Summary

Vespa velutina, a member of the Hymenoptera order, is a species of social hornets native to South Asia. The variant Vespa velutina nigrithorax has become secondarily established in the USA and in some European and African countries. Vespa velutina venom contains a greater proportion of toxins than venoms from other Hymenoptera species. Its sting can cause severe allergic and/or toxic (envenomation) reactions.

Hymenoptera stings cause 48% of severe anaphylactic reactions occurring in European adults, and 20% of those occurring in children. 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%. Beekeepers, greenhouse workers, and rural populations are at higher risk of developing Hymenoptera sting allergy and experiencing severe reactions. Mast cell disorders including hereditary α-tryptasemia, elevated baseline serum tryptase, or a family history of Hymenoptera venom 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.

Two molecular allergens have been characterized and so far in the Vespa velutina venom, phospholipase A1 Vesp v 1 and antigen 5 Vesp v 5 but are not yet available for in vitro diagnosis.

Venom immunotherapy for Vespa velutina anaphylaxis can be performed with therapeutic Vespula spp venom extracts.

Allergen

Nature

Vespa (V.) velutina venom consists of a complex mixture of allergenic and non-allergenic molecules contained in the venom sac at the distal extremity of the insect’s abdomen. Similar to most Hymenoptera, V. velutina can extract their stinger from the victim and are thus able to sting multiple times during their lifetime.

Taxonomy

Table 1: Taxonomy of Vespa velutina.

The order of Hymenoptera comprises the families Vespids (wasps and hornets), Apids (bees and bumblebees) and Formicids (stinging ants). The two Vespid subfamilies are Vespinae, with genera Vespula, Dolichovespula, and Vespa, and Polistinae, with Polistes and Polybia [1].

Tissue

Hymenoptera venoms contain three major biochemical groups: proteins such as allergens and enzymes; small peptides with neuroactive and antimicrobial activities; and substances of low molecular weight including bioactive amines [1]. Venom components can act as allergens and/or toxins [2]. V. velutina venom contains a larger proportion of toxins compared to other Hymenoptera venoms [3]

Epidemiology

Worldwide distribution

V. velutina is considered one of the most aggressive Vespids, with dozens of annual deaths reported in China and South Korea when taking into account both the toxic and allergic mechanisms [4]. Multiple stings from large numbers of individuals are frequently observed and contribute to the clinical severity [2].

Hymenoptera stings cause 48% of severe anaphylactic reactions occurring in European adults, and 20% of those occurring in children [1].

Self-reported systemic hypersensitivity to Hymenoptera stings is recorded in up to 7.5% of European adults, and in up to 3.4% in children [5]. In the US, Hymenoptera-induced systemic reactions are estimated to occur in 3% of adults and 1% of children [6]. The annual rate of fatalities due to Hymenoptera stings ranges from 0.003 to 0.48 per million inhabitants, a consistent finding across studies in Australia, Europe,  UK, Canada, and the US, possibly underestimated [5, 7].

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  [1, 8]. 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 [8].  

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  [9-12]. 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 [10].

Cardiovascular risk factors, male gender and older age have also been associated with an increased risk of severe reactions to Hymenoptera venom [13].

Pediatric issues

In children younger than 16 years experiencing a cutaneous reaction to Hymenoptera venom, the chance of anaphylaxis if re-stung is lower than 3% [6].

Environmental characteristics

Living environment

V. velutina presents with typical yellow distal segments of their legs [4]. During the warm season, V. velutina colonies use a primary nest for the first several weeks, then move to a larger secondary nest, often located on tops of trees and able to accommodate thousands of individuals [4]. V. velutina preys on pollinators, particularly honeybees, but also on a variety of other insects [14].

Worldwide distribution

V. velutina with up to 13 variants or subspecies is native to South Asia. It was reportedly introduced in the US during the 19^th century, in South Korea in 2003, in France in 2004 with further spread to continental Europe and the UK, and in Japan in 2012, with additional reports from Yemen [2, 14, 15].

Route of exposure

Exposure to V. velutina venom occurs through a sting when the insect’s stinger becomes embedded in the flesh and the venom is injected from the venom sac. Vespids are able to stings several times without dying, as they can extract their stinger from the victim [1].

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. While LLRs and systemic hypersensitivity reactions are the most common manifestations of allergy to Hymenoptera stings, V. velutina stings also carry an important risk of toxic reactions [2, 5].

Anaphylaxis

V. velutina has a proven potential as a major cause of Hymenoptera venom-induced anaphylaxis, even in regions where it was introduced recently. As an example, V. velutina-induced anaphylaxis accounted for 77 of 100 consecutive Spanish patients attending an allergy practice between December 2017 and June 2019 after an initial episode of Hymenoptera sting-induced anaphylaxis [16]. In most patients, V. velutina-induced anaphylaxis occurred without a prior history of sting by this hornet. Instead, previously diagnosed allergy to Vespula spp venom was frequent [16].

Hymenoptera sting-induced anaphylaxis must prompt investigations for an underlying mast cell disorder including hereditary α-tryptasemia [9-12, 17].

Local reactions

In the general population, the reported prevalence of LLR following a Hymenoptera sting ranges between 2.4% and 26.4%. 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 [18], or in the context of an underlying condition [5].

LLR patients exhibit a 10% risk of systemic reactions and a 3% risk of severe anaphylaxis if re-stung  [18, 19].

Diagnostic relevance

A convincing clinical history and proven V. velutina venom sensitization are required for the diagnosis of V. velutina venom allergy [1, 2, 8]. Generally, Hymenoptera venom sensitization is identified in approximately 10–30% of history-negative persons. Hence, only those with a history of a previous systemic reaction are usually eligible for diagnostic testing [1, 8].

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 [1, 20]. 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 [6, 8].

In most patients having experienced anaphylaxis after being stung by V. velutina, sensitization had occurred through previous exposure to other Hymenoptera venoms, such as Vespula spp or honeybee [2].

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 [21].

In vitro determination of serum IgE to whole V. velutina venom extracts were positive in 70% -100% of patients having experienced a first episode of anaphylaxis after being stung by this species [2, 16, 22].

Basophil activation test with V. velutina venom can be performed with extract or molecular allergens [2, 22].  

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 [1, 12]. Further investigations such as testing for the D816V c-kit mutation in peripheral blood may be considered [11].

Challenge tests

Live sting challenges are not a standard procedure in clinical practice [5]. Field sting history may be used as an indication of challenge tests during venom immunotherapy (VIT) [23].

Prevention and therapy

Allergen immunotherapy

VIT to V. velutina can be carried out with therapeutic Vespula spp extracts, since therapeutic V. velutina extracts are currently not available, and clinical and serological markers, including IgE and IgG4 to V. velutina extract, were improved after the first year of this therapeutic approach [2, 23].

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 [1]. During successful Vespid VIT, venom-specific IgE decrease while venom-specific IgG and IgG4 increase [21].

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 [1, 5].

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 [24] and may indicate the need for lifelong VIT [25].

Prevention strategies

Sting avoidance may be improved through caution during outdoor activities and removal of V. velutina nests during winter [1, 2]. A decrease in the prevalence of V. velutina field sting-induced anaphylaxis was reported following VIT initiation [23].

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 [1].

Molecular aspects

Allergenic molecules

Two venom allergens from V. velutina have been characterized and registered in the IUIS/WHO Allergen Nomenclature [26].  Vesp v 5, a member of the venom antigen 5 family, is the dominant allergen in V. velutina venom, binding IgE from up to 100% of sera from patients who have experienced anaphylaxis to V. velutina venom [2, 16, 22, 26]. Vesp v 1, a member of the Vespid phosholipase A1 (PLA1) family, is reported as a minor allergen, binding IgE from approximately 30% of sera from patients with V. velutina-induced anaphylaxis [2, 16, 22, 26]. Other V. velutina venom allergens have been reported, such as two hyaluronidase isoforms and a dipeptidyl peptidase IV [27, 28]. V. velutina allergens display substantial similarity to their homologs from other Vespid venoms, particularly Vespula spp [2, 27]. As opposed to most allergenic PLA1 described so far, Vesp v 1 is glycosylated, implying that IgE to cross-reactive carbohydrates (CCD) should also be assayed during in vitro diagnosis of V. velutina sensitization [2, 27]. The biochemical properties, molecular mass, and sensitization prevalence for V. velutina allergens are summarized below.

Table 2: Biochemical properties, molecular mass, and sensitization rate for Vespula velutina allergens [1, 16, 22, 26-28].

 Cross-reactivity

Sensitization to V. velutina venom is frequently associated to sensitization to other Hymenoptera venoms, mostly Vespids, and among these, Vespula spp [2, 16, 22]. Such autochthonous Hymenoptera might be the primary sensitizers in areas recently colonized by V. velutina [16]. As a general rule, double sensitization to Hymenoptera venoms, 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 [1, 8, 29].

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 Vespa spp and Vespula spp sensitization [1]. 

Explained results

Allergen Information

V. velutina venom contains a complex mixture of biologically active molecules, including two characterized allergens Vesp v 5 (predominant) and Vesp v 1, none of them currently available for in vitro diagnosis, and venom toxins which are proportionally more abundant than in other Hymenoptera venoms.

Clinical information

V. velutina stings may be life-threatening due to either toxic (envenomation) or allergic (anaphylactic) mechanisms, which require clinical and in vitro investigation including assessment of concurrent mast cell disorders and hereditary α-tryptasemia. VIT is currently performed with Vespula spp therapeutic extracts.

Cross-reactivity

Double sensitization to V. velutina and other Hymenoptera, especially Vespula spp, venom extracts is frequent. Currently available venom molecular allergens do not allow the differential diagnosis of V. velutina versus other Vespid sensitization.

Author: Dr. Joana Vitte

Reviewed: Dr. Michael Spangfort