Review Article

Übersicht

Update on venom allergy with special aspects of diagnostics and therapy

Arthur Helbling, Ulrich R. Müller Allergy Unit Ziegler Hospital, Medical Clinic Tiefenau-Ziegler, Bern Hospital Network, Switzerland

Summary Worldwide Hymenoptera venom allergy is one of clear-cut diagnosis is possible thereby the basophil Update zur the most important causes of allergic and anaphy- activation test may be used as an additional in Hymenopterengift­­ lactic reactions which may even lead to death. Even ­vitro assay. Therapeutically the specific immuno- allergie mit though other Hymenoptera species may spread therapy with venoms is still the only causal besonderen due to globalization and climate change, honeybee and effective treatment of Hymenoptera venom al- Aspekten der and () stings are the most preva- lergy. Almost all patients with a wasp allergy are Diagnostik und lent elicitors of Hymenoptera venom allergy in protected by the immunotherapy with wasp ven- Therapie Central Europe. The detection of an elevated basal om. In contrast, despite of the bee venom immu- serum tryptase value has been repeatedly con- notherapy about 20 % of patients develop a – most- firmed as a risk factor for severe allergic reactions ly mild – systemic reaction to sting re-exposure. due to insect stings, thus, their determination in By increasing the maintenance dose, almost all pa- diagnostics is mandatory nowadays. To date 12 tients can achieve full protection. In addition, im- Key words honeybee and 6 wasp venom allergens have been provement of therapy with bee venom is conceiv- Hymenoptera venom identified, whereas currently the non-glycosylated, able since current therapy extracts contain no or allergy – insect venom species-specific major allergens Api m1 (honey- only small concentrations of some relevant bee allergens – recombi­ bee), Ves v 5 and Ves v 1 (wasp) are commercially venom allergens such as Api m 10 or Api m 3. As nant allergens – available for diagnosis. In case of double positivity a result of the actual research direction, by identi- ­tryptase – double of specific serum IgE to both whole venoms these fying IgE-inducing allergens other therapeutic ap- ­positivity – allergen allergens are useful for the selection of the caus- proaches for the treatment of Hymenoptera venom specific immunotherapy ative venom for specific immunotherapy. If no allergy fade into the background.

Zusammenfassung Schlüsselwörter Die Hymenopterengiftallergie ist weltweit eine der globuline E (sIgE) gegen beide Gesamtgifte sind Hymenopterengift­ wichtigen Ursachen für allergische und anaphylak- diese für die Identifizierung des verantwortlichen allergie – Insekten­ tische Reaktionen, die bis zum Tod führen kann. Gifts für die Immuntherapie wertvoll. Falls damit giftallergene – rekom­ Auch wenn sich durch Globalisierung und Kli- keine klare Diagnose erzielt wird, bietet sich der Ba- binante Allergene – mawandel andere Hymenopterenarten verbreiten sophilenaktivierungstest als zusätzlicher In-vitro- Tryptase – Doppel­­­ können, sind in Mitteleuropa Honigbienen- und Assay an. Therapeutisch ist die spezifische -Im positivität – allergens­ Wespenstiche die häufigsten Auslöser der Hy- muntherapie mit Insektengiften immer noch die pezifische Immun­ menopterengiftallergie. Der Nachweis eines erhöht- einzige kausale und auch effektive Behandlung ein- therapie en basalen Tryptasewerts hat sich als Risikofaktor er Hymenopterengiftallergie. Während fast alle Pa- für schwere allergische Reaktionen nach Insekten- tienten mit Wespengiftallergie durch die Im- stichen mehrfach bestätigt, sodass dessen Bestim- muntherapie mit Wespengift geschützt sind, ent- mung heutzutage in der Diagnostik unerlässlich ist. wickeln etwa 20 % der Bienengiftallergiker trotz Bi- Bis heute sind zwölf Bienen- und sechs Wespen- enengiftimmuntherapie bei Reexposition noch – giftallergene identifiziert, wobei aktuell die nicht meist leichtere – Allgemeinreaktionen. Durch Stei- glykolysierten, speziesspezifischen Hauptallergene gerung der Erhaltungsdosis kann fast jeder Patient Eingang/Submitted Api m 1 (Biene), Ves v 5 und Ves v 1 (Wespe) kom- geschützt werden. Ferner ist eine Optimierung in October 8, 2012 merziell für die Dia­gnostik verfügbar sind. Im Fall der Behandlung mit Bienengift denkbar, da in den Annahme/Accepted einer Doppelpositivität der spezifischen Immun- präsenten Therapielösungen relevante Bienengiftal- December 10, 2012

Allergo J 2013; 22 (4) 265–73 265 Review Article Update Hymenopterengiftallergieon hmenoptera venom allergy

Übersicht

lergene wie Api m 10 oder Api m 3 nicht oder nur in geringer Konzentration vorhanden sind. Aufgr- Abbreviations und der aktuellen Forschungsrichtung mit Identi- ACE Angiotensin-converting-enzyme fizierung IgE-induzierender Allergene rücken an- dere Therapieansätze bei der Behandlung von Hy- CCD Cross -reactive carbohydrate menopterengiftallergie in den Hintergrund. determinants­ IgE Immunoglobulin E sIgE Specific immunoglobulin E SIT Specific immunotherapy Hymenoptera Stings and Anaphylaxis Besides to foodstuffs and drugs Hymenoptera stings SLIT Sublingual immunotherapy belong to the most common triggers of anaphylax- is [1, 2]. Of the more than 100,000 different Hyme- noptera species, in Europe particularly the stings of action caused by S. invicta in a female worker from and bees, more rarely of hornets or bumble- Malaga (Spain) who had handled imported wood bees and only exceptionally of ants are the cause of from South America was reported [14]. In systemic allergic or also toxic reactions. In Europe pilosula (““) causes a con- about 200 and in the United States about 100 people siderable portion of the allergic reactions induced die annually after an insect sting [3, 4]. The inci- by Hymenoptera stings [6, 15]. Our native wood and dence of death varies depending on region and is meadow ants (Formica spp.) possess only a rudi- reported between 0.09 and 0.48 per 1 million popu- mentary stinging apparatus, so that systemic reac- lation per year [3, 5–7]. Cases of death usually affect tions due to their stings are extremely rare [3, 16]. adults over 40 years with a cardiovascular or chron- ic pulmonary disease as well as occasionally persons Hymenoptera Venoms and Allergens with an as of yet undiagnosed mastocytosis [3, 6–9]. In a bee sting on average about 50 μg, after a wasp sting 3–5 μg of venom proteins are introduced to Entomological Aspects the body of the victim [3, 5, 6, 17]. Hymenoptera Of the of the order Hymenoptera particular- venom is composed of various components and con- ly the stings of the eusocial families of the wasps tains biogenic amines (e.g. histamine), peptides (), the bees (Apidae) and the ants (Formici- such as mellitin and species-specific allergens (pro- dae, Myrmicidae) are responsible for allergic sys- teins). The most important allergens in bee venom temic reactions [3, 5, 6, 10]. Besides the honeybees are phospholipase A1 (Api m 1), hyaluronidase (Api (Apis mellifera) the bumblebees (Bombus spp.) be- m 2) and acid phosphatase (Api m 3), in wasp ven- long to the Apidae. The family of the wasps Vespi( - om phospholipase A1 (Ves v 1) and antigen 5 (Ves dae) encompasses the subfamilies of the true wasps v 5) [3, 10, 18–21]. Currently twelve bee and six wasp (Vespinae) and the paper wasps (). The venom allergens have been identified (Table 1, Ta- short-headed wasp ( spp.), the long-headed ble 2). While most allergens of bee and wasp ven- wasp ( spp.) – both also known as oms are not related in their composition, the venom – and the hornet (Vespa spp.) belong of the short-headed wasps V. vulgaris and V. ger- to the true wasps. In Europe the short-headed wasps manica relevant for wasp venom allergy are practi- (Vespula germanica, ) are responsi- cally identical [10]. The venoms of hornet and long- ble for most allergic incidents. In contrast to the headed wasps also demonstrate high cross-reactiv- other wasp species, they are scavengers and carni- ity with that of the vespula. Distinct differences are vores, which frequently interact with humans, e.g. found between the venom of the short-headed and during outdoor eating. Stings of hornets and long- the paper wasps: Only about one-half of the prima- headed wasps occur almost exclusively in the vicin- ry sensitized reacted with the venom of the other ity of the . Paper wasps ( spp.) are espe- [10]. The venoms of honeybees and of bum- cially found in Mediterranean regions, small colo- blebees also exhibit only limited cross-reactivity, nies are, however, found all over Europe – with the which must be taken into consideration when mak- exception of Great Britain [11]. The Asian hornet ing the indication for specific immunotherapy (SIT) Vespa velutina has been newly introduced and has in bumblebee allergy. since 2005 rapidly spread from southern France [12]. In the Southern States of the USA as well as in Clinical Features in Hymenoptera Stings South and Middle America stings of ants not rarely The sting reactions are categorized as cause systemic allergic reactions. Particularly the ——normal local, fire ants Solenopsis( invicta, Solenopsis richteri) are ——severe local, responsible [3, 6, 13]. Recently an anaphylactic re- ——systemic toxic,

266 Allergo J 2013; 22 (4) 265–73 ——systemic allergic and In recent years the association between elevated ——unusual reactions [3, 5–7, 22]. basal serum tryptase levels and the occurrence of A normal reaction corresponds to a swelling < 10 allergic systemic reactions after insect stings has cm in diameter that usually fades again within sev- been confirmed repeatedly [9, 22, 26–28]. Patients eral hours. The pruritus at the sting site can contin- with tryptase levels > 5 μg/l have a somewhat in- ue for several days. creased risk to react systemically to bee or wasp Insect venom allergy is usually IgE-mediated. Se- stings [27]. In about 10 % of patients with a system- vere local reactions are accompanied by swelling > 10 cm in diameter and a duration of more than 24 hours, sometimes over one week, and are usually as- || Table 1 sociated with venom-specific IgE. Allergic systemic Identified allergens of bee venom reactions after Hymenoptera stings are classified Allergen MW Major/minor allergen* CCD with respect to severity according to the criteria of kDa H. L. Mueller or Ring and Messmer [3, 5–7, 22]. They Phospholipase A2 16 Major + Api m1 usually manifest within minutes up to an hour af- Hyaluronidase 45 Major + ter the sting and fade again after hours. Api m2 Toxic reactions occur after multiple Hymenoptera Acid phosphatase 49 Minor + stings. They are primarily due to the cytotoxic effect Api m3 of melittin, phospholipases and kinins that lead to Melittin 2,8 Minor - hemolysis, kidney and liver damage. -threaten- Api m4 Dipeptidyl peptidase 102 ? + ing toxic reactions can develop in children depend- Api m5 ing on age after 10–50, in adults after 50–100 stings. Protease inhibitor 8 Minor - Rarely persons have survived over 1,000 stings [3, Api m6 5–7, 22]. CUB serine protease 39 ? + The term “unusual reactions” is used for those Api m7 that are neither based on an IgE-mediated nor on a Carboxyl esterase 70 Minor + Api m8 toxic mechanism, such as lymphadenopathy, pe- Carboxypeptidase 60 ? + ripheral neuropathies, vasculitides, Henoch- Api m9 Schoenlein purpura or arthralgies. Unusual reac- Icarapin 55 Major + tions are rare and usually develop after hours and Api m10 can last for several days. MRJP 8 65 ? + MRJP 9 60 ? + Risk Factors for Hymenoptera Venom Allergy Api m11 Vitellogenin 200 ? + The prevalence of an allergy systemic reaction after Api m12 a Hymenoptera sting is estimated at between 1 and MW, molecular weight; CCD, cross-reactive carbohydrate determinants; MRJP, major royal jelly protein; + 7 % in Europe [3, 5–7, 22]. The risk increases with = present; - = not present *Major allergen: > 50 % of patients with bee venom allergy have specific IgE antibodies, the frequency of stings, which is why beekeepers or Minor allergen: < 50 % of patients with bee venom allergy have specific IgE antibodies persons with a risk of stings in their work are more highly endangered. The risk is particularly high, when two stings occur within a short time interval || [7]. After a mild systemic reaction the risk of a re- Table 2 Identified allergens of wasp venom Vespula( spp.) newed systemic reaction is about 30 %, after a severe reaction over 50 % [3, 5–7, 22]. Children (under the Allergen MW Major/minor allergen* CCD kDa age of 12 years) in general have a lower risk of recur- Phospholipase A1 34 Major - rence than adults. Older persons have a tendency to Ves v1 more severe systemic reactions due to preexistent Hyaluronidase 38 Minor + chronic cardiovascular or pulmonary diseases [7, 8, Ves v2 23]. Dipeptidyl peptidase 100 ? + Treatment with β-blockers or angiotensin-con- Ves v3 verting enzyme (ACE) inhibitors can increase the Protease Ves v4 severity of the systemic reaction. On the other hand, Antigen 5 23 Major - treatment with β-blockers and with ACE inhibitors Ves v5 does not increase the risk to react allergically after Vitellogenin 200 ? + an insect sting [23–25]. Atopic individuals do not Ves v 6 have a higher risk than non-atopic individuals to be MW, molecular weight; CCD, cross-reactive carbohydrate determinants; + = present; - = not present *Major allergen: > 50 %of patients with wasp venom allergy have specific IgE antibodies, allergic to Hymenoptera stings. Patients reacting Minor allergen: < 50 % of patients with wasp venom allergy have specific IgE antibodies with bronchospasm are frequently atopic.

Allergo J 2013; 22 (4) 265–73 267 Review Article Update Hymenopterengiftallergieon hmenoptera venom allergy

Übersicht

ic reaction after a Hymenoptera sting elevated one-half of all patients with insect venom allergy [3, tryptase values are found (> 11.4 μg/l) [27, 28]. In a 6, 10, 22]. This can be explained by cross-reactions portion of those affected a cutaneous mastocytosis as well as by true sensitizations for both venoms. is found. Cross-reactions can be due to partial sequence iden- In our collective in 13 of 81 patients (16 %) with tity of protein allergens (e.g. hyaluronidase, dipep- Hymenoptera venom allergy and a basal tryptase tidyl peptidase) or specific IgE antibodies against value > 11.4 μg/l a histologically confirmed cutane- carbohydrate determinants of allergens, the cross- ous mastocytosis was found in dermatologic evalu- reactive carbohydrate determinants (CCD) [32–34]. ation (Prof. T. Hunziker, Department of Dermatol- Various studies have shown that a considerable ogy, University Hospital of Bern, Switzerland). With share of double sensitizations is due to CCD. How- basal tryptase values > 20 μg/l the possibility of a ever, the clinical relevance of these IgE antibodies systemic mastocytosis is high [7, 9, 22, 28]. There- has not yet been clarified. CCD also occur in plants fore, differentiated examinations with skin and and in pollen, which might be a possible explana- bone marrow biopsies are required depending on tion for their suboptimal specificity. A differentia- the clinical findings and therapeutic consequences. tion is relevant with respect, as in true double sen- It is assumed that about one-third of patients with sitization specific immunotherapy (SIT) with both a documented mastocytosis develop allergic up to venoms should be performed. The determination of fatal systemic reactions after insect stings [29]. Clin- specific IgE against the recombinant, species-spe- ically often no cutaneous symptoms are observed or cific, non-glycosylated major allergens Api m 1, Ves they present with flushing and less with urticaria or v 5 and Ves v 1 have become available recently (Im- angioedema [30]. munoCAP®, Phadia AG, Thermo Fisher Scientific) [31, 35, 36, 37, 38]. While the specificity of Api m 1 Diagnosis is very good with over 0.95, the sensitivity in sole The basis for the diagnosis is the history of a system- use of this major allergen declines to about 0,8, ic reaction after an insect sting. The signs and symp- which is not optimal to identify a bee venom aller- toms can, however, be due to fear or strong pain via gy securely with a relevant history. In contrast, the a vasovagal reaction. An important indication of an sensitivity and specificity to secure the diagnosis of allergic reaction is the occurrence of acute symptoms wasp venom allergy when suspected is optimal with such as urticaria, angioedema, dyspnoe or collapse. use of Ves v 5 and Ves v 1 (Table 3) [36]. The allergic genesis must be confirmed by in vivo While in past years the complex IgE inhibition (skin) and/or in vitro tests (specific IgE antibodies) [3, tests were used for the differentiation between cross- 5–7, 22]. If diagnostics are performed within twelve reactivity and double sensitization, in recent years it months after a systemic reaction, the IgE-mediated has been attempted to solve the problem with the ba- sensitization to the respective venom can be recog- sophil activation test [39–41]. This is somewhat more nized in almost 100 % of cases. The specificity of specific than the skin tests or IgE determination these tests is, however, limited, as even in persons against total venoms, but also considerably more with no allergic symptoms even years after a Hyme- time-consuming and expensive and unfortunately noptera sting the sensitization can be detected in 10– not yet optimally standardized. Moreover, positive 25 % of cases [22]. In atopic individuals with high to- results to CCD have been reported [40, 41]. tal IgE values this finding is even significantly more frequent [31]. It must be remembered, that a sensiti- Double Negative Tests in Presence of a zation is usually acquired through a normally toler- Suggestive History ated insect sting. Skin tests with Hymenoptera ven- Even if rare, the test can turn out double negative [5, oms should be performed three to four weeks after a 22]. When the time interval between a severe sys- systemic reaction at the earliest [3, 5–7, 22]. The in- temic reaction until testing is under three weeks, tracutaneous endpoint titration, where 0.02 ml each this should be repeated three to four weeks later. of the venom solution from 0.00001 to 1.0 μg/ml are When prick tests were employed, the performance injected, is considered the test procedure with the of the more sensitive intracutaneous tests is recom- best validation. The detection of specific IgE antibod- mendable. The determination of specific IgE should ies against total venom can be performed using dif- also be repeated. Particularly in wasp venom aller- ferent assays. These are, however, somewhat less sen- gy the determination of specific IgE against Ves v 5 sitive than intracutaneous testing, which is especial- has proven distinctly more sensitive than against ly true for wasp venom. the total venom [36]. Additional information should be sought through measurement of the basal serum Double Positivity tryptase value as well as the basophil activation test Double positivity with the detection of specific IgE [22]. If the repetition is not able to detect a sensiti- antibodies against bee and wasp venom is found in zation in any test system, we consider the perfor-

268 Allergo J 2013; 22 (4) 265–73 || Table 3 Sensitivity and specificity of commercial recombinant major allergens of bee and wasp venom [36] ImmunoCAP® Positive with BV and WV Positive only with BV Positive only with WV Positive only with WV n = 76 n = 23 n = 22 n = 32 Positive with Api m 1 and Ves v 1/ Ves v 5 36 (47,4 %) 0 0 0 Positive with Api m 1 9 (11,8 %) 18 (78,3 %) 0 0 Positive with Ves v 1/ Ves v 5 30 (39,5 %) 0 22 (100 %) 1 (3,1 %) [positive with Ves v 1] Negative with all recombinants 1 (1,3 %) 5 (21,7 %) 0 31 (96,9 %) Positive with MUXF3 (CCD) 41 (54,0 %) 1 (4,4 %)* 0 0 BV, bee venom; CCD, cross-reactive carbohydrate determinants; sIgE, spezific immunoglobulin E; WV, wasp venom *Of all 45 single-positive patients 2.2 % had sIGE against MUXF3 (CCD).

mance of SIT as not indicated. An exception might is a high degree of exposure or special risks [44]. In be in mastocytosis with documented anaphylaxis the USA and in the recently newly published Ger- after a Hymenoptera sting [22]. We advise against man guideline SIT is abstained from in this situa- diagnostic exposition tests with living insects [42]. tion in children [22]. Severe local reactions are not Independent of the results of diagnostic tests pa- an indication for SIT even in the case of positive di- tients with a history of a systemic reaction after Hy- agnostic tests. Nonetheless, in a controlled study ef- menoptera stings should be provided emergency ficacy could be demonstrated, so that we today dis- medications – including an adrenalin autoinjector cuss SIT in greatly exposed patients and frequent – and be instructed on the correct use not only oral- stings [46]. SIT is not indicated in unusual or toxic ly and in written form, but also receive practical in- reactions. struction [3, 5–7, 18, 22]. Contraindications Specific Immunotherapy with Hymenoptera The contraindications of SIT with insect venoms are venoms the same as in other immunotherapies [47]. Based on new knowledge in recent years immunodeficien- Efficacy cies (e.g. HIV [human immunodeficiency virus] in- In the last 30 years the SIT with insect venoms has fections) or autoimmune disorders are no longer proven to be the only causal and effective treatment generally viewed as contraindications [48, 49]. This of insect venom allergy [3, 6, 18, 22, 42–45]. While position was also called into question in patients over 95 % of patients with wasp venom allergy de- with malignancies and Hymenoptera venom aller- velop no systemic reaction after renewed wasp gy [50]. In a retrospective study over five years we stings, about 80 % of patients with bee venom aller- analyzed patients with insect venom allergy with gy are fully protected (Table 4). If a systemic reac- respect to concomitant malignancies. In the collec- tion develops after a renewed sting during SIT, this is usually distinctly weaker than the index reaction. In a prospective study it could be shown that by in- || creasing the maintenance dose of both bee as well Table 4 Development of Hymenoptera allergy with and as wasp venom to 200–250 μg nearly all patients without ­ venom immunotherapy­ [42, 43] could be protected [43]. Recently it became public knowledge, that in commercially available thera- Index reaction Author, year % with systemic reaction at re-exposure peutic solutions relevant bee allergens such as Api Bee Wasp m 10 or Api m 3 are not present or present only in n (%) n (%) low concentration, which might explain the lower Systemic reaction van der Linden, 1994 27/52 (51,9) 203/272 (74,6) efficacy of SIT with bee venom [20]. (without immunotherapy) Blaauw, 1985 19/38 (50,0) 12/50 (24,0) Systemic reaction Hoffmann, 1981 5/25 (20,0) Indications (re-exposure during Müller, 1992 34/148 (23,0) 5/57 (8,8) ­immuno-therapy) According to guidelines in Europe and in the USA Urbanek, 1985 (Kinder) 4/66 (6,1) SIT with insect venoms is indicated in the presence Golden, 1981 3/18 (16,7) of a severe systemic reaction with respiratory and/ Van der Zwaan, 1983 0/11 (0) or cardiovascular symptoms and positive diagnos- Mosbech, 1986 0/19 (0) tic tests [44, 45]. Based on the European guideline Systemic reaction Ruëff, 2001 1/18 (5,5%) 0/22 (0) in face of the low risk of a severe systemic reaction (re-exposure during ­immuno-therapy with after only a cutaneous reaction in children and 200–250 μg) adults the indication for SIT exists only when there

Allergo J 2013; 22 (4) 265–73 269 Review Article Update Hymenopterengiftallergieon hmenoptera venom allergy

Übersicht

|| Table 5 Systemic SIT-induced side effects in relation to the basal serum tryptase value in 447 patients with Hymenoptera venom allergy (med. dissertation, S. Scheier, unpublished data) Tryptase µg/l Patients (%) Reactors during ultrarush (%) Reactors after 6 months SIT (%) > 20,0 24 (5,4)a 5 (20,9) 3 (12,5) 11,5–19,9 31 (6,9)a 7 (22,6) 0 7,1–11,4 48 (10,7)b 5 (10,5) 3 (6,3) 0,0–7,0 344 (76,9) 24 (6,9) 5 (1,5) SIT, specific immunotherapy; aConfirmed mastocytosis in ten patients; bConfirmed mastocytosis in one patient

tive of 2,595 patients with insect venom allergy, 2 % ——in rush and ultrarush protocols than in conven- had a tumor diagnosis. In 36 of the 51 patients tional as well as (71 %) the diagnosis of a malignancy was known be- ——with aqueous than with depot preparations. fore the insect venom allergy. According to the In contrast, they are rarer in purified venom prepa- guidelines SIT was initiated in 42 patients [22, 44]. rations than in unpurified preparations [52]. During the SIT in three of 27 patients (11 %) with The risk of a SIT-associated side effect increases previously known malignancy a secondary carci- particularly with wasp venom, if an elevated basal noma (2) or, respectively, a reactivation/ metastasis tryptase value is found [26, 51]. It is well-known that (1) was found. With respect to tolerability and effi- patients with a mastocytosis have a higher risk for cacy of SIT – 19 (45 %) were again stung by the rel- SIT-induced side effects than those with normal evant insect and in 1 (5 %) an easily treatable sys- tryptase values [28]. In a retrospective study over temic reaction developed – the collective did not five years we have analyzed all 447 patients with in- differ from the healthy. The question if SIT with in- sect venom allergy and ultrarush with respect to the sect venom provokes the development of tumors frequency of systemic side effects during treatment cannot be answered definitively at this time. in relation to the basal tryptase value. It was ob- served that SIT-induced systemic side effects in pa- Side Effects tients with a basal tryptase > 11.4 μg/l in compari- Systemic allergic reactions in connection with SIT son to those with a value < 11.4 μg/l were registered were observed in different frequencies, overall in twice as frequently (Table 5). Also during the fur- 5–20 % of cases, predominantly in the induction ther course after six months side effects were more phase [3, 6, 22, 28, 44, 51]. frequent in patients with elevated tryptase values. ——They occur more frequently All adverse reactions are transient and treatable; ——in SIT with bee than with wasp venom, deaths are not known. In the event of a switch of preparation, e.g. from an aqueous solution to depot preparations and/or premedication with antihista- || Table 6 Perspectives for diagnosis and immunotherapy mines is not successful and a minimal single dose of 50 μg especially of bee venom is not achieved, a Perspectives Current status Realization therapy attempt with omalizumab can be worth- Component-based diagnostics while [22, 53, 54]. In seven of eight published cases, Better sensitivity Advanced, but capable of Foreseeable —— three of these with documented mastocytosis, the Better specificity ­improvement —— maintenance dose of insect venom could be Clarification of double sensitivity —— achieved with the use of this recombinant, human- Immunotherapy with bee venom ized monoclonal antibody. In three patients, how- Better efficacy through: —— ever, after discontinuation of omalizumab recurrent —— Addition of Api m 3 and Planned Foreseeable Api m 10 allergic reactions developed. Unfortunately, the use —— Intralymphatic immunotherapy Successful in mice Possible of omalizumab is not a mandatory service of the —— Less side effects through: health insurers, so that in patients with a mast cell —— Modified allergens, In vitro studies, one Very time- and instability or mastocytosis usually the dose must be T-cell peptides ­clinical study cost-consuming increased individually, i.e. in smaller dose steps. —— DNA vaccination Theoretically interesting Very time- and cost-consuming Duration of Therapy —— SLIT Two clinical studies with Improbable questionable results The generally recommended SIT duration of three DNA, desoxyribonucleic acid; SLIT, sublingual immunotherapy to five years protects after discontinuation of treat- ment more than 90 % of the wasp venom and more

270 Allergo J 2013; 22 (4) 265–73 than 80 % of the bee venom allergic patients from cation after six months [62]. In those treated with further systemic sting reactions [55, 56]. A longer, verum as well as those treated with placebo there perhaps even lifelong SIT should be considered in was a reduction of the diamter of the swelling. Sig- patients with very severe systemic reactions, in the nificance, however, was only achieved in the verum case of chronic cardiovascular or respiratory co- group. In both studies there were shortcomings that morbidities, in systemic mastocytosis or in patients gave rise to criticism, so that SLIT for the time be- with distinctly elevated basal serum tryptase [8, 9, ing can not be considered a therapeutic option in 22, 27, 44]. Hymenoptera venom allergy [63].

Perspectives for Diagnosis and Treatment Prof. Dr. Arthur Helbling The current perspectives for diagnosis and treat- Allergy Unit Ziegler Hospital Medical Clinic Tiefenau-Ziegler Table 6 ment are presented in . Bern Hospital Network The component-based diagnostics for verification Morillonstraße 75 of a bee venom allergy – currently only the recom- 3001 Bern – Switzerland binant major allergen Api m 1 is available commer- cially – could be optimized by adding relevant spe- Conflicts of interest cies-specific allergens without CCD such as Api m The authors declare that no conflicts of interest exist.. 3 and Api m 10. It is hoped that by addition of the Der Verlag erklärt, dass die inhaltliche Qualität des Be­ itrags von zwei unabhängigen Gutachtern geprüft wurde. same allergens to therapy solutions the efficacy of Werbung in dieser Zeitschriftenausgabe hat keinen ­Bezug SIT with bee venom can be increased, as these are zur CME-Fortbildung. Der Verlag garantiert, dass die CME- lacking or only insufficiently represented in cur- Fortbildung sowie die CME-Fragen frei sind von werbli­ chen Aussagen und keinerlei Produktempfehlungen rently available preparations [20]. Based on the first enthalten. Dies gilt insbesondere für Präparate, die zur clinical results with intralymphatic immunothera- Therapie des dargestellten Krankheitsbildes geeignet pies it could be shown that a six-month treatment sind. with three injections in patients with pollen allergy protection over several years could be attained [57]. References If this form of administration can also be utilized 1. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; in insect venom allergies, must still be shown. In 125: S161–81 experimental studies with mice sensitized to bee 2. Worm M. Epidemiology of anaphylaxis. Chem Immunol venom the intralymphatic immunotherapy proved Allergy 2010: 95: 12–21 3. Müller U. Insektengiftallergie. In: Schultze-Werninghaus G, to be considerably more efficacious in comparison Fuchs T, Bachert C, Wahn U (eds). Manuale Allergologi­ to the subcutaneous route [58]. cum. 3. Aufl. München – Orlando: Dr. Karl Feistle, 2008: Allergic side effects of SIT, especially with bee 369–97 venom, might be reduced by using modified major 4. Tracy JM, Khan FS, Demain JD. Insect anaphylaxis: where are we? The stinging facts 2012. Curr Opin Allergy Clin allergens with reduced IgE binding, but retained ­Immunol 2012; 12: 400–5 specific T-cell interaction. Clinical studies with T- 5. Bilò MB, Ruëff F, Mosbech H, Bonifazi F, Oude-Elbering cell epitope peptides [59] as well as a recombinant JNG, Birnbaum J et al. Diagnosis of Hymenoptera venom allergy. EAACI Position Paper. Allergy 2005; 60: 1339–49 multiallergen vaccine consisting of Api m 1, Api m 6. Müller UR. Insect sting allergy. In: Kay AB, Bousquet J, Holt 2 and Api m 4 [60] have already demonstrated this PG, Kaplan AP (eds). Allergy and allergic diseases. 2nd possibility. In immunotherapy with T-cell epitope ­edition, Blackwell, 2008: 2010–24 peptides a systemic side effect was in fact not regis- 7. Bilò MB, Bonifazi F. The natural history and epidemiology of insect venom allergy: clinical implications. Clin Exp tered in any patient, but only three of five patients ­Allergy 2009; 39: 1467–76 tolerated a sting provocation without systemic al- 8. Mueller UR. Cardiovascular disease and anaphylaxis. Curr lergic symptoms [59]. Due to the current identifica- Opin Allergy Clin Immunol 2007; 7: 337–41 tion of numerous IgE-inducing insect venom aller- 9. Przybilla B, Müller U, Jarisch R, Ruëff F. Erhöhte basale ­Serumtryptasekonzentration oder Mastozytose als Risiko­ gens (Table 1, Table 2), the introduction of such faktor der Hymenopterengiftallergie. Leitlinie der DGAI. preparations as well as a DNA vaccination in the Allergo J 2004; 13: 440–2 near future appears unlikely. 10. Hemmer W. Kreuzreaktionen zwischen Hymenopteren­ Two studies from Italy examined sublingual im- giftallergenen. Allergo J 2009; 18: 359–72 11. Diwakar L, Noorani S, Huissoon AP, Frew AJ, Krishna MT. munotherapy (SLIT) in Hymenoptera venom aller- Practice of venom immunotherapy in the United King­ gy [61, 62]. In the one study 20 patients with wasp dom: a national audit and review of the literature. Clin Exp venom allergy were treated with SLIT [61]. Four of Allergy 2008; 38: 1651–8 12. Haro L de, Labadie M, Chanseau P, Cabot C, Blanc-Brisset I, the treated were re-exposed with one developing a Penouil F; National Coordination Committee for Toxico­ systemic reaction and another a severe local reac- vigilance. Medical conse-quences of the Asian black hor­ tion. In the second placebo-controlled study 26 pa- net (Vespa velutina) invasion in Southwestern France. tients with severe local reactions after bee stings ­Toxicon 2010; 55 (2–3): 650–2 13. Klotz JH, deShazo RD, Pinnas JL, Frishman AM, Schmidt JO, were treated with SLIT and underwent sting provo-

Allergo J 2013; 22 (4) 265–73 271 Review Article Update Hymenopterengiftallergieon hmenoptera venom allergy

Übersicht

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