Version May 2024
INTRODUCTION — The oral allergy syndrome (OAS; pollen-food allergy syndrome [PFAS or PFS]) is a relatively common form of food allergy, particularly in adults. It occurs in people who have pollen allergy, although not all patients have obvious hay fever or seasonal allergy symptoms. Patients typically report itching and/or mild swelling of the mouth and throat immediately following ingestion of certain uncooked fruits (including nuts) or raw vegetables. The symptoms result from contact urticaria in the oropharynx caused by pollen-related proteins in these foods. Only a small proportion of affected individuals experience systemic allergic reactions, although the disorder must be differentiated from more serious forms of food allergy.
This topic reviews the epidemiology, clinical manifestations, and diagnosis of OAS and describes associations between specific pollens and foods. The pathogenesis, management, and prognosis of OAS are presented separately. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)" and "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Terminology — At least two terms are used to describe this type of allergy:
Oral allergy syndrome — The term "oral allergy syndrome" (OAS) is widely recognized. However, it has been imprecisely applied in the literature to describe oropharyngeal reactions due to a variety of non-plant foods as well as both oropharyngeal and systemic symptoms due to plant foods in subjects with pollen allergy. This imprecision has led to considerable confusion. In this review, OAS is used to describe reactions caused by pollen-related foods that are limited to the oropharynx.
Pollen-food allergy syndrome — The terms "pollen-food allergy syndrome," "pollen-food syndrome," and "pollen-associated food allergy syndrome" (abbreviated PFAS or PFS) are increasingly used instead of OAS, both to emphasize the pathogenesis of these reactions and to describe the full range of oropharyngeal and systemic symptoms that can occur in response to pollen-related foods [1-3]. In this review, PFS is the preferred term for the entire spectrum of reactions caused by pollen-related plant foods.
Non-plant foods, such as cow's milk, hen's egg, or seafood, do not cause PFS. Isolated oropharyngeal symptoms to foods that are not related to pollens may precede more severe systemic allergic reactions. (See "Clinical manifestations of food allergy: An overview", section on 'IgE-mediated reactions'.)
EPIDEMIOLOGY — The prevalence of PFS in the United States has not been reported, although it is probably the most common food allergy in adult subjects, and there is a general impression that it has become more prevalent as respiratory allergy to pollen has increased over the past few decades [4]. Studies of prevalence include the following:
●In Central Europe, it has been estimated that approximately 5 percent of the general population suffers from PFS [5].
●A study of 1272 Danish young adults (aged 22 years) used questionnaires, skin prick tests, and oral food challenges [6]. Overall, 17 percent reported symptoms to pollen-associated foods (83 percent with oral symptoms), which represented 74 percent of those reporting possible pollen allergy.
●A systematic review of 36 population-based studies on prevalence of plant food allergies, with data from a total of over 250,000 children and adults, showed significant heterogeneity between studies regardless of food item or age group [7]. Only six studies included food challenge tests, with prevalences ranging from 0.1 to 4.3 percent each for fruits and tree nuts, 0.1 to 1.4 percent for vegetables, and <1 percent each for wheat, soy, and sesame.
PFS may first present in childhood, although the prevalence is difficult to estimate because data are based on selected allergy populations and not the general population. The following studies are examples:
●PFS to fruits and/or vegetables was reported in 93 percent of 72 children with severe rhinoconjunctivitis to birch pollen participating in a clinical trial of birch pollen immunotherapy [8].
●PFS was present in 24 percent of 1360 Italian children with pollen-induced allergic rhinitis and was associated with a longer duration of allergic rhinitis [9].
●In a cross-sectional study of children from a single Australian allergy center, PFS was reported in 4.9 percent overall, in 6.3 percent of children with allergic rhinitis, and in 12.1 percent in those with allergic rhinitis and demonstrable pollen sensitization [10].
●A cross-sectional study of 267 Mexican children found an overall prevalence of 8.9 percent [11]. In patients sensitized to pollen, the prevalence ranged from 9.6 to 12.2 percent, depending on the type of pollen; 62.5 percent of children with PFS were sensitive to pineapple [11].
●In Japan, oral symptoms to Rosaceae fruits and/or soybean were reported by 1 to 3 percent of the 76,568 surveyed school-age children; these symptoms were associated with the geographic sensitization to alder pollen, supporting the underlying sensitization to Bet v 1 [12].
●In South Korea, a multicenter, nationwide survey reported PFS in 41.7 percent of individuals with pollen allergy: 20 to 30 percent in individuals sensitized to a single-season pollen (only summer or only fall), and over 50 percent in those sensitized to all season pollens [13].
Natural history — PFS can develop in childhood or adulthood. Usually, patients develop allergic rhinitis to pollen first and then develop PFS following an increase in the severity of allergic rhinitis, although PFS might manifest in individuals with minimal allergic rhinitis symptoms. A small study found that the prevalence of PFS increased with age [14].
Occasionally, PFS is the first manifestation with no or minimal allergic rhinitis symptoms reported by the patient. However, immunoglobulin E (IgE) sensitization to pollen is always detectable with skin or serologic testing. The mechanisms underlying these variations in clinical presentation are unknown. It is our clinical experience that, when PFS develops in a child, the number of foods that cause symptoms tends to increase over time. Some adults with pollinosis also progress to experiencing PFS to an increasing number of plant foods. In many patients, PFS tends to be a persistent condition that is lifelong, unless the patient undergoes immunotherapy for treatment of the underlying pollen allergy, and this is only successful in controlling symptoms of PFS in a subset of patients. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Injection immunotherapy with pollen extracts'.)
RISK FACTORS — It is not known with certainty why some pollen-allergic patients develop PFS while others do not, although some risk factors have been identified:
●Sensitization to tree pollens (especially birch) – Sensitization to tree pollen, and specifically birch pollen, is associated with the highest rates of PFS. Allergy to grass pollen and weed pollen (commonly ragweed or mugwort) are less commonly associated with PFS. In a population of 936 unselected adults, for example, 24 percent were sensitized to pollen [15]. Pollen-sensitized individuals were evaluated for PFS with clinician-supervised oral food challenges. Symptoms to cross-reacting foods were recorded in 24, 10, and 4 percent of subjects sensitized to birch, mugwort, and grass, respectively.
●Higher levels of pollen-specific IgE – There is evidence that the higher the specific pollen IgE antibody levels, the greater the likelihood of PFS [16,17]. However, among patients with comparable serum levels of pollen-specific IgE antibodies, some patients react to one plant food, while others react to multiple foods. It is possible, although not proven, that both the affinity of the IgE antibodies as well as the recognition of the specific epitopes on pollen allergens affect the clinical expression of PFS.
●Sensitization to multiple pollens – Individuals sensitized to multiple pollens are most likely to be affected by PFS.
•In the study described previously, 52 percent of people allergic to three pollens reacted to related foods [15,18].
•In an Italian study of children with allergy to grass pollen (mean age of eight years), PFS was reported in 20 percent of those allergic to grass alone and up to 46 percent of those sensitized to both grass and birch [19].
●Having symptomatic pollinosis (nasal, ocular, or respiratory symptoms of pollen allergy) – Patients with nasal, ocular, and respiratory symptoms of pollen allergy (pollinosis) are at greater risk for PFS compared with patients who are sensitized to pollen but have no symptoms. In one large study of pollen-sensitized patients, the odds ratio of a clinical reaction to pollen-related fruits and vegetables was four times higher among those with symptoms of pollinosis [15]. Patients with pollen allergy can often be identified based on the history of suggestive symptoms during a known pollen season (figure 1).
Another study showed that adult birch-allergic patients with PFS were more likely to have a longer duration of birch tree pollen allergy and asthma compared with birch-allergic patients without PFS [18]. Pollinosis usually precedes the development of PFS by a number of years in adults and children [9,14].
●Living in areas where certain pollens are prevalent – Associations between pollen and plant foods are strongly affected by geographic location and indigenous flora. PFS is more prevalent in areas where birch trees are common, and the population demonstrates high levels of pollen-specific IgE (particularly to birch) [18,20,21]. Birch trees and birch pollinosis are common in Central and Northern Europe and Northern Japan [16,22,23]. In Japan, Japanese cedar and plane tree pollens are associated with PFS.
Sensitization to birch pollen is very common in the United States, although birch trees are not particularly prevalent. This finding most likely reflects extensive homology among trees of the Fagales order, such as birch, oak, alder, hazel, chestnut, and hornbeam [24,25]. In Mexico, trees from the Quercus species showed an association with PFS in children. In Japan, Japanese cedar pollinosis is associated with PFS to tomato [11,26].
CLINICAL MANIFESTATIONS — In most patients, symptoms are limited to the oropharynx. However, 2 to 10 percent may experience systemic symptoms, and patients with concomitant atopic dermatitis may notice a worsening of their cutaneous symptoms.
Oropharyngeal symptoms — The most common signs and symptoms are pruritus, tingling, mild erythema, and subtle angioedema of the lips, oral mucosa, palate, and throat, sometimes accompanied by a sensation of throat swelling. Symptoms occur while or shortly after (within 5 to 10 minutes of) ingesting the culprit fruit, nut, or vegetable. Oral papules or blisters are occasionally reported, although blisters or vesicles in isolation are not typical. Isolated oropharyngeal symptoms are reported by 75 to 95 percent of subjects with PFS [27-30].
Symptoms usually resolve within minutes when the food is swallowed due to disruption of the structure of the allergen by gastric acid and proteolytic digestive enzymes.
Particularly with fruits (eg, apple), patients may report that one variety of the food is more troublesome than another or that the symptoms do not develop after every exposure. Some patients may also notice that they can eat apples picked fresh from the tree, but, once the fruit has been stored for several days, it seems to cause more symptoms. This may be due to an increase in the proteins in the fruit that cause PFS, many of which are involved in the responses to stress and which increase as a result of picking and storage [31].
Seasonal pollen allergies — Most patients have clinical symptoms of allergy (rhinitis, conjunctivitis, asthma) in response to pollen. Other patients may be sensitized to pollen but do not have clinical symptoms of seasonal allergy. These individuals can only be identified by objective testing for pollen IgE sensitization. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Seasonal variation — PFS is an IgE-mediated reaction, and symptoms may increase during or following the pollen season because of seasonal boosting of pollen IgE levels.
Impact of cooking — In most cases, symptoms only develop in response to eating the raw, uncooked food. Some patients react predominantly to the peel of the raw fruit or vegetable and tolerate pulp [32]. Patients usually tolerate the culprit food in various cooked forms. Cooking, baking, or even briefly microwaving raw fruits and vegetables is usually sufficient to alter the allergens that are responsible for PFS. Tree nuts and peanuts are an important exception to this generalization, as roasted nuts can cause PFS. Implications for management are discussed separately. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Double-blind, placebo-controlled food challenges (DBPCFC) with roasted hazelnuts (140°C [284°F], 40 minutes) were performed in 17 birch pollen-allergic patients with DBPCFC-confirmed food allergy to raw hazelnuts. Challenge with roasted nuts was positive in 5 of 17 patients. The symptoms were generally mild and included PFS in all patients [33]. The allergens that cause PFS are reviewed elsewhere. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
Systemic reactions — Fewer than 10 percent of patients with allergies to fresh fruits and vegetables experience systemic symptoms. A few patients complain of nausea and abdominal discomfort, which may represent local esophageal and gastric symptoms that develop before the allergen is fully degraded. Some birch-allergic individuals develop analogous contact urticaria on their hands after handling raw potato. These two presentations are better classified as local reactions because the involved tissues are directly contacting the undigested food. Ingestion of large quantities of the raw plant foods tends to be associated with more severe symptoms.
True systemic reactions involve tissues that do not come into direct contact with undigested food. Symptoms may include the entire range of IgE-mediated allergic manifestations, such as urticaria, angioedema, nasal congestion, sneezing, flushing, wheezing, cough, diarrhea, and hypotension.
In a review of several studies of patients with PFS, which included a total of 1361 subjects, the following was reported [30]:
●9 percent experienced associated symptoms outside of the gastrointestinal tract
●3 percent at some time experienced systemic symptoms without oral symptoms
●1.7 percent experienced anaphylactic shock
Patients who react to plant foods but do not report allergic rhinitis in response to pollens are at higher risk for systemic reactions, because these patients may not be sensitized to pollen and may have an independent food allergy rather than PFS. Such patients may be sensitized to more stable allergens, such as nonspecific lipid transfer proteins (nsLTPs). In one study, 82 percent of patients with birch-related fruit allergy without allergic rhinitis had systemic symptoms, while only 45 percent of those with both fruit allergy and allergic rhinitis had systemic symptoms [34]. Anaphylactic shock occurred in 36 percent of those without allergic rhinitis versus 9 percent of those with allergic rhinitis. The high rate of systemic reactions in the subjects with allergic rhinitis in this preselected population was unusual and probably not representative of a general population of patients with PFS. A report of patients with severe hazelnut allergy without concomitant pollinosis documented IgE binding to heat-stable hazelnut proteins [35]. In contrast, the sera from patients with PFS to hazelnut and pollinosis did not bind to these heat-stable proteins.
Other factors that may predispose patients with PFS to systemic reactions include the following:
●Ingestion of large amounts of the raw plant food on an empty stomach.
●Increasing the pH of the stomach with medications, such as proton pump inhibitors, as this may impair digestion and destruction of the allergen. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Antiulcer therapies'.)
●The presence of "cofactors," such as nonsteroidal antiinflammatory drugs (NSAIDs) or exercise, presumably due to a transient increase in gastric or intestinal permeability [36].
Certain foods have been associated with higher rates of systemic reactions, including peanuts, tree nuts, peach, and mustard. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)" and "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Patients with concomitant atopic dermatitis — Patients with both OAS and atopic dermatitis can have eczematous reactions to fruits and vegetables, even after cooking:
●In one study, DBPCFC were performed with cooked apple, carrot, or celery in patients with atopic dermatitis and birch pollen allergy who experienced OAS and skin symptoms upon ingestion of the foods in raw form. Cooked versions of the culprit foods did not cause OAS, although they did cause worsening of eczema [37].
●T cell-mediated mechanisms may be responsible for the worsening of atopic dermatitis observed in some patients. Another study showed that heating and digestion abolished the IgE-binding ability of Bet v 1 cross-reactive food allergens in apple, celery, and carrot. However, there was no effect on the T cell-binding epitopes of those allergens [37,38]. Thus, T cell-mediated mechanisms may have been responsible for the worsening of atopic dermatitis observed in some patients.
IMPACT ON QUALITY OF LIFE — While PFS is considered a generally mild form of food allergy, studies have highlighted a potentially negative impact on quality of life [39]. In a United Kingdom study, quality-of-life data showed moderate impact across all domains, and parents of children with PFS were significantly more likely to have increased anxiety over time spent preparing food compared with children with allergic rhinitis without PFS [14].
REFERRAL — Patients with any of the following characteristics should be referred to an allergy expert for further evaluation:
●Definite or possible systemic symptoms. These patients should also be provided with one or more epinephrine autoinjectors. Instructions for prescribing epinephrine, as well as information for patients regarding the proper use of autoinjectors, are found separately. (See "Prescribing epinephrine for anaphylaxis self-treatment" and "Patient education: How to use an epinephrine autoinjector (The Basics)" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)
●Patients who report oropharyngeal symptoms but have no history of seasonal allergic symptoms to suggest pollen allergy since these patients may have a primary food allergy. (See 'Differential diagnosis' below.)
●Patients with reactions to foods that carry a higher risk of systemic reactions, such as peanuts, tree nuts, and mustard. In addition, peach is associated with systemic reactions in the Mediterranean region due to the sensitization to lipid transfer proteins (LTPs). The rates of systemic reactions to peach in other regions of the world are not known but are likely lower than in the Mediterranean region. LTP syndrome occurs in a non-Mediterranean area (north of Spain) and is related to multiple sensitizations to foods and pollens, such as plane tree and mugwort. In these pollen sensitizations, Pru p 3 seems to be the primary sensitizer [40].
POLLEN-FOOD ASSOCIATIONS — Most fruit and vegetable allergens are highly conserved proteins that demonstrate homology to proteins found throughout the plant world. This homology results in associations among pollens and plant foods (figure 2). Note that these relationships represent potential cross-reactivities. Prophylactic avoidance and testing are not recommended.
The plant foods that cause PFS can also cause independent food allergies (without pollen sensitization), which are associated with higher rates of systemic reactions. The allergens responsible for various types of reactions and the evaluation of patients with systemic reactions are presented in detail elsewhere. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
Foods associated with tree pollens
Birch — Patients allergic to birch pollen may develop oral symptoms after ingestion of the following plant foods (figure 2):
●Fruits and tree nuts in the Rosaceae and Betulaceae families – Apple, peach, apricot, cherry, plum, pear, almond, and hazelnut [41-44]
●Vegetables and spices in the Apiaceae family – Carrot, celery, parsley, caraway, fennel, coriander, and aniseed
●Legumes in the Fabaceae family – Soybean and peanut [45,46]
●Jackfruit, Sharon fruit
Plane — Patients sensitized to the pollen of the plane tree (also known as sycamore) may react to hazelnut, peach, apricot, plum, apple, kiwi, peanut, corn, chickpea, lettuce, and green beans [34,36,47].
Japanese cedar — Patients sensitized to the pollen of the Japanese cedar tree may react to tomato.
Cypress pollen — In Southern France, patients sensitized to the cypress pollen may develop PFS to peach and/or citrus fruit [48].
Foods associated with weed pollens
Ragweed — Patients sensitized to ragweed pollen may react to the following plant foods (figure 2):
●Melons and vegetables in the Cucurbitaceae family – Cantaloupe, honeydew, watermelon, zucchini, cucumber
●Bananas (the Musaceae family)
Mugwort — Patients sensitized to mugwort pollen may react to the following plant foods (figure 2) [49,50]:
●Celeriac-birch-mugwort-spice syndrome – Vegetables and spices in the Apiaceae family (eg, carrot, celery, parsley, caraway, fennel, coriander, and aniseed)
●Celeriac-mugwort-spice syndrome – Celery, carrot, bell pepper, black pepper, garlic, and onion (various plant families), as well as mango and paprika
●Mugwort-mustard syndrome – Vegetables and spices in the Cruciferae family (eg, mustard, cauliflower, cabbage, and broccoli)
●Mugwort-peach – Peach [36,47]
●Other – Lychee, mango, grape, sunflower seeds
Foods associated with grass pollen — Grass pollen-food crossreactivity is not as well described as tree pollen and weed pollen-food crossreactivity, so it may occur less frequently [51,52]. Patients sensitized to grass pollen (timothy, orchard, rye, Bermuda) may react to the following plant foods:
●Melons (Cucurbitaceae family)
●White potato and tomato (Solanaceae family)
●Orange (Rutaceae family)
●Swiss chard (Amaranthaceae family)
●Peanut (Fabaceae family)
●Kiwi (Actinidiaceae family)
Cupressaceae pollinosis (C. sempervirens, J. ashei, C. japonica) — Cypress pollen sensitization to allergens belonging to gibberellin protein family is associated with more severe reactions to peach among individuals sensitized to a cross-reactive Pru p 7. Allergens homologous to Pru p 7 have been described also in apricot, pomegranate, and cherry [53,54].
Specific syndromes — Certain types of PFS are associated with more severe reactions. Several of these have been recognized as specific syndromes.
Celery-mugwort-spice syndrome — Potentially severe allergic reactions may be seen in celery-allergic patients who are sensitized to both birch and mugwort. This is the "celery-spice-carrot-mugwort syndrome" [2,55,56]. In this syndrome, reactions to other foods of the Apiaceae family (carrot, caraway, parsley, fennel, coriander, and aniseed) as well as to paprika, pepper, mango, garlic, leek, and onion may be seen (figure 2).
Mugwort-mustard syndrome — Patients sensitized to mugwort (Artemisia vulgaris) may develop allergy to mustard and experience severe reactions (figure 2).
Among 38 adults with mustard allergy, 97 percent were sensitized to mugwort [57]. Approximately 10 percent reported anaphylaxis. Those without anaphylactic events in the past underwent double-blind, placebo-controlled food challenge (DBPCFC) with yellow mustard, and 14 of 20 patients reacted: 11 had PFS, and 3 had systemic symptoms. In addition, all patients were sensitized to other foods belonging to the Brassicaceae family (cauliflower, cabbage, broccoli), and 40 percent reported clinical symptoms upon ingestion of these foods.
Latex-fruit syndrome — Exposure to latex allergens, rather than pollen allergens, can also sensitize some individuals to plant foods. Approximately 30 to 50 percent of individuals who are allergic to natural rubber latex (NRL) show an associated hypersensitivity to some plant-derived foods, especially fresh fruits [4]. This is called latex-fruit or latex-food syndrome. An increasing number of plant foods, such as avocado, banana, kiwi, chestnut, peach, tomato, white potato, and bell pepper, have been associated with this syndrome (figure 3) [58-62]. The diagnosis of latex-fruit syndrome is reviewed separately. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Cross-sensitization among latex, fruit, and pollen' and "Latex allergy: Epidemiology, clinical manifestations, and diagnosis", section on 'Testing for allergy to latex-related foods'.)
Latex-fruit syndrome is frequently included in the discussion of PFS because of the analogous pathogenic mechanism. It is not always clear, however, 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-food associations — There are also patterns of interactions among plant foods that may involve grouping of foods associated with various pollens. Only a few such groupings have been reported, but the clinician should be aware that the foods to which a patient with PFS will react may not be easily predicted. As an example, patients who react to cantaloupe melon may also react to banana or watermelon, which would not be surprising as each of these is related to ragweed pollen (figure 2). However, patients who react to cantaloupe may also react to peach, which is usually considered to be related to birch pollen. Note that some plant foods (eg, peach) have been included in more than one botanical family.
Peach — Peach may be associated with both PFS and systemic reactions. Approximately one-half of individuals allergic to peach will react to other birch-related fruits (figure 4).
Peach is one of the most frequent causes of food allergy in Europe, both in the Northern regions and in Mediterranean areas [63,64]. Sensitization to peach and related Rosaceae fruits without clinical symptoms is also common, and sensitization alone is not sufficient to diagnose clinical allergy [64].
Peach allergy in Spain appears to be particularly prevalent and is associated with more systemic reactions [36,65]. A digestion-stable lipid transfer protein (LTP) has been implicated as a relevant allergen. Severity of the reactions to peach is enhanced by nonsteroidal antiinflammatory drugs (NSAIDs) and exercise [36]. In a cohort of 252 adults from Spain (Malaga and Barcelona), 93.2 percent had LTP syndrome (reactions to peach and at least another plant food with LTP), whereas 6.8 percent were LTP monoallergic. The LTP-monoallergic group reported more anaphylaxis and older age at the onset of peach allergy compared with those with LTP syndrome. Also, LTP-allergic individuals who were not sensitized to profilins had more frequent anaphylaxis compared with those who were sensitized to profilins (21.9 versus 9.9 percent) [66].
Another biomarker of a more severe reactions to peach is sensitization to a 7 kDa allergen belonging to the gibberellin-related protein (GRP) family, peach Pru p 7, that appears to be secondary to Cupressaceae pollinosis in Japan and Europe. Among 51 peach-allergic adults sensitized to Pru p 7, levels of specific IgE (sIgE) to GRP from cypress species (Cupressus sempervirens, Juniperus ashei, Cryptomeria japonica) were significantly higher that levels of Pru p 7-sIgE [53,54]. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Melons — In North America, the majority of patients reporting allergy to melons (Cucurbitaceae: watermelon, cantaloupe, and honeydew) have weed-pollen allergy and react clinically to at least one other related food (avocado, banana, kiwi, and peach) (figure 4) [27,67,68]. In contrast, in the central region of Spain, melon allergy is frequently associated with sensitization to several pollens, especially grass pollen [69]. In Australia, watermelon allergy is associated with sensitization to grass pollen (rye, timothy, Bermuda), tree pollen (birch, plane, acacia, eucalyptus), and weeds (dock/sorrel, plantain) [10].
Cannabis allergy — In the United States, cannabis sensitization, PFS, and anaphylaxis in adults are increasingly reported, in parallel with more widespread legal recreational use. Cases of cannabis-related food allergy have been attributed to crossreactivity between nonspecific lipid transfer proteins (nsLTPs) in cereals, fruits, tree nuts, tobacco, latex, wine, and beer [70]. The primary allergen is Can s 3, a nsLTP found in Cannabis sativa [71].
DIAGNOSIS — All of the following components should be present to make the diagnosis of PFS, although there are no established diagnostic criteria:
●A history of symptoms consistent with PFS (ie, pruritus, tingling, mild erythema, and sometimes very subtle angioedema of the lips, oral mucosa, palate, and throat) within 5 to 10 minutes of ingesting the culprit fruit, nut, or vegetable, with resolution shortly after the food is swallowed.
●Evidence of allergic sensitization to the plant food in question.
●Evidence of allergic sensitization to pollen.
●A known correlation between the plant food(s) in question and pollen(s) to which the patient is sensitized (figure 2).
EVALUATION — As with any form of food allergy, the evaluation of PFS combines a carefully gathered history, physical examination, objective testing for specific IgE (sIgE) to food and/or pollen, and possible oral food challenge [29]. All of these components may not be necessary in each case, and the extent of the evaluation, as well as the approach to management, is influenced by the food to which the patient reacted and the severity of the symptoms.
Most diagnostic allergy procedures, especially skin testing and food challenges, should be performed by allergy specialists with training in the management of serious allergic reactions. In vitro tests for sIgE may be performed by the nonspecialist, although definitive interpretation may require a specialist's input.
History — Important information obtained from the history includes the following:
●Has the patient experienced oropharyngeal symptoms, systemic symptoms, or both? Patients with systemic symptoms should be thoroughly evaluated by an allergy specialist and provided with one or more epinephrine autoinjectors. (See "Management and prognosis of oral allergy syndrome (pollen-food allergy syndrome)", section on 'Overview of management'.)
●Are symptoms of pollen allergy present? In many cases, pollen allergy (pollinosis) can be detected clinically as rhinitis, conjunctivitis, or asthma symptoms, which occur in a seasonal pattern (figure 1). If the patient does not have obvious symptoms of pollinosis, then testing for pollen sensitization should be performed.
●Has the patient reacted to other plant foods related to the one in question (figure 2)? Patients may not recall reactions to foods they uncommonly eat unless specifically asked. A seven-item diagnostic questionnaire for PFS has been validated in 110 adult subjects with tree pollen allergy [72]. It is a practical tool for identification of patients with PFS.
●Are cooked forms of the food tolerated? The development of symptoms with raw foods but not with the cooked forms is very suggestive of PFS.
Objective testing for food allergy — Our approach to most patients with suspected PFS is to test in parallel with both commercial extracts (when available) and prick-by-prick testing to fresh foods, except in the situations discussed below. (See 'IgE immunoassays' below.)
As in all forms of IgE-mediated food allergy, testing must be interpreted in the context of a careful clinical history. Both skin testing and in vitro testing in the diagnosis of PFS are complicated by the variable and unstable nature of the responsible allergens and the extensive crossreactivity among them. Both false-negative and false-positive results are common in patients with PFS. Positive tests may result from the presence of cross-reactive panallergens in fruits and vegetables from the same family, as well as in plant foods and the related pollens [64]. However, these may not be the allergens responsible for the patient's symptoms. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
Prick-by-prick skin testing with fresh foods — The preferred method of testing in most cases is skin prick testing with fresh fruits and vegetables using the prick-by-prick technique. Prick-by-prick testing is performed by inserting the test device into the fruit, withdrawing it, and then immediately pricking the patient's cleaned skin. It is important to prick all edible parts of the food (eg, both the outer skin and the flesh of fruits) with the testing device in order to recreate the allergen exposure that would result from eating these foods. (See "Diagnostic evaluation of IgE-mediated food allergy".)
Testing with fresh fruits and vegetables is sometimes confounded by natural variations in allergen levels due to differences among the various varieties (eg, cultivars), ripeness, or changes induced by storage. Despite this, the prick-by-prick method is more sensitive than skin prick testing with commercial extracts for most foods implicated in PFS [73,74].
In one study, the sensitivity of skin prick testing using a commercial extract of apple w.as 2 percent, compared with 82 percent when prick-by-prick technique was used with fresh apple [73]. The prick-by-prick technique also proved to be the more sensitive for carrot, celery, cherry, tomato, orange, and peach, although the difference was not as dramatic. Each of these plant foods contains unstable allergens.
Commercial food extracts — Commercial extracts have low sensitivity for detecting sensitization to the allergens that are typically responsible for PFS because PFS is usually caused by unstable allergens that tend to be destroyed during extract production [75].
Despite this limitation, skin testing with commercial extracts may be useful in the following settings:
●To evaluate for sensitization to tree nuts and legumes, such as peanut, hazelnut, and pea, which contain stable allergens [73]. Commercial extracts may be inadvertently enriched for stable allergens as a result of processing.
●To evaluate for sensitization to foods that might be difficult to prepare or irritating to the skin, such as spices.
●To help assess the risk of systemic reactions. Individuals with positive skin tests to commercial Rosaceae food extracts were more likely to experience systemic reactions than those with positive skin tests only to fresh extracts (64 percent versus 6 percent) [76]. Commercial extracts are often enriched for the stable allergens, which are associated with systemic reactions. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
IgE immunoassays — There are clinical situations in which the most appropriate initial test for sIgE is an in vitro immunoassay (which were previously called radioallergosorbent tests [RAST]). Examples include patients with a history of life-threatening anaphylaxis to a small amount of the implicated food, those with dermographism or extensive skin disease, those who cannot discontinue interfering medications, and those with unstable asthma. These issues are reviewed in more detail separately. (See "Diagnostic evaluation of IgE-mediated food allergy".)
IgE immunoassays for various foods have not been systematically evaluated in the diagnosis of PFS. The use of fresh food to coat the immunoassay disk has been used in some reports. However, this is impractical outside of research centers [77,78].
Component testing — Individual component testing with immunoassay or allergen microarray chip ISAC (immuno-solid-phase allergen chip) does not significantly increase the accuracy of diagnostic testing to plant foods in many instances [79]. However, there are circumstances in which component-resolved diagnostics may be helpful [80]:
●Peanut component testing might be useful in those with seasonal allergies who had oral symptoms with peanut ingestion. Isolated Ara h 8 sensitization (without detectable IgE to Ara h 1, 2, or 3) suggests low risk for systemic reactions to peanut.
●Subjects with suspected hazelnut allergy and isolated IgE sensitization to birch cross-reactive Cor a 1 are more likely to experience mild oral symptoms, while those who are sensitized to Cor a 9 and Cor a 14 are more likely to have systemic allergic reactions.
While an oral food challenge is necessary to confirm lack of sensitivity, the information from component testing can be used to identify patients at low risk for systemic symptoms during challenge. Component testing is reviewed in more detail separately. (See "Component testing for pollen-related, plant-derived food allergies", section on 'Allergen-specific use/interpretation'.)
Objective testing for pollen sensitization — Confirmation of pollen sensitization either by skin testing (most accurate) or by IgE immunoassays is necessary to make a conclusive diagnosis of PFS. The performance and interpretation of skin testing for environmental allergies is reviewed separately. (See "Overview of skin testing for IgE-mediated allergic disease".)
If skin testing is not available or not possible because the patient is taking interfering medications or for other reasons, then IgE immunoassays may be helpful in detecting sensitization to pollens. These are generally less sensitive than skin tests. (See "Overview of skin testing for IgE-mediated allergic disease".)
In reality, patients sometimes clearly describe symptoms of respiratory allergy during a specific pollen season, allowing for a reasonably certain diagnosis based solely on this history (figure 1). It may not be necessary to prove pollen sensitization if the patient's culprit food and seasonal symptoms match (ie, reactions to apple in a patient with rhinitis during tree pollen season) and if past reactions were consistently mild and limited to the oropharynx.
However, pollen sensitization should be confirmed by testing if either of the following is true:
●It is unclear from the history that the patient has pollen allergy.
●The patient has experienced systemic symptoms because patients without pollen sensitization may have an isolated allergy to a plant food (unrelated to pollen) and be at higher risk for systemic reactions.
Oral food challenges — Patients with PFS will frequently have positive skin or in vitro tests to several related foods within a plant family. However, as in other forms of IgE-mediated food allergy, positive tests do not necessarily predict clinical symptoms upon ingestion. Thus, oral food challenge remains the only definitive method of identifying clinical reactions.
Although oral food challenges are the most conclusive means of confirming food allergy, challenges in PFS may be impacted by some of the same issues that affect skin testing. Allergen levels can vary among cultivars, within different parts of the fruit (peel versus flesh), with ripeness, or due to changes induced by storage [81]. Challenge studies suggest that a history of clinical reactivity can be confirmed by oral food challenges in only one-third of melon-allergic patients, in two-thirds of patients allergic to fruits from the Rosaceae family (peach, plum, pear, apple, almond, apricot, and strawberry), and in approximately 80 percent of patients allergic to fruits from the Prunoideae family (peach, apricot, plum, and cherry) [64,67,82].
The importance of obtaining a definitive diagnosis depends on the severity of the reaction, nutritional needs, food preferences, and social issues. In many cases, diet is empirically limited based on the clinical history and the results of skin prick testing, rather than formal food challenges. However, food challenge may be indicated in certain situations:
●In patients with past systemic reactions to mixed foods, when the culprit food could not be unequivocally identified through skin or in vitro testing. In this case, the challenge would be performed in order to ascertain that the responsible food had been correctly identified.
●In patients reporting symptoms to a specific food, in whom testing failed to demonstrate sensitization to that food. Challenge would be done in this situation because testing may have been falsely negative due to allergen variability. (See 'Objective testing for food allergy' above.)
●In patients in whom it is unclear if cooking or other processing eliminates the symptoms. Challenge can be performed with raw and cooked forms of the food.
●In patients with past systemic reactions to one food who have not been previously exposed to the related foods (eg, systemic reactions to hazelnut in a patient who has not eaten other tree nuts or systemic reactions to peach in a patient who has not eaten other Rosaceae fruits).
In deciding on the challenge procedure (office versus hospital setting, intravenous access, the rate and quantity of administered food), risks should be assessed based on the severity of previous reactions, food involved, and test results. An open challenge with the food in its natural form should always follow a negative-blinded challenge. (See "Diagnostic evaluation of IgE-mediated food allergy".)
Special care is needed in preparing food for blinded challenges to confirm PFS because freeze drying, heating, and other processing methods can destroy the fragile allergens, leading to false-negative results [67]. Standardized protocols for challenges to raw fruits and vegetables are not available, although research protocols for double-blind, placebo-controlled food challenges (DBPCFC) to fresh apple, peach, celery, carrot, and melon have been published [44,64,67,83-86].
Endoscopic challenge — The colonoscopic allergen provocation (COLAP) test has been evaluated in adult patients with gastrointestinal symptoms in response to foods, such as nausea, vomiting, and diarrhea. This form of testing induces wheal-and-flare reactions in the cecal mucosa within 20 minutes of the endoscopic challenge with recombinant Bet v 1 (rBet v 1) [87]. A wheal-and-flare reaction in COLAP was observed in 13 of 16 patients (81 percent) with a positive history of gastrointestinal symptoms associated with Bet v 1-related food ingestion compared with 4 of 18 patients (22 percent) with pollinosis and negative history of adverse food reactions. Nonallergic control subjects had no wheal-and-flare response in the cecal mucosa. The mucosal reaction to rBet v 1 was correlated with tissue eosinophil activation on biopsy, presence of pollinosis, and history of adverse reaction to Bet v 1-associated food allergens. The mucosal challenge with rBet v 1 may be a diagnostic tool that could facilitate the diagnosis of Bet v 1-associated allergy manifesting with gastrointestinal symptoms.
DIFFERENTIAL DIAGNOSIS — Other conditions that can mimic PFS include the following:
●An isolated food allergy (ie, primary food allergy) – Most of the foods that cause PFS can also cause food allergy without pollen sensitization. Thus, the primary condition that must be differentiated from PFS is an isolated allergy to the food in question. Any patient who does not have evidence of sensitization to pollens should be considered to have a primary food allergy and managed accordingly, including referral to an allergy expert, avoidance of all forms of the food (raw and cooked), and training in the use of epinephrine autoinjectors. (See "Clinical manifestations of food allergy: An overview".)
●Local irritation of the mouth, tongue, or throat caused by spicy, tart, or gritty foods – Examples include oral irritation from pineapple.
●Contact urticaria – Certain foods, such as tomato sauce, citrus fruit, garlic, and berries, can cause a local irritant contact urticaria of the lips and perioral skin. This condition is more common in children and would be suggested by the absence of pollen sensitization.
●Perioral dermatitis or oral contact dermatitis – Perioral dermatitis presents as small papules, vesicles, and/or tiny pustules with erythema and scaling located around the mouth, nose, or periorbital region. Perioral dermatitis can be caused by cosmetic products or by contact with mango or cashews in individuals with a history of contact dermatitis in response to poison ivy [88,89]. Contact dermatitis of the lips involves painful swelling or blistering of the lips, followed by peeling during resolution, which occurs over the course of days [90]. The presence of persistent skin lesions distinguishes these conditions from PFS.
●Gastroesophageal reflux disease (GERD) – Patients with GERD can usually be distinguished clinically by less prominent oral symptoms or objectively by the absence of sensitization to the food or related pollen in question. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)
●Eosinophilic esophagitis (EoE) – EoE can sometimes present with the sensation of food becoming lodged in the throat and may mimic PFS and other forms of food allergy. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)", section on 'Clinical manifestations'.)
●Burning mouth syndrome – This disorder presents predominantly in middle-aged and older females and consists of a sensation of burning in the structures of the oral cavity [91,92]. Patients describe burning rather than itching but specific foods can sometimes exacerbate the symptoms, leading the patient to suspect an allergy. (See "Overview of craniofacial pain", section on 'Burning mouth syndrome'.)
FUTURE DIAGNOSTIC TESTS — Tests using recombinant allergens are being developed, which could determine more precisely the allergens to which a patient is sensitized. In theory, these tests could distinguish individuals sensitized to labile antigens, such as Bet v 1 homologs or profilins, from those sensitized to heat and digestion-resistant antigens and thus differentiate between PFS and primary plant food allergy. They are discussed elsewhere. (See "Future diagnostic tools for food allergy".)
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 email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Oral allergy syndrome (Beyond the Basics)" and "Patient education: Food allergy symptoms and diagnosis (Beyond the Basics)" and "Patient education: Food allergen avoidance (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definitions – Oral allergy syndrome (OAS), also called pollen-food allergy syndrome (PFAS or PFS) describes contact urticaria of the oropharynx upon ingestion of certain fresh fruits, nuts, or vegetables in individuals who are sensitized to plant pollens. Reactions are immunoglobulin E (IgE) mediated and caused by allergens in plant foods that are homologous to pollen allergens. PFS is a more general term that encompasses both oropharyngeal and systemic reactions due to these allergens. (See 'Introduction' above.)
●The most common form of food allergy – PFS is believed to be the most common type of food allergy in adults and likely affects at least 5 percent of the population. It is also seen in children, although the prevalence is not known. (See 'Epidemiology' above.)
●Risk factors – Patients sensitized to tree pollen, and specifically birch pollen, have the highest rates of PFS. Individuals with nasal, ocular, and respiratory symptoms in response to pollen are at greater risk for PFS than pollen-sensitized subjects without clinical pollen allergy. (See 'Risk factors' above.)
●Signs and symptoms – PFS usually presents with pruritus and swelling of the mouth and throat during or just after ingestion of fresh, uncooked fruits and vegetables. Oropharyngeal symptoms usually resolve promptly when food is swallowed, and cooked forms of the culprit foods are generally tolerated because the responsible allergens are susceptible to gastric acid, digestive enzymes, and heat. (See 'Clinical manifestations' above and "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
●Systemic symptoms are unusual – Although uncommon, systemic symptoms and reactions to cooked foods are both possible in PFS. Fewer than 10 percent of patients with PFS experience systemic symptoms, although they may be severe. Peanuts, tree nuts, peaches, and mustard are associated with more systemic reactions than other foods. (See 'Systemic reactions' above.)
●Relationships between specific pollens and foods – Homology among protein allergens results in patterns of associations among fruits, vegetables, nuts, and pollens (figure 2 and figure 4). A similar phenomenon affects up to one-half of latex-allergic individuals and is called the latex-fruit syndrome (figure 3). (See 'Pollen-food associations' above.)
●Diagnosis – The diagnosis of PFS requires suggestive symptoms in a patient who has evidence of specific IgE to the food in question accompanied by a clinical history of pollinosis or demonstrated sensitization to a pollen related to the culprit food. (See 'Diagnosis' above.)
●Evaluation – Evaluation of patients suspected of having PFS involves history, physical examination, objective testing for specific IgE (sIgE) to food and/or pollen, and possible oral food challenge. Extensive evaluation may not be necessary if symptoms are mild and limited to the oropharynx. In contrast, any patient with systemic symptoms requires a thorough evaluation. (See 'Evaluation' above.)
•Testing to confirm pollen sensitization – Confirmation of pollen sensitization either by skin testing (most accurate) or by IgE immunoassays is necessary if it is unclear if the patient has pollen allergy or if there were any systemic symptoms. Patients without pollen sensitization may have an isolated allergy to a plant food and therefore be at higher risk for systemic reactions. (See 'Objective testing for pollen sensitization' above.)
•Indications for oral food challenge – Oral food challenge remains the only definitive diagnostic maneuver in some cases. In addition, challenge may be helpful for patients with past systemic symptoms who do not know if they tolerate cooked versions of the food or other closely related foods. (See 'Oral food challenges' above.)
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