doi:10.1111/j.1365-2222.2011.03788.x Clinical&ExperimentalAllergy,41,1201–1220 BSACI GUIDELINES (cid:2)c2011BlackwellPublishingLtd Diagnosis and management of hymenoptera venom allergy: British Society for Allergy and Clinical Immunology (BSACI) guidelines M.T.Krishna1,P.W.Ewan2,L.Diwakar1,S.R.Durham3,A.J.Frew4,S.C.Leech5andS.M.Nasser2 1BirminghamHeartlandsHospital,Birmingham,UK,2CambridgeUniversityHospitalsNHSFoundationTrust,Cambridge,UK,3RoyalBromptonHospitalandImperial CollegeofScienceandTechnology,London,UK,4BrightonGeneralHospital,Brighton,UKand5DepartmentofChildHealth,King’sCollegeHospital,London,UK Clinical & Summary Thisguidanceforthemanagementofpatientswithhymenopteravenomallergyhasbeen Experimental preparedbytheStandardsofCareCommittee(SOCC)oftheBritishSocietyforAllergyand ClinicalImmunology(BSACI).Theguidelineisbasedonevidenceaswellasonexpertopinion Allergy andisforusebybothadultphysiciansandpediatricianspractisingallergy.Duringthe developmentoftheseguidelines,allBSACImemberswereincludedintheconsultation Correspondence: processusingaweb-basedsystem.Theircommentsandsuggestionswerecarefullyconsidered DrShuaibM.Nasser,Cambridge bytheSOCC.Whereevidencewaslacking,consensuswasreachedbytheexpertsonthe UniversityHospitalsNHSFoundation committee.Includedinthisguidelineareepidemiology,riskfactors,clinicalfeatures, Trust,AllergyClinic,CambridgeCB2 diagnostictests,naturalhistoryofhymenopteravenomallergyandguidanceonundertaking 0QQ,UK. venomimmunotherapy(VIT).Therearealsoseparatesectionsonchildren,elevatedbaseline E-mail: [email protected] tryptaseandmastocytosisandmechanismsunderlyingVIT.Finally,wehavemade Citethisas:M.T.Krishna,P.W.Ewan,L. recommendationsforpotentialareasoffutureresearch. Diwakar,S.R.Durham,A.J.Frew,S.C. KeywordsACEinhibitor,anaphylaxis,baselinetryptase,bee,b-blocker,hornet,hymenoptera, LeechandS.M.Nasser,Clinical& ExperimentalAllergy,2011(41) IgE,immunotherapy,venom,wasp 1201–1220. Submitted5March2011;revised1April2011;accepted29April2011. ExecutiveSummary clinicalallergytoasinglememberofthehymenop- terafamily. 1. Patients experiencing a systemic reaction (SR) to 5. Baselinetryptase should bemeasuredinallpatients wasp or bee stings should be referred to an allergy with SRs, as those with raised levels have a higher specialistforinvestigationandmanagement. riskofsevereSRs. 2. IntheUnitedKingdom,waspvenomallergyismore 6. Patients with a history of SR should be immediately common. Bee venom allergy usually occurs in bee- providedwithawrittenemergencymanagementplan, keepers, their household members or where there is anadrenalineauto-injectorandeducatedinitsuse. occupationalrisk. 7. Venom immunotherapy (VIT) is effective in 95% of 3. Venom allergy is a common cause of anaphylaxis patients allergic to wasp venom and about 80% of and may be fatal. The main features of SRs are thoseallergictobeevenom. rapid onset generalized urticaria, angio-oedema, 8. VITisrecommendedforallpatientswithasevereSR bronchospasm/laryngeal oedema and hypoten- after a sting and in many patients after a SR of sion with collapse and loss of consciousness. moderateseverity. Hypotension is the dominant feature and may 9. VIT is usually not indicated for less severe sting- occuralone. inducedSRsunlessadditionalriskfactorsarepresent 4. Demonstration of venom-specific IgE is the corner- forexample:araisedbaselinetryptase,ahighlikeli- stone of diagnosis and skin testing (skin prick and hood of future stings, (bee keeping,or occupational intradermal) remains the first line of investigation. exposure),oreffectonqualityoflife(QOL). Allpatientsshould be tested tobothvenoms.While 10. Children generally have less severe reactions than double-positive intradermal skin tests to both bee adultsandabetterprognosisandthereforeVITshould and wasp venoms are rare, dual-positive serum- onlybeconsideredforthesmallpercentagethathave specific IgE is common even in the presence of severesting-inducedsystemicallergicreactions. 1202 M.T.Krishnaetal 11. VIT must not be undertaken in the absence of prevalence of sensitization varies between 9.3% and demonstrablevenom-specificIgE.Inpatientswitha 38.7% [3] in the adult population, large local reactions recent history of anaphylaxis or SR, where venom- (LLR) occur in 2.4–26.4% [3–6] and SRs in 0.3–7.5% specific IgE is not demonstrable, allergy testing [5–10].Thedifferences betweenstudies havebeenattrib- shouldberepeated. uted at least in part to confounding variables including 12. VITshouldbecarriedoutonlybyallergyspecialists geographical location, data collection technique, defini- with experience and knowledge in this field and in tionofanaphylaxisanddegreeofexposure.Inbeekeepers centres undertaking VIT in significant numbers of and their family members, the sensitization rate to bee patientsandwheretheteamhasexpertiseintreating venomis30–60%[11],theprevalenceoflocalreactionsis anaphylaxis. 9–31%, and the prevalence of SRs is 14–32%. Venom 13. IntheUnitedKingdom,theusualdurationofVITis3 allergy is an important cause of anaphylaxis accounting years. Longer or even life-long treatment in patients for about one quarter of cases where the cause was witharaisedbaselinetryptaseisnotadvocatedinthe determined in adults [12]. Fatalities following insect UnitedKingdombecausethisisnotevidence-based. stings are rare and occur in 0.03–0.48 per 100000 14. Many patients with a raised baseline tryptase and a inhabitantsperyear[2,3,11].Thesedataarelargelyfrom SRhaveanindolentformof‘mastocytosis’andareat studiescarriedoutintheUnitedStatesandEurope.There higher riskof SRs during VITalthough VIT remains are no published data on prevalence of hymenoptera thetreatmentofchoice. venomallergyfromtheUnitedKingdom.However,Pum- 15. An adrenalineautoinjector should be provided dur- phrey[12,13]reportedthatbetween1992and2001inthe ingup-dosingofVITandBritishSocietyforAllergy United Kingdom, 47 out of 214 deaths, due to anaphy- and Clinical Immunology (BSACI) also recommends laxis,were caused by beeor waspstingsandtheaverage itslong-termprescriptionforthefollowing: ageofdeathwas50years[13]. a. If during VIT the patient continued to experi- enceallergicreactions Riskfactors b. After VIT, those at continuing risk of multiple stings, e.g. those with an occupational risk or a The frequency of a systemic reaction is affected by the beekeeper followingfactors c. After VIT, patients with an elevated baseline i. Preceding reaction: The risk for SRs in the normal tryptaseormastocytosis. populationisincreasedby58%ifprecededbyasting 16. Patients should be advised on ways of minimizing within 2 months even if the first sting was well theirriskoffurtherstings. tolerated [14]. The estimated risk of a SR is 5–15% [7]afterapreviousLLRand40–60%[15]afteraSR. ii. Sensitizationtovenom:IgEsensitizationtovenomis Introduction a risk factor for subsequent SRs [16]. However the Thisguidanceisintendedforusebyspecialistsinvolvedin level of venom-specific IgE does not correlate with the investigation and management of patients with hy- the severity of the SR and some patients with barely menoptera venom allergy. This updates the previous detectable venom-IgE can have near-fatal anaphy- BSACI position paper [1]. It is recommended that all laxis [17, 18] In addition, positive skin tests and patientsexperiencingaSRinresponsetoinsectstingsbe venom-specificIgEarealsofoundinpatientswithout referredtoanallergyspecialistforfurtherinvestigation. ahistoryofreactionsorwithonlylocalreactionsand Evidence for these recommendations was collected by therefore these tests cannot be used as a screening electronic literature search using the key words – hyme- toolforseverevenomallergy. noptera, venom, allergy, VIT in combination with skin iii. Venom: The risk for a SR is greater in a bee venom test, anaphylaxis, mastocytosis, bee keeper, rush, ultra- sensitized patient compared with those sensitized to rush, protocols, antihistamine, epidemiology, cross reac- waspvenom[11]. tivity, b-blockers, angiotensin-converting enzyme (ACE) iv. Bee keepers: Bee keepers are frequently stung and inhibitors, basophil activation test (BAT) and CD63. Each most bee venom allergy occurs in bee keepers and articlewasassessedforitssuitability. their household members. SRs are more common in the early years of bee keeping and those who have o15–25 stings per year are at higher risk for SRs Epidemiology afterbeestingscomparedwithbeekeepersreceiving Questionnaire-basedstudieshaveshownthat56–94%[2] 4200stingswhoappeartobeprotected[11]. ofthepopulationarestungbyaninsectofthehymenop- v. Atopy: Venom allergy does not appear to be more tera family at least once in their lifetime. While the commoninatopicindividuals[9]. (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 BSACIvenomallergyguidelines 1203 The severity of a systemic reaction is affected by the Entomologyofhymenoptera followingfactors Insectsoftheorderhymenopteraincludebees,waspsand i. Age: The majority of SRs in the pediatric age group ants. Stings from these insects can cause fatal anaphy- are cutaneous but in adults cardio-respiratory com- laxis. Knowledge of this classification is helpful in the promise is common [2, 19]. Near-fatal or fatal out- managementofhymenopteravenomallergy,particularly comesareextremelyrareinchildrenandmorelikely with diagnostic testing and choosing the correct venom to occur in those with elevated baseline serum forimmunotherapyinpatientswhohaveexperiencedlife- tryptaseormastocytosisandco-existingcardiacand threateningallergicreactions.Theinsectsofhymenoptera respiratorydisease[2,20]. relevanttoUKclinicalpractice(Fig.1)arewasp(Vespula ii. Cardiac and respiratory disorders: Diseases compro- vulgaris) and honey bee (Apis mellifera). Hornets (Vespa mising cardiac or respiratory reserve may increase crabo) are also found in Britain, but are relatively theseverityofSRs[20].Concurrenttreatmentwithb- uncommon and largely confined to southern parts of the blockerscouldadverselyaffecttheresponsetoadrena- country. The description and habitat of these insects is line, and a recent study has shown that treatment summarized in Table 1. The scientific and common withACEinhibitorsisariskfactorforSRs[21,22]. nomenclature of Hymenoptera insects worldwide are iii. Baseline tryptase and mastocytosis: Tryptase is a listedinTable2[27]. specificmarkerformastcellandbasophildegranula- tion in type-1 hypersensitivity reactions. Studies in thelastdecadehaveshownthatupto25%ofpatients Venomallergens experiencing severe anaphylaxis (i.e. with loss of Hymenoptera venom contains several low molecular consciousnessand/orcardiacarrest)haveanelevated weight components, but most are glycoproteins baseline tryptase [23, 24] with or without systemic (10–50kDa). Vespids usually do not lose their sting after mastocytosis.Interestingly,mostofthesepatientsdo stinging and hence are capable of stinging the victim notsufferfromsymptomsofmastocytosisasitisthe severaltimes.Incontrast,beestypicallylosetheirbarbed anaphylaxis to insect stings that prompts investiga- sting. While bees release a large amount of venom per tion [25]. There are reports of fatalities [26] from sting(50–140mg),theamountofvenominavespidsting insectstingsinsuchpatientsaswellasahigherrate isrelativelyless(2–17mg).ThevenomsofrelevancetoUK ofadversereactionstoVIT[25]. clinicalpracticearesummarizedinTable3. Hymenoptera (Order) Apocrita (Sub order) Aculeata (Legion) (Super family) Apidae Vespidae (family) Apinae (family) Bombinae Vespinae Polistinae Vespula Dolichovespula Vespa Apis mellifera Bombus terrestris Polistes Significant venom Limited venom Significant venom Limited venom cross-reactivity cross-reactivity cross-reactivity cross-reactivity Apis mellifera: honey bee; Bombus terrestris: Bumble bee; Vespula Species: wasp; Dolichovespula Species: Yellowjacket, bald-faced hornet;Vespa: Hornet; Polistes: Paper wasp (not seen in United kingdom) Fig.1.ClassificationofhymenopterainsectsrelevanttoUKpractice. (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 1204 M.T.Krishnaetal Table1.DescriptionandhabitatofstinginginsectsintheUnitedKingdom Fieldstings–usualtimeof (cid:2) Insect Description Image year Wasp(Vespulavulgaris) (cid:3)19mmlong,yellowheadwithblack March–October stripes,blackthoraxwithyellowsides, yellowabdomenwithblackbands,black antennaeandyellowlegs. EuropeanHornet(Vespacrabo) 35mmlong,reddishbrownhead,blackand March–October brownshadedthorax,yellowandblack shadedabdomen. Honeybee(Apismellifera) 12.7–25.3mm,coveredwithshortdense March–October,occasionally hair,usuallygoldenbrownandblack, eveninwarmwinterdays abdomenstriped. BumbleBee(Bombuspascuorum, 19.1–38mmheadtotail,blackandyellow February–October Bombuslapidarius,Bombus softbodyhairsandappearfuzzy,oftenin pratorum,Bombusterrestris, bands,somehaveorangeorredintheir Bombuslucorum,Bombus bodies,orentirelyblack. hortorum) (cid:2) Blackbarbelowtheimageindicatesrelativesizeofthehymenopteraspecies,thedashedlineindicatesvariationwithinthespecies(imagesobtained withpermissionfromhttp://www.naturalvisions.co.uk(waspimage)andfromhttp://www.naturephoto-cz.eu(bee,bumblebeeandhornetimages). There is substantial IgE and clinical cross-reactivity venom[31].Venomsfrombumblebeeandhoneybeeare betweenwaspsandhornets(subfamilyvespinae)[28–30]. highly cross-reactive clinically which is consistent with There is only limited [31] specific IgE cross-reactivity the degree of structural homology found in the enzymes between wasp and bee venoms due to the hyaluronidase [36,37].About75%ofserafrompatientsallergictohoney component but this is rarely clinically relevant [32–35]. beevenomreacttoinvitrotestswithbumblebeevenom, Paper wasps are not currently found in the United King- and85%ofserafrompatientswithahistoryofallergyto dom but occur in other parts of Europe. There is limited bumblebeestingsdemonstratepositiveteststohoneybee IgEcross-reactivitybetweenwasp/hornetandpaperwasp venom[37].However,bumblebeevenomcontainsseveral (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 BSACIvenomallergyguidelines 1205 Table2.Scientificandcommonnamesofhymenopteraworldwide(reproducedandadaptedwithpermissionfromFernandez[27]) Scientific UK USA Danish Dutch French German Italian Spanish ApisMellifera Honeybee Honeybee Honningbi Bij Abeille Biene Ape Abeja Bombus Bumblebee Bumblebee Havehumle/Humlebi Hommel VraiBourdon Hummel Bombo Abejorro Vespula Wasp YellowJacket Hveps/Gedehams Wesp Gueˆpe Wespe Vespa Avispa (Giallone) Dolicho-vespula Wasp Hornetoraerial Hveps/Gedehams Wesp FauxFrelons Wespe Calabrone Avispa YellowJacket americano Vespa Hornet EuropeanHornet Storgedehams Horzel VraisFrelons Hornisse Calabrone Avispo´n Europeo (cid:2) (cid:2) Polistes PaperWasp Paperhveps Veldwesp Gueˆpepoliste Feld-Wespe Polistes Avispa Papelera (cid:2) NotfoundintheUnitedKingdomandtheNetherlands. Table3.HymenopteraVenomAllergensrelevanttoUKpractice Intradermal skin tests rarely show double positives (33). Another approach is to use RAST inhibition tests with Component(inboldaremajor venoms and cross-reactive carbohydrate determinants Venom allergens) [35, 39, 40], but in the United Kingdom this remains a Honeybee(Apismellifera) PhospholipaseA2(PLA2) researchtool.Arecentreporthashighlightedtheutilityof Hyaluronidase estimation of IgE to species-specific recombinant major AcidPhosphatase allergens including Api m1 (bee venom) and Ves v5 Mellitin (vespula) for identifying true sensitization when dual AllergenC(dipeptidylpeptidase) positivityispresent[41].Resultsfrom alldiagnostictests SerineProtease 10kDaprotein must be interpreted in the context of the clinical history Bumblebee(Bombusspp.) PhospholipaseA2 in order to choose the appropriate venom for immuno- Hyaluronidase therapy. AcidPhosphatase Protease(oftrypticamidasespecificity) Allergicreactionstohymenopteravenom Fraction-4 Wasp(Vespulaspp.and Antigen5 Minor local reactions to insect stings are normal and do (cid:2) Dolichovespulaspp.) PhospholipaseA1 notwarrantallergytesting.However,somelocalreactions Hyaluronidase can be large and troublesome and are characterized by Hornet(Vespaspp.) Antigen5 oedema,erythemaorpruritis.Anareaofindurationwitha PhospholipaseA1 diameterof410cmandwhichpeaksbetween24and48h Hyaluronidase and then subsides is referred to as a LLR [42]. The (cid:2) CalledyellowjacketintheUnitedStates.Waspspeciesencounteredin literature relating to LLR is poor and fragmentary. It is UnitedKingdomisVespulavulgaris. estimated that the risk of developing a SR after a LLR is relatively low (5–15%) and this observation is consistent in adults and children [16, 19, 43]. Another study has minor allergens that are not found in honey bees [37] suggested that a LLR does not significantly increase the (Table3). riskofaSRtofuturestings[8]. Thirty percent of patients with a clinical history of SRs are usually of rapid onset within minutes of the hymenoptera venom allergy are positive to both bee and sting.Theyvaryinseverity,fromminorurticariathrough wasp allergens on in vitro testing for serum-specific IgE tolossofconsciousness (Table5).Hypotensionisthekey but clinical double-reactivity to apidae and vespidae is severe feature, but there is also a high incidence of rare [9, 38]. Double positivity seen in diagnostic tests, respiratory and cutaneous involvement. Patients with particularlywithinvitromethods,isdueto50%sequence severe SRs often suffer a feeling of impending doom. identity of hyaluronidases and cross-reactive carbohy- In some patients, there is sudden hypotension, (collapse drate allergenic determinants between venoms (hyaluro- and loss of consciousness) with no other features. Con- nidases, acid phosphatase and phospholipase A2) and junctivitis may occur but is often not noticed; rhinitis plants (e.g. pollens). The double positivity seen with in isuncommon.Raremanifestationsareseizuresandincon- vitromethodscanoftenbediscriminatedbyskintests[38] tinence.Lesscommonlypatientsdevelopabiphasicanaphy- where positive results are more likely to be seen only to lacticresponse.Fatalreactionsarerarebutalmostcertainly the venom to which the individual is truly sensitized. under-recognized.Wheredatawasascertained,insectstings (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 1206 M.T.Krishnaetal Table4.Naturalhistoryofvenomallergy Incidenceofsystemicreactionto Natureofindex subsequentsting[numbersof reaction patients(orstingswherespecified)] Natureofsubsequentsting Author Mild/ 4/13(31%)(bee) Challengesting BlaauwandSmithuis[144] Moderatesystemic 2/7(29%)(wasp) Challengesting BlaauwandSmithuis[144] 2/14(14%)(ofstings;wasp/bee) Challengesting Engeletal.[146] 15/42(36%)(wasp) Challengesting KampelmacherandvanderZwan[147] 4/9(44%)(bee) Challengesting KampelmacherandvanderZwan[147] 4/9(44%)(wasp/bee/hornet) Challengesting Parkeretal.[148] 0/11(0%)(ofstings) Fieldsting SavliwalaandReisman[149] 6/18(33%)(ofpatients;wasp/bee) Fieldsting Reismanetal.[47] 8/74(11%)(wasp/yellowjacket/ Fieldsting Schuberthetal.[150] hornet/bee) Severesystemic 15/25(60%)(bee) Challengesting BlaauwandSmithuis[144] 10/17(59%)(wasp) Challengesting BlaauwandSmithuis[144] 3/33(9%)(wasp) Challengesting KampelmacherandvanderZwan[147] 3/7(43%)(bee) Challengesting KampelmacherandvanderZwan[147] 3/7(43%)(wasp/bee/hornet) Challengesting Parkeretal.[148] 3/14(21%)(ofstings;wasp/bee) Fieldsting SavliwalaandReisman[149] 11/41(27%)(wasp/bee) Fieldsting LantnerandReisman[151] 8/10(80%)(ofpatients;wasp/bee) Fieldsting Reismanetal.[47] Systemic(severitynotreported) 7/12(58%)(wasp/bee) Challengesting Huntetal.[44] 72/119(61%)(wasp/yellowjacket/ Fieldsting Settipaneetal.[46] hornet/bee) Responsetosubsequentstingsinpatientswhohavepreviouslysustainedasystemicreaction. Table5.Classificationofsystemicallergicreactionstobeeorwaspstings challenge,i.e.42%hadnoreactiontosting[44].Thiseffect hasbeendemonstratedinresponsetobothfieldstingsand Type Severity Features sting challenge in untreated patients. A SR was less likely Systemic Mild Pruritus,urticaria,erythema,mild after a mild–moderate SR than if the initial reaction had angio-oedema,rhinitis,conjunctivitis been severe. Children do particularly well; one study Moderate Mildasthma,moderateangio-oedema, showed that 81% with a history of mild generalized abdominalpain,vomiting,diarrhoea, reactionsdidnotreacttoasubsequentstingandnoreaction minorandtransienthypotensive wasmoreseverethantheprecedingone[45]. symptoms(lightheadedness,dizziness) In routine clinical practice, it may be difficult to Severe Respiratorydifficulty(asthma/laryngeal oedema),hypotension,collapseorlossof quantifytheriskofanaphylaxisinapatientwithahistory consciousness,Rare:double ofmild–moderateSR.Inonestudy,theseverityofaSRto incontinence,seizures,lossofcolour asubsequentstingwasreducedin45%ofpatients,similar vision in 43% and in only 12% more severe [46]. However, the coursecanalsobevariable:aseriesofstingsmayresultin a generalized reaction, no reaction, and then another accountedforonequarterofallanaphylacticdeathsinthe generalized reaction. When the initial SR is mild (cuta- UnitedKingdom each year[12].In fatalcases, theaverage neous features only) the prognosis in adults is good: in timefromstingtodeathwas10–15min[13]. one study 98% of patients had either a similar or no reactiontothesubsequentsting[47].Amorerecentstudy has shown that a less severe SR to hymenoptera insect Naturalhistory sting is a risk factor for anaphylaxis to future stings Asubstantialproportionofpatients(20–100%indifferent althoughtheproportionwithprecedingmild(cutaneous- studies)withahistoryofageneralizedreactiontoasting only) SRs was not specified [22]. A problem with inter- have no such reaction to a subsequent sting; that is, preting older studies is that other risk factors such as spontaneousimprovementiscommon(Table4).Thiswas raisedbaselinetryptase,whichwouldinfluenceoutcome, evidentfromtheoriginaldouble-blindplacebo-controlled werenotrecognized.Reasonsforthevariableoutcomeare trialof pure VIT, where after 6–10 weeks treatment, only notwellunderstoodbutmayincludetheintervalfromthe 58%ofthegrouponplaceboinjectionshadaSRtosting last sting (the longer the interval the lower the risk of (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 BSACIvenomallergyguidelines 1207 another generalized reaction), the patient’s immune re- Table6.Unusualnon-allergicmanifestationsattributedtohymenoptera sponseatthetimeofthesting(thiswillchangeovertime), insectstings[53–61] thedoseofvenominjected,andthesiteofthesting. Type Manifestations CNS Acutedisseminatedencephalopathy Clinicalfeatures GuillainBarre´Syndrome MyastheniaGravis Whentakingamedicalhistoryitishelpfultoclassifythe PeripheralNeuritis severity of each sting as local or systemic and any SR as Haematological ThrombocytopeniaPurpura mild, moderate or severe as this influences management. Henoch–SchonleinPurpura Table 5 shows a classification of systemic allergic reac- Haemolysis tionstostings. Coagulationdefects Muscle Rhabdomyolysiswithacuterenalfailure Renal AcuteRenalFailureduetointerstitialnephritis/tubular Venomallergyinchildren damage Hymenoptera stings in children occur usually during Nephroticsyndrome outdoor play. Children with venom allergy are usually Respiratory AlveolarHaemorrhage non-atopic and those with food allergy are not at Eye Directstingcausingcornealdamageandcataract increased risk [48]. LLR are common in children and no Toxic(from Renalfailure,rhabdomyolysis,cerebraloedema, multiple haemolysis,clottingdisorders,stingsitenecrosis. furtherinvestigationisnecessary. stingsusually The prevalence of SRs to hymenoptera stings in the 450) pediatricpopulationisunknown[48].Mostchildrenwith systemic allergic reactions to insect stings have skin CNS,centralnervoussystem. manifestations only. A small percentage of children will have more severe sting-induced systemic allergic reac- stingchallengeinassessingclinicalreactivityispoorand tionsbutfatalreactionsarerare[12,49,50].Theseverity therefore not recommended in routine clinical practice of the initial reaction is of prognostic value. In children [62]. An elevated baseline tryptase increases the risk and with a history of a mild SR, there was no SR to 91% of severity of a SR. Clinical factors must also be considered subsequent stings. 32% of children who have moderate– forexamplethepatient’soccupationinfluencingthelike- severe SRs to insect stings have reactions of similar lihood of further stings, the interval from the last sting severity following re-stings [51]. When subsequent SRs andtheseverityoftheinitialSR. haveoccurredinchildrenalmostallwerelesssevereand none more severe [43]. The risk of systemic allergic Investigationsforhymenopteravenomallergy reactions to subsequent stings declines slowly with time althoughtheriskofaSRcanpersistinupto20%onlong- AllpatientswithahistoryofSRsshouldbereferredtoan termfollow-up[51,52]. allergy specialist for further investigation. A detailed history is key to accurate diagnosis. A clear account of the symptoms and progression of the allergic reaction Non-allergicmanifestations following the sting should be obtained. Details of the Rare toxic reactions can occur with multiple simultaneous timing of previous stings and subsequent allergic reac- stings manifesting as delayed haemolysis, nephropathy, tions are important. Clues to enable identification of the coagulopathyandneurologicalsymptoms.Thereareisolated culpritinsectshouldbesought,e.g.iftherewasaknown casereportsofunusualreactionsattributedtohymenoptera wasp’s nest or whether the insect left the stinger behind insectstings[53–61].ThereisnoevidencethattheseareIgE- (bees usually leave a barbed stinger behind). The treat- mediated although the underlying mechanisms are not ment provided including scrutiny of emergency room known. A multi-disciplinary approach with input from recordsmayaidthedecisiononwhethertoofferimmuno- other specialists may be required and treatment is usually therapy. conservative. Reports of unusual reactions to hymeno- Demonstrationofvenom-specificimmunoglobulinE ptera insect stings are summarized in Table 6. Immuno- therapyisnotindicatedandshouldnotbeattempted. i. Skin testing:Skin testingisthegoldstandardinvesti- gationforhymenopteravenomallergybecausearesult isimmediatelyavailableduringtheinitialconsultation Factorsinfluencingtheriskofafuturereaction and provides greater discrimination between bee and Sensitization per se and levels of venom-specific IgE do wasp sensitization than serum-specific IgE to whole notpredictthelikelihoodandseverityofafuturereaction venom. Skin tests are also more often positive than [2].Aswithfieldstings,thenegativepredictivevalueofa serum-specific IgE and correlate better with history. (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 1208 M.T.Krishnaetal Serology alone may thus result in under-diagnosis or Table7.InvestigationsinHymenoptera venomallergy(Referencessee incorrect identification of the insect [38]. Skin prick Table8) testing (SPT) should be undertaken with standardized Aimedresult Testdetails venom extracts (1–100mg/mL) [3] with both bee and wasp venoms and positive (histamine) and negative Demonstrationof Skinpricktest(10–100mg/mL)standardizedvenom controls.Awealdiameterofatleast3mmgreaterthan specific extract the negative control indicatesthe presence of specific IgEtobeeand Intradermaltest(0.001–1mg/mL)standardizedbee waspvenom andwaspvenomextract IgE. If SPT are negative in patients with a strong SerumspecificIgEstandardizedenzyme clinical history, intradermal testing (IDT) is recom- immunoassay mendedusingconcentrationsofbetween0.001and1 SerumtotalIgE mg/mLvenom[3,4,63,64].Avolumeof0.03mLofthe extract is injected intradermally to raise a bleb of Baselineserum Ifbaselinetryptaseiselevatedconsiderfollow-up diameter3–5mmandanincreaseinwealdiameterof tryptase investigationsforsystemicmastocytosis Others Considerfollowupinvestigationsforsystemic 3mm at 20min is considered positive [65]. A lower mastocytosisincludingbonemarrowstudiesfor starting concentration for IDT can be considered in histology,immunophenotypingandckit patientswithahistoryofsevereanaphylaxis.SRshave mutations. beenreportedduringskintesting,hencetheseinvesti- gations should be carried out only by experienced personnelandinaclinicwheretreatmentforanaphy- symptom[68].Baselinetryptaseshouldbecheckedin laxisisreadilyavailable. allpatientswithahistoryofSRs[23–25,66,68,69]. ii. Serum-specificIgE:Thisshouldbeundertakeninacli- iv. SerumtotalIgE:Thisisgenerallyregardedasanon- nical pathology accredited laboratory. Serum-specific specificmarkerbutthereislimitedevidence[70]that IgE is estimated by standardized solid phase enzyme a total serum IgE of 4250kU/L is more likely to immunoassay and a level of X0.35kU/L considered indicate asymptomatic sensitization and such positive. Skin test reactivity and levels of serum- patients may be protected from severe anaphylactic specific IgE do not correlate with clinical reactivity shock and loss of consciousness, i.e. only mild– andhencetheresultmustbeinterpretedinconjunction moderateSRsoccur.However,thisinterestingobser- withclinicalhistory.Serum-specificIgEshouldbeused vation requires confirmation in a larger patient as an adjunct to skin testing, particularly when the population. A summary of investigations for hyme- latter are negative or indeterminate. Double positivity nopteravenomallergyisshowninTable7. to wasp and bee venom occurs in about 30% of v. BAT:Thisiscurrentlyaresearchtoolandisnotroutinely patients,wherethepatientisclinicallyallergictoonly available in UK National Health Service laboratories. one insect [38] and is often due to cross-reactivity of Basophilactivationisanalysedinwholebloodbyflow venom-specific IgE with certain carbohydrate ligands cytometry following incubation with appropriate stan- [40].Skintesting,particularlyintradermalskintesting dardized allergens. Surface expression of CD63/203c is usually clarifies the situation; intradermal double used as a surrogate for basophil activation. BATcorre- positivityisuncommon[38]. lates well with serum-specific IgE and has comparable iii. Baseline tryptase: A significant proportion of pa- sensitivity and specificity to skin tests and serum- tients presenting with anaphylaxis to hymenoptera specificIgE[71–74].Onestudy[75]suggestedthatBAT stinghaveanelevated(411.4mg/L)baselinetryptase could predict adverse reactions during VIT but this [23, 24]. Such patients fall into the ‘mastocytosis’ findingcouldnotbeconfirmed[76].BATisanexpensive spectrum and further investigations including bone investigationrequiringspecializedequipmentandskilled marrowexaminationtoexcludesystemicmastocytosis personnel and currently has no role in the routine ormonoclonalmastcellactivationsyndrome[23,24, diagnosisofhymenopteravenomallergyormonitoring 66, 67] may be necessary. The majority of these orpredictingadversereactionstoVIT.Comparisonofthe patients do not have any evidence of systemic mas- performanceofskintestingwithinvitroallergytestingis tocytosisorurticariapigmentosa.Ithasbeenreported summarizedinTable8. that patients with elevated baseline tryptase with or without systemic mastocytosis develop significantly more severe, mostly cardiovascular anaphylactic Sourcesoferrorindiagnosis sting reactions as opposed to those with normal The following are the most common reasons for diagnostic baseline tryptase [68]. Interestingly, the latter group error: experience urticaria and angio-oedema more often than patients with elevated baseline tryptase who 1. Insectidentification–acommonerrorisforpatientsto oftenpresentwithflushingasadominantcutaneous state the insect was a bee, when it was a wasp. This (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 BSACIvenomallergyguidelines 1209 Table8.Performanceofskintests(ST),basophilactivationtest(BAT)andserum-specificIgE(SSIgE)inhymenopteravenomallergy[71–74] Sensitivity Specificity Serumspecific Serumspecific Study ST IgE BAT ST IgE BAT (cid:2) Eboetal.2007[71] 81.8% 86.4% 83.8% Notreported 100% 100% Sturmetal.2004[74] 93%(cid:2),w 91.2% 87.7% Notdetermined 91.2% 87.7% (cid:2) Erdmannetal.2004[72] 100% 76% 92% Notreported 85% 80% (cid:2) Sainte-Laudyetal.2000[73] 85% 88% 100% Notreported (cid:2) Intradermalskintest(IDT). wSkinpricktest(SPT). informationshouldnotbeacceptedatfacevaluewith- 3. VIT: This is the only specific treatment that is cur- outfurtherquestioningandmoredetailedhistory. rently availableforpatientswithahistory of SRtoa 2. Double-positive serum-specific IgE (positive to both hymenoptera insect sting. Currently in the United beeandwaspvenoms)whenthepatientisallergicto Kingdom, licensed standardized allergen extracts oneonly[38].Thiscanoftenbeclarifiedbyskinprick (Pharmalgens, ALK ABELLO´, Hungerford, UK) are orintradermaltestssupportedbythehistory.Ifdoubt available for honey bee (A. mellifera) and wasp remains, assay of specific IgE to major venom aller- (Vespulaspp).ThevenomextractsareusedforVITto gensusingtherecombinantallergensApim1andVes honey bee and wasp sting allergy respectively. In v5oftenidentifiesthecausativeinsect[41]. patientswithahistoryofanaphylaxistohornets,VIT 3. Difficulty in interpreting skin tests. This is a less with Vespula spp. venom should provide effective commonproblembutskintestwealstovenommaybe treatment for both wasp as well as hornet stings due smallandonlypositiveathigherconcentrations[77]. to significant allergenic cross-reactivity (Fig. 1) 4. Falsenegativeserum-specificIgE.Thisisnotuncommon. [80–83].Epidemiological studies suggest a(cid:3)60–70% a. Inoneserieswheretherewasanegative serum- riskoffurtherSRtoafuturestingwithareductionof specific IgE and negative SPT in patients with a risk after VIT to o5% [44, 84]. VIT is 95–100% and clear history of SR, IgE blots revealed positive about 80% successful in preventing SRs in wasp and venom-specificIgEin75%[78]. bee sting allergy, respectively [44, 85–89]. Patients b. In patients with SRs, the serum-specific IgE is with venom-specific IgE and an elevated baseline negative in about 18% but the IDT is negative in tryptase or mastocytosis have a dual mechanism for only about 2% (C. Lim, personal communication). anaphylaxis, and VIT reduces the risk of a systemic ANorthAmericanseriesreportednegative serum- allergic reaction and by corollary fatal reactions. specificIgEandskintestsin18%ofpatientswitha Importantly,VIThasbeenshowntoinduceaclinically previoushistoryofSRbutonstingchallengeonly significant improvement in health-related QOL in pa- two of 14 (14%) developed a SR. This compared tientswithanaphylacticreactionsaswellasgeneralized with positive sting challenges in 30 of 141 (21%) non-life-threatening responses to yellow jacket stings subjectswithevidenceofspecificIgE[79]. [90, 91]. This is often an important consideration in selectingpatientsforimmunotherapy. 4. VIT is recommended for all patients with a severe SR Management afterastingandinmanypatientsafteraSRofmoderate 1. Minimizeexposuretofurtherstings(seeAppendixA). severity. VIT is usually not indicated for sting-induced 2. Provision of management plan for self-treatment of cutaneousSRsbutmaybeconsideredinthepresenceof acuteallergicreactions:PatientswithahistoryofSR additional risk factors for example: raised baseline and those with elevated baseline tryptase or masto- tryptase, age, likelihood of future stings, (bee keeping, cytosisandwhereappropriatetheircarers(orguardians/ or occupational exposure), remoteness from medical parents) should be trained to self-manage allergic help, effect on QOL, patient preference and co-morbid reactions. This should include provision of a written conditions.VITisnotindicatedinpatientswithahistory treatment plan with appropriate instructions on the ofonlylocalreactionsirrespectiveoftheirseverity. use of antihistamine and self-injectable adrenaline andtoadoptasupineposturewithlegsraisedshould Indicationsforvenomimmunotherapyinchildren they develop symptoms of hypotension. With chil- dren, appropriate liaison with the school is recom- VIT should be considered for the small percentage of mended. Patients with previous SRs may also be children who have severe sting-induced systemic allergic advisedtowearamedicalalertbracelet. reactions. It is likely that they will have similar severe (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220 1210 M.T.Krishnaetal Box1. IndicationsforVIT (cid:2) (cid:2) Yes Sometimes Notusually No Systemicreactionwith Mildasthma,moderateangio-oedema, Cutaneoussystemicreaction,e.g. Localreaction hypotension(cid:4)laryngeal abdominalpain,vomiting,diarrhoea,mild cutaneous:urticaria1/(cid:5)mild Toxicreaction oedema(cid:4)asthma hypotensivesymptoms(lightheadedness, angio-oedema Anysystemic Musthavepositivevenom dizziness) reaction, specificIgE Inthoseathighriskoffurtherstings,e.g. independentof beekeeper/proximitytobees,oroccupational severity,if exposure,e.g.fruitfarmers,gardeners,etc. negativespecific Otherfactors,e.g.proximitytomedicalhelp, IgE patientpreference,effectonqualityoflife. (cid:2) Co-morbidconditionsincludingasthmaorotherrespiratorydisease,cardiacconditions,raisedbaselineplasmatryptase/mastocytosisconstitute‘risk factors’andshouldbecarefullyconsideredbeforemakingadecisionforVIT. Box2. PrecautionswithVIT VITiscontraindicatedinpatientswithbrittleasthmaorchronicsevereasthma,althoughmaybecautiouslyinitiatedinpatientswithmoderatelysevere asthmaafterestablishinggoodcontrol. VITshouldnotbeinitiatedinpatientswithpsychiatricdisordersthatwillinterferewithcompliance. TheeffectsofVITinpatientswithdisordersoftheimmunesystemsuchasactivesystemicautoimmunity,immunodeficiencyandlymphoid malignanciesarenotknownandthereforethedecisiontooffertreatmentshouldbebasedonanindividual‘risk-benefit’analysis. VITshouldnotbeinitiatedinpregnancybutmaybecontinuedduringpregnancyinpatientsonmaintenancetherapywhohavetoleratedVITwell. Howeverthepatientshouldbeinformedoftheriskofanaphylaxisevenduringmaintenancetreatmentthatcouldpotentiallyaffectthefoetus. InpatientsonACEinhibitorsandb-blockers(seefollowingsections) TricyclicantidepressantsshouldideallybewithdrawnbeforecommencementofVITandreplacedifappropriatebyselectiveserotoninreuptake inhibitors(SSRI)becauseofpotentialdruginteraction(arrhythmiaandhypertension)withadrenaline. reactions with subsequent stings. Symptoms and signs significantlyhigherwithbeevenomcomparedwithvespid include: bronchospasm and/or upper-airway oedema immunotherapy[98,100,107].Thesignificantvariationin and/orhypotension[51].However,VITisnotindicatedfor reportedratesofSRsbetween studieshavebeenattributed themajorityofchildrenwhohavelesssevereSRs(urticaria atleastinparttodifferencesinpatientselectioncriteriafor and angio-oedema distant from the sting site) [45] (Box 1 VIT, methods of grading SRs, use of antihistamine pre- and2). medication and dose regimens (in particular cumulative dosesinacceleratedprotocols). Protocols for venom immunotherapy (Appendix B). The Rush and ultrarush methods are usually reserved for time required to reach the maintenance dose varies special circumstances and require in-patient management, according to the induction protocol employed. Most UK which almost certainly explains their unpopularity in the centresuseconventional[92–95]orslowup-dosingregi- United Kingdom. However, given the convenience and mens (490% respondents in a national audit [96]). This relative cost-effectiveness of accelerated protocols, these requires aminimum of 12 weeks with weekly up-dosing. maybeconsideredinselectedlowerriskcases. Rush up-dosing [97–99] takes place over 4–7 days and Irrespective of the protocol employed, once the main- ultrarush [99–101] over 1–2 days. Cluster up-dosing tenance dose is achieved, further injections are adminis- [102–104]comprisesamodifiedrushprotocolwithseveral teredregularlyatintervalsof4–8weeksfortheremaining injections at 15–30min intervals each week reaching period[108].Theoptimumtargetmaintenancedoseis100 maintenance dose in 7 weeks. These protocols have been mg [108]. However, with treatment failures (i.e. those who establishedwithsomesuccessandsomeofthestudiesare develop SRs despite a maintenance dose of 100mg) an summarizedinTable9. increase in maintenance dose to 150–200mg should be Some studies have shown comparable safety profiles considered and this approach has been shown to confer [98–100,103–106]forconventionalandacceleratedproto- protection in some patients only [108, 109]. However, if cols. Most studies have shown that the accelerated VIT therearesevereSRsto100mg,cautionshouldbeexercised, protocols are associated with a significant increase in the thedosereducedandiffurtherSRsoccur,VITdiscontinued. incidenceofSRscomparedwithconventionalprotocols[97, Inpatientswitharaisedbaselineserumtryptase,recurrent 101, 102, 107]. This was confirmed in a large multi-centre SRs to VIT may result for two reasons: (i) failure of European study, where rapid dose increase was associated desensitization,and(ii)mastcellabnormalityindependent withincreasedriskofside-effects[107].Thesestudieshave ofspecificIgE.Thereisnoevidencethatthelatterwouldbe also shown that irrespective of the protocol the SR rate is amelioratedbyfurtherVIT. (cid:2)c2011BlackwellPublishingLtd,Clinical&ExperimentalAllergy,41:1201–1220