asthma, immunotherapy, meta analysis, specific BHR, medication use

1. Immunotherapy for Asthma:
practical use based on updated meta analysis
Prof Ariyanto Harsono MD PhD SpA(K)

2. Background
Allergen specific immunotherapy has long been a
controversial treatment for asthma. Although
beneficial effects upon clinically relevant
outcomes have been demonstrated in
randomized controlled trials, there remains a risk
of severe and sometimes fatal anaphylaxis. The
recommendations of professional bodies have
ranged from cautious acceptance to outright
dismissal. With increasing interest in new allergen
preparations and new methods of delivery, it was
time to conduct another systematic review of
allergen specific immunotherapy for asthma.
2Prof Ariyanto Harsono MD PhD SpA(K)

3. The World Health Organization and various
allergy, asthma, and immunology societies
throughout the world met on January 27
through 29, 1997, in Geneva, Switzerland to
write guidelines for allergen immunotherapy.
Over the ensuing year, the editors and panel
members reached a consensus about the
information to include in the WHO position
paper “Allergen immunotherapy: Therapeutic
vaccines for allergic diseases.”
3Prof Ariyanto Harsono MD PhD SpA(K)

4. GINA Asthma guideline

5. Component 4: Asthma Management and Prevention Program
Allergen-specific Immunotherapy
 Greatest benefit of specific immunotherapy using
allergen extracts has been obtained in the
treatment of allergic rhinitis
 The role of specific immunotherapy in asthma is
limited
 Specific immunotherapy should be considered only
after strict environmental avoidance and
pharmacologic intervention, including inhaled
glucocorticosteroids, have failed to control asthma
 Perform only by trained physician
Prof Ariyanto Harsono MD PhD SpA(K)

6. Hierarchy of Evidence
Prof DR Dr Ariyanto Harsono SpA(K) 6
Meta Analysis of RCT
Large RCT
Small RCT
Non Randomized Trials
Observational Studies
Case series/reports
Anecdotes, experts, consensus
Weight of
Scientific
Scrutiny
Level 1
Level 2
Level 3
Level 4
Rec
A
B
C

7. Objectives
The objective of this review was to assess the
effects of allergen specific immunotherapy for
asthma.
7Prof Ariyanto Harsono MD PhD SpA(K)

8. Search strategy
Search the Cochrane
Airways Group trials register
up to
date, MEDLINE, Dissertation
Abstracts, Current Contents
and reference lists of
articles
Selection criteria
Randomized controlled trials
using various forms of
allergen specific
immunotherapy to treat
asthma and reporting at
least one clinical outcome.
8Prof Ariyanto Harsono MD PhD SpA(K)

9. Statistical Considerations
The planned comparisons were:
1. Allergen immunotherapy versus placebo
2. Allergen immunotherapy versus antigenically inactive
control
3. House dust versus placebo
4. Allergen immunotherapy versus untreated control
5. Allergen immunotherapy versus inhaled steroid
Performance of these comparisons separately for each outcome,
namely asthma symptoms, medication, lung function, non-specific
BHR and allergen specific BHR, whenever the results were
reported.
9Prof Ariyanto Harsono MD PhD SpA(K)

10. Results
Allergen immunotherapy significantly reduced
allergen specific BHR. Stratifying the meta-
analysis for the allergen administered and
expressing the results as Log PD20 achieved
homogeneity. It would be desirable for future
studies to use a standardized protocol for
bronchial allergen challenges and to report the
results in a more consistent fashion. Not
surprisingly it would appear that allergen
immunotherapy has a greater effect upon
allergen specific BHR than upon nonspecific BHR.
10Prof Ariyanto Harsono MD PhD SpA(K)

11. Bronchial hyper reactivity (BHR)
Indices of nonspecific BHR were reported by 12 studies. There
were significant improvements in PD20 FEV1 to
methacholine challenge (SMD ±0.30, 95% CI ±0.54 to 0.05)
and in PC35 s Gaw to acetylcholine after immunotherapy
with allergen ± antibody complexes. The improvement in
PC20 FEV1 to histamine challenge failed to achieve
statistical significance in a random effects model. Although
there was significant heterogeneity between the results of
these studies (x2=22.7, P,0.025), there was an overall
reduction in nonspecific BHR after immunotherapy (SMD
±0.48, 95% CI ±0.81 to ±0.14) (Fig. 7). Nonspecific BHR was
simply reported as increased, unchanged, or reduced in five
small studies.
11Prof Ariyanto Harsono MD PhD SpA(K)

12. There was homogeneity between these
studies, and the combined OR of 0.22 (95% CI
0.10±0.48) indicated that patients randomized
to immunotherapy were significantly less
likely to develop increased nonspecific BHR
than those randomized to placebo (Fig. 8).
12Prof Ariyanto Harsono MD PhD SpA(K)

13. 13

14. Indices of allergen-specific BHR (such as PD20 FEV1 to
allergen challenge) were reported by 14 studies.
There was homogeneity between these studies with
an overall SMD of ±0.70 (95% CI ±0.91 to
±0.48), indicating a significant reduction in allergen-
specific BHR after immunotherapy (Fig. 9).The effect
was most marked for mite immunotherapy (SMD
±1.14, 95% CI ±1.62 to ±0.65), and similar for pollen
(SMD±0.69,95%CI ±1.09 to ±0.30) and animal
dander(SMD±0.71, 95% CI ±1.08 to ±0.34), but not
significant for other allergens.
14Prof Ariyanto Harsono MD PhD SpA(K)

15. Allergen-specific BHR was simply reported as
increased, unchanged, or reduced by 16
studies. There was homogeneity between
studies, and the combined OR of 0.28 (95% CI
0.19±0.41) indicated that patients randomized
to immunotherapy were significantly less
likely to develop increased allergen-specific
BHR (Fig. 10).
15Prof Ariyanto Harsono MD PhD SpA(K)

16. 16

17. Asthma symptoms
The results of the individual placebo-controlled trials and combined
effects for each outcome are presented in Figs. 1±10. Symptom
scores were reported by 22 studies, although neither Dreborg et
al. nor Olsen et al. published the standard deviations (SDs), thus
preventing the calculation of the standardized ean difference
(SMD) for these studies. The combined SMD for symptom scores
after mite immunotherapy was ±0.71 with a 95% confidence
interval of ±1.37 to ±0.05, which excluded 0, thus indicating a
significant reduction in asthma symptoms (Fig. 1). The combined
SMD after pollen immunotherapy was ±0.72 (95% CI ±1.14 to
±0.31) also indicating significant symptomatic provement.
However, there was no significant improvement after
immunotherapy with cat, dog, or multiple allergen extracts. For all
allergens combined, the SMD was ±0.73 (95% CI ±1.07 to
±0.39), but there was significant heterogeneity between studies
(x2=86.2,
17Prof Ariyanto Harsono MD PhD SpA(K)

18. P,0.0005), with three studies not finding any reduction in
symptoms. Symptoms were simply reported as worse, the
same, or improved in another 22 studies. The combined
odds ratio (OR) was 0.26, with a 95% CI from 0.17 to
0.41, which excluded 1, again indicating that patients
randomized to immunotherapy were significantly less likely
to report a deterioration in asthma symptoms than those
randomized to placebo. There were significant
homogeneous improvements after immunotherapy with
extracts of pollen (OR 0.13, 95% CI 0.04±0.42), animal
dander (OR 0.20, 95% CI 0.05±0.87), and other allergens
(OR 0.17, 95% CI 0.09± 0.32).
18Prof Ariyanto Harsono MD PhD SpA(K)

19. 19

20. Less improvement was seen after mite
immunotherapy (OR 0.39, 95% CI 0.21±0.75), and
there was significant heterogeneity between these
studies (x2=21.3, P,0.05). Although the results of
studies of children were relatively homogeneous
(data not shown), there was significant
heterogeneity between the results of adult studies
(x2=40, P,0.001), two studies actually finding
symptoms to be more likely in treated patients
20Prof Ariyanto Harsono MD PhD SpA(K)

21. Symptoms were simply reported as worse, the same, or
improved in another 22 studies. The combined odds ratio
(OR) was 0.26, with a 95% CI from 0.17 to 0.41, which
excluded 1, again indicating that patients randomized to
immunotherapy were significantly less likely to report a
deterioration in asthma symptoms than those randomized to
placebo (Fig. 2). There were significant homogeneous
improvements after immunotherapy with extracts of pollen
(OR 0.13, 95% CI 0.04±0.42), animal dander (OR 0.20, 95% I
0.05±0.87), and other allergens (OR 0.17, 95% CI 0.09±0.32).
Less improvement was seen after mite immunotherapy (OR
0.39, 95% CI 0.21±0.75), and there was significant
heterogeneity between these studies (x2=21.3, P,0.05).
21Prof Ariyanto Harsono MD PhD SpA(K)

22. 22

23. Although the results of studies of children were relatively
homogeneous (data not shown), there was significant
heterogeneity between the results of adult studies
(x2=40,P,0.001), two studies actually finding symptoms to be
more likely in treated patients.
23Prof Ariyanto Harsono MD PhD SpA(K)

24. 24Prof Ariyanto Harsono MD PhD SpA(K)

25. Lung Function Test
Lung-function results were reported by 14 studies, with
several studies failing to provide SDs for peak
expiratory flow, FEV1, or thoracic gas volume. There
was no overall improvement in lung-function
parameters after immunotherapy (Fig. 5), and there
was marked heterogeneity in peak expiratory flow
between studies (x2=27.6, P,0.0005). Indeed, there was
even a suggestion that FEV1 deteriorated after
immunotherapy in a small study by Paranos &
Petrovic, in which the baseline lung unction of patients
randomized to mite immunotherapy and placebo was
poorly matched. Lung function was simply reported as
worse, the same, or improved in seven studies. 25Prof Ariyanto Harsono MD PhD SpA(K)

26. 26

27. Typical Spirometric (FEV1) Tracings
1
Time (sec)
2 3 4 5
FEV1
Volume
Normal Subject
Asthmatic (After Bronchodilator)
Asthmatic (Before Bronchodilator)
Note: Each FEV1 curve represents the highest of three repeat measurements

28. Asthma Medication
Asthma medication scores were reported by 13 studies, with
Cantani et al. (27), Dreborg et al. (32), and Olsen et al.
failing to publish the SDs. The combined SMD was ±0.71
(95% CI ±1.09 to ±0.32), indicating a significant reduction in
medication after immunotherapy (Fig. 3). There was a large
reduction after mite immunotherapy, although this was
accompanied by significant heterogeneity
(x2=16.1,P,0.005). The reduction after pollen
immunotherapy achieved statistical significance in a fixed
effects model (SMD=±0.54,95%CI ±0.85 to ±0.23).
28Prof Ariyanto Harsono MD PhD SpA(K)

29. Medication requirements were simply reported as
increased, unchanged, or decreased in 16 studies.
The combined OR was 0.32 (95% CI
0.22±0.46), indicating that patients randomized
to immunotherapy were significantly less likely to
require increased medication than those
randomized to placebo (Fig. 4). Although there
was significant heterogeneity between the
studies reporting medication scores
(x2=28.7,P,0.001), there was substantial
homogeneity between the latter 15 studies.
29Prof Ariyanto Harsono MD PhD SpA(K)

30. 30

31. 31Prof DR Dr Ariyanto Harsono SpA(K)

32.  Retrieval of 1111 publications of which 51 satisfied our inclusion
criteria. In total there were 2871 participants (1645 active, 1226
placebo), each receiving on average 18 injections. Duration
of immunotherapy varied from three days to three years. Symptom
score data from 15 trials were suitable for meta-analysis and showed
an overall reduction in the immunotherapy group (SMD -0.73 (95%
CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials
showed an overall reduction in the immunotherapy group (SMD of -
0.57 (95% CI -0.82 to -0.33, p<0.00001)). Clinical interpretation of
the effect size is difficult. Adrenaline was given in 0.13% (19 of
14085 injections) of those on active treatment and in 0.01% (1 of
8278 injections) of the placebo group for treatment of adverse
events. There were no fatalities.
 Injection immunotherapy has a known and relatively low risk of
severe adverse events. We found no long-term consequences from
adverse events. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001936
32Prof DR Dr Ariyanto Harsono SpA(K)

33. Conclusion
This report confirms the efficacy of immunotherapy; in
particular, we emphasize the clinically useful outcomes
of decreased medication requirements and improved
allergen specific BHR. Not only did these two outcomes
show statistically significant improvement, but also the
results were homogeneous. We believe that a
reduction in medication and decreased allergen-
specific BHR are clinically important findings and can
lead to improved asthma control. These results give no
direct guidance concerning the clinical application of
allergen immunotherapy. We have previously stated
the well-accepted principles that we follow in using
immunotherapy in asthma.
33Prof Ariyanto Harsono MD PhD SpA(K)

34. These issues are discussed more fully in a joint
position statement of the Thoracic Society of
Australia and New Zealand and the
Australasian Society of Clinical Immunology
and Allergy and the WHO position paper.
These results would fully endorse these
position papers and recommend that
interested readers refer to them.
34Prof Ariyanto Harsono MD PhD SpA(K)

35. Thank you
Prof Ariyanto Harsono MD PhD SpA(K) 35