Abstract

Abstract and Introduction Abstract Subcutaneous venom immunotherapy is the only effective treatment for patients who experience severe hymenoptera sting-induced allergic reactions, and the treatment also improves health-related quality of life. This article examines advances in various areas of this treatment, which include the immunological mechanisms of early and long-term efficacy, indications and contraindications, selection of venom, treatment protocols, duration, risk factors for systemic reactions in untreated and treated patients as well as for relapse following cessation of treatment. Current and future strategies for improving safety and efficacy are also examined. However, although progress in the past few years has been fruitful, much remains to be accomplished. Introduction Hymenoptera stings can induce allergic systemic and occasionally fatal reactions. The offending hymenoptera belong to the suborder Aculeate, which are made up of the Apoidea (Apis mellifera and Bombus species) and Vespidae (Vespinae and Polistinae subfamilies) superfamilies, [1] Detailed clinical features of insect sting reactions and their pathogenesis are described elsewhere. Authors and Disclosures Classification by HL Mueller Grade I -Generalized urticaria, itching, malaise and anxiety Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 1 of 22 6/4/2011 9:10 μμ In the USA, the prevalence of SRs to hymenoptera sting in the general population ranges from 0.5 to 3.3%. European epidemiological studies from the last decade report a prevalence of 0.3-8.9% for SRs, with anaphylaxis reported in 0.3-42.8% of cases. To date, there is no existing parameter that enables clinicians to predict who will have a future reaction and whether it will be a LLR or generalized anaphylaxis. Several concomitant factors, which include the environment, genetics and individual elements, may account for the occurrence of a SR in any one patient. [11] Mechanisms of Action of VIT The underlying immunological mechanisms of VIT are continuously being elucidated. Different mechanisms involving specific cell populations, play a role in the different phases of VIT, [10] The proposal of blocking antibodies has been Grade II -Any of the above plus two or more of the following: angioedema, chest constriction, nausea, vomiting, diarrhea, abdominal pain and dizziness Grade III -Any of the above plus two or more of the following: dyspnea, wheezing, stridor, dysarthria, hoarseness, weakness, confusion and feeling of impending disaster Grade IV -Any of the above plus two or more of the following: fall in blood pressure, collapse, loss of consciousness, incontinence and cyanosis Classification by J Ring Grade I -Generalized skin symptoms (e.g., flush, generalized urticaria and angioedema) Grade II -Mild to moderate pulmonary, cardiovascular and/or gastrointestinal symptoms Grade III -Anaphylactic shock and loss of consciousness Grade IV -Cardiac arrest and apnea Adapted from Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 2 of 22 6/4/2011 9:10 μμ re-evaluated on the basis of observations of altered specificity and affinity during immunotherapy and effects on memory B cells and antigen-presenting cells. Very early effects of VIT are also associated with an early decreased mediator release from mast cells and basophils, although the mechanism of this desensitization effect is, as yet, unknown. [24] 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. 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. 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] However, some patients reported having only manifest sensitization in the first week after being stung. 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, [1] If in vitro tests are negative in approximately 20% of positive skin tests, [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. [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. [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%. [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. [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. [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. [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, Contrary to previous findings, [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; [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. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 5 of 22 6/4/2011 9:10 μμ Contraindications In Europe, the standards for practical allergen-specific immunotherapy [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. [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. 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. [59] Selection of Venoms Selection is based on the identification of the hymenoptera species that is involved, on the results of the diagnostic tests and on venom cross-reactivity. In North America, allergists and immunologists believe it prudent to prescribe VIT with any venom, which gives a positive skin test, or sIgE result, since there have been cases where VIT was tailored towards the primary culprit insect but the patients subsequently reacted to an insect to which they had previously been sensitized. In Europe, the geographical distribution of each species and the ample cross-reactivity among venoms of Vespula, Dolichovespula and Vespa, usually makes treatment with Vespula venom alone sufficient in the temperate European climate. Double diagnostic positivities to wasp (Polistes) and yellow jacket (Vespula species) venoms have been observed in Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 6 of 22 6/4/2011 9:10 μμ more than 50% of vespid allergic patients. Owing to the incomplete cross-reactivity between vespinae and paper wasps (Polistes) in the Mediterranean area, patients who test positive to both venoms should be treated with both, unless RAST-inhibition reveals cross-reactivity. [10] The same approach is used in the Gulf states of the USA, where Polistes is common as a species. [31] A weaker cross-reactivity between European and American paper wasps was recently demonstrated. [27] The species P. dominulus and Polistes gallicus are European paper wasps; P. dominulus has spread to northeastern USA and has also been reported in Australia. The species Polistes exclamans, Polistes annularis and Polistes fuscatus are indigenous to North America and are not present in Europe. All these findings raise the need to introduce, at least in Europe, the P. gallicus or P. dominulus extract (the latter only recently being available in some European countries) into clinical practice for diagnostic and therapeutic purposes to replace the American Polistes species mixture presently being used. [55] V. crabro venom has some antigens in common with Vespula venom; however, a third of V. crabro-allergic individuals have positive skin and sIgE tests restricted to only V. crabro venom. Italy, it is a common practice to use V. crabro extract for both diagnostic and therapeutic purposes. Dual positivity of diagnostic tests with Vespula and honeybee is also frequent, especially in some European countries where bee venom allergy is more frequent than vespid venom allergy. [33] Honeybee and bumblebee venoms show high cross-reactivity. [1] Immunotherapy with honeybee venom alone may be sufficient in nonprofessionally exposed bumblebee-allergic patients with bee venom primary sensitization, whose reaction is most likely due to cross-reactivity. In occupationally exposed patients, who are frequently stung by bumblebees, purified bumblebee venom for immunotherapy, when available, is recommended owing to the low or absent cross-reactivity with honeybee venom. [47] In the USA, whole-body fire ant extract immunotherapy, which contain sufficient venom allergens to provide reasonable clinical protection is used; fire ant venoms are available in Australia (Jack Jumper) where a very successful controlled trial was performed. [69] By contrast, allergic reactions to ants are rare in Europe, Efficacy Subcutaneous VIT is probably the most effective allergen treatment currently available to physicians. The efficacy of VIT has been confirmed in prospective controlled and uncontrolled studies [72] The recommended maintenance dose is 100 µg of venom, both in children and adults. This dose was originally proposed because it was believed to be equivalent to two stings. Indeed, between 50 and 140 µg venom are delivered by a bee sting compared with up to 3 µg by that of a Vespula sting and up to 17 µg by that of a Polistes sting. [4] For the first time, a recent paper demonstrated the efficacy of a P. dominulus extract after a field sting. [65] A dose of 200 µg is recommended when a SR follows an insect sting in spite of VIT with 100 µg and in highly exposed populations, such as beekeepers. [51] Most American patients receive mixed vespid venoms, with an injectable maintenance dose of 300-400 µg, which provides approximately 98% protection. [68] Some authors have demonstrated that VIT efficacy in mastocytosis sufferers may be reduced. [75] Box 2 presents risk factors currently known to predispose a patient to a SR at sting challenge or an in-field sting during VIT. Treatment Protocol Many treatment protocols for the VIT induction phase have been designed. [10] They vary with respect to the number of injections, venom doses and time needed to reach the final dose [ Question marks indicate the existence of discordant data on these topics. [76] They performed two different protocols, a rush protocol in 62 inpatients, and a modified rush protocol in 670 outpatients, thereby demonstrating that by starting with 1 µg of venom there was no SR. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 9 of 22 6/4/2011 9:10 μμ If two or more venoms are required, they should be administered in separate protocols a few days apart. While the build-up phase of VIT should be performed by an allergist, in some countries, maintenance treatment is eventually continued by the general practitioners. In Europe, VIT may be performed with nonpurified aqueous (NPA), purified aqueous (PA) extracts and purified aluminium hydroxide adsorbed (PAHA) preparations (so-called 'depot' extracts) of yellow jacket and honeybee venoms, administered by subcutaneous injection. Purified venom extracts do not contain vasoactive amines (e.g., dopamine, histamine and serotonin) and have a reduced presence of small peptides (e.g., apamine, kinins and mast-cell degranulating peptide in the final product). [77] Polistes species and P. dominulus PA and PAHA extracts for diagnostic and therapeutic purposes are not currently commercially available in Europe. The efficacy of PA and depot extracts is supported by studies using both sting challenge and in-field stings, and is comparable to that of nonpurified preparations. [31] The NPA and PA extracts can be used for ultrarush, rush, clustered and maintenance phases, while PAHA preparations are only administered for the conventional build-up and maintenance schedule. Many European specialists switch to depot preparations following the up-dosing phase. [77] The general consensus is that the maintenance interval should be kept at 4 weeks for the first year, extended to 6 weeks in the second year, and then to 8 weeks if VIT is continued for more than 5 years, provided that the treatment is tolerated. [77] A longer interval is not recommended for honeybee allergic patients since beekeepers with less than ten stings a year were those who developed SRs most frequently. Side Effects Although highly effective, patient compliance with VIT may be impaired by LLRs and SRs, Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 10 of 22 6/4/2011 9:10 μμ 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. [2] The literature reports a large variation (0-46%) in the incidence of VITs side effects, 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. [87] However, there may be a difference between honeybee and vespid venoms with respect to the tolerability of the different protocols. [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, [52] However, risk factors for adverse reactions in these patients (e.g., type of mastocytosis and protocol) require further evaluation. [91] Question marks indicate the existence of discordant data on these topics. ymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 11 of 22 6/4/2011 9:10 μμ 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. How can VIT Safety be Improved? Pretreatment with a H1 antihistamine has been demonstrated to reduce the number and severity of LLRs and mild SRs to VIT, such as urticaria and angioedema. Pretreatment with a combination of H1 antihistamine and a corticosteroid have not yet been performed in honeybee and vespid VIT, except in patients with mast-cell diseases. [52] In a prospective, double-blind, randomized, placebo-controlled pilot study the occurrence of local reactions following VIT was significantly delayed by pretreatment with the leukotriene antagonist montelukast. [96] Pretreatment with anti-IgE monoclonal antibodies may permit more rapid and higher doses of allergen immunotherapy while improving its safety. Moreover, this pretreatment could play an important role in insect-venom allergic patients who are intolerant to VIT. There are several case reports of bee venom allergic patients, [99] Until now, the optimal time for its administration during VIT (should it be administered 6 months, 2 weeks, 1 week or 1 h before VIT?), the appropriate dosage (should we use the the recommended dose of 150 or 300 mg?), the long-term effects (should omalizumab be discontinued after first administration or administered before each shot?) and the best incremental protocol of VIT (should the protocol be conventional or rush/ultrarush?) to be used are still unknown. It is important to underline that omalizumab is not approved for the prevention of anaphylaxis and it must be prescribed as off-label. In addition, taking into account its high cost, omalizumab should be limited to patients with repeated severe SAR to VIT injections preventing reaching the maintenance dose. Although the object of a certain amount of criticism, [101] Even though LLRs are not an indication for VIT, in a placebocontrolled, double-blind study on bee venom SLIT in patients with a history of LLRs, the diameter of LLR to a bee sting challenge was reduced by more than 50% in 57% of active-treated patients. [102] However, on the basis of these findings alone (a partial or complete treatment failure in 43% of patients with LLRs) and without experimental data on the pharmacokinetics of venom SLIT, caution should be exercised when considering SLIT as a therapeutic option for patients with severe SRs. [77] VIT Monitoring The current options for monitoring VIT include skin tests, in vitro tests and sting challenge tests. The level of venomHymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 12 of 22 6/4/2011 9:10 μμ specific IgE level and skin-test sensitivity usually increase in the first months of therapy, return to baseline after 12 months and then decline steadily during maintenance VIT. [106] The reduction of skin reactivity may be attributable to a factor present in the patient's serum, since serum of VIT-treated patients is able to neutralize skin reactions to yellow jacket extracts in vivo Specific IgG antibodies increase and remain elevated at least as long as VIT is continued. antibodies, and later on IgG 4 antibodies. The ratio of venom-specific IgE:IgG 4 first increases, then later decreases during VIT, [109] In one study by Ebo et al., no effect of VIT on BAT was observed after a 5-day incremental phase, but a significant decrease in CD63 expression after 6 months of VIT was. [109] By contrast, there was no change in basophil CD63 expression compared with pretreatment values in 20 vespid-venom allergic patients who received VIT and had already tolerated a sting challenge. [110] Recently, a small but continuous decrease in baseline tryptase concentration over time was reported, which correlated with VIT duration, suggesting a dampened mast-cell function or decline in mast-cell burden. [111] However, despite the availability of new laboratory techniques, it is not yet possible to measure clinical efficacy based on laboratory parameters, [5] A sting challenge with a single, live insect can be used in treated patients to identify those who are not protected. Whether protected patients also tolerate several stings is unknown. In the case of incomplete VIT protection, revealed by sting challenge or in-field stings, increasing the maintenance dose to 200 µg almost invariably bestows complete protection. [113] Annual appointments with the allergist serve to review the treatment plan, ensure that the patient has not been prescribed any new medication or has a medical condition that could influence VIT or has not tolerated an in-field sting. According to some authors, there is no need for annual skin or blood tests, although repeating the skin tests every 2-3 years is recommended so that patients who can be taken off VIT can be identified. [45] Duration of VIT The question of how long VIT should last so that long-term protection can be achieved after discontinuation is a long-standing one. It is likely that short-and long-term results are more favorable with the much higher total dose administered in the USA than that with the 100 µg applied elsewhere. More European data on the discontinuation of VIT in allergic vespid patients with 100 µg maintenance dose are needed. [116] A number of risk factors for the recurrence of SRs following hymenoptera stings after discontinuing VIT have since been identified and are summarized in Box 4. [120] However, the study was mostly carried out via email and telephone interviews, patients were not stratified by the severity of their initial reaction, by the venom they were allergic to or by the occurrence of reaction during VIT, but in relation to the duration of VIT alone. According to EU guidelines, longer-term treatment (or life-long treatment) should be considered in patients with: A higher risk of very severe sting reactions (e.g., older age, history of very severe previous sting reactions, elevated basal serum tryptase, mastocytosis or use of β-blockers); Generalized allergic reactions to stings or to immunotherapy injections or during VIT; Highly exposed patients, such as beekeepers and their immediate family members. [10] However, some patients at a low risk of relapse prefer to perform long-term VIT out of a sense of personal safety and improved quality of life. At present, we do not know if an improvement in HRQL remains even after discontinuing VIT. According to some authors, [112] After ending VIT, patients should continue to avoid being stung. Some authors agree that patients should still carry an emergency kit. Conclusion Insect sting allergy and VIT remain an excellent model for the study of anaphylaxis and immune tolerance. VIT is probably the most effective form of specific allergen immunotherapy. Patient knowledge that VIT prevents anaphylactic reactions to future stings improves HRQL, which, in itself, is an important reason for offering immunotherapy to patients with insect allergies. However, neither the efficacy nor the safety of the treatment are optimal, especially as regards to bee VIT, and so there is considerable room for further improvement in these all-important areas. A number of new strategies for VIT, mostly based on genetic engineering, have been described and we are eagerly awaiting the advent of their application in clinical practice. Future Perspective Modern molecular biology has provided us with a considerable number of major honeybee and various vespid venom allergens in recombinant form, Major T-cell epitope peptides can be prepared synthetically or expressed as recombinant fragments. A mixture of three dominant T-cell peptides of phospholipase (PLA) has, so far, only been used for immunotherapy in a preliminary bee venom allergy study in five patients where complete protection was bestowed in three subjects and partial protection in the remaining two after a bee sting challenge with no side effects. [123] In a double-blind, randomized, placebo-controlled trial in bee venom allergic patients, using three long, synthetic, overlapping peptides (LSPs), mapping the entire PLA2 amino acid sequence, this therapy induced T-cell anergy, immune deviation toward a Th1-type T-cell cytokine response, enhanced IL-10 secretion, and PLA2-specific IgG 4 production. LSP immunotherapy was safe and did not cause any severe systemic reactions. The efficacy of treatment with these long peptides, however, was not verified by a sting challenge. [124] DNA vaccination is where DNA plasmids encoding the relevant allergens are injected. The successful DNA vaccination of sensitized mice has, among other allergens, been reported with plasmids from bee venom PLA2. However, many hymenoptera venom-allergic patients are sensitized to more than one vespid or honeybee venom allergen, signifying that treatment with one major allergen in recombinant unrefolded or point mutated form, with peptides or DNA plasmids encoding it, may be insufficient. A fusion protein composed of the two major allergens of bee venom PLA2 and hyaluronidase (HYA) was constructed through genetic engineering and characterized by destroyed conformational B-cell epitopes but intact T-cell epitopes of the two allergens. [126] Another model used a recombinant chimeric protein consisting of the whole amino acid sequences of three major bee venom allergens (PLA2, HYA and melittin). The fragments were designed to preserve all relevant T-cell epitope peptides while conformational B-cell epitopes were destroyed. Use of this chimeric protein in mouse models has led to a significant reduction of specific IgE development towards the native allergen, which has produced a protective vaccine effect in vivo. [128] The therapeutic potential of bee venom intralymphatic immunization was then analyzed in sensitized mice using an anaphylaxis model. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 15 of 22 6/4/2011 9:10 μμ Sidebar Executive Summary Hymenoptera venom allergic reaction Hymenoptera stings may cause systemic reactions of varying severity up to fatal anaphylaxis. Several new factors influencing the severity of hymenoptera sting reactions in untreated patients have been identified and include an elevated baseline serum tryptase level and treatment with angiotensin-converting enzyme inhibitors. Owing to its clinical implications, serum tryptase should be measured in patients with a history of a severe sting reaction. Venom immunotherapy indications Venom immunotherapy (VIT) is indicated both in children and adults with a history of severe systemic reactions, including respiratory and cardiovascular symptoms, and documented sensitization to the respective insect with either skin tests and/or specific serum IgE tests. VIT is not indicated in large, local reactions. As for systemic, non-life-threatening reactions (e.g., urticaria, erythema and pruritus), other factors may influence the decision to commence VIT and should include occupation and/or hobbies where the risk of exposure is high, the culprit insect itself, concomitant cardiovascular diseases, other diseases (e.g., mastocytosis) and psychological factors arising from anxiety, which can seriously impair patient health-related quality of life. Selection of venoms Selection is based on identification of the hymenoptera species involved, on the results of the diagnostic tests and on venom cross-reactivity. The current availability of recombinant venom allergens may contribute to a 'component resolved diagnosis' and, subsequently, to a more accurate prescription of VIT. Efficacy Subcutaneous VIT is the only effective treatment for hymenoptera venom allergic patients. Certain risk factors for treatment failure or reduced effectiveness have been identified such as the type of venom (honeybee), a lower maintenance dose, repeated side effects during VIT, mast-cell diseases and an elevated baseline serum tryptase concentration. Safety VIT may induce large local and systemic reactions. Treatment with honeybee venom, the build-up phase, the rapid dose-increase schedule, mastocytosis and an elevated baseline serum tryptase concentration (during the build-up phase) are among the most important risk factors for side effects during VIT. Patients with one or more risk factor should be treated and monitored with special care. VIT duration Certain risk factors for relapse after discontinuing VIT have been identified. The duration of VIT should be decided after a thorough patient-physician discussion of the individual risk factors and also patient choice. Owing to the small but relevant risk of re-sting reactions, self-administering emergency kits should be discussed with every patient when discontinuing VIT. Future strategies A number of new strategies for VIT, mostly based on genetic engineering, have been described, as well as different routes of VIT administration (e.g., intralymphatic). However, the majority of these approaches have not been used for VIT in humans. References Hymenoptera Venom Immunotherapy (printer-friendly)