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 Oral allergy syndrome (pollen-food allergy syndrome)

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Anna Nowak-Węgrzyn, MD extracted from uptodate and edited by Bob Lanier

INTRODUCTION — The oral allergy syndrome (OAS) 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 hayfever or seasonal allergy symptoms. Patients typically report itchingand/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.

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 lead 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" (all abbreviated PFAS) 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 [ 

Non-plant foods, such as cow's milk, egg, or seafood, do not cause OAS. Isolated oropharyngeal symptoms to foods that are not related to pollens may precede more severe systemic allergic reactions.  

.EPIDEMIOLOGY — The prevalence of pollen-food allergy syndrome (PFAS) 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 two decades Studies of prevalence include the following:

●In central Europe, it has been estimated that about 5 percent of the general population suffers from PFAS  

●A study of 1272 Danish young adults (aged 22 years) used questionnaires, skin prick tests, and oral food challenges  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   Only six studies included food challenge tests with prevalences ranging from 0.1 percent to 4.3 percent each for fruits and tree nuts, 0.1 percent to 1.4 percent for vegetables, and <1 percent each for wheat, soy, and sesame.

PFAS may first present in childhood, although the prevalence is difficult to estimate because data are based upon selected allergy populations and not the general population. The following studies are examples:

●PFAS to fruits and/or vegetables was reported in 93 percent of a group of 72 children with severe rhinoconjunctivitis to birch pollen participating in a clinical trial of birch pollen immunotherapy [8].

●In a study of 1360 Italian children with pollen-induced allergic rhinitis, 24 percent reported oral symptoms to plant foods. Longer duration of allergic rhinitis was associated with oral allergy [9].

●In a cross-sectional study of children from a single Australian allergy center, PFAS 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 [

Natural history — PFAS can develop in childhood or adulthood. Usually, patients develop allergic rhinitis to pollen first, then develop PFAS following an increase in the severity of allergic rhinitis. However, PFAS is occasionally the first manifestation with no or minimal allergic rhinitis symptoms reported by the patient. The mechanisms underlying these variations in clinical presentation are unknown. It is our clinical experience that when PFAS develops in a child, the number of foods that cause symptoms tends to increase over time. Some adults with pollinosis also progress to experiencing PFAS to an increasing number of plant foods. PFAS 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 PFAS in a subset of patients.  

RISK FACTORS — It is not known with certainty why some pollen-allergic patients develop pollen-food allergy syndrome (PFAS) while others do not, although some risk factors have been identified:

Sensitization to tree pollens (especially birch) – Sensitization to tree pollens, and specifically birch pollen, is associated with the highest rates of PFAS. Allergy to grass pollens and weed pollens (commonly ragweed or mugwort) are less commonly associated with PFAS. In a population of 936 unselected adults, for example, 24 percent were sensitized to pollen Pollen-sensitized individuals were evaluated for PFAS 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 immunoglobulin E (IgE) antibody levels, the greater the likelihood of PFAS [ However, among patients with comparable serum levels of pollen-specific IgE antibodies, some patients react to one plant food, while other 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 PFAS.

Sensitization to multiple pollens – Individuals sensitized to multiple pollens are most likely to be affected by PFAS.

•In the study described previously, 52 percent of people allergic to three pollens reacted to related foods  

•In an Italian study of children with allergy to grass pollen (mean age of eight years), PFAS was reported in 20 percent of those allergic to grass alone, and up to 46 percent of those sensitized to both grass and birch  

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 PFAS, 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  Patients with pollen allergy can often be identified based upon the history of suggestive symptoms during a known pollen season  

Another study showed that adult birch-allergic patients with PFAS were more likely to have a longer duration of birch tree pollen allergy and asthma, compared with birch-allergic patients without PFAS [14]. Pollinosis usually precedes the development of PFAS by a number of years in adults and children [9].

Living in areas where certain pollens are prevalent – Associations between pollen and plant foods are strongly affected by geographic location and indigenous flora. PFAS is more prevalent in areas where birch trees are common and the population demonstrates high levels of pollen-specific IgE (particularly to birch) ]. Birch trees and birch pollinosis are common in central and northern Europe and northern Japan  ].

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 [

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 pollen-food allergy syndrome (PFAS) 

Symptoms resolve promptly when the food is swallowed due to disruption of the structure of the allergen by gastric acid and proteolytic digestive enzymes.

Particularly with fruits, patients may report that one variety of the food is more troublesome than another, or that the symptoms do not develop after every exposure.

Seasonal pollen allergies — Most patients have clinical symptoms of allergy (rhinitis, conjunctivitis, asthma) in response to pollen, as mentioned previously. 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 sensitization

Seasonal variation — PFAS is an immunoglobulin E (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 [26]. 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 PFAS. Tree nuts and peanuts are an important exception to this generalization, as roasted nuts can cause PFAS. Implications for management are discussed separately. (

Double-blind, placebo-controlled food challenges (DBPCFC) with roasted hazelnuts (140°C, 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 oral allergy syndrome (OAS) in all patients   The allergens that cause PFAS are reviewed elsewhere.  

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 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 PFAS, which included a total of 1361 subjects, the following was reported 

●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 PFAS. 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 [28]. 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 pre-selected population was unusual and probably not representative of a general population of patients with PFAS. A report of patients with severe hazelnut allergy without concomitant pollinosis documented IgE binding to heat-stable hazelnut proteins [29]. In contrast, the sera from patients with PFAS to hazelnut and pollinosis did not bind to these heat-stable proteins.

Other factors that may predispose patients with PFAS 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.   

●The presence of "co-factors" such as nonsteroidal antiinflammatory drugs (NSAIDs) or exercise, presumably due to a transient increase in gastric or intestinal permeability [ .

Certain foods have been associated with higher rates of systemic reactions, including peanuts, tree nuts, peach, and mustard

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, double-blind, placebo-controlled food challenges 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  

●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 [31,32]. Thus, T cell-mediated mechanisms may have been responsible for the worsening of atopic dermatitis observed in some patients.

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  

As stated previously, the plant foods that cause pollen-food allergy syndrome (PFAS) 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.  

Foods associated with tree pollens

Birch — Patients allergic to birch pollen may develop oral symptoms after ingestion of the following plant foods ( 

●Fruits and tree nuts in the Rosaceae and Betulaceae families: apple, peach, apricot, cherry, and plum, pear, almond, and hazelnut 

●Vegetables and spices in the Apiaceae family: carrot, celery, parsley, caraway, fennel, coriander, and aniseed

●Legumes in the Fabaceae family: soybean and peanut  

Plane — Patients sensitized to the pollen of the plane tree (also known as Sycamore) may react to hazelnut, fruits such as peach, apple, kiwi, peanut, corn, chickpea, lettuce, and green beans  

Foods associated with weed pollens

Ragweed — Patients sensitized to ragweed pollen may react to the following plant foods  

●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  ):

●Vegetables and spices in the Apiaceae family: carrot, celery, parsley, caraway, fennel, coriander, and aniseed

●Bell pepper, black pepper, garlic, and onion (various plant families)

●Vegetables and spices in the Cruciferae family: mustard, cauliflower, cabbage, and broccoli

●Peach  

Foods associated with grass pollen — Grass pollen-food cross-reactivity is not as well described as tree pollen and weed pollen-food cross-reactivity, so it may occur less frequently [40,41]. 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)

●Swiss chard (Amaranthaceae)

●Peanut (Fabaceae)

●Kiwi

Specific syndromes — Certain types of PFAS 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  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  .

Mugwort-mustard syndrome — Patients sensitized to mugwort (Artemisia vulgaris) may develop allergy to mustard and experience severe reactions  .

Among 38 adults with mustard allergy, 97 percent were sensitized to mugwort [44]. 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 oral allergy syndrome (OAS) 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  The diagnosis of latex-fruit syndrome is reviewed elsewhere.  

Latex-fruit syndrome is frequently included in the discussion of PFAS 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 PFAS 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 . 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 OAS 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 []. Sensitization to peach and related Rosaceae fruits without clinical symptoms is also common, and sensitization alone is not sufficient to diagnose clinical  

Peach allergy in Spain appears to be particularly prevalent and is associated with more systemic reactions   A digestion-stable lipid transfer protein has been implicated as a relevant allergen. Severity of the reactions to peach is enhanced by nonsteroidal antiinflammatory drugs (NSAIDs) and exercise  

Melons — In northern 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) (  In contrast, in the central region of Spain, melon allergy is frequently associated with sensitization to several pollens, especially grass pollen  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)  .

DIAGNOSIS — All of the following components should be present to make the diagnosis of pollen-food allergy syndrome (PFAS), although there are no established diagnostic criteria:

●A history of symptoms consistent with PFAS, 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 a pollen(s) to which the patient is sensitized  

EVALUATION — As with any form of food allergy, the evaluation of pollen-food allergy syndrome (PFAS) combines a carefully gathered history, physical examination, objective testing for specific immunoglobulin E (IgE) to food and/or pollen, and possible oral food challenge  . 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.