Efficacy of Inhaled Budesonide in the Treatment of Childhood Asthma
Ariyanto Harsono, Mario B Nara, Anang Endaryanto
Division of Allergy-Immunology of Child Health Dr. Soetomo Hospital/
Airlangga University Surabaya
Abstrak
Latar belakang: Budesonid hirupan merupakan glukokortikoid dengan rasio efek topical yang lebih baik
dari efek sistemik. Perbaikan klinis pada penggunaan budesonide untuk asma ringan telah banyak
dilaporkan, tetapi perbaikan fungsi paru masih banyak perselisihan. Penelitian ini mempelajari
penggunaan budesonid hirupan pada pengobatan asma anak dengan menggunakan parameter uji fungsi
paru.
Tujuan: Untuk mengevaluasi efektifitas budesonid hirupan pada asma anak dengan menggunakan
parameter uji fungsi paru.
Metode: Penelitian Prospektif, longitudinal, buta ganda tersamar membandingkan budesonid hirupani
dengan plasebo pada anak dengan asma sedang. Randomisasi dilakukan dengan cara “Systematic random
sampling”. Besar sampel ditentukan 30 pasien tiap grup untuk memenuhi distribusi normal. FEV-1 dan
FVC diukur mengambil 3 terbaik sebelum dan sesudah hirupan terbutalin pada waktu pemeriksaan awal
dan sesudah 2 tahun perlakuan. Nilai % prediksi FEV-1 dan FVC didapatkan dari nilai yang didapat
dibandingkan dengan harga normal menurut ras, umur, jenis kelamin dan tinggi badan. Perubahan FEV-1,
FVC, % prediksi FEV-1, % prediksi FVC pada kedua grup pada pemeriksaan awal dan akhir dianalisa
menggunakan “paired t-test”. Mann Whitney U test dipakai untuk membandingkan karakteristik grup
budesonid dan plaasebo.
Hasil: Tidak ada perbedaan pada nilai FEV-1 (mean 1.68+0.35: 1.65+0.48), FVC (mean 1.86+0.39:
1.92+0.57) and FEV-1 Reversibility (mean 7.42%+5.86%: 11.08+9.20) antara grup budesonide
dan placebo setelah pengamatan 2 tahun, tetapi ada perbedaan bermakna pada % prediksi FEV-1
antara kedua grup (mean: 94%+9.62%) pada grup budesonid dengan p=0.004.
Kesimpulan: terjadi perbaikan uji fungsi paru yang ditunjukkan dengan perbaikan % prediksi
FEV-1 pada pemakaian budesonid hirupan selama 2 tahun pada penderita asma anak
ABSTRACT
BACKGROUND: Budesonide is an inhaled glucocorticosteroid with a favorable ratio between
topical anti-inflammatory activity and systemic activity. The improvement of clinical indices is
well establish in the use of budesonide in mild asthma, but the beneficial effect of this drug
indicated by lung function test is inconsistent. We prospectively investigated the use of inhaled
budesonide in controlling asthma in children by lung function tests evaluation.
OBJECTIVE: To evaluate the efficacy of budesonide inhaler in children with asthma using Lung
Function Tests.
METHODs: This was a 2 years prospective longitudinal study, double blind, randomized, controlplacebo study comparing budesonide inhalation or placebo in 51 children ages 6 to 12 years old,
with mild asthma. The best of three FEV-1 and FVC value were measure before and after
terbutalin inhaler in baseline and after 2 years observations. The value of % predicted FEV-1 and
FVC were measure by compare the FEV-1 measurement with normal value for race, age, sex and
2
height. The
change of FEV-1, FVC, % predicted FEV-1, % predicted FVC from budesonide
and placebo groups at baseline and after 2 years were analyzed by use paired t- test statistical
test. Mann-Whitney test was used to compair between budesonide and placebo groups
characteristics.
RESULTS: There were no different in the value of FEV-1 (mean 1.68+0.35: 1.65+0.48), FVC
(mean 1.86+0.39: 1.92+0.57) and FEV-1 Reversibility (mean 7.42%+5.86%: 11.08+9.20) between
budesonide and placebo group after 2 years observation, but there was significant different in the
value of %predicted FEV-1 (94%+9.62%) in favour of Budesonide group in the end of
investigation (p.0.004)
CONCLUSION: There is significant improvement of the Lung Function Test (% predicted FEV-1)
after the use of budesonide in the treatment of asthma in children.
Key words: Asthma, budesonide, lung function tests
Abreviation used:
FEV-1: Forced Expiratory volume in 1 second
FVC: Forced volume Capacity.
LFT: Lung Function Test.
INTRODUCTION
Asthma is chronic inflammatory disease with clinical manifestation that result from variable airflow
obstruction. The incidence and prevalence of asthma in children in the world were variable
between 0.06% until 11.4%. National statistics in USA show that asthma prevalence, morbidity,
and deaths are increasing, and children appear to be at highest risk. Hospitalization rates for
asthma from 1980 to 1993 were highest among persons 4 years of age and younger, and asthma
accounts for one third of pediatric emergency department visits. (1,2,3)
Childhood asthma is one of the most common illnesses, good clinical skills are essential for
optimal treatment. Lung Function Test (LFTs) are an important part of good asthma management.
However, clinical impressions of the degree and severity of the disease may be unreliable unless
made in conjunction with results of LFTs. (4) While LFTs are not diagnostic of specific lung
diseases, they provide an objective assessment of airway function, airway narrowing and changes
in airway caliber. They offer a method to determine whether airway obstruction exists, its degree
and its response to triggers and treatment. One of the major planks of the Asthma Management
Plan is to assess severity accurately and this can only be done with LFTs. Because growth has a
major effect on lung function, spirometer values need to be interpreted with the aid of a table or
graph giving normal values for FEV-1, FVC in relation to the sex and height of the child. (5,6))
Spirometric measures, principally FEV-1, have long been used as marker of the degree of airway
obstruction. The National Asthma Education and Prevention Program as an important means for
grading quality of life endorse FEV-1. FEV-1 had been used widely in the world as an instrument
of evaluation of disease progressions. (1) The disadvantages of FEV-1 to test of the lung function
are FEV-1 use same categories in measured pediatric and adult population, whereas the growth
has a major effect on lung function. (7)
In children, pyrometer is an indispensable tool for assessing the degree of inflammatory airway
obstruction and providing accurate information for medication adjustment. Pyrometer is the most
reliable tool to make an accurate assessment of lung function. The problem of using FEV-1 in a
test of lung function in children is the inconsistent result between clinical and functional
3
improvement. In long-term follow-up study before reported that the improvement of clinical indices
is well establish in the use of budesonide in mild asthma, but the beneficial effect of this drug
indicated by LFTs is in consisted. While FEV-1 and other parameter of LFTs are inconsistent
between the result and the clinical impressions of the degree and severity of the disease, they
provide an objective assessment of airway function, airway narrowing and changes in airway
caliber. (5,6,7)
Managing asthma, assessing the degree of inflammatory airway obstruction and providing
accurate information for medication adjustment without measuring spirometry is impossible.
Therefore, an exertion to find the precise parameter of LFTs to asses the improvement of lung
function as well as the clinical indices must to be done. The long-term follow-up study needed to
found it. The purpose of this study was to evaluate the LFTs, such as FEV-1, FEV-1 Reversibility,
FVC and % predicted FEV-1 (a predicted normal range, based on age, sex, height and race) in
the use of Budesonide inhaler in children with asthma.
METHODS
Patients with asthma aged between 6-14 years with onset of disease of less than 2 years were
selected to take part in this study. Thorax photo, Mantoux test, peripheral blood, urine and feces
examination was done before the visit to exclude the possibility of other diseases causing chronic
cough. Patients should not take antihistamines, corticosteroids, symphatomimetics and xanthenes
48 hours prior to allergy testing. Patients who fulfill all of the inclusion criteria and none of the
exclusion criteria were recruited in this study.
Inclusion criteria:
1. Prior to conducting any study related procedures, signed informed consent from Patient or
parent or legal guardian must be obtained. The investigator inform obviously about
the
purposes and procedures of the study.
2. Outpatients of either sex, aged between 6-14 years.
3. Ability to use Turbuhaler correctly confirmed with a Turbuhaler Usage Trainer (TUT). The
patient should be able to light at least two of three indicator lamps on the TUT display.
4. Asthma diagnosis made preferably within I year but not more than 2 years prior to the visit.
The diagnosis should be verified by both of the following: Symptom at least once a week, but
not as often as everyday during 3 month. Preceding the visit patient must have experienced
one of the following: Wheeze, cough, dyspnea, chest tightness or night wakening due to any
of these symptoms. Cough, as an isolated symptom may be present everyday.
Reversible airway obstruction, demonstrated as historical data or assessed at the visit as one of
the following:
A. Increase of FEV-1 of more than 12% compared with baseline after inhalation of a short acting
bronchodilator, in this study is 0,5mg Terbutalin Turbuhaler. Reversibility in FEV-1 relative to
predicted normal is formulated as:
FEV-1 after bronchodilator-FEV-1 before bronchodilator
----------------------------------------------------------------------- X 100%
FEV-1 Predicted normal
4
B. PEF variation of more than 15% without bronchodilator, calculated out of 14 days period after
discarding the first 3 days, is formulated as:
(A1+A2)-(B1+B2)
----------------------- X 100%
(A1+A2)
A1=highest PEF A2=second highest PEF B1=lowest PEF
B2=second lowest PEF
Exclusion criteria:
1. Symptom compatible with diagnosis of asthma for more than 2 years prior to the visit.
2. Patient for whom it would be inappropriate to delay chronic treatment with Glucocorticoids as
judged by physician at the visit.
3. Patient with a history of more than 30 days per year of oral or inhaled Glucocorticoids, or one
depot injection per year of glucocorticoid irrespective of reason within 2 years prior to the
visit.
4. Regular, at least once daily antiasthma treatment for more than two years prior to the visit.
5. Pre bronchodilator FEV-1 less than 60% predicted normal value at the visit.
6. Post bronchodilator FEV-1 less than 80% of predicted normal value at the time of visit.
7. Other concomitant cardiopulmonary diseases such as Cystic Fibrosis, active untreated
tuberculosis, bronchopulmonary displasia, and severe congenital heart disease.
8. Immunosuppressive therapy.
9. Cancer as past and present diagnosis.
10. Patients with known or suspected difficulty in complying with the study protocol as judged by
investigator.
Data collection:
Demographic data consisted of age, sex are recorded along with weight and height. The medical
record of each patient is reviewed to confirm the diagnosis of asthma including BCG scar,
Mantoux test, thorax photo, atopy status, history of other atopic disease, history of atopic disease
in the family, onset of asthma, frequency of attack, total days of each asthmatic attack, intensity of
asthmatic attack, frequency of nocturnal asthma total days of nocturnal asthma, addition of drugs,
total loss of school day between two visit, total loss of daily activity between two visit, adverse
reaction related to Tilade,adverse event unrelated to Tilade and symptoms at the time of visit.
Study design:
The study is an open comparative study comprising of two groups: Group A (with Budesonide
inhaler treatment) and group B (control). Variable that will be compared between these two group
are: FEV-1 pre and post Brochodilator, FVC pre and post bronchodilator, % predicted FEV-1 pre
and post Bronchodilator, FEV-1 reversibility pre and post Bronchodilator.
The dose of Budesonide is estimated 200 mcg daily for children age 6-11 years, and 400 mcg for
children age more than 11 years . Assessment of lung functions at the visit 1 and at the end of
study.
Assessment of the lung functions:
During the LFTs, the patient sits and may use nose clip. The patient must not have inhaled short
acting or long acting bronchodilator 6 hours and 24 hours respectively prior to the procedures.
The largest FEV-1 value and the largest FVC are recorded out of three technically satisfactory
expiration even if two values do not come from the same curve. The largest FEV-1 and FVC, and
the second largest FEV-1 and FVC from acceptable curves should preferably not vary more than
5
5%. If they differ by more, further measurement should be performed until this condition is met.
Pre bronchodilator FEV-1 should be compared predicted normal value. This should be not below
60% of predicted normal value at visit 1. Inhalation of terbutalin 0.5 mg turbuhaler than to be
initiated. Fifteen minutes then the procedure to be repeated. The post bronchodilator FEV-1 value
should not be below 80% of predicted normal value at visit 1. Reversibility in FEV-1 relative to
predicted normal value should not be less than 13% at visit 1.If it is less than 13%, PEF variability
examination should be performed. The result of PEF variation should not be less than 15%.
Analysis of result:
All of data were computerized as database. Paired samples t-test was used to compare variables
of the two groups. Mann Whitney U test was used to compare the characteristics of Budesonide
and Placebo group.
RESULT
A total of 63 subjects was randomized to study treatment: 25 to the placebo group and 26 to the
budesonide inhaler groups, respectively. LFTs and demographic characteristics at enrollment are
shown in Table I .
Table 1. Patients Characteristic
Budesonide (n=26)
Placebo (n=25)
16(61.5%)
15(57.7%)
10(38.5%)
10(38.5%)
Age (y)
8.4+1.7
9.0+1.3
Weight (kg)
26.4+7.1
24.7+6.9
Height (cm)
126.3+11.2
127.1+9.1
FEV-1
1.08+0.2
1.15+0.3
% Predicted FEV-1
75.1+10.1
76.2+9.5
Reversibility (%)
21.1+8.4
19.0+10.0
FVC
1.25+0.2
1.32+0.3
%Predicted FVC
76.0+10.5
75.8+10.7
Sex: Male
Female
Two subject (1 in each of the budesonide and placebo groups) were excluded in this study
because they were not control routinely. . There were no significant differences among the groups
in sex, age, height, weight and pulmonary function (FEV-1, % predicted FEV-1, FEV-1
Reversibility, FVC and % predicted FVC) at baseline of the study. The mean of % predicted FEV1 in each groups are 75.1+10.1 and 76.2+ 9.5, so the patients include to mild-moderate asthma
Table 2. Lung function test in Budesonide group
Baseline
After 2 years
Means
change
P
6
FEV-1 before bronchodilator
1.08+0.20
1.56+0.35
-0.49
0.00
FEV-1 after bronchodilator
1.31+0.22
1.67+0.35
-0.36
0.00
% Predicted FEV-1 before
bronchodilator
75.11+10.95
88.15+11.46
-13.03
0.00
% Predicted FEV-1 after
bronchodilator
90.12+9.18
94.19+9.62
-4.07
0.04
Reversibility (%)
21.11+8.4
7.42+5.85
13.69
0.00
FVC before bronchodilator
1.25+0.23
1.84+0.37
-0.59
0.00
FVC after bronchodilator
1.45+0.25
1.86+0.38
-0.40
0.00
% Predicted FVC before
bronchodilator
76.03+10.54
90.42+10.80
-14.38
0.00
% Predicted FVC after
bronchodilator
87.38+9.76
92.84+10.19
-5.46
0.01
There are significant improvement (p<. 05) in The value of FEV-1, % predicted FEV-1, FEV-1
reversibility, FVC and % predicted FVC in Budesonide group after 2 years observation (Table 2).
But in placebo group, there is no significant improvement in %predicted FEV-1 value after 2 years
observation (means before inhalation 76.16 + 9.49:: 80.2 +9.69,p=0.07, after inhalation
90.36+8.73: 84.72+18.11, p=0.13) (Table 3)
Table 3. Lung Function Test in Placebo group
Baseline
After 2
years
Means
change
P
FEV-1 before bronchodilator
1.15+0.28
1.42+0.42
-0.33
0.00
FEV-1 after bronchodilator
1.36+0.28
1.65+0.48
-0.29
0.00
7
% Predicted FEV-1 before
bronchodilator
76.16+9.49
80.20+9.69
-4.04
0.074
% Predicted FEV-1 after
bronchodilator
90.36+8.73 84.72+18.11
5.64
0.132
Reversibility (%)
19.00+10.01 11.08+9.20
7.92
0.009
FVC before bronchodilator
1.32+0.35
1.81+0.52
-0.49
0.00
FVC after bronchodilator
1.49+0.34
1.92+0.56
-0.42
0.00
75.80+10.77 85.32+10.95
-9.52
0.001
86.12+9.04 90.16+11.27
-4.04
0.018
%
Predicted
bronchodilator
%
Predicted
bronchodilator
FVC
FVC
before
after
Next, after compare the result of pulmonary function test in budesonide and Placebo groups used
Mann-Withney statistic test, we found there are significant different in the value of % predicted
FEV-1 before inhalation (88.15+ 11.46:80.20+9.69, p 0.01) and after inhalation (94.19+9.62: 84.72
+18.11,p 0.01). (Table 4)
Table 4. Comparison between Budesonide and placebo group after 2 years observation
Budesonide
Placebo
P
Mean
rank
Sum of
rank Mean rank
Sum of
rank
FEV-1 before bronchodilator
29.25
760.50
22.62
565.50
0.11
FEV-1 after bronchodilator
27.33
710.50
24.62
615.50
0.52
% PredictedFEV-1 before
bronchodilator
31.29
813.50
20.50
512.50
0.01
bronchodilator
31.00
8.06
20.80
520.00
0.01
Reversibility (%)
22.46
584.00
29.68
742.00
0.08
FVC before bronchodilator
27.29
709.50
24.66
616.50
0.53
FVC after bronchodilator
26.08
678.00
25.92
648.00
0.97
bronchodilator
29.25
760.50
22.62
565.00
0.11
% Predicted FVC after bronchodilator
28.10
730.50
23.82
595.50
0.30
% Predicted FEV-1 after
% Predicted FVC before
Fig.1. The graph of FEV-1 (pre and post bronchodilator) comparison between budesonide and
placebo groups at the end of the study
8
4.0
3.5
49
49
3.5
3.0
3.0
2.5
2.5
2.0
2.0
1.5
FEVPOS
FEVPRE
1.5
1.0
.5
N=
26
25
budesonide
kontr ol
1.0
.5
N=
26
25
budesonide
kontr ol
KELOMPOK
KELOMPOK
(FEV-1 pre bronchodilator)
(FEV-1 post bronchodilator)
120
140
110
120
100
100
90
80
80
60
70
40
PRDFEVPS
PRDFEVPR
Fig.2. The graph of % Pred.FEV-1(pre and post bronchodilator) comparison between budesonide
and placebo groups at the end of the study
23
60
50
N=
26
25
budesonide
kontr ol
KELOMPOK
20
50
0
N=
26
25
budesonide
kontr ol
KELOMPOK
(% predicted FEV-1 pre bronchodilator)
bronchodilator)
(% predicted FEV-1 post
DISCUSSION
Objective assessments of pulmonary function are necessary for the diagnosis of asthma because
medical history and physical examination are not reliable means of excluding other diagnoses or
of characterizing the status of lung impairment. Although physicians generally seem able to
identify a lung abnormality as obstructive they have a poor ability to assess the degree of airflow
obstruction or to predict whether the obstruction is reversible [6,7,8,9].
This study was undertaken to evaluate whether the Lung Function Tests(LFTs), such as FEV-1,
FEV-1 Reversibility, FVC,% predicted FEV-1 and % predicted FVC (a predicted normal range,
based on age, sex, height and race) in the use of Budesonide inhaled in children with asthma are
different with placebo.
Jonasson et al, 1998 in a long-term follow up mild-asthma study for 2 year, found that budesonide
treatment produced dose-related improvement of FEV-1 and the exercise-induced fall in FEV-1.
9
(10)
Shapiro et al in 2001 reported that once daily budesonide inhalation powder maintains
pulmonary function in symptoms of asthmatic children previously receiving inhaled corticosteroid.
(11)
Vervloet et al(2001) in a long-term follow-up moderate-asthma study for 2 year, reported
budesonide treatment produced dose-related improvement of FEV-1, morning PEF, and rescue
bronchodilator use and proportion night without asthma. (12) In the literature the studies about
LFTs, such as FEV-1, FEV-1 Reversibility, FVC and % predicted FEV-1 (in the use of Budesonide
inhaled especially compared with placebo was difficult to found. Even, many studies about
budesonide only evaluated the absolute value of LFTs without compared with placebo.
In this study, absolutely (without compared with placebo) all parameters of LFTs in Budesonide
group were improve. The result of this study demonstrate that the administration of Budesonide
inhaled resulted in significant improvement after 2 years of LFTs such as FEV-1, %predicted FEV1, Reversibility, FVC, and % predictive value of FVC compared with baseline. This is consistent
with the finding of several studies about the efficacy of Budesonide inhaled in infant and young
children with asthma before. (10) Selroos O et al, 1995 in their study of inhaled budesonide in 105
mild-moderate asthmatic children describe that improvement of FEV-1 was influenced by duration
of asthma symptom, if the patient have duration of symptom more than 1 year; there is no
improvement of FEV-1. But like as this study, they also report that in the whole patient population,
there was significant improvement of FEV-1 compared with baseline after 2 years study. (11) All
parameters of LFTs in Placebo group improve, except % PREDICTIVE FEV-1. The administration
of Placebo inhaled resulted in significant improvement after 2 years in FEV-1, Reversibility, FVC,
and % predictive value of FVC compared with baseline. Only % predictive FEV-1 was not
different. Nevertheless, % predictive value of FEV-1 was precisely different between Budesonide
and Placebo group. Consistent with it, Table 4 shows significant different between Budesonide
and placebo group in % predictive FEV-1. In asthma control, patient cannot be achieved inhaled
steroid only, and they need combination with the symptomatic therapy, elimination diet or
immunotherapy. Therefore, the results of absolute of LFTs were increase significantly compared
with baseline although only given placebo.
All parameters of LFTs in Budesonide group in this study did not significant different compared
with Placebo group, except % Predictive FEV-1 This study found that there were no different in
the value of FEV-1, FVC, and FEV-1 reversibility between Budesonide and placebo group after 2
years observation, but there was significant different in the value of % predicted FEV-1 in favor of
Budesonide group in the end of investigation.
Theoretically, the disadvantages of FEV-1 if used for measure Lung function are (1) does not
reflect disease progression well. (2) Results can be highly variable. (3) does not add any useful
information on a longitudinal basis (4) as an absolute value, the result of FEV-1 assessment must
be controlled with the variable of age, sex, and height. These explanation clarify that FEV-1
cannot be used precisely to assess the degree of inflammatory airway obstruction and providing
accurate information for budesonide medication adjustment, cause of some disadvantages of
FEV-1 above and influence of the children growth factor on lung function. (6,7,8,9)
FVC in this case clarify likewise. The disadvantages of FVC are (1) may not be a sensitive early
indicator; may have a 1 to 3 year lag compared with maximal expiratory pressure (MEP). (2)
patients with airway obstruction may produce low and variable reading. Asthmatics can have FVC
greater than normal, normal, or less than normal in attack condition. Because of that, neither FVC
nor % predictive value of FVC cannot be used in assessing he degree of inflammatory airway
obstruction in children. (6,7,8,9)
10
In this study, % Predictive FEV-1 in placebo group did not improve in 2 years, in budesonide
group compared with placebo group improved. Maybe % Predictive FEV-1 is the most
representative value to measure improvement of lung function, because FEV-1 evaluated by
comparison of the patient's results with reference values based on age, height, sex, and race.
(6,7,8,9)
The used% Predictive FEV-1 in this study based on published equations, after matched with age,
height, sex and race.(9). An advantage of % Predictive FEV-1 as marker of asthma severity is it
objectivity and reproducibility.(7,8) It is frequently acquired in clinical trials, and the efficacy of new
therapies is often expressed in term of impact on FEV-1.
National Asthma Education and Prevention Program (NAEPP) endorsed FEV-1 as an important
means for grading asthma severity,(2) However, this statement still need to evaluation especially in
children, because this study confirmed that the most precise of LFTs to evaluate asthma outcome
is % predictive FEV-1 and other study of risk asthma attack by Fuhlbrigge et al, 2001 in
retrospective cohort of 13,832 children also found the strong association between % predictive
FEV-1 and risk of asthma attack during the subsequent year. (14)
Although asthma is typically associated with an obstructive impairment that is reversible, neither
absolute of FEV-1 nor any other absolute parameter measure is adequate to diagnose asthma.
Many factors of the children growth are associated with the LFTs. Many previous studies usually
stressed to compare absolute value of two different time of observation or LFTs associate dose of
drug without compare it with placebo group. The most common parameter of LFTs used
previously is FEV-1.
CONCLUSION
Significant improvement of the LFTs (% predictive FEV-1) was seen after the use of Budesonide
inhaler in asthmatic children.
REFFERENCE
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9. Wang X, Dockery D, Wypij D, Fay M, Ferris B. Pulmonary function between 6 an 18 years of
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