Long-term preventive effects of allergen specific immunotherapy: a systematic review and meta-analysis

1
Long-term preventive effects of allergen specific
immunotherapy a systematic review and
meta-analysis
2
Azevedo L Cardoso P Coelho J Gonçalves A
Maranhas M Oliveira A Pereira E Pereira J
Silva V Teixeira C pedrojcardoso_at_gmail.com
Regente da disciplina Prof Dr. Altamiro da
Costa Orientador Dr. João Fonseca
3
SUMMARY

• Introduction
• Objectives
• Participants and methods
• gt Criteria Selection
• gt Search Strategy
• Results
• gt Identification and selection of the literature
• gt Description of the included articles
• gt Methodological quality assessment
• gt Data extraction and analysis
• Preliminary Discussion
• References

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INTRODUCTION

• Allergic diseases and asthma have increased
• dramatically during the past 2 decades2

• Today these diseases are very frequent 2.7
  million children in the United States suffer from
  asthma and over a hundred million people suffer
  from asthma, allergy and chronic obstructive
  pulmonary disease in Europe.3

1. TePas EC, Umetsu DT. Immunotherapy of asthma and
   allergic diseases. California (USA) Department
   of Pediatrics, Stanford University 2000 Dec
   12(6)574-8.
2. Chin ES. Pediatrics, Reactive Airway Disease.
   Slapper D, Windle ML, Young GM, Halamka J, Bachur
   RG, editors. EMedicine from WebMD. 2006 Nov.

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There is a chance that immunotherapy can prevent
the evolution from rhinitis to asthma and the
appearance of new sensitivities
HOWEVER

• There is no systematic review proving its
  long-term efficacy on the prevention of new
  sensitivities and the evolution from rhinitis to
  asthma.

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SIT group
Progression from rhinitis to asthma?
Patients with allergic diseases
New allergic sensitivities?
Control group
End of the intervention
During the study
Follow -up
End of Follow-up
- Decrease symptoms - Decrease medication.
Figure 1 Graphic contextualising the problem of
this systematic review.
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OBJECTIVES
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Search strategy

• To search PUBMED DATABASE
• Query
• ("Immunotherapy"MeSH Terms OR
  "Immunotherapy"All Fields OR
• ("desensitization, immunologic"MeSH Terms OR
  "desensitization"All Fields) AND
• (("asthma"MeSH Terms OR "asthm"All Fields)
  AND
• ("rhinitis"MeSH Terms AND "rhinitis"All
  Fields) OR
• ("airway diseases"All Fields)) AND
• sensitive clinical query from PUBMED

9
Search strategy
Furthermore

• We also searched the references of the included
  studies and consult the review articles that
  already exist about the subject. 7, 9,13

• Cox L, Cohn JR. Duration of allergen
  immunotherapy in respiratory allergy when is
  enough, enough?. Annals of allergy, asthma
  immunology official publication of the American
  College of Allergy, Asthma Immunology. 2007
  May 98(5)416-26.
• Passalacqua G, Durham SR. Allergic rhinitis and
  its impact on asthma update allergen
  immunotherapy. The Journal of Allergy and
  Clinical Immnunoly. 2007 Apr119(4)881-91.
• 13. Calamita Z, Saconato H, Pela AB, Atallah
  AN. Efficacy of sublingual immunotherapy in
  asthma systematic review of randomized-clinical
  trials using the Cochrane Collaboration method.
  Allergy. 2006 Oct61(10)1162-72.

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PARTICIPANTS AND METHODS
Article criteria selection
Inclusion criteria
Exclusion criteria
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Inclusion criteria

• Articles which refer to patients with allergic
  rhinitis or asthma treated with SIT
• Studies with, at least, one year of follow-up
  after the treatment ceases
• Articles reporting original data on the effects
  of immunotherapy on the
• - progression from rhinitis to asthma
• - appearance of new allergic sensitivities
• Controlled studies.

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Exclusion criteria

• Studies without a rigorous definition about the
  existence or not of asthma in the patients, at
  the beginning of the treatment
• Studies that combine SIT with other types of
  treatment or medication
• Studies in other language than the English.

13
RESULTS
14
Identification and selection of the literature
125 excluded - review articles
392 excluded based on title/abstract
14 electronically screened for detailed evaluation
10 reports excluded - 9 without one year, at
least, of follow-up - 1 not relative to patients
suffering from asthma and/or rhinitis
3 articles included after consulting the
references of review papers on this subject
4 reports included
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Description of the included articles
The articles were analyzed according to

• Study identification author, year, country
• Type of study
• Studys objective
• Participants number, age (children or adults),
  sex, health condition
• Interventions use of SLIT or SCIT, type of
  allergen administrated
• Variables analysed progression from rhinitis
  to asthma in patients treated with SIT and in
  group control, severity of the symptoms (if
  developed), development of new sensitivities in
  both patient groups, type of sensitivity
  developed (if developed), behaviours differences
  in both groups

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• Type of treatment
• Treatment duration
• Follow-up duration
• Control or placebo group
• Time seasonal, not-seasonal, co-seasonal
• Results development or not of asthmas
  symptoms in patients with rhinitis that didnt
  have asthma at the beginning of the study
  appearance or not of new allergic sensitivities
  development of other kinds of symptoms.

17

• The participants of the included studies werent
  completely equals

4 studies gt participants were children
3 Studies gt participants were adults
18

• In two of them (L. Jacobsen et al. and B.
  Niggmenn, et al.)
• Participants at the beginning suffered
  from rhinoconjunctivitis

• In other four
• Participants initially had rhinitis and/or asthma

• Eng PA, et al 2002 study
• Participants suffered from a sensitivity to
  grass pollen with or without tree pollen

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• Type of treatment administrated

L. Jacobsen et al. and B. Niggmenn, et al.
Three studies
Di Rienzo V, et al
P. A. Eng et al. 2002
Didnt specify the type of SIT administrated.
SCIT - Phleum pratense and Betula verrucosa
SLIT
SCIT  - grass pollen allergen extracts  
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• Period of treatment duration
• 3 - 5 years

• Period of follow up
• It ranged from 3 to 12 years

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Methodological quality assessment
Delphi list
D1 Was a method of randomization performed? Was a method of randomization performed? Was a method of randomization performed?
D2 Was the treatment allocation concealed? Was the treatment allocation concealed? Was the treatment allocation concealed?
D3 Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators? Were the groups similar at baseline regarding the most important prognostic indicators?
D4 Were both inclusion and exclusion criteria specified? Were both inclusion and exclusion criteria specified? Were both inclusion and exclusion criteria specified? Were both inclusion and exclusion criteria specified?
D5 Was the outcome assessor blinded? Was the outcome assessor blinded? Was the outcome assessor blinded?
D6 Was the care provider blinded? Was the care provider blinded?
D7 Was the patient blinded?
D8 Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures? Were point estimates and measures of variability presented for the primary outcome measures?
D9 Did the analysis include an intention-to-treat analysis? Did the analysis include an intention-to-treat analysis? Did the analysis include an intention-to-treat analysis? Did the analysis include an intention-to-treat analysis?
D10 Was the withdrawal/drop-out rate lt20 of the total study population? Was the withdrawal/drop-out rate lt20 of the total study population? Was the withdrawal/drop-out rate lt20 of the total study population? Was the withdrawal/drop-out rate lt20 of the total study population? Was the withdrawal/drop-out rate lt20 of the total study population? Was the withdrawal/drop-out rate lt20 of the total study population?
D11 Was the withdrawal/drop-out rate unlikely to cause bias? Was the withdrawal/drop-out rate unlikely to cause bias? Was the withdrawal/drop-out rate unlikely to cause bias? Was the withdrawal/drop-out rate unlikely to cause bias? Was the withdrawal/drop-out rate unlikely to cause bias?
Table 1 Items of the Delphi-list for the
assessment of the methodological quality of the
articles.
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Methodological quality assessment

Article D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 Total Delphi
L. Jacobsen, et al.2007 1 0 1 0 1 0 0 1 1 0 0 5
B. Niggemann, et al.2006 1 0 1 0 1 0 0 1 1 0 0 5
Pajno GB, et al.2001 0 0 1 1 0 0 0 1 1 1 1 6
Di Rienzo V, et al.2003 0 0 1 0 0 0 0 1 1 1 1 5
Eng, PA, et al. 2006 0 0 1 0 0 0 0 1 1 1 1 5
Eng, PA, et al. 2002 0 0 1 0 0 0 0 1 1 1 1 5
Durham SR., et al.1999 0 0 1 1 0 0 0 1 1 0 0 4
Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality Total Delphi (range 0-11) total score gt/ 6 high quality lt6 low quality
Total Delphi (range 0-11) total score gt/ 6
high quality lt6 low quality
Table 2 - Results of the methodological quality
assessment.
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Data extraction and analysis

• DEVELOPMENT OF NEW SENSITIVITIES

24
Data extraction and analysis

• Pajno GB, et al. 2002
• 75.4 of the children in SIT group didnt show
  any sensitization
• 33.3 in control group
• (p lt 0.0002)

• Eng PA, et al. 2002
• 61 (8 out of 13) of the SIT patients developed
  a new sensitivity
• 100 (10 out of 10) in control group

• Eng PA, et al. 2006
• the prevalence of sensitizations was - 90 in
  the control group
• - 67 in the SIT group
• In comparison to a previous observation that has
  been made six years before none of the patients
  (control or SIT group) have developed new
  sensitizations in this period

25
Data extraction and analysis

• Stephen R. Durham, et al.
• decrease of late skin response to an allergen
  after the discontinuation of SIT gtgt No numbers or
  percentages

26
Data extraction and analysis
Control Group
SIT Group
Study
67
25
Pajno GB, et al. 2002
100
61
Eng PA, et al. 2002
0
0
Eng PA, et al. 2006
Table 3 - Results obtained by the included
studies on the development of new sensitivities.
27
Data extraction and analysis
Figure 2 - Graphic of the results obtained by the
included studies on the development of new
sensitivities.
28
Data extraction and analysis

• DEVELOPMENT OF ASTHMA SYMPTONS

29
Data extraction and analysis

• Di Rienzo V, et al.
• 91 of the patients of SLIT group didnt develop
  asthma
• 4 in the control group
• Increase of the number of patients with multiple
  sensitizations in SLIT group, in comparison with
  the control group.

• L. Jacobsen, et al.
• 25 (16 out of 64) patients in SIT group
  developed asthma symptons
• 45 (24 out of 53) in control group

• B. Niggemann, et al.
• 20 (15 out of 75) of the patients in SIT group
  evoluted from rhinitis to asthma
• 43 (29 out of 87) in control group

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Data extraction and analysis
Control Group
SIT Group
Study
Di Rienzo V, et al. 2003
96
9
45
25
L. Jacobsen, et al. 2007
43
20
B. Niggemann, et al. 2006
Table 4 - Results obtained by the included
studies on the progression from rhinitis to
asthma.
31
Data extraction and analysis
Figure 3 - Graphic of the results obtained by the
included studies on the progression from rhinitis
to asthma.
32
Data extraction and analysis
DEVELOPMENT OF ASTHMA SYMPTONS
DEVELOPMENT OF NEW SENSITIVITIES
2 trials SIT is preventive
3 trials SIT is preventive
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META ANALYSIS
Figure 4 - Meta-analysis of development of asthma
symptoms (all included studies on this subject)
odds ratio (OR) with 95 confidence interval
(CI) for each study and all studies combined
(include test for heterogeneity).
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META ANALYSIS
Figure 5 - Meta-analysis of development of asthma
symptoms odds ratio (OR) with 95 confidence
interval (CI) for each study and all studies
combined (include test for heterogeneity).
35
META ANALYSIS
Figure 6 - Meta-analysis of development of new
sensitivities odds ratio (OR) with 95
confidence interval (CI) for each study and all
studies combined (include test for heterogeneity).
36
PRELIMINARY DISCUSSION
Allergen specific immunotherapy
reduces
Symptoms of allergies
Decrease the development of new sensitivities
long after the treatment finished
Stop the progression from rhinitis to asthma
37
REFERENCES
1. Abramson MJ, Puy RM, Weiner JM. Allergen
immunotherapy for asthma. Cochrane Database of
Systematic Reviews. 2003 (4)CD001186.   2.
TePas EC, Umetsu DT. Immunotherapy of asthma and
allergic diseases. Current Opinion in Pediatrics.
2000 Dec 12(6)574-8.   3. Chin ES. Pediatrics,
Reactive Airway Disease. Slapper D, Windle ML,
Young GM, Halamka J, Bachur RG, editors.
EMedicine from WebMD. 2006 Nov.   4. James T. Li,
MD, PhD Richard F. Lockey, MD I. Leonard
Bernstein, MD Jay M. Portnoy, MD and Richard A.
Nicklas, MD, editors. Allergen immunotherapy a
practice parameter. The Journal of allergy and
clinical immunology. 2003 Jan 90(1)13-4.   5.
OHehir RE, Sandrini A, Anderson GP, Rolland MJ.
Sublingual allergen immunotherapy immunological
mechanisms and prospects for refined vaccine
preparation. Current Medicinal Chemistry.
200714(21)2235-44.   6. Greenberger PA, Ballow
M, Casale TB, Platts-Mills TA, Sampson HA.
Sublingual immunotherapy and subcutaneous
immunotherapy Issues in the United States. The
Journal of Allergy and Clinical Immnunoly. 2007
Oct 12 In Press, Corrected Proof.  
38
REFERENCES
7. Cox L, Cohn JR. Duration of allergen
immunotherapy in respiratory allergy when is
enough, enough?. Annals of allergy, asthma
immunology official publication of the American
College of Allergy, Asthma Immunology. 2007
May 98(5)416-26.   8. Malling HJ.
Allergen-specific immune therapy in the treatment
of asthma. Ugeskrift for Laeger. 2000 Jan 24
162(4)477-9.   9. Passalacqua G, Durham SR.
Allergic rhinitis and its impact on asthma
update allergen immunotherapy. The Journal of
Allergy and Clinical Immnunoly. 2007
Apr119(4)881-91.   10. Jacobsen L, Nuchel
Petersen B, Wihl JAÊ , et al. Immunotherapy with
partially purified and standardized tree pollen
extracts. IV Results from long-term (6-year)
follow-up. Allergy. 1997 52914920.   11.
Johnstone DE, Dutton A. The value of
hyposensitization therapy for bronchial asthma in
children a 14-year study. Pediatrics. 1968
42793802.  
39
REFERENCES
12. Des Roches A, Paradis L, Menardo JL, et al.
Immunotherapy with a standardized
Dermatophagoides pteronyssinus extract. VI
Specific immunotherapy prevents the onset of new
sensitizations in children. The Journal of
Allergy and Clinical Immnunoly. 1997
99450453.   13. Calamita Z, Saconato H, Pela
AB, Atallah AN. Efficacy of sublingualimmunothera
py in asthma systematic review of
randomized-clinical trialsusing the Cochrane
Collaboration method. Allergy. 2006
Oct61(10)1162-72.