Part I: Insect stings and bites—Beyond the realm of bee and wasp allergies A survey of the literature and our own cases

imported ﬁre ants, frequently lead to severe anaphylaxis, and their venom can elicit systemic toxic effects. Stings and bites of various other ant species can also lead to severe allergic reactions. Mosquito stings and horseﬂy or other Diptera stings may elicit severe local and IgE-mediated systemic reactions. True bugs (Hemiptera) are hematophagous insects and can also cause severe allergic reactions, in addition to being feared for transmitting diseases.


Introduction
Arthropods are a phylum of invertebrate animals, including insects, crustaceans, spiders, mites, ticks, and others. Fig. 1 provides a summary of the phylogenetic relationships within arthropods [1].
Insects are invertebrates with three pairs of legs and form the largest group within the arthropod phylum. In fact, insects are the most diverse animals on the planet, encompassing more than a million described species, thus representing over 90% of animal life forms on earth [2]. Their stings, bites, and excrements can cause mild to life-threatening allergic reactions, illicit toxic effects, lead to various skin changes and act as vectors of disease transmission. Diagnosing illness following insect stings, bites, inhalation, or ingestion can be challenging due to their often hidden character and because of mimicry of other conditions [3]. Table 1 provides an overview of allergologically relevant insects, allergy mechanisms, and typical clinical findings.  Klotz (2009) [11], Pinnas (1986) [81] Red wood ant (Formica rufa) Bite, spray with venom Mild LR, IgE-Anaphylaxis rare No NA Europe, North America Schmid-Grendelmeier (1997) [23], Seebach (2000) [7] Chinese needle ants (Pachycondyla chinen- cause severe, IgE-mediated anaphylaxis. Due to the effects of global warming, which increases climatic suitability for the IFA and reduces the resistance of native ant communities, this invasive species has spread to the United States, the Caribbean, and some Asian countries and is also invading Australia and parts of New Zealand. IFA is the most common cause of antinduced allergic reactions worldwide [8]. Allergies to ants other than IFA are less common. In Southeast Asia, imported fire ants and Chinese needle ants (Pachycondyla spp.), in Australia, Jack jumper ants (Myrmecia spp.) and Green-head ants (Rhytidoponera metallica), and in the USA, the harvester ant (Pogonomyrmex spp.) can also cause allergies [9][10][11]. Some cases of allergies induced by the red wood ant (Formica rufa), endemic in Europe and North America, have also been reported [7].
After an IFA sting, a dermal flare with wheal, a small vesicle, or a sterile pustule develops within minutes to hours due to direct toxic effects of the ant venom and tissue inflammation caused by the venom ( [12]; Fig. 2). The IFA venom is composed of alkaloids, which explains sterile pustule formation after stings [5]. Some patients (17 to 56%) develop a large local reaction consisting of an extremely large and pruritic lesion persisting for up to 72 h [13]. IgE-mediated severe allergic reactions following IFA stings are well documented and sometimes even lead to severe endorgan damage, including rhabdomyolysis, renal failure, and neurotoxic effects, which can also be induced by direct toxic effects of multiple ant stings [14][15][16][17].
The diagnosis of immediate-type hypersensitivity to ants is made by correlating the clinical manifestations of the sting reactions with ant-specific IgE determined by skin testing and/or radioallergosorbent test. Major protein allergens were isolated from IFA venoms (Sol I 1-4) and several allergens from other Solenopsis species (Sol g2-4 from Solenopsis geminata, Sol r2-3 from Solenopsis richteri, and Sol s2-3 from Solenopsis saevissima), the Australian jack jumper ant (Myr p1-3, Myrmecia pilosula) and the Asian needle ant (Pac c3, Pachycondyla chinensis) [8]. Whole-body extracts contain relevant venom allergens and can be used for skin testing and immunotherapy for IFA allergy, Jack jumper ant allergy, Chinese needle ant allergy, and Samsum ant allergy ( [18][19][20][21][22]. The following two cases of ant allergy stem from the outpatient department in Zurich [7,23]:  [24]). The consecutively performed skin prick test with commercially available whole-body extract was strongly positive, and specific IgE to Sol i 1 was now positive. However, it remains unclear why IFA-specific IgE and skin testing were negative at the first presentation. Specific venom immunotherapy was initiated following a rush protocol. A sting was well tolerated after the immunotherapy was stopped after five years of continuous treatment (Fig. 4).

Diptera-True flies
Diptera, or true flies, occur in numerous habitats and have spread to all continents [25]. Numerous hematophagous insects belong to this order, with representatives of the Tabanidae and mosquitoes being particularly relevant in medicine. Respiratory and occupational allergies to Diptera, e.g., common houseflies or fruit flies, are rare [26,27].

Tabanidae-Horse flies and deer flies
The family Tabanidae contains about 4500 species and subspecies and has a worldwide distribution [27]. The clinically most relevant representatives of the Tabanidae family belong to the genera Tabanus and Chrysops, all of which occur in Central Europe ( [28]; Fig. 5). Local reactions after a tabanid bite are common, but anaphylaxis and systemic symptoms are rare [28,29]. There are only single cases and small case series describing allergies to Tabanidae [28,[30][31][32][33][34][35]. Tabanid allergens in saliva are still incompletely characterized. Only three allergens have been identified so far, some of which overlap with mosquito and wasp venom allergens [36]. The diagnosis of an allergy to tabanids is therefore difficult. In cases with significant local reactions, no further investigation is necessary. In patients with anaphylaxis, prick tests are possible, albeit not standardized. A whole-body extract for Chrysops vittatus is commercially available (Stallergenes Greer, London, UK). The same limitation applies to in vitro tests, where sensitivity and specificity remain unclear. Although specific immunotherapy was performed in individual cases [37,38], extracts are not commercially available or standardized and are usually performed using whole-body extracts.

Culicidae-Mosquitoes
Mosquitoes (Nematocera) are insects within the Diptera order and encompass more than 3500 species worldwide [39,40]. In allergology, the most important mosquito species are Aedes aegypti and Aedes vexans [41]. Allergic reactions to mosquito bites are caused by sensitization to mosquito salivary antigens [40,42]. Specific IgE and IgG antibodies and T-cell mediated delayed-type hypersensitivity reactions are involved in the pathogenesis of mosquito allergy [43]. Common reactions to mosquito stings include immediatetype reactions minutes after the sting, consisting of wheals and flares and delayed reactions manifesting 24 to 36 h after the sting as itchy papules. Late type reactions manifest as vesicles, bullae, ecchymosis, and even Skeeter syndrome and Arthus-type local and systemic reactions [44,45]. Albeit rare, severe anaphylaxis to mosquito stings is also possible [46][47][48].
Different mosquito saliva proteins were identified as potential allergens. A correlation of immediate type reactions and mosquito bite-induced anaphylaxis with elevations of serum-specific IgE levels was shown [43]. Immunoassays using recombinant mosquito salivary allergens (rAed a one and rAed a 3) are sensitive and specific for the diagnosis of mosquito allergy [42].
Nevertheless, diagnosing mosquito allergy remains challenging. Skin prick reagents commercially used for diagnosing mosquito allergy contain whole body parts of mosquito and small concentrations of allergenic saliva proteins [49]. To date, no robust studies could prove the effect of desensitization with wholebody extract in treating mosquito allergic patients. Therefore, the most important treatment of mosquito allergy remains prevention from being stung using repellents and mosquito nets. Studies suggest that natural desensitization in mosquito-allergic children may occur during adolescence [46].
In addition to mosquito allergies, bacterial superinfections resulting from scratching itchy lesions after a bite, and transmission of pathogens such as Plasmodium (malaria) transmitted by Anopheles spp. mosquitoes or Flaviviridae (the causes of yellow fever or dengue fever) are of global health importance [50,51].
Other Nematocera families like Ceratopogonidae (e.g., biting midges) and Chironomidae have been shown to have allergenic potential both after stinging humans and also as airborne allergens [52,53].

Hemiptera-True bugs
Hemiptera, or true bugs, are an insect order within the Neoptera. In 2008, there were 82,000 described species, and the total number of species worldwide was estimated to be over 200,000 [54]. Allergic reactions following bed bug (Cimex lectularius) and kissing bug (subfamily Triatominae) bites are common, but lesser-known true bugs can also cause allergies when used as food additives, such as cochineal lice (Dactylopius coccus) or lac bugs (Kerria lacca) [55][56][57][58]. Reactions to insects and insect compounds as food will be further discussed in part II of this article. Hemiptera are also important vectors of diseases such as Chagas disease, where kissing bugs transmit the parasite Trypanosoma cruzi [59].

Cimicidae-Bed bugs
Bed bugs such as Cimex lectularis or C. hemipterus were nearly eradicated in Western countries in the 1940s due to pesticides. However, a re-emergence of bed bugs began in the mid-1990s, and their infestation is currently increasing and spreading worldwide [60][61][62]. Partially, their re-emergence may be due to a resistance to pesticides [63].
Bed bugs are nocturnal bloodsuckers that can live up to 1 year without feeding. The primary hosts are humans and other mammals. Bed bugs are insensitive to cold and die only at temperatures above 41°C [64]. Due to their small size and adjustability, bed bugs can hide in small loopholes in mattresses or wallpaper and K original article travel long distances, for example, in suitcases [65]. The bed bug's bite usually occurs at night and is not noticed at first due to the anesthetic effect of its saliva.
A bed bug bite may give rise to localized cutaneous responses of various manifestations and anaphylactic reactions of different grades [64,66,67]. Classification of cutaneous reactions after bed bug bites has been proposed (i.e., usual, common, and complex reactions) [68]. "Usual reactions" occur within one hour and consist of pruritus and no local reaction save for punctiform visibility of the bite site. "Common reactions" occur within hours and manifest as pruritic macules or papules resembling papular urticaria. "Complex reactions" are bullous, pruritic, and may be painful and persist for several days [68][69][70][71][72].
Bullous rashes occurring days after stings could represent late-phase responses of IgE-mediated hypersensitivity [66,73]. However, severe immediatetype anaphylactic reactions have not been documented with certainty, but sometimes multiple stings can imitate the picture of generalized urticaria, and one case of severe anaphylaxis following bed bug bite mimicking acute coronary syndrome was reported in 2006 [69]. Salivary proteins of bed bugs (nitrophorin, factor X, apyrase-like nucleotide-binding enzymes) are of immunological importance, and specific IgEs to C. lectularis crude extract and C. lectularius nitrophorin recombinant protein can be present in individuals with a history of bed bug bites [55,[74][75][76]. The use of high-potency topical corticosteroids and oral antihistamines is the treatment of choice in local bullous reactions, and severe reactions may even require systemic corticosteroids ( [68] ; Fig. 6).

Triatominae-Kissing bugs
Triatomine insects (also called: kissing bugs, Mexican bed bugs, and cone-nosed bugs) are found mainly in the western and southern United States, Central and South America, and Mexico (Fig. 7). They are ectoparasites on small mammals and feed on their blood. Bites usually occur on exposed body parts (face, hands, feet) at night and are painless. Kissing bug bites are among the common causes of insectbite-related allergies [77,78]. Initial bites produce little to no reaction, and repeated exposure leads to a range of local reactions with variable presentation (erythema, papules, vesicles, hemorrhagic bullae). In addition to cutaneous hypersensitivity reactions, lifethreatening immediate-type reactions have been described ("nocturnal anaphylaxis") [79].
The primary allergen identified in triatomine saliva is a 20 kDa protein, which interestingly belongs to the same protein family (lipocalins) as known of inhalation allergens of dogs, cats, and other mammals [80]. Reactivity to two salivary gland extracts of two Triatominae species was demonstrated and immunotherapy using a salivary gland extract showed benefits in a small patient cohort. No commercial testing or treatment allergen is available [81,82]. While feeding, triatomines defecate parasiteladen feces and can transmit Trypanosoma cruzii, the causative organism of Chagas disease [56]. a widespread infestation, especially in children. Few allergic reactions to head lice have been described, including one case of allergic asthma and one case of nasal and ocular allergy induced by a specific IgEmediated reaction to louse body proteins [86][87][88]. To date, no allergic reactions to the body or pubic lice have been reported.

Siphonaptera-Fleas
Fleas are small blood-sucking ectoparasites [89] and include more than 2500 species. Fleas play an essential role in veterinary medicine since they frequently lead to allergic flea dermatitis in cats and dogs (FAD) [89]. The common cat flea (Ctenocephalides felis felis) is mainly responsible for the development of allergic flea dermatitis ( [90] ; Fig 9). Albeit rarer, flea allergic dermatitis can also manifest in humans, especially those more commonly exposed to ectoparasites, e.g., homeless people [91]. After a flea bite, the components of flea saliva (polypeptides, phosphorus, amino acids, aromatic amines) cause severe pruritus and papules, crusts, and excoriations [92]. In veteri- nary medicine, an intradermal skin test with glycerinated flea antigens can be used to diagnose FAD [93]. Cte f 1 and Cte f 2 are the major allergens described from Ctenocephalides felis [94].
In humans, papular urticaria after a flea bite is common [95][96][97]. In children living in areas where flea bites frequently induce papular urticaria, like in South America, Cte f 2 induces both IgE and IgG production as well as T-cell proliferation [95]. Furthermore, disease transmission by fleas is possible in humans, cats, and dogs, e.g., flea-borne murine typhus [98].

Conclusion
Allergic reactions and direct poisoning following insect stings or bites are common, occur worldwide, and are associated with significant morbidity. Ant stings and bites, especially from imported fire ants, can cause severe anaphylaxis, and their venom can lead to systemic poisoning and end-organ damage. Mosquito and tabanid stings but also as inhaled allergens rarely trigger IgE-mediated reactions. True bugs, such as bed bugs or kissing bugs, are nuisance pests that can cause allergies but can also be a vector for disease transmission, such as kissing bugs causing Chagas disease. Other blood-sucking insects like lice and fleas often cause dermatitis, papular urticaria, whereas severe IgE-mediated reactions are infrequent. Allergic reactions following insect stings or bites may not be detected or diagnosed if the causative insect cannot be identified. For this reason, patients should be encouraged to keep causative insects for identification and diagnostic testing. In uncertain cases, an entomologist should be consulted.
Funding No funding to declare Author Contribution C. Guillet: Conception and design, acquisition of data, interpretation, drafting of the manuscript, final approval; O.Y. Martin: Conception and design, acquisition of data and visuals, drafting of the manuscript, critical revision of the manuscript for important intellectual content, final approval; C. Meincke: Critical revision of the manuscript for important intellectual content, final approval; L. Joerg: Acquisition of data, drafting and critical revision of the manuscript for important intellectual content, final approval, P. Schmid-Grendelmeier: Conception and design, acquisition of data and visuals, drafting of the manuscript, critical revision of the manuscript for important intellectual content, final approval.

Funding Open access funding provided by University of Zurich
Conflict of interest P. Schmid-Grendelmeier has acted as consultant or speaker for Bühlmann Laboratory, Euroimmun, and Thermo Fisher; Research grants received from Bühlmann Laboratories and Thermo Fisher. C. Guillet, O.Y. Martin, C. Meincke and L. Joerg declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.