Oral allergy syndrome (OAS) is the collective name for the symptoms of the mouth and throat that are provoked in patients with pollen allergy by eating raw plant foods – mainly fruits, vegetables, nuts and spices. The underlying disorder is called pollen-food allergy syndrome (PFAS), which British literature refers to as pollen food syndrome. The syndrome is a so-called class 2 (secondary) food allergy: sensitization mediated by immunoglobulin E (IgE) does not develop through eating the food, but through the airways, by inhaling pollen. The IgE antibodies produced against the pollen allergen subsequently also recognize structurally similar (homologous) proteins of plant foods, and on eating them release histamine from the mast cells of the mucosa. Symptoms typically appear within minutes of consumption, in the form of itching, tingling or mild swelling of the lips, oral mucosa, tongue and throat, and usually resolve spontaneously within a short time. The condition is therefore mostly benign, yet it cannot be regarded as harmless without exception: according to the data of a review article, symptoms extending beyond the oral cavity, that is systemic symptoms, occurred in 8.7% of patients, and anaphylactic shock in 1.7%. The severity of symptoms is determined primarily by which protein family mediates the cross-reaction: with proteins sensitive to heat and gastric acid (PR-10 proteins, profilins) the complaints are typically confined to the oral cavity and the heat-processed food can usually be eaten without symptoms, whereas the heat-stable non-specific lipid transfer proteins (nsLTPs) may also cause systemic reactions.
Terminology and conceptual history The connection between pollen allergy and complaints following the consumption of fresh fruit was first described by Louis Tuft and George I. Blumstein in 1942. In their hay fever patients sensitive to birch pollen they observed itching of the palate and swelling of the oral mucosa after eating fresh fruit, while heat-processed forms caused no complaints; they confirmed the reactivity with skin tests using freshly pressed fruit juices and explained the phenomenon by the presence of a "labile antigen". The term "oral allergy syndrome" (OAS) was introduced by Amlot and colleagues in 1987 as an umbrella term for food-induced, IgE-mediated symptoms localized to the oropharyngeal region. The concept was narrowed by Ortolani and colleagues to fruit and vegetable sensitivity associated with pollen allergy; in 1988 they demonstrated the characteristic associations of pollen and food sensitivity in a study of 262 hay fever patients, and in 1989 they showed in 100 patients that the skin prick test performed with fresh food is more sensitive than testing with commercial extracts. With the development of molecular allergology it became clear that OAS is merely the name of a symptom complex and does not indicate the origin of the disorder. Rudolf Valenta and Dietrich Kraft therefore proposed the term "pollen-food allergy syndrome" in 1996, which clearly expresses that this is a secondary food allergy, the precondition of which is primary respiratory sensitization to pollen. Current international position papers and guidelines use the designation pollen food syndrome or PFAS for the disorder as a whole, and reserve the term oral allergy syndrome (OAS) in a narrower sense, exclusively for symptoms confined to the oral cavity.
Epidemiology The frequency of PFAS in the pollen-allergic population varies widely, which is explained primarily by the pollen flora of the geographical region studied and by methodological differences between surveys. According to one literature review, reported prevalence values range from 13–58% in adults and 4.7–20% in children. Food allergy associated with birch pollen allergy is the most common form of food allergy in the birch-rich regions of Western and Central Europe. The condition has traditionally been regarded as a disease of adolescents and adults, since the development of respiratory sensitization requires repeated pollen exposure over years. According to more recent studies, however, it is also common in childhood: in a South Korean survey it affected 42.7% of children with pollinosis. A characteristic north–south difference can be observed in Europe. In Northern and Central Europe, trees of the order Fagales, primarily birch pollen, are the main sensitizers, and cross-reactions are predominantly mediated by heat-labile PR-10 proteins. In the Mediterranean Basin birch is absent or rare, and pollens of plane tree, olive and weeds, as well as the foods themselves, play a greater role in sensitization; here the so-called LTP syndrome, linked to heat-stable lipid transfer proteins, is the most common primary food allergy.
Mechanism
Molecular basis of cross-reactivity Cross-reactivity is based on structural and amino acid sequence similarity: clinically relevant cross-reaction between related proteins is typically expected at sequence identity above 70%, and is rare below 50% identity. The linear sequence, however, is not the only determining factor, because IgE binding may also be enabled by the three-dimensional structure of the protein, that is by the similarity of spatial surface epitopes.
Epitopes and symptom severity From a clinical point of view it is decisive what type of epitope the IgE recognizes. Linear epitopes – continuous chains of amino acids – resist heat treatment and digestion, so an allergen recognized in this way may also trigger a systemic reaction after absorption from the digestive tract. Most pollen–food cross-reactions, by contrast, are mediated by conformational epitopes, which arise from the spatial folding of the protein and lose their structure under the effect of heat or the acidic–proteolytic environment of the stomach. This explains the characteristic course of the condition: the raw food still triggers a reaction on the oral mucosa, but on reaching the stomach the structure of the allergen disintegrates, so systemic symptoms usually do not develop and the boiled or baked food can be eaten without symptoms.
Protein families mediating cross-reaction
PR-10 proteins The prototype of the PR-10 (pathogenesis-related protein 10) family is the major birch pollen allergen Bet v 1; the family comprises proteins of 15–17 kDa molecular mass, produced in plants in response to stress and containing a hydrophobic pocket. Their homologues are found in numerous plant foods: in apple (Mal d 1), cherry (Pru av 1), hazelnut (Cor a 1), carrot (Dau c 1), celery (Api g 1), soybean (Gly m 4) and peanut (Ara h 8). Structural analysis of the peanut allergen Ara h 8 confirmed a spatial structure and ligand-binding cavity similar to that of Bet v 1. Since these proteins are heat-labile and readily degraded by pepsin, the complaints associated with them are typically confined to the oral cavity. Exceptions are nevertheless known: in patients with birch pollen allergy the PR-10 protein of soy (Gly m 4, formerly known as SAM22) may trigger severe, even anaphylactic reactions after the consumption of large amounts of soy drink or soy protein isolate, and celery is likewise a known trigger of more severe reactions. The diagnostic significance of PR-10 proteins also lies in the fact that they distinguish benign cross-sensitivity from true, primary food allergy: in the case of peanut, sensitivity to Ara h 8 typically indicates mild oral complaints, whereas sensitivity to the seed storage protein Ara h 2 carries a risk of anaphylaxis.
Profilins Profilins are actin-binding proteins of 12–15 kDa that are present in all eukaryotic cells and, because of their fundamental role in the functioning of the cytoskeleton, are evolutionarily highly conserved; sequence identity between the profilins of different plant species generally exceeds 75%. For this reason they belong to the classic panallergens. Their best-known respiratory representatives are birch Bet v 2, mugwort Art v 4 and ragweed Amb a 8 profilin. Profilin sensitization is very common, but its clinical relevance is variable and in many cases remains asymptomatic; when it does cause complaints, these are typically oral symptoms after eating melon, watermelon, tomato, banana or citrus fruits. Profilins are highly sensitive to heat and digestion, and therefore rarely trigger systemic reactions.
Non-specific lipid transfer proteins Non-specific lipid transfer proteins (nsLTPs), which belong to the PR-14 family, are basic polypeptides of 7–10 kDa that transport the lipids required for the build-up of the plant cutin and wax layer. Their structure is stabilized by four disulfide bonds, so they resist both heat treatment and the digestive enzymes of the gastrointestinal tract. It has been shown experimentally that neither autoclave heat treatment nor subsequent microwave and ultrasound treatment abolished the IgE-binding capacity of the peach allergen Pru p 3. The clinical severity of nsLTP sensitization accordingly differs from that of cross-reactions mediated by PR-10 proteins and profilins: LTP syndrome, most common in the Mediterranean region, may be accompanied by systemic symptoms, urticaria and anaphylaxis, in the development of which cofactors – physical exertion, non-steroidal anti-inflammatory drugs, alcohol – also play a role. The route of sensitization from pollen is typically the lipid transfer protein of mugwort, Art v 3, or of plane tree, Pla a 3; the celery allergen Api g 2 cross-reacts with both Art v 3 and Pru p 3. In a Chinese study of food allergy associated with mugwort pollen allergy, symptom severity correlated with sensitization to lipid transfer proteins.
Further allergen families In recent years further protein families have come into the focus of clinical interest, among them gibberellin-regulated proteins (GRPs) and thaumatin-like proteins. In East Asia, for example, a clinically relevant cross-reaction has been described between the allergen Cry j 7 of Japanese cedar pollen and the bell pepper protein Cap a 7.
Characteristic pollen–food associations
Signs and symptoms Complaints appear within a few minutes of eating the raw trigger food: itching, tingling and burning of the lips, tongue, palate and throat, and less often circumscribed swelling. The symptoms usually resolve within a short time even without treatment. Less frequently the reaction may be accompanied by rhinorrhoea, conjunctival symptoms, urticaria, abdominal complaints or dyspnoea, and exceptionally anaphylaxis also occurs; the latter is linked primarily to heat-stable allergens and to reactions involving nuts, soy drink and celery. In some patients the symptoms are more pronounced during the corresponding pollen season and are milder or absent outside it. Although the symptoms are typically mild, the condition may significantly affect quality of life, on the one hand because of the wide range of foods to be avoided, and on the other because of anxiety about reactions to new foods.
Diagnosis In many cases the condition can be established from the targeted history alone: characteristic features are a pre-existing pollen allergy, the typical range of trigger foods and oropharyngeal symptoms occurring immediately after consumption. Further investigations are required mainly in reactions involving nuts and soy drink, or in atypical or severe reactions. Conventional skin tests performed with commercial food extracts often give false negative results, because the labile proteins degrade during manufacture. This is why the skin prick test with fresh food (prick-to-prick) was developed, in which the lancet is first pricked into the raw fruit or vegetable and then directly into the skin; this method has proved more sensitive than testing with extracts. The skin test is, however, not suitable for comparing the allergenicity of individual cultivars. In in vitro diagnostics, component-resolved (molecular) IgE testing has brought a major change: with the help of recombinant and purified allergen molecules it is possible to distinguish primary pollen sensitization, the range of cross-reacting food components, and sensitization to molecules that carry a risk of systemic reaction (nsLTPs, seed storage proteins). Numerous studies have reported on the clinical use of multiplex microarray and macroarray systems capable of testing several hundred components simultaneously; their interpretation requires knowledge of the clinical picture, because sensitization in itself is not identical with clinical allergy. In doubtful cases the reference method for confirming the diagnosis and for determining the eliciting dose is the double-blind, placebo-controlled food challenge, the performance of which is regulated by a European position paper; in ordinary cases of pollen food syndrome, however, it is rarely needed.
Management
Dietary measures The basis of treatment is avoidance of the symptom-provoking foods in raw form. In complaints associated with heat-labile PR-10 proteins and profilins, a complete elimination diet covering every method of preparation is not warranted, because heat treatment – boiling, baking, pasteurization – destroys the conformational epitopes responsible for the cross-reaction, so the boiled, baked or otherwise heat-treated product can usually be eaten without symptoms. By contrast, in reactions associated with heat-stable lipid transfer proteins, heat treatment does not abolish allergenicity, and therefore guidelines consider stricter avoidance, attention to cofactors (physical exertion, non-steroidal anti-inflammatory drugs, alcohol) and consideration of prescribing an epinephrine autoinjector for patients at risk on the basis of their history to be justified. Planning dietary restrictions is not always simple, especially when the patient also suffers from other food allergies or follows a vegetarian or vegan diet. Since the intensity of symptoms is also linked to the pollen season and to the pollen load on a given day, patients may find it useful in practice to use digital tools that combine pollen concentration with an individual symptom diary and forecast future exposure, helping to identify whether a particular episode of malaise on a given day may have been triggered by pollen, UV load or another environmental factor.
Allergen-specific immunotherapy Allergen-specific immunotherapy (AIT) is an accepted causal treatment for respiratory pollen allergy, but its effect on the food-related symptoms of pollen food syndrome is not proven. According to the British guideline, immunotherapy directed at pollen is not an effective treatment for the condition, and according to a 2024 systematic review no firm conclusion can be drawn from the available studies about the effect of subcutaneous and sublingual birch pollen immunotherapy on birch pollen-associated food allergy: most of the ten included studies carried a high risk of bias, and among the studies with moderate risk of bias only some showed improvement in the severity of symptoms observed during challenge or in the symptom-eliciting dose. Oral and sublingual desensitization performed with food allergens appears more promising, but large controlled trials are needed to assess it.
Central European and Hungarian features
Ragweed In Hungary and in the Pannonian Basin region, the pollen of common ragweed (Ambrosia artemisiifolia) accounts for the greatest aeroallergen load; the region is among the most heavily affected areas of the continent. The pollen season usually begins at the end of July and peaks in the late summer and autumn months, although in some years exceptionally high pollen concentrations have been recorded a month earlier than usual, in June. The cross-reactions described in ragweed-sensitive patients are typically linked to the consumption of cucurbits and banana: melon, watermelon, cucumber, zucchini and banana are among the most common triggers. Shared allergenic components of watermelon and ragweed were already demonstrated in the 1980s. The intensity of symptoms often varies seasonally and may be milder outside the pollen season.
Mugwort The flowering of mugwort (Artemisia vulgaris) partly coincides with that of ragweed. Mugwort pollen sensitization is associated with an extensive, clinically relevant network of cross-reactivity towards the Apiaceae and spices; the classic manifestation of this is the mugwort–celery–spice syndrome, in which celery, carrot, as well as caraway, coriander, anise, pepper and paprika are the characteristic triggers. In Central Europe celery is a known trigger of more severe, systemic reactions, and sensitization to the heat-stable lipid transfer protein Api g 2 also plays a role in the severity of the symptoms linked to it.
Birch and cultivar-dependent allergenicity Sensitization to spring tree pollens – alder, hazel, birch – is likewise accompanied in Central Europe by the classic symptoms mediated by PR-10 proteins, most often after eating apple, hazelnut, cherry, peach and carrot. The allergenicity of individual foods is not constant: substantial differences have been described between apple cultivars in their Mal d 1 content and symptom-eliciting capacity. In a double-blind challenge study the cultivars Elise and Santana were identified as less allergenic in patients with oral allergy syndrome, and further studies have also confirmed that in birch pollen-allergic individuals certain cultivars cause considerably fewer symptoms than others. According to a release of Semmelweis University, Hungarian observations indicate that ripening, storage and the choice of cultivar all modify symptoms, and that certain local cultivars – for example Jonathan – cause more pronounced complaints.
References
External links WHO/IUIS Allergen Nomenclature – the official nomenclature of allergen molecules European Academy of Allergy and Clinical Immunology (EAACI) Biomorg – a Hungarian system for recording and forecasting individual symptoms triggered by pollen and other environmental factors (solar flares, UV load, etc.)
See also Allergy Allergen Anaphylaxis Hay fever Urticaria Common ragweed