Shajitha Melethil*
Ejaz Yousef
- Division of Allergy and Immunology, Nemours Children’s Health, Jacksonville, FL, United States
This review provides a comprehensive overview of rare causes of pediatric anaphylaxis related to obscure allergens. Anaphylaxis, a severe hypersensitivity reaction, can occur without typical symptoms, posing diagnostic challenges, especially in children. Idiopathic anaphylaxis, where no trigger is identified despite thorough evaluation, is notably challenging in this population. This review synthesizes current literature, highlighting obscure triggers such as food additives, spices like fenugreek, and cross-reactive allergens, including lupine and gelatin. These allergens are often overlooked and can lead to misdiagnosis of idiopathic cases. Understanding these uncommon triggers is crucial for clinicians to ensure accurate diagnosis and effective management of pediatric anaphylaxis, emphasizing the need for heightened clinical awareness and further research. This review raises awareness among health care providers about these lesser-known causes, aiming to improve outcomes and quality of life for pediatric patients at risk of anaphylactic reactions.
1 Introduction
Anaphylaxis is a rapid-onset, severe systemic hypersensitivity reaction that can compromise the airway, breathing, and/or circulation, occurring with or without skin or cutaneous symptoms (1, 2). In children, common triggers include food, medications, and venom. Idiopathic anaphylaxis (IA) is diagnosed when no triggers are identified despite thorough evaluation (3–6). IA is more common in adults than in children; based on available data, 30%–60% of adult case of anaphylaxis are considered idiopathic, while approximately 10% of pediatric cases are considered idiopathic (7–9). In Asia-Pacific territories like Thailand, Singapore, Hong Kong, and China, 22% of pediatric cases were idiopathic (10). IA poses a significant diagnostic challenge and affects patients' quality of life. Hidden and uncommon allergens should be thoroughly considered before diagnosing IA (11–13). Currently, there is scarce information in medical literature about the rare causes in children. This review emphasizes rare causes of pediatric anaphylaxis, urging clinicians to remain vigilant.
2 Food and drug additives
Food additives can preserve, flavor, sweeten, thicken/emulsify, color, or stabilize food. These substances, either natural or synthetic, are not typical nutritive food ingredients and are rarely consumed alone. Up to 2% of children have reported adverse reactions to food additives, most of which are not likely immune-mediated, with higher rates (2%–7%) in those with atopic backgrounds (14–17). The U.S. Food and Drug Administration (FDA) has approved over 3,000 compounds as food additives and around 773 chemical agents for drug products (18, 19). U.S. and European Union (EU) regulations require the declaration of all intentionally added ingredients. However, certain composite foods like spices and natural or artificial flavors can be listed collectively, risking exposure to hidden allergens.
2.1 Spices
Allergy to spices is rare (2%–6.4% of total food allergies) and usually presents in adulthood (20).
Mustard is an important spice crop worldwide and belongs to the family Brassicaceae. Oral ingestion of mustard can trigger allergic reactions, including oral allergy syndrome, anaphylaxis, allergic rhinitis, asthma, and atopic dermatitis. In a study involving 49 mustard-allergic children in France, clinical manifestations included skin reactions (urticaria, angioedema) in 21 patients (42.8%), gastrointestinal reactions in 1 patient (2%), and conjunctivitis in 2 patients (4%) (21). Additionally, oral allergy syndrome and anaphylaxis were reported in 2% of the children (21).
There are very few studies that report angioedema and anaphylaxis after spice ingestion in children. Yazıcı et al. reported a case of a 13-year-old who developed angioedema upon exposure to three plants of the Lamiaceae family: Salvia officinalis (common sage), Mentha piperita (peppermint), and Origanum onites L (oregano) confirmed by oral food challenge (22).
Another case report discusses a 17-month-old child developing anaphylaxis after consuming venison seasoned with black pepper; skin and sIgE tests were positive for black pepper (23).
Another spice rarely reported as causing anaphylaxis in the pediatric age group is fenugreek. Fenugreek (Trigonella foenum-graecum) belongs to the Leguminosae family, along with other legumes like peanuts, soybeans, green peas, lentils, beans, chickpeas, and lupins. Fenugreek is an aromatic spice often used in Indian-style cooking. Faeste et al. found considerable homologous IgE-binding epitopes between fenugreek protein and major peanut allergens Arah1, Arah2, and Arah3, resulting in significant cross-reactivity (24). Che et al. reported a case of a 14-year-old with known allergies to peanuts, lentils, chickpeas, and peas who developed anaphylaxis to fenugreek after eating curry at a restaurant (25). They also reported a case of another 14-year-old with known food allergies to cashews who developed anaphylaxis possibly to sumac spice after eating a fattoush salad (25). Sumac (Rhus coriaria L.) and cashew both belong to the Anacardiaceae family, causing the possibility of cashew-sumac cross-reactivity resulting in anaphylaxis.
2.2 Food preservatives
Sulfites are used as food or drug additives for several different technical purposes, including to prevent enzymatic and non-enzymatic browning of fresh fruits and vegetables for their antioxidant properties and bleaching effects (19). Although sulfite-induced asthma has been reported in the pediatric age group, anaphylaxis is rare. There is a case report presented by Vitaliti et al. about a 5-year-old who developed anaphylaxis secondary to sodium metabisulphite sensitization (26). This child, who has a strong atopic background, reacted to multiple preserved foods and drugs, but skin prick tests for these foods and medications were negative (26). Diagnosis of sulfite allergy was established based on clinical history, specific IgE test for sulfite by ELISA immuno-enzymatic-reaction and patch test, as well as abatement of her symptoms following cessation of sulfite-containing foods and medications (26). Authors raised concerns regarding the treatment of patients who develop anaphylaxis to sulfites, which can be challenging since adrenaline and epinephrine products can contain sulfites, thus limiting treatment options (26).
2.3 Food additives
2.3.1 Food coloring
There are no reported studies resulting in anaphylaxis due to food coloring in children. Leung et al. reported a case of a 17-year-old who developed anaphylaxis as well as biphasic reaction to patent blue vital dye (PBV), which is frequently used as a perioperative drug for lymphangiography (27). Interestingly, it also is used as a food additive. One case reported a 2-year-old with recurrent urticaria and angioedema upon exposure to annatto dye (28).
2.3.2 Sugar alcohols
A double-blind placebo-controlled food challenge for an 11-year-old confirmed anaphylaxis to erythritol (29). The patient developed anaphylaxis after ingesting a diet sauce and health food containing erythritol (29).
Anaphylaxis to xylitol was reported in a 2-year-old with a history of allergy to cow's milk and hen's egg. This was confirmed by the skin prick test and basophil activation test (30).
2.3.3 Food thickening agents/emulsifiers
Pectin is used as an emulsifier in jellies, jams, and candies, as a thickening agent in drinks, dessert fillings, and medicines, and as a source of dietary fiber. It is a structural heteropolysaccharide and shares common antigenic determinants with tree nuts like cashews and pistachios from the Anacardiaceae family. Pectin is commercially derived from apple or citrus fruits. Inhalation of pectin has been associated with rhinitis and occupational asthma, but there are few cases of IgE-mediated anaphylaxis in pediatric patients after ingestion of pectin. Pectin allergy should be considered in unexplained anaphylaxis, particularly in patients with cashew or pistachio allergies (31–34).
Gelatin is a partially denatured protein from animal collagen (bovine or porcine skin and bones). It is found in foods like gummy candies, medications like capsules or ointments, cosmetics, and vaccines (35). Though known to cause anaphylaxis, some patients do not consistently react to gelatin. Extensive hydrolyzation lowers its molecular weight and gel melting point, making it less allergenic. Thus, processing and dosing variability can affect its allergenicity (35, 36). Fish gelatin, prepared from fish like tuna, pollock, cod, and salmon, is available for dietary or religious reasons. There are few reports of fish gelatin causing anaphylaxis (37). Kuehn et al. reported an anaphylaxis case after ingestion of marshmallows with fish gelatin (38).
Fish gelatin may not be declared on allergy labels in the EU, as certain ingredients have temporary exemptions (39). With the use of fish gelatin-containing products expanding, it should be considered in children with idiopathic anaphylaxis, especially those with fish allergies.
2.3.4 Lupine
Lupin, or lupini, is a legume of the genus Lupinus. Among the three Mediterranean species (blue, white, and yellow), white lupin is mainly used in the food industry, while yellow and blue lupin serve as livestock fodder. Lupin is versatile in food products, often added to milled flour to enhance flavor, color, and texture in baked goods, pasta, and vegan substitutes. It's also a growing plant-based protein source in gluten-free products.
Allergic reactions to lupin can be a primary lupin allergy or due to cross-reactivity with other legumes, especially peanuts. Reports in Europe indicate peanut-allergic patients reacting to lupin (40). In Canada, Soller et al. documented the first anaphylactic case in a 10-year-old who has allergies to peanuts and tree nuts, leading to a Health Canada advisory on lupin allergy (41). The U.S. Food Allergen Labeling and Consumer Protection Act does not require lupin labeling. Bingemann et al. noted an 11-year-old, with no prior food allergy, experiencing anaphylaxis from waffles containing lupine (42).
A French study by Muller et al. found that approximately two-thirds of peanut-allergic children were sensitized to other legumes, including lupin, and one-quarter were diagnosed with legume allergies (43). Half of the reactions were severe, including anaphylaxis. With the global rise in legume consumption, recognizing cross-allergies is crucial. In the United Kingdom and EU, only three legumes are priority allergens: peanut, soy, and lupin. Other legumes like pea protein and fenugreek also can cause severe allergic reactions.
2.4 Anisakis
Anisakiasis is a parasitic disease first described in the 1960s in the Netherlands. IgE-mediated allergy was reported in the 1990s (44). It is caused by the consumption of raw or undercooked seafood contaminated by third-stage larvae of the nematode Anisakidae family (Anisakis simplex, A. pegreffii, and Pseudoterranova decipiens). IgE-mediated allergy to Anisakis simplex has been described in Europe (especially Spain) and Asia (mainly Japan) (44–46). Food globalization has led to culinary diversity and an increase in the consumption of raw fish in different parts of the world, leading to reports of Anisakiasis from North and South America including the U.S. (47). Anisakis is a rare cause of anaphylaxis in the pediatric age group (45, 46). Centonze et al. reported the case of an 8-year-old who initially presented with anaphylaxis and progressively worsening right testicular pain (48). A histological exam confirmed extra-gastrointestinal anisakiasis (48). If there is clinical suspicion, a skin prick test and sIgE levels of the total extract or specific allergen components will help confirm the diagnosis.
2.5 Pancake syndrome
Oral mite anaphylaxis (OMA), or pancake syndrome, was first described by Erben et al. in 1993 (49). OMA can occur at any age, including in young children (50–54). It is characterized by anaphylaxis after consuming foods made with mite-contaminated flour, including wheat, oats, and corn flour. A recent update by Sánchez-Borges et al. reports over 200 OMA patients worldwide from countries such as Spain, Ireland, Belgium, the U.S., Venezuela, Peru, Panama, Japan, Singapore, Thailand, and Taiwan (55). The pathogenesis involves the rapid absorption of mite allergens in sensitized individuals. Various species of domestic and storage mites are responsible for OMA. Notably, approximately 40% of OMA patients also have non-steroidal anti-inflammatory drug (NSAID) hypersensitivity (56), and exercise-induced anaphylaxis has been reported with OMA (57, 58).
2.6 Lipid transfer protein syndrome
Nonspecific lipid transfer proteins (nsLTP) are heat-stable, pepsin digestion-resistant small proteins that are plant pan allergens (59). IgE-mediated reactions, including anaphylaxis to nsLTPs, have been reported in multiple studies in Southern European countries, but there is significant data emerging from other parts of the world (60). To date, there have been only three reported cases of pediatric lipid transfer protein (LTP) in the U.S (61). It frequently involves a co-factor for eliciting the reaction, involving exercise and NSAIDs. Fruits belonging to the Rosaceae family are the main culprits for nsLTP-induced anaphylaxis, especially peach (Pru p3), as per the European studies (60). However, a recent retrospective chart review conducted in Latin America found tree-nuts, like walnut and almond, trigger anaphylaxis instead of peach likely due to difference in dietary patterns (62). There also is an increasing body of evidence that suggests against primary sensitization to a pollen source (63).
Cabrera-Freitag et al. reported nsLTP-related anaphylaxis after passive exposure to cannabis in two adolescents, proposing that nsLTP Can s 3 involved in cannabis-fruit and vegetable syndrome as the culprit allergen (64).
3 Drug and vaccine excipients
Excipients and residues in drugs and vaccines can function as hidden allergens (65–67). Dextran, a vaccine stabilizer, caused hypersensitivity reactions post-MMR vaccination in Brazil (68). Rotarix, a live rotavirus vaccine, contains dextran. The yellow fever (YF) vaccine, grown in chicken eggs, may contain residual egg ovalbumin, potentially triggering severe reactions. Limited data exists on YF vaccine use in egg-allergic patients. Tanos Lopes et al. reported 435 children, of which approximately 33% had a possible history of egg anaphylaxis, 95.2% had no reactions, and of the 4.8% who had reactions, only one patient had possible anaphylaxis, implying the YF vaccine can be safely administered in egg-allergic children (69).
3.1 Carboxymethylcellulose
Carboxymethylcellulose (CMC) is an anionic hydrosoluble substance used in food and pharmaceutical industries as a stabilizing agent. IgE-mediated anaphylaxis has been reported in adults following intra-articular steroid injections and in barium sulfate suspensions used as contrast media. Pediatric anaphylaxis to CMC in drugs has not been reported, but there is a case of a 14-year-old who experienced anaphylaxis after consuming a CMC-containing ice lolly/popsicle (70).
3.2 Mannitol
In 1979, Lamb and Keogh first reported a case of anaphylactoid reaction to mannitol infusion in a 16-year-old with an atopic background (71). Lightner et al. reported a case of a 19-month-old who experienced anaphylaxis to mannitol (72). The child had a history of drug hypersensitivity and received mannitol for diuresis after chemotherapy (72). The authors concluded that patients with atopic backgrounds should be carefully monitored when receiving mannitol. Mannitol also has been used as a food additive (E421 as per European Directives on food labeling) and a low-calorie sweetener.
3.3 Polysorbate
Polysorbates, akin to Polyethylene glycol, are utilized in various injectable medications such as local anesthetics, glucocorticoids, biologics (e.g., omalizumab, adalimumab, ustekinumab), erythropoietin, darbepoetin, antibiotics, creams, and vaccines due to their emulsifying and stabilizing properties. Perino et al. documented a case involving a 15-year-old who experienced anaphylaxis after the initial omalizumab injection for asthma (73). The patient tested positive for omalizumab and polysorbate 20 (an excipient), suggesting polysorbate sensitization leading to omalizumab-induced anaphylaxis (73).
3.4 Polymyxin
Contact dermatitis has been reported after the use of topical antimicrobial medication, but anaphylaxis is extremely rare. Henao et al. reported a 2-year-old who developed anaphylaxis after administering polymyxin B-trimethoprim eye drops for the second time (74). IgE-mediated hypersensitivity to polymyxin was confirmed by skin testing, which included full-strength polymyxin, and was negative for the trimethoprim component.
Polymyxin also is used as a vaccine additive, so physicians must exercise caution if there is a reported history of sensitization.
3.5 2-Phenoxyethanol
Nakayama et al. reported a cluster of anaphylaxes in children following the administration of a trivalent split inactivated influenza vaccine (TIV) that contained 2-phenoxyethanol (2-PE) as the preservative in 2011–12 in Japan (75). IgE antibodies were detected against influenza vaccine materials, but the mechanisms that resulted in this influence of 2-PE are not yet clear. The incidence of anaphylaxis events reduced after 2-PE was changed to thimerosal in the 2012–13 season.
3.6 Polyethylene glycol
Type I hypersensitivity reactions to polyethylene glycol (PEG)/macrogls 3350 (76), specifically PEG-2000-N used in COVID-19 mRNA vaccines, have gained significant attention post-pandemic. PEG serves as an additive in medications (e.g., laxatives, steroids), chemotherapeutic agents for stabilization, and in food and cosmetics. Anaphylaxis to PEG in children is exceedingly rare. Khalid and Bundy reported an 11-year-old experiencing anaphylaxis to intravenous pegaspargase and oral Miralax (PEG-3350) (77). Hamano et al. documented a 3-year-old with anaphylaxis to oral olopatadine hydrochloride (PEG 4000) and oral xylocaine pump spray 8% (PEG 400) (78). The mechanism of PEG hypersensitivity, likely IgE-mediated Type I reactions, remains poorly understood. Issues such as inconsistent terminology, inadequate labeling, and gaps in knowledge contribute to potential misdiagnosis (79).
3.7 Human serum albumin
Adverse reactions to human serum albumin (HSA) are rare. Wang et al. reported a case of a 10-year-old who underwent plasmapheresis for Guillain-Barré syndrome and immediately developed anaphylaxis to the HSA in the replacement fluid (80). Basu et al. reported a case series, which includes a 15-year-old with anaphylaxis to 5% HSA (81). In both cases, titrated intra-dermal testing was employed to establish diagnosis as no standardized skin test was available. Basu et al. also proposed a diagnostic algorithm consisting of a histamine release test and titrated intravenous provocation if skin testing is equivocal (81). HSA hypersensitivity should be considered, especially when reactions happen in peri-operative settings or in relation to infusions. It could be seen as an occult allergen as it may not be the main ingredient in the formulation.
3.8 Airborne anaphylaxis
Both food and medications can trigger anaphylaxis via the inhaled route, albeit rare (82). Multiple foods have been reported to be elicitors, including cow's milk, legumes, seafood, grains like rice, buckwheat, seeds, and potatoes. Foods used as drug excipients, like lactose, also can trigger anaphylaxis in food-allergic individuals (83). Morikawa et al. reported on a 6-year-old with a cow milk allergy who developed anaphylaxis after inhaling laninamivir octanoate hydrate to treat influenza, which contained lactose as an excipient (84). Dry powder inhalers may contain lactose as excipients and precipitate anaphylaxis (85).
4 Uncommon food allergy syndromes causing anaphylaxis
4.1 Bird-egg syndrome
This is uncommon in children. In 1993, Añíbarro et al. described a 5-year-old child who developed asthma triggered by bird feathers and a year later developed anaphylaxis to egg which was the first reported case in the pediatric age group (86). Serum albumins are the highly cross-reacting allergens responsible for this syndrome. They can be found in bird feathers, muscle tissue and egg yolk (α-Livetin or Gal d 5) (87).
4.2 Pork-cat syndrome
This IgE-mediated hypersensitivity reaction stems from cross-reactivity between cat serum Albumin (Fel d 2) and porcine (Sus s 1) and beef (Bos d 6) serum albumins. Cases in children are rare (88–91). Symptoms typically occur post-consumption of raw or smoked meats, as pork serum albumin is heat-labile. Reduced exposure to cats may lower sIgE to cats, potentially improving tolerance to pork.
4.3 Alpha-gal syndrome
This allergic syndrome can lead to either immediate hypersensitivity to drugs containing alpha-gal (e.g., Cetuximab) or delayed hypersensitivity from consuming red meat from non-primate mammals (beef, pork, lamb). It typically follows a tick bite (Amblyomma americanum/lone star tick in North America, Ixodes ricinus in Europe, Ixodes holocyclus in Australia, and Ixodes nipponensis in Asia). The factors triggering alpha-gal IgE production post-tick bite remain unclear. Pediatric studies on alpha-gal syndrome (AGS) indicate lower incidence than in adults, lower sIgE levels to α-gal, mainly gastrointestinal symptoms, limited trigger foods, and relevance to cofactors like sports (92–95). AGS should be considered in the differential in children presenting with anaphylaxis in the absence of any apparent reason.
4.4 Exotic food anaphylaxis
Ballardini et al. reported a 13-year-old with a known allergy to chicken meat who presented with anaphylaxis after ingesting crocodile meat (96). It was hypothesized that IgE cross-reactivity between α-parvalbumins in chicken and crocodile meat was the culprit.
Anaphylaxis after ingestion of fish roe has been reported in a few pediatric cases and should be suspected in patients who develop anaphylaxis after consuming seafood but have absent seafood allergy (97–101).
4.5 Food-dependent exercise-induced anaphylaxis
Although it is a distinct clinical entity, clinicians often miss anaphylaxis triggered by physical activity, especially when it occurs in conjunction with hidden food ingredients such as wheat, celery, and cabbage consumed before exercise (102).
5 Conclusion
This review highlights the challenge of “idiopathic anaphylaxis” in children, emphasizing rare triggers like food additives, spices (e.g., fenugreek), and cross-reactive allergens (e.g., lupine, gelatin). Awareness of these obscure causes remains on a careful and detailed clinical history, potentially with the aid of food diaries, and then targeted investigations based on these findings. This is crucial for accurate diagnosis and effective management of pediatric anaphylaxis, emphasizing the need for heightened clinical awareness.
Author contributions
SM: Conceptualization, Writing – original draft, Data curation, Project administration. EY: Supervision, Writing – review & editing, Project administration, Resources.
Funding
The authors declare that financial support was received for the publication for this article. Publication made possible in part by support from the Nemours Children's Health Grants for Open Access from Library Services (GOALS).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
1. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M, Fineman S, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. (2020) 13:100472. doi: 10.1016/j.waojou.2020.100472
2. Golden DBK, Wang J, Waserman S, Akin C, Campbell RL, Ellis AK, et al. Anaphylaxis: a 2023 practice parameter update. Ann Allergy Asthma Immunol. (2024) 132:124–76. doi: 10.1016/j.anai.2023.09.015
3. Carter MC, Akin C, Castells MC, Scott EP, Lieberman P. Idiopathic anaphylaxis yardstick: practical recommendations for clinical practice. Ann Allergy Asthma Immunol. (2020) 124:16–27. doi: 10.1016/j.anai.2019.08.024
4. Burrows AG, Ellis AK. Idiopathic anaphylaxis: diagnosis and management. Allergy Asthma Proc. (2021) 42:481–8. doi: 10.2500/aap.2021.42.210081
5. Gulen T, Akin C. Idiopathic anaphylaxis: a perplexing diagnostic challenge for allergists. Curr Allergy Asthma Rep. (2021) 21:11. doi: 10.1007/s11882-021-00988-y
6. Conner JE, Steinberg JA. Approach to idiopathic anaphylaxis in adolescents. Med Clin North Am. (2024) 108:123–55. doi: 10.1016/j.mcna.2023.05.018
7. Kemp SF, Lockey RF, Wolf BL, Lieberman P. Anaphylaxis. A review of 266 cases. Arch Intern Med. (1995) 155:1749–54. doi: 10.1001/archinte.155.16.1749
8. Ditto AM, Harris KE, Krasnick J, Miller MA, Patterson R. Idiopathic anaphylaxis: a series of 335 cases. Ann Allergy Asthma Immunol. (1996) 77:285–91. doi: 10.1016/S1081-1206(10)63322-4
9. Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. (2006) 97:39–43. doi: 10.1016/S1081-1206(10)61367-1
10. Leung ASY, Tham EH, Pacharn P, Xing Y, Trinh HKT, Lee S, et al. Disparities in pediatric anaphylaxis triggers and management across Asia. Allergy. (2024) 79:1317–28. doi: 10.1111/all.16098
11. Tomei L, Muraro A, Giovannini M, Barni S, Liccioli G, Paladini E, et al. Hidden and rare food allergens in pediatric age. Nutrients. (2023) 15:1386. doi: 10.3390/nu15061386
12. Skypala IJ. Food-induced anaphylaxis: role of hidden allergens and cofactors. Front Immunol. (2019) 10:673. doi: 10.3389/fimmu.2019.00673
13. Nanagas VC, Baldwin JL, Karamched KR. Hidden causes of anaphylaxis. Curr Allergy Asthma Rep. (2017) 17:44. doi: 10.1007/s11882-017-0713-2
14. Treudler R, Simon JC. Anaphylaxis to food additives. Allergo J Int. (2022) 31:141–4. doi: 10.1007/s40629-022-00203-y
15. Randhawa S, Bahna SL. Hypersensitivity reactions to food additives. Curr Opin Allergy Clin Immunol. (2009) 9:278–83. doi: 10.1097/ACI.0b013e32832b2632
16. Fuglsang G, Madsen C, Saval P, Osterballe O. Prevalence of intolerance to food additives among Danish school children. Pediatr Allergy Immunol. (1993) 4:123–9. doi: 10.1111/j.1399-3038.1993.tb00080.x
17. Fuglsang G, Madsen G, Halken S, Jørgensen S, Ostergaard PA, Osterballe O. Adverse reactions to food additives in children with atopic symptoms. Allergy. (1994) 49:31–7. doi: 10.1111/j.1398-9995.1994.tb00770.x
18. Andreozzi L, Giannetti A, Cipriani F, Caffarelli C, Mastrorilli C, Ricci G. Hypersensitivity reactions to food and drug additives: problem or myth? Acta Biomed. (2019) 90:80–90. doi: 10.23750/abm.v90i3-S.8168
19. Bush RK, Taylor SL. Reactions to Food and Drug Additives. Middleton’s Allergy: Principles and Practice. 8th ed. Vol. 2-2. Philadelphia, PA: Elsevier Inc. (2014). p. 1340–56. doi: 10.1016/B978-0-323-08593-9.00083-8
20. Moneret-Vautrin DA, Morisset M, Lemerdy P, Croizier A, Kanny G. Food allergy and IgE sensitization caused by spices: cICBAA data (based on 589 cases of food allergy). Allerg Immunol (Paris). (2002) 34:135–40.12078423
21. Rancé F, Kanny G, Dutau G, Moneret-Vautrin DA. Food hypersensitivity in children: clinical aspects and distribution of allergens. Pediatr Allergy Immunol. (1999) 10:33–8. doi: 10.1034/j.1399-3038.1999.101008.x
22. Yazıcı S, Nacaroglu HT, Bahçeci Erdem S, Karaman S, Can D. Angioedema due to Lamiaceae allergy. Iran J Allergy Asthma Immunol. (2018) 17:97–9.
24. Faeste CK, Christians U, Egaas E, Jonscher KR. Characterization of potential allergens in fenugreek (Trigonella foenum-graecum) using patient sera and MS-based proteomic analysis. J Proteomics. (2010) 73:1321–33. doi: 10.1016/j.jprot.2010.02.011
25. Che CT, Douglas L, Liem J. Case reports of peanut-fenugreek and cashew-sumac cross-reactivity. J Allergy Clin Immunol Pract. (2017) 5:510–1. doi: 10.1016/j.jaip.2016.12.024
26. Vitaliti G, Guglielmo F, Giunta L, Pavone P, Falsaperla R. Sodium metabisulphite allergy with multiple food and drug hypersensitivities in a five-year-old child: a case report and literature review. Allergol Immunopathol (Madr). (2015) 43:106–8. doi: 10.1016/j.aller.2013.10.003
27. Leung M, McCusker C, Ben-Shoshan M. Anaphylaxis to patent blue dye in a 17-year-old boy. BMJ Case Rep. (2019) 12:e226191. doi: 10.1136/bcr-2018-226191
28. Myles IA, Beakes D. An allergy to goldfish? Highlighting the labeling laws for food additives. World Allergy Organ J. (2009) 2:314–6. doi: 10.1097/WOX.0b013e3181c5be3
29. Shirao K, Inoue M, Tokuda R, Nagao M, Yamaguchi M, Okahata H, et al. “Bitter sweet”: a child case of erythritol-induced anaphylaxis. Allergol Int. (2013) 62:269–71. doi: 10.2332/allergolint.12-LE-0517
30. Okamoto K, Kagami M, Kawai M, Mori Y, Yamawaki K, Nakajima Y, et al. Anaphylaxis to xylitol diagnosed by skin prick test and basophil activation test. Allergol Int. (2019) 68:130–1. doi: 10.1016/j.alit.2018.08.001
31. Ferdman RM, Ong PY, Church JA. Pectin anaphylaxis and possible association with cashew allergy. Ann Allergy Asthma Immunol. (2006) 97(6):759–60. doi: 10.1016/S1081-1206(10)60966-0
32. Capucilli P, Kennedy K, Kazatsky AM, Cianferoni A, Spergel JM. Fruit for thought: anaphylaxis to fruit pectin in foods. J Allergy Clin Immunol Pract. (2019) 7:719–20. doi: 10.1016/j.jaip.2018.11.047
33. Baker MG, Saf S, Tsuang A, Nowak-Wegrzyn A. Hidden allergens in food allergy. Ann Allergy Asthma Immunol. (2018) 121:285–92. doi: 10.1016/j.anai.2018.05.011
34. Harada K, Zhang S, Sicherer S. M230 the plot thickens: fruit pectin and food allergy. Ann Allergy Asthma Immunol. (2021) 127:S113. doi: 10.1016/j.anai.2021.08.359
35. Wang J, Sicherer SH. Anaphylaxis following ingestion of candy fruit chews. Ann Allergy Asthma Immunol. (2005) 94:530–3. doi: 10.1016/S1081-1206(10)61128-3
36. Kelso JM. The gelatin story. J Allergy Clin Immunol. (1999) 103:200–2. doi: 10.1016/s0091-6749(99)70490-2
37. Ueno R, Takaoka Y, Shimojo N, Ohno F, Yamaguchi T, Matsunaga K, et al. A case of pediatric anaphylaxis caused by gummy tablets containing fish collagen. Asia Pac Allergy. (2020) 10(4):e35. doi: 10.5415/apallergy.2020.10.e35
38. Kuehn A, Hilger C, Hentges F. Anaphylaxis provoked by ingestion of marshmallows containing fish gelatin. J Allergy Clin Immunol. (2009) 123:708–9. doi: 10.1016/j.jaci.2008.12.012
39. Taylor SL, Hefle SL. Food allergen labeling in the USA and Europe. Curr Opin Allergy Clin Immunol. (2006) 6:186–90. doi: 10.1097/01.all.0000225158.75521.ad
40. Pouessel G, Sabouraud-Leclerc D, Beaumont P, Divaret-Chauveau A, Bradatan E, Dumond P, et al. Lupin, a potential “hidden” food anaphylaxis allergen: an alert from the allergy-vigilance network®. Allergy. (2024) 79(8):2267–70. doi: 10.1111/all.16107
41. Soller L, La Vieille S, Chan ES. First reported case in Canada of anaphylaxis to lupine in a child with peanut allergy. Allergy Asthma Clin Immunol. (2018) 14:64. doi: 10.1186/s13223-018-0303-4
42. Bingemann TA, Santos CB, Russell AF, Anagnostou A. Lupin: an emerging food allergen in the United States. Ann Allergy Asthma Immunol. (2019) 122:8–10. doi: 10.1016/j.anai.2018.09.467
43. Muller T, Luc A, Adam T, Jarlot-Chevaux S, Dumond P, Schweitzer C, et al. Relevance of sensitization to legumes in peanut-allergic children. Pediatr Allergy Immunol. (2022) 33(9):e13846. doi: 10.1111/pai.13846
44. Pravettoni V, Primavesi L, Piantanida M. Anisakis simplex: current knowledge. Eur Ann Allergy Clin Immunol. (2012) 44:150–6.23092000
45. Morishima R, Motojima S, Tsuneishi D, Kimura T, Nakashita T, Fudouji J, et al. Anisakis is a major cause of anaphylaxis in seaside areas: an epidemiological study in Japan. Allergy. (2020) 75:441–4. doi: 10.1111/all.13987
46. Pontone M, Giovannini M, Barni S, Mori F, Venturini E, Galli L, et al. IgE-mediated anisakis allergy in children. Allergol Immunopathol (Madr). (2023) 51:98–109. doi: 10.15586/aei.v51i1.692
47. Nieuwenhuizen NE, Lopata AL. Anisakis–a food-borne parasite that triggers allergic host defences. Int J Parasitol. (2013) 43:1047–57. doi: 10.1016/j.ijpara.2013.08.001
48. Centonze A, Capillo S, Mazzei A, Salerno D, Sinopoli D, Prosperi Porta I, et al. Acute scrotum in a 8-year-old Italian child caused by extraintestinal anisakiasis in a seaside area. Allergy. (2021) 76:1601–2. doi: 10.1111/all.14779
49. Erben AM, Rodriguez JL, McCullough J, Ownby DR. Anaphylaxis after ingestion of beignets contaminated with dermatophagoides farinae. J Allergy Clin Immunol. (1993) 92:846–9. doi: 10.1016/0091-6749(93)90062-k
50. Takahashi K, Taniguchi M, Fukutomi Y, Sekiya K, Watai K, Mitsui C, et al. Oral mite anaphylaxis caused by mite-contaminated okonomiyaki/pancake-mix in Japan: 8 case reports and a review of 28 reported cases. Allergol Int. (2014) 63:51–6. doi: 10.2332/allergolint.13-OA-0575
51. Sánchez-Borges M, Suárez Chacón R, Capriles-Hulett A, Caballero-Fonseca F, Fernández-Caldas E. Anaphylaxis from ingestion of mites: pancake anaphylaxis. J Allergy Clin Immunol. (2013) 131:31–5. doi: 10.1016/j.jaci.2012.09.026
52. Wen DC, Shyur SD, Ho CM, Chiang YC, Huang LH, Lin MT, et al. Systemic anaphylaxis after the ingestion of pancake contaminated with the storage mite Blomia freemani. Ann Allergy Asthma Immunol. (2005) 95:612–4. doi: 10.1016/S1081-1206(10)61027-7
53. Matsumoto T, Satoh A. The occurrence of mite-containing wheat flour. Pediatr Allergy Immunol. (2004) 15:469–71. doi: 10.1111/j.1399-3038.2004.00175.x
54. Rangkakulnuwat P, Sanit S, Lao-Araya M. Anaphylaxis after ingestion of dust mite (Dermatophagoides farinae)-contaminated food: a case report. Trop Biomed. (2020) 37:318–23.33612801
55. Sánchez-Borges M, Capriles-Hulett A, Fernandez-Caldas E. Oral mite anaphylaxis: who, when, and how? Curr Opin Allergy Clin Immunol. (2020) 20:242–7. doi: 10.1097/ACI.0000000000000624
56. Usui M, Akashi M. A case of a child diagnosed as hypersensitivity reactions to nonsteroidal anti-inflammatory drugs after onset of oral mite anaphylaxis. Arerugi (Japan). (2018) 67:148–52. doi: 10.15036/arerugi.67.148
57. Sánchez-Borges M, Iraola V, Fernández-Caldas E, Capriles-Hulett A, Caballero-Fonseca F. Dust mite ingestion-associated, exercise-induced anaphylaxis. J Allergy Clin Immunol. (2007) 120:714–6. doi: 10.1016/j.jaci.2007.04.017
58. Adachi YS, Itazawa T, Okabe Y, Higuchi O, Ito Y, Adachi Y. A case of mite-ingestion-associated exercise- induced anaphylaxis mimicking wheat-dependent exercise-induced anaphylaxis. Int Arch Allergy Immunol. (2013) 162:181–3. doi: 10.1159/000351778
59. Anagnostou A. Lipid transfer protein allergy: an emerging allergy and a diagnostic challenge. Ann Allergy Asthma Immunol. (2023) 130:413–4. doi: 10.1016/j.anai.2023.01.033
60. Barradas Lopes J, Santa C, Valente C, Presa AR, João Sousa M, Reis Ferreira A. Allergy to lipid transfer proteins (LTP) in a pediatric population. Eur Ann Allergy Clin Immunol. (2023) 55:86–93. doi: 10.23822/EurAnnACI.1764-1489.229
61. Schutt M, Palmieri J. M339 two novel case reports of pediatric lipid transfer protein syndrome. Ann Allergy Asthma Imunol. (2023) 131:S172. doi: 10.1016/j.anai.2023.08.530
62. Muñoz-Osores E, Aguirre J, Concha S, Borzutzky A, Hoyos-Bachiloglu R. Lipid transfer protein allergy and anaphylaxis in children. Ann Allergy Asthma Immunol. (2023) 130:520–2. doi: 10.1016/j.anai.2023.01.014
63. Asero R, Brusca I, Cecchi L, Pignatti P, Pravettoni V, Scala E, et al. Why lipid transfer protein allergy is not a pollen-food syndrome: novel data and literature review. Eur Ann Allergy Clin Immunol. (2022) 54(5):198–206. doi: 10.23822/EurAnnACI.1764-1489.206
64. Cabrera-Freitag P, Infante S, Bartolomé B, Álvarez-Perea A, Fuentes-Aparicio V, Zapatero Remón L. Anaphylaxis related to passive second-hand exposure to Cannabis sativa cigarette smoke in adolescents. J Investig Allergol Clin Immunol. (2019) 29:298–300. doi: 10.18176/jiaci.0376
65. Bruusgaard-Mouritsen MA, Nasser S, Garvey LH, Krantz MS, Stone CA Jr. Anaphylaxis to excipients in current clinical practice: evaluation and management. Immunol Allergy Clin North Am. (2022) 42:239–67. doi: 10.1016/j.iac.2021.12.008
66. Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone CA Jr. Hidden dangers: recognizing excipients as potential causes of drug and vaccine hypersensitivity reactions. J Allergy Clin Immunol Pract. (2021) 9:2968–82. doi: 10.1016/j.jaip.2021.03.002
67. Mahler V, Junker AC. Anaphylaxis to additives in vaccines. Allergo J Int. (2022) 31:123–36. doi: 10.1007/s40629-022-00215-8
68. Novadzki IM, Rosario Filho N. Anaphylaxis associated with the vaccine against measles, mumps and rubella. Rev Saude Publica. (2010) 44:372–6. doi: 10.1590/s0034-89102010000200020
69. Tanos Lopes FT, Maia de Castro Romanelli R, Isabela de Oliveira L, Abrantes MM, Rocha W. Safe administration of yellow fever vaccine in patients with suspected egg allergy. J Allergy Clin Immunol Glob. (2023) 2:100089. doi: 10.1016/j.jacig.2023.100089
70. Ohnishi A, Hashimoto K, Ozono E, Sasaki M, Sakamoto A, Tashiro K, et al. Anaphylaxis to carboxymethylcellulose: add food additives to the list of elicitors. Pediatrics. (2019) 143:e20181180. doi: 10.1542/peds.2018-1180
71. Lamb JD, Keogh JA. Anaphylactoid reaction to mannitol. Can Anaesth Soc J. (1979) 26:435–6. doi: 10.1007/BF03006461
72. Lightner DD, De Braganca K, Gilheeney SW, Khakoo Y, Kramer K, Balas M. A case of mannitol hypersensitivity. J Pediatr Hematol Oncol. (2013) 35:e274–5. doi: 10.1097/MPH.0b013e31828d5b3e
73. Perino E, Freymond N, Devouassoux G, Nicolas JF, Berard F. Xolair-induced recurrent anaphylaxis through sensitization to the excipient polysorbate. Ann Allergy Asthma Immunol. (2018) 120:664–6. doi: 10.1016/j.anai.2018.02.018
74. Henao MP, Ghaffari G. Anaphylaxis to polymyxin B-trimethoprim eye drops. Ann Allergy Asthma Immunol. (2016) 116:372. doi: 10.1016/j.anai.2016.01.014
75. Nakayama T, Kumagai T, Nishimura N, Ozaki T, Okafuji T, Suzuki E, et al. Seasonal split influenza vaccine induced IgE sensitization against influenza vaccine. Vaccine. (2015) 33:6099–105. doi: 10.1016/j.vaccine.2015.05.106
76. Stone CA Jr, Liu Y, Relling MV, Krantz MS, Pratt AL, Abreo A, et al. Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized. J Allergy Clin Immunol Pract. (2019) 7:1533–40.e8. doi: 10.1016/j.jaip.2018.12.003
77. Khalid MB, Bundy V. Hypersensitivity to different polyethylene glycol-containing products. Ann Allergy Asthma Immunol. (2021) 126:734–5. doi: 10.1016/j.anai.2021.03.004
78. Hamano S, Nishima D, Satake M, Kudo K, Yanagita K, Tezuka J. Recurrent immediate type hypersensitivity reaction induced by macrogol in a 3-year-old boy. J Investig Allergol Clin Immunol. (2020) 30:72–3. doi: 10.18176/jiaci.0447
79. Bianchi A, Bottau P, Calamelli E, Caimmi S, Crisafulli G, Franceschini F, et al. Hypersensitivity to polyethylene glycol in adults and children: an emerging challenge. Acta Biomed. (2021) 92:e2021519. doi: 10.23750/abm.v92iS7.12384
80. Wang KY, Friedman DF, DaVeiga SP. Immediate hypersensitivity reaction to human serum albumin in a child undergoing plasmapheresis. Transfusion. (2019) 59:1921–3. doi: 10.1111/trf.15194
81. Basu MN, Melchiors BB, Mortz CG, Garvey LH. Hypersensitivity reactions to human albumin-A case series and diagnostic algorithm. Allergy. (2024) 79:752–4. doi: 10.1111/all.15971
82. Ridolo E, Incorvaia C, Schroeder JW. Airborne anaphylaxis: highlighting an invisible enemy. Curr Opin Allergy Clin Immunol. (2022) 22:283–90. doi: 10.1097/ACI.0000000000000848
83. Leonardi S, Pecoraro R, Filippelli M, Miraglia del Giudice M, Marseglia G, Salpietro C, et al. Allergic reactions to foods by inhalation in children. Allergy Asthma Proc. (2014) 35:288–94. doi: 10.2500/aap.2014.35.3755
84. Morikawa M, Kanemitsu Y, Tsukamoto H, Morikawa A, Tomioka Y. A case of anaphylaxis in the pediatric patient with milk allergy due to traces of milk protein in the lactose used as an excipient of inavir inhalation. Arerugi (Japan). (2016) 65:200–5. doi: 10.15036/arerugi.65.200
85. Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA. Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol. (2004) 113:558–60. doi: 10.1016/j.jaci.2003
86. Añíbarro B, García-Ara C, Ojeda JA. Bird-egg syndrome in childhood. J Allergy Clin Immunol. (1993) 92:628–30. doi: 10.1016/0091-6749(93)90089-x
87. Hemmer W, Klug C, Swoboda I. Update on the bird-egg syndrome and genuine poultry meat allergy. Allergo J Int. (2016) 25:68–75. doi: 10.1007/s40629-016-0108-2
88. Yamada S, Matsubara K, Chinuki Y, Hori M, Masaki T. Early childhood-onset pork-cat syndrome due to sensitization by both cats and dogs -a case report. Arerugi (Jpn). (2019) 68:1141–7. doi: 10.15036/arerugi.68.1141
89. Sagawa N, Inomata N, Suzuki K, Sano S, Watanabe Y, Aihara M. Pork-cat syndrome caused by ingestion of beef intestines in an 8-year-old child. Allergol Int. (2021) 70:395–7. doi: 10.1016/j.alit.2020.12.001
90. Posthumus J, James HR, Lane CJ, Matos LA, Platts-Mills TA, Commins SP. Initial description of pork-cat syndrome in the United States. J Allergy Clin Immunol. (2013) 131:923–5. doi: 10.1016/j.jaci.2012.12.665
91. Shiratsuki R, Chinuki Y, Fukushiro S, Morita E. A case of pork-cat syndrome that developed as food-dependent exercise-induced anaphylaxis. Acta Derm Venereol. (2020) 100:adv00233. doi: 10.2340/00015555-3584
92. Saretta F, Giovannini M, Mori F, Arasi S, Liotti L, Pecoraro L, et al. Alpha-gal syndrome in children: peculiarities of a “tick-borne” allergic disease. Front Pediatr. (2021) 9:801753. doi: 10.3389/fped.2021.801753
93. Wilson JM, Schuyler AJ, Workman L, Gupta M, James HR, Posthumus J, et al. Investigation into the α-gal syndrome: characteristics of 261 children and adults reporting red meat allergy. J Allergy Clin Immunol Pract (2019) 7:2348–58.e4. doi: 10.1016/j.jaip.2019.03.031
94. Mabelane T, Basera W, Botha M, Thomas HF, Ramjith J, Levin ME. Predictive values of alpha-gal IgE levels and alpha-gal IgE: total IgE ratio and oral food challenge-proven meat allergy in a population with a high prevalence of reported red meat allergy. Pediatr Allergy Immunol. (2018) 29:841–9. doi: 10.1111/pai.12969
95. Commins SP. Diagnosis & management of alpha-gal syndrome: lessons from 2,500 patients. Expert Rev Clin Immunol. (2020) 16:667–77. doi: 10.1080/1744666X.2020.1782745
96. Ballardini N, Nopp A, Hamsten C, Vetander M, Melén E, Nilsson C, et al. Anaphylactic reactions to novel foods: case report of a child with severe crocodile meat allergy. Pediatrics. (2017) 139:e20161404. doi: 10.1542/peds.2016-1404
97. Minhas J, Saryan JA, Balekian DS. Salmon roe (ikura)-induced anaphylaxis in a child. Ann Allergy Asthma Immunol. (2017) 118:365–6. doi: 10.1016/j.anai.2016.11.020
98. Shimizu Y, Nakamura A, Kishimura H, Hara A, Watanabe K, Saeki H. Major allergen and its IgE cross-reactivity among salmonid fish roe allergy. J Agric Food Chem. (2009) 57:2314–9. doi: 10.1021/jf8031759
99. Takeuchi M, Oda Y, Suzuki I. Intussusception secondary to anaphylactic reaction to salmon roe (ikura). Pediatr Int. (2013) 55:649–51. doi: 10.1111/ped.12168
100. Kondo Y, Kakami M, Koyama H, Yasuda T, Nakajajima Y, Kawamura M, et al. Ige cross-reactivity between fish roe (salmon, herring and pollock) and chicken egg in patients anaphylactic to salmon roe. Allergol Int. (2005) 54:317–23. doi: 10.2332/allergolint.54.317
101. Pagès AS, Leduc V, De Lacoste de Laval A, Nelson JR, Péré B, Rondeleux E. Salmon roe allergy without concomitant fish allergies, three pediatric cases. French J Allergol. (2015) 55:301–4. doi: 10.1016/j.reval.2015.02.181
Keywords: anaphylaxis, pediatric, rare, additives, excipients, obscure occult, allergen
Citation: Melethil S and Yousef E (2024) Rare causes of pediatric anaphylaxis due to obscure allergens. Front. Allergy 5:1456100. doi: 10.3389/falgy.2024.1456100
Received: 2 July 2024; Accepted: 6 August 2024;
Published: 26 August 2024.
Edited by:
Maryam Ali Al-Nesf Al-Mansouri, Hamad Medical Corporation, QatarReviewed by:
Asaad Abdelhalim, Clinical Immunology Council, SudanStuart Carr, Snö Wellness, United Arab Emirates
Copyright: © 2024 Melethil and Yousef. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shajitha Melethil, shajitha.melethil@gmail.com