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Hymenoptera venom immunotherapy: Determining duration of therapy

Hymenoptera venom immunotherapy: Determining duration of therapy
Literature review current through: Jan 2024.
This topic last updated: Oct 17, 2022.

INTRODUCTION — Venom immunotherapy (VIT) is highly effective for the treatment of patients with systemic allergic reactions (SARs) to Hymenoptera venom. Overall, VIT reduces the chance of having a serious SAR to an insect sting by 90 percent [1]. Specifically, more than 95 percent of patients allergic to vespid (ie, yellow jacket, hornet, and wasp) venom and 80 to 90 percent of those allergic to honey bee venom will not develop any systemic allergic symptoms if re-stung while receiving VIT, and those who do have some reaction will usually experience only mild symptoms [2-8]. VIT has also been demonstrated to significantly improve health-related quality of life beyond what is achieved with access to epinephrine and Hymenoptera avoidance [1,9-11].

This topic will review the studies that have addressed the issue of duration of therapy and discuss the risk factors for recurrent SARs to Hymenoptera stings after the discontinuation of VIT. The efficacy, indications, and other issues concerning VIT are presented separately. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action" and "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring".)

BACKGROUND AND OVERVIEW — After the introduction of VIT in the 1970s, it was initially believed that therapy would need to be continued indefinitely in most patients. However, reports began to appear describing relatively good outcomes in patients who chose to stop their venom injections for various reasons. In addition, a subset of patients on VIT appeared to lose sensitivity (ie, skin tests to venom converted to negative and/or serum levels of venom-specific immunoglobulin E [IgE] antibodies fell to low levels). Finally, the cost and inconvenience of lifelong injections are not insignificant. For these reasons, studies were initiated beginning in the 1980s to try to determine if and when VIT could be safely stopped, which demonstrated that most patients will have achieved lasting protection after three to five years of treatment. As a result, this is now the minimal duration of treatment that is recommended. (See 'Minimal duration of treatment' below.)

After VIT is stopped, there is some persistent risk of a recurrent systemic allergic reaction (SAR), which may be as high as 10 percent per sting in unselected groups of patients, although most recurrent SARs that do occur are mild [12]. Of note, the risk is higher in patients whose initial reaction was life-threatening, those with comorbidities that put them at risk for more severe reactions or poor outcomes as a result of anaphylaxis, those who are stung repeatedly after stopping VIT, and those with several other characteristics. (See 'Risk factors of recurrent reactions or poor outcomes' below.)

It is the approach of most guidelines and of the UpToDate contributors to continue VIT indefinitely for patients with one or more of the risk factors for relapse or poor outcomes (table 1). However, the decision should also incorporate the patient's comfort with risk and other preferences. No two situations are identical, and experts may come to different conclusions given the same situation. The results of repeat skin testing or venom-specific serum IgE are secondary to these clinical factors. (See 'The role of testing' below.)

MINIMAL DURATION OF TREATMENT

Current guidelines — American and European guidelines, with which we agree, recommend that VIT be continued for at least three to five years because most patients who stop VIT after this period of time will remain protected from recurrent systemic allergic reactions (SARs), with five years providing better protection than shorter periods of treatment [13,14]. (See 'Society guideline links' below.)

Evidence of lasting protection — The recommendation that patients complete a minimum of three to five years of VIT is based on the following studies:

One year of treatment – An early retrospective study evaluated recurrent SARs to stings in 82 patients who chose to stop VIT after a mean duration of 14 months of treatment [15]. Over the ensuing three to four years, 22 percent of those who were re-stung had SARs, compared with 1 to 3 percent of patients who remained on VIT. Thus, one year of VIT did not provide sufficient protection for nearly one-quarter of patients.

Four or more years – Several prospective studies evaluated the protection afforded by VIT if it was given for periods of time ranging between 3 and 10 years and then stopped, with a mean of greater than four years (table 2) [16-22]. In these studies, 83 to 100 percent of patients remained protected against recurrent SARs in the first one to three years after stopping. In addition, most or all of the patients who did develop SARs with repeat stings after stopping VIT had only mild symptoms. However, it is important to note that the majority of the patients in these early studies were selected because they showed evidence of a reduction in sensitivity to venom in response to VIT, either through skin tests or serum tests or because they had done well with a subsequent sting, so their prognosis as a group may have been better.

At least five years of treatment – Studies of ≥5 years of treatment show protection rates of 90 to 100 percent, even in unselected groups of patients [16,20,22,23].

In one study, the percentage of patients who developed SARs after stopping VIT was significantly lower (5 percent) among patients who had received VIT for ≥50 months, compared with 18 percent among those who received treatment for 33 to 49 months [16].

Another study evaluated 74 patients treated with VIT for at least five years who volunteered to stop treatment and undergo periodic testing and sting challenges every one to two years [23]. Over the ensuing two to five years, systemic symptoms occurred in 7 of 74 patients (10 percent) or in 8 of 270 challenges (3 percent), and just two reactions required epinephrine injection.

In a third study of 29 adults with vespid venom allergy treated for at least five years, there were no recurrent SARs upon challenge one year after stopping treatment [22].

In a fourth study of 51 Hymenoptera sting-sensitive patients treated with VIT for 2 to 10 years, sting challenges were done to show clinical immunity. Patients treated with VIT five or more years showed the greatest protection, with only 2 percent recurrence with sting challenge. Those treated less than five years had a 10 percent risk of reaction with sting challenge and those treated one to two years had a 25 percent risk of reaction with sting challenge. The authors concluded that VIT be continued for five years, although many patients benefit with three or four years of VIT [20].

In summary, the vast majority of patients were protected if they received five or more years of VIT. However, some patients may require indefinite therapy. (See 'Candidates for indefinite therapy' below.)

CANDIDATES FOR INDEFINITE THERAPY

Risk factors of recurrent reactions or poor outcomes — A number of patient-specific risk factors for the recurrence of a systemic allergic reaction (SAR) to Hymenoptera stings following VIT were identified by analyzing the studies reviewed above (table 3) [24]. Other characteristics, such as sex or the presence of atopic disorders, do not influence the risk of a relapse [16,18]. These risk factors may be grouped into intrinsic patient characteristics, response to venom injections or stings during VIT, and comorbidities, as discussed below.  

Patient characteristics

Adults versus children – Adults have a higher risk for recurrent SARs than children after discontinuing VIT [17,18]. In a representative study, SARs were reported in 13 percent of adults, compared with 8 percent of children who were stung within seven years after stopping VIT [16]. Another study reported that 16 percent of adults (with initial moderate-to-severe reactions) experienced recurrent SARs when evaluated more than 10 years after stopping VIT, compared with only 5 percent of children [12,25]. Patients in these studies were unselected for other risks, such as severity of initial reaction or comorbidities.

Severe pretreatment SAR – Patients with severe initial sting reactions are at higher risk for a recurrent SAR both during and after completion of VIT [26]. Combining the data from four prospective studies involving 386 patients, relapses were observed in 14 percent of those with severe pretreatment reactions, compared with 4 percent of those with mild initial reactions (table 4) [16,23,27,28].

Honey bee venom allergy – Patients with honey bee venom allergy are at higher risk for recurrent SARs than those allergic to vespid venoms, both before and after VIT. Before treatment, 51 percent of bee-allergic patients develop recurrent SARs upon sting challenge, compared with 25 percent of those allergic to vespid venoms [29,30].

During and after VIT, patients allergic to honey bee venom remain at higher risk [16,18]. In a study of VIT of three to five or more years duration, the relapse rate in 120 patients allergic to bee venom was 16 percent, compared with 8 percent in 80 patients allergic to vespid venoms [16].

The reasons for this difference are not entirely clear [5,6]. One study found that a predominant sensitization (>50 percent) to a major allergen in honey bee, Api m 10, was seen in patients with treatment failure, such that this pattern of sensitization may be a risk factor [31]. Consistent with this, Api m 10 was found to be present in low amounts in honey bee venom and underrepresented in honey bee VIT [32]. The venom content of a honey bee sting is also much higher than that of a vespid sting. It is also possible that vespid stings are more variable in venom content than honey bee stings, because vespids retain their stingers after stinging, and thus, can sting more than once, while honey bees lose their sting apparatus. (See "Stinging insects: Biology and identification".)

Extreme sensitivity on diagnostic testing – Some studies have reported an association between recurrent SARs after stopping VIT and persistent high sensitivity on diagnostic tests for venom sensitization [12]. However, others have not been able to confirm this finding [16,18]. (See 'The role of testing' below.)

Response to venom injections or stings during VIT — Approximately 10 percent of patients undergoing VIT will have a systemic allergic reaction of any severity to treatment [1]. Patients who develop general allergic reactions to VIT injections or to repeat stings during VIT are at higher risk for reactions to stings after stopping VIT [18,23]. In one study, those who had SARs to injections during treatment had a 38 percent chance of relapse, compared with a 7 percent chance among those who had no SARs to injections [18].

Patients who have recurrent SARs during maintenance VIT should be evaluated for mast cell disorders with a baseline serum tryptase level if this was not previously done. In addition, a higher maintenance dose of venom is recommended to achieve protection in such individuals [33]. These issues are discussed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Treatment failure' and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Comorbidities

Mast cell disorders – Patients with mast cell disorders can experience severe anaphylaxis with Hymenoptera stings. Most of these patients have skin test or serologic evidence of venom allergy, although some do not [34-37]. Conversely, a significant percentage of patients with severe shock reactions following Hymenoptera stings have evidence of a mast cell disorder. Up to one-third of patients with severe anaphylactic reactions from stings demonstrate an elevated baseline serum tryptase level (ie, >11.4 ng/mL), whereas an elevated serum tryptase level is observed in less than 5 percent of an unselected adult population [38-40]. A study demonstrated that KIT D816V variant was identified in 18.2 percent of patients with severe anaphylaxis following Hymenoptera sting and had normal basal tryptase level [41]. Therefore, testing for this variant may be considered when evaluating these patients.

Patients with mast cell disorders, including an elevated baseline serum tryptase and venom allergy, can be successfully treated with VIT, and they appear to be at high risk for recurrent SARs if treatment is discontinued. Two female patients with urticaria pigmentosa and vespid allergy died from stings sustained three and nine years after stopping VIT [42]. Based on such reports, it has been recommended that patients with mastocytosis and Hymenoptera venom allergy receive lifelong VIT [43]. These patients must also understand that they remain at elevated risk despite treatment and must carry at least one epinephrine autoinjector at all times [33]. The management of venom allergy in patients with systemic mastocytosis is reviewed separately.

Cardiovascular disease and cardiovascular medications – Adults with concomitant cardiovascular disease are at increased risk for severe SARs to Hymenoptera stings and poor outcomes resulting from stings, including myocardial and cerebrovascular infarction or death [44]. This is probably also true for patients with chronic pulmonary diseases, such as chronic obstructive pulmonary disease or asthma, although it is less well documented [44].

It is less clear how the use of angiotensin-converting enzyme (ACE) inhibitors or beta-blockers impact the risk of a recurrent SAR or poor outcome. Given the suspected risk associated with these medications before and possibly during VIT, it is prudent to consider all the relative risks when making decisions about discontinuing VIT [13]. Studies examining the safety of these medications during VIT are reviewed separately. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients requiring ACE inhibitors or beta-blockers'.)

Our approach — The risk of recurrent SARs among patients who continue VIT indefinitely is believed to remain low [45,46]. Among the various risk factors discussed above, those that are most critical and can be known in advance are used to identify candidates for indefinite therapy (table 1). Understanding that recommendations may vary slightly among guidelines, we advise patients with one or more of the following risk factors to continue VIT indefinitely:

Life-threatening initial SARs.

A high likelihood of recurrent stings in the future due to occupational or recreational activities.

Honey bee allergy and a high likelihood of recurrent stings in the future (eg, bee keepers and their family members).

Significant cardiovascular disease and/or concomitant use of ACE inhibitors or beta-blockers.

Recurrent SARs to VIT injections or recurrent SARs to re-stings during maintenance VIT. The management of recurrent SARs to VIT injections is reviewed separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Systemic reactions to VIT'.)

Requirement for higher venom doses to achieve adequate protection.

Limitations in work or leisure activities due to anxiety concerning the residual risk of a repeat reaction. If despite discussion with the patient there remains significant concern or anxiety, then prolonged VIT may be considered.

Mast cell disorders, an elevated baseline level of serum tryptase, or a positive KIT D816V.

Dosing interval — To make VIT as convenient as possible for patients continuing treatment indefinitely, the clinician should consider prolonging the interval between maintenance injections, if this was not already done. American practice parameter suggests that patients receiving VIT should receive maintenance doses at monthly intervals for at least 12 to 18 months, after which the dosing interval can be extended to six or eight weeks during several years of treatment. For patients who continue VIT for longer than four years, a 12-week interval is safe and effective, provided the patient has not experienced breakthrough reactions to the VIT injections or to field stings [13]. Maintenance intervals are discussed in more detail separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Interval between maintenance injections'.)  

Need to carry epinephrine — Patients on indefinite VIT often ask if they should continue to carry an epinephrine autoinjector. The answer depends on the patient's specific circumstances, and the clinician and patient can decide together what is best. Although VIT reduces the risk substantially, it is not reduced to zero. In patients with a life-threatening initial reaction or risk factors for a poor outcome from anaphylaxis, it may be more a reassurance than a burden to carry epinephrine. In contrast, the obligation to carry an autoinjector and fear of using it can impair quality of life in others, so the decision should be individualized.  

Periodic re-evaluation — For patients with one or more of the indications for indefinite VIT who are content to continue it, we usually do not perform repeat testing, since the results would not override the decision to continue VIT. However, if the patient's situation changes or they become interested in stopping VIT later on, repeat testing may be appropriate. The decision then becomes similar to that discussed below (See 'The role of testing' below.)

PATIENTS WHO CAN SAFELY STOP VIT — If a patient with a moderate severity initial systemic allergic reaction (SAR) to a sting and no indications for indefinite therapy has completed five years of treatment and has not had systemic reactions to either the VIT injections or to a recurrent field sting, then it is reasonable to discontinue VIT. The decision can be made with greater confidence if the patient has had one or more field stings that did not result in a SAR.

The role of testing — Repeat diagnostic testing is not required prior to discontinuing VIT after three to five years in straightforward situations, although it may be helpful when the decision to stop is not clear [13]. In these situations, repeat testing may help by providing information about whether the patient has responded as expected to treatment [45]. If it is decided to perform skin testing and measure venom-specific immunoglobulin E (IgE) antibodies prior to discontinuation, the results should be compared with the pretreatment results. If testing is repeated, it is logical to repeat the same type of testing (skin testing, in vitro testing, or both) that was used for diagnosis, so that results can be compared.

The following observations have been made about the impact of VIT on various testing parameters:

Skin test reactivity to venoms may increase initially but usually declines after a year of treatment and then falls further during the following three to five years. However, these changes are not reliably predictive of protection for recurrent SARs. If a patient's skin testing becomes negative but the patient has some higher risk features, we measure venom-specific serum IgE as well before deciding to stop therapy, because studies have shown that patients can have negative skin tests and positive venom-specific serum IgE and subsequently experience recurrent SARs.

Venom-specific serum immunoglobulin G (IgG) is not used in the decision to stop VIT, because levels usually rise early in the course of VIT and remain elevated during treatment, but do not correlate closely with protection, especially after several years of treatment. After discontinuation of VIT, venom-specific IgG usually decreases significantly within months, despite persistent protection.

Persistent high sensitivity on diagnostic tests (either skin or in vitro tests) may be a risk factor for recurrent SARs after stopping VIT. Therefore, continuation of VIT until diagnostic tests show a clear decrease in sensitivity has been recommended in this situation [12].

The combination of a negative intradermal skin test at a venom concentration of 1 mcg/mL and the absence of venom-specific serum IgE antibodies (ie, <0.35 international units/mL in most laboratories) is associated with a low risk of recurrent SARs after VIT [16,18,27]. However, only about 25 percent of patients become skin test-negative after five to six years of VIT [22,23], and an even smaller group achieves both negative skin tests and in vitro tests.

An example of a scenario in which repeat testing would be helpful is a farmer with a history of moderate SARs to stings who had completed five years of vespid VIT, tolerated it without difficulty, and was stung twice during VIT without developing systemic symptoms. The patient is anxious about stopping because he often works alone and frequently encounters yellow jackets. Thus, he doesn't have specific indications for lifelong VIT, but he is unsure about stopping. In this case, skin testing and/or venom-specific IgE might be useful, because if both were significantly reduced or negative upon repeat testing, both the allergist and patient would feel more comfortable stopping therapy. However, if the same patient had a persistently high level of serum-specific IgE or skin testing was only minimally reduced, the allergist might reasonably advise the patient to continue VIT for some additional years and repeat testing again in the future. In the latter scenario, testing could be repeated at some point (eg, 10 to 15 years) in the future.

FACTORS AFFECTING RISK AFTER STOPPING — After a patient has completed a course of VIT, their risk may increase slightly over time. This appears to be most likely in patients who are stung repeatedly. Therefore, patients should continue their efforts to avoid being stung after stopping VIT. (See "Stinging insects: Avoidance".)

Repeated stings after stopping VIT — Patients who are stung repeatedly after stopping VIT have a greater risk of eventually having a recurrent systemic allergic reaction (SAR) compared with those who are stung infrequently [12,22]. Thus, the chance of systemic reaction to a sting after five years of VIT is 10 percent with each sting, but the cumulative reaction rate 10 years after stopping VIT (and after more than one sting in many of the patients) was reported to be more than 16 percent [12]. The severity of SARs may also increase in response to repeated stings in patients who have discontinued VIT. In a study of 200 patients treated with at least three years of VIT, 25 patients were re-stung, and 84 percent of them experienced no reaction or only a mild SAR to the initial post-treatment sting (table 5) [16]. Additional stings occurred in 17, and these were moderate-to-severe in 53 percent (table 5). Another study reported similar findings [47].

Time since stopping therapy — There appears to be no loss of effect over time in the majority of patients who stop VIT after five or more years of treatment. However, in patients with known high-risk factors, the chance of systemic reaction to a sting increases during the first three to five years after stopping VIT [13,16]. Those who experience SARs generally (but not always) have mild symptoms. Protection up to seven years after discontinuing VIT was analyzed in several studies [12,16,23,27,28]. These studies reported complete protection in 80 to 91 percent of patients, a slightly lower percentage than in studies of the first three years off therapy. In many cases this was due to some patients being stung more than once over a period of years.

Counseling the patient — The allergist should ensure that patients who discontinue VIT understand the following about their risk for a recurrent SAR:

Because there is some residual risk after stopping VIT, the patient should continue to take measures to avoid Hymenoptera. (See "Stinging insects: Avoidance".)

It is possible to react to one sting and not another, so an uneventful sting does not prove the patient is "cured" of the allergy. Rather, it is important for the patient to understand that the risk has been reduced to a level that is similar to that in the general population, but not to zero.

It is also possible, although rare, for a person who received VIT for wasp venom allergy, for example, to develop a new allergy to a different Hymenoptera, such as yellow jacket or honey bee, since VIT is specific to the venom that was administered.

Any serious SARs should be reported to the allergy specialist so that the patient's situation can be re-evaluated.

We usually do not suggest that patients need to continue to carry an epinephrine autoinjector if they do not have features that put them at high risk for a recurrent SAR and the decision has been made to stop treatment after an appropriate course of VIT, an approach that is also supported by some guidelines [48]. However, some may feel more comfortable doing so, and the decision can be individualized for each patient's values and preferences [45]. We explain that carrying epinephrine is no longer medically necessary, but if doing so provides peace of mind, then it is valuable for that reason alone. In contrast, other patients can feel burdened by carrying epinephrine.

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 [49,50].

SUMMARY AND RECOMMENDATIONS

Efficacy of VIT – Venom immunotherapy (VIT) is highly effective and reduces the risk of a recurrent systemic allergic reaction (SAR) to less than 10 percent per sting in most patients while they continue to receive maintenance injections. In addition, those SARs that do occur in patients receiving VIT tend to be mild. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action".)

Determining the length of treatment – Observational studies of patients who stopped VIT indicate that treatment for five years gives lasting protection to the majority of patients. If VIT is stopped, there is residual risk of a recurrent SAR of approximately 10 percent per sting in unselected populations of patients (ie, all levels of risk combined). However, the risk is higher in patients with certain risk factors for recurrent stings or for poor outcomes as a result of anaphylaxis. (See 'Evidence of lasting protection' above and 'Risk factors of recurrent reactions or poor outcomes' above.)

For patients with one or more of the identified risk factors (table 1), we suggest continuing VIT indefinitely (Grade 2C). In most cases, the interval between maintenance injections can be prolonged to make continued therapy more convenient for patients. (See 'Our approach' above.)

For patients who do not have any of the risk factors for relapse or poor outcomes from anaphylaxis and who prefer to stop treatment, we suggest completion of five years of VIT rather than shorter periods (Grade 2B). (See 'Patients who can safely stop VIT' above.)

When considering the discontinuation of VIT for a specific patient, the clinical factors of the patient's case are more important than the results of repeat testing, which is not usually indicated. However, when the decision is not straightforward, repeat venom skin test or venom-specific immunoglobulin E can sometime provide additional helpful information. (See 'The role of testing' above.)

Patient education after stopping VIT – Because there is residual risk of a recurrent SAR after stopping VIT, it is important to counsel the patient. (See 'Factors affecting risk after stopping' above and 'Counseling the patient' above.)

We advise patients to continue measures to avoid Hymenoptera exposure and report any future systemic reactions to an allergist for re-evaluation.

It is possible to react to one sting and not another, so an uneventful sting does not mean the patient is "cured" of the allergy.

We usually do not suggest that patients need to continue to carry an epinephrine autoinjector if the decision has been made to stop treatment after an appropriate course of VIT. However, some may feel more comfortable doing so, and the decision can be individualized.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ulrich Muller, MD, who contributed to earlier versions of this topic review.

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Topic 4089 Version 17.0

References

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