Summary

Hymenoptera of the Vespula genus are social wasps native to the Northern hemisphere, secondarily established in Australia, New Zealand, and South Africa.

Hymenoptera stings cause 48% of severe anaphylactic reactions occurring in European adults, and 20% of those occurring in children. In the United States, the prevalence of Hymenoptera-induced anaphylaxis is estimated at 3% in adults and 1% in children, with 40 to 100 Hymenoptera sting-induced fatalities being documented annually. Anaphylaxis is more common in adults than in children. Systemic reactions usually occur within minutes of being stung. The risk of repeated anaphylaxis is 30% to 70%. An estimated 9 to 42% of the general population is sensitized to Hymenoptera venom. Beekeepers, greenhouse workers, and rural populations are at higher risk of developing bee sting allergy. Mast cell disorders including hereditary α-tryptasemia, elevated baseline serum tryptase, or a family history of honeybee allergy are associated with an increased risk of occurrence and severity of Hymenoptera sting-induced reactions. A history of Hymenoptera-induced anaphylaxis is a red flag for an underlying clonal mast cell disorder.

Six molecular allergens have been characterized so far in the Vespula spp venom, of which two, Ves v 1 and Ves v 5, are available for in vitro diagnosis. Ves v 1 and Ves v 5 are marker allergens for genuine sensitization to Vespid venom.

Epidemiology

Worldwide distribution

Hymenoptera stings cause 48% of severe anaphylactic reactions occurring in European adults, and 20% of those occurring in children.

It is estimated that the worldwide annual incidence of immunologic reactions to Hymenoptera stings ranges from 0.3–3.0% which equates to almost 100 million cases per year. Severity ranges from local wheal-and-flare reactions to death from anaphylactic shock.

In the US, Hymenoptera-induced systemic reactions are estimated to occur in 3% of adults and 1% of children, and approximately 40 to 100 fatalities are reported each year, although the figure is likely to be higher. An Australian study reported honeybee to be the main cause of fatal insect venom anaphylaxis, however, there is a relatively high prevalence of honeybee allergy in Australia, and UK and European studies found that wasp was the most common cause of fatal and nonfatal venom anaphylaxis, respectively. A consistent finding across studies in Australia, Canada, UK and US was that fatal insect venom anaphylaxis occurs at an approximate rate of 0.1 cases per million population. In Europe, the prevalence of systemic reactions to Hymenoptera stings is 0.3% to 7.5%.[JV1]

Risk factors

Identifying patients at risk for severe reactions to Hymenoptera venom requires a careful record of clinical history and a stepwise procedure in the use of diagnostic tests. The severity of past reactions to Hymenoptera stings is the best predictor of the severity of recurrent reactions, while the most significant risk factor for severe reactions is an underlying mast cell disorder.

The prevalence and severity of Hymenoptera venom reactions are increased in patients with mast cell disorders including hereditary α-tryptasemia, with or without an elevated baseline serum tryptase concentration. Hymenoptera venom allergy was observed in 50% of patients with systemic mastocytosis without hereditary α-tryptasemia and in 82% of those with concurrent hereditary α-tryptasemia.

Cardiovascular risk factors, male gender and older age have also been associated with an increased risk of severe reactions to Hymenoptera venom. On the other hand, sensitization to Hymenoptera venom is frequent, estimated at 9.2% to 42% of the adult population, and comprises a majority of asymptomatic individuals.

Pediatric issues

The prevalence of systemic reactions to Hymenoptera venoms is estimated at 3.4% in children. In children younger than 16 years experiencing a cutaneous reaction to Hymenoptera venom, the chance of anaphylaxis if re-stung is lower than 3%.

Route Of Exposure

Main

Exposure to Vespula spp venom occurs through a sting when the insect’s stinger becomes embedded in the flesh and the venom is injected from the venom sac. Wasps, hornets and yellow jackets are able to stings several times without dying, as they can extract their stinger from the victim.

Clinical Relevance

Five types of reactions to Hymenoptera stings are recognized: normal local reactions, large local reactions (LLR), systemic anaphylactic reactions, systemic toxic reactions, and unusual reactions. Of these, LLRs and systemic anaphylactic reactions are the most common.

Anaphylaxis

Systemic reactions limited to cutaneous signs only carry a risk of anaphylaxis to a future sting below 3%. Conversely, a history of systemic sting-induced reaction and detectable venom IgE put the risk of a second systemic reaction at 60%. The patient’s prior sting history – the severity and pattern of reactions, baseline tryptase level, age and concurrent medications all influence future risk. Hymenoptera sting-induced anaphylaxis must prompt investigations for an underlying mast cell disorder including hereditary α-tryptasemia.

Local reactions

In the general population, the reported prevalence of LLR ranges between 2.4% and 26.4%. If local inflammation is contiguous with the sting site, it may be considered and managed as a local reaction. LLR are not dangerous unless they cause compression, and compartment syndrome develops, or if a patient is stung in the oropharynx, when airway obstruction becomes a risk, or in the context of an underlying condition

LLR patients exhibit a 10% risk of systemic reactions and a 3% risk of severe anaphylaxis if re-stung.

Other topics

Diagnostics

A convincing clinical history and proven Vespula venom sensitization are required for the diagnosis of Vespula venom allergy. As venom sensitization is identified in approximately 10–30% of history-negative persons, only those with a history of a previous systemic reaction are usually eligible for diagnostic testing.

In vitro tests to whole venom extracts are negative in approximately 20% of patients with positive skin tests, and positive in an estimated 10% of patients with negative skin tests, therefore the European guidelines recommend sequential skin and venom specific IgE testing as a standard protocol in all patients with a history of systemic reactions, ensuring a high diagnostic sensitivity of 94%. Recent data confirmed that in vitro and skin tests with Vespid venom extracts yielded complementary rather than overlapping results, and suggested that in vitro diagnosis might suffice, or might be performed as the first-line test.

As Hymenoptera venom IgE persist for extended periods, in vitro and skin testing can be done even a long time after the reported clinical reaction, however, it is recommended to observe a 2-week interval after the reaction before performing skin tests. If, based on clinical history, the index of suspicion for anaphylactic reaction is high, but in vitro and skin tests are negative, testing should be repeated after one to six months.

In vitro diagnostics

In vitro testing is devoid of clinical risk of adverse reactions to applied venom and is less labor-intensive than skin testing.

In a prospective diagnostic study, the positive predictive value of ImmunoCAP in vitro testing of Hymenoptera extracts was 77% and the negative predictive value 59%, while intradermal skin tests yielded 87% and 55% respectively. The diagnostic sensitivity of the whole allergen extract of Vespula spp venom is 83-91%, with improved performance since its spiking with Ves v 5

Besides allergen-extract specific IgE, in vitro investigation of Hymenoptera sting-induced reactions comprises allergen component IgE and CCD IgE determination to assess genuine versus cross-reactive sensitization, as double positivity to bee and wasp venom extracts during in vitro testing occurs in up to 50% of venom-allergic patients.

A combination of the Vespula spp recombinant allergen components rVes v 1 and rVes v 5 has been reported to yield a sensitivity as high as 92–98% for the identification of genuine sensitization to Vespula spp venom. Conversely, a patient who tests negative for specific IgE to both rVes v 1 and rVes v 5 is unlikely to have genuine wasp venom sensitization, regardless of IgE to other wasp components.

Total IgE could be useful, particularly in cases with low levels of specific IgE, for calculating the specific-to-total IgE ratio, a proposed indicator for clinically relevant sensitization.

Diagnostic investigation of Hymenoptera sting-induced systemic reactions also requires determination of baseline tryptase in search for a mast cell disorder, with levels at 8 µg/L or higher suggesting hereditary α-tryptasemia. Further investigations such as testing for the D816V c-kit mutation in peripheral blood may be considered.

In the approximately 5% of Hymenoptera venom-allergic patients with elevated baseline tryptase levels and/or mastocytosis, diagnostic sensitivity is enhanced by using molecular components and a cut-off level of 0.1 kUA/L for specific IgE positivity.

Skin tests

Skin tests with Vespid venom extracts can be performed as skin prick tests or intradermal tests. Their diagnostic sensitivity is estimated at 64%.

The skin test reaction to venom extracts is not correlated to the severity of past or recurrent reactions to a future sting. The sensitivity of the skin prick test is lower than that of the intradermal test, which is used to confirm a negative result. Diagnostic intradermal testing is usually carried out using venom extracts of concentrations of between 0.001 µg/mL and 1.0 µg/mL. The accuracy of the test is subject to proportionate representation of the relevant allergens in the extract, as false-negatives may be the result of underrepresented components and, conversely, irritant compounds may lead to false-positives.

Challenge tests

Live sting challenges are not a standard procedure in clinical practice.

Other topics

Prevention And Therapy

Allergen immunotherapy

Venom immunotherapy (VIT) is the only treatment that can prevent future sting-induced anaphylaxis in Hymenoptera venom-allergic patients, effectively inducing tolerance in 91–99% of Vespid venom allergic patients. During successful Vespid VIT, venom-specific IgE decrease while venom-specific IgG and IgG4 increase.

VIT is most successful when the treatment is selected based on specific IgE to venom allergens, i.e., bee and/or wasp molecular allergens. Candidates for VIT must have a documented history of a systemic reaction to a sting and evidence of IgE reactivity to a specific venom. Treatment with the incorrect venom, or with more than one venom without evidence of sensitization, can induce de novo sensitization, increase the likelihood of adverse effects, risk insufficient protection, and increase costs.

The usual duration of VIT is 3 to 5 years, although more prolonged or even lifelong VIT should be considered in patients with mast cell disorders, due to an increased risk of severe reactions and a lower efficacy of VIT in these patients.

An elevated baseline serum tryptase in a venom-allergic patient, even without a formal diagnosis of systemic mastocytosis, may be associated with severe anaphylactic reactions and may indicate the need for lifelong VIT.

Prevention strategies

Sting avoidance is difficult to achieve as it requires caution during outdoor activities.

Other topics

An emergency kit comprising autoinjectable epinephrin should be carried by Hymenoptera venom-allergic patients having experienced systemic reactions, including those having completed a successful VIT.

Cross-Reactivity

Sensitization to Vespula spp venom is frequently associated to sensitization to other venoms, such as honeybee venom, Polistes spp venom, hornet venoms, or others. Double sensitization, whether resulting from genuine double sensitization or cross-reactivity, may be clinically relevant and put the patients at risk of severe reactions to stings from various Hymenoptera species, especially in subjects with underlying mast cell disorders.

In vitro diagnosis with marker molecular allergens allows the identification of the genuine sensitizers in cases of Vespid/honeybee venom double positivity, however, there is no currently available diagnostic marker to distinguish between Vespula spp and Polistes spp sensitization, nor between Vespula spp and hornet sensitization. Double positivity to bee and wasp venom during in vitro testing, seen in 40% to 50% of venom-allergic patients, is solved by the use of marker allergens (Ves v 1 and Ves v 5 or Pol d 5 for Vespids, and Api m 1, Api m 3, Api m 4 and Api m 10 for honeybee venom) and CCD, allowing distinction between genuine bee-wasp cosensitization and sensitization to only bee or wasp with cross-reactivity through shared allergens or CCD.