5 11%). The incidence of exacerba- ter, Prof. A. Milner, Dr. A. Speight, Dr. D. A. Spencer. Thanks are also due tions was 37% in the placebo group compared with 20% in the to Lisa Williams (Glaxo Wellcome) for the statistical analysis, and to MartinPrice (Glaxo Wellcome) for the evaluation of the parent questionnaire data.
FP200 group. These results confirm the concept that inhaledcorticosteroids within a pediatric dose range are efficacious inyoung children with moderate persistent asthmatic symptoms.
However, in clinical practice an improvement of this magni-tude may be insufficient to warrant continued treatment of the 1. Silverman, M., editor. 1995. Childhood Asthma and Other Wheezing whole group of children. The treatment effect is probably Disorders. Chapman & Hall Medical, London.
2. Martinez, F. D., A. L. Wright, L. M. Taussig, C. J. Holberg, M. Halonen, driven by a subgroup of children responding to inhaled corti- and W. J. Morgan. 1995. Asthma and wheezing in the first six years of costeroid treatment, whereas other children with apparently life. N. Engl. J. Med. 3:133–138.
comparable symptoms may profit less or not at all. We are at 3. Dodge, R., F. D. Martinez, M. G. Cline, M. D. Lebowitz, and B. Bur- Bisgaard, Gillies, Groenewald, et al.: Fluticasone Propionate in Young Asthmatic Children rows. 1996. Early childhood respiratory symptoms and the subsequent 1997. Randomised placebo-controlled trial of inhaled sodium cromogly- diagnosis of asthma. J. Allergy Clin. Immunol. 98:48–54.
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Taussig. 1988. Diminished lung function as a predisposing factor for 10. Wilson, N. M., and M. Silverman. 1990. Treatment of acute, episodic wheezing respiratory illness in infants. N. Engl. J. Med. 319:1112– asthma in pre-school children using intermittent high dose inhaled ste- roids at home. Arch. Dis. Child. 65:407–410.
5. Gerritsen, J., G. H. Koeter, D. S. Postma, J. P. Schouten, and K. Knol.
11. Connett, G., and W. Lenney. 1993. Prevention of viral induced asthma 1989. Prognosis of asthma from childhood to adulthood. Am. Rev. attacks using inhaled budesonide. Arch. Dis. Child. 68:85–88.
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12. Wilson, N., K. Sloper, and M. Silverman. 1995. Effect of continuous 6. Bisgaard, H., S. L. Munck, J. P. Nielsen, W. Petersen, and S. V. Ohlsson.
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13. British Thoracic Society. 1997. The British Guidelines on Asthma Man- 7. Connett, G. J., C. Warde, E. Wooler, and W. Lenney. 1993. Use of agement. Thorax 65(Suppl.):S1–S21.
budesonide in severe asthmatics aged 1–3 years. Arch. Dis. Child. 69:351– 14. Anhøj, J., A. M. Bisgaard, and H. Bisgaard. 1998. Systemic activity of in- haled fluticasone propionate and budesonide in 1–3 years old asth- 8. De Blic, J., C. Delacourt, M. Le Beourgeois, B. Mahuut, J. Ostinelli, C.
matic children. Eur. Respir. J. 12(Suppl. 28):268s.
Caswell, and P. Scheinmann. 1996. Efficacy of nebulized budesonide 15. Bisgaard, H. 1993. Systemic activity from inhaled topical steroid in tod- in treatment of severe infantile asthma: a double-blind study. J. Al- dlers studied by knemometry. Acta Paed. Scand. 82:1066–1071.
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