Honeybee Venom Immunotherapy

Certainties and Pitfalls

M Beatrice Bilò; Leonardo Antonicelli; Floriano Bonifazi


Immunotherapy. 2012;4(11):1153-1166. 

In This Article

Indications for HB VIT

Indications for HB VIT are the same as for vespid allergy.[27] The history of an SR, the demonstration of an IgE-mediated mechanism and knowing the risk factors for a severe outcome are prerequisites for prescribing VIT.[2] Nevertheless, the risk of a future allergic reaction can only be assessed statistically as none of the tests available are able to accurately predict the outcome of the next sting. This circumstance makes it difficult to specify what level of statistical risk justifies VIT.[28]

Diagnostic venom tests are positive in 10–20% of asymptomatic individuals, underlining the importance of patient history as a factor. The patient is asked to describe his/her symptoms and course of the sting reaction. In patients who experience unclear or psychovegetative reactions, the treating doctor's report and any records of the reaction and related treatment should be requested and reviewed. Individual risk factors for anaphylaxis must be investigated. The number of stings and the culprit insect are also requested. Besides BKs, the vast majority of patients are unable to positively identify the stinging Hymenoptera. For normal HB exposed subjects, a single HB is usually unintentionally encountered by direct interaction as HBs are relatively docile.[3] After a sting, the stinger usually remains embedded in the skin because of the multiple small barbs. After shedding its stinger, the HB typically dies within hours or days. Moreover, it is interesting to note that quickly removing the stinger may minimize a reaction as most of the venom is delivered within the first 5–10 s.[3]

Diagnostic Testing

The advantages (in terms of specificity and sensitivity) as well as limitations of the standard diagnostic tests (skin test and detection of venom-specific IgE antibodies) have been discussed extensively elsewhere.[1,29] Even though the diagnosis is often simple, some pitfalls persist, which include the presence of IgE-negative anaphylaxis and of double positivity to both bee and vespid venoms in diagnostic tests with a single-positive history, which has been observed in 25–40% of hymenoptera venom allergy patients, thus making the choice of venom immunotherapy prescription a difficult one.[1] Double positivity may arise from double sensitization, cross-reactivity between epitopes on hyaluronidase in the two venoms or more frequently to CCDs of venoms and common allergens.[15] The IgE-inhibition test is of use when distinguishing between cross-reactivity and double sensitization. However, this is costly and results are sometimes difficult to interpret.

Since several major venom allergens have been expressed in recombinant form, some of which are now commercially available for diagnostic purposes, the so-called molecular diagnosis or component resolved diagnosis (CRD) should also be applicable in the field of HB venom allergy. In the first study published on this topic double IgE positivity to whole venoms was documented in 59% of 200 venom-allergic patients by ImmunoCAP, but only 17% were double positive to rApi m 1 and rVes v 5 (species-specific major allergens without CCDs of the HB and Vespula). The author concluded that double positivity to both Api m 1 and Ves v 5 indicates true double sensitization, thus suggesting immunotherapy with both venoms.[30] More recent studies[31–35] found a lower diagnostic sensitivity of ImmunoCAP rApi m 1 for the detection of HB venom allergy, one of which[34] hypothesized a European north–south difference in Api m1 sensitization. However, different laboratory methods,[35] different sources of HB allergens[36] as well as different selection of patients with HBV allergy[32,33] may be responsible for these differences in sensitivity.

The addition of other recombinant species-specific bee venom allergens without CCDs (like Api m 3 or Api m10) would further increase diagnostic accuracy.[33,35] In addition, the detection of CCD-specific IgE is also possible, using different methods and carbohydrate antigens (bromelain, MUXF3, horseradish peroxidase and ascorbic acid oxidase).[37,38] In conclusion, provided that the majority of relevant venom allergens are available in recombinant form, CRD enables physicians to discriminate between genuine double sensitization and cross-reactivity to CCDs in patients with double-positive IgE results to conventional venom extracts, optimizing patient selection for VIT. At the moment it does not seem that CRD is able to distinguish between more and less severe systemic sting-induced reactions.

Additional in vitro tests, like the cellular antigen stimulation test (CAST) or basophil activation test (BAT), although more expensive, can be used to determine immunological sensitization in difficult-to-diagnose patients in laboratories with an expert technician;[39] however, their predictive value in relation to a sting challenge has not been analyzed in large patient populations yet.

Finally, even if evidence suggests that HB yield more reliable sting challenge results than vespids, sting challenges should not be used as a diagnostic tool in untreated patients, as the absence of systemic symptoms does not rule out the possibility of an SR reaction to a future sting.[40]

Natural History & Risk Factors

In many cases the natural history of venom allergy is self-limiting, as many patients spontaneously lose their sensitivity.[2] After a LLR, about 10% of HB venom-allergic patients will develop a SR when next stung by a sting challenge.[41] According to sting challenge studies non-VIT treated bee venom-allergic patients are at a greater risk of a SR on re-sting (44–52%) than those who are vespid venom allergic (24–25%).[42,43] However, the well-known association between bee allergy and more severe SRs[2] could be untrue for field stings, as demonstrated by a European prospective multicenter study in which vespid venom allergy was significantly associated with severe reactions after a field sting.[44] It is possible that less HB venom is delivered at a field sting as most sting victims attempt to rapidly remove the stinger, thereby reducing the amount of bee venom delivered.

Other risk factors associated with the occurrence of a severe sting SR in untreated patients are cutaneous and/or systemic mastocytosis,[45] clonal mast cell disorders,[46] at least in adults, and even an increased baseline serum tryptase concentration (BSTC).[44] BSTC should therefore be measured in all patients with SRs[29,44,47] who should also undergo a dermatological examination for cutaneous mastocytosis.[40]

Even if in general the risk of recurrence of SRs is linked to the severity of the previous reaction, more recently it seems that preceding less severe SRs would produce a booster effect and predispose the patient to subsequent severe reactions.[44]

Elderly patients and patients with pre-existing cardiovascular diseases develop particularly severe, even fatal, SRs more often.[48] A recent study confirmed that treatment with angiotensin-converting enzyme inhibitors is a risk factor for SRs.[44]


VIT is indicated in patients who have a history of a severe Hymenoptera sting-induced SR and detection of IgE-mediated sensitization to the venom that triggered the reaction.[27,29,47] The 2005 European guidelines state that in both children and adults with a history of a systemic, nonlife-threatening reaction (urticaria, erythema, pruritus), other factors may influence the decision to commence VIT, which include occupations or hobbies where the risk of exposure is high, the culprit insect itself, concomitant cardiovascular diseases, other pathologies, like mastocytosis, and psychological factors due to anxiety, which can seriously impair patient health-related quality of life.[27]

Very recent English guidelines prescribe more restricted additional risk factors for VIT in less severe SRs, which include a raised baseline tryptase, a high likelihood of future stings, or effect on quality of life.[47]

VIT may benefit venom-allergic patients with mast cell diseases, albeit to a lesser extent than patients without.[45]

Even though subcutaneous VIT is effective even in LLRs,[49] it is not usually recommended. However, the specialist may consider it as treatment in highly exposed subjects who need repeated corticosteroid shots yearly, like BKs.[29]


In Europe, serious immunological diseases, cancer and chronic infections are absolute contraindications for inhalant immunotherapy as well as for VIT. Indeed, in some selected venom-allergic patients the advantages of VIT might outweigh the potential side effects, particularly where risk of sting exposure is high and there is a history of a near-fatal sting reaction, and perhaps in the presence of mast cell diseases.[28,47] Nevertheless, multicenter studies are required to better evaluate the effectiveness and safety of VIT in these patients.

In contrast to inhalant immunotherapy guidelines, major cardiovascular diseases are not contraindications for serious insect venom allergies. Untreated elderly cardiopathic patients are at increased risk of developing severe or even fatal sting reactions. Also, severe cardiovascular or respiratory disorders are almost always an urgent indication for VIT. Again, patients who developed myocardial infarction during sting anaphylaxis and had positive diagnostic tests are candidates for VIT.[48] VIT in patients on β-blockers is not a contraindication if the cardiac risk in venom-allergic patients is greater than the risk of a SR during VIT, however, VIT must be performed in an appropriate hospital setting.[48]

In women of childbearing age, VIT should be started before pregnancy. However, a well-tolerated maintenance VIT may be continued to prevent the risk of further SRs, even for the fetus.[27]