Hymenoptera Venom Immunotherapy

Beatrice M Bilò; Floriano Bonifazi


Immunotherapy. 2011;3(2):229-246. 

In This Article

Indications & Contraindications

Indications for VIT are based on the history of a SR, a positive venom skin or specific IgE, knowledge of the natural history and established risk factors for a severe outcome.[1,6,25] Nevertheless, the risk of a future allergic reaction can only be expressed statistically since none of the available tests 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.

Patient History

The history is especially important as diagnostic tests with venoms are positive in 10–20% of asymptomatic individuals. The patient is asked to describe his/her symptoms and course of the sting reaction, number of stings, cues to the type of insect involved and individual risk factors for anaphylaxis. In general, cutaneous manifestations are more common in children than in adults, respiratory symptoms occur with equal frequency in approximately 40% of children and adults, while cardiovascular signs and symptoms are common in adults, whereas these are infrequent in children.[2,5] In patients with equivocal clinical histories, the treating physician's report and any records of the reaction and related treatment should be requested and reviewed. Positively identifying the stinging insect as a bee or wasp is a common confusing issue, except for beekeepers.

Diagnostic Testing

The decision to commence VIT requires confirmation of allergic sensitivity to venom allergens by positive venom skin tests and/or detection of venom-specific IgE antibodies in the serum.

The European Academy of Allergology and Clinical Immunology (EAACI)[1] and the American Academy of Allergy, Asthma and Immunology (AAAAI)[4] have recently published clinical practice parameters on diagnosis. Only those patients with a history of a previous SR are suitable candidates for diagnostic testing,[1,4] even though physicians in certain countries perform diagnostic tests in patients who have a history of LLRs despite being rated as having a reduced risk of a future SR.[6] Skin tests are the methods of choice and should be performed at least 2 weeks after a reaction to a sting in order to rule out a false negative during the refractory period.[1] Because the duration of refractoriness may be longer, they should, if negative in the presence of a definite history of a SR, be repeated after 1–2 months.[1] However, some patients reported having only manifest sensitization in the first week after being stung.[26] Guidelines recommend stepwise incremental venom skin tests, starting with a skin-prick test (from a concentration of 0.01 up to 100 µg/ml).

Even at venom concentrations of 100 µg/ml, the sensitivity of the skin prick test is lower than that of the intradermal test, which has to be used in order to confirm the negative result (from a concentration of 0.001 up to 1 µg/ml).[1] Skin tests with hymenoptera venoms are generally safe; nevertheless, SRs do occur, although these are very rare.[2]

Hymenoptera venom products, such as lyophilized protein extract for honey bee, bumble bee, yellow jacket and Polistes wasp venoms, are commercially available in many countries, the latter two being mixtures of the clinically relevant species. Due to incomplete cross-reactivity between venoms of the European and American species of Polistes,[27] commercial preparations of European Polistes dominulus venom have become available.[28]In vitro tests, such as the dosage of specific IgE to hymenoptera venom, can be applied to detect sensitization. The most recently developed tests are usually the most sensitive.[1,29] However, their sensitivity in patients with a history of systemic sting reactions is lower than that of intradermal skin tests, especially when more than 1 year has elapsed after the reaction.[1]

If in vitro tests are negative in approximately 20% of positive skin tests,[30] the converse is also true, since approximately 10% of negative skin tests yield a positive in vitro result. Therefore, European allergists recommend skin testing and evaluation of venom-specific IgE in all patients with a history of SRs.[31]

There is no positive correlation between the severity of previous sting reactions and skin-test reactivity, or the concentration of venom sIgE.[1] Indeed, the most reactive skin tests often occur in patients with only LLRs, while almost 25% of patients who are referred for evaluation of a sting SR are intradermal skin-test positive only at the 1 µg/ml concentration, thus demonstrating the importance of testing with the full diagnostic range of venoms.[31] In a study that measured IgE antibody levels in sera from 51 venom anaphylaxis fatalities, IgE antibodies were not detected in 10% of the sera, indicating that fatal sting anaphylaxis is a potential occurrence in the presence of widely varying amounts of specific IgE antibody.[32]

Double positivity to both bee and vespid venoms in diagnostic tests has been observed in 25–40% of HVA patients, the majority of whom have a single-positive history and are unable to identify the culprit insect. Double positivity may arise from double sensitization, cross-reactivity between epitopes on hyaluronidase in the two venoms or to cross-reactivity between cross-reactive carbohydrate determinants (CCDs) of venoms and common allergens.[1,33] These widespread pan-allergens are not necessarily clinically irrelevant and are found on bromelain or horseradish peroxidase, which can be used in screening for such antibodies, as well as MUFX (neo-glycoprotein fucosylated/xylosylated N-glycans from bromelain). The IgE-inhibition test is of use when distinguishing between cross-reactivity and double sensitization. However, it is costly and results are sometimes difficult to interpret. In a recent study of 200 patients with a history of reaction to honey bee or Vespula sting, 59% had double positivity for specific IgE using the ImmunoCAP test, and 32% had double positivity using ADVIA Centaur® (Siemens).[34] Specific IgE to the recombinant nonglycosylated major allergen, Api m 1, was detected in 99% of cases of whole bee venom-positive allergy, while sIgE to Ves v 5 was present in 96% of whole Vespula venom-positive allergic patients when tested by ADVIA Centaur, thus reducing the double positivity to 17%.[34] Similarly, a combination of nonglycosylated recombinant bee and wasp venom major allergens (rApi m 1, rApi m 2 and rVes v 5) enabled clinicians to diagnose patients with HVA, which should facilitate the accurate prescription of VIT.[35] According to other authors, the recombinant availability of Ves v 1 from yellow jacket could also contribute to a more detailed 'component resolved diagnosis' of HVA and subsequently to better VIT prescription.[36]

On the other hand, there are those patients with a clear history of a SR but negative skin and in vitro radioallergosorbent test (RAST) results.[30] Negative test results can be due to the involvement of a different pathogenetic mechanism, mastocytosis, the time interval between sting reactions, poor test sensitivity or use of the wrong venom for the diagnostic test.[1,37]

In this respect, a modified assay (ImmunoCAP) to detect very low concentrations of venom-specific IgE,[38] as well as a dialyzed yellow jacket venom extract for skin testing,[39] have been suggested. Additional in vitro tests, such as 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.[40–43] However, their use should be restricted to laboratories with expert technicians, bearing in mind that a positive result may also point to a non-IgE mediated mast-cell activation mechanism.[44]

Finally, live insect 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 a SR to a future sting.[45]

Recently, the first comprehensive audit of the diagnosis and management of HVA patients in the UK revealed a wide variation in practice and suggested the need for the development of better educational programmes for specialists and trainees involved in the management of the patients in question.[46]

Natural History & Risk Factors

Reaction severity, confirmation of venom IgE sensitivity, current knowledge of the natural history of HVA and risk factors form the selection criteria for suitable VIT candidates, when deciding whether to start VIT and for how long to treat them for. In general, the risk of recurrence of SRs is linked to the severity of the previous reaction: the more serious the initial reaction, the greater the risk of recurrence. Linking the estimated risk of a future SR with reaction severity, age and sting interval, adults and children with LLRs are a low-risk category for a SR (5–15%) when re-stung.[3,6] Adults with a recent history of severe anaphylaxis have a 40–60% chance of reacting to a re-sting, whereas those with mild SRs have a 20% chance of a subsequent SR.[47] The prognosis for children is better than that of adults with respect to the risk of SRs to re-stings. However, those who experience a moderate-to-severe SR continue to have a high risk of reactions even 15–20 years later.[48] According to recent data provided by an EAACI multicenter study, preceding less severe SRs would appear to produce a booster effect and predispose the patient to subsequent severe reactions.[25]

In the absence of a history of a sting-induced allergic reaction, sensitization by an asymptomatic sting has been reported by Golden et al. to be associated with a 17% chance of a SR to a future sting,[49] while Fernandez et al. suggests that this condition is not a clear risk for a future SR, at least in the case of vespids.[50]

Other risk factors associated with the occurrence of a severe field-sting SRs in untreated patients are represented by an increased baseline tryptase concentration,[25] cutaneous and/or systemic mastocytosis[51,52] and even clonal mast-cell disorders,[53] at least in adults. Baseline serum tryptase levels should, therefore, be measured in all patients with SRs as well as a dermatological examination for cutaneous mastocytosis.

Contrary to previous findings,[2,6] vespid stings seem to be associated with more severe reactions than do bee stings.[25,54] The relative risk for life-threatening sting reactions in the Mediterranean area is approximately three-times higher for hornet (Vespa crabro) stings than for honeybee or yellow jacket stings.[55]

Recommendations for the use of VIT vary from country to country. While there is a strong consensus that VIT is indicated for severe systemic sting reactions, there is less agreement on whether adults, and especially children, with mild (cutaneous) reactions are suitable candidates, as the prognosis in dermal reactors is usually considered to be good.[2,4] Although current opinion on providing patients with a history of a mild reaction with autoinjectable epinephrine differs among experts,[4,5,31] its negative effect on HRQL could mean that treatment with autojectable epinephrine alone is probably inappropriate.[56] Since the occurrence and severity of anaphylaxis depends on several factors, the advantages and disadvantages of not administering VIT should be thoroughly discussed on an individual patient basis. Furthermore, even in children with mild SRs, management should also take the child's behavioral risks into consideration. Indeed, the updated European Guidelines state that in both children and adults with a history of a systemic, non-life-threatening reactions (e.g., urticaria, erythema and pruritus) other factors may come to bear on the decision to commence VIT, which include occupation and/or hobbies with a high risk of exposure, the culprit insect itself, concomitant cardiovascular diseases, others pathologies, such as mastocytosis, and psychological factors arising from anxiety that can seriously impair patient HRQL (Table 1).[10]

Venom immunotherapy is indicated in HVA patients with mast-cell diseases as the treatment can reduce SRs, albeit to a lesser extent than in otherwise healthy subjects with HVA;[52] moreover, an elevated level of baseline serum tryptase should be included in the decision of which patients should be offered the treatment.[25]

Venom immunotherapy is able to reduce the severity and duration of LLRs and its efficacy improves over a period of 2–4 years.[57] Although VIT is not usually recommended in patients with such reactions, as the risk of a subsequent systemic sting reaction is low, physicians may consider it as a treatment option when confronted with extremely anxious patients with HRQL impairment or highly exposed subjects who require repeated per annum corticosteroid shots.


In Europe, the standards for practical allergen-specific immunotherapy[58] underlines that serious immunological diseases, cancer and chronic infections are absolute contraindications for immunotherapy in general; major cardiovascular diseases are contraindications, except in the case of serious insect venom allergies. Untreated, elderly, cardiopathic patients are at increased risk of developing severe, or even fatal, sting reactions[59] and severe cardiovascular or respiratory disorders are almost practically always an urgent indication for VIT.[45] Untreated patients with anaphylaxis should not be given β-blockers, except under circumstances where the administration of these drugs is urgently required as in the case of certain heart rhythm disorders.

Administration of VIT to patients receiving β-blockers (even in eye drops) is contraindicated as they can aggravate anaphylactic reactions and also interfere with treatment. However, if the cardiac risk in venom allergic patients outweighs the risk of a systemic reaction during VIT, then VIT is appropriate for use in subjects receiving β-blockers but must be performed in an emergency care setting.[60]

Severe allergic reactions, including anaphylaxis, have been described in patients on angiotensin-converting enzyme (ACE)-inhibitors subsequent to being stung or receiving immunotherapy.[10] According to the results of a recent EAACI multicenter study, ACE-inhibitors should be withdrawn in untreated patients.[25]

Currently, there are no data to support or exclude the potentially harmful role of angiotensin-receptor blockers in patients with anaphylaxis in general, or in HVA-untreated patients.[61]

As regards the other contraindications, such as serious immunological diseases and cancer, the European guidelines need to be reviewed in order to cater for cases of severe sting allergic reactions, particularly where there is a high risk of sting exposure, a history of a near-fatal sting reaction and perhaps for mast-cell diseases given the treatment's life-saving potential. Indeed, in some selected cases the advantages of VIT might outweigh the potential negative effects.[45,62] Nevertheless, multicenter studies are required to better evaluate the safety of VIT in these patients, as an acute worsening of these diseases cannot be ruled out, particularly if the diagnosis was made prior to commencing VIT, and the possible reduced effectiveness of VIT in patients with autoimmune diseases, or in immunosuppressant therapy, should be taken into consideration.

Venom immunotherapy should not be begun during pregnancy, but well-tolerated maintenance VIT may be continued in order to prevent the risk of further SRs in the mother as well as in the fetus.[10] Patients who develop sting reactions such as Henoch–Schoenlein syndrome, vasculitis, acute disseminated encephalomyelitis or interstitial nephritis should not be treated with VIT.[2,10] By contrast, those who developed cerebrovascular or myocardial infarction during sting anaphylaxis and have positive diagnostic tests are candidates for VIT.[59]


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