Summary

Hymenoptera of the Polistes genus are social wasps present on all continents. American Polistes species (including P. annularis, P. exclamans, P. fuscatus, P. metricus) are not present in Europe. Polistes spp wasps are also called “paper-nest wasps” or “paper wasps” in reference to the shape of their nests.

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. 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.

Eight molecular allergens belonging to the molecular families of phospholipase A1 (PLA1), hyaluronidase, antigen 5, and serine protease have been characterized so far in the American Polistes spp venom. None of these molecules is currently available for in vitro diagnosis. Polistes spp venom is devoid of cross-reacting carbohydrate determinants (CCD).

Allergen          

Nature

Polistes spp 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 [1]. Similar to most Hymenoptera, Polistes spp can extract their stinger from the victim and are thus able to sting multiple times during their lifetime.

Polistes spp extract contains a mix of venoms from four American species of Polistes: P. annularis, P. exclamans, P. fuscatus, and P. metricus [2].

Taxonomy

Domain:   Eukaryota

Kingdom:  Metazoa (Animalia)

Phylum     Arthropoda

Subphylum:  Hexapoda

Class:        Insecta

Order:       Hymenoptera

Suborder: Apocrita

Family:      Polistinae

Genus:      Polistes

Species:    P. annularis, P. exclamans, P. fuscatus, P. metricus

The order Hymenoptera includes 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

Wasp venoms contain three major molecule groups: proteins such as allergens and enzymes; small peptides with neuro- and antimicrobial activities; and substances of low molecular weight including bioactive amines. Peptides and proteins in wasp venom can be grouped according to their activity for example, mastoparans, chemotactic peptides, wasp kinins and enzymes [1, 3].

Epidemiology

Worldwide distribution

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 [4]. 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 [5]. In the USA, it is estimated that 0.5 to 3.3% of people being stung by a Hymenoptera develop a systemic reaction [6].

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 [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, 9]. 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 [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  [6, 10]. 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 [11]. 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]. Lifestyle, including outdoor leisure activities or occupational exposure, may result in an increased prevalence of Hymenoptera stings, sensitization and systemic reactions [1, 12].

Pediatric issues

The prevalence of systemic reactions to Hymenoptera venoms is estimated at 3.4% in children [8]. In children younger than 16 years experiencing a cutaneous reaction to Hymenoptera venom, the chance of anaphylaxis if re-stung is lower than 3% [5].

Environmental characteristics                       

Living environment

The nests of Polistes species are usually found in hidden locations, for example in building frames, shutters and wall cracks, shrubs and consist of paper-like or wood pulp material [5, 13]. Vespids are unlikely to be aggressive, except in defense of their nests [5, 13].

Worldwide distribution

Polistes (known as wasps in Europe and paper wasps in the USA) have a worldwide distribution with more than 200 species [14]. P. annularis, P. exclamans,  P. fuscatus and P. metricus belong to the group of American (New World) Polistes species, that are not found in other world regions; conversely, Polistes species clinically relevant in Europe, such as P. dominula and P. gallicus, are also found in the Middle East, Central Asia, and Eastern Asia [14]. In addition, P. dominula has been recently introduced to the Northeast of the USA and Australia [1].

Route of exposure                  

Main

Exposure to Polistes spp venom occurs through a sting when the stinger of the insect becomes embedded in the flesh and the venom is injected from the venom sac. Polistes spp, hornets and Vespula spp are able to sting multiple times without dying, as they can extract their stinger from the victim [1].

Secondary

Ingestion of Polistes olivaceus larvae resulted in anaphylaxis in a 27-year old patient with a history of asthma [15]. As wasps are major edible insects worldwide [16, 17], and wasp venom allergens display stable structures with multiple disulfide bonds [1], ingestion may become a relevant route of exposure with the worldwide increase of entomophagy.

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% [18]. The patient’s prior sting history – the severity and pattern of reactions, baseline tryptase level, age and concurrent medications - influences future risk [19]. Hymenoptera sting-induced anaphylaxis must prompt investigations for an underlying mast cell disorder including hereditary α-tryptasemia [6, 9, 10].

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 [20]. If local inflammation is contiguous with the sting site, it may be considered and managed as a local reaction [19]. 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 [21], or in the context of an underlying condition [8].

LLR patients exhibit a 10% risk of systemic reactions and a 3% risk of severe anaphylaxis if re-stung  [19, 21].

Other diseases

Post-sting electrocardiographic changes with and without systemic symptoms have been described in patients who have been stung by insects [22]. Epileptic attacks have been associated with wasp stings [23].

Diagnostics sensitization      

A convincing clinical history and proven Polistes venom sensitization are required for the diagnosis of Polistes venom allergy [1, 9]. 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 [1, 9].

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% despite the fact that 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 [1, 8, 9]. 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  [18, 24].

As Hymenoptera venom IgE persists 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, 18]. 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 [5, 9].

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 [24]. Of note, Polistes venom is devoid of CCD, a feature shared by North American, European and neotropical Polistes and other Polistinae species [25, 26]. 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 considered by some authors as a means for improving analytical and clinical diagnostic performance [1, 9, 27].

Improved diagnostic performance was also achieved following spiking the Polistes spp extract with Pol d 5 since 2012, similar to Ves v 5 spiking of Vespula spp extract [27, 28].

Besides allergen-extract specific IgE, in vitro investigation of Polistes sting-induced reactions allows molecular allergen-based diagnostics. As no molecular allergen of American Polistes spp is currently available for routine in vitro investigation, an alternative solution is using Pol d 5 from the European P. dominula [1, 27, 28].

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].

In children under five years of age, positive specific IgE for venom components has been shown to have no correlation with positive sting history and does not support the screening of children for Hymenoptera venom allergy (HVA) [29].

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].

Skin tests

Skin tests with Vespid venom extracts can be performed as skin prick tests or intradermal tests [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, 8, 19].

Prevention and therapy

Allergen immunotherapy

VIT is the only treatment that can prevent future sting-induced anaphylaxis in HVA patients, effectively inducing tolerance in 91–99% of Vespid venom allergic patients [1, 31]. During successful Vespid VIT, venom-specific IgE decreases while venom-specific IgG and IgG4 increase [24].

VIT is most successful when the treatment is selected based on the patient’s genuine sensitization to venom allergens [1]. 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 [8].

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 eight characterized venom allergens of American Polistes spp, most are enzymes, such as Vespid group 1 PLA1 (Pol a 1, Pol e 1), hyaluronidase (Pol a 2), serine protease (Pol e 4), while group 5 antigens are of unknown function (Pol a 5, Pol e 5, Pol f 5, Pol m 5). The biochemical properties, molecular mass, and sensitization rate for the paper wasp allergens are summarized in table 2. None of these allergens is available for routine in vitro diagnosis.

Table 2: Biochemical properties, molecular mass, and sensitization rate for American Polistes spp allergens [1, 32, 33].

Cross-reactivity

Cross-reactivity between Polistes spp and Vespula spp is relatively low, estimated at 50% in a recent review [31]. Polistes spp-specific IgE displayed a prevalence of 76% in a cohort of Vespula-allergic patients, however, lower levels of specific IgE were observed with Polistes spp extract than with Vespula extract, and basophil activation tests with multiple antigen 5 molecules showed that Pol a 5 from P. annularis was less effective than Ves v 5 for the induction of a functional basophil response in these patients [30].

As a rule, venoms within the Polistes genus display high cross-reactivity, however, incomplete cross-reactivity is observed between American and European Polistes venom [1, 31]. Thus, venom extract of American Polistes spp is not an optimal tool for the diagnosis of European Polistes-allergic patients, where P. dominula venom extract is more performant [1, 2]. Following the spiking of Polistes spp venom extract with Pol d 5 since 2012, the discordance rate between Polistes spp venom extract and Pol d 5-specific IgE has decreased from 21% to 4% [27].

Sensitization to Polistes spp venom is frequently associated to sensitization to other Hymenoptera venoms. Double sensitization, whether resulting from genuine double sensitization or cross-reactivity, may be clinically relevant and puts the patients at risk of severe reactions to stings from various Hymenoptera species, especially in subjects with underlying mast cell disorders [1, 9].

In vitro diagnosis with marker molecular allergens allows the identification of the genuine sensitizers in cases of Vespid/honeybee venom double positivity. Conversely, there is currently no available marker allergen for discriminating between Vespula spp and Polistes spp sensitization [1].  Double positivity to bee and Vespid 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-Vespid co-sensitization and sensitization to only bee or Vespid with cross-reactivity [1].

Explained results

 Allergen Information

Polistes spp venom contains a complex mixture of biologically active molecules from four American Polistes species. Polistes spp venom is devoid of CCD.

Clinical information

Polistes spp 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

Polistes spp venom displays limited cross-reactivity with other Vespid venoms, including Vespula venom and European Polistes venom, mainly P. dominula. No marker allergen is currently available for the identification of genuine sensitization to American Polistes spp venom.

Author: Dr. Joana Vitte

Reviewer: Dr. Michael Spangfort