INTRODUCTION
Food allergy is a syndrome of ailments that result from immune mechanisms triggered by the ingestion of food containing a specific allergen or allergens [1]. Two primary mechanisms are responsible for the development of allergic reactions: type I hypersensitivity and/or type IV hypersensitivity [2]. In the absence of efficacious therapeutic options for food allergies, patients are advised to adhere to an elimination diet [3–5].
Frequently, food allergies manifest as pruritus, rash, and other cutaneous symptoms [2, 6]. Other manifestations of food allergy may include angioedema, disturbed intestinal peristalsis, rhinorrhea, respiratory wheezing, and anaphylaxis [2]. Anaphylaxis is defined as a systemic, acute, and potentially fatal allergic reaction. It presents with cutaneous lesions, respiratory distress, gastrointestinal distress, and cardiovascular complications. A currently recommended anaphylaxis severity grading system includes 5 grades of reaction severity, with anaphylactic shock, cardiac arrest and respiratory arrest classified as the most severe forms of anaphylaxis [7]. Since several other anaphylaxis grading systems have been published, severity assessment may vary with regard to the same anaphylactic event [8], which may lead to inaccuracies and potential misunderstandings in the interpretation of clinical findings [7, 9–11].
Idiopathic anaphylaxis (IA) is a rare and potentially life-threatening condition that is characterized by the onset of anaphylaxis in the absence of an identifiable cause. A diagnosis of idiopathic anaphylaxis is made through the process of exclusion. In some cases, diagnostic tests such as skin tests, measurement of specific IgE, and assessment of tryptase levels may prove beneficial. This ailment can affect patients of any age; however, the population in which its incidence is recorded the highest is adult women [12].
Immediate intramuscular administration of epinephrine is essential for the prompt treatment of every incident of anaphylaxis, although severity-driven specific indications and recommendations vary. In cases of recurrent IA episodes exceeding six per year, the use of preventive therapy, such as glucocorticosteroids or antihistamines, is recommended [12].
Allergic reactions caused by non-specific lipid transfer proteins (nsLTPs) are referred to as lipid transfer protein (LTP) syndrome. Due to the resistance of these proteins to high temperatures and the action of digestive enzymes, they can cause allergic reactions even after prior food processing. The occurrence of crossreactions, even between taxonomically disparate plants, is responsible for the extensive range of foods that elicit symptoms in individuals with LTP syndrome. The typical foods that induce LTP syndrome are peaches, apricots, and apples, as well as nuts, cereals, and vegetables [13]. Clinical symptoms are identical to those observed in individuals with food allergies, as previously described. However, the severity of the symptoms is correlated with the degree of sensitization to various nsLTPs [13].
Projections by the Food and Agriculture Organization of the United Nations (FAO) indicate that the global population will exceed the 9-billion threshold even before 2050 [14]. In light of these considerations, it seems prudent to pursue the identification of alternative food sources that are rich in essential micronutrients and macronutrients, while also demonstrating environmental sustainability. The utilization of edible insects is regarded as a promising avenue of exploration. By September 2024, the European Union had approved the consumption of Tenebrio molitor, Acheta domesticus, Locusta migratoria, and Alphitobius diaperinus [15]. At present, they are primarily utilized as enrichment ingredients in food products, including protein bars, snacks, pasta, and baked goods. Despite the optimistic outlook on the use of edible insects, it is important to acknowledge the potential risks, including the possibility of food allergies.
AIM
The objective of this case report is to describe the diagnostic process undertaken in a patient presenting with LTP syndrome and a history of apparently IA. Assessments performed in the described patient were elements of a routine diagnostic workup applicable for allergic conditions. This case report will also examine the potential adverse side effects of consuming food additives derived from edible insects. Furthermore, the applicability of the Allergy Explorer 2 (ALEX2) (Macro Array Diagnostics GmbH, Vienna, Austria) molecular test in the diagnostic process of unexplained anaphylaxis will be discussed. The patient consented for diagnostic procedures and for inclusion of the results into description provided in the manuscript.
CASE REPORT
A 66-year-old Caucasian male, professional driver residing in a rural area was referred to the outpatient allergy clinic for diagnostic evaluation of the three episodes of anaphylaxis of seemingly unknown etiology. Family and personal history revealed no evidence of allergic disease. The patient has not been regularly taking any medications and has not reported having suffered from any condition. No abnormalities were observed on the physical examination at the first medical visit.
MEDICAL HISTORY
In January 2023, the patient experienced his first episode, presenting with hives and localized edema. The patient did not seek medical attention and instead limited his treatment to the topical application of a moisturizing cream, with good effect.
The second episode occurred in May 2023. The patient was conveyed to the emergency department by the emergency medical team, exhibiting symptoms of hives, nausea, hypotension, and weakness, with no loss of consciousness. The symptoms manifested while the patient was engaged in activities within a garden setting, with no apparent causative factor having been identified. Intramuscular epinephrine, as well as intravenous corticosteroids and antihistamines were administered and the symptoms subsided promptly.
In December 2023, the third incident of anaphylaxis presumably occurred. The patient self-administered adrenaline following the onset of initial symptoms in the form of hives, without consulting a physician. He did not subsequently seek further medical assistance.
The patient was not able to identify any potential triggers or cofactors, such as exercise, alcohol, drugs, or infections for any of the three above-listed incidents.
DIAGNOSTIC PROCEDURES
In December 2023, an ALEX2 (Macro Array Diagnostics GmbH, Vienna, Austria) test was performed, revealing IgE-mediated sensitization to: hazel (Cor a 1), Bermuda grass (Cyn d 1), mugwort (Art v 3), quinoa (Che a 1), mites (Der p 5 and Blo t 21) and mold (Asp f 1 and Cla h 8) allergens. Moreover, sensitization to ω-5-gliadin (Tri a 19), storage proteins (2S albumin) of hazelnut, walnut, cashew and nsLTPs of mugwort, apple, kiwi, hazelnut was also demonstrated. In addition, presence of sIgE was ascertained with regard to the allergens of the following edible insects: the house cricket (Acheta domesticus), the migratory locust (Locusta migratoria), and the mealworm (Tenebrio molitor). Positive results of specific IgE to allergen extracts and components are presented in Table 1.
Table 1
Specific IgE concentrations in allergen extracts and components as detected through ALEX2 multiple molecular diagnostic test
FOLLOW-UP
The patient was prescribed intramuscular epinephrine in an autoinjector and oral prednisone and antihistamine to be used on-demand. Information about symptoms of imminent anaphylaxis was provided to the patient and indications as well as modalities of administration were discussed in detail. The patient was also instructed to immediately seek medical assistance in case of the appearance of symptoms consistent with developing generalized reaction, irrespective of its severity and identification of triggers. Until October 2024, the patient has not reported any generalized reaction.
DISCUSSION
LTP syndrome represents a significant clinical challenge due to the high prevalence of severe symptoms, the high resistance of antigens to heat treatment and digestive enzymes, and the numerous cross-reactions between nsLTPs of distinct species [13]. A potential factor contributing to increased exposure to nsLTPs may be the changes in dietary habits of consumers, which have resulted in a greater consumption of imported plant products. Consequently, this may result in an increased prevalence of allergic symptoms, an elevated risk of adverse health outcomes (including allergic reactions) and a rise in healthcare expenditure.
The consumption of edible insects, such as Tenebrio molitor, Acheta domesticus, Locusta migratoria, and Alphitobius diaperinus, and their derived products is becoming increasingly prevalent on a global scale. This is due to the fact that insects have a high protein content and require much less natural resources, water, feed, and breeding area than traditional animal husbandry [16].
Nevertheless, entomophagy may be associated with certain health risks, particularly in the context of food allergies. Such reactions may result from primary sensitization to insect allergens or cross-reactions between insect allergens and other invertebrates, including crustaceans (e.g., shrimp) or mites [17]. This phenomenon can be attributed to the presence of specific allergens, including tropomyosin, arginine kinase, and aldehyde-3-phosphate dehydrogenase, which are ubiquitous across these groups [14]. In the case we present, no association with exposure to sensitizing nsLTP or allergen of edible insects could be established. However, since those proteins may be ingested as part of complex food products, constant vigilance is advised. Furthermore, apparently unexplained anaphylaxis incidents in the patient with confirmed IgE-sensitization to both multiple nsLTPs and 3 out of 4 EU-approved edible insects underline the necessity for further elaboration of proper food labeling.
It is also recommended that the introduction of new species of edible insects and their products to the market in the European Union be preceded by appropriate education about the potential health risks associated with specific groups (e.g., individuals with allergies to crustaceans), in addition to proper labeling.
The Allergy Explorer (ALEX2) test is a state-of-the-art multiplex test that enables the simultaneous assessment of IgE reactivity to 295 allergens derived from 165 sources. Moreover, the use of advanced molecular technology enables the determination of specific IgE antibody levels and total IgE levels [18]. Utility of ALEX2 has been assessed and proved in several large-scale studies assessing IgE-sensitization profile in various populations [19]. The ability of ALEX2 to detect a vast array of allergens makes it a valuable tool for identifying lipid transfer protein syndrome and edible insect allergies [18].
In the case of LTP syndrome, the ALEX2 test allows for the simultaneous diagnosis of multiple nsLTPs responsible for the allergy, which is difficult to achieve with traditional methods. Furthermore, the test enables the evaluation of the likelihood of cross-reactions between disparate products [18].
In the context of allergies to edible insects, the ALEX2 test enables the diagnosis of both primary food allergies and predisposition to cross-reactions (e.g., in individuals allergic to other shellfish) [18].
CONCLUSIONS
Molecular diagnostic panels may be an efficient method for identifying sensitization to multiple allergens and their components. Inclusion of allergenic proteins of edible insects to multiplex diagnostic tools used in the assessment of IgE-sensitization should be aimed at and promoted. This is of particular importance in the light of possible cross-sensitization to phylogenetically non-related plant or animal allergens as well as to allergenic proteins coming from newly approved alternative sources of nutritional products. In light of the evolving dietary patterns, including the incorporation of edible insects and an increase in the consumption of imported plant products, it is necessary to prioritize consumer education and accurate product labeling. Such measures may help to prevent potential allergic reactions.
