Key Points
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OAS is an IgE-mediated allergy that is due to cross-reactivity between pollens and homologous food proteins.
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There is significant regional variation in OAS prevalence.
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Several pollen-food associations have been described.
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Although symptoms are generally mild and limited to the oropharyngeal area, systemic reactions can occur.
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Management entails avoiding the foods that trigger symptoms; heated food forms are often well-tolerated when the relevant allergens are heat-labile proteins.
Oral allergy syndrome (OAS) is an IgE-mediated allergy that is due to cross-reacting, homologous proteins between pollens and food proteins. First reported over 70 years ago, OAS involves primarily localized oropharyngeal symptoms in pollen allergic individuals ingesting fresh fruits and vegetables. The increased prevalence of allergic rhinitis and OAS in recent years, along with advances in identification of relevant allergenic proteins, have led to a better understanding of the diverse associations characterizing OAS.
Epidemiology
Few studies have examined the prevalence of OAS in children; a recent Italian study reported that approximately 25% of children with pollen-induced allergic rhinitis have OAS. Since OAS develops after sensitization to pollens is established, symptoms can develop to food(s) that were previously tolerated. Thus, it is not surprising that the prevalence of OAS in adults is higher, ranging from 30% to 70% among individuals with allergic rhinitis. Those who are sensitized to multiple pollens have a higher likelihood of developing clinical allergy to plant-derived foods. In addition, data suggest that OAS is more likely in those who have had a longer duration of allergic rhinitis.
Significant regional variations in OAS prevalence have been reported. Differences in pollen exposures as well as differences in relevant proteins contribute to the variations in clinical features. For example, OAS to apple is primarily due to birch pollen sensitization in northern and central Europe, whereas grass pollen sensitization is the main driver of symptoms for OAS to apple in Spain. Regionally distinct allergen sensitization patterns are also reported for kiwi. These geographic differences may be due to regional pollen exposures as well as differing dietary patterns. In addition, changes in environmental exposures can lead to new sensitizations. For example, two patients who previously tolerated jackfruit while living in the Philippines (a birch-free region) were reported to later develop OAS to jackfruit while in Switzerland, a birch-endemic area.
Molecular Basis/Pathogenesis
Different phenotypes of IgE-mediated food allergies exist depending on whether the allergy is due to primary or secondary sensitization to food allergens. OAS develops as a result of secondary sensitization, since pollen allergens are the primary sensitizers, and the symptoms elicited by homologous proteins in plant-derived foods are a secondary phenomenon. Conformational epitopes of relevant pollen allergens involved in OAS are generally heat-labile and highly susceptible to gastric digestion, resulting primarily in limited symptoms in the oropharyngeal areas. However, in some cases, systemic reactions or reactions to cooked forms of the foods can occur.
A number of plant proteins that are widely distributed throughout the plant kingdom are mediators of OAS. Pathogenesis-related (PR) proteins are commonly involved. IgE antibodies to the major birch tree pollen (Bet v 1) cross-react with homologous plant food allergens belonging to the PR-10 protein family, often resulting in symptoms to fruits of the order Rosaceae (i.e. apple, pear, cherry and apricot). Other plant-derived foods that contain homologous proteins include peanut, hazelnut and soy, foods that also trigger classic IgE-mediated food allergies.
Profilin is a second category of proteins involved in mediating OAS. The birch tree pollen Bet v 2 is a profilin protein. Although Bet v 2 is reported to be responsible for a broader spectrum of cross-reactivity than Bet v 1, this broad sensitization is not always correlated with clinical reactivity.
Cross-reactive carbohydrate determinants (CCDs) are a group of high molecular weight allergens (45–60 kDa) contained in various pollens and foods that are highly cross-reactive IgE-binding structures. In vitro studies show that 30% to 40% of pollen-allergic individuals have specific IgE against CCDs, but their role in OAS remains less clear.
As more is learned about plant proteins involved in triggering IgE-mediated reactions to foods, a broader term, pollen food allergy syndrome (PFAS), has been coined. Plant-related proteins not only trigger localized symptoms seen in OAS, but also systemic symptoms. Thus, PFAS is used to describe the wide spectrum of symptoms, ranging from localized oropharyngeal to systemic symptoms, that can result from plant-derived foods.
Lipid transfer proteins (LTPs), belonging to the PR-14 family, are major allergens involved in systemic reactions to plant-related foods that occur in individuals without pollen allergies. Unlike the PR-10 proteins and profilin, LTPs are not susceptible to heat and gastric digestion. LTPs have been identified in a wide variety of foods, including Rosacea fruits as well as other unrelated plant-derived foods (i.e. peanut, corn, asparagus, grape, lettuce, sunflower seeds).
Pollen-Food Associations/Syndromes
Several associations and syndromes have been described ( Table 46-1 ).
| Associations | Examples of Foods That may Trigger Symptoms |
|---|---|
| Birch-fruit-vegetable syndrome | Apple, pear, peach, almond, hazelnut, peanut, soy |
| Celeriac-mugwort-spice syndrome | Carrot, caraway, parsley, fennel, coriander, fenugreek, cumin, dill, aniseed |
| Ragweed-melon-banana association | Banana, cantaloupe, honeydew, watermelon, cucumber, zucchini |
| Lipid transfer protein (LTP) syndrome | Peach, apple, hazelnut, peanut |
| Latex-fruit syndrome | Avocado, banana, chestnut, potato, tomato |
Birch-Fruit-Vegetable Syndrome
Many individuals with birch pollen allergy report symptoms when ingesting foods belonging to the order Rosaceae (e.g. apple, pear, peach). The major birch tree pollen allergen, Bet v 1, accounts for most of this cross-reactivity. There is high variability in prevalence of birch-fruit-vegetable syndrome depending on geographic location, with higher rates in birch endemic areas. Birch trees are more common in northern and central Europe and higher rates of OAS to apple are reported in Denmark (34% of birch pollen allergic patients) as compared to Italy (9% of birch pollen allergic patients). Although birch trees are not as common outside the northeastern states in the USA, there is a high degree of homology among trees of the Fagales order (e.g. birch, oak, walnut, beech, alder, hazel). Thus, a very high rate of OAS is seen in the USA, with one study reporting that 75.9% of birch pollen allergic patients had clinical symptoms from exposure to apple.
Bet v 1-related proteins have also been identified in peanut, hazelnut and soy. Individuals sensitized to the Bet v 1-homologs in these foods often have no symptoms or localized, transient symptoms with ingestion, despite having detectable IgE levels to these foods. In recent years, there is improved understanding and new technology that allows identification of the relevant allergenic proteins for individuals in order to distinguish between those who have IgE to the major allergens of peanut (Ara h 1, 2, 3) and who are more likely to have systemic reactions, versus those who have elevated IgE to the birch pollen homologous protein (Ara h 8) who have a high chance of tolerance. Similar work has been done for hazelnut and soy.
Celeriac-Mugwort-Spice Syndrome
Celeriac (also known as turnip-rooted or knob celery) contains Bet v 1 homologs that can trigger OAS in birch endemic areas. However, celeriac allergy has also been reported in birch-free areas; in these cases, mugwort pollen allergens are the primary sensitizers. Unlike individuals with celeriac-birch allergy who generally have undetectable IgE levels to celery, those affected by celeriac-mugwort syndrome often have elevated IgE levels to cooked and uncooked celeriac, supporting the finding that different allergens are involved in these two groups. In these individuals who react to cooked celeriac the relevant allergens have been identified to be profilins and cross-reactive carbohydrate determinants. Other foods in the Apiaceae family that may trigger similar symptoms include carrot, caraway, parsley, fennel, coriander, fenugreek, cumin, dill and aniseed.
Ragweed-Melon-Banana Association
Many ragweed allergic patients have detectable IgE to at least one member of the gourd family Cucurbitaceae (e.g. watermelon, cantaloupe, honeydew, zucchini, cucumber). The relevant allergen in these cases is profilin; thus, symptoms are usually limited to the oropharyngeal areas. Banana also has homologous proteins and can trigger similar symptoms in ragweed allergic individuals. Although these symptoms are often mild, reports of systemic reactions to melon range from 11% to 20%, suggesting that more stable allergens such as LTPs may be involved at least for some. Moreover, individuals with ragweed-melon-banana association have higher rates of asthma than pollen-allergic individuals without melon allergy, further lending support for a more severe phenotype in these individuals.
Lipid Transfer Protein Syndrome
Allergies to plant-derived foods can occur in individuals without associated pollen allergies. LTPs act as the primary sensitizer for individuals with allergies to fruits and/or vegetables but no reported symptoms of allergic rhinitis and negative skin tests to pollens, particularly in Mediterranean areas. Affected individuals have significantly higher rates of systemic reactions (82% vs 45%), including anaphylaxis (73% vs 18%), less frequent oral symptoms (64% vs 91%) and later onset of symptoms to plant-derived foods (19 years of age vs ~12 years) when compared to those who have concurrent pollen allergy. Furthermore, those without pollen allergy have symptoms primarily to the fruits of the order Rosaceae, whereas those with pollen allergy tend to have more diverse sensitizations to different families of fruits, resulting in symptoms to a greater number of foods in general. While the nonpollen allergic group have a higher rate of systemic reactions, the risk of asthma is reported to be higher in those who have concurrent pollen allergy.
The stability of LTPs in the acidic and proteolytic conditions of the gastrointestinal tract as well as their resistance to heating are important factors contributing to the higher rates of systemic reactions reported for this syndrome as compared to the birch-fruit-vegetable syndrome. Data also suggest that LTPs may sensitize via the gastrointestinal route in addition to the respiratory route; thus, LTP may be considered to be a true food allergen.
Latex-Fruit Syndrome
Significant cross-reactivity between latex and various fruits has been demonstrated, with reports of up to 88% of latex allergic adults having evidence of specific IgE to plant-derived foods. While a high degree of immunologic cross-reactivity exists between latex and plant food allergens, the clinical significance appears to be much lower. In a German study of 136 adults with latex allergy, 42.5% reported symptoms with fruit ingestion, but only 32.1% of those reporting symptoms had detectable fruit-specific IgE. In another study that included 57 fruit-allergic individuals, 86% were sensitized to latex, but only 10.5% (6 of 57) had clinically relevant latex allergy.
Primary sensitization to latex occurs via inhalation. Latex-fruit syndrome can manifest with only localized oral symptoms or trigger systemic reactions. The diversity of symptoms is due to the variety of latex allergens that have been identified, including profilins (Hev b 8) as well as more stable allergens such as hevein. A major allergen that belongs to the PR-3 protein family, Hev b 11, retains its IgE-binding epitopes even after the allergen is extensively degraded in simulated gastric fluid.
Diagnosis
The most important aspect of food allergy diagnosis is the history. Since allergic reactions to plant-derived foods may be due to either primary sensitization from a major food allergen or to a secondary phenomenon with pollens being the primary sensitizer, documentation of the onset and type of symptoms can be very informative for characterizing and managing the allergy. OAS symptoms are generally mild, with localized oropharyngeal symptoms such as lip/mouth itching and swelling that develop acutely with exposure; however, systemic reactions, including anaphylaxis, can occur as well ( Table 46-2 ). Severity of symptoms can have seasonal variations with worsening during the pollen season. In one study of 159 individuals with birch pollen allergy and food-related symptoms, 44% reported worsening of their symptoms during the birch pollen season. This is believed to be a result of up-regulation of birch pollen (Bet v 1 and 2)-specific IgE due to the seasonal pollen exposure.
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The utility of skin prick tests (SPTs) and serum specific IgE levels (sIgEs) for the diagnosis of OAS is variable depending on the food allergen in question. In general, SPTs and sIgEs are poor predictors for clinical reactivity to foods. In particular for OAS, commercial extracts used for SPTs may not contain all the relevant allergens and/or may have low potency for the heat labile allergens as a result of extract processing. Proteases contained in fruits can significantly affect potency as well. For pineapple, bromelain destroys profilin in extracts prepared without protease inhibitors.
Although not technically standardized, using fresh fruits and vegetables for SPTs generally has improved diagnostic utility compared to commercial extracts. In one study of 36 grass and/or birch pollen allergic individuals, SPTs with fresh hazelnut, apple and melon had high sensitivity (89–97%) and specificity (>70%). The negative predictive value was >90%, but the positive predictive value was more variable, ranging from 50% to 85%. Since it is not always possible to have fresh fruits and vegetables available for SPTs, use of frozen fruits is an acceptable alternative as freezing does not alter the antigenic properties of fresh fruits.
Several other factors can significantly affect the sensitivity of fresh food SPTs. Allergenicity increases with ripening in several foods, including banana and peach. Time of storage and storage conditions can further influence allergenicity. The apple allergen, Mal d 1, has been shown to increase significantly with storage. Differing levels of allergen are also noted among different cultivars. For example, high variations in Mal d 1 and LTP content are found across different apple cultivars.
Measurement of sIgE may also be used to support the diagnosis of OAS. In a study of patients with a clinical history of OAS to melons, the positive predictive value was comparable for sIgE (ImmunoCAP ® ; Thermo Fisher Scientific, Waltham, MA, USA) and fresh food SPT (44% for sIgE vs 42% for SPT), and a slightly higher negative predictive value was observed for fresh food SPT (77% SPT vs 70% sIgE). Similar to SPTs, the utility of sIgE measurement varies for different food allergens.
With advances in the identification and characterization of relevant allergens, recombinant proteins for the detection of sIgE are increasingly being used for food allergy diagnostic purposes. While component resolved diagnosis (CRD) has been shown to be useful to distinguish between phenotypes of allergy for some foods such as peanut and hazelnut, the utility of CRD for other plant-derived food allergies is variable. In one study of individuals with birch pollen allergies, CRD was not shown to have added diagnostic utility in predicting clinical reactivity to raw fruits and vegetables. Another group reported improved sensitivity of CRD with individual celeriac allergens compared with extract-based ImmunoCAP diagnosis (88% for CRD vs 67% for extract). However, sIgE levels to individual allergens or extract did not predict severity of reactions to celeriac. Similarly, while some studies note the value of measuring sIgE to individual peach proteins for characterization of peach reactions, these levels were not predictive of systemic symptoms. Further studies are needed to determine the role of CRD in the diagnosis of OAS.
Since SPT and sIgE results do not always correlate with clinical reactivity, double-blind, placebo-controlled food challenge remains the gold standard for food allergy diagnosis. While standardized protocols are established for challenges to food allergens that are the primary sensitizer, there are currently no standardized protocols for diagnosing OAS. Adequate blinding of fresh foods is also a challenge. In many cases, a convincing history is sufficient to diagnose OAS; Anhoej et al reported high sensitivity and specificity of case histories in predicting challenge outcome for apple and melon.
Management
Since consensus guidelines for the management of OAS do not exist, management of OAS is highly variable among practicing physicians. In a survey of US allergists, responses ranged from advising avoidance of only the offending fruits or vegetables to recommending elimination of entire botanical families of foods. It is important to note that clinical reactivity to one member of a botanical family does not guarantee that symptoms will occur to all foods in a botanical family. In one study of 23 individuals with OAS to peach, 63% reported symptoms to more than one Prunoideae fruit, and another study of 26 individuals with fruit allergy reported that 46% had reactions to more than one Rosaceae fruit. Thus, elimination of entire botanical families is not necessary and will be overly restrictive for many affected individuals.
As previously stated, allergenicity can vary between different cultivars of fruits. Therefore, choosing lower allergenic cultivars may reduce symptoms for some. In addition, the distribution of allergen is not uniform throughout the fruit. Much higher concentrations of LTP are found in the skin of apples and peaches compared to the pulp. In one small study, over 40% of individuals with allergies to apple and pear were able to tolerate the flesh, but had symptoms upon ingestion of the whole fruit.
When heat-labile proteins are the main elicitor of symptoms, heating or cooking the fruits and vegetables denatures the relevant proteins, which allows affected individuals to ingest the foods without incurring symptoms. For foods that are more typically eaten in the uncooked form (e.g. apples), brief heating in the microwave can sufficiently denature the Bet v 1-homolog while maintaining the integrity of the fruit. A recent study showed that continuous consumption may be of benefit for OAS triggered by apple; frequent consumption was associated with reductions in OAS symptoms. This has not been explored in controlled trials or reported for other foods.
Since plant-derived foods can also trigger systemic reactions, prescription of self-injectable epinephrine and education on the management of severe reactions is advisable. A study of Spanish children with peach allergy found that 28% reported having severe reactions that required treatment with epinephrine. Factors identified to increase an individual’s risk for systemic reactions include prior history of a systemic reaction to the food, reaction to cooked forms of the food, positive SPT to the commercial food extract, lack of pollen sensitization and sensitization to LTP. Additionally, concurrent atopic conditions and medications are important details to consider. For example, individuals taking daily antihistamines for allergic rhinitis may not notice early, mild OAS symptoms, leading to increased consumption of the triggering foods and thus increasing the risk of systemic symptoms.
Immunotherapy
Immunotherapy has been explored for the treatment of OAS as it has proven to be an effective treatment for allergic rhinitis. Several small studies have demonstrated reductions in oral symptoms in over half of subjects receiving immunotherapy to pollens for the treatment of OAS; however, these studies were limited by the lack of objective outcome measures and/or placebo controls. Other studies have shown no significant benefit of immunotherapy (subcutaneous, oral or sublingual) for OAS. Immunotherapy using specific food allergens has also been explored, but relapse of symptoms occurs quickly after discontinuation immunotherapy. Moreover, a case report of OAS developing after a patient started on birch pollen sublingual therapy has been published. Therefore, immunotherapy remains an unproven approach for treating OAS.
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