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2. GLORIA Module 4:Allergen Specific Immunotherapy

3. Global Resources in Allergy (GLORIA™) Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.

4. World Allergy Organization (WAO) The World Allergy Organization is an international coalition of 74 regional and national allergy and clinical immunology societies.

5. WAO’s Mission WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

7. GLORIA Module 4:Allergen Specific Immunotherapy

8. Lecture objectives • Following this presentation, you will be able to: • Discuss and define indications for specific allergen immunotherapy (SIT) • Describe the safety and benefits of SIT • Explain the mechanisms of action of SIT • Discuss the current status of alternative methods of immunotherapy

9. Source Documents • EAACI Immunotherapy Position Paper 1993 • Position Paper on Allergen Immunotherapy. Report of BSACI Working Party 1993 • WHO Position Paper on Immunotherapy 1998 • EAACI Local Immunotherapy 1998 • ARIA: Allergic Rhinitis – Its Impact on Asthma 2001 • Allergen Immunotherapy: A Practice Parameter ACAAI 2003

10. WAO Expert Panel • G Walter Canonica, Italy, Chair • Carlos Baena-Cagnani, Argentina • Stephen R Durham, UK • Richard Lockey, USA • Daniel Vervloet, France Invited Contributor • Giovanni Passalacqua, Italy

11. Definition Extracts and standaridization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

12. Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

13. Definition • Allergen immunotherapy is the administration of gradually increasing quantities of an allergen vaccine to an allergic subject, reaching a dose which is effective in ameliorating the symptoms associated with subsequent exposure to the causative allergen. WHO Position Paper 1998

14. Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

15. Allergen Extracts - 1 • Allergen extracts are a preparation of an allergen obtained by extraction of the active constituents from animal or vegetable substances with a suitable menstruum.

16. Allergen Extracts - 2 • For allergen immunotherapy, products may be either unmodified vaccines or vaccines modified chemically and /or by absorption onto different carriers: • Aqueous vaccines • Depot and modified vaccines • Mixtures of allergen vaccines

17. Allergen Extracts- 3 • The quality of the allergen vaccine is critical for both diagnosis and treatment. Where possible, standardized vaccines of known potency and shelf-life should be used. ARIA, JACI, 2001

18. Allergen Standardization - 1 • Standardization allows definition of the “potency” of allergenic extracts and warrants that the batches of vaccine produced from different lots of raw material are consistent and have comparable activities.

19. Allergen Standardization - 2 • The standardization can be made: Biologically; the potency of the vaccine is compared to the cutaneous response obtained in a reference population; Immunologically; the potency of the vaccine is based on RAST-inhibition experiments using standard pools of sera.

20. Allergen Standardization - 3 • Many different units are used: • Protein nitrogen units (PNU- world wide) • Allergy unit (AU- U.S.FDA) • Bioequivalent allergy unit (BAU) • Biologic units (BU- Europe) • International unit (IU- WHO) • Index of reactivity (IR- Europe) • Specific treatment unit (STU) • Activity Units by RAST (AUR- Europe)

21. Allergen Standardization - 4 • The major allergen(s) content in micrograms per ml is provided for most products. • Standardized allergen extracts should be preferred for allergy diagnosis and therapy.

22. Allergen Immunotherapy Indications • Hymenoptera venom immunotherapyis the only effective preventive treatment for insect sting-induced anaphylaxis. • Inhalant allergen immunotherapyreduces symptoms and/or medication needs for patients with allergic asthma and/or rhinoconjunctivitis.

23. Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

24. Efficacy - 1 • Allergen immunotherapy is the only treatment that can modify the immune response to allergens and alter the course of allergic diseases. • In some guidelines the indication for allergen immunotherapy for asthma and rhinitis has been separated. This separation is incorrect - respiratory allergy is a unique immunological disorder of the airways. ARIA 2001

25. Efficacy - 2 • Allergen immunotherapy should be based on allergen sensitization not on thedisease

26. Allergens of Proven Efficacy in Double Blind Placebo Controlled Studies Pollens Cat House dust mites Hymenoptera venoms Few data (though encouraging) are available for dog dander and mould allergens

27. Stinging Insects Apis melifera. Bombus spp. Vespula spp. Polistes spp. Solenopsis invicta Vespa Crabro.

28. Clinical Features of Hymenoptera Allergy MüllerHL. J Asthma Res 1966

29. Venom Immunotherapy – When to Start Müller Clin. Exp. Allergy 1998

30. Effects of Immunotherapy • Symptom improvement and/or reduction of the need for symptomatic drugs in allergic rhinitis and asthma. • Long-lasting effect once discontinued. • Prevention of the onset of new skin sensitizations. • Prevention of the onset of asthma (?).

31. Parameters of Efficacy - Paraclinical • Systemic immunological changes Immunoglobulins Cells Mediators • Local immunological changes Specific organ reactivity Nonspecific hyperreactivity

32. Allergen Immunotherapy for Asthma • 76 trials with 3,188 patients • Significant improvement in asthma symptom scores • Significant reduction of allergen specific bronchial hyperreactivity • Some reduction also in non-specific bronchial hyperreactivity Abramson, Weiner and Puy Cochrane Database Systematic Review 2003

33. Allergen Immunotherapy for Asthma It would have been necessary to treat 4 (95% CI 3 to 5) patients with immunotherapy to avoid one deterioration in asthma symptoms, and overall to treat 5 (95% CI 4 to 6) patients with immunotherapy to avoid one requiring increased medication. Abramson, Weiner and Puy Cochrane Database Systematic Review 2003

34. Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

35. Safety • Millions of subcutaneous immunotherapy injections are administered annually. The risk of a fatal or near-fatal systemic reaction is extremely small, but not completely absent. • Physicians prescribing or administering subcutaneous immunotherapy should be aware of these risks and institute appropriate procedures to minimize them.

36. Grading of Systemic Reactions - 1 • 1. Non-specific reactions (likely non-IgE-mediated), discomfort, nausea, headache, arthralgia. • 2. Mild systemic reactions; mild rhinitis/asthma (PEFR > 60%), responding to β2 agonists/antihistamines.

37. Grading of systemic reactions - 2 • 3. Non-life-threatening systemic reactions; urticaria, angioedema, severe asthma (PEFR < 60%). Responding well to treatment. • 4. Anaphylaxis; itching, urticaria, bronchospasm, withhypotension, requiring intensive care. Malling and Weeke, Allergy, 1993

38. Fatalities Period 1945-1984 46 Fatalities Lockey RF et al JACI 1987 Period 1985-1989 17 Fatalities Reid MJ et al, JACI 1993 Estimated risk for fatal reactions less than 1 per 2 million injections

39. Safety • The safety of immunotherapy; a prospective study • 2,989 patients • Period 7 months • Systemic reactions 25/2898 (0.8%) • No fatalities Hepner M et al, JACI 1987

40. Evaluation of Risk Factors for Systemic Reactions 1-year prospective study; nonstandardized extracts, titrated W/V Tinkelman, JACI, 1995

41. Systemic Allergic Reactions to SIT Correlation with: • a) severity of systemic reactions; • b) time of onset. 242 patients 11.045 injections 10 years 112 systemic reactions 4 near-fatal Petalas K et al. Allergy 2000

42. Risk Factors Based on Fatal and Non-Fatal Reactions • Uncontrolled asthma • Severe asthma • Use of betablockers • Rush immunotherapy • Build-up phase • Use of new vials • Technical errors

43. Contraindications for Allergen Immunotherapy - 1 • Serious immunopathologic diseases and immunodeficiencies. • Malignancies. • Severe psychological disorders. • Treatment with beta blockers, even when administered topically.

44. Contraindications for Allergen Immunotherapy - 2 • Poor compliance. • Severe asthma, or uncontrolled by pharmacotherapy (FEV1< 70%). • Significant cardiovascular diseases. • Children under 5 years (relative contraindication).

45. Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary Allergen Specific Immunotherapy

46. Long-Lasting Efficacy of Subcutaneous IT: Controlled Studies Author Hedlin, 1995 Ariano, 1999 Durham, 2000 Eng, 2002 Allergen Cat/dog Parietaria Grass Grass Duration 3 yrs 4 yrs 5 yrs 3 yrs

47. IT: Prevention of New Sensitizations New sensitizations after 3 years: 55% SIT group vs 100% control group. Des Roches et al, JACI 1997 New sensitizations after 3 years: 25% SIT group vs 67% control group. Pajno et al, Clin Exp Allergy 2001 New sensitizations after 4 years 23% SIT group vs 68% control group. Purello D’Ambrosio et al, Clin Exp Allergy 2001

48. Specific immunotherapy prevents the development of asthma in children with allergic rhinitis (the PAT study) Moller C et al, JACI 2002 No asthma % Asthma 60 205 children with rhinitis age: 6-14 yrs grass or birch allergy 3 yrs immunotherapy 40 32 19 SIT CONTROL

49. Grass pollen immunotherapy: longterm efficacy Durham SR et al New Engl J Med 1999;341:468-75

50. Duration of benefit • Add slide showing asthma data from Johnson, that patients were still symptom free after 7 years