Hymenoptera Venom Immunotherapy

Beatrice M Bilò; Floriano Bonifazi


Immunotherapy. 2011;3(2):229-246. 

In This Article

Side Effects

Although highly effective, patient compliance with VIT may be impaired by LLRs and SRs,[4,10] the latter explaining why, in some European countries, only selected allergy centers usually opt for treatment. However, some studies demonstrate that the side effects of VITs are less frequent than those caused by subcutaneous immunotherapy for inhalant allergens.[82,83]

Large local reactions to injections are commonplace, especially during the incremental phase, and occur in up to 50% of patients. Although LLRs during VIT are not a risk factor for a SR and do not usually necessitate a reduction in venom dose or prevent the protective dose from being reached, they can be particularly bothersome, sometimes requiring corticosteroid and antihistamine treatment for several days. However, anaphylaxis represents the biggest risk posed by VIT. Other side effects of VIT, such as serum sickness, are extremely rare.[2] The literature reports a large variation (0–46%) in the incidence of VITs side effects,[2,10] with the tolerance of vespid VIT (0–15%) faring better than honeybee VIT (20–40%). Indeed, looking at the results of two multicenter studies[84,85] and one review of eight trials of at least 100 patients,[52] the percentage of patients with VIT-induced SRs is between 2 and 20%, and adrenaline was administered to 0.2–5% of patients who experienced a SR.[52] SRs during VIT pose a serious problem and, at present, there is no reliable test that is able to predict the extent of the risk. The finding that increased basophil sensitivity to allergen-specific in vitro stimulation is significantly associated with major side effects to VIT needs to be confirmed by further studies.[86] To reduce the incidence of VIT-induced SRs, the risk factors need to be defined. Box 3 summarizes old and new potential risk factors for side effects during VIT.

In a European, multicenter study, published in 2000, a greater risk of SRs was demonstrated during the incremental phase of VIT in female patients, in subjects receiving bee venom vaccines and in patients undergoing the rapid incremental phase, but not in patients with a history of a severe, original SR.[85] Similar findings for several of these parameters were observed in a previously conducted, larger, retrospective study in the USA, which reported that SRs were most likely to occur at venom doses between 1 and 50 µg and at maintenance dosage.[84] In a recent review, which evaluated eight VIT studies in the general population, honeybee VIT was confirmed to be a risk factor for an SR; side effects occurred in 26.6% of patients treated with honeybee venom and in 11.2% of patients treated with yellow jacket venom.[52] In contrast to the findings of the previously mentioned old, European, multicenter study,[85] several retrospective studies concluded that treatment with rush and ultrarush protocols are tolerated at least as well as, or even better than, treatment with slower protocols.[87] However, there may be a difference between honeybee and vespid venoms with respect to the tolerability of the different protocols.[88–90] The results of a very recent European, multicenter study, collecting data from more than 600 patients, confirmed the rapid dose increase (ultrarush > rush > conventional phase) during the build-up phase of VIT as a risk factor for a SR.[91]

At present, ultrarush protocols should only be used by specialists who are experienced in managing VIT and preferably only in an emergency care setting, particularly in bee venom allergic patients.

Even though there are good theoretical grounds for the contraindication of β-blockers during immunotherapy, this does not seem to apply to VIT.[60] ACE-inhibitors may possibly contribute to the onset of SRs during VIT in some highly selected patients,[92] although further data are required to confirm this.[93]

Side effects during VIT are probably more frequent in mastocytosis patients, especially in those with a yellow jacket venom allergy.[52] However, risk factors for adverse reactions in these patients (e.g., type of mastocytosis and protocol) require further evaluation.[51] Moreover, baseline tryptase concentration correlates significantly with the frequency of severe side effects during the build-up phase of VIT.[91] However, the extent of this effect depends on the type of venom and is more marked in patients treated with vespid VIT.[91]

In general, repeated anaphylactic reactions are rare. In these cases, it should be assumed that VIT will not prevent further SRs following a sting. Moreover, treatment should be continued for approximately 6 months with the highest tolerated dose of insect venom (injection interval 1–2 weeks) and then renewed attempt at dose increase.[45]

In conclusion, risk factors for VIT-induced SRs must be taken into account and patients with one or more risk factor should be treated and monitored with special care.


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