Pediatric Cofactor-Enhanced Food Anaphylaxis (PCEFA): A Narrative Review of Epidemiology, Pathophysiology and Clinical Features

Cofactors are external factors that can lower the threshold dose of an allergen and amplify the severity of allergic reactions, turning mild or moderate responses into severe anaphylaxis. These include exercise, nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, menstruation, and infections. Initially described in relation to food allergens and physical activity or NSAIDs, these reactions have been labeled under various terms, such as food-dependent exercise-induced anaphylaxis (FDEIA), wheat-dependent exercise-induced anaphylaxis (WDEIA), and food-dependent NSAID-induced anaphylaxis (FDNIA). However, cofactor-enhanced food allergy (CEFA), a recently proposed concept, serves as an umbrella term to encompass these conditions and is applied in this text for consistency. Pediatric cofactor-enhanced food anaphylaxis (PCEFA) is a rare but severe condition in which a food allergy becomes significantly more severe in the presence of one or more cofactors. Cofactors are documented in 14–18.3% of pediatric food anaphylactic reactions, however, the true burden is likely higher due to frequent underdiagnosis from variable and unpredictable presentations. Exercise and infections are the most common cofactors in PCEFA, while ω-5 gliadin is the predominant allergen. CEFA is frequently misdiagnosed as idiopathic anaphylaxis, exercise-induced anaphylaxis (EIA), or asthma when subtle or delayed food triggers go undetected. Some cases may represent high-threshold food allergies rather than true cofactor-dependent anaphylaxis, challenging conventional definitions. Research on cofactors in anaphylaxis is still in its early stages, with most studies focusing on adults. More research is needed to improve diagnostic accuracy and treatment strategies for pediatric cases. Pediatric Cofactor-Enhanced Food Anaphylaxis (PCEFA): A Narrative Review of Epidemiology, Pathophysiology and Clinical Features not-yet-known not-yet-known not-yet-known unknown Alpana Mohta,1 Emilio Narvaez,2 Patricia Mir-Ihara,2,3,4 Joan Bartra,2,3,4 Rosa Muñoz-Cano2,3,4 Affiliations: 1. Department of Dermatology, venerology and Leprosy, Sharda Multispeciality Clinic, Bikaner, India. 2. Allergy Department. Hospital Clinic. University of Barcelona. Barcelona. Spain. 3. METRI2A – Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS). Barcelona. Spain. 4. RICORS – REI. Instituto de Salud Carlos III. Madrid. Spain. Conflicts of Interest: Nil

Cofactors are external factors that can lower the threshold dose of an allergen and amplify the severity of allergic reactions, turning mild or moderate responses into severe anaphylaxis. These include exercise, nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, menstruation, and infections. Initially described in relation to food allergens and physical activity or NSAIDs, these reactions have been labeled under various terms, such as food-dependent exercise-induced anaphylaxis (FDEIA), wheat-dependent exercise-induced anaphylaxis (WDEIA), and food-dependent NSAID-induced anaphylaxis (FDNIA). However, cofactor-enhanced food allergy (CEFA), a recently proposed concept, serves as an umbrella term to encompass these conditions and is applied in this text for consistency. Pediatric cofactor-enhanced food anaphylaxis (PCEFA) is a rare but severe condition in which a food allergy becomes significantly more severe in the presence of one or more cofactors. Cofactors are documented in 14–18.3% of pediatric food anaphylactic reactions, however, the true burden is likely higher due to frequent underdiagnosis from variable and unpredictable presentations. Exercise and infections are the most common cofactors in PCEFA, while ω-5 gliadin is the predominant allergen. CEFA is frequently misdiagnosed as idiopathic anaphylaxis, exercise-induced anaphylaxis (EIA), or asthma when subtle or delayed food triggers go undetected. Some cases may represent high-threshold food allergies rather than true cofactor-dependent anaphylaxis, challenging conventional definitions. Research on cofactors in anaphylaxis is still in its early stages, with most studies focusing on adults. More research is needed to improve diagnostic accuracy and treatment strategies for pediatric cases.

Cofactor-enhanced food anaphylaxis, not-yet-known not-yet-known not-yet-known unknown Food-dependent exercise-induced anaphylaxis, wheat-dependent exercise-induced anaphylaxis, Food-dependent NSAID-induced anaphylaxis (FDNIA), pediatric food anaphylaxis. Word count (excluding abstract and references): 4479 Key Message Pediatric cofactor-enhanced food anaphylaxis is vastly underdiagnosed due to its variable presentation and overlap with atopic conditions in children. While exercise remains the most documented cofactor, infections, NSAIDs, and alcohol play a more significant role in children and adolescents than previously acknowledged. Unlike in adults, infections are a major cofactor in children, and multiple cofactors can act together to amplify reaction severity, a phenomenon known as summation anaphylaxis. Emerging evidence also shows that children undergoing oral immunotherapy may develop exercise-induced allergic reactions on desensitization, even after successful treatment. 1. Introduction “What is food to one man may be fierce poison to others.” – Lucretius (99-55 BC) 1 These words aptly capture the unpredictability of food-induced anaphylaxis, where a substance that is harmless to most can provoke a life-threatening reaction in others. Among allergic conditions, food allergies are notably more common in children than in adults, with milk and wheat ranking among the leading causes of pediatric anaphylaxis. 2,3 However, allergic reactions often display unpredictable severity, with the same dose of an allergen triggering different reactions in different circumstances. This variability is often attributed to cofactors, which can influence reaction severity. 4 The role of cofactors in anaphylaxis was first described in 1979 by German researchers who reported a case of ‘exercise-induced anaphylaxis to shellfish’. Subsequent studies have expanded the list of known cofactors to include drugs, alcohol, infections, menstruation, stress, and sleep deprivation. 5 Initially described in relation to food allergens and physical activity or NSAIDs, these reactions have been labeled under various terms, such as food-dependent exercise-induced anaphylaxis (FDEIA), wheat-dependent exercise-induced anaphylaxis (WDEIA), and food-dependent NSAID-induced anaphylaxis (FDNIA). However, cofactor-enhanced food allergy (CEFA), a recently proposed concept by Cardona et al., serves as an umbrella term to encompass these conditions and is applied in this text for consistency. 6 CEFA is a severe variant of food allergy in which one or more cofactors: • Are required to trigger an allergic reaction, or • Lower the threshold dose of a food allergen needed to elicit a reaction, or • Amplify reaction severity. Any of these scenarios can occur alone or in combination. Although CEFA is reported to be relatively uncommon in children, it is widely believed to be severely underdiagnosed due to its variable presentation and overlapping clinical symptoms with atopic diathesis in children. In children, this condition can manifest in its most severe form as pediatric cofactor-enhanced food anaphylaxis (PCEFA). not-yet-known not-yet-known not-yet-known unknown Studies indicate that adolescents and young adults have a higher rate of fatal food-induced anaphylaxis than adults.7 A study on young adults found that 76% of anaphylactic episodes occurred when they consumed food outside the home despite known risks.8 Most teenagers reportedly fail to carry adrenaline auto-injectors (AAIs), leaving them unprepared for emergencies. Many adolescents also neglect to fill prescriptions or hesitate to use AAIs when required.9,10 Beyond behavioral risks, some of the most prevalent cofactors are disproportionately distributed in children like physical exertion, seasonal flu, and fresh introduction of alcohol in lifestyle, all lowering the threshold of allergic reactions. While exercise is one of the most well-documented cofactors, evidence regarding other cofactors remains limited. Given these factors, addressing the role of cofactors in PCEFA is critical. This narrative review examines the current understanding of PCEFA in children, examining its epidemiology, pathophysiology, and clinical presentation. It also explores the subtle yet significant differences between pediatric and adult FDEIA with potential diagnostic and treatment implications. 2. Cofactors in Pediatric Food Anaphylaxis Food allergens account for 81% of all anaphylactic episodes in children. 11 Cofactors play a crucial role in increasing the severity and/or lowering the reaction threshold by reducing the amount of allergen needed to trigger a reaction in food anaphylaxis, especially in children with borderline to low allergen sensitization. 12 Cofactors are involved in 14% to 18.3% of food anaphylactic reactions in children. 4 While exercise is the defining cofactor in CEFA in children, concurrent infection is the next most commonly reported. In contrast, adults more frequently experience CEFA linked to alcohol and medications, particularly NSAIDs. Other identified cofactors include stress, menstruation, sleep deprivation, and dehydration. These cofactors increase allergen absorption, modify immune responses, or enhance mast cell reactivity, leading to unpredictable symptom severity with different reactions in the same patient. 13 not-yet-known not-yet-known not-yet-known unknown 2.1 Exercise not-yet-known not-yet-known not-yet-known unknown Exercise is the most common cofactor in food-induced anaphylaxis in children. In a study of the anaphylaxis registry from Germany, Austria, and Switzerland, PCEFA was identified in 14% of children, with physical activity being the most common trigger, reported in 8.6% of cases.14 not-yet-known not-yet-known not-yet-known unknown Exercise is also the defining trigger in food-dependent exercise-induced anaphylaxis (FDEIA), where allergic reactions occur only when allergen ingestion is followed by physical activity.15 Most pediatric studies on FDEIA originate from East and Southeast Asia, primarily Japan, Korea, and Thailand, where dietary habits and genetic factors may contribute to the higher prevalence of wheat- and seafood-induced FDEIA. 16-19 A Japanese epidemiological study found that FDEIA affected 0.017% of junior high school students and 0.0047% of elementary school students. 16,17 Similarly, a multicenter anaphylaxis registry in Korea reported that FDEIA accounted for 1.2% of pediatric anaphylaxis cases. 18 Data from Western countries is limited, with only a few studies and case reports available. A Portuguese study of 26 children with lipid transfer protein (LTP) allergy identified exercise as the most common cofactor, present in 27% of cases. In more than two-thirds of these cases, exercise amplified reaction severity, while in 7.7% of children, it was essential for triggering a reaction. 20 not-yet-known not-yet-known not-yet-known unknown An analysis of the European Anaphylaxis Registry also identified peanuts as a major trigger of food anaphylaxis in children. Cofactors influencing the allergenic threshold were reported in 29% of peanut anaphylaxis cases, compared to 22% for other food triggers, with physical exercise being the most common cofactor, present in 80% of cases.21 Symptoms can appear at any stage of physical activity—warm-up, peak exertion, or recovery—but most commonly occur within 10 minutes to 4 hours of allergen ingestion. In children, reactions have been reported during both high-intensity activities like running, swimming, playing basketball, soccer, and lower-intensity tasks like walking, gardening or shoveling snow. 22,23 Interestingly, reactions may also occur if allergenic food is consumed immediately after exercise, further complicating diagnosis. Rare instances of delayed FDEIA have also been documented, where anaphylaxis occurs 24 hours after food consumption but immediately following exercise, adding further complexity to diagnosis and risk stratification. 19 not-yet-known not-yet-known not-yet-known unknown FDEIA is more prevalent in children with atopic diathesis, with concurrent atopy reported in 59.7% of cases.24,25 The condition is most commonly diagnosed during adolescence, likely due to increased participation in sports and exercise. Adolescents are also at a higher risk due to lifestyle factors, including the fresh introduction of alcohol as a new cofactor in their lifestyle.26 Younger children may go undiagnosed due to overlapping symptoms with other conditions like asthma or idiopathic urticaria. Pathogenesis Increased Intestinal Permeability and Enhanced Allergen Absorption A widely accepted hypothesis is that exercise increases gastrointestinal permeability, allowing larger allergenic proteins to pass through the intestinal mucosa and enter systemic circulation in an immunologically active form. 27 In a study involving children, adolescents, and adults, Matsuo et al. demonstrated that patients with WDEIA exhibited increased absorption of ω-5 gliadin when exercise was performed after ingestion. 28 In animal models, exercise-induced intestinal ischemia and subsequent reperfusion damage have increased gut permeability, allowing incompletely digested allergenic peptides to be passed. 4 This mechanism of increased gut permeability may also explain why other co-factors, including NSAIDs, alcohol, and infections, act as cofactors in FDEIA. Infections can cause transient mucosal inflammation, potentially enhancing allergen absorption, though clinical evidence remains limited. Redistribution of Allergens and Tissue-Specific Immune Activation Another proposed mechanism suggests that allergens, after absorption, redistribute to different tissues, particularly mast cell-rich areas such as the skin, lungs, and muscles, which are key sites for anaphylactic reactions. This could explain why FDEIA is frequently associated with cutaneous (urticaria, flushing, angioedema), respiratory (wheezing, dyspnea), and cardiovascular (syncope, hypotension) symptoms. During exercise, blood flow shifts from the splanchnic circulation toward active muscles and peripheral tissues. This redistribution could lead to an accumulation of allergens in peripheral tissues, making them more likely to trigger mast cell and basophil activation in those areas. However, direct evidence for this theory remains limited. 29 Basophil/Mast Cell Hyperreactivity and Plasma Osmolarity Changes not-yet-known not-yet-known not-yet-known unknown Exercise is also known to increase plasma osmolarity directly and cause acidosis, which may contribute to mast cell degranulation in susceptible individuals.30 Barg et al. found that patients with FDEIA exhibit heightened sensitivity to osmotic changes, suggesting that physical exertion might create an environment where mast cells become more prone to degranulation.31 However, according to Bartra et al., osmolarity shifts alone are unlikely to explain the phenomenon entirely, as high-intensity exercise is typically required to trigger this effect. In contrast, in some cases, FDEIA can be induced by even mild exertion.4 Histamine Degranulation Exercise naturally increases histamine release, a normal physiological response contributing to vasodilation and regulating blood pressure. However, in FDEIA patients, this process may be dysregulated, leading to excessive mast cell and basophil activation, resulting in severe anaphylactic responses. Role of Tissue Transglutaminase Specific to WDEIA, a unique mechanism involving tissue transglutaminase (tTG) has been proposed. Exercise is thought to activate tTG, which cross-links ω-5 gliadin peptides, creating neo-antigens with enhanced IgE-binding capacity. This may explain why ω-5 gliadin is the predominant allergen in WDEIA cases. However, direct in vivo evidence for this mechanism remains lacking, and further research is needed to confirm its clinical significance. 32 not-yet-known not-yet-known not-yet-known unknown Beyond exercise, data on the prevalence of other cofactors involved in PCEFA is ever more obscure and limited only by a handful of case reports. Based on the limited data from a handful of studies and case reports, wheat, crustaceans, and shellfish are the most commonly reported foods involved in pediatric FDEIA. 2.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs are the most common cause of drug-induced anaphylaxis in both adults and children, accounting for over 40% of cases. 11 They are linked to 22% of severe food-induced anaphylaxis in adults, with an odds ratio exceeding 11. 4,33 Food-dependent NSAID-induced anaphylaxis (FDNIA) is a variant of CEFA where NSAIDs either reduce the reaction threshold in food-dependent anaphylaxis or anaphylaxis occurs only when both an NSAID and a food allergen are present. These patients typically tolerate NSAID drug challenges in the absence of food exposure. 34 Some individuals may experience mild reactions such as oral allergy syndrome or contact urticaria when consuming food alone. 35 In pediatric patients with FDNIA, the most frequently implicated foods are wheat, peach, apple, and shrimp. 36,37 In Mediterranean regions, nearly 40% of lipid transfer protein (LTP)-related anaphylaxis involves NSAIDs as a cofactor, across all age groups. NSAIDs also amplify reactions to other allergens, including shellfish, sunflower seeds, gliadin, and peanuts. However, most studies have primarily focused on adults, with limited data on pediatric cases. 11 Barradas Lopes et al. identified NSAIDs as the only cofactor in 4% of children with LTP allergy. 20 Recently, Pinto et al. reported a case of CEFA triggered by a soy storage protein with NSAID as a cofactor. However, data on NSAIDs as cofactors in storage protein allergies remains limited. 38 Apart from the dose of NSAIDs, environmental factors such as temperature and humidity may influence reactions. 35 Furthermore, atopy, an increasingly common comorbidity in children, is also a risk factor for NSAID hypersensitivity. 15 not-yet-known not-yet-known not-yet-known unknown NSAIDs are also recognized as cofactors in FDEIA, lowering the reaction threshold, particularly in wheat-induced cases in children. 34-36 Studies show that NSAIDs can precipitate anaphylaxis in FDEIA and other forms of CEFA, even if not involved in the initial reaction. 37,38 Aspirin, at 10 mg/kg, is commonly used in food challenge tests to enhance test reproducibility in pediatric FDEIA. 36,37,39,40 However, the cofactor effect of NSAIDs is less pronounced in children than adults, possibly due to the ‘gut resistance hypothesis,’ which suggests that pediatric patients’ intestines are more resistant to NSAID-induced permeability changes, similar to findings in neonatal rat models. Pathogenesis 1. Increased Intestinal Permeability NSAIDs may disrupt the gut barrier, allowing greater allergen absorption and increasing the likelihood of an allergic reaction. 15 2. Direct Mast Cell Activation NSAIDs activate mast cells, a key mechanism in NSAID-exacerbated respiratory disease (N-ERD). Steinke et al. demonstrated that aspirin triggers mast cell activation through calcium influx and prostaglandin D₂ (PGD₂) release. N-ERD patients also exhibit reduced EP2 receptor expression, which limits prostaglandin E₂ (PGE₂)’s anti-inflammatory effects. Decreased PGE₂ production has been linked to N-ERD and may also play a role in FDNIA. 4,41 3. Eicosanoid Metabolism Disruption not-yet-known not-yet-known not-yet-known unknown NSAIDs inhibit cyclooxygenase (COX) enzymes, altering eicosanoid metabolism, which regulates inflammation and immune responses. Prostaglandin E₂ (PGE₂) normally inhibits IgE-mediated mast cell degranulation, acting as a protective factor against anaphylaxis. While some studies suggest lower baseline PGE₂ levels in anaphylaxis cases, Muñoz-Cano et al. found no significant variability in food anaphylaxis patients.40 However, these authors identified altered prostaglandin receptor expression in FDNIA and food-induced anaphylaxis patients. These patients exhibited reduced expression of EP4 (anti-inflammatory) and increased EP3 (pro-inflammatory) receptors in basophils.40, suggesting that, although PGE2 may be normal, the response to it may be altered, favouring the inflammation. Finally, Pascal et al. found that NSAIDs enhance IgE-mediated activation of human basophils via COX-1 inhibition. In Pru p 3-sensitized FDNIA patients, aspirin increased basophil activation, whereas valdecoxib, a COX-2 inhibitor, partially reduced activation. This suggests COX-2 inhibitors may be a safer alternative.42 Additional research is required to clarify adenosine metabolism’s role in food-triggered anaphylaxis and its possible connection to PGE₂ pathways, both seemingly contributing to FDNIA in children. 2.3 Infections Viral and bacterial infections lower reaction thresholds and increase anaphylaxis severity by inducing systemic inflammation, disrupting immune homeostasis, and enhancing histamine release. Early-stage and mild upper respiratory tract infections, including the common cold, are the most frequently identified infectious triggers for PCEFA. Infections are a more common cofactor in children than adults, implicated in 2.6–14% of pediatric anaphylaxis cases. 21,43 Despite frequent clinical recognition, research on infection-triggered CEFA often fails to distinguish between pediatric and adult cases, highlighting the need for more targeted studies. Data from the Germany-Austria-Switzerland Anaphylaxis Registry identified infections as a cofactor in 2.6% of pediatric food anaphylaxis cases, compared to 1.3% in adults. 14 Similarly, a Polish study found infections to be a cofactor in 5% of cases, though it did not differentiate between food, drug, and insect venom-induced anaphylaxis. 12,43 Although, an updated European Anaphylaxis Registry (10+ countries and Brazil) study of patients under 18 years, reported a much higher burden, with infections as the second most common cofactor after exercise, present in 14% of peanut anaphylaxis cases and 13% of other food-induced anaphylaxis cases. 12 In yet another study on oral tolerance induction, 12 out of 25 children undergoing desensitization to milk or egg experienced cofactor-induced anaphylaxis, with acute infections being the most frequent trigger. 44 not-yet-known not-yet-known not-yet-known unknown Unlike many cofactors, infections are unpredictable and unavoidable, making them a serious risk factor in CEFA. Because infections are transient, Wölbing et al. proposed using alternative cofactors like NSAIDs or exercise in provocation testing to better assess risk.43 Mechanisms of Infection-Triggered Anaphylaxis The exact mechanisms remain unclear due to lack of human provocation studies or suitable animal models, but several immune pathways are implicated. One proposed mechanism involves pathogen-derived structures acting as allergens, leading to IgE sensitization or cross-reactivity. Infections also induce IgG and IgM immune complexes, which—if not properly cleared—activate complement pathways, producing C3a and C5a anaphylatoxins that promote mast cell degranulation. Additionally, basophils and mast cells express activating Fcc receptors (FccR), which can induce degranulation independent of FceRI stimulation, mimicking IgE-mediated responses. 44 Another mechanism involves innate immune activation via pathogen-associated molecular patterns (PAMPs). These microbial molecules bind to pathogen recognition receptors (PRRs) on mast cells and basophils, altering their reactivity. Studies show that peptidoglycan (PGN), a bacterial PAMP, triggers mast cell degranulation, while other PAMPs modulate or inhibit mast cell activation, suggesting a complex, context-dependent immune response. Additionally, complement activation generates anaphylatoxins (C3a, C5a), with C5a being a potent mast cell stimulator, though its role in anaphylaxis remains uncertain due to lack of receptor expression on mucosal mast cells. 44 2.4 Menstruation not-yet-known not-yet-known not-yet-known unknown Menstruation has been described as a significant but often overlooked cofactor in food anaphylaxis in adolescent females. While food-induced anaphylaxis is male-predominant until puberty, incidence shifts toward females post-puberty, who also have a higher prevalence of exercise-induced anaphylaxis (EIA).45-49 Experimental studies link estrogen to increased vascular permeability, which may amplify allergic reactions, yet catamenial anaphylaxis occurs when estrogen and progesterone are lowest, suggesting a complex hormonal influence. 4,50 Current data on menstruation as a cofactor in PCEFA is largely limited to FDEIA. De Silva et al. reported a case where a patient experienced six FDEIA episodes exclusively during menstruation, despite otherwise tolerating wheat and exercise. 51 not-yet-known not-yet-known not-yet-known unknown A German anaphylaxis registry found menstruation as a cofactor in 10% of adolescent girls (13–17 years) with anaphylaxis.52 Furthermore, according to a recent meta-analysis, menstruation is more strongly associated with pediatric FDEIA than adults and more likely to present with isolated cutaneous symptoms.53 Menstruation has also been proposed as a cofactor in unexpected allergic reactions during desensitization. 2.5 Alcohol Adolescents are at higher risk for CEFA due to the fresh introduction of alcohol into their lifestyle, which can act as a strong augmentation factor. 54 A systematic review by Kulthanan et al. identified alcohol to be a major cofactor in CEFA along with menstruation. 25 not-yet-known not-yet-known not-yet-known unknown Alcohol contributes to allergic reactions by directly triggering mast cell degranulation (notably via acetaldehyde in Japanese cohorts, similar to alcohol-induced asthma) and increasing intestinal permeability. Alcohol’s proinflammatory effects include the release of IL-6, IL-10, interferon-gamma, and stimulation of eicosanoid metabolites like PGE₂. It may also temporarily inhibit adenosine uptake and work synergizes with other cofactors like exercise in precipitating FDEIA.4 not-yet-known not-yet-known not-yet-known unknown 3. Culprit Food Allergens A wide range of foods can trigger CEFA, but some allergens are more commonly implicated based on allergen structure, regional dietary patterns, and genetic predisposition. Current studies and case reports almost exclusively focus on FDEIA and FDNIA, leaving significant gaps in understanding how other cofactors interact with specific food allergens in PCEFA. Specific structural and biochemical properties of food proteins contribute to a food allergen’s allergenic potential by influencing IgE binding, stability, and immune recognition. Key factors include high protein concentration, multiple linear IgE-binding epitopes, resistance to enzymatic digestion and food processing, and structural motifs favoring immune activation. During physical exertion, these properties may be further modulated, potentially increasing gastrointestinal permeability, altering antigen processing, and lowering reaction thresholds, leading to transient loss of immune tolerance and an increased risk of anaphylaxis. 22 The most frequently reported culprit foods in PCEFA include wheat, crustaceans, peanuts, soy, tree nuts, cow’s milk, and legumes. However, rarer cases involving fruits, vegetables, and meat have also been documented. 22 The underlying allergens responsible for CEFA vary, and studies have identified specific proteins, including ω-5 gliadin (wheat), tropomyosin (shrimp), and lipid transfer proteins (LTPs) (wheat, fruits, and nuts) as major triggers. 54,55 Some FDEIA cases have been linked to foods contaminated with house dust mites and Penicillium mold, suggesting that environmental allergens may act as hidden triggers. 56 3.1 LTP So far, lipid transfer protein (LTP) is the most studied allergen associated with cofactors in anaphylaxis, though pediatric-specific research remains extremely limited overall. not-yet-known not-yet-known not-yet-known unknown LTP is a pan allergen ubiquitously present in the plant kingdom. LTP is a dominant allergen in plants belonging to the Rosaceae family, and the most common food allergen in the Mediterranean region. This protein is a primary allergen in the Rosaceae family for individuals without birch pollen sensitization (i.e., not due to cross-reactivity). It has also been identified in various plant-based foods such as corn, rice, dried fruits, wheat, spelt, grape, citrus fruits, asparagus, beer, lettuce, and cabbage. Additionally, significant allergens from Artemisia, Olea, and Parietaria pollen belong to the LTP family.57 LTP sensitization is common in children, but its clinical relevance remains unclear due to frequent co-sensitization with other plant-food pan allergens (storage proteins, profilins, PR-10). Pascal et al. reported an LTP sensitization rate of 26.2% (34/130) in children with plant-food allergies, with the highest rates for peach (83.1%), walnut (77.7%), peanut (56.2%), hazelnut (55.4%), and wheat (26.2%). Despite this, not all sensitized children develop symptoms, as 69% and 63% of peach- and walnut-tolerant children still had positive IgE to rPru p 3 and nJug r 3, respectively. 58 Nevertheless, in a large proportion of cases, LTP anaphylaxis is only triggered in the presence of one or more cofactors. Co-factors such as NSAIDs , physical exercise, and alcohol are often necessary for eliciting the reaction. In a study involving only pediatric LTP allergic cases, 8% had reactions only in the presence of a cofactor, in the form of anaphylaxis. In 19% of subjects, cofactors augmented the reaction severity stepping them up from urticaria and oral allergy syndrome to anaphylaxis or from oral allergic syndrome to urticaria. 20 Ciprandi et al. found that LTP sensitization declines with age, while IgE levels peak in early adulthood (21–30 years) before decreasing. Pastorello et al. also showed an inverse correlation between age at peach allergy onset and rPru p 3 IgE levels, indicating that younger onset is linked to stronger LTP sensitization. 59 NSAIDs and exercise remain the most consistent co-factors in PCEFA in LTP allergic cases. 60 As observed by Pascal et al., local symptoms such as oral allergy syndrome, urticaria, and mild gastrointestinal issues may serve as early indicators of anaphylaxis risk in LTP allergic patients, as patients with cofactor-dependent reactions often had prior mild responses to the same food but developed severe reactions when a cofactor, such as NSAIDs or exercise, was present. Their report also involved 2 adolescent patients, one of whom had the involvement of exercise as a cofactor during the reaction. 61 Furthermore, Aruanno et al.suggested that gastrointestinal symptoms, which are often overlooked in pediatric food allergy, may precede urticaria and angioedema, particularly when cofactors are involved. 57 3.2 Wheat specific allergens Wheat is the leading trigger of pediatric FDEIA worldwide, known as wheat-dependent exercise-induced anaphylaxis (WDEIA). 22 The most well-established wheat allergen responsible for FDEIA is ω-5 gliadin, a component of gluten. Palosuo et al. first identified ω-5 gliadin as a major IgE-binding protein in WDEIA patients, and subsequent studies in the early 2000s further confirmed its role. 62-64 It is estimated that ω-5 gliadin accounts for over 80% of WDEIA cases, though other wheat proteins such as high molecular weight glutenins, α/β/γ-gliadins, and wheat lipid transfer proteins (Tri a 14) have also been implicated in a smaller subset of patients. 28,65 Notably, Tri a 14 appears to be more prevalent in European WDEIA cases than in Asian populations. 22 Variants of Wheat-Dependent FDEIA Several distinct phenotypes of WDEIA have been described: • Conventional WDEIA (CO-WDEIA): Classic form caused by ω-5 gliadin sensitization, with symptoms requiring exercise or another cofactor. 66 • Hydrolyzed Wheat Protein-WDEIA (HWP-WDEIA): A unique subtype of FDEIA linked to percutaneous exposure to allergens in cosmetics like hydrolyzed wheat protein (HWP), reported from Japan and Europe. Fukutomi et al. described the first cases in five adult females who developed HWP-WDEIA through rhino-conjunctival sensitization from facial soap. Percutaneous FDEIA has also been reported with rice bran. 66,67 • Grass Pollen–Associated WDEIA: In ω-5 gliadin-negative patients, cross-reactivity between grass pollen allergens and wheat proteins has been suggested as a cause. 66 Ogino et al. documented cases where grass pollen hypersensitivity was linked to the development of WDEIA, possibly due to shared peroxidase-1 and β-glucosidase allergens. 68 3.3 Crustacean and Shellfish Crustaceans, particularly shrimp and shellfish, are the second most commonly reported triggers of PCEFA in East Asian countries. Studies estimate that 3.4% of the Japanese population has crustacean-induced immediate-type allergies, with a subset developing FDEIA. 69 The primary allergen in shrimp-CEFA is tropomyosin (37 kDa), a heat-stable muscle protein in multiple crustacean species. 55 Interestingly, studies show that only 48% of patients with shrimp allergies exhibit tropomyosin-specific IgE, suggesting that other crustacean proteins contribute to shrimp-FDEIA. 70 Other allergens that have been implicated include: • Arginine kinase (40 kDa) 55 • Sarcoplasmic calcium-binding protein (20 kDa) 55 • Myosin light chain (18–20 kDa) 55 A 43-kDa soluble protein from Litopenaeus vannamei (Pacific white shrimp) and Penaeus monodon (black tiger shrimp) was also identified as an FDEIA-specific allergen. However, further studies are needed to characterize its role. 71 3.4 Oral Immunotherapy Oral immunotherapy (OIT) is increasingly used in pediatric food allergy management, particularly for peanuts, cow’s milk, hen’s eggs, and wheat. 53,72-74 However, exercise and infections have been documented as a cofactor in triggering allergic reactions during and after desensitization protocols in children, even in individuals who tolerate the allergen under resting conditions. The phenomenon, termed exercise-induced allergic reactions on desensitization (EIARDs), has been reported in rushed and slow OIT protocols. The incidence of EIARDs is highest with wheat (49–66.7%), followed by cow’s milk (42–53%), and hen’s egg (21%) in children under 17 years. 53,72,73 Exercise-Induced Allergic Reactions on Desensitization (EIARDs) EIARDs, a recently proposed entity, are observed in wheat, milk, and egg allergies post-OIT. The mechanism remains unclear but may involve incomplete tolerance acquisition and increased epithelial permeability during exercise. Unlike FDEIA, no co-factors like NSAIDs have been implicated. According to Furata et al., symptoms of EIARDs are often less severe than traditional FDEIA but still capable of progressing to anaphylaxis in some cases, particularly with milk allergy. 73 Furthermore, for patients with wheat OI, cases prone to EIARD tend to show significantly higher sIgE levels of all gliadin and glutenin components than EIARD-negative patients before OIT. 73 EIARDs can persist long after successful OIT completion, with Furata et al. reporting reactions occurring up to 5 years post-OIT for wheat and up to 9 years for cow’s milk and egg. 53 However, as per a study by Tsuji, EIARDs are more common and more likely to persist longer with milk than eggs. 72 Despite the overall success of OIT in children, the risk of exercise-induced breakthrough reactions remains a critical limitation. Due to these concerns, Japan does not recommend OIT for patients with a history of food anaphylaxis. In contrast, the EAACI permits its use in moderate-to-severe cases, provided it is conducted in specialized centers with expertise in immunotherapy. 73,74 not-yet-known not-yet-known not-yet-known unknown 4. Summation Anaphylaxis and High-Threshold Food Allergy Emerging evidence suggests that some cases of PCEFA may be high-threshold food allergies, where cofactors like exercise only lower the threshold rather than being an absolute requirement. For instance, Christensen et al. found that 37% of WDEIA cases reacted to very high doses of wheat without exercise. 27 This supports that cofactors primarily lowers the reaction threshold but is not always essential for symptom onset. The absence of similar findings with other foods likely reflects limited research rather than a lack of physiological mechanisms. not-yet-known not-yet-known not-yet-known unknown Sopo et al. described pediatric cases where more than two cofactors—including, but not limited to, food, exercise, NSAIDs, and viral infections—could be required to induce anaphylaxis, leading to the concept of summation anaphylaxis, where multiple augmentation factors collectively push the immune system into a hyperreactive state.75 Thus, at least in a subset of cases, PCEFA may also be conceptualized as a high-threshold food allergy, with cofactors just serving as modulators rather than prerequisites for allergic reactions. not-yet-known not-yet-known not-yet-known unknown 5. Conclusion CEFA is a potentially life-threatening allergic condition in children, characterized by the interaction of food ingestion with cofactors. Diagnosis remains challenging due to variable presentations and the involvement of multiple cofactors. Although the literature in children is scarce, ω-5 gliadin appears to be the most common trigger. The pathophysiology involves increased intestinal permeability, mast cell hyperreactivity, and immune dysregulation. Despite a high clinical burden of PCEFA, the demographics and clinical features in pediatric population remain understudied. Accurate diagnosis requires a high index of suspicion, systematic provocation testing, and allergen identification. Further research is needed to standardize diagnostic protocols and understand the pathophysiological mechanisms in pediatric patients. 6. References 1. Elghoudi A, Narchi H. Food allergy in children—the current status and the way forward. World J Clin Pediatr. 2022;11(3):253-269. 2. Sicherer SH, Warren CM, Dant C, Gupta RS, Nadeau KC. Food allergy from infancy through adulthood. J Allergy Clin Immunol Pract. 2020;8(6):1854-1864. 3. 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Acta Biomed. 2020;92(1):e2021068. doi:10.23750/abm.v92i1.10093 Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Authors Metrics & Citations Metrics Article Usage 538views 365downloads Citations Download citation Alpana Mohta, Emilio Narváez Fernández, Patricia Mir-Ihara, et al. Pediatric Cofactor-Enhanced Food Anaphylaxis (PCEFA): A Narrative Review of Epidemiology, Pathophysiology and Clinical Features. Authorea. 27 February 2025. DOI: https://doi.org/10.22541/au.174064714.44281517/v1 DOI: https://doi.org/10.22541/au.174064714.44281517/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.