INTRODUCTION — This topic reviews clinically relevant features regarding food allergen cross reactivity. Other topic reviews discuss molecular aspects of food allergens, evaluation of food allergies, avoidance of food allergens, the natural history of food allergy, and oral allergy syndrome. (See "Molecular features of food allergens" and "Diagnostic evaluation of IgE-mediated food allergy" and "Management of food allergy: Avoidance" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution" and "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
The clinical characteristics, diagnosis, and management of specific food allergies are also discussed in detail separately. (See appropriate topic reviews.)
OVERVIEW OF CROSS-REACTIVITY — When a patient has a confirmed allergy to one food, evaluation of related foods may be indicated to determine if these foods are also problematic. However, a "positive" allergy test to a related food may simply represent immunologic vers-reactivity due to the presence of a homologous protein that does not have clinical significance, which is more common than true clinical cross-reactivity [1,2]. Thus, a person with an allergy to peanut (a legume) is likely to have "positive" serum immunoglobulin E (IgE) tests or skin prick tests to multiple legumes that are clinically tolerated (see 'Legume cross-reactivity' below). Approximate rates of clinical cross-reactivity are summarized in the figure (figure 1).
Concern about allergy can arise if a related food was never ingested or was not a regular part of the diet and was not recently ingested. In these cases, it may be reasonable to evaluate the patient for allergy to the related food to determine clinical tolerance, depending upon epidemiologic, social, and nutritional consequences and concerns. Further evaluation is generally not needed if a related food is already ingested routinely without reactions.
●Tree nuts, fish, and shellfish are more commonly clinically cross-reactive. Caution and possible allergy testing (including oral food challenges) are warranted if ingestion of related foods not already tolerated is being considered.
●Grains, fruits, vegetables, and legumes are less cross-reactive, and evaluation/individualization is generally recommended to expand the diet.
COW'S MILK — Most of the mammalian milks or milk products that are commonly consumed, such as those from sheep or goat, will trigger allergic reactions in a person with cow's milk allergy (CMA). Studies of in vitro assays and skin prick testing have shown extensive cross-reactivity between milk from cows, sheep (ewe), goats, buffalo, deer, and ibex (wild mountain goat) but only weak cross-reactivity with proteins from donkeys, mares, and reindeer and no significant cross-reactivity to camel's and pig's milk [3-6]. Significant amino acid sequence homology and a resulting high rate of clinical cross-reactivity between milk from ruminants (eg, approximately 90 percent of children with IgE-mediated CMA react to goat's milk) make milk from sheep and goats inappropriate feeding alternatives for most persons with CMA [7,8]. In contrast, clinical studies on allergenicity of equine milk (mare's and donkey's milk) and camel's milk suggest that it may be tolerated by most children with CMA, except those who have a history of anaphylaxis to cow’s milk [4,8-14]. Studies on clinical tolerability of reindeer and pig milks are lacking. Some patients with primary goat's or sheep's milk allergy may tolerate cow's milk [15-18].
Human milk does not contain beta-lactoglobulin, unlike other mammalian milks. However, there is significant amino acid sequence homology between other bovine and human milk proteins, suggesting that cross-reactivity between conserved regions of bovine and human casein may exist [19,20]. Clinical allergy to human milk was shown in one case report, and sensitization to human milk was reported in two studies, although confirmatory clinical data are missing and the clinical significance is largely unknown [21-23].
Infants with IgE-mediated CMA usually tolerate soy (approximately 85 percent) [24], even if cosensitized [5], or extensively hydrolyzed cow's milk-based formulas (approximately 95 percent) [25]. Children with non-IgE-mediated CMA may be less likely to tolerate soy [26]. Other alternatives to mammalian milks are available for toddlers and older children. These alternatives are discussed in detail separately. (See "Food protein-induced allergic proctocolitis of infancy" and "Management of food allergy: Nutritional issues", section on 'Cow's milk allergy'.)
Serum albumin is found in both milk and meat. This protein is thought to be involved in cosensitization to cow's milk and beef, with 13 and 20 percent of children with IgE-mediated CMA in referred populations also reacting to beef [27]. Heating and other cooking processes can reduce the allergenicity of beef [28,29]; therefore, well-cooked beef is less likely to cause a problem for those with CMA.
The diagnosis and management of CMA is described elsewhere. (See "Milk allergy: Clinical features and diagnosis" and "Milk allergy: Management" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Cow's milk'.)
HEN'S EGG — Cross-reactive proteins among various avian egg proteins are common [30], but the clinical implications have not been systematically studied. Reactions to duck and goose egg, in the absence of hen's egg allergy, have been described [31]. Some patients with hen's egg allergy also react to chicken meat. (See 'Meats' below.)
The diagnosis and management of hen's egg allergy is described elsewhere. (See "Egg allergy: Clinical features and diagnosis" and "Egg allergy: Management" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Hen's egg'.)
Dietary substitutes for hen's egg are also discussed in detail separately. (See "Management of food allergy: Nutritional issues", section on 'Egg allergy'.)
LEGUMES: PEANUT, SOY, AND OTHERS — Peanut and soy are prominent legume allergens. Legumes share homologous proteins (conserved proteins), but features of clinical reactions vary [32]. Regional dietary habits and pollen exposure may influence the epidemiology of legume allergy. As an example, allergy to lentil is more common than peanut allergy in Turkey [33].
Peanut — The majority of peanut-allergic persons react to non-pollen-related stable proteins that result in systemic and potentially severe reactions. However, peanut also contains birch pollen-related proteins [34,35] and may cause oral allergy syndrome in a subset of birch pollen-allergic individuals. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Peanut'.)
Clinical features of peanut allergy are described elsewhere. (See "Peanut, tree nut, and seed allergy: Clinical features" and "Peanut, tree nut, and seed allergy: Diagnosis" and "Peanut, tree nut, and seed allergy: Management" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Peanut and tree nuts'.)
Soybean — Soybean, a legume-like peanut, is responsible for a variety of clinical manifestations of allergy, both IgE mediated and cell mediated. The amount of protein in various soy derivatives and the characteristics of these products and their proteins (eg, cross-reactivity) may influence allergy outcomes. As an example, products containing soy protein isolate/soy protein concentrate or concentrated soy products may trigger allergic reactions, including severe ones, in persons with sensitization to birch pollen [36]. These patients are most commonly sensitized to the soy protein Gly m 4.
Processed soybean oil is typically considered safe for patients with soy allergy [37]. Soy lecithin is a phospholipid derivative of soy that contains a trace amount of soy protein [38,39]. It is used commonly as a processing aid in food products. The risk of residual protein in soy lecithin triggering a reaction in a person with soy allergy has not been extensively studied. We generally do not instruct patients with soy allergy to avoid soy lecithin. Fermentation of soy may reduce the allergenicity, but no studies have evaluated the relative risks of ingestion of these foods, such as soy sauce, by persons with soy allergy. Presumably, soy protein content/allergenicity varies among these products (eg, soy sauce, miso, tempeh, and natto), and reactions may depend upon the product and the individual's sensitivity (see "Management of food allergy: Nutritional issues", section on 'Soybean allergy'). However, there are case reports of Japanese adults and children with late-onset, IgE-mediated anaphylaxis to natto mucilage thought to be related to development of an allergy to poly-gamma-glutamic acid (PGA) after a jellyfish sting, akin to sensitization to the carbohydrate allergen alpha-gal after a multiple tick bites and development of red meat allergy [40-45]. Although PGA may be found in a variety of products other than natto, reactions have been rarely reported [46]. (See "Molecular features of food allergens", section on 'Protein stability' and "Allergy to meats", section on 'The role of ticks in red meat allergy'.)
Legume cross-reactivity — It is common to find positive IgE antibody tests to several legumes in persons who are clinically reactive to one type. Clinical cross-reactions are uncommon despite the high rate of cross-sensitization [32,47-50]. Thus, most patients with legume allergy need not avoid the entire legume family.
●In vitro IgE tests were performed in 62 children with at least one positive legume prick skin test. Seventy-nine percent had serologic evidence of IgE binding to more than one legume, and 37 percent bound all six legumes that were tested (peanut, soybean, lima bean, pea, garbanzo bean, and green bean) [47].
●Open or double-blind, placebo-controlled food challenges (DBPCFCs) were performed in 69 atopic children with at least one positive skin test to a legume [48]. Oral challenges to five legumes (peanut, soybean, pea, lima bean, green bean) resulted in 43 reactions in 41 patients (59 percent). Only 5 percent (2 of 41) of patients reacted to more than one legume when challenged, while 52 percent (36 of 69) reacted to two or more legumes on prick skin testing.
Particular legumes may be more allergenic or have greater cross-reactivity, for example, green pea, chickpea, and lentil [32,50,51]. Children with lentil allergy frequently react to other legumes. In one series, 35 of 43 children with allergy to lentil also reacted to at least one other legume, most commonly chickpea (n = 8), pea (n = 6), or both chickpea (garbanzo bean) and pea (n = 23) [52]. Cross-reactivity among types of lentils is also variable and not easily predictable [53].
There are reports of sensitization and allergy to lupine flour, particularly in Europe [54-56]. Allergy to lupine is related to peanut allergy in some patients and is a distinct allergy in others [57-60]. Eleven of 24 children with peanut allergy in France had positive skin tests to lupine, and seven of eight children who underwent DBPCFCs (n = 6) or labial challenges (n = 2) to lupine reacted [50]. Among 47 peanut-allergic children in the United Kingdom, 16 were sensitized to lupine, and two out of nine reacted during oral challenges (ie, minimum risk 4 percent) [57]. However, many lupine-sensitized individuals do not react upon ingestion, so individualized evaluations are warranted [56].
TREE NUTS — Allergic reactions to tree nuts can range from mild to severe [61,62]. Variation in severity of clinical reactions may be related in part to the particular proteins to which immune responses are directed, particularly regarding labile proteins that crossreact with pollens.
As an example, certain nuts (eg, almond, hazelnut) contain labile proteins that are pollen cross-reactive (eg, birch). Exposure to these proteins leads to localized symptoms of oral allergy syndrome (pollen-food allergy syndrome). These nuts also contain stable proteins. Sensitization to these proteins most likely occurs through the gastrointestinal route or possibly the skin. Stable proteins are more likely to trigger systemic reactions.
Certain tree nuts also share homologous proteins with peanut and other tree nuts, as shown by inhibition assays [63,64]. A high rate of coallergy to peanut and some tree nuts (30 to 50 percent) is observed among referral populations [65,66]. The clinical relevance of such observations is not fully explored [63].
Serologic studies have indicated a high degree of IgE binding to multiple tree nuts [64,66]. Challenges to one or more tree nuts were performed in 14 children, and at least two reacted to multiple nuts (as many as five types) [67].
Certain tree nut allergies appear to coexist more commonly, such as cashew and pistachio or walnut and pecan [35,64,66,68,69]. Cross-reactivity is seen among pistachio, cashew, and mango seed (but not the fruit) [70]. Proteins homologous to cashew may also be found in fruit seeds, with rare reports of reactions if the seeds are eaten [71-73] or from fruit pectin [74]. Coconut is sometimes considered a nut because it shares homologous proteins with walnut; however, it is not a common allergen [66,75].
Some authorities suggest avoidance of all tree nuts for people with peanut allergy or any single tree nut allergy because of safety concerns (eg, cross-contact) and epidemiologic risks. However, others feel individualization is possible when tree nuts known to be tolerated are eaten without risk of cross-contact with causal ones [76]. We take into consideration the age of the child, test results, potential cross-reactivity of the nuts (eg, we do not typically allow pistachio if a patient has an allergy to cashew), and patient/family preferences before suggesting liberalization of the diet to include some nuts and not others. If certain nuts are consumed, we review issues of cross-contact and avoidance. As an example, we may instruct the patient to only eat the allowed nut(s) from the shell. (See "Management of food allergy: Avoidance".)
The prevalence, clinical characteristics, and management of tree nut allergy are reviewed elsewhere. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Peanut and tree nuts' and "Peanut, tree nut, and seed allergy: Clinical features" and "Peanut, tree nut, and seed allergy: Diagnosis" and "Peanut, tree nut, and seed allergy: Management".)
FISH AND SHELLFISH — Clinical features and cross-reactivity to fish and shellfish are discussed separately. Briefly, there is a high rate of clinical cross-reactivity among fish and among shellfish because of homologous proteins (tropomyosin for shellfish and parvalbumin for finned fish) but not between fish and shellfish. The amount of expressed parvalbumin may partly account for variation among allergenicity of various finned fish [77]. (See "Seafood allergies: Fish and shellfish".)
GRAINS — Wheat allergy is the most common of the cereal grain allergies [78]. The prevalence of allergy to other cereal grains (eg, rye, barley, oat, rice) is not well studied. Cereal grains share homologous proteins with grass pollens and each other. This may account for the high rate of sensitization to these foods. However, rates of clinical reactivity are much lower [79]. There are few studies of clinical cross-reactivity. In a study of 23 children with food challenge-proven wheat allergy, only 20 percent also reacted to rye or barley [79]. In 10 patients with severe wheat allergy, 60 percent reacted to barley and 33 percent to oat [80].
Food allergy to grains is discussed in greater detail separately, as are dietary alternatives to wheat. (See "Grain allergy: Allergens and grain classification" and "Management of food allergy: Nutritional issues", section on 'Wheat allergy'.)
SEEDS — Allergies to seeds (eg, sesame, poppy, mustard, flax, sunflower, and rape) are being reported with increasing frequency [81-88]. Some of the causal allergens have been identified as homologous seed storage proteins [81,89-91]. Cross-reactivity with foods (peanut, hazelnut, kiwi, other seeds) and pollens is potentially important, but the full clinical implications are not established. (See "Peanut, tree nut, and seed allergy: Clinical features" and "Peanut, tree nut, and seed allergy: Diagnosis" and "Peanut, tree nut, and seed allergy: Management".)
FRUITS/VEGETABLES — IgE-mediated reactions to fruits and vegetables are the most common type of food allergy reported by adults. Reactions are typically mild, confined to the oral cavity, and related to initial sensitization to pollens that share homologous proteins with the implicated fruits/vegetables. They are discussed in detail separately. (See "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)" and "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)" and "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
LATEX-FRUIT SYNDROME — Associated hypersensitivity to plant-derived foods is common in individuals who are allergic to natural rubber latex (NRL). It is not always clear whether latex sensitization precedes or follows the onset of food allergy or which route of sensitization (skin, mucous membrane contact, or inhalation) underlies the condition. Food allergy reactions in these patients can be severe. This syndrome is discussed in detail separately. (See "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)" and "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
MEATS — Allergy to mammalian and avian meats is uncommon in children and typically affects those with atopic dermatitis and/or multiple food allergies. Meat allergy is usually outgrown in childhood and is rare in adults. Three general patterns of cross-reactivity or coallergy are noted in patients with meat allergy: reactions to meats from related species, reactions to meat and other foods (such as milk or egg), and reactions to meat and animal danders. Sensitization to a carbohydrate allergen, galactose-alpha-1,3-galactose (alpha-gal), which is found in tissues of nonprimate mammals including cows, sheep, and pigs, is associated with delayed-onset (ie, typically three to six hours after ingestion) systemic reactions to ingestion of meat from these animals. Meat allergy is discussed in greater detail separately. (See "Allergy to meats".)
SHORT-CHAIN GALACTOOLIGOSACCHARIDE — Most known food allergens are proteins. However, carbohydrate epitopes can also act as allergens, as is seen with delayed IgE-mediated reactions to galactose-alpha-1,3-galactose (alpha-gal) in meat (see 'Meats' above). Another potential carbohydrate allergen is the prebiotic short-chain galactooligosaccharide (scGOS). There are several case series of acute allergic reactions to beverages containing scGOS, including cow's milk formula, in children over two years of age and adults [92-94]. Reported symptoms included an itchy rash and lower respiratory symptoms (wheezing, difficulty breathing). These patients tolerated other dairy products and had no history of cow's milk allergy (CMA). All reported cases were from Southeast Asia (Japan, Vietnam, and Singapore), suggesting that there is a primary sensitizing agent specific to the region. (See "Allergy to meats" and "Prebiotics and probiotics for prevention of allergic disease".)
SPICES AND NATURAL FOOD ADDITIVES — The term "spice" is often used to describe a variety of flavoring agents. Spices represent a huge array of types of foods, including many seeds and peppers, and plant leaves, tubers, bulbs, and bark. Many spices have been the culprit in an allergic reaction.
Clinical cross-reactivity between peanut and fenugreek seed (both in the Fabaceae family) and cashew and sumac berries (both in the Anacardiaceae family) have been reported [95,96]. Fenugreek is used in cooking in the Mediterranean, Western and Southern Asia, and Southern Europe and is a common ingredient in curry. Sumac is used in Middle Eastern and Mediterranean cuisine.
Allergic reactions associated with specific spices and natural food additives are discussed separately. (See "Allergic and asthmatic reactions to food additives".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Food allergy symptoms and diagnosis (Beyond the Basics)" and "Patient education: Food allergen avoidance (Beyond the Basics)")
SUMMARY
●Cross-reactive food proteins versus clinical cross-reactivity – Many related foods contain homologous proteins (conserved proteins), which present potential for clinical cross-reactions. However, allergy testing to related foods reveals a higher rate of positive tests to cross-reactive proteins than true clinical reactions to the related foods. (See 'Overview of cross-reactivity' above.)
●Common clinically cross-reactive related foods – Certain related foods are more commonly clinically cross-reactive (eg, tree nuts, fish, shellfish, animal milk). Caution and possible allergy testing (including oral food challenges) are warranted if ingestion of related foods not already tolerated is being considered. (See 'Cow's milk' above and 'Tree nuts' above and "Seafood allergies: Fish and shellfish".)
●Related foods that are less likely to be clinical cross-reactive – Certain related foods are less likely to be involved in clinically relevant cross-reactions (eg, grains, fruits, vegetables, legumes), and each case must be considered on an individual basis. (See 'Legume cross-reactivity' above and 'Grains' above and "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
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