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Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action
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Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Apr 14, 2017.

INTRODUCTION — Systemic allergic reactions to the venom of insects in the order Hymenoptera (which includes bees, yellow jackets, wasps, hornets, and fire ants) can be life-threatening. Immunotherapy for venom allergy has been available for over four 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].

The indications for treatment with venom immunotherapy (VIT), as well as patient selection, effectiveness, and mechanism of action, will be reviewed here. Protocols and safety of VIT and the diagnosis of venom allergy are discussed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring" and "Diagnosis of Hymenoptera venom allergy".)

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, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".)

An anaphylactic 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 [2-4].

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 is usually widespread and involves 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 [5].

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 [5].

RISK OF RECURRENT REACTIONS — Recurrent systemic reactions to venom tend to be similar in severity to the initial reaction in an individual patient [6]. This means that individuals with severe (near-fatal) reactions are at increased risk for similar reactions to future stings [7-9]. 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 [10,11]. Thus, the patients who benefit most from VIT are those whose initial reactions were moderate-to-severe systemic allergic reactions.

The following generalizations can be made:

In adult patients with past anaphylactic reactions and evidence of venom-specific immunoglobulin E (IgE), the risk of a anaphylactic reaction to a subsequent sting is approximately 35 to 60 percent if VIT is not administered [2,7,10]. Patients with the most severe initial reactions have the highest risk of a recurrence. The variability in reaction rates may arise from differences in Hymenoptera species, the amount of venom delivered during a particular sting, whether the sting was sustained in-hospital or in the field, fluctuations in the patient's immunologic status, or other intrinsic and extrinsic factors [11].

Children (defined in most studies as younger than 17 years of age) with past anaphylactic reactions and evidence of venom-specific IgE who have had moderate or severe anaphylactic reactions are at increased risk for anaphylactic reactions during childhood and adulthood if not treated with VIT [12,13]. However, this risk is lower than that in adults and has been estimated at approximately 30 percent [13].

Patients with cutaneous systemic reactions have about 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 [14]. The chance of an anaphylactic reaction in the next 10 to 20 years is estimated to be <3 percent. In the largest series, no severe reactions were reported [13-15]. One retrospective study of children found a higher rate of more severe repeat reactions [12], but these data are highly unusual in that none of the patients had repeat mild systemic reactions similar to their initial reactions, in contrast to the observations of multiple other studies. An exception is a cutaneous reaction that involves angioedema of the tongue or throat, which could potentially compromise the airway and warrants treatment as systemic reactions.

Patients with large local reactions also have a low (4 to 10 percent) risk of a systemic reaction to future stings [13,16-18]. These patients are usually not evaluated for or treated with VIT, although there are exceptions. (See 'Patients with large local reactions' below.)

EFFECTIVENESS OF VIT — VIT is the most effective form of immunotherapy in use. Protection from recurrent anaphylactic reactions appears to be established in most patients within one week of reaching maintenance doses [19]. 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 [20,21]. In contrast, quality of life is not improved by avoidance and having self-administered epinephrine available [22].

Reduced risk of recurrent reactions — An adult's risk of a recurrent systemic reaction is approximately 30 to 60 percent in the absence of VIT [2,7,10]. After completing a course of VIT, the risk is reduced to 5 percent or lower [2,23-26]. The few patients who do have recurrent anaphylactic reactions tend to have much milder symptoms than their pretreatment sting reaction.

The effectiveness of VIT in adults with past systemic reactions was demonstrated in several observational studies [23-25] and a small number of randomized controlled trials [2,27]. A systematic review included seven trials, but the reviewers combined patient groups that did not have equivalent types of reactions or natural histories [28]. Just two randomized trials have directly addressed the question of how well VIT prevents recurrent systemic reactions in adults allergic to winged Hymenoptera species [2,27]. There is an additional randomized, placebo-controlled trial demonstrating the effectiveness of jack jumper ant (another Hymenoptera species) VIT [29].

One of the randomized trials mentioned above involved 60 adults with anaphylactic reactions of similar severity who were treated with either VIT (using a maintenance dose of 100 mcg of purified venom), immunotherapy with Hymenoptera whole body extract, or placebo injections for six weeks [2]. In-hospital challenge stings resulted in systemic reactions in 1 of 18 (6 percent) in the VIT group, compared with 7 of 12 (58 percent) in the placebo group. The placebo-treated patients were then crossed over to VIT, and at the conclusion of the study, only 1 of 55 VIT-treated patients had an anaphylactic reaction to challenge sting. The whole body extract contained minimal venom and proved no better than placebo. Hence, this approach was subsequently abandoned.

The most effective dose of venom for use in VIT is discussed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Dosing'.)

The development of long-term tolerance to venoms is also influenced by the duration of VIT. This is discussed separately. (See "Hymenoptera venom immunotherapy: Determining duration of therapy".)

Honey bee versus vespid VIT — Honey bee stings cause higher rates of recurrent anaphylactic reactions compared with stings of vespids (ie, yellow jackets, hornets, and wasps) [10]. Unfortunately, honey bee VIT is less effective in preventing future anaphylactic reactions than vespid VIT (eg, 77 percent versus 91 percent in one study) [30], and the protection provided by honey bee VIT does not last as long as that from vespid VIT [31]. For these reasons, the duration of honey bee VIT is often extended beyond five years, as reviewed separately. (See "Hymenoptera venom immunotherapy: Determining duration of therapy", section on 'Risk factors for recurrent SARs or poor outcomes'.)

INDICATIONS AND PATIENT SELECTION — Guidelines have been published regarding the selection of patients for VIT, and the approach presented here is consistent with these guidelines [5,32]. The indications for VIT are summarized in the table (table 2). VIT is administered through a series of subcutaneous injections. Very few data are available on sublingual VIT, and the technique is considered investigational [33,34]. The information in this review pertains only to subcutaneous injection immunotherapy.

Patients with past anaphylactic reactions — 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 immunoglobulin E (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 an indication for therapy, since approximately one-quarter of the general population has demonstrable venom-specific IgE [35]. 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. Up to 50 percent of asymptomatic-sensitized individuals will have negative tests if re-evaluated 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. This diagnostic dilemma is discussed separately. (See "Diagnosis of Hymenoptera venom allergy", section on 'Systemic reactions with no evidence of venom IgE'.)

Children — Children with moderate or severe anaphylactic reactions to a Hymenoptera sting have an increased risk of anaphylactic reactions during adulthood if not treated with VIT. The risk is estimated to be about 30 percent [13]. Therefore, these children should be treated with VIT.

Adults — Adults with past anaphylactic reactions to stings and positive skin tests have a 30 to 60 percent chance of a similar reaction to a future sting [2,7,10]. The decision to pursue VIT should be a shared decision between the clinician and patient. Relevant potential risk factors for a poor outcome following a future sting include concomitant cardiovascular disease, the use of certain medications, such as angiotensin-converting enzyme (ACE) inhibitors or beta-blockers, abnormal basal tryptase level, a greater probability of future stings, and negative effects on quality of life. The risk is relatively greater for those with the following characteristics [7,14,30]:

Severe past reactions

Allergy to honey bee venom rather than vespid (ie, yellow jacket, hornet, and wasp) venom (see 'Honey bee versus vespid VIT' above)

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

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 [36,37].

VIT is particularly advantageous for individuals with the following characteristics:

Individuals with occupations or leisure activities that involve significant time spent outdoors (eg, landscapers) or in direct contact with Hymenoptera (eg, beekeepers and their family members [38])

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

Older adults because deaths from insect stings appear to increase with age [39]

On occasion, it is not entirely clear from the clinical history if a patient had a true anaphylactic reaction. For example, it would be difficult to categorize an adult with widespread hives and angioedema, who also felt some mild subjective dyspnea that could have been either bronchospasm or anxiety. Because the clinical history is the most important factor in determining appropriate therapy, we recommend discussing with the patient his/her unclear level of risk and getting a sense for his/her preferences regarding VIT before performing venom skin testing (or in vitro testing). Testing can be falsely positive in recently-stung patients and in the general population, so testing results should not be given more weight than the clinical history, and the clinician should have a clear idea about how the outcome will influence management.

Special populations

Pregnant women — During pregnancy, VIT is not initiated nor are doses increased, which is the practice with other forms of injection immunotherapy. However, women who are already receiving VIT when they become pregnant may continue treatment. The few reports of VIT administration during pregnancy are reassuring [40]. 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 [40]. The overall rate of pregnancy complications in this group was not higher than expected with pregnancy in the general population.

Patients requiring ACE inhibitors or beta-blockers — There is uncertainty about the safety of ACE inhibitors and beta-blockers during VIT, which is reflected in different guidelines. A 2015 European position paper has stated that ACE inhibitors are relatively contraindicated in patients receiving VIT, while beta-blockers are not contraindicated [41]. The 2016 American practice parameter update concluded that for patients with medical need for these medications, the risk of reacting to VIT is lower than the risk of a severe sting reaction in the absence of VIT [5]. Other forms of allergen immunotherapy, such as that for allergic rhinitis or asthma, are not usually administered to individuals with significant cardiovascular disease who require these medications. However, recommendations for VIT are different because of the life-threatening nature of untreated Hymenoptera anaphylaxis, especially in an older patient with cardiovascular disease.

Most of the available data are reassuring, and the current understanding of the situation is that these medications do not appear to increase the risk of an anaphylactic reaction (to VIT or to a sting), but may increase the severity. Despite this, stopping these medications can lead to a deterioration in the patient's underlying cardiovascular condition, so the risks and benefits need to be considered on a case-by-case basis. 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. Overall, it is the author and section editor's preference to continue patients on these medications through VIT if there are clear indications for both. However, the decision about whether to continue these medications should be made jointly between the allergist and the prescribing clinician.

Patients receiving VIT and concomitant treatment with ACE inhibitors appear to be at risk for more severe anaphylaxis in response to treatment [42-44], although not all studies found this [45]. This may be due to the inhibited conversion of angiotensin I to angiotensin II, resulting in poorer responsiveness to hemodynamic stress during hypotension or to the accumulation of bradykinin, a potent vasodilator. However, there does not appear to be a correlation between ACE inhibitor therapy and a higher overall incidence of anaphylaxis, either during VIT or during other types of immunotherapy [46,47]. The 2016 practice parameter suggests that in patients with indications for both VIT and ACE inhibitor therapy, alternatives to ACE inhibitors should be considered. If no equally effective alternative medication is available, the clinician should make an individualized decision about the use of ACE inhibitors, considering the risks and benefits and the patient's preferences [48]. Another option is to hold the ACE inhibitor for 24 hours before each injection, although the effectiveness of this has not been specifically studied. Of note, angiotensin-receptor blockers have not been implicated in severe anaphylaxis in immunotherapy patients, although the data are similarly limited [49].

Patients taking beta-adrenergic blockers may not respond as readily to treatment of an allergic reaction, since epinephrine may not have full access to beta-receptors. The small number of available studies are reassuring [45,50]. If a suitable alternative to a beta-blocker is available, then the patient could be permanently changed to a different class of drug, but in many cases, there will not be an equivalent alternative, and VIT can proceed with caution [51]. Another option is to withhold the beta-blocker for one to two half-lives of the specific drug in question before each injection. Rebound hypertension or tachyarrhythmias are unlikely to occur in this setting.

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 [52-54]. However, systemic reactions to the immunotherapy injections are more common and occasionally require pretreatment with omalizumab to control [55]. In addition, concomitant use of ACE inhibitors or beta-blockers should be assessed and discontinued if possible [5].

Mast cell disorders are identified in approximately 2 percent of patients with insect sting anaphylaxis, and about one-quarter of patients with systemic mastocytosis have anaphylaxis in response to insect stings [52,56]. In patients with various forms of mastocytosis, insect stings are the most common cause of anaphylaxis [57,58]. 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'.)

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 lips, mouth, or other structures near the airway.

Children — Children with past reactions limited to the skin are at low risk of developing an anaphylactic reaction to subsequent stings, even if VIT is not administered [13]. Thus, although VIT is effective in children with cutaneous systemic reactions, it is not necessary.

This was demonstrated in a study of 242 children (ages 2 to 16 years) who had experienced cutaneous systemic reactions to insect stings [14]. All had positive skin tests to venom. VIT was administered to 68 children. About one-half of children were randomized to the treatment they received, while parent 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. Thus, although VIT is effective in children with cutaneous systemic reactions, it does not appear to be necessary.

Adults — For adults with systemic reactions limited to the skin (erythema, pruritus, urticaria, or angioedema), there has been a shift in the suggested approach, which was introduced in the 2016 Joint Task Force practice parameter update [5]. 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 and with studies of sting challenges, suggesting that this patient group is not at significant increased risk for anaphylaxis with subsequent stings [10,11]. However, there is no study in adults similar to the one described above for children, in which outcomes from stings were directly 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 anaphylaxis to future stings is low (4 to 10 percent). However, most patients will develop large local reactions if stung again [16,17]. Some individuals may be sufficiently debilitated, 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.

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

A nonrandomized study found that VIT reduced the severity and duration of recurrent large local reactions in patients with positive skin tests to venom [59]. 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.

RISKS OF VIT AND INFORMED CONSENT — It is important to discuss the risks of VIT with patients when obtaining informed consent. Briefly, 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 and safety of VIT'.)

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 immunoglobulin E (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 [60-64]:

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 [65]. 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 [66]. 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 [63].

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 immunoglobulin G4) [67-70].

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 [6]. 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".)

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".)

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SUMMARY AND RECOMMENDATIONS

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

Anaphylactic reactions (ie, involving multiple organ systems)

Cutaneous systemic reactions (signs/symptoms limited to the skin but widespread)

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

Adults who have experienced an anaphylactic reaction have a 30 to 60 percent chance of a recurrent anaphylactic 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. Venom immunotherapy (VIT) is safe and highly effective and reduces the risk of a recurrent anaphylactic reaction with a subsequent sting to <5 percent, improving 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. (See 'Risk of recurrent reactions' above and 'Effectiveness of VIT' above.)

Patients with cutaneous systemic reactions and large local reactions tend to have the same type of reactions again with subsequent stings. These patients have a low risk of a future anaphylactic reaction, and the rare systemic allergic reactions that do occur are usually mild. (See 'Risk of recurrent reactions' above.)

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 1A). (See 'Patients with past anaphylactic reactions' above.)

We suggest not giving VIT to patients with cutaneous systemic reactions if patients did not experience symptoms involving 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 reactions are frequent and sufficiently debilitating. (See 'Patients with large local reactions' above.)

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 IgG antibodies that interfere with the IgE-mediated allergic mechanism. (See 'Mechanism of action' above.)

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