INTRODUCTION — Hymenoptera stings can result in life-threatening anaphylaxis, and the most severe reactions can be refractory to single or multiple doses of epinephrine [1,2]. Venom immunotherapy (VIT) is highly effective and well-tolerated by most patients.
VIT for patients with allergies to honey bee, yellow jacket, yellow hornet, white-faced hornet, and wasp is administered using purified venoms, whereas whole body extracts are used in immunotherapy for fire ant allergy. The techniques, adverse effects, and safety of VIT will be reviewed here. Efficacy, indications, and mechanism of action of VIT, as well as immunotherapy for fire ant allergy, are discussed elsewhere. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment", section on 'Treatment'.)
TECHNICAL ISSUES — Issues in the administration of VIT include venom selection, dosing, injection protocol, premedications, and adverse effects.
Availability — The venoms used for immunotherapy are the same as those used for skin testing. In the United States, two companies, Hollister-Stier Laboratories and ALK-Abelló, had supplied venom extracts for skin testing and treatment for over 35 years. However, since late 2016, Hollister-Stier Laboratories has been the only venom source. A task force report from the American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology discussed the potential problems of changing the patient's supplier of venoms (since slight differences existed between the Hollister-Stier Laboratories and ALK-Abelló venoms) and the reduced availability of venoms [3].
In North America, the most common flying Hymenoptera insect to cause allergy is the yellow jacket, except for some areas of the south central and southwestern United States, where wasps and honey bees are predominant, respectively. Hornets are variably important across areas of the United States. The same insects are the important culprits in Europe although some species differences exist. As examples, Dolichovespula media, D. saxonica, and D. sylvestris are the more common species of the genus Dolichovespula in Europe, whereas D. maculata and D. arenaria are more common in the United States (significant cross-reactivity exists). Also, there are some Polistes differences, and Vespo crabo are more common in Europe.
In the United States, the following venoms are available for use in immunotherapy:
●Honey bee venom
●Yellow jacket venom protein
●Yellow hornet venom protein
●White-faced hornet venom protein
●Wasp venom protein
●Mixed vespid venom protein (contains equal parts yellow jacket, yellow hornet, and white-faced hornet venom proteins)
Depot preparations are available in some countries [4], although not in the United States. The discussion in this topic review does not apply to depot products.
Venom selection — Skin testing is the preferred method of determining sensitivity to venoms, but sometimes measurement of venom-specific immunoglobulin (Ig)E may provide additional information. In vitro testing is most often recommended when all of the venom skin tests are negative. This is discussed in more detail elsewhere. (See "Diagnosis of Hymenoptera venom allergy", section on 'In vitro testing'.)
Multiple versus single venom — In the United States, patients are usually treated with all of the venoms to which they had a positive skin test, with the goal of providing maximal coverage for future sting events [2]. This approach ensures that a patient who has reacted to a yellow jacket sting, for example, is not left with doubts about the expected outcome of a sting from a different Hymenoptera insect (to which he/she had a positive venom skin test but had never been stung, such as a honey bee).
The vast majority of yellow jacket-allergic patients also have positive skin tests to yellow hornet and white-faced hornet venoms due to cross-reactivity because these insects are in the same Hymenoptera subfamily (figure 1). These patients are usually treated with a mixed vespid extract containing the full dose of each venom (yellow jacket, yellow hornet, white-faced hornet). Similarly, if a patient has positive test results to two vespid venoms, such as yellow jacket and white-faced hornet, but not to other vespid venoms, the patient could be treated with either yellow jacket and white-faced hornet as two separate injections or with commercially prepared mixed vespid. However, the author prefers giving mixed vespid venom because the cross-reactivity of the vespid venoms results in a higher equivalent dose of the other venoms than would be received by giving each separately. Additionally, the author has seen patients who were initially negative to one of the vespids and later were shown to be positive to that venom. Finally, most patients would prefer a single injection. About 50 percent of yellow jacket-allergic patients are also sensitized to Polistes wasp (same family) and should receive this venom as a separate injection.
Single VIT is used at some centers, such as treating only with yellow jacket venom where that is that suspected cause of the reaction and skin tests are positive to yellow jacket, yellow hornet, and white-faced hornet. Available data indicate that the effectiveness of this approach is also high, at 75 to 95 percent [2,5]. No head-to-head comparative studies are available. Clues such as geographic location and when and how the sting occurred, as well as the appearance of the insect and its nest can help determine the culprit stinging insect, but patient identification of the various stinging insects had been shown to be unreliable. In vitro radioallergosorbent inhibition tests (where available) can distinguish those yellow jacket allergic patients who are cross-sensitized to Polistes wasp venom from those with true dual sensitivity, which would inform the choice of venoms for VIT. This approach has also been used for honeybee and yellow jacket double positivity. In addition, the use of recombinant venom allergens has resolved dual sensitivity to honeybee and yellow jacket from cross-reactivity that may be due to cross-reacting venom allergens or their cross-reacting carbohydrate determinants. (See "Diagnosis of Hymenoptera venom allergy".)
Venoms should not be mixed — Venoms should not be mixed, with the exception of the commercially prepared mixed vespid products. Mixing of other venoms can result in proteolytic degradation of venom proteins [2].
Dosing
Initial — VIT is traditionally initiated with a dose between 0.001 and 0.05 mcg of venom (table 1 and table 2). However, a higher initial dose of 1 mcg is also well-tolerated [6]. This relatively wide range of starting doses necessitates that clinicians use judgment in choosing a starting point for an individual patient.
Maintenance — A maintenance dose of 100 mcg per venom (or 300 mcg for the mixed vespid preparation that contains three venoms) was initially chosen for both adults and children because it represented approximately twice the venom content of a honey bee sting or three to four times that of a vespid sting. This dose has been used as maintenance in the majority of published protocols and is recommended in the Hollister-Stier Laboratories prescribing information. Studies of lower or higher maintenance doses in adults and children are more limited:
●One center reported a 10-year experience with a maintenance dose of 50 mcg, in which most patients received treatment with a single venom (the majority received yellow jacket venom) [5]. There were 258 subsequent stings, of which only 3 resulted in systemic reactions. However, a smaller prospective study compared the outcomes in patients treated with 50 mcg with patients treated with 100 mcg and found that the lower dose protected 79 percent of subjects from systemic reactions on challenge, while the higher dose protected 96 to 100 percent [7]. Therefore, we suggest a maintenance dose of 100 mcg for adults.
●Doses higher than 100 mcg per injection are occasionally needed to achieve protection. (See 'Treatment failure' below.)
●Lower venom doses may provide adequate protection in children. A small study found that children produced a more vigorous IgG response to VIT (approximately twice that of adults), suggesting that one-half of the dose of venom might be protective in this age group [8,9]. A retrospective study found that 50 mcg of honey bee venom (single venom VIT) protected children from recurrent systemic reactions in 94 percent of field stings [10]. In another report of 54 children treated with 50 mcg maintenance doses of various venoms, 21 were stung during or after a five-year course of VIT, and none had a systemic reaction, including several with initially severe reactions [11]. A 50 mcg maintenance dose might be effective in children. However, the author prefers to use a 100 mcg dose for children as well as adults.
Choice of protocol — Various schedules of injections may be used, and the manufacturer provides a suggested injection schedule in the package insert. The choice of schedule is based upon the urgency of the patient's need for treatment, convenience, and the clinician's experience and comfort with specific protocols.
Traditional protocols — Traditional protocols involve one to three injections per week and reach maintenance doses in two to four months. Traditional protocols are widely used in the United States.
●The schedule provided by Hollister-Stier Laboratories in their package insert involves once weekly injections. Maintenance is reached in 15 weeks (table 1).
●A more rapid, requiring three injections per week and reaching the maintenance dose in 8 weeks is also in common use (table 2).
The two approaches above are equally effective, and the frequency of systemic reactions is equivalent [2]. However, at least one study found that there were more systemic reactions overall in patients following the slower regimen, perhaps because they received more injections during the build-up phase [12].
Accelerated protocols — Accelerated protocols include "rush" and "ultra-rush" schedules. Accelerated protocols are popular in some European centers and United States military hospitals and offer certain advantages, such as the rapid achievement of clinical protection for the patient at very high risk for recurrent sting (eg, a beekeeper) who suffered a severe initial reaction. Rush schedules also require fewer visits, which is helpful for patients who do not live near a medical facility.
Ultra-rush protocols, in which the maintenance dose is reached in one or two days, may carry an increased risk of systemic reactions and are usually performed in the hospital setting. Accelerated protocols for venom immunotherapy are discussed in more detail separately. (See "Rush and ultra-rush venom immunotherapy for Hymenoptera allergy".)
Interval between maintenance injections — The maintenance dose of 100 mcg is given every four weeks initially [2,13,14]. In most patients, the interval between maintenance injections can be lengthened further without impacting the efficacy of VIT. There are no specific tests to identify patients in whom this is appropriate. Rather, it has been safely accomplished in patients who have not experienced systemic reactions to either the injections or to subsequent stings. In this lower-risk group, extending the maintenance interval gradually to as long as three months appears to be safe. The studies supporting this statement are reviewed below.
Several approaches to lengthening the period between maintenance injections have been described, although these have not been compared directly:
●A 2016 update to the practice parameter published by the Joint Council of Allergy, Asthma, and Immunology (a group representing the leading American allergy societies) notes that a maintenance interval of four weeks is recommended for indefinite treatment in the US Food and Drug Administration-approved product package inserts. However, it states that "experts in the field support the regimen of a four-week maintenance interval for 12 to 18 months, followed by a six-week interval for 12 to 18 months and then eight-week intervals" [14]. For example, the author of this topic favors the following approach: every four weeks for one year, then every six weeks for one year, then every eight weeks for one year, and then extend some patients to 10- to 12-week intervals. The section editor's approach is similar but progresses every 18 months instead of yearly.
●At least two studies support maintenance intervals as long as three months and advancing to those intervals more rapidly.
•One observational study started with either conventional build-up (weekly over three to four months) or a three-day rush protocol and then lengthened the interval between maintenance injections as follows: once at one month, once at six weeks, once at two months, and three-month intervals thereafter [15]. While on three-month intervals, 36 patients experienced 49 field stings, 47 of which were tolerated without a systemic reaction. The other two stings resulted in mild systemic reactions, which resolved without treatment.
•In another observational study, 186 patients receiving single venom VIT were built-up to maintenance over three weeks and then given the choice of conventional intervals of four to six weeks between injections or extended intervals. In the latter group (76 patients, one-half of which were allergic to honey bee), the intervals between maintenance injections were lengthened in a stepwise manner until an interval of three months was reached after 4.5 months of treatment [16]. Three-month intervals were continued until the start of the fifth year of VIT, at which point the interval was extended to four months. While receiving every three-month maintenance injections, patients in this cohort sustained 205 stings, 7 of which resulted in a systemic reaction. After four years of VIT, the patients getting injections at four-month intervals sustained 39 stings, 1 of which resulted in a systemic reaction. In the conventional group, there were 167 stings, 11 of which resulted in a systemic reaction. Thus, the three-month interval was as effective as the four- to six-week interval at maintaining protection from recurrent systemic reactions.
Maintenance intervals longer than three months have been studied, although with mixed results. Specifically, the authors of one of the above studies determined that a 24-week interval was not adequate to maintain protection [17]. However, a study from Greece found that progressively prolonging the maintenance interval up to 26 weeks appeared to be safe and effective [18].
In light of the above studies, it is reasonable to extend the interval between maintenance injections in those patients who have not had systemic reactions to stings using one of the approaches above. We suggest extending this interval to 6 to 8 weeks in most cases, and up to 12 weeks at the discretion of the allergist.
GENERAL SAFETY ISSUES
Premedication — Pretreatment with the H1 antihistamine terfenadine (no longer available) reduced VIT reactions (local and systemic) in randomized-controlled trials [19,20]. It is our practice to advise the patient to take a minimally sedating H1 antihistamine each day that an injection is to be administered. Some experts advise patients to take premedications throughout the duration of VIT, while others discontinue it over time if the patient has not had local reactions. One study suggested that pretreatment with antihistamines can also improve the efficacy of VIT [20]. A report suggested that montelukast may also reduce local reactions, but we have not found this necessary in most cases [21].
Observation after injections — Patients should wait 30 minutes (or longer in selected individuals) after each injection, as systemic allergic reactions to the injections are most likely to occur within the first 30 minutes after administration. In addition, VIT should be administered by staff who are trained to recognize and treat systemic allergic reactions and in a setting equipped to manage anaphylaxis. In most cases, VIT is given in the prescribing allergist's office, although exceptions are sometimes made. The risks associated with administration of immunotherapy in remote locations are reviewed elsewhere. (See 'Systemic reactions to VIT' below and "Anaphylaxis induced by subcutaneous allergen immunotherapy".)
Measurement of baseline tryptase — Baseline tryptase measurements are helpful in assessing a patient's risk for systemic reactions in response to the dose escalation phase of VIT. Baseline levels should be measured after the sting reaction has fully resolved and the patient is in his/her usual state of health. Baseline serum levels above 11.4 ng/mL should prompt an evaluation for a mast cell disorder. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".) Baseline tryptase levels above 8 ng/mL are seen in patients with hereditary alpha tryptasemia, and these individuals may also be at higher risk for systemic reactions. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Hereditary alpha tryptasemia'.)
In a prospective, observational study of 680 patients receiving honey bee or vespid VIT, serum tryptase values correlated with the risk of adverse systemic reactions to therapy, such that an increase in baseline tryptase from 4.2 ng/mL to 20 ng/mL increased the risk for a systemic reaction by a factor of approximately 3.8 [22]. Of note, this study defined an adverse systemic reaction as a systemic symptom requiring any measure or medication for treatment, as determined by the supervising clinician, so even very mild reactions were included.
The measurement of baseline tryptase is also useful in assessing other aspects of a patient's risk. Specifically, elevated baseline tryptase is associated with more severe reactions to stings in general, more frequent treatment failure (ie, failure to achieve protection), and a greater risk of relapse after stopping VIT [22-24].
Caution if changing manufacturers — One should be cautious if a switch is necessary from the venom of one company to another once a patient has begun VIT because source materials may vary, and the venom products may not be equivalent. Suggestions regarding changing venom extracts in a patient already undergoing VIT have been published, which take into account the individual patient's history, duration of treatment, and known risk factors [3].
ADVERSE EFFECTS — VIT is well-tolerated by most patients. The most significant adverse effect of VIT is a systemic allergic reaction to the venom injections. Local reactions at the site of administration are far more common, although these are not dangerous.
Systemic reactions to VIT — Approximately 3 to 12 percent of patients have treatment-induced systemic reactions with traditional protocols. The majority of these reactions are mild and easily treated [12,25]. This systemic reaction rate is similar to that seen in conventional pollen immunotherapy when effective immunizing doses are used [26]. Patients receiving honey bee VIT and those with elevated baseline tryptase measurements are at increased risk [22].
The majority of systemic reactions to VIT occur in the dose escalation phase of treatment. For this reason, many clinicians prefer that VIT be administered in an allergist's office until the maintenance dose is reached.
If a systemic reaction occurs, the patient should be evaluated by a clinician as soon as possible after the event to determine if there were any patient-related or external factors that may have contributed to the reaction, such as a dosing error, failure to premedicate, or an increase in the patient's baseline asthma or allergy symptoms.
A baseline serum total tryptase should be measured if not done in the past. If tryptase is persistently elevated and the patient is found to have an underlying mast cell disorder (and this caveat may also apply to those with hereditary alpha tryptasemia), VIT should be continued because the patient is at high risk for severe reactions to stings. In this situation, pretreatment with one or more doses of omalizumab (ie, anti-IgE therapy) can help the patient tolerate continued treatment. The use of omalizumab in patients with mastocytosis and venom allergy is discussed separately.
Most patients who have a treatment-induced systemic reaction will not have elevated tryptase. In this setting, the schedule should be interrupted and adjusted when a systemic reaction occurs. We typically ask the patient to return one week later and administer one-half of the causal dose as the next injection. If tolerated, the dose is increased on a weekly basis until the patient again reaches the maintenance dose.
Recurrent systemic reactions — Rarely, patients experience repeated systemic reactions to the venom injections. In this situation, the nature of the patient's symptoms should be carefully evaluated, and a serum tryptase should be obtained after the reaction (ideally 30 minutes to 3 hours from the onset of symptoms) if there is doubt about whether these symptoms are anaphylaxis. In the experience of the author and section editor, a large proportion of these patients have constitutional symptoms that are not anaphylaxis and may be related to release of inflammatory mediators or cytokines at the local injection site. Most of these reactions will resolve spontaneously with further escalation of the dose. However, other explanations for recurrent reactions to VIT are extreme sensitivity to venom or the presence of an underlying mast cell disorder.
When recurrent systemic reactions to VIT occur in a patient who has not yet reached the full maintenance dose, we suggest attempting to get the patient to tolerate a full maintenance dose. This can usually be achieved either by performing a two-day rush protocol to reach maintenance [27], during which the patient is hospitalized, or by administering one or more doses of omalizumab (ie, anti-IgE therapy) and then continuing dose escalation [28,29].
Anaphylaxis to human serum albumin in the diluent used for VIT was described in a case report [30]. The patient described had been tolerating VIT for over two years and then developed anaphylaxis after two consecutive maintenance injections.
Local reactions — A less serious but more frequent problem with VIT is the large local reactions that occur in 25 percent of children and 50 percent of adults, usually at doses of 20 to 30 mcg of venom. Although bothersome, local reactions do not predict an increased risk of future systemic reactions to treatment. The best way to manage these is to reassure the patient and proceed with the injection schedule, as these reactions generally do not continue to occur at the higher doses [2].
If a patient is experiencing significant discomfort and/or inconvenience because of large local reactions to the injections, one or more of the following may be helpful:
●Apply cold packs to the site of the injection(s) immediately after administration.
●Make sure that the patient is taking an antihistamine several hours before the injections are administered.
●Divide the problematic dose(s) between the patient's arms, such that one-half of the volume is delivered to each site. As the dose increases, it should be given again as a single injection.
●Consider adding premedication with montelukast, 10 mg orally, several hours before the injections [21].
●We have also had some anecdotal success in reducing large local reactions at a specific step in VIT by giving the same venom dose using a smaller volume of a higher concentration venom solution [31].
Long-term safety — No long-term toxicity or side effects have been associated with VIT thus far.
MONITORING VIT — We usually assess patients after the initial four to six weeks of VIT and then again at six months. Patients who are tolerating VIT without difficulty can generally be reassessed annually after the first year of treatment. At these visits, the patient's injection schedule should be reviewed, noting that dose and frequency of injections have reached the desired parameters. The patient should be questioned about any stings that may have occurred since the last visit and the symptoms that resulted.
Assessing effectiveness — There is no simple test to determine with certainty how well VIT is protecting a given patient from a future sting reaction. One study using sting challenges suggested that most patients are protected from recurrent systemic reactions after six weeks of conventional (nonrush) VIT [32]. The following tests provide some information about how well VIT is working, but none of them are conclusive.
Venom-specific IgG — Venom-specific IgG may be measured, and a serum level of >3 mcg/mL is characteristic of patients who are protected from repeat stings in the first three years of VIT [33]. However, values <3 mcg/mL may also be seen in patients with adequate protection, and after four years of VIT, most patients are protected from recurrent systemic reactions, regardless of their venom-specific IgG level. Thus, venom-specific IgG must be interpreted in the context of the patient's other clinical and laboratory data. The utility and cost-effectiveness of measuring venom-specific IgG routinely is unclear, since there are so few treatment failures with VIT [34]. We do not measure venom-specific IgG in all patients in our practice but rather use this determination to assess patients with apparent treatment failures. (See 'Treatment failure' below.)
Venom-specific IgE — Venom-specific IgE is used in research but is not routinely used in clinical practice to monitor the progress or success of VIT.
Venom skin tests — Over time, venom skin tests tend to become smaller and will revert to negative in a significant proportion of patients. In children, 45 percent of those who had received three to six years of VIT developed negative venom skin tests to one or more venoms [35]. In adults, 20 percent had negative venom skin tests after five years of VIT [36]. The role of repeat skin testing in determining the duration of VIT is reviewed elsewhere. (See "Hymenoptera venom immunotherapy: Determining duration of therapy".)
Sting challenges — Sting challenges are frequently used in research but are not recommended for routine clinical practice. These procedures are associated with some risk, and the lack of response on a single sting challenge does not guarantee that the patient will not react to a subsequent sting [37].
Treatment failure — Treatment failure (ie, recurrent systemic reaction[s] to sting[s] despite VIT) may be seen in patients with indolent systemic mastocytosis or other mast cell disorders [38,39]. A serum tryptase level should be obtained as an initial screen for an underlying mast cell disorder. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
Another possible cause for treatment failure was suggested by a retrospective European study, which utilized component-resolved sensitization profiles to demonstrate predominant IgE sensitization to Api m 10 as a risk factor for treatment failure in honey bee VIT [40]. These tests are not commercially available.
Increasing the maintenance dose up to 200 mcg is effective in most individuals who experienced sting reactions while receiving the 100 mcg maintenance dose [41].
Some clinicians measure venom-specific IgG in such patients, since a level <3 mcg/mL is consistent with incomplete protection. However, aside from observing the response to a subsequent sting, there is no entirely reliable way to identify patients who are not adequately protected by standard doses of VIT.
Duration of therapy — This is discussed in detail separately. (See "Hymenoptera venom immunotherapy: Determining duration of therapy".)
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".)
Recommendations during the coronavirus pandemic — Expert groups in both North America and Europe have advised that there should be no change in initiation or buildup of VIT in patient with a history of a systemic reaction to venom during the COVID-19 pandemic [42,43].
SUMMARY AND RECOMMENDATIONS — Venom immunotherapy (VIT) is administered to patients with past systemic allergic reactions to stings of honey bees, yellow jackets, yellow hornets, white-faced hornets, and wasps for the purpose of preventing recurrent reactions. (See 'Introduction' above.)
●Most commonly, the patient is treated with all of the venoms relevant to a geographic location to which that individual tested positive. (See 'Venom selection' above.)
●We suggest premedicating all patients with an H1 antihistamine prior to each venom injection (Grade 2B). (See 'Premedication' above.)
●Schedules of injections vary but may be divided into traditional and accelerated (rush and ultra-rush). (See 'Choice of protocol' above.)
●Prior to initiating VIT, we recommend measurement of baseline tryptase values in all patients with severe reactions and/or reactions involving hypotension. The utility of measuring tryptase in patients with mild systemic reactions is less clear. (See 'Measurement of baseline tryptase' above.)
●Approximately 3 to 12 percent of patients have treatment-induced systemic reactions with both traditional and rush schedules. The majority of these reactions are mild and easily treated. Doses should be reduced temporarily following a systemic reaction. (See 'Systemic reactions to VIT' above.)
●Local reactions to the injections occur in 25 to 50 percent of patients and are not associated with an increased risk of a systemic reaction. Local reactions do not require dose adjustment. (See 'Local reactions' above.)
●There is no one accepted approach to monitoring VIT and no simple test to determine with certainty how well VIT is protecting a given patient from a future sting reaction. However, most patients do not experience recurrent systemic reactions to stings once receiving VIT, so this is not a common clinical problem. (See 'Monitoring VIT' above.)
●For patients who have not experienced systemic reactions to either the VIT injections or to subsequent stings, we suggest lengthening the interval between maintenance injections to 6 to 8 weeks in most cases and as long as 12 weeks at the discretion of the allergist (Grade 2C). There are several approaches for doing this. (See 'Interval between maintenance injections' above.)
