2. Module 4: Immunotherapy Updated: June 2011

4. 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.

5. World Allergy Organization (WAO) The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.

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

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

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

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 immunotherapy is the only effective preventive treatment for insect sting-induced anaphylaxis.  Inhalant allergen immunotherapy reduces symptoms and/or medication needs for patients with allergic asthma and/or rhinoconjunctivitis.

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

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 the disease

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

28. Clinical Features of Hymenoptera Allergy Large local reactionOedema >10cm > 24 hr IUrticaria IIStage I + angioedema or rhinoconjunctivitis or abdominal pain IIIStage I + dyspnoea, dysphonia, dysphagia IVAnaphylaxis Müller HL. J Asthma Res 1966

29. Venom Immunotherapy – When to Start Severe systemic reactions stages III - IV Yes Mild systemic reactions stages I - II Adults: only if at risk Children (age <10 yrs): No Large local reactionNo Unusual reactionsNo 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. Allergen Specific Immunotherapy Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary

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 β 2 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, with hypotension, requiring intensive care. Malling and Weeke, Allergy, 1993

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

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 Build UpMaintenance Patients Visits Reactions Rate/pts Rate/visits 1.887 38.287 36 1/32 1/1063 2.691 113.550 62 1/47 1/1831 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. Allergen Specific Immunotherapy Definition Extracts and standardization Efficacy Safety Long-term benefit Practical aspects of immunotherapy Mechanisms Non injection routes Novel approaches Summary

46. Long-Lasting Efficacy of Subcutaneous IT: Controlled Studies Author Hedlin, 1995 Ariano, 1999 Durham, 2000 Eng, 2002 Allergen Cat/dog Parietaria 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) 205 children with rhinitis age: 6-14 yrs grass or birch allergy 3 yrs immunotherapy SITCONTROL % 60 19 40 32 No asthma Asthma Moller C et al, JACI 2002

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

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

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

52. Injection Technique Use upper outer surface of arm Ensure sterile technique Use 1ml syringe and orange needle Inject at 45º by deep subcutaneous route Record any local/systemic reaction

53. Administration of Immunotherapy

54. Recommendations - 1 Specific allergen immunotherapy must be prescribed by a specialist in the field of allergy and immunology. (Delete for US:Subcutaneous IT should be administered by physicians and other care professionals who are trained to recognize and treat anaphylaxis.) Patients sensitive to a single allergen versus those who are polysensitized benefit more from immunotherapy.

55. Recommendations - 2 Allergen immunotherapy is more effective in children and young adults. Patients with non-allergic triggers may not benefit from IT. Allergen immunotherapy preferably should be initiated as early as possible, in the earliest phases of the disease, hopefully to prevent additional sensitization and/or the onset of asthma. WHO, 1998

56. Factors to be Considered Before Prescribing Immunotherapy - 1 Presence of an IgE-mediated disease (allergic rhinitis, allergic asthma) hymenoptera hypersensitivity. Symptoms are caused by specific allergen(s). Exclude other triggers. Severity and duration of symptoms. Response to allergen avoidance and pharmacotherapy.

57. Factors to be Considered Before Prescribing Immunotherapy - 2 Contraindications Cost/ benefit ratio Patient compliance Availability of standardized extracts Documented efficacy Modified from WHO, 1998

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

59. Mechanisms It has been demonstrated that IT decreases allergen-induced inflammation in allergic rhinitis and allergic asthma. ARIA 2001

60. The Experimental Evidence SIT decreases the migration of eosinophils Nagayata H, 1996 SIT decreases eosinophil numbers and airways BHR Van Oosterhat AJ, 1988 SIT decreases the number of mast cells Durham, S R, 1997 SIT decreases the number and activity of eosinophils Rak 1988, Durham 1996

61. Mechanisms Studies have provided insight into the mechanisms of immunotherapy. The efficacy of immunotherapy may be secondary to alteration in the T-cell response to allergen. Mechanisms are probably heterogeneous, depending on the nature of allergen, the site of allergic disease and the route, dose and duration of immunotherapy. Durham S R, N Eng J Med 1999

62. APC IgE IL-4 IL-5 Allergic response Eosinophils Th2 B-cell + + Tr1 IL-10 TGF - b - - + IT Th1 IgG IFN- g B-cell IT - CD4 CD80/86 T cell Allergen TCR HLA CD28

63. Th1 Th2 TCD4+ IT IMMUNE DEVIATION? ANERGY? BOTH? IL-4 IL-5 IL-9 IL-2 INF-g Mechanisms

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

65. Non-Injection or Local Routes - 1 Oral immunotherapy (OIT): allergen immediately swallowed, as drops, tablets or capsules. Sublingual immunotherapy (SLIT): allergen kept under the tongue for 1-2 minutes, then swallowed (the sublingual- spit mode is no longer in use).

66. Non-Injection or Local Routes - 2 Local nasal (LNIT): allergen sprayed into the nostrils as aqueous solution or dry powder. Local bronchial (LBIT): allergen inhaled with a deep inspiration.

67. Non-Injection or Local Routes Bronchial and oral route are not recommended for clinical use, due to insufficient demonstration of efficacy and the occurrence of side effects. Nasal IT (LNIT) and Sublingual IT (SLIT): “Based on the available literature, local nasal immunotherapy and sublingual immunotherapy can be considered as viable alternatives to subcutaneous administration”. WHO Position Paper 1998

68. Local Nasal Immunotherapy (LNIT)-1 May be indicated in carefully selected adult patients with rhinitis caused by pollen and possibly by mites. Potential candidates are patients who: 1. Cannot be properly controlled by standard pharmacotherapy; 2. Have experienced previous systemic reactions induced by subcutaneous allergen immunotherapy; 3. Who refuse injections. ARIA 2001

69. Local Nasal Immunotherapy (LNIT)-2 LNIT requires a careful administration technique, and premedication with cromolyn is suggested. It acts only on rhinitis symptoms, and seems not to have a long lasting effect. For these reasons, its use is progressively declining.

70. SLIT-Swallow: Efficacy - 1 A meta-analysis of 22 DBPC trials has shown that SLIT is effective in rhinitis caused by pollens and mites. There are few studies showing additional efficacy on asthma symptoms. More studies about efficacy in children are required.

71. SLIT-Swallow: Efficacy - 2 The long-lasting effect has been demonstrated in children with mite-induced asthma. Di Rienzo et al Clin Exp Allergy 2003 The preventive effect on new skin sensitizations has been demonstrated. Marogna et al Allergy 2004

72. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a ten-year prospective study V.Di Rienzo, F.Marcucci, P.Puccinelli, S.Parmiani, F.Frati, L.Sensi, GW Canonica, G. Passalacqua Clin Exp Allergy, 2003 60 pts 35 SLIT + drugs 25 only drugs 0510YEARS No More SLIT

73. 4 2 32 1 SLIT CTRL BASELINE 10 YEARS 0.001 10 20 30 40 31 17 1 SLITCTRL END SLIT n 0.001 NS No asthma Asthma 4 31 23 24 3 DiRienzo et al Clin.Exp.Allergy. 2003 Long-Lasting Efficacy of SLIT: Children with Asthma

74. SLIT: Safety - 1 In post-marketing studies, the overall rate of side effects (all grades) ranges between 3% and 8% of patients. The most frequently reported side effects are local (gastrointestinal); oral itching/swelling, nausea, stomach-ache. The side effects are usually mild and treatment discontinuation is rarely required.

75. SLIT: Safety - 2 Gastrointestinal side effects are dose-dependent. No life-threatening side effect or fatality has ever been reported since the introduction of SLIT in 1986. The occurrence of systemic effects in controlled trials does not differ from the placebo treated patients.

76. Local Routes: Sublingual-Swallow Immunotherapy May be indicated in pollen and mite induced rhinitis and asthma in adults and children, using maintenance dosages 5 -100 times higher then injection IT.

77. SLIT-Swallow in the ARIA Document “Sublingual immunotherapy can be administered in adults and children” ARIA, JACI, 2001

78. Efficacy of sublingual immunotherapy in allergic rhinitis in pediatric patients 4 to 18 years Meta-analysis of RCT Penagos M., Compalati E., Tarantini F.,Baena Cagnani R., Huerta Lopez J., Passalacqua G., & Canonica G.W. Annals of Allergy Asthma and Immunology 2006

79. Purpose: To assess the efficacy of Immunotherapy delivered by the sublingual route, whether or not the allergen was subsequently swallowed in the treatment of allergic rhinitis in children. Study Selection: Randomized, placebo- controlled and double-blind trials that studied SLIT in pediatric patients (4 to 18 years) with allergic rhinitis. Penagos et al. Annals of Allergy Asthma and Immunology 2006

81. Data Sources: Comprehensive searches of the EMBASE, LILACS, OVID and MEDLINE databases from 1966 to November 2005 and references of identified articles and reviews. Penagos et al. Annals of Allergy Asthma and Immunology 2006

82. Outcomes measured in the active treatment and placebo groups were symptom scores and concomitant use of anti-allergic medication. Review Manager 4.2.7 Program (Cochrane Collaboration) was used for data synthesis.

83. Outcomes were extracted from original articles. When this information was not available, authors of each trial were contacted. Some graphics were digitalized. Penagos et al. Annals of Allergy Asthma and Immunology 2006

84. Results: The initial scanning identified 102 articles, 60 of which were potentially relevant trials on SLIT use in pediatric patients with allergic rhinitis. 16 studies were randomized. 10 met inclusion criteria for the meta-analysis. All randomized clinical trials included 491 participants, 251 allocated to SLIT group and 240 to placebo group. Penagos et al. Annals of Allergy Asthma and Immunology 2006

85. Interpreting Effect Size Results Cohen’s “Rules-of-Thumb” –standardized mean difference effect size small = 0.20 medium = 0.50 large = 0.80 –correlation coefficient small = 0.10 medium = 0.25 large = 0.40 –odds-ratio small = 1.50 medium = 2.50 large = 4.30

86. Symptom Score Effect Size Penagos et al. Annals of Allergy Asthma and Immunology 2006

87. Medication score Effect Size Penagos et al. Annals of Allergy Asthma and Immunology 2006

88. Conclusion: SLIT reduces both symptom and medication scores in pediatric patients with allergic rhinitis. Penagos et al. Annals of Allergy Asthma and Immunology 2006

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

90. Novel Approaches New immunological treatment modalities for allergic diseases are presently under investigation: Liposome vaccines Adjuvants Anti-IgE antibodies combined with IT Peptide vaccination Recombinant allergens cDNA vaccines

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

92. allergen avoidance indicated when possible allergen avoidance indicated when possible pharmacotherapy safety effectiveness easy to be administered pharmacotherapy safety effectiveness easy to be administered immunotherapy effectiveness specialist prescription may alter the natural course of the disease immunotherapy effectiveness specialist prescription may alter the natural course of the disease patient's education always indicated patient's education always indicated patient Modified from

93. Allergen Immunotherapy Can Modify the Natural History of Allergy - 1 Allergen immunotherapy is the only treatment that can modify the natural history of allergic disease. SCIT and SLIT- swallow can prevent the onset of new sensitizations.

94. Allergen Immunotherapy Can Modify the Natural History of Allergy - 2 SCIT and SLIT-swallow administered for several years (3 to 5 years) - efficacy is maintained for up to 3 or more years after discontinuation. SCIT could prevent the onset of asthma in children with allergic rhinitis.

95. Allergen Specific Immunotherapy VS Pharmacologic Treatment Specific immunotherapy does not take the position of being an ultimate treatment principle. It should be part of the global treatment, and should be used in the early phase of disease. Modified from ARIA JACI 2001

96. Conclusion Allergen Specific Immunotherapy is an effective and safe treatment of allergic rhinitis, allergic asthma and hymenoptera venom allergy

97. Immunotherapy for Hymenoptera Venom Allergy

98. In countries with a predominantly temperate climate over half the population receives a sting at least once in their first 20 years of life and virtually the entire adult population has been stung at least once. Hymenoptera Venom Kemp S F et al JACI 2000

99. Epidemiology Epidemiologic studies of the general population indicate similar data in Australia (17.5%) and England (16%) Brown AF et al JACI 2001 Stewart AG et al QJ Med 1996 Insect stings cause 29% of anaphylaxis in adults in Italy Cianferoni A et al Ann Allergy Asthma Immunol 2001 1.36 million to 13.6 million of people in USA are at risk for anaphylaxis from insect stings Neugut A I et al JAMA 2001

100. Epidemiology - 2 The incidence of insect sting mortality is low but probably underestimated. The presence of specific immunoglobulin E to venoms was found in 23% of the post-mortem sera samples obtained from victims between 15 and 65 years of age, who died suddenly and inexplicably between the end of May and the beginning of November 1997. Schwartz HJ et al Clin Allergy 1988

101. Apis mellifera Scutellata Apis mellifera Bombus spp. Ants Bees Solenopsis invicta

102. Polistes spp. Vespa crabro Vespula spp. Vespids

103. Stinging Insects by Region Hymenoptera in USA Yellow jackets Imported fire ants African honey bee Wasps Domestic honey bee Bumblebees Hymenoptera in Australia Jack jumper ant Domestic honey bee Yellow jacket wasp Hymenoptera in Europe Yellow jackets Wasps Bumblebees

104. The normal reaction of the skin to an Hymenoptera sting consists of a painful, sometimes itchy, local wheal, developing up to 2 cm diameter, surrounded by a swelling of the subcutaneous tissue several centimetres in diameter. Clinical Features

105. Clinical Features of Hymenoptera Allergy Large local reactionOedema >10cm > 24 hr IUrticaria IIStage I + angioedema or rhinoconjunctivitis or abdominal pain III Stage I + dyspnoea, dysphonia, dysphagia IVAnaphylaxis Müller HL J Asthma Res 1966

106. Skin Tests in Europe Skin prick test with venom 100 mcg/mL ↓ Intradermal injection of 0.05 mL venom 0.1 mcg/mL; if negative ↓ Intradermal injection of 0.05 ml venom 1 mcg/mL Reisman RE Allergol Int 1998

107. Skin Tests in Europe - 2 Skin prick test with venom 100 mcg/mL Higher venom concentrations may cause irritant reactions, which are not immunologically specific Stop skin tests when one intradermal injection is positive Perform test for all Hymenoptera venoms Systemic reactions following tests: 1.4% Severe systemic reactions following tests: 0.25% Reisman RE Allergol Int 1998

108. Skin Tests in USA Skin prick test with venom 100 mcg/mL ↓ Intradermal tests usually start with a concentration in the range of 0.001 to 0.01 µg/mL ↓ If intradermal tests at this concentration are non- reactive, the test dose is increased by 10-fold increments until a positive skin test response occurs, to a maximum concentration of 1.0 µg/mL Portnoy et al JACI 1999

109. Venom Immunotherapy – When to Start Europe Severe systemic reactions stages III - IV Yes Mild systemic reactions stages I - II Adults: only if at risk Children (age <10 yrs): No Large local reactionNo Unusual reactionsNo Müller Clin Exp Allergy 1998

110. Venom Immunotherapy – When to Start USA Severe systemic reactions stages III - IV Yes Mild systemic reactions stages I - II Adults: only if at risk Children (age <16 yrs): Yes if stung by fire ants Large local reactionNo Unusual reactionsNo Portnoy et al JACI 1999

111. Induction Regimens of Hymenoptera Venom Immunotherapy Sturm G et al JACI 2002

112. Induction Regimens of Hymenoptera Venom Immunotherapy Conventional (increasing doses in weekly intervals for outpatients) rush (induction phase over 4-7 days for inpatients) Ultrarush (the maintenance dose is reached within 1-2 days) Cluster (a modified rush approach schedule, which involves giving several injections at 15- to 30-minute intervals during the first visits and reaches a maintenance does in about 6 weeks

113. Induction Regimens of Hymenoptera Venom Immunotherapy - 2 In rush protocols patients receive higher doses of venom in a shorter time period and thus reach the maintenance dose of 100 µg faster than in conventional schedules; this might be of great importance before the onset of the flying season of insects Rush (induction phase over 4-7 days for inpatients) Sturm G. et al JACI 2002

114. Mechanisms of Efficacy of VIT Induction VIT induces a shift from a Th2 cytokine response to a Th1 dominant pattern The immediate drop in IL-4 production in rush VIT suggests profound down-regulation in T-cell responsiveness to allergen The mechanism might be due to T-cell anergy or activation induced apoptosis O‘Hehir RE et al J. Immunol 1991 Radvanyi LG et al J Immunol 1996

115. Mechanisms of efficacy of VIT - 2 Induction of allergen-specific IgG provides a possible mechanism by which immunotherapy might inhibit co- stimulation of allergen-specific T cells T cells producing IL-10 and IFN-gamma play a key role for the inhibition of histamine and sulphidoleukotriene release of effector cells Barcy S et al Int Immunol 1995 Pierkes M et al JACI 1999

116. Bee Venom Immunotherapy (VIT) Allergic side-effects are a significant problem when honeybee venom is used (up to 20-40% of patients treated) VIT has been shown to be protective in approximately 80% of bee and 95% of wasp venom-allergic patients Müller Clin Exp Allergy1998 Müller et al JACI 1992

117. Hymenoptera Immunotherapy: When to Stop 3 years Müller et al JACI 1991 5 years Golden et al JACI 1996 The risk of systemic sting reactions when immunotherapy is stopped after 5 years reaches 15% in 5 to 10 years after stopping VIT Golden et al JACI 2000 Most Hymenoptera venom allergic patients can be safely and effectively treated with 8 to 12-weekly injections of 100 mcg venom Reisman R. Allergol Int 1998

118. G Passalacqua, C Baena-Cagnani, G W Canonica

119. World Allergy Organization (WAO) For more information on the World Allergy Organization (WAO), please visit www.worldallery.org or contact the: www.worldallery.org WAO Secretariat 555 East Wells Street, Suite 1100 Milwaukee, WI 53202 United States Tel: +1 414 276 1791 Fax: +1 414 276 3349 Email: info@worldallergy.orginfo@worldallergy.org