Part II: Insect allergies—Inhalation and ingestion

Allergies to insect stings and bites are common and were partly discussed in part I of this article series. Other mechanisms leading to allergen contact, sensitization, and potential allergy to insects or insects’ compounds can be hard to suspect and diagnose due to their sometimes-hidden character in food or dust. We aim to provide an overview of allergic reactions to insects elicited by mechanisms other than sting or bite reactions. A PubMed search on allergy and insects apart from bees and wasps was conducted, articles were selected and included, and a series of relevant publications and cases of our outpatient units are used as examples. Allergies to insects following direct contact, inhalation, and accidental and deliberate ingestion are common and various insect species can elicit these allergies. Sensitization may occur transcutaneously, upon inhalation, and through ingestion. Allergic reactions to edible insects, such as grasshoppers and mealworms, as genuine allergies or as tropomyosin or other protein cross-reactivities in seafood or house dust mite allergic individuals are possible. In Europe, with the licensing of mealworms to be consumed as food and sold commercially in January 2021, allergies and cross-reactivity to insects or insect compounds as foods will become more common and relevant.


IgE-Anaphylaxis No Not available
Worldwide Mankouri (2021) [10], Nebbia (2019) [11], Leni (2020) [12] Blattodea: Ectobiidae  lady beetle (Harmonia axyridis; Fig. 1), initially imported as a pest control in North America and Europe in the 1970s, has become an invasive pest in the last few decades. Ladybirds usually invade human homes in fall and winter, causing asthma, allergic rhinitis, and angioedema [40]. Specific IgE to two proteins (Har a 1 und Har a 2) were identified [1,2,4]. Hemolymph externalized during 'reflex bleeding' (a defensive behavior in some Coleoptera where a fluid is excreted when threatened) contains these allergens of H. axyridis. It may lead to the culprit allergen exposure through inhalation. Since there are no commercial ladybird extracts, diagnosis and specific immunotherapy are not standardized. However, there are reports of successful immunotherapy with whole-body extracts [3].  [41]. A diagnosis of seasonal allergic rhinoconjunctivitis and asthma due to ladybird sensitization and a mild grass pollen allergy. The attic was profoundly cleaned and isolated; from then on, the winter symptoms disappeared.

Dermestidae-Carpet beetles
Dermestidae are a family within Coleoptera, including 500-700 species. They can be found all over the world and in a wide variety of habitats. Most are scavengers and eat dead, dried animals and insect remains. These beetles can cause considerable damage to woolen fabrics, furs, and insect and animal collections. However, Dermestes maculatus is used intentionally by museums to clean soft tissue from animal skeletons. IgE-mediated allergy and asthma to dermestid larvae as part of house dust is possible [5]. Furthermore, Dermestidae may lead to T-cell mediated, late-type allergic reactions, as shown in a 2-year-old girl with negative skin prick test but positive skin patch test after 5 days [6]. Dermestidae can also cause histamine liberation and wheals on the affected skin area after contact with their toxic hair [42].

Blattodea-Cockroaches
Currently, over 460 genera with 4600 species of cockroaches are described worldwide. Cockroaches are common and highly adaptable insects with the ability to survive in various climates from Antarctica to the tropics. Cockroaches feed on human food and animal feed. They can transport and spread pathogenic germs on their surface. Cockroaches often trigger inhalant allergies, first demonstrated in New York in the 1960s [13,16,20]. Especially in developing countries, cockroach sensitization is associated with a high risk of asthma development. Especially in inner cities, children with asthma are very frequently sensitized to cockroaches [18,19]. In the past 20 years, 12 cockroach allergens have been identified and are either excreted in feces or are found in the cockroach bodies [14,15,21]. In clinical practice, cockroach extracts and recombinant cockroach allergens can be used for in vitro and in vivo diagnostics. Therapeutically, specific immunotherapies can lead to the improvement of existing asthma ( [43][44][45] ; Fig. 2).

Diptera-Chironomidae
Many inhaled insect allergens are highly concentrated in the air when larvae living in water undergo a metamorphosis in high individual densities [46]. This is the case, for example, for chironomid midges (twitch flies), which occur locally in high concentrations in Japan and can frequently trigger asthma [23,24]. Chironomid midges can also cause allergies in aquarium owners, as these larvae are often used for feeding fish [25].
Chironomid midges do not sting or bite and cannot directly transmit disease. However, egg masses of chironomids have been found to act as a natural reservoir of cholera bacteria ( [22] ; Fig. 3).

Insect allergies as occupational diseases
Occupational insect allergies were described in entomologists, laboratory workers, and farmers. Flour contaminated with insect components causes allergies in bakers and associated occupations. In general, insect-related occupational diseases are caused by direct and deliberate contact with insects or because the workplace is infested with insects [47].
In an American study in 1980, 60% of insect farmers were affected with an inhalant insect allergy [48]. In a recent study, 50% of greenhouse workers who use insects as pest control were sensitized to insects [49].
Direct toxic or allergic reactions on the skin Meloidae, Oedemeridae, and Staphylinidae-Beetle dermatitis Beetle dermatitis (or blistering beetle dermatitis [BBD]) is an inflammatory and non-allergic, blistering skin disorder, sometimes resembling contact dermatitis [55]. Skin lesions are caused by toxic body fluids (cantharidin or pederin) and occur hours after direct contact [39,42]. Beetle dermatitis is a problem worldwide, especially in warmer climates with increasing incidence due to global warming [7,55]. Typically, beetle dermatitis presents as toxic-irritative dermatitis with blistering eruptions, most frequently caused by Meloidae, Oedemeridae, and Staphylinidae [8]. Diagnosis of beetle dermatitis is made by the clinical history and typical cutaneous lesions, and sometimes histopathology provides additional diagnostic clues. To prevent beetle dermatitis, repellents and mosquito nets treated with insecticide can be used, and avoidance of crushing beetles on the skin reduces the risk of beetle dermatitis [9]. No specific treatment for beetle dermatitis exists, and the effect of topical corticosteroids or systemic antihistamines is limited. Sometimes even analgesics are needed because of severe pain [55]. contact dermatitis due to the wooden necklace the patient was wearing. He referred the patient to a local primary care physician who ruled out herpes zoster by PCR and diagnosed irritant dermatitis, most probably due to the locally endemic beetle Paederus littoralis (Family: Staphylinidae) [56]; Fig. 5). Approximately 1 week later, the patient presented at our dermatology department with a widespread eczematous and rash on his face (Fig. 4). Again, microbial swabs (herpes, bacteria, and fungi) were negative, and we treated the patient with topical fusidic acid and hydrocortisone cream. Within 2 weeks, the rash had resolved. Patch testing performed later showed no contact sensitization to common allergens, including fragrances and plants.

Lepidoptera and lepidopterism-Thaumetopoeinae
The Lepidoptera order includes different butterfly and moth species. An important subfamily of the Lepidoptera are the Thaumetopoeinae, commonly called processionary caterpillars in their larval stage (Fig. 6). They are the typical triggers of lepidopterism. In lepidopterism, stinging hairs (setae) of caterpillars containing the protein thaumetopoein can be transmitted to the skin and mucous membranes by air and directly elicit toxic effects [26]. Epidemic-like outbreaks were described in cases of heavy infestation [27]. Different disease mechanisms, including irritant-toxic dermatitis, immediate and late-type hypersensitivity reactions, are thought to elicit symptoms ( [26] ; Fig. 6).

Insects as food
Insects consumed as food or insect compounds hidden in food can cause food allergies. Even though they do not (yet) play a relevant role as a direct food source in Western cultures, insects have been consumed for centuries in developing countries and form a cornerstone of a regular diet. Worldwide, more than 1600 different species are consumed [57]. With the world population growing, the question arises whether finite resources will be able to meet the food needs of so many people. Concerns about food security are directing research into alternative food sources for humans and feed for animals [58]. Edible insects could suit today's consumers seeking nutrient-rich and sustainable food sources. In Switzerland, three insect species can be used as food in processed form since May 2017, namely yellow mealworms (Tenebrio molitor), house crickets (Acheta domesticus), grasshoppers (Locusta migratoria) [59]. In the EU, mealworms are permitted to be sold as food since January 2021 and are considered to be a "novel food".
There are two possibilities to develop allergies to insects. On the one hand, genuine insect allergies to various incompletely characterized insect allergens are possible. On the other hand, and probably much more frequent, a cross-allergy to edible insects must be expected in patients with seafood, crustacean, and potentially also house dust mite allergies [60]. Here, sensitizations to cross-reactive proteins like tropomyosin and also arginine kinase are in the foreground. Due to the large sequence homology within many invertebrate species, cross-reactivity can be expected and has already been described in smaller clinical studies [32,61]. Fig. 7 shows commercially available, freezedried insects in Switzerland.

Orthoptera-Grasshoppers, locusts, crickets
Various Orthoptera species are consumed as food worldwide. Chapulines (genus Sphenarium), for example, are consumed after deep-frying, especially in Mexico [33]. In Asia, crickets (Acheta domesticus) are roasted, grilled, or fried and are nowadays considered to be one of the most promising insect species for global consumption because they have a beneficial nutritional profile. The farming of crickets requires little feed ("low feed conversion ratio") which makes them particularly attractive as "novel food" [62]. However, allergic reactions to Orthoptera, especially in seafood or house dust mite sensitized patients are possible and may be caused by tropomyosin crossreactivity [32,33,63]. In principle, however, genuine food allergies and not only cross-allergies to Orthoptera are possible.

Coleoptera-Mealworms
Allergies to mealworms are of relevance especially in owners of animals who use them as animal feed or bait. After inhalative or transcutaneous sensitization, allergic symptoms such as rhinoconjunctivitis or respiratory symptoms may occur [46,64,65]. Tropomyosin-mediated cross-allergies to mealworms after ingestion as well as genuine mealworm food allergies are possible [10,37,66].

Lepidoptera-Silkworms
The use of Lepidoptera as food is especially common in China, where silk moth pupae (Bombyx mori) are grilled and eaten and can cause immediate type allergic reactions [28,29,46]. An allergic reaction after consuming mopane worms (Imbrasia belina) in Botswana was described [67]. In a recent study, a series of potential Bombyx mori allergens and potential cross-reactive species were identified [30].

Dactylopius coccus-Cochineal lice
Cochineal red (carmine, E120) is a dye obtained by drying and extracting scale insects of the genus Dactylopius. Carmine is approved for coloring various foods and is also used in cosmetics (e.g., blush) and paint colors. Allergic reactions to carmine are rare but often severe. Since the allergen often remains unrecognized for a long time, repeated episodes are characteristic [34]. For example, possible food products containing carmine include Campari (until 2006), fruit juices, and ice cream [34,68].  [69]. The patient denied having symptoms suggestive of house dust mite allergy and remembered having experienced an episode of oral itching, nausea, and vomiting shortly after eating shrimp in her youth and had since avoided eating seafood altogether. During the diagnostic workup, we learned that citrus fruit is coated in a protective wax after harvesting. This wax coating is applied as a seal to prevent the fruit from water loss and to enhance the shininess of the shell. Citrus fruit wax coatings usually contain shellac, a resin produced by the female lac bug (Kerria lacca) [70]. Chewing on the orange slice decorating the drink before the anaphylaxis episode probably led to the culprit allergen exposure. Since no other allergenic source could be identified in the orange peel, our diagnosis was an anaphylactic reaction due to insect compounds in fruit wax based on a tropomyosin sensitization.

Kerria lacca-Lac bug
This case presents a severe allergic reaction to orange peel in a seafood allergic patient documented by a positive skin prick test. Sensitized to various tropomyosins, the patient has reacted to insect compounds, potentially tropomyosins, from the female lac bug (Kerria lacca) in the wax coating of the orange peel induced anaphylaxis. Multiple studies have reported delayed-type hypersensitivity (allergic contact dermatitis) to shellac but not immediate-type hypersensitivity [71]. We assume this is the first case of immediate type allergy to insect compounds in fruit wax.
262 Part II: Insect allergies-Inhalation and ingestion K original article

Conclusion
Bees and wasps are the leading cause of insect-related immediate-type allergies worldwide. Other insect stings and bites may, however, also cause significant morbidity and were discussed in part I of this article series. However, insects are also a relevant cause of inhalant allergies in various settings, patient populations and professions. Direct toxic effects on the skin and immediate or late type allergic cutaneous reactions are all possible after contact with insects or insect parts, such as caterpillar setae. Allergic reactions and direct toxicities after intentional or unintentional ingestion of insects or insect compounds appear to be diverse yet are currently potentially underestimated or underdiagnosed.
Since food safety authorities are licensing insect species to be used in processed foods, and sustainable protein sources will be needed with the growing world population, food allergies involving insect products could become more common. Especially in tropomyosin sensitized patients, they will have to be considered due to cross-reactivity between tropomyosins [59,60,72]. It is, therefore, crucial to determine the allergenic potential of edible insects in detail and to investigate these allergies to "insects as novel food", and strategies must be developed to better assess the associated risks [73,74].
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.
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