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Diagnosis of Hymenoptera venom allergy

Diagnosis of Hymenoptera venom allergy
Author:
James M Tracy, DO
Section Editor:
David BK Golden, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Feb 2022. | This topic last updated: Oct 07, 2021.

INTRODUCTION — Systemic allergic reactions to the venom of insects in the order Hymenoptera (which includes bees, yellow jackets, wasps, and hornets) can be life-threatening. Accurate diagnosis of venom allergy is important because patients with venom allergy are candidates for venom immunotherapy, a treatment which can dramatically reduce the risk of recurrent severe reactions [1]. The diagnosis of Hymenoptera allergy (not including stinging ants), which is based upon the clinical history and supported by testing for the presence of venom-specific immunoglobulin E (IgE) antibodies, will be reviewed here. The indications and protocols for venom immunotherapy are presented separately.

(See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action".)

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

(See "Bee, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management".)

Other types of Hymenoptera of medical importance are stinging ants (fire ants, harvester ants, bulldog ants, and jack jumper ants). Patients with allergy to winged Hymenoptera should not be presumed to be allergic to stinging ants, unless there is a clinical history to suggest this. Allergy to fire ant venom is discussed separately. (See "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".)

TYPES OF REACTIONS — Reactions to Hymenoptera stings are broadly divided into local and systemic reactions. These reactions are described briefly here and discussed in more detail separately. (See "Bee, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management".)

Local reactions — A local reaction is defined as any reaction in which the signs and symptoms are confined to tissues contiguous with the sting site. Most people develop only minor local reactions to Hymenoptera stings, which are not considered a form of allergic reaction.

Less commonly, patients may develop large local reactions (LLRs). A LLR 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 [2].

Systemic reactions — Systemic allergic reactions cause signs and symptoms distant from the site of the sting and include a spectrum of manifestations, ranging from mild to life-threatening. Systemic reactions can be further divided into reactions involving multiple organ systems and reactions limited to the skin:

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 (figure 1). 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].

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 [2].

HISTORY — Hymenoptera stings are acutely painful, and patients are usually aware that a sting has occurred, although they may not have visualized the insect clearly. Witnesses who know the patient's normal appearance and behavior may have noticed signs and symptoms during anaphylaxis that the patient does not recall, including changes in voice (laryngeal angioedema), fluctuating or reduced level of consciousness, inability to communicate clearly, flushing, or visible angioedema.

A comprehensive history should review the patient's past stings and risk for future stings (ie, occupation and hobbies) and determine whether the patient's reaction was local or systemic. The following questions need to be addressed:

How long ago did the sting event occur?

How many stings were sustained?

After the stings occurred, how much time elapsed before symptoms first appeared?

Where on the body did the sting occur? As an example, a sting on the face could cause extensive facial angioedema as part of a local reaction, but the same symptom from a sting on the leg would indicate a systemic response.

Patients should be asked specifically about symptoms affecting various organ systems, as the most memorable symptom is typically reported while other symptoms are overlooked.

Which insect does the patient believe stung him/her (although often not reliable)?

Was the patient taking any medications that might have worsened the response to the sting, such as angiotensin-converting enzyme (ACE) inhibitors or beta-blockers? This information is relevant to risk assessment.

How was the reaction treated, and were there any delayed symptoms?

Were there any previous stings, and if so, did those result in normal, large local, or systemic symptoms? A large local reaction (LLR) consists of an area of redness and swelling at the site of the sting (typically approximately 10 cm in diameter) that enlarges over 48 hours and gradually resolves over 5 to 10 days.

Have there been any subsequent stings, and if so, what symptoms developed?

Does the patient have regular exposure to Hymenoptera insects (ie, resulting from occupational or recreational activities)?

If possible, any records that can be retrieved from emergency medical services or emergency departments should be reviewed to see if additional information is recorded that was not known or remembered by the patient.

Patients with systemic reactions should be evaluated further with testing for venom-specific immunoglobulin E (IgE). Testing of patients with local reactions is not usually necessary, although there are exceptions. (See 'Patients with large local reactions' below.)

Identification of the culprit species — Attempts should be made to determine which specific insect stung the patient, based on its appearance and behavior. The two families of winged Hymenoptera that account for most stings are:

The Apidae family (honey bees)

The Vespidae family (yellow jackets, yellow hornets, white-faced hornets, and paper wasps)

If the patient cannot describe the insect in question, it can sometimes be identified based upon the patient's geographic location or setting in which the sting occurred. In addition, nests may be seen. Physical features and behaviors of the different Hymenoptera species are presented in detail elsewhere. (See "Stinging insects: Biology and identification".)

DIAGNOSIS OF VENOM ALLERGY — The diagnosis of allergy to Hymenoptera venom requires both of the following elements [6]:

History of a sting event that resulted in a systemic allergic reaction. (See 'Systemic reactions' above.)

Evidence of venom-specific immunoglobulin E (IgE), either by skin testing or in vitro testing (ie, IgE immunoassay).

Referral — The evaluation and diagnosis of venom allergy can be challenging. Venom skin testing, which should only be performed by clinicians trained in the technique, is preferred over IgE immunoassays as an initial testing modality in most cases. In addition, patients with demonstrable IgE-mediated venom allergy should be offered venom immunotherapy, which is highly effective and significantly reduces the patient's chance of experiencing systemic reactions to future stings. For these reasons, any patient with a possible systemic reaction to a Hymenoptera sting should be referred to an allergy specialist for evaluation, diagnosis, and treatment. Patients with other types of sting reactions (eg, bothersome large local reactions [LLRs] or cutaneous systemic reactions) may also benefit from referral.

INDICATIONS FOR TESTING — To understand the indications for testing for venom allergy, it is important to understand the significance of positive results, the limitations of negative results, and how this information applies to specific groups of patients.

Significance of venom-specific IgE — The presence of venom-specific immunoglobulin E (IgE) antibodies, without the history of a systemic reaction to a previous sting, is not sufficient to make the diagnosis of a venom allergy or predict that the patient is at elevated risk for a systemic reaction to a future sting. This is true because depending on the study, 27 to 40 percent of adults in the general population have detectable venom-specific IgE in the serum [7,8], yet only 0.3 to 7.5 percent of adults report ever experiencing a systemic reaction to a sting [9-11]. Thus, the positive predictive value of venom-specific IgE for the detection of clinically significant venom allergy is low in the general population. For this reason, testing is usually only indicated in patients with suspected or known systemic allergic reactions to stings. (See 'Patients with past systemic reactions to stings' below.)

Indications for testing in specific patient groups — Testing is most clearly indicated in patients with suspected or known systemic allergic reactions to stings. The purpose of testing in these patients is the confirmation of venom allergy and determination of which venoms should be used in immunotherapy. Testing is occasionally indicated in patients with other types of reactions. The indications for testing parallel the indications for venom immunotherapy, which are reviewed separately. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Indications and patient selection'.)

Patients with past systemic reactions to stings — Testing for venom allergy is indicated in any patient with a history that is suggestive or convincing for a past systemic allergic reaction to a sting that involved organs other than the skin (ie, with or without cutaneous symptoms). This includes patients in whom the sting event and systemic reaction occurred decades earlier because the risk of another reaction can persist for many years [12-14].

Patients with cutaneous systemic reactions — In patients with isolated urticaria/angioedema, the chance of a future systemic reaction has been estimated at about 7 to 10 percent per sting, and most of these reactions will also be limited to the skin (ie, fewer than 3 percent will have severe anaphylaxis). Therefore, testing and immunotherapy are not indicated in most cases. Studies supporting a low risk of future severe systemic reactions are reviewed elsewhere. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Risk of recurrent reactions'.)

However, there may be individuals who find these reactions sufficiently distressing or have unavoidable exposure (eg, bee keepers, landscapers, outdoor enthusiasts) and are motivated to undergo venom immunotherapy to mitigate future similar reactions. In such cases, testing would be appropriate to determine which venoms to include in treatment.

Because of the low risk of future anaphylaxis, it is the author's and editors' approach not to prescribe epinephrine autoinjectors in this situation. However, some allergists do prescribe epinephrine for such patients. If this is done or if there are other quality of life issues affecting the patient/family (such as fear surrounding stings), the allergist should follow-up with the patient in one year to review any subsequent stings and determine if epinephrine is still needed.

Patients without a sting history — On occasion, an individual who has no history of an allergic reaction may present with concern about the possibility of developing a severe reaction to a sting, often because one or more family members has Hymenoptera venom allergy. Testing for venom-specific IgE is not indicated in this situation. Asymptomatic sensitization to honey bee and vespid venoms may be as high as 40 percent, and the meaning of a positive result without the history of a systemic reaction is unclear [15]. Epidemiologic studies have shown that most patients with venom anaphylaxis have no family history of venom allergy, although there are occasional families in which several members are affected [7]. The best approach to assisting such patients is to recommend against testing and instead explain that the patient's risk of ever experiencing a systemic reaction is approximately 0.4 to 0.8 percent in children and 3 percent in adults (as in the general population in the United States), and then address any specific issues that concern the patient [16]. Many people can be simply reassured that they are not at increased risk for a serious reaction, despite their family history. Others are reassured by the advice to carry an epinephrine autoinjector, accompanied by clear instructions on how and when to use it, although we discourage this approach for most patients because it sends a fundamentally mixed message. (See "Patient education: Using an epinephrine autoinjector (Beyond the Basics)" and "Patient education: Anaphylaxis symptoms and diagnosis (Beyond the Basics)".)

Patients with large local reactions — Testing is not indicated in most patients with large local reactions (LLRs). LLRs carry no more than a 5 to 10 percent risk of a future systemic reaction (with a <3 percent risk of severe anaphylaxis) [17,18], so venom testing and venom immunotherapy are generally not indicated. However, as in the case of cutaneous systemic reactions, there may be individuals with frequent, severe LLRs that compromise quality of life or ability to work. Such patients may be motivated to undergo venom immunotherapy, in which case testing is indicated to determine which venoms to include in treatment. LLRs are usually caused by an IgE-mediated late-phase response, and venom immunotherapy can successfully reduce future LLRs [19,20]. Studies of efficacy in this subset of patients are discussed in more detail separately. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with large local reactions'.)

COMPARISON OF TESTING METHODS — Testing for venom-specific immunoglobulin E (IgE) can be performed by skin testing or in vitro testing. Skin testing is preferred over in vitro methods for initial testing in most patients because skin testing is somewhat more sensitive and less expensive than in vitro tests in most health care systems. Skin testing is positive in 66 to 90 percent of patients with a history suggestive of venom allergy [3,11,21-24]. In addition, 15 to 20 percent of patients with positive skin tests will have negative in vitro testing. Therefore, if skin testing is positive and the results support the clinical history (ie, reliable identification of culprit insect), then in vitro testing is not needed. However, 5 to 10 percent of patients with negative skin tests may have positive in vitro results [21,25,26]. Thus, if skin testing is negative with a suggestive clinical history or skin testing cannot be performed, then in vitro testing is indicated.

In vitro testing is also helpful when the results of skin testing and the clinical history are not fully consistent or leave unanswered questions. An example would be the patient who developed anaphylaxis following a sting while eating outdoors but never visualized the insect, and skin testing shows sensitization only to honey bee. The clinician might be reasonably concerned that honey bee was not the true culprit insect, based on the tendency of yellow jackets to be more aggressive and attracted to human food. In this case, in vitro testing might be pursued in order to determine if the patient was sensitized to yellow jacket or other species, as well as to honey bee, before initiating venom immunotherapy. (See 'In vitro testing' below.)

The combination of skin testing and in vitro testing with the commercial assays in common use should detect approximately 95 percent of patients who will have a systemic reaction to a subsequent sting. The remaining patients pose a diagnostic dilemma that is discussed below. (See 'Systemic reactions with negative testing' below.)

SKIN TESTING — Skin testing should be performed by an allergist/immunologist or other clinician who has training and experience in the diagnosis and treatment of insect allergy, in a setting equipped to manage anaphylaxis, although this rarely occurs with skin testing. (See 'Technique' below and "Overview of skin testing for allergic disease", section on 'Safety'.)

Timing of testing — If the sting event was recent, we suggest waiting at least four to six weeks before performing skin testing, when possible. Many patients demonstrate reduced skin sensitivity to venom within the first few weeks after a systemic reaction [22]. Despite these issues, there are clinical scenarios in which it is advantageous to test immediately in order to initiate venom immunotherapy. However, if testing is performed during this period, a negative result (ie, lack of response) should be interpreted with great caution, and testing should be repeated at a later date.

Choice of venoms for testing — Testing should be performed with venoms from all potentially relevant insects from the geographic area in question.

Common species — Skin testing should include all of the venoms relevant to the patient's geographic area. In the United States, this would generally include all of the following venoms:

Honey bee

Yellow jacket

Yellow hornet

White-faced hornet

Wasp

Africanized honey bees are less common, but skin testing with domestic honey bee venom will detect sensitization to Africanized honey bee as well. Africanized honey bees were imported to South America from Africa and have continued to migrate north though the southern United States [27]. While domestic honey bees are generally not aggressive, Africanized honey bees are very aggressive and often attack and sting in large numbers [16].

Bumble bees — Allergic reactions to bumble bee field stings are rare compared with honey bees and other Hymenoptera because of their nonaggressive behavior. However, allergic reactions have been reported, particularly among greenhouse workers, as a result of occupational exposure [28,29]. In the absence of a specific history to suggest a bumble bee sting, patients with sting reactions do not need to be screened for this allergy. If a bumble bee allergy is suspected, specific bumble bee venom would be optimal for skin testing. This is available in some countries (not in the United States). However, there is a commercially available immunoglobulin E (IgE) immunoassay to bumble bee venom available in the United States and elsewhere. Bumble bee-allergic patients should also be tested for allergy to honey bee because there is some cross-reactivity between the two venoms, and some individuals may be sensitized to both. Once a bumble bee venom allergy is confirmed, bumble bee venom would be the best choice for immunotherapy if available (eg, in limited areas of Europe) because honey bee venom immunotherapy may not protect the patient against bumble bee stings. If the patient is sensitized only to bumble bee and bumble bee venom is not available, then the best management is avoidance and the availability of self-administered epinephrine.

Venomous ants — Clinicians practicing in areas inhabited by venomous ants should also be mindful of these insects as a possible cause of systemic reactions to stings. Patients can usually tell ant stings from other Hymenoptera stings, but the history is sometimes ambiguous (eg, a sting on a child's scalp may not be noticed until well after an event) [30]. If there is uncertainty, then the patient should be tested for ant venom allergy also. The geographic location of fire ants and testing for fire ant allergy are reviewed in detail separately. (See "Entomology and control of imported fire ants" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment".)

Technique — Skin testing with Hymenoptera venoms is most commonly performed using the intracutaneous (intradermal) technique, accompanied by appropriate positive and negative controls. Unlike skin testing for other types of allergies, prick (epicutaneous) testing is not necessarily done first, although this may be prudent in patients who experienced severe anaphylaxis and may be highly sensitive to venom. A concentration of 100 mcg/mL is used for prick testing.

Safety — Skin testing to venom allergens rarely results in systemic allergic reactions, and the amount of venom introduced into the skin is significantly less than that of a single sting. However, this adverse effect is possible with any type of skin testing, as discussed elsewhere. (See "Overview of skin testing for allergic disease".)

Traditional approach — The most widely practiced approach to intradermal venom testing is to begin with venom concentrations between 0.001 to 0.01 mcg/mL. Testing then proceeds at intervals of 20 to 30 minutes with incremental 10-fold increases in concentration until a positive skin test response occurs or a maximum concentration of 1 mcg/mL is reached. Concentrations higher than 1 mcg/mL should not be used, because they may result in irritant reactions [31]. This sequential approach is generally considered the safest and is recommended by practice parameters. It is also the preferred approach in research studies because changes in sensitivity can be assessed over time using an "endpoint dilution" technique. (See "Overview of skin testing for allergic disease", section on 'End-point dilution technique'.)

Simplified protocols — Simplified skin testing protocols that are quicker to perform have been developed and appear to be safe but have been tested in relatively limited numbers of patients (fewer than 1000) and have not been incorporated into practice parameters [32-34]. The author and editors of this topic review do not use these protocols routinely. However, they may be useful, particularly in patients with milder past systemic reactions. Additional reports in more patients will be helpful.

In one series of 478 consecutive patients with a history of sting anaphylaxis, testing was performed with intradermal injections of 0.02 mL of 0.001, 0.01, 0.1, and 1 mcg/mL of honey bee and wasp venom, administered simultaneously. Three presumed allergic reactions occurred, but two of these patients had positive reactions only to the 1 mcg/mL concentration and thus would have had all of the other skin tests placed anyway with the traditional approach [32]. A 2016 study retrospectively reviewed the records of 300 patients evaluated for venom allergy using a simplified protocol in a single practice [34]. All patients had been tested with an identical protocol using five commercial bee and vespid venoms, which consisted of a single intradermal dose of 0.02 mL of a 1 mcg/mL concentration of each venom. The patient population included individuals with all severities of sting reactions (24 percent had severe anaphylaxis), as well as those taking beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. All patients had at least one positive skin test. There were no immediate reactions to skin testing and just one delayed reaction (hours later) consisting of generalized urticaria.

Interpretation — Venom skin test results are either positive or negative. For patients with positive venom skin tests, neither the size of the wheal-and-flare reaction nor the concentration to which the patient reacts reliably predicts the severity of future systemic reactions [23,35].

Venom skin testing is positive in 66 to 90 percent of patients with a convincing clinical history of a systemic reaction [3,11,22-24]. Approximately 25 percent of patients are positive only to the 1 mcg/mL concentration [10,16]. If skin testing is positive and the results support the clinical history (ie, reliable identification of culprit insect), then in vitro testing is not needed. If skin testing is negative in a patient with a suggestive history, then in vitro testing should be performed. If in vitro testing is positive, then the diagnosis is confirmed. If in vitro testing is also negative, skin testing should be repeated after 6 to 12 weeks. (See 'Systemic reactions with negative testing' below.)

There is some variability in the precise definition of a positive intradermal test result, although any of these definitions is acceptable to confirm the presence of venom-specific IgE antibodies:

In North America, Europe, and many other countries, venom extract sufficient to produce a bleb of 3 mm is injected, which is usually a volume of 0.02 to 0.03 mL. A wheal 3 to 5 mm greater than the negative control, with appropriate erythema at a concentration ≤1 mcg/mL, is considered positive [36,37].

One manufacturer's package insert suggests the injection of 0.05 mL of venom and defines a positive reaction as 5 to 10 mm wheal and 11 to 20 mm erythema at 1 mcg/mL [38].

In the United Kingdom, 0.03 mL of venom extract is injected to raise a bleb of 3 to 5 mm. A wheal diameter of 3 mm greater than the negative control at 20 minutes is considered positive [39].

A general discussion of allergy skin testing, including medications which may interfere with interpretation of the results, is found separately. (See "Overview of skin testing for allergic disease".)

Discrepancies between history and testing — Patients may test positive to species to which they have no known exposure, which is attributed to various patterns of cross-sensitivity. Many patients show sensitivity to both yellow jackets and hornets, whereas cross-sensitivity between honey bee and other venoms is unusual [40-42]. However, positivity to both honey bee and yellow jacket venom is occasionally observed and is believed to be due to cross-reacting carbohydrate determinants, which are not believed to be clinically relevant. Despite this, the approach to treatment in the United States is to include all of the venoms to which the patient tested positive in immunotherapy to maximize the patient's chance of avoiding future systemic reactions. Practice varies around the world. Choice of venoms for use in immunotherapy is discussed in more detail separately. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Venom selection'.)

Data suggest that recombinant allergen-based IgE testing may have a potential role in distinguishing between honey bee and yellow jacket allergy [11]. (See 'Component-resolved diagnostics' below.)

False-positive and false-negative results — False-positive or false-negative results may arise from the following:

Nonspecific irritant responses may result in false-positive results with intradermal injection of venom at concentrations above 1 mcg/mL [31].

False-negative results may occur if a patient is tested too soon after a systemic reaction. (See 'Timing of testing' above.)

Patients with mastocytosis and other mast cell disorders may experience anaphylaxis in response to insect stings, as well as a variety of other triggers. These individuals usually have demonstrable venom-specific IgE, but some do not [43]. Those without apparent IgE may be reacting nonspecifically to vasoactive components in venom. Elevations in serum tryptase may be used to screen for systemic mastocytosis. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

IN VITRO TESTING — In vitro testing is somewhat less sensitive and usually more costly than skin testing, although there are several situations in which it is valuable.

Indications — In vitro testing for venom-specific immunoglobulin E (IgE) is indicated for purposes of diagnosis in the following circumstances [23,35,44]:

Patients with a convincing clinical history of systemic symptoms to a sting and negative skin testing.

Patients who cannot be skin tested, because they have dermatographism or severe or active skin diseases.

Patients who cannot be skin tested, because they are unable to discontinue medications that can render the skin unreactive (eg, high-dose tricyclic antidepressants). (See "Overview of skin testing for allergic disease", section on 'Medications that should be discontinued'.)

There is a need for evaluation in the initial weeks following a systemic event and concern about skin reactivity being suppressed. Some studies report that the serum immunoglobulin E (IgE) can be falsely-negative in the one to two weeks after a sting reaction, although the data about this are not consistent [15,22].

The results of skin testing are not fully consistent with the clinical history or leave unanswered questions.

IgE immunoassays — Many commercial laboratories perform venom-specific IgE testing, but the assays used are not necessarily equivalent, and the utility of different tests, even within one system, is variable [25]. ImmunoCAP is recognized as a reliable commercial assay. It retains reasonable accuracy in patients on anti-IgE therapy (ie, omalizumab) [45]. Other commercial assays may also perform well, although it is important to obtain information about the sensitivity and specificity of the assay used.

Interpretation — The results of venom-specific IgE immunoassays are interpreted simply as positive or negative. Any elevation is considered positive. The degree of positivity does not reliably predict the severity of a future systemic reaction, although it does correlate with the frequency in sting challenge studies [12,23,35].

Component-resolved diagnostics — Component-resolved diagnostics (CRD) for venom have been widely available in Europe for some time and were approved by US Food and Drug Administration for venom allergy diagnosis in April 2020.

The primary use for CRD will likely be in differentiating patients who are truly sensitized to both vespid (specifically yellow jacket; Ves v 2) and honey bee venoms (Api m 1, Api m 2, Api m 3, Api m 5, Api m 10) from patients who test positive to both because of cross-reacting carbohydrate determinants but are clinically reactive to just one [46-49]. This would allow clinicians to ensure that all venoms in a patient's immunotherapy are clinically relevant. Similar cross-sensitization between Ves v 5 and Pol d 5 in wasp venom has been observed, but only a Polistes allergen Pol d 5 component test has been approved in the United States, and clinical validation studies are needed.

Although CRD have not been shown to improve diagnostic sensitivity, there may be special circumstances in which this would be true, eg, patients with a history of venom-induced anaphylaxis but negative whole-venom testing [50,51].

CRD may also reveal sensitivity to novel allergens that are underrepresented in commercial venom preparations [52].

Investigational tests and sting challenges — If both skin testing and in vitro testing are negative and serum tryptase is normal and yet there is a convincing history of a systemic reaction, then investigational testing methods may be considered on an individual patient basis.

The Johns Hopkins University laboratory (Baltimore, Maryland) performs an investigational assay that is able to detect very low levels of venom IgE by using a high-density, particle-based methodology. This technique can identify up to 6 percent of cases not detected by the ImmunoCAP (when both assays are performed in parallel) and >10 percent of cases not detectable with other assays [21]. However, this may not be continued in the future, as commercial assays continue to improve.

Another research technique involves spiking routine assays with additional allergen to improve sensitivity [26].

Basophil activation tests, although not commonly used in the United States, are used in some European centers in the diagnosis of venom allergy, particularly when skin testing is negative [43,53-55]. Basophil activation tests may also identify patients with greater risk of severe reactions to stings or venom immunotherapy or higher risk after discontinuation of venom immunotherapy.

Sting challenges are rarely performed outside of research settings because they carry risk and are impractical in most settings. Some investigators have proposed that a sting challenge be used to diagnose venom allergy and to select patients for venom immunotherapy [1]. However, challenge results are not always reproducible or representative of the outcome of field stings [1,56].

SYSTEMIC REACTIONS WITH NEGATIVE TESTING — The combination of skin testing and in vitro testing should detect 95 percent of patients who will have a systemic reaction to a subsequent sting. Thus, a negative skin or serum test result for venom-specific immunoglobulin E (IgE) should be interpreted with caution, especially when done within the first few weeks following a sting reaction [23,35]. (See 'Timing of testing' above.)

Rare occurrences of anaphylaxis have been reported in individuals with both negative skin testing and negative venom-specific IgE [35]. The pathogenesis of these reactions may involve non-IgE mechanisms, such as mast cell disorders, although no specific evidence for this mechanism exists [44]. Such patients should have baseline serum tryptase levels to exclude the presence of occult mastocytosis [57,58]. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

If the patient has no clinical features or elevations in baseline tryptase to suggest mastocytosis, then we repeat skin testing and in vitro testing in three to six months. While the patient is waiting to be retested, he/she should carry one or more doses of epinephrine for autoinjection at all times and avoid contact with Hymenoptera. (See "Prescribing epinephrine for anaphylaxis self-treatment" and "Stinging insects: Avoidance".)

Occasionally, even upon repeat testing, a patient with a history of a severe sting reaction will not have demonstrable venom-specific IgE. Of those patients who have a history of a past systemic reaction and react again to a subsequent sting, 95 percent have demonstrable venom-specific IgE by skin tests or in vitro tests, and 5 percent do not. We counsel this remaining group of patients about Hymenoptera avoidance and instruct them in how and when to self-administer epinephrine. One study found that this group had a 6 percent chance of a systemic reaction in the future and that future reactions were not necessarily severe [23].

This 5 percent is probably made up of individuals with mast cell/basophil disorders, other disorders that predispose to anaphylaxis that have yet to be defined, and/or venom allergy that is not detectable using available assays. Patients with these characteristics also account for some portion of the 95 percent with detectable venom IgE, although there is no way to distinguish most of them at the outset.

SCREENING FOR OCCULT MASTOCYTOSIS — Anaphylaxis to insect stings is one of the most common presenting signs of indolent systemic mastocytosis [59-62]. We screen for mast cell disorders in any patient who experienced a moderate or severe systemic reaction to a sting, particularly if urticaria/angioedema were absent or there was significant hypotension [5,63]. Some experts favor testing baseline tryptase in all patients who require venom immunotherapy, and practice is evolving as more data become available.  

To screen for mast cell disorders, a baseline serum tryptase level should be obtained once the systemic reaction has fully subsided and the patient has returned to a baseline state. Further evaluation for systemic mastocytosis (ie, with additional laboratory studies and bone marrow biopsy) is indicated in patients with baseline serum tryptase >20 ng/mL and should be considered for levels >11.4 ng/mL if the patient has signs or symptoms suggestive of a mast cell disorder. The threshold baseline tryptase that is considered abnormal is evolving, and other experts may use slightly different values in this setting. There are data to suggest that baseline tryptase levels >8 ng/mL are associated with more severe insect sting anaphylaxis. Note that the most likely explanation for an elevated baseline tryptase is not systemic mastocytosis, but rather hereditary alpha tryptasemia (HaT), which is far more common than mastocytosis and occurs in approximately 5 percent of the general population [64] and in more than 15 percent of patients with mastocytosis, insect sting anaphylaxis, or idiopathic anaphylaxis [64,65]. HaT may also present with severe sting reactions, but data about this associations are still limited. Patients with HaT have baseline tryptase values >6 ng/mL. HaT is discussed in greater detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Hereditary alpha tryptasemia'.)

Consensus is lacking about how extensively patients should be screened for mast cell disorders beyond obtaining a baseline serum tryptase level. Some experts suggest that all patients who develop hypotensive syncope after a sting should be tested for the presence of the D816V mutation in the peripheral blood or even have a bone marrow biopsy, as individuals have been described who presented in this manner and were found to have occult mast cell disorders despite normal serum tryptase and no cutaneous findings suggestive of mastocytosis [66-69]. In the largest prospective series, 374 adults with Hymenoptera allergy and no obvious signs of mastocytosis were screened for the KIT D816V mutation in peripheral blood [64]. The presence of the mutation was highly correlated with severe venom anaphylaxis. Among patients with normal baseline tryptase, the frequency of KIT D816V was 18.2 percent in the subgroup with the most severe anaphylaxis, compared with 1.8 percent of patients with lower grade reactions. Thus, testing of peripheral blood for KIT D816V can detect occult mastocytosis in patients with venom anaphylaxis, even when baseline tryptase is normal. The diagnosis of mastocytosis is discussed in more detail separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

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 5th to 6th 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 10th to 12th 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 topics (see "Patient education: Insect allergy (The Basics)" and "Patient education: Allergy shots (The Basics)")

Beyond the Basics topics (see "Patient education: Bee and insect stings (Beyond the Basics)" and "Patient education: Anaphylaxis treatment and prevention of recurrences (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The initial step in diagnosis of Hymenoptera venom allergy is to determine whether the patient's past sting reaction was local or systemic, based upon the clinical history. (See 'Types of reactions' above and 'History' above.)

The diagnosis of Hymenoptera allergy requires both a history of a sting event that resulted in a systemic reaction and evidence of venom-specific immunoglobulin E (IgE), either by skin testing or in vitro testing. (See 'Diagnosis of venom allergy' above.)

Testing is most clearly indicated in patients with suspected or known systemic allergic reactions to stings, for the purpose of confirming venom allergy and determining which venoms should be used in immunotherapy. Testing is occasionally indicated in patients with other types of reactions. (See 'Indications for testing' above.)

In most cases, skin testing is the preferred initial method for demonstrating venom-specific IgE because it is more sensitive. Venom skin testing is positive in 70 to 90 percent of patients with a history suggestive of venom allergy. (See 'Skin testing' above.)

Skin testing should be performed using the venoms of all the Hymenoptera insects known to reside in the patient's geographic area. (See 'Choice of venoms for testing' above.)

If skin testing is negative, venom-specific IgE immunoassays should be obtained. The combination of skin testing and in vitro testing can detect about 95 percent of patients who will suffer another systemic reaction if stung again. (See 'In vitro testing' above.)

All patients who experienced a moderate or severe systemic reaction to a Hymenoptera sting should be screened with a baseline serum tryptase to detect hereditary alpha tryptasemia and occult mast cell disorders. Any elevation in serum tryptase should be evaluated further. Some experts recommend screening any patient for whom venom immunotherapy is recommended, and practice in this area is evolving as data become available. Additionally, patients with severe anaphylaxis but normal baseline tryptase can still have occult mast cell disease, and screening of peripheral blood for the KIT D816V mutation is prudent if available. (See 'Screening for occult mastocytosis' above.)  

If both skin testing and venom-specific IgE are negative and serum tryptase is normal and yet there is a convincing history of a systemic reaction, then the patient should be retested for venom-specific IgE in three to six months. In addition, the patient should be educated about appropriate sting avoidance and treatment of reactions. (See 'Systemic reactions with negative testing' above.)

DISCLOSURE — None of the people involved in the writing, editing, or review of this topic have any financial interest in the diagnostic tests discussed.

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Topic 4095 Version 27.0

References

1 : Lack of reproducibility of a single negative sting challenge response in the assessment of anaphylactic risk in patients with suspected yellow jacket hypersensitivity.

2 : Stinging insect hypersensitivity: A practice parameter update 2016.

3 : A controlled trial of immunotherapy in insect hypersensitivity.

4 : Physiologic manifestations of human anaphylaxis.

5 : Over- and underestimated parameters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medication and absence of urticaria/angioedema.

6 : Clinical practice. Hypersensitivity to hymenoptera stings.

7 : Epidemiology of insect venom sensitivity.

8 : Asymptomatic sensitization to hymenoptera venom is related to total immunoglobulin E levels.

9 : Prevalence of hymenoptera venom allergy and poor adherence to immunotherapy in Austria.

10 : Diagnosis of Hymenoptera venom allergy.

11 : Natural history of Hymenoptera venom sensitivity in adults.

12 : Clinical and entomological factors influence the outcome of sting challenge studies.

13 : Unusual reactions following insect stings. Clinical features and immunologic analysis.

14 : Unusual reactions to insect stings.

15 : Sensitization to Hymenoptera venoms is common, but systemic sting reactions are rare.

16 : Stinging insect hypersensitivity: a practice parameter update 2011.

17 : A prospective study of the natural history of large local reactions after Hymenoptera stings in children.

18 : Natural history of large local reactions from stinging insects.

19 : Venom immunotherapy reduces large local reactions to insect stings.

20 : Rush immunotherapy for the prevention of large local reactions secondary to imported fire ant stings

21 : Diagnostic methods for insect sting allergy.

22 : Timing of venom skin tests and IgE determinations after insect sting anaphylaxis.

23 : Insect sting allergy with negative venom skin test responses.

24 : Evaluation of Hymenoptera-sting sensitivity with deliberate sting challenges: inadequacy of present diagnostic methods.

25 : Responsibility for quality IgE antibody results rests ultimately with the referring physician.

26 : Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom.

27 : Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom.

28 : Occupational allergy to bumblebees: allergens of Bombus terrestris.

29 : Allergy to bumblebees.

30 : Allergy to bumblebees.

31 : Venom skin tests in insect-allergic and insect-nonallergic populations.

32 : Simultaneous intradermal testing with hymenoptera venoms is safe and more efficient than sequential testing.

33 : Safety and efficiency of an accelerated method for venom skin testing.

34 : Venom allergy testing: is a graded approach necessary?

35 : Insect sting allergy: the dilemma of the negative skin test reactor.

36 : Skin testing: a survey of allergists.

37 : Allergy diagnostic testing: an updated practice parameter.

38 : Allergy diagnostic testing: an updated practice parameter.

39 : Diagnosis and management of hymenoptera venom allergy: British Society for Allergy and Clinical Immunology (BSACI) guidelines.

40 : Allergens in Hymenoptera venom. XXV: The amino acid sequences of antigen 5 molecules and the structural basis of antigenic cross-reactivity.

41 : Antigenic cross-reactivity of venom proteins from hornets, wasps, and yellow jackets.

42 : Comparison of the allergenicity and antigenicity of yellow jacket and hornet venoms.

43 : Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy.

44 : Negative venom skin test results in patients with histories of systemic reaction to a sting.

45 : Accuracy of US Food and Drug Administration-cleared IgE antibody assays in the presence of anti-IgE (omalizumab).

46 : Component resolved diagnostics for hymenoptera venom allergy.

47 : Double positivity to bee and wasp venom: improved diagnostic procedure by recombinant allergen-based IgE testing and basophil activation test including data about cross-reactive carbohydrate determinants.

48 : High sensitivity of CAP-FEIA rVes v 5 and rVes v 1 for diagnosis of Vespula venom allergy.

49 : Low sensitivity of commercially available rApi m 1 for diagnosis of honeybee venom allergy.

50 : Identification of Hymenoptera venom-allergic patients with negative specific IgE to venom extract by using recombinant allergens.

51 : Recombinant allergens rarely allow identification of Hymenoptera venom-allergic patients with negative specific IgE to whole venom preparations.

52 : Component resolution reveals additional major allergens in patients with honeybee venom allergy.

53 : Importance of basophil activation testing in insect venom allergy.

54 : Basophil responsiveness in patients with insect sting allergies and negative venom-specific immunoglobulin E and skin prick test results.

55 : Diagnostic value of the basophil activation test in evaluating Hymenoptera venom sensitization.

56 : Insect-sting challenge in 324 subjects with a previous anaphylactic reaction: current criteria for insect-venom hypersensitivity do not predict the occurrence and the severity of anaphylaxis.

57 : Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.

58 : Elevated baseline serum tryptase, mastocytosis and anaphylaxis.

59 : Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis.

60 : Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients.

61 : Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity.

62 : Mastocytosis and insect venom allergy.

63 : Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels.

64 : Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone.

65 : Heritable risk for severe anaphylaxis associated with increasedα-tryptase-encoding germline copy number at TPSAB1.

66 : Prospective evaluation of the diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis.

67 : Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels.

68 : Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both?

69 : Hymenoptera venom immunotherapy while maintaining cardiovascular medication: safe and effective.