Allergy School on Investigating allergic effects of environmental exposures. Brindisi, Italy, 2-5 July Venom Allergy. M.

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1 Allergy School on Investigating allergic effects of environmental exposures Brindisi, Italy, 2-5 July 2014 Venom Allergy M.Beatrice Bilò Department of Internal Medicine Allergy Unit University Hospital, Ancona Italy

2 Hymenoptera venom allergy - relevant species Hymenoptera Bilò MB et al, Allergy 2005 Superfamily Apoidea Vespoidea Family Apidae bees and bumblebees Vespidae wasps Formicidae ants Vespinae Subfamily Polistinae Apis honeybees Bombus bumblebees Vespula yellow jackets Dolichovespula hornets Polistes paper wasps Solenopsis Myrmecia Pachycondyla Pogonomyrmex Vespa European hornet

3 Prevalence of HVA obtained by questionnaire. Epidemiological population-based studies for the last decade References Country Study population Incorvaia 2004 Navarro 2004 Nittner- Marszalska 2004 Fernandez 2005 Italy Spain Poland Spain Factory workers Foresters Working population (Ford Factory) General population Rural area population Graif 2006 Israel High school children Onbasi 2008 Turkey General population Marques Spain General 2009 population Number of subjects Systemic reactions (%) Severe Systemic reactions (%) Not specified 1, (IV grade Mueller s class.) (IV grade Mueller s class.) (IV grade Mueller s class.) 10, (moderate to severe) , Bilò MB. Insect sting anaphylaxis. 2013

4 NATURAL HISTORY Estimated risk of systemic reaction in skin test positive untreated patients according severity, age and time elapsed Previous Reaction to insect sting Risk of Systemic Reaction Severity Age After 1-9 yrs After yrs No reaction Large local Cutaneous systemic Cutaneous systemic Anaphylaxis Anaphylaxis Adult All Child Adult Child Adult 17% 10% 10% 20% 40% 70% (adapted from Golden 2002) 10% 5% 10% 30% 40%

5 Clin Exp Allergy 2009 Factors determining the severity of a re-sting reaction History of a prior severe sting reaction (with respiratory or cardiovascular symptoms) Older age Insect type (honeybee, European hornet) Pre-existing disease: cardiovascular diseases, asthma Drugs: particularly beta-blockers (also eye drops), angiotensinconverting enzyme inhibitors Sting site (e.g. head) Mast cell diseases (including monoclonal mast cell activation syndrome) Elevated baseline serum tryptase concentration

6 Optimizing the diagnostic s of Hym enoptera venom allergy R Allergen components Hymenoptera venoms Table 2. Allergen components Hymenoptera venom. Species IUIS nomenclat ure Allergen M W (kda) Gly Wasp (Vespula vulgaris) Ves v 1 Ves v 2a and b Ves v 3 Ves v 4 Ves v 5 Ves v 6 Phospholipase A1 Hyaluronidase Dipeptidylpeptidase CUB protease Antigen 5 Vitellogenin Polistes Pol d 1 Pol d 4 Pol d 5 Phospholipase A1 Serine protease Antigen 5 family Honey bee (Apis mellifera) Api m 1 Api m 2 Api m 3 Api m 4 Api m 5 Api m 6 Api m 7 Api m 8 Api m 9 Api m 10 Api m 11 Api m 12 Phospholipase A2 Hyaluronidase Acid phosphatase Mellitin Dipeptidylpeptidase Protease inhibitor CUB serine protease Carboxyl esterase Carboxypeptidase Icarapin MRJP 8 MRJP 9 Vitellogenin Bumblee bee (Bombus pennsylvanicus) Bom p 1 Bom p 4 Phospholipase A2 Protease 16 28

7 Allergy 2005 JACI 2011

8 Current diagnostic tolls: Pitfalls Multiple positive diagnostic tests Most patients with stinging insect allergy react on allergy testing with more than one venom Usually single-positive history Identification of culprit insect by patients often unreliable Common diagnostic dilemma relevant for selection of vaccine(s) for VIT estimating the risk after a sting from a different species

9 Double-positivity to honeybee and yellow jacket 30% to >50% of all patients with venom allergy (especially with in vitro methods) 1.True double-sensitization to both venoms (30-40% of cases) Relevant carbohydrate epitope: Alfa 1,3-fucosylated N-glycans Major venom N-glycans are of MMF and MUF type 2. Cross-reactivity through common venom proteins (hyaluronidases) (~10% of cases) 3. Cross-reactivity through carbohydrates (CCDs) (50-60% of cases, probably clinically irrelevant) MUF 3 (F 6 ) MMF 3 (F 6 ) a1,6 a1,3 fuc a1,6 a1,3 fuc

10 Muller U et al, Allergy % double-positive to bee and wasp venom (ImmunoCAP) 37% had sige to CCD 99% of bee venom allergic patients had sige to rapi m 1 (non-glycosylated PLA2) 96% of wasp venom allergic patients had sige to rves v 5 (antigen 5) Conclusions: IgE both to Api m1 and Ves v5 indicates true double sensitization and immunotherapy with both venoms Double positivity of IgE to bee and Vespula venom is often caused by crossreactions, especially to CCD

11 Surprisingly, we found that more subjects had positive specific IgE responses for napi m 1 (153/169 [91%]) than for rapi m 1 (100/175 [57%]; P <.0001). These marked differences were even more prominent in subjects who had experienced severe anaphylactic reactions. 9% of patients showed IgE reactivity to CCDs Korosec P etal, JACI 2011

12 JACI 2014 Diagnostic sensitivity of sige to different combinations of HBV allergens.

13 JACI patients with YJV allergic reactions 31 in vitro YJV single positivity 105 YJ and HB venom in vitro double positivity rves v 1 and rves v 5 were each recognized by ~90% of sera CRD with rves v 1 and rves v 5 would detect virtually all patients with YJ venom allergy (97%)

14 Clinical Routine Utility of Basophil Activation Testing for Diagnosis of Hymenoptera-Allergic Patients with Emphasis on Individuals with Negative Venom-Specific IgE Antibodies Table 2. Sensitivity in Patients with Negative sige 23 16/57 25/71 pos. 27/65 49 pos. pos. 17 pos. 23/86 pos. 16 Key Words 19 16/30 pos. pos pos. Introduction 17 19/25 15/46 pos. 72/87 36 pos. pos Abstract Background: 19 pos /84 pos. 26/65 pos. pos /95 pos Materials and Methods: Korosec P e tal, Int Arch Allergy Immunol 2013

15 Efficacy of VIT in prospective studies with sting challenge Author VIT with No pts SR after CH (%) Chipps Mostly Vespula Children 42 1 (2) Hoffman Honey bee 25 5 (20) Golden Mostly Vespula (3) Mosbech Vespula 19 0 Urbanek Honey bee Children 66 4 (6.1) Muller Honey bee (23) Muller Vespula 57 5 (9) Meta-analysis (Ross, 2000): Level of evidence Ia Systematic Review (Watanabe 2010)

16 Venom immunotherapy for preventing allergic reactions to insect stings (Review) insect stings (Review) 2012 munotherapy for preventing allergic reactions to eli M, Hockenhull J, Cherry MG, Bulsara MK, DanielsM, Oude Elberink J BoyleRJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, DanielsM, OudeElberink J hranereview, prepared and maintained by TheCochraneCollaboration and published in TheCochraneLibrary VIT reduces the chance of having a serious allergic reaction to an insect sting by 90%. VIT also significantly improves the quality of life of people who have had a serious allergic reaction to an insect sting by reducing anxiety and possible limitation of activities caused by fear of insects. or preventing allergic reactions to insect stings (Review) chrane Collaboration. Published by John W iley & Sons, Ltd. We were unable to find out whether venom immunotherapy prevents fatal allergic reactions to insect stings, because Venom immunotherapy for preventing allergic reactions to insect stings (Review) these are so rare. BoyleRJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, DanielsM, Oude Elberink J

17 High adherence to hymenoptera venom SCIT: a real life Italian experience Aim of the study: To evaluate, in retrospective manner, real-life adherence to the recommendation to continue VIT for a 5-year period (maintenance phase) in an Italian population. 508 hymenoptera venom allergic patients VIT DURATION 1 year 99 % 3 years 95 % 5 years 84 % PATIENTS WHO COMPLETED THE TREATEMENT (%) Kamberi E, Brianzoni MF, Garritani MS, Antonicelli L, Bonifazi F, Bilò MB Copenhagen 2014 (abstract)

18 VIT is effective in most patients immediately after the conventional maintenance dose has been reached, even after a 3-5 day rush protocol. Goldberg A and Confino-Cohen R, Allergy 2009 LONG TERM PROTECTION AFTER STOPPING VENOM IMMUNOTHERAPY The studies where long-term protection, up to 7 years after discontinuing VIT of at least a 3-year duration, were evaluated on the basis of field stings or sting challenges revealed a protection rate of % (Bonifazi Allergy 2005) 18 Bilò MB, Bonifazi F. Immunotherapy 2011

19 Bonifazi F, Jutel M, Bilo BM, Birnbaum J, Muller U, EAACI Interest Group on Insect Venom Hypersensitivity. Allergy 2005

20 VIT Maintenance Dose 50 mcg 100 mcg 200 mcg Single sting venom Vespula and Polistes: 2-10 mcg Apis m.: mcg Vespa crabro: 100 mcg

21 Predictors of clinical effectiveness of Hymenoptera venom Immunotherapy p value Odds ratio Therapy with honeybee venom < ACE-inhibitors < ,24 Systemic allergic reaction during VIT < BTC > 20 mcg/l and/or adult-onset MIS (high likelihood to suffer from SM) Time interval between the end of build-up and sting challenge Double VIT for a simultaneous bee and vespid venom allergy High venom dose (200 mcg) during maintenance therapy Rueff F et al, Clin Exp Allergy. 2014

22 What about VIT safety? Systemic reactions during VIT 2-20% Bilò MB et al, Curr Op Allergy Clin Immunol 2010

23 How to improve VIT safety? (and preserve or increase efficacy) Defining the risk factors for SRs to VIT Premedication Antihistamines Leukotrienes Monoclonal Anti-IgE antibodies Route of administration Purified aqueous and purified depot extracts Modified allergens

24 Factors influencing the risk of a systemic anaphylactic reaction to venom immunotherapy Bilò MB. Bonifazi F. Immunotherapy 2011 (modified) Honeybee venom > vespid venom Build-up phase > maintenance phase Dose increase phase (?) Treatment with beta-blockers (?) Cardiovascular diseases (?) Mastocytosis Elevated baseline serum tryptase concentration Question marks indicate the existence of discordant data on these topics.