Hymenoptera venom immunotherapy: Indications, efficacy, and mechanism of action

INTRODUCTION — 

Systemic allergic reactions to the venom of insects in the order Hymenoptera (which includes bees, yellowjackets, wasps, hornets, and fire ants) can be life threatening. Immunotherapy for venom allergy has been available for decades and is highly effective. Unfortunately, many patients with sting-induced anaphylactic reactions are not referred to an allergist/immunologist for evaluation and are never offered this potentially lifesaving therapy [1,2].

The indications for treatment with venom immunotherapy (VIT), as well as patient selection, effectiveness, and mechanism of action, will be reviewed here. Other issues related to Hymenoptera venom allergy and its treatment are discussed separately:

●(See "Diagnosis of Hymenoptera venom allergy".)

●(See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring".)

●(See "Rush and ultra-rush venom immunotherapy for Hymenoptera allergy".)

●(See "Hymenoptera venom immunotherapy: Determining duration of therapy".)

TYPES OF REACTIONS TO HYMENOPTERA STINGS — 

There are three common types of allergic reactions to Hymenoptera sting: anaphylactic reactions, cutaneous systemic reactions, and large local reactions. These are reviewed briefly here and discussed in more detail elsewhere. (See "Bee, yellowjacket, wasp, and other Hymenoptera stings: Reaction types and acute management" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".)

●Anaphylaxis – An anaphylactic reaction, or a systemic allergic reaction, involves signs and symptoms of immunoglobulin E (IgE) mediated allergy, typically affecting more than one organ system (table 1). The skin (urticaria and angioedema) is commonly involved, but respiratory or circulatory symptoms are also prominent. Some of the most severe reactions (eg, sudden hypotension) occur in the absence of any skin findings or can be refractory to single or multiple doses of epinephrine [3-5].

●Cutaneous systemic reaction – A cutaneous systemic reaction (or a generalized cutaneous reaction) consists of signs and symptoms limited to the skin (ie, pruritus, erythema, urticaria, and/or angioedema), which are usually widespread and involve skin that is not contiguous with the sting site. Reactions involving angioedema of the tongue or throat, which could compromise the airway, are generally excluded from this category and considered anaphylactic reactions [6].

●Large local reaction – A large local reaction consists of painful swelling and erythema limited to skin and subcutaneous tissues contiguous with the sting site. The affected area is typically >10 cm and may be much larger. The reaction usually peaks at 24 to 48 hours and may last 3 to 10 days [6].

PROGNOSIS OF VENOM ALLERGY WITHOUT VIT — 

In patients with past systemic reactions and evidence of venom-specific IgE, the risk of a systemic reaction to a subsequent sting, if VIT is not administered, is estimated as follows:

●For adults with a severe systemic reaction in the past, there is a 50 to 75 percent chance of a systemic reaction and a 30 to 40 percent chance of severe anaphylaxis [3,7,8].

●For adults with a moderate systemic reaction, there is an approximately 30 percent chance of a systemic reaction: A 15 to 20 percent chance of another moderate reaction and a <5 percent chance of severe anaphylaxis [3,7,8].

●For children (less than 17 years of age), the risks are somewhat lower in that, for a child with a moderate-to-severe past reaction, there is a 30 to 60 percent chance of any systemic reaction, and less than one-half of those would be expected to be severe [9].

Note that these estimates are based on relatively limited data. Recurrent systemic reactions to venom tend to be similar in severity to the initial reaction in an individual patient [10]. This means that individuals with severe (near-fatal) anaphylaxis are at increased risk for similar reactions to future stings if VIT is not administered [7,11,12]. It is also true that the chance of a patient experiencing a more severe reaction to a future sting by the same insect is small (<5 percent) and remains relatively steady or declines only slightly over time [7,8,13]. Thus, the patients who are at greatest risk (and who benefit most from VIT) are those whose initial reactions were moderate-to-severe anaphylaxis. (See 'Indications and efficacy' below.)

There is some variability in reaction rates per sting, which may arise from differences in Hymenoptera species, the amount of venom delivered during a particular sting (which differs seasonally), whether the sting was sustained in a controlled setting (hospital or challenge) or in the field, fluctuations in the patient's immunologic status, or other intrinsic and extrinsic factors [13]. Consistent with this, one report of challenge stings noted that, among patients who had no response to an initial sting challenge, 20 percent had a systemic reaction to a subsequent sting challenge [14].

INDICATIONS AND EFFICACY — 

Guidelines have been published regarding the selection of patients for VIT, and the approach presented here is consistent with these guidelines [6,15]. The indications for VIT are summarized in the table and discussed in this section (table 2).

Patients with past anaphylaxis — An individual is a candidate for VIT if both of the following are true:

●There is a reliable history of an anaphylactic reaction to an insect sting

and

●The patient has either a positive venom skin test or elevated serum levels of venom-specific IgE

Note that a positive venom skin test or the presence of venom-specific IgE in the absence of a history of a sting-induced anaphylactic reaction is not normally an indication for therapy, since approximately one-quarter of the general population has demonstrable venom-specific IgE [16]. One possible exception to this statement is the patient with a mast cell disorder. Some experts advocate for preemptive VIT in this situation, although this is controversial and discussed in more detail separately [17,18]. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Hymenoptera venom allergy'.)

VIT is not normally offered to patients (without mast cell disease) unless they have both a positive skin or in vitro test to venom and a history of sting-induced anaphylaxis. As with many other types of allergy, patients may be sensitized to an allergen (ie, have IgE specific to that allergen) without actually reacting to it upon exposure. Sensitization in such patients may be transient, as up to 50 percent of asymptomatic-sensitized individuals will have negative tests if reevaluated in two to five years.

In contrast, a patient with a convincing history of an anaphylactic sting reaction but negative tests for venom-specific IgE may in fact be at risk for future anaphylactic reactions (mechanisms unclear). Such patients require further evaluation. The diagnosis of venom allergy is discussed in detail separately. (See "Diagnosis of Hymenoptera venom allergy".)

Adults and children — We recommend VIT for adults and children with a moderate-to-severe past systemic allergic reaction to a sting (ie, involving respiratory or hemodynamic compromise) and elevated levels of venom-specific IgE (either on skin testing or in vitro testing).

Additional potential risk factors for a poor outcome following a future sting include the following [7,19,20]:

●Severe past reactions. VIT should be firmly advocated for individuals who had life-threatening anaphylaxis, and these patients should be advised that insect avoidance/access to epinephrine is not considered an adequate alternative to VIT [21,22].

●Concomitant cardiovascular disease.

●The use of certain medications, such as angiotensin-converting enzyme (ACE) inhibitors or beta blockers.

●Older adults because deaths from insect stings appear to increase with age [23].

●Allergy to honey bee venom rather than vespid (ie, yellowjacket, hornet, and wasp) venom. (See 'Honey bee VIT' below.)

●Elevated baseline tryptase. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Measurement of baseline tryptase'.)

VIT has practical advantages for individuals with the following characteristics:

●A greater probability of future stings (ie, bee keepers and their family members [24], people who work outdoors)

●Individuals living or spending time in remote areas far from emergency medical services

●Those (either the patient or a family member) in whom the uncertain risk of anaphylaxis causes significant anxiety

Efficacy — VIT is the most effective form of immunotherapy in use. A systematic review evaluated all available studies in adults and children for both winged Hymenoptera and stinging ants (also Hymenoptera) to provide an estimate of the overall effectiveness of VIT in preventing recurrent systemic allergic reactions [25]. In the pooled randomized trials, 3/113 (2.7 percent) participants treated with VIT had a subsequent systemic allergic reaction to a sting compared with 37/93 (39.8 percent) untreated participants (risk ratio [RR] 0.10, 95% CI 0.03-0.28).

In a representative trial, which was the first randomized trial of VIT, 60 adults with anaphylactic reactions of similar severity were randomized to three treatment options: VIT (100 mcg maintenance dose), whole-body extract immunotherapy (standard therapy at the time), or placebo for six weeks. In-hospital challenge stings resulted in systemic reactions in 1 of 18 (6 percent) in the VIT group compared with 7 of 11 (64 percent) in the whole-body extract group and 7 of 12 (58 percent) in the placebo group. Patients who were in the whole-body extract and placebo-treatment groups were then offered VIT for six weeks; 31 were treated, and, when restung, only one patient reacted (urticaria) [3]. Thus, the total efficacy of VIT was 46/49 (94 percent). Based on these findings, the use of whole-body extracts was not pursued further, except for imported fire ant immunotherapy. (See "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment", section on 'Venom immunotherapy'.)

VIT is highly effective but not equally so for all species of Hymenoptera. Just two randomized trials have directly addressed the question of how well VIT prevents recurrent systemic reactions in adults allergic to different winged Hymenoptera species [3,26]. Thus, from a baseline risk of repeat systemic reactions of 35 to 60 percent per sting, VIT reduces the risk as follows:

●To 2 percent per sting for mixed vespid (most of whom received a 300 mcg maintenance dose) [3] and jack jumper ant [27]

●To 5 to 10 percent for single vespid [19,28,29]

●To 15 to 25 percent for honey bee with a 100 mcg maintenance dose but to 10 percent with a 200 mcg maintenance dose [19,30] (see 'Honey bee VIT' below)

In most longer-term observational studies of patients treated with VIT, the few patients who did have recurrent systemic allergic reactions had much milder symptoms compared with their pretreatment sting reaction [3,31-34].

Honey bee VIT — Honey bee stings cause higher rates of recurrent anaphylactic reactions compared with stings of vespids (ie, yellowjackets, hornets, and wasps) [8]. Unfortunately, honey bee VIT is less effective in preventing future systemic reactions than yellowjacket VIT at the 100 mcg maintenance dose (eg, 75 percent for honey bee versus 91 percent for yellowjacket in one study) [19]. In this study, 20 percent of the honey bee-treated patients received a maintenance dose of 200 mcg; their protection rate was 90 percent. Furthermore, the protection provided by honey bee VIT does not last as long as that from vespid VIT [30]. Issues with dosing and adverse effects of honey bee VIT are discussed in detail separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Dosing'.)

Quality of life — In addition to reducing the risk of recurrent systemic reactions, VIT improves quality of life by reducing anxiety and allowing patients to participate in outdoor activities as they desire [35-37]. In contrast, quality of life is not usually improved by avoidance and having self-administered epinephrine available [38,39]. In a 2017 systematic review, VIT was associated with a significant improvement in disease-specific quality of life after one year of therapy (1.41, 95% CI 1.04-1.79) [40].

Time to protection — Protection from recurrent anaphylactic reactions appears to be established in most patients within one week of reaching maintenance doses, regardless of the speed of build-up [41].

Pregnant patients — VIT is not initiated during pregnancy, nor are doses increased, which is the practice with other forms of injection immunotherapy. However, patients who are already receiving VIT when they become pregnant may continue treatment. (See 'Pregnancy' below.)

CONDITIONAL USES OF VIT — 

VIT is not usually recommended for patients with cutaneous systemic reactions and large local reactions, because, although effective, it is not felt to be necessary. However, there may be scenarios in which patients choose to receive it.

Patients with past cutaneous systemic reactions — Cutaneous systemic reactions include widespread hives, pruritus, erythema, and/or angioedema. Although limited to the skin, these reactions can be very distressing to patients, may take days to resolve fully, and can be dangerous if they involve angioedema of the tongue or other structures in or near the airway. When reactions do involve the tongue or throat, they are generally treated as systemic allergic reactions, and VIT is offered.

Children — Children with past cutaneous systemic reactions have approximately a 10 to 15 percent chance per sting of a future systemic reaction, and most of these reactions will also be limited to the skin [20]. The chance of an anaphylactic reaction in the next 10 to 20 years is estimated to be <3 percent [9,42]. Thus, although VIT is effective in children with cutaneous systemic reactions, it is not necessary.

●In the study mentioned above, 242 children (ages 2 to 16 years) who had experienced cutaneous systemic reactions to insect stings all had positive skin tests to venom [20]. VIT was administered to 68 children. Approximately one-half of children were randomized to the treatment they received, while parent/caregiver preference determined the treatment of the others. During four years of observation, there were 280 accidental stings in 122 of the children. In the children receiving VIT, 1.2 percent of the stings resulted in systemic symptoms compared with 9.2 percent in the untreated group, but none of the stings caused more severe symptoms than the original event, and 16 of 18 reactions were milder.

●A 10- to 20-year follow-up survey of 512 children with cutaneous systemic reactions revealed a <3 percent risk of more severe reactions [9].

Adults — For adults with cutaneous systemic reactions, there has been a shift in the suggested approach, which was introduced in the 2016 reaction Joint Task Force practice parameter update [6]. VIT was previously advocated by the American practice parameter for this group, but it is no longer believed to be necessary. The change brings the American guidelines into closer agreement with those of other countries [43]. The change was based on evidence that this patient group is not at significantly increased risk for anaphylaxis with subsequent stings, including two studies of sting challenges of adults with a history of cutaneous systemic reactions and positive venom IgE (serum or skin test) [8,13]. In these studies, <2 percent (2/128) had systemic reactions to challenge stings that were moderate (not just cutaneous), and none were severe. There is a 15 to 20 percent chance such patients will have cutaneous systemic reactions again. However, there is no study in adults similar to the one described above for children, in which outcomes from stings were prospectively measured for patients who were treated with VIT compared with those who were not.

Despite this change in recommendations, there may be situations in which VIT is still appropriate for adults with cutaneous systemic reactions. Specifically, if the individual has underlying medical conditions or medications that could affect the outcome of an anaphylactic reaction; frequent, unavoidable exposure to Hymenoptera; or impaired quality of life (ie, fear of future reactions), then it is appropriate to proceed with VIT.

The change in recommendations for adults with cutaneous systemic reactions raises the question about whether to continue or stop VIT in adult patients previously started on VIT for this type of reaction according to earlier guidelines. This also is a shared decision with the patient, after considering the variables of the patient's case, as well as reactions to stings since starting VIT, reactions to VIT, and patient preferences. In most cases, VIT can be discontinued in such patients.

Patients with large local reactions — Individuals with large local reactions are not usually candidates for VIT, because the risk of a systemic reaction of any severity to future stings is low (4 to 10 percent) and the risk of anaphylaxis is <3 percent [9,44-46]. An Italian study reported a higher rate of 24 percent, but its methodology has been criticized [47,48]. Most patients will develop large local reactions if stung again [44,45]. However, some individuals may be sufficiently debilitated by local swelling, despite the use of post-sting medications, that they seek more effective treatment. This is particularly true of patients with frequent Hymenoptera exposure. Therefore, if a patient's quality of life is sufficiently reduced by these reactions, VIT should be offered.

If VIT is given for the prevention of future large local reaction, it is effective. In a nonrandomized study, VIT reduced the severity and duration of recurrent large local reactions in patients with positive skin tests to venom [49]. Nineteen patients with large local reactions were treated with VIT and compared with 10 untreated patients. Sting challenges were performed after 7 to 11 weeks of VIT, after which the untreated patients were crossed over to VIT for up to four years with annual sting challenge. A response to VIT was defined as a reduction in size or duration of the local reactions by at least 50 percent. In the first season, a response was observed in 50 percent of the treated patients compared with 20 percent of the untreated controls. After two to four years of VIT, 100 percent of the treated group had responded.

Acute treatment of large local reactions to Hymenoptera stings is reviewed separately. (See "Bee, yellowjacket, wasp, and other Hymenoptera stings: Reaction types and acute management".)

MECHANISM OF ACTION — 

The mechanism of action of VIT is only partially understood. A systemic allergic reaction to venom requires sting-induced production of venom-specific IgE antibodies that subsequently bind to tissue mast cells and circulating basophils. A future sting may then result in cross-linking of these IgE molecules by venom proteins, triggering the activation and degranulation of mast cells and basophils and the release of mediators of anaphylaxis (histamine, leukotrienes, and others). Successful VIT is associated with several humoral and cellular changes that may interfere with this pathologic mechanism [50-54]:

●The production of venom-specific IgG – Venom-specific immunoglobulin G (IgG) typically increases, peaking at two to four months after starting VIT, and then remains fairly constant over five to six years of treatment. These IgG antibodies are referred to as "blocking" antibodies because they are capable of blocking in vitro mediator release from allergen-stimulated mast cells and basophils. The production of blocking antibodies has been considered the most likely therapeutic mechanism. One study demonstrated that honey bee-allergic patients could tolerate challenge stings after passive immunization with the gamma-globulin fraction of pooled beekeeper's serum, which contained high titers of blocking antibodies [55]. Another study found that the serum level of venom-specific IgG was inversely correlated with the likelihood of challenge sting-induced systemic reactions in patients on VIT [56]. However, after four years of treatment, that correlation no longer held true, so other factors may be important in determining clinical benefit. Additionally, serum from children receiving bee VIT significantly inhibited allergen-IgE binding to B cells [53].

●Changes in T cell responses – VIT appears to shift the T cell phenotype away from the T helper type 2 (producing interleukin 4 and interleukin 5) and toward the T helper type 1 (interferon gamma) or a regulatory type of T response (interleukin 10 and the production of IgG4) [57-60].

●Reduction of venom-specific IgE – Venom-specific IgE initially rises, peaks at 8 to 12 weeks, and then declines slowly over three to five years to pretreatment levels [10]. This is believed to be an epiphenomenon of VIT rather than a therapeutic mechanism.

The immunologic changes that result from injection immunotherapy of any type are discussed in greater detail elsewhere. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms".)

RISKS OF VIT AND INFORMED CONSENT — 

It is important to discuss the risks of VIT with patients when obtaining informed consent.

Systemic reactions — Overall, 3 to 12 percent of patients have treatment-induced systemic reactions, although the majority of these reactions are mild and easily treated. Adverse effects and safety are reviewed in more detail separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Adverse effects'.)

Safety in special populations

Pregnancy — As mentioned above, VIT is not initiated during pregnancy, and the doses are not increased if a patient is already receiving immunotherapy when they become pregnant. The few reports of VIT administration during pregnancy are reassuring [61]. In one, 15 women had 22 pregnancies, resulting in 19 normal infants, 1 first-trimester miscarriage, 1 miscarriage secondary to placenta previa, and 1 child with multiple congenital abnormalities of unknown cause [61]. The overall rate of pregnancy complications in this group was not higher than expected with pregnancy in the general population.

Patients with known or possible mast cell disorders — In patients with mastocytosis, sting-induced anaphylaxis is more common and more likely to be life threatening compared with patients without mast cell disorders. VIT is effective in this group and is felt to be sufficiently safe in that the benefits outweigh the risks for most patients [62-64]. However, systemic reactions to the immunotherapy injections are more common and occasionally require pretreatment with omalizumab to control [65]. In addition, concomitant use of angiotensin-converting enzyme (ACE) inhibitors or beta blockers should be assessed and discontinued if possible [6].

Mast cell disorders are identified in 10 to 20 percent of patients with insect sting anaphylaxis, and approximately one-quarter of patients with systemic mastocytosis have anaphylaxis in response to insect stings [62,66]. In patients with various forms of mastocytosis, insect stings are the most common cause of anaphylaxis [67,68]. Serum tryptase is an easily obtained screening test for mast cell disorders, and the evaluation of patients with sting-induced anaphylaxis, as well as the diagnosis of mast cell disorders, are reviewed in detail elsewhere. (See "Diagnosis of Hymenoptera venom allergy", section on 'Screening for occult mastocytosis' and "Mast cell disorders: An overview", section on 'Diagnostic approach' and "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Hymenoptera venom allergy' and "Hereditary alpha-tryptasemia" and "Hereditary alpha-tryptasemia", section on 'Hymenoptera venom anaphylaxis'.)

Patients requiring ACE inhibitors or beta blockers

●Concerns – There have been concerns regarding the use of beta blockers and angiotensin-converting enzyme (ACE) inhibitors in patients receiving immunotherapy, based initially on theoretical reasons, animal studies, and a few clinical reports [69-75]. Specifically, these medications could counteract the body's compensatory responses to anaphylaxis or make anaphylaxis more difficult to treat. Beta blockers may inhibit the response to endogenous or administered epinephrine and may lower the threshold for mast cell activation. ACE inhibitors block the conversion of angiotensin I into angiotensin II (a vasoconstrictor) and prevent the breakdown of the vasodilator bradykinin, potentially prolonging anaphylaxis or making it more severe. Of note, angiotensin receptor blockers (ARBs) have not been implicated in severe anaphylaxis in immunotherapy patients, although the data are limited [76].

For patients requiring inhalant allergen immunotherapy for allergic rhinitis or asthma, American practice parameters suggest caution in patients taking these medications as the need for immunotherapy for respiratory disease is rarely critical [77]. However, venom immunotherapy is different because untreated Hymenoptera anaphylaxis is potentially life threatening, especially in older patients with cardiovascular disease, which itself is a risk factor for poor outcomes following a sting. Additionally, there is risk in discontinuing beta blockers or ACE inhibitors or changing to potentially less effective medications, and this may be greater than the increased risk of more severe anaphylaxis.

●Our approach – It is the preference of the author and section editor to continue VIT-treated patients on beta blockers and/or ACE inhibitors when they cannot be safely changed or stopped. However, the decision about whether to continue these medications should be made jointly among the allergist, the clinician prescribing the medications, and the patient. Important factors to consider are the severity of previous sting reaction, the risks of future severe reactions, the likelihood of being stung again, the relative medical necessity of the beta blocker or ACE inhibitor (post-myocardial infarction, heart failure, hypertension, etc), the relative efficacy of alternative medications for the particular medical indication, and patient preferences. More caution may be warranted if a patient is taking these medications during the build-up phase of VIT, when the risk of VIT-induced reactions is greater.

Of note, the continuation of beta blockers and/or ACE inhibitors in patients with mastocytosis requires careful consideration as these patients are at much higher risk for severe reactions involving hypotension. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Hymenoptera venom allergy'.)

●Studies – For many years, data were sparse and often contradictory on this subject. The current understanding of the situation is that beta blockers and ACE inhibitors do not appear to increase the risk of an anaphylactic reaction (to VIT or to a sting) but may increase the severity. However, stopping these medications can lead to deterioration in the patient's underlying cardiovascular conditions, and death from cardiovascular disease is far more common than that from Hymenoptera stings, so the risks and benefits need to be considered on a case-by-case basis.

Representative studies are summarized here:

•A study of patients with a history of severe sting anaphylaxis and cardiovascular disease treated with beta blockers or not during VIT reported that systemic symptoms to venom injections occurred in 12 percent of the patients receiving beta blockers and in 16.7 percent of those not on beta blockers [78]. Most of the data reported were on patients receiving maintenance doses of VIT.

•A 2019 systematic review and meta-analysis evaluated 21 studies that assessed the impact of beta blockers and ACE inhibitors on the incidence (no increase found) and severity (increase seen; odds ratio for beta blockers and ACE inhibitors were 2.19 and 1.56, respectively) of anaphylaxis [79]. It was not possible to adjust for the inherent risk of more severe anaphylaxis in patients with cardiovascular disease, because only one study had adjusted data.

•In a case-control study of 3612 patients with venom-induced anaphylaxis, beta-blocker and ACE inhibitor use was associated with a higher severity of anaphylaxis in both venom- and non-venom-induced anaphylaxis [80]. However, the role of these medications could not be isolated from the effect of concomitant cardiovascular conditions.

•A prospective, observational study that enrolled 1425 patients with systemic sting reactions and indications for VIT found that the severity of the initial sting reaction was not affected by taking ACE inhibitor and/or beta-blocker medications [81]. Of 1342 VIT-treated patients, approximately one-third took ACE inhibitors and/or beta blockers, and, of these, a lower percentage had systemic adverse events during VIT compared with patients not taking these medications (5.6 versus 7.4 percent).

●Guidelines – As studies have accumulated, there has been a gradual change in the approach taken by different guidelines regarding the safety of beta blockers and ACE inhibitors during VIT:

•A 2018 European Academy of Allergy and Clinical Immunology (EAACI) guideline on Hymenoptera venom allergy stated that both beta-blocker and ACE inhibitor therapy may be continued during VIT, but the patient should be informed about possible risks [43].

•A 2023 American anaphylaxis practice parameter update made conditional recommendations that VIT may be prescribed for patients who are treated with a beta blocker or ACE inhibitor, with shared decision-making regarding the benefits and potential harms of concurrent VIT treatment and medication, and that, in most cases, treatment with a beta blocker or ACE inhibitor need not be changed or discontinued in patients receiving maintenance VIT [17].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stinging insect allergy".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Allergy shots (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Types of hypersensitivity reactions to stings – There are three common types of allergic reactions to stings of Hymenoptera insects (ie, bees, yellowjackets, wasps, hornets, and fire ants) (see 'Types of reactions to Hymenoptera stings' above):

•Systemic allergic reactions/ anaphylaxis (ie, involving multiple organ systems)

•Cutaneous systemic reactions (widespread urticaria or angioedema but no involvement beyond the skin)

•Large local reactions (signs/symptoms limited to the skin immediately contiguous to the sting site)

Venom immunotherapy (VIT) is usually recommended only for the first type of reaction (anaphylaxis) (table 2). (See 'Indications and efficacy' above.)

●Risk of recurrent anaphylaxis without VIT – Without VIT, adults who have experienced a systemic reaction to a sting have a 30 to 60 percent chance of a recurrent systemic reaction with each subsequent sting, while the risk for children is somewhat lower, at approximately 30 percent. These reactions can be severe and even fatal. (See 'Prognosis of venom allergy without VIT' above.)

In contrast, the risk of anaphylaxis for patients with cutaneous systemic reactions or large local reactions is much lower, and VIT is not believed to be necessary.

•Patients with cutaneous systemic reactions have approximately a 15 to 20 percent chance per sting of a future similar reaction, but the risk of a serious systemic reaction is <2 to 3 percent.

•Patients with large local reaction have a risk of a systemic reaction of any severity to future stings of 4 to 10 percent, and most will be mild.

●Effectiveness of VIT – After receiving a course of VIT, the risk of a recurrent serious systemic reaction is approximately 2 percent for mixed vespid, 5 to 10 percent for single vespid, and 10 to 20 percent for honey bee (depending on the maintenance dose of VIT used). VIT improves the patient's quality of life beyond what is achieved with access to epinephrine and Hymenoptera avoidance. Unfortunately, most patients are not referred to an allergy specialist to determine if they are candidates for treatment.

•We recommend VIT for patients with a moderate-to-severe past systemic allergic reaction to a sting (ie, involving respiratory or hemodynamic compromise) and elevated levels of venom-specific immunoglobulin E (IgE; either on skin testing or in vitro testing) (Grade 1B). (See 'Patients with past anaphylaxis' above.)

•We suggest not giving VIT to patients with cutaneous systemic reactions (widespread urticaria and angioedema but no symptoms/signs affecting other organ systems) (Grade 2C). However, VIT is effective in reducing the severity of future reactions and may still be offered in specific situations. (See 'Patients with past cutaneous systemic reactions' above.)

•We suggest not giving VIT to patients with large local reactions (Grade 2C). However, VIT is effective for reducing future large local reactions and may still be offered if the local reactions are frequent and sufficiently debilitating. (See 'Patients with large local reactions' above.)

●Mechanism of action – VIT results in several immunologic changes, none of which fully account for the therapeutic effect. The leading hypothesis is that VIT results in the production of venom-specific immunoglobulin G (IgG) antibodies that interfere with the IgE-mediated allergic mechanism and initiates a change in T cell and cytokine responses with increased levels of interleukin 10. (See 'Mechanism of action' above.)

●Safety and special populations – Overall, 3 to 12 percent of patients have treatment-induced systemic reactions, although the majority of these reactions are mild and easily treated. (See 'Risks of VIT and informed consent' above.)

•VIT is not initiated during pregnancy, and the doses are not increased if a patient is already receiving immunotherapy when they become pregnant. (See 'Pregnancy' above.)

•Patients with mast cell disorders can have life-threatening reactions to stings, and VIT is effective. However, systemic reactions to the immunotherapy injections are more common and occasionally require pretreatment with omalizumab to control. (See 'Patients with known or possible mast cell disorders' above.)

•Beta blockers and angiotensin-converting enzyme (ACE) inhibitors may be continued in patients with cardiovascular conditions who require VIT after consideration of the risks of not administering VIT, the risk of cardiovascular problems related to stopping these medications, patient preferences, and other factors. (See 'Patients requiring ACE inhibitors or beta blockers' above.)