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Pediatr Neonatol 2010;51(1):14−18
O R IGINAL ART ICL E
Clinical Efficacy of House Dust Mite-specific
Immunotherapy in Asthmatic Children
Tzu-Chun Tsai, Jen-Her Lu, Shu-Jen Chen, Ren-Bin Tang*
Department of Pediatrics, Taipei Veterans General Hospital and School of Medicine,
National Yang-Ming University, Taipei, Taiwan
Received: Mar 3, 2009
Revised: Apr 23, 2009
Accepted: May 22, 2009
KEY WORDS:
asthma;
children;
house dust mite;
immunotherapy
Background: Immunotherapy has been widely used in the treatment of allergic
diseases. We evaluated the clinical efficacy of specific immunotherapy with extracts
of Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) in children with asthma.
Methods: All 40 children had moderate-to-severe asthma and positive allergen
tests for Dp and Df. All required daily medication. They were randomly assigned to
two groups: Half of them received immunotherapy with subcutaneous injections of
Dp and Df extracts, while the other half were not given immunotherapy. Participants
were followed up for more than 6 months.
Results: Children in both groups had apparent improvements in medication use and
symptoms after 6 months. The mean medication scores declined from 3.6 ± 1.14 to
1.7 ± 0.66 in the immunotherapy group (p < 0.01) and from 3.35 ± 0.87 to 2.4 ± 1.09
in the control group (p < 0.01). There was a significant difference between the two
groups (mean difference 0.95; p < 0.01). The symptom score improved in the immunotherapy group from 2.65 ± 0.98 to 1.20 ± 1.00 (p < 0.01) and in the control group
from 2.55 ± 0.99 to 1.40 ± 0.88 (p < 0.01), with a significant difference between the
two groups (mean difference 0.3; p < 0.01). The number of office visits in the immunotherapy group was greater than that of the controls, but the frequencies of
emergency room visits and hospitalization decreased.
Conclusion: Our study showed that specific immunotherapy with Dp and Df was
beneficial for asthmatic children.
1. Introduction
Immunotherapy using injected aeroallergen extracts
was first evaluated for the treatment of seasonal
pollinosis in 19111 and has been widely used as a
treatment for respiratory allergies, especially allergic rhinitis and asthma.2 Controlled trials have
shown that immunotherapy, using high-quality extracts in sufficient doses, relieves the symptoms
of allergic rhinoconjunctivitis with minimal side
effects.3,4 Studies of immunotherapy for allergic
asthma have shown that single-allergen immunotherapy reduces airway sensitivity to allergens,
decreases symptoms and signs, and improves basal
pulmonary function in some cases.5,6
Immunotherapy with crude extract or partially
purified allergen has been used in adults with allergic
asthma,7−9 however, controlled clinical trials in children with allergic asthma have revealed no discernible benefits of multiple-antigen immunotherapy.10
*Corresponding author. Department of Pediatrics, Taipei Veterans General Hospital, 201 Shih-Pai Road, Section 2,
Taipei 11217, Taiwan.
E-mail: rbtang@vghtpe.gov.tw
©2010 Taiwan Pediatric Association
Immunotherapy in asthmatic children
Nevertheless, although specific immunotherapy (SIT)
is recommended for adults with asthma in the Global
Initiative for Asthma (GINA) guidelines, its therapeutic role in children with asthma is still uncertain.11
House dust mites, especially Dermatophagoides
pteronyssinus (Dp) and Dermatophagoides farinae
(Df), have been shown to comprise the most important allergens in airway hypersensitivity,12 and
are well known inhalant allergens responsible for
certain Immunoglobulin E(IgE)-mediated disorders,
such as allergic rhinitis and asthma.13 Available tests,
including the skin prick test and specific antibody
tests, can precisely detect reactions to Dp and Df in
allergic children.14
The current study aims to evaluate the additive
benefits of SIT using the specific injected allergens,
Dp and Df, in allergic children with asthma who
were receiving satisfactory medical care, including
asthma pharmacotherapy.
15
national health insurance and adjusted in a stepwise
fashion as follows: step 0, no need for medication;
step 1, use of rapid-acting inhaled β2 agonist as
needed; step 2, regular use of single medication such
as low-dose inhaled corticosteroids (ICS), sustainedrelease theophylline, or leukotriene modifier; step
3, regular combined use of two drugs, such as lowto-medium dose ICS plus long-acting β2 agonist, or
medium-dose ICS plus sustained release theophylline or leukotriene modifier; step 4, regular use of
high-dose ICS plus long-acting β2 agonist, and additional sustained release theophylline or leukotriene
modifier; step 5, the use of oral corticoste-roids
such as prednisolone. Acute exacerbations of
asthma were treated by prescriptions from the
children’s physicians. Emergency room care and
inpatient treatment were provided at the physicians’ discretion.
2.3. Specific immunotherapy (SIT)
2. Materials and Methods
2.1. Patients
We recruited 40 children (21 boys and 19 girls). All
eligible children underwent an initial period of observation and had medical records for more than 1
year with a diagnosis of moderate persistent to severe persistent asthma, according to the severity
classification of the GINA guidelines.11 During the
year of observation, the children had daytime or
nocturnal asthma symptoms and suffered from frequent exacerbations. They also used daily asthma
medications, including rapid-acting β2 agonists,
either for prophylaxis or rescue use. The children
and their parents were instructed on how to manage their asthma and were evaluated for medical
compliance. All enrolled children were monosensitized to house dust mites, as demonstrated by a skin
prick test or specific antibody test. Enrolled children and their parents were informed about the
details and risks of treatment, and guardians of all
the children provided signed informed consent.
Allergies to Dp and Df were confirmed by skin prick
or specific antibody tests prior to randomization.
Children were divided randomly into two groups:
an immunotherapy group and a control group.
Children in the immunotherapy group received
subcutaneous injections of extracts of Dp and Df
(10,000 AU/mL, Allermed Laboratories Inc., San
Diego, CA, USA), respectively, at an initial dose of
0.5 AU/mL once a week. The dosage was increased
weekly by 25−100% to reach an optimal maintenance
dose. A large local reaction has previously been
shown to predict a systemic reaction.15 If a dose
produced a systemic reaction, the next dose was
adjusted to 1/5 of the previous dose and was used as
the optimal maintenance dose. Maintenance therapy was given every 2 weeks for at least 3 months.
Dosage adjustments and safety procedures were
based on large local reactions or systemic reactions
combined with the authors’ long-term experience
and systematic attempts to rationalize the treatment by identifying risk factors and improving
safety, while balancing time consumption, patient
inconvenience, and the risk of inducing systemic
reactions.16
2.2. Management of asthma
2.4. Outcome variables
At each visit, a team of clinical pediatricians, who
were unaware of the treatment assignments, reviewed the patients’ daily diaries, including records
of symptom scores, diurnal peak-flow readings,
and medications. They administered the medical
treatment to the children according to their individual conditions of asthma control. The medication
was increased or reduced by stepping up or down
to gain control of clinical symptoms and/or lung
function. Asthma medications were provided by
The principal outcome measure was the amount of
medication required to control symptoms and maintain peak flows within acceptable limits. We used
a 5-point ordinal scale of daily medication usage
scores, modified according to the management of
the GINA guideline.11 Briefly, a score of 0 indicated
no medication; scores 1−4 reflected the respective
steps 1−4 of the medical algorithm; and score 5
reflected the use of systemic prednisolone.
16
T.C. Tsai et al
Secondary outcome measures included the daily
peak expiratory flow rate, asthma symptom score,17
and number of contacts with health care providers.
2.5. Statistical analysis
Nonparametric statistics were used to determine
p values for group comparisons of all outcome
measures. In the subgroup analysis of daily medication use, we used rank transformation and two-way
analysis of variance to determine if the effect of immunotherapy differed among subgroups of children.
All p values reported were two-sided and were calculated using SPSS version 14.0 (SPSS Inc., Chicago,
IL, USA) and Excel software for the signed-rank
test, rank-sum test, and analysis of variance.
visit) are listed in Table 2. The mean score declined
significantly from randomization to the last follow-up
visit in both groups (p < 0.01). However, there were
no significant between-group differences at baseline or at the last follow-up visit.
We compared the mean change in medication
scores between baseline and the last follow-up
visit to identify any treatment-related changes in
daily medication use. The magnitude of the changes
was significant in the two groups (mean difference
0.95, 95% CI −0.92 to −0.97; p < 0.01) (Table 2).
3.3. Other outcomes
Other clinical outcomes are shown in Table 2. Both
groups had significant reductions in symptom scores.
The changes in both groups were significantly different and were related to the different treatments
3. Results
Table 1
3.1. Patients
A total of 40 children (21 boys and 19 girls) were enrolled in the study. Their average age at randomization was 8.5 years, ranging from 5 to 14 years. The
baseline characteristics did not differ significantly
between the two treatment groups (Table 1).
3.2. Primary outcomes
The mean daily medication scores before randomization (baseline) and 6 months later (last follow-up
Table 2
Characteristics of 40 children with allergic
asthma randomly assigned to specific immunotherapy or control group
Characteristics
Mean age (yr)
Sex (M/F)
Symptom score
Medication score
Peak flow
(% of predicted value)
Immunotherapy
(n = 20)
Control
(n = 20)
8.6 ± 2.99
14/6
2.65 ± 0.98
3.60 ± 1.14
83.15 ± 7.49
8.35 ± 2.43
7/13
2.55 ± 0.99
3.35 ± 0.87
84.98 ± 5.50
Changes in outcome measures from baseline to the last follow-up visit
Measure
Immunotherapy (n = 20)
Control (n = 20)
Mean difference
p
Medication score
Baseline
Last follow-up
Change
p
3.6 ± 1.14
1.7 ± 0.66
−1.90
< 0.01
3.35 ± 0.87
2.4 ± 1.09
−0.95
< 0.01
0.25
−0.7
0.95
0.44
0.02
< 0.01
Symptom score
Baseline
Last follow-up
Change
p
2.65 ± 0.98
1.20 ± 1.00
−1.45
< 0.001
2.55 ± 0.99
1.40 ± 0.88
−1.15
< 0.01
0.1
−0.2
0.3
0.75
0.51
< 0.01
83.15 ± 7.49
84.3 ± 5.56
1.15
0.056
84.98 ± 5.50
84.12 ± 4.72
−0.86
0.099
−1.83
0.18
−2.01
0.39
0.92
−
17.25 ± 4.6
12.4 ± 5.87
4.8
0.006
0.95 ± 0.21
−0.19
0.267
PEFR (% of predicted value)
Baseline
Last follow-up
Change
p
Medical contact (no. in 6 mo)
Clinic visit
Emergency room or hospitalization
PEFR = peak expiratory flow rate.
0.76 ± 0.17
Immunotherapy in asthmatic children
(mean difference 0.3, 95% CI 10.29 to −0.31; p < 0.01).
The peak expiratory flow rate increased in the immunotherapy group but declined slightly in the
control group, though the difference was not significant. In summary, the immunotherapy group
had a significantly greater improvement in symptoms than the control group. The immunotherapy
group had a higher peak expiratory flow rate than
the control group after treatment, but neither the
differences before and after treatment, nor between groups were significant (Table 2).
3.4. Treatment-related adverse events
The most common adverse effect was local, reddish swelling at the injection site, which was experienced by eight children in the immunotherapy
group. There was no apparent systemic reaction to
the injections in our study.
4. Discussion
In this study, children with allergic asthma specific
to Dp and Df were treated according to a protocol
designed to approximate current standards for immunotherapy and pharmacotherapy. Immunotherapy
using injections of specific allergen or allergens
affected the course of asthma in children during
the 6-month follow-up period, by decreasing their
daily medication use and relieving symptoms.
These results are contrary to those of a previous study, where no discernible benefit of immunotherapy with injections of allergens in children
with asthma already receiving pharmacotherapy
was reported.7 Studies of subcutaneous SIT in children have not been as numerous as those in adults,
and their results have usually assigned this therapy
a controversial role in pediatric asthma treatment.
However, Adkinson et al7 used therapeutic extracts
containing mixtures of up to seven allergens, including pollen, molds, and dust mites. They presumed that dilution of multiple allergens may
result in suboptimal doses of individual allergens,
or mixtures with other allergens may reduce the
potency of individual allergens. As a result, they
suggested that the use of allergen mixtures be
avoided. The current study showed beneficial results by utilizing mite-specific immunotherapy, but
not allergen mixtures, indicating that SIT may be
more appropriate for treating asthma in children
than immunotherapy using mixtures of multiple
allergens. Thus, our conclusions are different from
those of the Adkinson et al study,7 but consistent
with those from other recent reports.18
Although SIT has been used in the treatment of
childhood asthma, the recommendations of this
17
therapy have varied from cautious acceptance to
outright dismissal. Both the European Academy of
Allergy and Clinical Immunology and the British
Society for Allergy and Clinical Immunology advised
against its use in patients under 5 years of age,
and raised doubts about its use for the treatment
of pediatric asthma.4,19 Moreover, the National Heart,
Lung, and Blood Institue Working Group and the
World Health Organization stressed that SIT should
be considered only in cases where exposure to allergens cannot be avoided, or when a suitable
pharmacological therapy has proved unable to
control the disease.20 Immunotherapy was omitted
from the recommended asthma treatment for children, although it remains a choice of standard asthma
treatment for adults.11 In our study, SIT had additive
benefits and produced no marked side effects in the
children, who were all above 5 years old and receiving suitable medical care. However, investigations
and observations in larger populations are needed to
further demonstrate the effectiveness of SIT.
In our study, SIT effectively reduced the medication requirements and symptoms in children with
allergic asthma. However, while a trend towards better performance was observed in the SIT group, the
improvement in peak flow rate failed to reach statistical significance. Some reports suggested that SIT
may improve bronchial reactivity,6 while others remained controversial. Immunotherapy provides the
potential to downregulate the inflammatory
cascade,21 reduce IgE antibody production,22,23 and
attenuate symptoms in patients with asthma.24 If
these patients are left untreated, they would undergo airway remodeling and eventually progress to
permanent abnormalities of the bronchial wall. Such
remodeling processes are likely to play a considerable role in lung function decline and bronchial
obstruction.25,26 Conceptually, early intervention in
allergic disease is the most promising strategy for arresting disease progression, altering its severity, and
preventing the development of the respiratory disease process.27−29 It could be reasonably supposed
that early management with SIT in children with
asthma may alleviate bronchial reactivity and even
reverse bronchial obstruction before the natural progression to airway remodeling. Recent studies of SIT
might support this possibility by demonstrating its
long-term efficacy30 and its preventive effect in reducing the onset of new sensitizations.31
A few children in our study experienced side effects of SIT with Dp and Df; eight children had
local reddish swelling in injection site. It cannot
be overemphasized that immunotherapy should be
performed carefully because of the risk of side effects, which include itching, flushing, erythema,
local swelling, urticaria, rhinitis, conjunctivitis,
bronchospasm, and anaphylactic shock.32
18
T.C. Tsai et al
In conclusion, our results further support the
idea that SIT using individual injections of extracts
of house dust mites is effective in children with allergic asthma, and can reduce medication use and
alleviate asthma symptoms.
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