Diagnosis and management of hymenoptera venom allergy - AInotes

1204 M. T. Krishna et alTable 1. Description and habitat of stinging insects in the United KingdomInsect Description Image yearField stings–usual time ofWasp (Vespula vulgaris)19 mm long, yellow head with blackstripes, black thorax with yellow sides,yellow abdomen with black bands, blackantennae and yellow legs.March–OctoberEuropean Hornet (Vespa crabo)35 mm long, reddish brown head, black andbrown shaded thorax, yellow and blackshaded abdomen.March–OctoberHoney bee (Apis mellifera)12.7–25.3 mm, covered with short densehair, usually golden brown and black,abdomen striped.March–October, occasionallyeven in warm winter daysBumble Bee (Bombus pascuorum,Bombus lapidarius, Bombuspratorum, Bombus terrestris,Bombus lucorum, Bombushortorum)19.1–38 mm head to tail, black and yellowsoft body hairs and appear fuzzy, often inbands, some have orange or red in theirbodies, or entirely black.February–October Black bar below the image indicates relative size of the hymenoptera species, the dashed line indicates variation within the species (images obtainedwith permission from http://www.naturalvisions.co.uk (wasp image) and from http://www.naturephoto-cz.eu (bee, bumble bee and hornet images).There is substantial IgE and clinical cross-reactivitybetween wasps and hornets (subfamily vespinae) [28–30].There is only limited [31] specific IgE cross-reactivitybetween wasp and bee venoms due to the hyaluronidasecomponent but this is rarely clinically relevant [32–35].Paper wasps are not currently found in the United Kingdombut occur in other parts of Europe. There is limitedIgE cross-reactivity between wasp/hornet and paper waspvenom [31]. Venoms from bumble bee and honey bee arehighly cross-reactive clinically which is consistent withthe degree of structural homology found in the enzymes[36, 37]. About 75% of sera from patients allergic to honeybee venom react to in vitro tests with bumble bee venom,and 85% of sera from patients with a history of allergy tobumble bee stings demonstrate positive tests to honey beevenom [37]. However, bumble bee venom contains severalc 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

BSACI venom allergy guidelines 1205Table 2. Scientific and common names of hymenoptera worldwide (reproduced and adapted with permission from Fernandez [27])Scientific UK USA Danish Dutch French German Italian SpanishApis Mellifera Honey bee Honey bee Honningbi Bij Abeille Biene Ape AbejaBombus Bumble bee Bumble bee Havehumle/Humlebi Hommel Vrai Bourdon Hummel Bombo AbejorroVespula Wasp Yellow Jacket Hveps/Gedehams Wesp Guêpe Wespe Vespa Avispa(Giallone)Dolicho-vespula Wasp Hornet or aerial Hveps/Gedehams Wesp Faux Frelons Wespe Calabrone AvispaYellow JacketamericanoVespa Hornet European Hornet Stor gedehams Horzel Vrais Frelons Hornisse Calabrone AvispónEuropeoPolistesPaper Wasp Paper hveps Veldwesp Guêpe poliste Feld-Wespe Polistes AvispaPapelera Not found in the United Kingdom and the Netherlands.Table 3. Hymenoptera Venom Allergens relevant to UK practiceVenomComponent (in bold are majorallergens)Honey bee (Apis mellifera) Phospholipase A2 (PLA2)HyaluronidaseAcid PhosphataseMellitinAllergen C (dipeptidylpeptidase)Serine Protease10 kDa proteinBumble bee (Bombus spp.) Phospholipase A2HyaluronidaseAcid PhosphataseProtease (of tryptic amidase specificity)Fraction-4Wasp (Vespula spp. and Antigen 5Dolichovespula spp.) Phospholipase A1HyaluronidaseHornet (Vespa spp.) Antigen 5Phospholipase A1Hyaluronidase Called yellow jacket in the United States. Wasp species encountered inUnited Kingdom is Vespula vulgaris.minor allergens that are not found in honey bees [37](Table 3).Thirty percent of patients with a clinical history ofhymenoptera venom allergy are positive to both bee andwasp allergens on in vitro testing for serum-specific IgEbut clinical double-reactivity to apidae and vespidae israre [9, 38]. Double positivity seen in diagnostic tests,particularly with in vitro methods, is due to 50% sequenceidentity of hyaluronidases and cross-reactive carbohydrateallergenic determinants between venoms (hyaluronidases,acid phosphatase and phospholipase A2) andplants (e.g. pollens). The double positivity seen with invitro methods can often be discriminated by skin tests [38]where positive results are more likely to be seen only tothe venom to which the individual is truly sensitized.Intradermal skin tests rarely show double positives (33).Another approach is to use RAST inhibition tests withvenoms and cross-reactive carbohydrate determinants[35, 39, 40], but in the United Kingdom this remains aresearch tool. A recent report has highlighted the utility ofestimation of IgE to species-specific recombinant majorallergens including Api m1 (bee venom) and Ves v5(vespula) for identifying true sensitization when dualpositivity is present [41]. Results from all diagnostic testsmust be interpreted in the context of the clinical historyin order to choose the appropriate venom for immunotherapy.Allergic reactions to hymenoptera venomMinor local reactions to insect stings are normal and donot warrant allergy testing. However, some local reactionscan be large and troublesome and are characterized byoedema, erythema or pruritis. An area of induration with adiameter of 410 cm and which peaks between 24 and 48 hand then subsides is referred to as a LLR [42]. Theliterature relating to LLR is poor and fragmentary. It isestimated that the risk of developing a SR after a LLR isrelatively low (5–15%) and this observation is consistentin adults and children [16, 19, 43]. Another study hassuggested that a LLR does not significantly increase therisk of a SR to future stings [8].SRs are usually of rapid onset within minutes of thesting. They vary in severity, from minor urticaria throughto loss of consciousness (Table 5). Hypotension is the keysevere feature, but there is also a high incidence ofrespiratory and cutaneous involvement. Patients withsevere SRs often suffer a feeling of impending doom.In some patients, there is sudden hypotension, (collapseand loss of consciousness) with no other features. Conjunctivitismay occur but is often not noticed; rhinitisis uncommon. Rare manifestations are seizures and incontinence.Less commonly patients develop a biphasic anaphylacticresponse. Fatal reactions are rare but almost certainlyunder-recognized. Where data was ascertained, insect stingsc 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

BSACI venom allergy guidelines 1207another generalized reaction), the patient’s immune responseat the time of the sting (this will change over time),the dose of venom injected, and the site of the sting.Clinical featuresWhen taking a medical history it is helpful to classify theseverity of each sting as local or systemic and any SR asmild, moderate or severe as this influences management.Table 5 shows a classification of systemic allergic reactionsto stings.Venom allergy in childrenHymenoptera stings in children occur usually duringoutdoor play. Children with venom allergy are usuallynon-atopic and those with food allergy are not atincreased risk [48]. LLR are common in children and nofurther investigation is necessary.The prevalence of SRs to hymenoptera stings in thepediatric population is unknown [48]. Most children withsystemic allergic reactions to insect stings have skinmanifestations only. A small percentage of children willhave more severe sting-induced systemic allergic reactionsbut fatal reactions are rare [12, 49, 50]. The severityof the initial reaction is of prognostic value. In childrenwith a history of a mild SR, there was no SR to 91% ofsubsequent stings. 32% of children who have moderate–severe SRs to insect stings have reactions of similarseverity following re-stings [51]. When subsequent SRshave occurred in children almost all were less severe andnone more severe [43]. The risk of systemic allergicreactions to subsequent stings declines slowly with timealthough the risk of a SR can persist in up to 20% on longtermfollow-up [51, 52].Non-allergic manifestationsRare toxic reactions can occur with multiple simultaneousstings manifesting as delayed haemolysis, nephropathy,coagulopathy and neurological symptoms. There are isolatedcase reports of unusual reactions attributed to hymenopterainsect stings [53–61]. There is no evidence that these are IgEmediatedalthough the underlying mechanisms are notknown. A multi-disciplinary approach with input fromother specialists may be required and treatment is usuallyconservative. Reports of unusual reactions to hymenopterainsect stings are summarized in Table 6. Immunotherapyis not indicated and should not be attempted.Factors influencing the risk of a future reactionSensitization per se and levels of venom-specific IgE donot predict the likelihood and severity of a future reaction[2]. As with field stings, the negative predictive value of aTable 6. Unusual non-allergic manifestations attributed to hymenopterainsect stings [53–61]TypeCNSHaematologicalMuscleRenalRespiratoryEyeToxic (frommultiplestings usually450)ManifestationsCNS, central nervous system.Acute disseminated encephalopathyGuillain Barré SyndromeMyasthenia GravisPeripheral NeuritisThrombocytopenia PurpuraHenoch–Schonlein PurpuraHaemolysisCoagulation defectsRhabdomyolysis with acute renal failureAcute Renal Failure due to interstitial nephritis/tubulardamageNephrotic syndromeAlveolar HaemorrhageDirect sting causing corneal damage and cataractRenal failure, rhabdomyolysis, cerebral oedema,haemolysis, clotting disorders, sting site necrosis.sting challenge in assessing clinical reactivity is poor andtherefore not recommended in routine clinical practice[62]. An elevated baseline tryptase increases the risk andseverity of a SR. Clinical factors must also be consideredfor example the patient’s occupation influencing the likelihoodof further stings, the interval from the last stingand the severity of the initial SR.Investigations for hymenoptera venom allergyAll patients with a history of SRs should be referred to anallergy specialist for further investigation. A detailedhistory is key to accurate diagnosis. A clear account ofthe symptoms and progression of the allergic reactionfollowing the sting should be obtained. Details of thetiming of previous stings and subsequent allergic reactionsare important. Clues to enable identification of theculprit insect should be sought, e.g. if there was a knownwasp’s nest or whether the insect left the stinger behind(bees usually leave a barbed stinger behind). The treatmentprovided including scrutiny of emergency roomrecords may aid the decision on whether to offer immunotherapy.Demonstration of venom-specific immunoglobulin Ei. Skin testing: Skin testing is the gold standard investigationfor hymenoptera venom allergy because a resultis immediately available during the initial consultationand provides greater discrimination between bee andwasp sensitization than serum-specific IgE to wholevenom. Skin tests are also more often positive thanserum-specific IgE and correlate better with history.c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

1210 M. T. Krishna et alBox 1.Indications for VITYes Sometimes Not usually NoSystemic reaction withhypotensionlaryngealoedemaasthmaMust have positive venomspecific IgEMild asthma, moderate angio-oedema,abdominal pain, vomiting, diarrhoea, mildhypotensive symptoms (light headedness,dizziness)In those at high risk of further stings, e.g.beekeeper/proximity to bees, or occupationalexposure, e.g. fruit farmers, gardeners, etc.Other factors, e.g. proximity to medical help,patient preference, effect on quality of life.Cutaneous systemic reaction, e.g.cutaneous: urticaria1/ mildangio-oedemaLocal reactionToxic reactionAny systemicreaction,independent ofseverity, ifnegative specificIgE Co-morbid conditions including asthma or other respiratory disease, cardiac conditions, raised baseline plasma tryptase/mastocytosis constitute ‘riskfactors’ and should be carefully considered before making a decision for VIT.Box 2.Precautions with VITVIT is contraindicated in patients with brittle asthma or chronic severe asthma, although may be cautiously initiated in patients with moderately severeasthma after establishing good control.VIT should not be initiated in patients with psychiatric disorders that will interfere with compliance.The effects of VIT in patients with disorders of the immune system such as active systemic autoimmunity, immunodeficiency and lymphoidmalignancies are not known and therefore the decision to offer treatment should be based on an individual ‘risk-benefit’ analysis.VIT should not be initiated in pregnancy but may be continued during pregnancy in patients on maintenance therapy who have tolerated VIT well.However the patient should be informed of the risk of anaphylaxis even during maintenance treatment that could potentially affect the foetus.In patients on ACE inhibitors and b-blockers (see following sections)Tricyclic antidepressants should ideally be withdrawn before commencement of VIT and replaced if appropriate by selective serotonin reuptakeinhibitors (SSRI) because of potential drug interaction (arrhythmia and hypertension) with adrenaline.reactions with subsequent stings. Symptoms and signsinclude: bronchospasm and/or upper-airway oedemaand/or hypotension [51]. However, VIT is not indicated forthe majority of children who have less severe SRs (urticariaand angio-oedema distant from the sting site) [45] (Box 1and 2).Protocols for venom immunotherapy (Appendix B). Thetime required to reach the maintenance dose variesaccording to the induction protocol employed. Most UKcentres use conventional [92–95] or slow up-dosing regimens(490% respondents in a national audit [96]). Thisrequires a minimum of 12 weeks with weekly up-dosing.Rush up-dosing [97–99] takes place over 4–7 days andultrarush [99–101] over 1–2 days. Cluster up-dosing[102–104] comprises a modified rush protocol with severalinjections at 15–30 min intervals each week reachingmaintenance dose in 7 weeks. These protocols have beenestablished with some success and some of the studies aresummarized in Table 9.Some studies have shown comparable safety profiles[98–100, 103–106] for conventional and accelerated protocols.Most studies have shown that the accelerated VITprotocols are associated with a significant increase in theincidence of SRs compared with conventional protocols [97,101, 102, 107]. This was confirmed in a large multi-centreEuropean study, where rapid dose increase was associatedwith increased risk of side-effects [107]. These studies havealso shown that irrespective of the protocol the SR rate issignificantly higher with bee venom compared with vespidimmunotherapy [98, 100, 107]. The significant variation inreported rates of SRs between studies have been attributedat least in part to differences in patient selection criteria forVIT, methods of grading SRs, use of antihistamine premedicationand dose regimens (in particular cumulativedoses in accelerated protocols).Rush and ultrarush methods are usually reserved forspecial circumstances and require in-patient management,which almost certainly explains their unpopularity in theUnited Kingdom. However, given the convenience andrelative cost-effectiveness of accelerated protocols, thesemay be considered in selected lower risk cases.Irrespective of the protocol employed, once the maintenancedose is achieved, further injections are administeredregularly at intervals of 4–8 weeks for the remainingperiod [108]. The optimum target maintenance dose is 100mg [108]. However, with treatment failures (i.e. those whodevelop SRs despite a maintenance dose of 100 mg) anincrease in maintenance dose to 150–200 mg should beconsidered and this approach has been shown to conferprotection in some patients only [108, 109]. However, ifthere are severe SRs to 100 mg, caution should be exercised,the dose reduced and if further SRs occur, VIT discontinued.In patients with a raised baseline serum tryptase, recurrentSRs to VIT may result for two reasons: (i) failure ofdesensitization, and (ii) mast cell abnormality independentof specific IgE. There is no evidence that the latter would beameliorated by further VIT.c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220Table 9. Summary of different VIT protocols and associated systemic reactionStudy No. of subjects Protocol Systemic reactions (SR) % Venom/s CommentMosbech et al. 2000 [107] 840 Various protocols in 19European centres combinedanalysis20% HB, vespula Mild systemic reactions only, inhaled/injected adrenalineused in six subjects, one subject kBP; risk factors:females, accelerated protocols and bee venomChipps et al, 1980 [93] 44 children Conventional 6% HB, YJWyss et al. 1993 [95] 35 Conventional 8.6% HB, YJ No severe systemic reactions, all systemic reactions to beevenomLockey et al. 1990 [94] 1410 Conventional 12% HB, waspReimers et al. 2000 [101] 57 Ultra-rush 39% BV DBPC study with fexofenadine; helped local reactions andgeneralized skin reactions including urticaria, pruritisand angio-oedema less in fexofenadine groupBirnbaum et al. 1993 [106] 284 46 (rush, 4 days), 21 (ultra-rush-1, 6 h) and 217 (ultra-rush-2,3 h 40 min)Rush (28%), ultra-rush-1(28%) and ultra-rush-2(6.9%)YJ, HBUltra-rush protocol-2 with lesser cumulative dose wassaferBrehler et al. 2000 [99] 1055 1st: 7–9 days; 1st: 22%; HB and wasp No severe systemic reactions in any group2nd : 3–6 days;2nd:14%;3rd: 2 days 3rd: 10%Laurent et al. 1997 [97] 97 Rush 27% HB, wasp and Polistes Adrenaline not needed in any oneBernstein et al. 1994 [104] 52 Cluster 5.2% 50 mg over 2–3 h on day-1 and maintenance doseachieved over 3 weeks.Bernstein et al. 1989 [103] 33 Cluster 12% 50 mg over 2–3 h on day-1 and maintenance doseachieved over 3 weeks.Berchtold et al. 1992 [102] 52 Rush 67% HB DBPC study with terfenadine and placebo premedication.Terfenadine group reduced local and cutaneoussystemic reactions only, no effect on cardio-respiratorysymptomsSturm et al. 2002 [98] 101 Rush 7% HB, YJ and Hornet More systemic reactions with HBBirnbaum et al. 2003 [100] 258 (51 children, 201 adults) Ultra-rapid (50 mg, day-1, 2doses of 50 mg on day-15 and11% HB, YJ, Wasp More systemic reactions with HB (30%) than YJ (3%) andwasp (6%)one 100 mg injection on day-45Ewan & Stewart 1993 [152] 26 (727 injections) Conventional prospective study 23% wasp Bee and wasp Most SR within 30 min. Severe – 3 (0.5%) requiring10% bee1.1% severe requiringparenteral treatmentadrenaline, early onset at 3, 7 and 17 min Mild SRcommon. Late SR42 h were mild: rhinitis and minorurticaria.Youlten et al. 1995 [153] 109 (2735 injections) 7.5% initial Bee and wasp 80% within 30 min, 90% within 1 h.2.1% maintenance 5.5% 42hHunt et al. 1978 [44]Muller et al. 2002 [154]59 patients, three treatmentgroups including placebo,whole body extract (WBE)and venom52, 26 patients premedicatedwith terfenadine and 26 withplacebo during inductionphaseHB, honey bee; YJ, yellow jacket; VIT, venom immunotherapy.Single-blind placebo-controlledstudy; first dose 0.1 mg, 10-fold dose increase every30 min until 10 mg is reachedor patient develops systemicor large local reaction.Subsequent weekly doublingdose incrementsDouble-blind placebo-controlledstudy, rush protocol in 4 daysNo reported systemicreactionsNo reported systemicreactionsBee and WaspBee venom —Sting Challenge:1. Venom group: 5% urticaria only2. WBE group: 69% SRs3. Placebo group: 58% SRsBSACI venom allergy guidelines 1211

1212 M. T. Krishna et alAntihistamine pre-medication. Pre-medication with antihistaminebefore injection in rush immunotherapyreduces the frequency and severity of local and mild SRs[101, 102, 110] but not anaphylaxis. A recent study inpatients undergoing bee venom VIT did not confirm theenhancement of efficacy with antihistamine pre-medicationas previously suggested [111]. Therefore, it is worthconsidering antihistamine prophylaxis in those who repeatedlyexperience local or mild SRs to VIT.Venom immunotherapy and b-blockers. b-blockers inhibitsome of the pharmacological effects of endogenous as wellas exogenously administered adrenaline in anaphylaxis andenhance the end organ effects of released mediators. Onestudy reported that patients on b-blockers were nine timesmore likely to be hospitalized after anaphylaxis to radiocontrastmedium (RCM) suggesting a more prolonged andsevere reaction [112]. Therefore, b-blockade can makeanaphylaxis more protracted and difficult to treat [20, 113].Hence, caution should be exercised when undertakingallergen-specific immunotherapy in patients on b-blockersand only considered in exceptional circumstances.In patients with hypertension, b-blockers should beideally replaced with alternative agents before commencementof VIT.If co-morbid cardiac conditions are present withdrawalrequires careful consideration and discussion with thepatient’s cardiologist or general practitioner. If a risk-benefitanalysis suggests treatment with a b-blocker is essential,appropriate measures should be put into place to mitigatethe additional risk and only patients with severe venomallergy considered for VIT [114].If b-blockers are continued, VIT must be carried outcautiously. Glucagon activates adenyl-cyclase withoutinvolving the b-receptor on the cell membrane [115, 116].Therefore, glucagon should be available and administeredpromptly if the patient fails to respond to adrenaline inanaphylaxis. Another strategy to consider would be towithdraw b-blockade during up-dosing and recommenceafter the patient has reached the maintenance dose.Venom immunotherapy and angiotensin-convertingenzyme inhibitors. Case reports raised concern about theconcurrent use of ACE inhibitors in patients undergoing VIT[117]. Until recently no studies had reported on patientstaking ACE inhibitors during VIT. However, in a retrospectivestudy over 6 years of 79 patients undergoing VIT,17 had been on ACE inhibitors for a mean of 72 months.During VIT there were no SRs in these patients comparedwith a SR rate of 21% in the other 62 patients [118].Venom immunotherapy and anti-immunoglobulin E. Thereare case reports of anti-IgE therapy with omalizumab reducingthe risk of SRs during induction of VIT in patients whohave either failed treatment or in those with mastocytosis[119, 120]. However, there are no data on dose regimens, orduration of treatment and current NICE guidelines in theUnited Kingdom on the use of omalizumab do not allow itsuse in VIT. Therefore although not recommended, anti-IgEtherapy is a strategy that could be considered in exceptionalcases.Venom immunotherapy and mastocytosis. In mastocytosisuncontrolled proliferation of mast cells occurs intissue thus pre-disposing to severe anaphylaxis as well asexaggerated responses to exogenous insults such as drugs(e.g. aspirin, non-steroidal anti-inflammatory drugs,RCM) and insect stings. Even in relatively milder variantsof mastocytosis, insect stings may induce severe anaphylaxis[23, 24]. However, VIT is only recommended forpatients with a SR and raised baseline tryptase in thepresence of specific IgE. The available data are conflictingon how well VIT is tolerated by patients with indolentforms of systemic mastocytosis and urticaria pigmentosa[25, 69]. The two reported studies involved relativelysmall cohorts of patients with indolent mastocytosis andemployed both conventional and cluster up-dosing protocols.While Bonadonna et al. [69] did not pre-medicatewith antihistamine, Gonzalez de Olano et al. [25] premedicateda significant proportion of their patients. It isdifficult to assess the efficacy and safety of VIT inmastocytosis based on the data from these two small butimportant studies. Nevertheless, based on the data fromthe latter two reports and other relatively smaller caseseries it has been suggested that VIT should be carried outcautiously in this group of patients [121]. Furthermore, asthe safety of accelerated VIT protocols has not beenclearly established in those with mastocytosis, up-dosingwith conventional schedules is recommended.Currently, there are no data available on the long-termefficacy of VIT in patients with mastocytosis. In view ofthe severe pre-VIT anaphylaxis to field stings in thisgroup, some authors have advocated continuation ofVIT indefinitely if well tolerated [25, 69] althoughin the United Kingdom the standard recommendation isfor 3 years treatment and for these patients to continue tocarry emergency treatment including adrenaline.Patients with a history of a SR but who lack specific IgE,should not be offered VIT but require emergency managementand provision of an adrenaline auto-injector.When to discontinue venom immunotherapy. In UK practice,a duration of 3 years for VIT is recommended [51,122–124]. There are no specific biomarkers that can reliablyassess how long to continue in individual cases. There arealso conflicting views with Mueller proposing that a negativeIDT at the end of VIT predicts long-term protection [124]and Golden suggesting continuing risk despite negative skintest [125]. Live sting challenges are not recommended inroutine clinical practice for assessment of treatment successsince they have poor reproducibility [62, 122, 126, 127].c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

BSACI venom allergy guidelines 1213Local reaction onlyNo further investigations.Adrenaline auto-injector not requiredHymenoptera insect stingSystemic reactionPrescribe adrenaline auto-injector whilepatient is awaiting investigationCheck baseline tryptase. If increasedconsider as a significant ‘risk factor’Milde.g. cutaneousinvolvementSkin test (SPT± IDT) andSerum-specific IgEModeratee.g. mild asthma, angio-oedema, GIor mild hypotensive symptomsSkin test (SPT± IDT) andSerum-specific IgESeveree.g. hypotension,upper airwayoedema, bronchospasmSkin test (SPT± IDT) andSerum-specific IgEBoth negative Either positive Either positive Both negative Either positiveVIT not usually indicatedunless likelihood of restingis high or elevatedbaseline tryptase*VIT sometimes indicateddepending on ‘risk factors’and clinical features*If severe and the history isconvincing, re-investigate in2–3 monthsVIT recommended**Continue adrenaline auto-injector in all patients at risk of a systemic reactionwho do not undergo VIT; for those undergoing VIT see section venomimmunotheropy and mastocytosisFig. 2. Schematic representation of diagnosis and management of hymenoptera venom allergy (bee and wasp venom). IDT, intradermal testing; SPT,skin prick test; VIT, venom immunotherapy.The majority of patients at the end of 3–5 years of VIThave detectable specific IgE despite being protected fromfuture stings [124]. Long-term follow-up studies have shownthat the cumulative risk for SRs is 5–15% in adults and atleast 5% in children after 5–13 years and 10–15 years offVIT, respectively [51, 122, 124]. Although one study suggesteda longer duration of VIT wasassociatedwithfewerrelapses, confounding factors were that most (80%) were beeallergic and baseline tryptase status was unknown [124].There was also a very high re-sting rate (62%) unlike that inUnited Kingdom.VIT administered indefinitely has been proposed inpatients with mastocytosis on the basis of four deaths[128–130]. However of these four patients at least one, andprobably two, who died after discontinuing bee VIT, werestung by a wasp. The third patient failed immunotherapy,which was then discontinued after 2.5 years,following allergic reactions during VIT, a field sting andskin testing. In the fourth patient, VIT was successful in thatvenom-specific IgE became negative, so the death is attributableto the mastocytosis rather than the IgE-mediatedcomponent of the disease. Hence there is no evidence tosupport indefinite VIT in mastocytosis and this cannot berecommended in the United Kingdom without furtherevaluation [108, 121, 128–130].Who should carry an adrenaline autoinjector followingvenom immunotherapy. All patients undergoing VITshould carry an adrenaline auto-injector during up-dosing.Although not evidence-based, BSACI also recommendsthat the following groups are provided with anadrenaline autoinjector even after successful up-dosingand completion of VIT:1. Those at continuing risk of multiple stings, for examplea gardener with an occupational risk of multiple waspstings or a beekeeper after bee VIT.2. If during immunotherapy the patient continued toexperience allergic reactions.3. Patients with an elevated baseline tryptase or mastocytosis.Effect of venom immunotherapy in childrenVIT reduces the frequency and severity of SRs amongchildren who have previously had moderate-severe SRs [45,51]. The prolonged benefit is greater than that seen in adultsand persists for many years after stopping treatment [51, 52].A schematic pathway for the management of hymenopteravenom allergy is shown in Fig. 2.Practical aspects of venom immunotherapyAs with other forms of immunotherapy, safety measuresare paramount. VIT should be carried out only by aspecialist with experience and knowledge in this field.Children should undergo skin testing and receive immunotherapyin the same way as adults. Shorter inductionprotocols such as rush and ultrarush protocols can be usedc 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

1214 M. T. Krishna et alto reduce the number of hospital visits, but their use mustbe limited to specialist centres [131].reaction) followed by careful dose escalation and premedicationwith antihistamine considered.Safety measuresa. Assessment of a patient before injection: Beforeeachinjection the patient should be asked a series of questions.Establish if there were anylate-reactions(systemicor large local) to the last injection and if so the nature,severity, time of onset and treatment. Enquire if stungduring the interval and if so the nature of any reaction.b. Pre-treatment measurements: Measure baseline pulse,blood pressure and peak expiratory flow rate (PEFR). Withaccelerated protocols check pulse, blood pressure andPEFR at baseline and before each dose escalation step.c. Administration of correct allergen and dosage: Thename and identity of the patient must be checkedbefore administration of the injection.d. Any changes in the patient’s medical status (e.g.having been diagnosed with a cardiac/respiratorycondition; commencement on a b-blocker or othermedication) should be enquired before each injection.e. Injections should not be administered if the patienthas an intercurrent infection, particularly thoseaffecting the respiratory tract or during sepsis.f. The correct venom, dosage and shelf life of theproduct should be checked by two health professionalsexperienced in VIT before administration.g. Although not mandatory, it is good clinical practice todocument the batch number of the product that hasbeen administered in the patient’s hospital records.h. Injections must be given by the subcutaneous routeand appropriate precautions taken to ensure that thevenom is not given intravascularly.i. Patients must be observed for a minimum of 60 minfollowing each injection. It is important to ensure thatthe patient is well before discharge including measurementof PEFR (pulse and blood pressure where appropriate)and documentation of local reactions.A VIT questionnaire for assessment before VIT injectionsis shown in Appendix C.Dosage adjustmenta. This is necessary when patients miss scheduled injectionsduring the induction and maintenance phases.b. In the event of LLR (410 cm), a dose reduction to theprevious tolerated dose in the initial course is recommended.In patients with recurrent troublesome localreactions, pre-medication with an antihistamine shouldbe considered or the dosage split between different sites.c. In patients developing SRs to VIT, the subsequent doseshould be reduced (depending upon the severity of theMechanism of venom immunotherapyVIT exerts its effects by modulating both T and B cellresponses to allergen [132]. The early production of IL-10and induction of T cell ‘anergy’ appears to be the key eventin this process [133–135]. Allergen immunotherapy hasbeen shown to increase production of IL-10 by antigenpresenting cells, including B cells, monocytes and macrophages,a phenomenon that might lead to the increasedgeneration of IL-10 secreting T regulatory cells(CD4(1)CD25(1)Foxp3(1) cells) [134, 136]. Furthermore,increased production of TGF-b has also been reportedfollowing allergen immunotherapy and has been shown tocontribute to regulatory T cell function. IL-10 initiates Tcell ‘anergy’ or ‘hyporesponsiveness’ to venom by blockingtyrosine phosphorylation of CD28 and inhibitingCD28 co-stimulatory signal [137, 138].VIT induces an early shift in the Th1/Th2 balance, i.e.,there is a change from a Th2 to Th1 dominant pattern [139].With rapid VIT initiation protocols, there was a markedreduction in in vitro proliferation of peripheral blood mononuclearcells to venom and IL-4/IL-5 production togetherwith an increased generation of IFN-g and IL-10 within days[139, 140]. Addition of anti-IL-10 antibodies to cell culturesprevented the downregulation of venom-induced proliferationshowing that IL-10 played a key role in T cell ‘anergy’or ‘hyporesponsiveness’ [134]. Also, there is some evidencethat IL-10 inhibits IgE-dependent mast cell activation,which may explain the efficacy of VIT despite the continueddetection of venom-specific IgE in most patients at the endof the treatment phase [141].VIT is also associated with an increase in venomspecificIgG4 and a gradual decrease in specific IgE, witha consequent increase in IgG4 : IgE ratio [142–145]. Theincrease in venom-specific IgG4 after VIT is greater inwasp-allergic patients compared with bee-allergicpatients although no correlation was found betweenreactions to sting challenges and venom-specific IgG4,IgE or IgG4 : IgE ratio [142–145].Future research areas1. Epidemiological studies to determine the prevalenceof hymenoptera venom allergy in United Kingdom.2. Natural history of venom allergy in patients notundergoing VIT.3. Investigation of the role of recombinant allergens inenhancing the sensitivity and specificity of diagnostictesting in hymenoptera venom allergy.4. Studies to investigate the efficacy, safety and durationof VIT in patients with increased mast cell load.c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

BSACI venom allergy guidelines 12155. Feasibility of sublingual VIT and other routes of administrationincluding a direct intralymphatic approach.6. Prospective controlled studies to assess safety and efficacyof standardized aqueous and depot venom extracts.7. Newer approaches for VIT including using modifiedrecombinant allergen, T cell epitopes and DNAvaccination.8. Studies on the role of anti-IgE during up-dosing toreduce reactions.9. Studies on the role of antihistamine pre-medication.10. Effect of VIT on QOL in children.AcknowledgementsThe preparation of this document has benefited fromextensive discussions within the Standards of CareCommittee (SOCC) of the BSACI and we would like toacknowledge the members of this committee for theirvaluable contribution namely Nicola Brathwaite, AndrewClark, Tina Dixon, Pierre Dugué, Sophie Farooque,Nasreen Khan, Rita Mirakian, Ian Pollock, Richard Powell,Angela Simpson and Samantha Walker. We would likethank Karen Brunas, a non-medical lay person, whoreviewed a draft of these guidelines and whose suggestionslead to changes in the final document. Also, specialthanks to Pia Huber for her valuable help in editing andincorporating critiques provided by the members of SOCC.Conflicts of interests were recorded by the SOCC, nonejeopardized unbiased guideline development.These guidelines inform the management of venomallergy. Adherence to these guidelines does not constitutean automatic defence for negligence and conversely nonadherenceis not indicative of negligence. It is anticipatedthat these guidelines will be reviewed 5 yearly.References1 BSACI working party. Position paper onallergen immunotherapy. Report of aBSACI working party. January-October1992. Clin Exp Allergy 1993; 23 (Suppl.3):1–44.2 Antonicelli L, Bilo MB, Bonifazi F. Epidemiologyof Hymenoptera allergy.Curr Opin Allergy Clin Immunol 2002;2:341–6.3 Bilo BM, Rueff F, Mosbech H, BonifaziF, Oude-Elberink JN. 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Clinical andimmunologic features and subsequentcourse of patients with severe insectstinganaphylaxis. J Allergy Clin Immunol1989; 84:900–6.152 Ewan PW, Stewart AG. A prospectivestudy of systemic reactions to venomimmunotherapy (VIT). Clin Exp Allergy1993; 23 (Suppl. 1):82; Abstract.153 Youlten LJ, Atkinson BA, Lee TH. Theincidence and nature of adverse reactionsto injection immunotherapy inbee and wasp venom allergy. Clin ExpAllergy 1995; 25:159–65.154 Muller U, Hari Y, Berchtold E. Premedicationwith antihistamines may enhanceefficacy of specific-allergenimmunotherapy. J Allergy Clin Immunol2001; 107:81–6.Appendix A: Measures to avoid hymenoptera stingsa. Wear light coloured clothing.b. Avoid strong fragrances, perfumes and highly scentedshampoos.c. Wear shoes while outdoors and cover bodywith clothing, cap/hat and use gloves whilegardening.d. Avoid picking fruit from the ground or trees. Exercisecaution in gardens, picnic areas and outdoors wherefood is served and near refuse.e. Avoid drinking out of opened drink bottles/cans toprevent being stung inside the mouth.f. Wash hands after eating or handling sticky or sweetfoods outdoors (especially children)g. Keep uneaten foods covered especially when eatingoutdoors.h. Avoid high-risk hobbies if possible, e.g. bee keeping inbee venom allergic subjects.i. Always contact professionals to remove bee or wasp nests.j. Wear full protective clothing while handling bees.k. For bee keepers: to avoid family members being stung,the beehives should be kept away from the house andbee keepers advised to change clothing before enteringtheir home. Honey extraction at home increasesthe risk of being stung.c 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220

1220 M. T. Krishna et alAppendix B: Examples of venom immunotherapy protocolsTables B1–B3Table B1. Conventional VITWeek no.1 0.01 2 0.13 1.04 55 106 207 308 409 5010 6011 8012 100Table B2. Rush VITDay no.1 0.0010.010.10.20.42 0.81.02.04.06.03 8.0102040604 80100Injections in 60-min intervals on each day [98].Dosage micrograms of bee or waspvenom subcutaneously May be lower depending on patient’s sensitivity.As per manufacturer’s recommendation – ALK Pharmalgen Bee andWasp venom; for a more detailed description refer to the manufacturer’sproduct information.Dosage micrograms of bee or waspvenom subcutaneouslyTable B3. Ultra-rush VIT [99]Day no.1 0.010.11.0102040802 100100Dosage micrograms of bee orwasp venom subcutaneouslyNine injections over 2 days; Day 1: seven injections at 30–60 minintervals; Day 2: two injections at 2–4 h interval; days 1 and 2 as inpatient;maintenance dose of 100 mg given on days 7, 14, 28, 42, 63, 84and then monthly as out patient [99].Appendix C: Assessment before venom immunotherapyHistory required before each injection to decide if suitableto proceed or if dose modification requiredDid you have a large local reaction to the last Yes/Noinjection?If you said yes to the above question: How largewas this reaction and how long did it last?_______________________________Did you have any reaction to the last injection Yes/Noafter leaving the clinic?Have you been stung since your last injection? Yes/NoIf you said yes to the above question: Whichinsect stung you? Was it a full sting, partialsting, single sting or multiple stings? What wasthe outcome?__________________________________________________________________________Have you had a ‘cold’, ‘chest infection’, or Yes/Noother infection in the last week?Have you been diagnosed with any new illness Yes/Norecently?Have there been any problems with your Yes/Noasthma control since your last injection?Do you have any other active allergy?Yes/NoHave you changed your medicines since your Yes/Nolast injectionc 2011 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 41 : 1201–1220