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Whole Allergen

i204 Horse fly

i204 Horse fly Scientific Information

Type:

Whole Allergen

Display Name:

Horse fly

Family:

Tabanidae

Species:

Injection (bite)

Latin Name:

Tabanus spp.

Other Names:

Cleg, gadfly, tabanid fly, Marchfly (Australia)

Summary

Tabanid flies are among the most commonly encountered blood-feeding insects worldwide, however, tabanid allergy may be under-reported as reliable identification of a biting insect is rarely possible. Tabanus spp. introduce allergens to humans and animals via a painful bite, usually on the upper part of the body. Local transient cutaneous reactions to a tabanid bite are common, and systemic reactions of variable severity from generalized urticaria to anaphylaxis have been reported. Three allergenic molecules have been characterized in Tabanus spp. that cross-react to some degree with homologous proteins of wasp (Hymenoptera spp.) and mosquitoes.

Allergen

Nature

Flies from the family Tabanidae, known generically as “tabanids”, are among the most commonly encountered blood-feeding insects (2). Tabanidae includes 144 genera and more than 4,500 species and sub-species worldwide, many of which have medical relevance to allergy (2).

Taxonomy      

Taxonomic tree of Tabanus spp. (horsefly) (1)

Domain

Eukaryota

Kingdom

Metazoa

Phylum

Arthropoda

Subphylum

Uniramia

Class

Insecta

Family

Tabanidae

Genus

Tabanus

Taxonomic tree of Tabanus spp. (horsefly) (1)

Tissue

Horsefly saliva, introduced to humans via a bite, contains a range of anticoagulants, potential allergens, and pharmacologically active compounds that inhibit the body’s innate immune system and impair anti-inflammatory processes (2-4).

Environmental Characteristics

Living environment

Tabanid flies are most prevalent in areas with plentiful grazing livestock (2). Eggs are grey in color, approximately 2 mm long, and laid in clusters of 100‒1,000 on moist soil, vegetation, or water (5, 6). Larvae are 6 cm long, white/tan in color, and undergo several molts lasting between 3 months to 3 years before moving to dry soil to pupate (5). The pupal stage lasts 5‒21 days depending on the species, and adults emerge from the soil to mate almost immediately (5, 6).

Worldwide distribution 

Tabanus spp. can be found worldwide, except in extreme northern and southern latitudes and some islands (2, 6). 

Route of Exposure

Main 

Exposure to venom allergens from horseflies is primarily via a bite. Female Tabanus spp. are hematophagous and require a blood meal to complete egg development, whereas the males are phytophagous (nectar feeders) and incapable of biting (2, 5, 6). Most tabanids feed on mammals, while some feed on birds, reptiles, or amphibians (6). Female tabanids wait in vegetation for a suitable host to pass nearby and are attracted to large dark moving objects and to carbon dioxide (6). Tabanids are strong fliers (4) and have been described as “relentless” biters that bombard and follow people outdoors (5, 6).

Tabanus spp. are telmophages (pool feeders) and use two sharp and slender mandibles within their mouthparts to penetrate the skin to the superficial dermal vessels, macerate the tissue, and lap up the resulting pool of blood with their tongue (2, 5, 6). Larger species can collect up to 200 mg of pooled blood in 1‒3 minutes, and these bites can cause open bleeding wounds (4). The horsefly bite is reported to be very painful and is usually located on the upper part of the body (4-6). Of note, tabanid larvae, voracious predators of invertebrates, have also been reported to inflict a painful bite to humans (6). 

Clinical Relevance

Tabanid bites usually leave little more than a transient immediate wheal and flare reaction, however large local cutaneous reactions are common, and systemic allergic reactions of varying severity have been reported (2, 7).

An observational report of 7 Caucasian adults who were bitten by Tabanus bovinus in Bolivia described identical clinical presentations with multiple, erythematous, roundish, flattened, large plaques, often with a central point corresponding to the horsefly bite, surrounded by satellite smaller and similar lesions (5). All of the lesions described in this report appeared between 1‒3 hours after a painful bite and were located on the upper body (e.g. face, shoulders, neck, and/or upper chest) (5). No systemic signs or symptoms other than pain at the site of the bite were recorded, and rapid recovery in all cases was achieved with topical corticosteroids (5).

Horsefly bites can also cause hemorrhagic blisters, which could lead to diagnostic confusion with other causes of hemorrhagic blisters such as autoimmune bullous diseases, polymorphic erythema, orf, and other bullous diseases which have a different clinical evolution (3). In Brazil, an adult female stung by horseflies on both hands developed local hemorrhagic blisters of various diameters, which were treated by emptying the liquid content and applying topical antibiotics in the exulcerations (3).

Freye & Litwin (8) published the first report of anaphylaxis caused by Tabanus spp, in a male aged 56 years who developed rapid onset generalized urticaria, presyncope, lip angioedema, and collapse following a bite from Tabanus americannus in North America (8). The patient recovered after receiving emergency treatment with epinephrine, diphenhydramine, intravenous steroids, and oxygen (8).

While a number of severe allergic reactions to tabanid bites have been published, the extent to which these reports were categorically attributable to Tabanus spp., versus species belonging to related genera such as Chrysops or Haematopota, is unclear (9, 10). Reliable identification of a biting insect is rarely possible, and diagnosis of insect bite hypersensitivity is often based on medical history (9). As such, allergy to tabanids may be under-reported (10).

Other reactions

The saliva of Tabanus spp. contains a wide range of physiologically active molecules including antihemostatic, fibrinolytic, and immunosuppressant compounds that can interact with host processes (3, 11-13). Tabanids take frequent and rapid meals from many different individual hosts, and in so doing can transmit a variety of viruses, bacteria, parasites, and protozoa, either biologically (as an intermediate host) or more commonly mechanically via contaminated blood on the mouthparts (2). Tabanids are considered a serious pest due to their important role in spreading diseases that can impact livestock production, such as anthrax, tularemia, and trypanosomiasis, among many others (2, 6, 14). Tabanids may also be potential vectors of disease between animals and humans: a sheep breeder in Italy developed skin lesions attributable to cutaneous anthrax after being stung by gadflies, despite being 3 km away from the affected farm (15).

Prevention and Therapy

Allergen immunotherapy

The importance and feasibility of allergy diagnostics for insect bites may be limited for a number of reasons, including high rates of sensitization in the general population, low discrimination by tests between ‘normal’ and ‘hypersensitive/anaphylactic’ reactions, significant variation in locally relevant insect species, and the numerous pathomechanisms that underlie skin reactions (9). Importantly, some authors have cautioned that the exact identification of the insect is essential before beginning or changing any treatment, such as immunotherapy (10, 16).

Molecular Aspects

Allergenic molecules

The following allergens and molecular epitopes have been characterized from Tabanus saliva (Allergome 2021):

Name

Type

Mass (kDa)

Tab y 1 and Tab y 1.0101

Apyrase

 

70

Tab y 2 and Tab y 2.0101 (previously Tab a 2)

Hyaluronidase

35

Tab y 5 and Tab y 5.0101 (previously Tab a 1)

Antigen 5

26

Name

Type

Mass (kDa)

Tab y 1, originally purified from the salivary glands of Tabanus yao Macquart, demonstrated positive skin-prick tests (SPT) in 70% (7/10) of patients with horsefly allergy, while 81% (30/37) of patients reacted to Tab y 1 on western blots (17). Tab y 1 displayed enzymatic activity to hydrolyze ATP and ADP, as well as potent antiplatelet aggregation and antithrombotic activities (17).

Immunoblotting demonstrated that Tab y 2 and Tab y 5 bind IgE in 91.8% and 86.5% of subjects’ sera, respectively (18). Tab y 5 significantly inhibited angiogenesis in vitro and in vivo (chicken chorioallantoic membrane angiogenesis assay (19).

Cross-reactivity

Tab y 2 and Tab y 5 in the saliva of horseflies exhibit some cross-reactivity with their homologs of wasp venom (Ves v 2 and Ves v 5, respectively), providing support for the presence of a postulated ‘wasp-horsefly syndrome’ in which wasp venom-allergic patients also experience systemic reactions after bites of horseflies (18, 20, 21). In particular, Tab y 2, Tab y 5, and Vesp ma 2 (wasp) have been shown to bind simultaneously to corresponding IgEs in patients with allergic reactions to horsefly or wasp, inhibit binding in a dose-dependent manner, and induce allergic reactions in sensitized subjects by SPT (21). Another study demonstrated that while Tab y 1, Tab y 2, and Tab y 5 from Tabanus yao showed up to 40% sequence identity with homologous proteins from mosquitoes and Hymenoptera venoms, recombinant Tab y 2 did not significantly inhibit IgE binding to crude wasp venom even at very high allergen concentrations (18). There is still insufficient evidence to substantiate the clinical relevance of this cross-reactivity (9).

Coexistent hypersensitivity to both orders Diptera and Hymenoptera has been rarely reported. A male aged 56 years in North America with previous anaphylactic reactions to yellow jacket and white-faced hornet was bitten by a horsefly (Tabanus americannus) and within five minutes presented generalized urticaria, dizziness, swollen lips and tongue, and collapsed (8). The patient recovered after receiving emergency treatment with epinephrine, diphenhydramine, intravenous steroids, and oxygen (8). Of note, this study also described cross-reactivity testing of 20 control subjects with documented Hymenoptera sensitivity and confirmed positive intradermal tests to Hymenoptera, who only developed local reactions after receiving a horsefly bite (8). Within this cohort of 20 subjects, there was no discernable correlation between positive or negative responses of skin testing and RAST with Tabanidae antigens (8).

20 control subjects with Hymenoptera sensitivity and positive SPT, intradermal or RAST to mixed Tabanidae extract had a clinical history of reaction to horsefly bite (8).

In Italy, a case report described a male patient aged 51 with allergy to Hymenoptera venom who developed rapid onset generalized pruritus and oral paresthesia followed by syncope after being bitten by Tabanus bovinus (22). This patient had been receiving venom immunotherapy for Vespula spp. for three years and had tolerated a Vespula sting during treatment, but required emergency treatment for the horsefly bite including adrenaline, intravenous antihistamines, and corticosteroid (22).

Other species which may cross-react with horseflies include honeybee (Api m 2), mosquitoes, black flies, biting midges, tsetse flies, and fleas (9). 

Compiled By

Author: RubyDuke Communications

Reviewer: Dr. Christian  Fischer

 

Last reviewed:March 2022

References
  1. CABI. Tabanidae Wallingford, UK2021 [cited 2022 04.01.22]. Available from: https://www.cabi.org/isc/datasheet/105617.
  2. Whyte AF, Popescu FD, Carlson J. Tabanidae insect (horsefly and deerfly) allergy in humans: A review of the literature. Clin Exp Allergy. 2020;50(8):886-93.
  3. Haddad V, Jr., Fonseca CGF, Mendes AL. Acute bullous hemorrhagic prurigo: a diagnostic challenge. An Bras Dermatol. 2020;95(6):724-7.
  4. Kazimírová M, Sulanová M, Trimnellt AR, Kozánek M, Vidlicka L, Labuda M, et al. Anticoagulant activities in salivary glands of tabanid flies. Med Vet Entomol. 2002;16(3):301-9.
  5. Veraldi S, Esposito L. Skin lesions caused by Tabanus bovinus bites. Journal of Travel Medicine. 2017;24(5).
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  13. Ahn MY, Hahn BS, Lee PJ, Wu SJ, Kim YS. Purification and characterization of anticoagulant protein from the tabanus, Tabanus bivittatus. Arch Pharm Res. 2006;29(5):418-23.
  14. Krinsky WL. Animal disease agents transmitted by horse flies and deer flies (Diptera: Tabanidae). J Med Entomol. 1976;13(3):225-75.
  15. Fasanella A, Garofolo G, Galella M, Troiano P, De Stefano C, Pace L, et al. Suspect vector transmission of human cutaneous anthrax during an animal outbreak in Southern Italy. Vector Borne Zoonotic Dis. 2013;13(10):769-71.
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  17. An S, Ma D, Wei JF, Yang X, Yang HW, Yang H, et al. A novel allergen Tab y 1 with inhibitory activity of platelet aggregation from salivary glands of horseflies. Allergy. 2011;66(11):1420-7.
  18. Ma D, Li Y, Dong J, An S, Wang Y, Liu C, et al. Purification and characterization of two new allergens from the salivary glands of the horsefly, Tabanus yao. Allergy. 2011;66(1):101-9.
  19. Ma D, Gao L, An S, Song Y, Wu J, Xu X, et al. A horsefly saliva antigen 5-like protein containing RTS motif is an angiogenesis inhibitor. Toxicon. 2010;55(1):45-51.
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