1. Subject: Introdução à Medicina Long-term preventive effects of allergen specific immunotherapy: a systematic review and meta-analysis

2. Subject: Introdução à Medicina Regente da disciplina: Prof Dr. Altamiro da Costa Orientador: Dr. João Fonseca Azevedo L; Cardoso P; Coelho J; Gonçalves A; Maranhas M; Oliveira A; Pereira E; Pereira J; Silva V; Teixeira C; pedrojcardoso@gmail.com

3. Subject: Introdução à Medicina SUMMARY Introduction Objectives Participants and methods > Criteria Selection > Search Strategy Results > Identification and selection of the literature > Description of the included articles > Methodological quality assessment > Data extraction and analysis Preliminary Discussion References

4. Subject: Introdução à Medicina INTRODUCTION “Allergic diseases and asthma “have increased dramatically during the past 2 decades” 2 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 2.TePas EC, Umetsu DT. Immunotherapy of asthma and allergic diseases. California (USA): Department of Pediatrics, Stanford University; 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.

5. Subject: Introdução à Medicina There is a chance that immunotherapy can prevent the evolution from rhinitis to asthma and the appearance of new sensitivities There is no systematic review proving its long-term efficacy on the prevention of new sensitivities and the evolution from rhinitis to asthma. HOWEVER…

6. Subject: Introdução à Medicina SIT group Control group Progression from rhinitis to asthma? New allergic sensitivities? End of the intervention During the studyFollow -up Patients with allergic diseases - Decrease symptoms; - Decrease medication. End of Follow-up Figure 1 – Graphic contextualising the problem of this systematic review.

7. Subject: Introdução à Medicina OBJECTIVES Search if allergen specific immunotherapy has long-term preventive effects after the treatment ceases Development of new sensitivities The evolution from rhinitis to asthma This has motivated us to make a systematic review, to investigate the veracity of this hypothesis

8. Subject: Introdução à Medicina 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 Search strategy

9. Subject: Introdução à Medicina Search strategy We also searched the references of the included studies and consult the review articles that already exist about the subject. 7, 9,13 Furthermore … 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. 9.Passalacqua G, Durham SR. Allergic rhinitis and its impact on asthma update: allergen immunotherapy. The Journal of Allergy and Clinical Immnunoly. 2007 Apr;119(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 Oct;61(10):1162-72.

10. Subject: Introdução à Medicina PARTICIPANTS AND METHODS Article criteria selection Inclusion criteriaExclusion criteria

11. Subject: Introdução à Medicina 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.

12. Subject: Introdução à Medicina 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. Subject: Introdução à Medicina RESULTS

14. Subject: Introdução à Medicina Identification and selection of the literature 10 reports excluded - 9 without one year, at least, of follow-up - 1 not relative to patients suffering from asthma and/or rhinitis 14 electronically screened for detailed evaluation 392 excluded based on title/abstract 125 excluded - review articles 531 references identified electronically 4 reports included 3 articles included after consulting the references of review papers on this subject 7 studies included on the systematic review

15. Subject: Introdução à Medicina The articles were analyzed according to: Study identification: author, year, country Type of study; Study’s 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), behaviour’s differences in both groups; Description of the included articles

16. Subject: Introdução à Medicina Type of treatment; Treatment duration; Follow-up duration; Control or placebo group; Time: seasonal, not-seasonal, co-seasonal; Results: development or not of asthma’s symptoms in patients with rhinitis that didn’t have asthma at the beginning of the study; appearance or not of new allergic sensitivities; development of other kinds of symptoms.

17. Subject: Introdução à Medicina  The participants of the included studies weren’t completely equals 4 studies > participants were children 3 Studies > participants were adults

18. Subject: Introdução à Medicina  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

19. Subject: Introdução à Medicina  Type of treatment administrated: L. Jacobsen et al. and B. Niggmenn, et al. Di Rienzo V, et al Three studies P. A. Eng et al. 2002 SCIT: - Phleum pratense and Betula verrucosa SLITSCIT : - grass pollen allergen extracts Didn’t specify the type of SIT administrated.

20. Subject: Introdução à Medicina  Period of treatment duration: 3 - 5 years  Period of follow – up: It ranged from 3 to 12 years

21. Subject: Introdução à Medicina Methodological quality assessment Delphi list D1Was a method of randomization performed? D2Was the treatment allocation concealed? D3Were the groups similar at baseline regarding the most important prognostic indicators? D4Were both inclusion and exclusion criteria specified? D5Was the outcome assessor blinded? D6Was the care provider blinded? D7Was the patient blinded? D8Were point estimates and measures of variability presented for the primary outcome measures? D9Did the analysis include an intention-to-treat analysis? D10Was the withdrawal/drop-out rate <20% of the total study population? D11Was 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.

22. Subject: Introdução à Medicina Methodological quality assessment ArticleD1D2D3D4D5D6D7D8D9D10D11Total Delphi* L. Jacobsen, et al.2007101010011005 B. Niggemann, et al.2006101010011005 Pajno GB, et al.2001001100011116 Di Rienzo V, et al.2003001000011115 Eng, PA, et al. 2006001000011115 Eng, PA, et al. 2002001000011115 Durham SR., et al.1999001100011004 * Total Delphi (range 0-11): total score >/= 6 = high quality; <6 = low quality Table 2 - Results of the methodological quality assessment.

23. Subject: Introdução à Medicina Data extraction and analysis  DEVELOPMENT OF NEW SENSITIVITIES

24. Subject: Introdução à Medicina Data extraction and analysis  Pajno GB, et al. 2002 75.4% of the children in SIT group didn’t show any sensitization 33.3% in control group (p < 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. Subject: Introdução à Medicina Data extraction and analysis  Stephen R. Durham, et al. decrease of late skin response to an allergen after the discontinuation of SIT >> No numbers or percentages

26. Subject: Introdução à Medicina Data extraction and analysis 0% Eng PA, et al. 2006 100%61%Eng PA, et al. 2002 67%25%Pajno GB, et al. 2002 Control GroupSIT GroupStudy Table 3 - Results obtained by the included studies on the development of new sensitivities.

27. Subject: Introdução à Medicina Data extraction and analysis Figure 2 - Graphic of the results obtained by the included studies on the development of new sensitivities.

28. Subject: Introdução à Medicina Data extraction and analysis  DEVELOPMENT OF ASTHMA SYMPTONS

29. Subject: Introdução à Medicina Data extraction and analysis  Di Rienzo V, et al. 91% of the patients of SLIT group didn’t 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

30. Subject: Introdução à Medicina Data extraction and analysis Table 4 - Results obtained by the included studies on the progression from rhinitis to asthma. 43%20% B. Niggemann, et al. 2006 45%25%L. Jacobsen, et al. 2007 96%9% Di Rienzo V, et al. 2003 Control GroupSIT GroupStudy

31. Subject: Introdução à Medicina Data extraction and analysis Figure 3 - Graphic of the results obtained by the included studies on the progression from rhinitis to asthma.

32. Subject: Introdução à Medicina Data extraction and analysis DEVELOPMENT OF ASTHMA SYMPTONSDEVELOPMENT OF NEW SENSITIVITIES 2 trials: SIT is preventive 3 trials: SIT is preventive

33. Subject: Introdução à Medicina 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).

34. Subject: Introdução à Medicina 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. Subject: Introdução à Medicina 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. Subject: Introdução à Medicina Allergen specific immunotherapy reduces Symptoms of allergies Stop the progression from rhinitis to asthma Decrease the development of new sensitivities long after the treatment finished PRELIMINARY DISCUSSION

37. Subject: Introdução à Medicina 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. O’Hehir RE, Sandrini A, Anderson GP, Rolland MJ. Sublingual allergen immunotherapy: immunological mechanisms and prospects for refined vaccine preparation. Current Medicinal Chemistry. 2007;14(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. Subject: Introdução à Medicina 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 Apr;119(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; 52:914±920. 11. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children: a 14-year study. Pediatrics. 1968; 42:793±802.

39. Subject: Introdução à Medicina 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; 99:450±453. 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 Oct;61(10):1162-72.