i77 European paper wasp

Summary

Polistes (P.) dominula, also called “European paper wasp”, is a social wasp of clinical relevance for Southern Europe and the Mediterranean areas. This species has recently spread from its native Eurasia to all continents except Antarctica.

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 in the United States. The risk of repeated anaphylaxis is 30% to 70%. An estimated 9 to 42% of the general population is sensitized to Hymenoptera venom.

Hunters, greenhouse workers, and rural populations are at higher risk of developing Hymenoptera venom allergy (HVA). Mast cell disorders including hereditary α-tryptasemia and elevated baseline serum tryptase 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.

Five molecular allergens belonging to the molecular families of phospholipase A1 (PLA1), hyaluronidase, dipeptidyl peptidase IV, antigen 5, and serine protease have been characterized so far from P. dominula venom (PDV). Pol d 5 is the only one widely currently available for routine in vitro diagnosis. PDV, like venom from other Polistes spp, is devoid of cross-reacting carbohydrate determinants (CCD).

Allergen          

Nature

PDV 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 [1]. Similar to most Hymenoptera, P. dominula can extract its stinger from the victim and is thus able to sting multiple times during its lifetime.

Taxonomy

Domain:   Eukaryota

Kingdom:  Metazoa (Animalia)

Phylum     Arthropoda

Subphylum: Hexapoda

Class:        Insecta

Order:       Hymenoptera

Suborder: Apocrita

Family:      Polistinae

Genus:      Polistes

Species:    P. dominula

The order 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

Vespid venoms contain three major constituents: proteins, including allergens; small peptides, e.g. neurotoxic and antimicrobial peptides; and substances of low molecular weight such as bioactive amines [2]. PDV contains multiple allergens, with five currently included in the IUIS/WHO Allergen Nomenclature [3]. Of these, phospholipase A₁ (PLA1) Pol d 1 and CAP (cystein-rich, antigen 5 and pathogenesis-related proteins) member Pol d 5 represent a significant portion of dry PDV weight [1].

Epidemiology

Worldwide distribution

In Southern Europe, PDV allergy is frequent, either as monosensitization or in association with Vespula (yellow jacket) venom (YJV). Its prevalence could be underestimated in other regions, where PDV is not included in Vespid allergy investigation [4]. Primary PDV sensitization was demonstrated in 34-56% of the double PDV/YJV sensitized patients in Southern Europe [4-8].

Double sensitization, whether resulting from genuine double sensitization or cross-reactivity, may be clinically relevant and puts the patients, especially those with underlying mast cell disorders, at risk of severe reactions to stings from various Hymenoptera species [1, 9].

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

It is estimated that the worldwide annual incidence of immunologic reactions to Hymenoptera stings, ranging from local wheal-and-flare reactions to fatal anaphylaxis, is comprised between 0.3 and 3.0%, which equates to almost 100 million cases per year [10]. An estimation for the USA suggests that Hymenoptera-induced systemic reactions occur in 3% of adults and 1% of children, leading to approximately 40 to 100 fatalities each year, a figure likely to be higher [11]. Among people being stung by a Hymenoptera, it is estimated that 0.5 to 3.3% in the USA and 0.3 to 7.5% in Europe will develop a systemic reaction [12, 13].

Fatal insect venom anaphylaxis occurs at an approximate rate of 0.1 cases per million population, a consistent finding across studies in Australia, Canada, the UK and the USA [14].

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, 9, 13]. 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 [5, 9]. 

The prevalence and severity of Hymenoptera (including Polistes) venom reactions are increased in patients with mast cell disorders including hereditary α-tryptasemia, with or without an elevated baseline serum tryptase concentration  [12, 15]. In a European study, HVA was reported in 50% of patients with systemic mastocytosis without hereditary α-tryptasemia and in 82% of those with concurrent hereditary α-tryptasemia [15]. In a 1-year US survey for 2018 using a health database, mastocytosis was 9.7 times more prevalent among HVA patients (odds-ratio 2.4 in children and 14.3 in adults) than in general population [12].

Cardiovascular risk factors, male gender and older age have also been associated with an increased risk of severe reactions to Hymenoptera venom [16]. Lifestyle, including outdoor leisure activities or occupational exposure, may result in an increased prevalence of Hymenoptera stings, sensitization and systemic reactions [1]. 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 [1].

Pediatric issues

The prevalence of systemic reactions to Hymenoptera venoms is estimated at 3.4% in children [13]. In children younger than 16 years experiencing a cutaneous reaction to Hymenoptera venom, the chance of anaphylaxis if re-stung is lower than 3% [11].

Environmental characteristics                        

Living environment

The nests of Polistes species consist of paper-like or wood pulp material with simple, single-layer paper cones, a maximum of about 100 cells, and no protective outer covering. They are usually found in hidden locations, such as sheltered and little-used parts of buildings, but also food factories and food shops placing humans in inadvertent danger of stings [11, 17]. Vespids are unlikely to be aggressive, except in defense of their nests [11, 17].

Worldwide distribution

European and American species of Polistes belong to different subgenera and are phylogenetically distant. P. dominula and other European species belong to the subgenus Polistes sensu stricto, native to Southern Europe, the Middle East, Central and Eastern Asia [18]. P. dominula has spread in recent decades to Central and Northern Europe, North America, South Africa and Australia [2, 18]. P. gallicus, P. biglumis and, to a lesser extent, P. nimpha are other Polistes species widely spread in Europe [18].

Route of Exposure

Exposure to PDV occurs through a sting when the stinger of the insect becomes embedded in the flesh and the venom is injected from the venom sac. P. dominula, like the other Vespids, is able to sting multiple times without dying, since it can extract its stinger from the victim [1].

During a sting, Polistes inject 4.2 to 17 µg of venom protein [19].

Clinical Relevance

Five types of reactions to Hymenoptera stings are recognized: normal local reactions, large local reactions (LLR), systemic allergic reactions, systemic toxic reactions, and unusual reactions. Of these, systemic allergic reactions and LLRs are relevant for the practicing allergist as the patient might benefit from venom immunotherapy (VIT). 

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% [20]. The patient’s prior sting history – the severity and pattern of reactions, baseline tryptase level, age and concurrent medications - influences future risk [5, 21]. Hymenoptera sting-induced anaphylaxis must prompt investigations for an underlying mast cell disorder including hereditary α-tryptasemia [9, 12, 15].

Local reactions

In the general population, the reported prevalence of LLRs after Hymenoptera stings ranges between 2.4% and 26.4%, however in children, this figure is lower [5]. If local inflammation is contiguous with the sting site, it may be considered and managed as a local reaction [21]. LLRs 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 [22], or in the context of an underlying condition [13].

LLR patients exhibit a 10% risk of systemic reactions and a 3% risk of severe anaphylaxis if re-stung  [5, 21, 22].

Diagnostics sensitization      

A convincing clinical history and proven PDV sensitization are required for the diagnosis of PDV allergy [1, 9]. In areas of high P. dominula exposure, double IgE positivity to PDV and YJV extracts, but also to PDV and honeybee venom (HBV), is frequent and poses the problem of identifying genuine sensitization for appropriate VIT prescription [1, 7, 23, 24].

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% [1, 13]. 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  [20, 25].

Hymenoptera venom IgE persists for extended periods, allowing for in vitro and skin testing 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 [9, 11].

As venom sensitization is identified in up to 40% of asymptomatic subjects, only patients with a history of a previous systemic reaction are usually eligible for diagnostic testing [1, 9, 26].

In vitro diagnosis

In vitro testing is devoid of clinical risk of adverse reactions to applied venom and is less labor-intensive than skin testing [25]. Of note, PDV extract is devoid of CCD, a feature shared by other Polistes venoms [27, 28].

PDV extract is more sensitive than Polistes spp extract for the detection of PDV-specific IgE, since the latter contains a mix of American Polistes species [29]. However, improved detection of PDV -specific IgE was achieved with the Pol d 5-spiked Polistes spp extract, available since 2012 [30].

Besides allergen-extract specific IgE, in vitro investigation of PDV-induced reactions allows molecular allergen-based diagnostics. Pol d 1 and Pol d 5 are PDV marker allergens, but the prevalence of Pol d 5 sensitization in PDV allergic patients is highly variable from 20% to 80%, while Pol d 1 is not widely available for routine investigations [1, 6, 31]. Therefore, genuine PDV or Vespid sensitization cannot be excluded in a patient without detectable Pol d 5-specific IgE.

In vitro diagnosis with marker allergens (Ves v 1/Pol d 1 and Ves v 5/Pol d 5 for Vespids, and Api m 1, Api m 3, Api m 4 and Api m 10 for HBV) allows distinction between genuine Vespid/HBV cosensitization and sensitization to either Vespid or HBV with cross-reactivity [1].

Conversely, there is currently no available marker allergen for clear-cut discrimination between YJV and Polistes, including PDV, sensitization. The relative amount of specific IgE to Pol d 5 versus Ves v 5 (ratio Pol d 5/Ves v 5) or Pol d 1/Ves v 1 has also been investigated as a tool for identifying the primary Vespid sensitization [7, 24, 31, 32]. These studies showed that in selected cases with Pol d 5/Ves v 5 ratio of 2 or greater, primary PDV sensitization is probable [24, 32]. Pol d 1 availability allowed to build receiver operator curves with combined ratios of Pol d 5/Ves v 5, Pol d 1/Ves v 1 and whole PDV/YJV extracts resulting in the best diagnostic accuracy for PDV sensitization  [31].

No marker allergen is available to distinguish between PDV sensitization and sensitization to other Polistes species.

The historical cut-off for a positive IgE result for Hymenoptera venom specific IgE is 0.35 kUA/L, however, a lower cut-off of 0.10 kUA/L is applied by some investigators as a means for improving analytical and clinical diagnostic performance [1, 5, 9, 30].

Although venom-specific IgE can be detected immediately post-sting, one to four weeks later is thought to be the optimal time to perform allergen specific IgE testing because the sting most likely will have induced a boost of IgE production [1].

Total IgE could be useful alongside allergen-specific IgE, particularly in cases with low level of specific IgE, for calculating the specific-to-total IgE ratio, a proposed indicator for clinically relevant sensitization [1].

Diagnostic investigation of Hymenoptera sting-induced systemic reactions must be completed by the determination of baseline tryptase in search for a mast cell disorder [1, 9, 12].

In vitro investigations of PDV sensitization may also comprise IgE-inhibition assays and functional cellular tests. IgE inhibition assays can be performed using whole PDV and YJV extracts or molecular allergens. They are useful for the identification of the primary sensitizer in patients with double or multiple Hymenoptera venom sensitization, especially in cases not solved with the use of molecular allergens [4, 7, 24, 32, 33].

Skin tests

Skin testing with Vespid venom extracts can be performed as skin prick tests or intradermal tests [5, 9].

The skin test reaction to venom extracts is not correlated to the severity of past or recurrent reactions to a future sting [1, 9]. 

Challenge tests

Live sting challenges are not a standard procedure in clinical practice [1, 13].

Prevention and therapy

Allergen immunotherapy

Multiple PDV therapeutic preparations are available for VIT [8]. VIT is the only treatment that can prevent future sting-induced anaphylaxis in PDV allergic patients, effectively inducing tolerance in 91–99% of Vespid venom allergic patients [1, 12]. VIT is recommended by the EAACI in adults and children with detectable Hymenoptera sensitization and systemic sting reactions exceeding generalized skin symptoms, and in adult patients with systemic sting reactions confined to generalized skin symptoms if quality of life is impaired [13].

VIT is most successful when the treatment is selected based on the patient’s genuine sensitization to venom allergens [1, 8]. In PDV allergic patients, therapeutic PDV preparations are preferred to preparations based on American Polistes venom [4].  In Spain, a survey of PDV VIT prescriptions reported a 36% increase over 10 years, 2009 - 2019 [23].

During successful Vespid VIT, venom-specific IgE decreases while venom-specific IgG and IgG4 increase [13]. 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, 9, 12, 13].

An elevated baseline serum tryptase in an HVA patient, even without a formal diagnosis of systemic mastocytosis, may be associated with severe anaphylactic reactions and may indicate the need for lifelong VIT [13].

Prevention strategies

Sting avoidance is difficult to achieve as it requires caution during outdoor activities [1].

Other topics

An emergency kit comprising autoinjectable epinephrin should be carried by HVA patients having experienced systemic reactions, including those having completed a successful VIT [1].

Molecular aspects                  

Allergenic molecules

Among the five PDV allergens currently characterized and included in the IUIS/WHO Allergen Nomenclature [3], four are enzymes: Vespid group 1 PLA₁ (Pol d 1), hyaluronidase (Pol d 2), dipeptidyl peptidase IV (Pol d 3), and serine protease (Pol d 4), while the biological function of group 5 antigen Pol d 5 is unknown. Pol d 1 and Pol d 5 are marker allergens for genuine Vespid venom sensitization, Pol d 2 and Pol d 3 are cross-reactive with homologues from Vespid venom and HBV, while Pol d 4 and its homologue Pol e 4 from P. exclamans are serine proteases present in venoms from Polistes and honeybee, but not from other Vespids [1, 34].

The biochemical properties, molecular mass, and sensitization rate for these PDV allergens are summarized in table 2. Other PDV allergens have been identified, with preliminary research suggesting the existence of further potential Polistes-specific venom allergens, but their diagnostic value is not yet established and they are not commercially available [2, 35].

Table 2: Biochemical properties, molecular mass, and sensitization rate for allergens from P. dominula venom [1, 3, 4, 31, 34, 36, 37].

Cross-reactivity

As a rule, high cross-reactivity is observed within European Polistes venoms on one hand and American Polistes venoms on the other hand, while incomplete cross-reactivity is observed between the two groups, American and European Polistes [1]. Incomplete PDV/YJV cross-reactivity is also observed [1].

Explained results

Allergen Information

PDV contains a complex mixture of biologically active molecules relevant for European Polistes species and is devoid of cross-reactive carbohydrate determinants.

Clinical information

PDV allergy may manifest as life-threatening systemic reactions, which require clinical and in vitro investigation including assessment of concurrent mast cell disorders and hereditary α-tryptasemia and are eligible for VIT. The prevalence of systemic reactions to Hymenoptera stings in adults ranges from 0.3% to 7.5%. Conversely, asymptomatic sensitization to Hymenoptera venoms is found in a substantial proportion of the general population, precluding its use for Hymenoptera venom allergy screening.

Cross-reactivity

PDV displays cross-reactivity with other Vespid venoms, including YJV and American Polistes. The marker allergens Pol d 1 and Pol d 5 are currently available for the identification of genuine sensitization to Vespid venom, especially in areas of high P. dominula exposure.

Author: Dr. Joana Vitte

Reviewed: Dr. Michael Spangfort