Pollen food syndrome: learning from a case series

Pollen food syndrome (PFS) is an IgE-mediated food hypersensitivity reaction that results in oral and oropharyngeal symptoms within minutes of exposure in individuals who are sensitized to pollen. The term oral allergy syndrome (OAS) is often used interchangeably with PFS, but PFS is a more specific term¹ that better characterizes the pathogenesis.² PFS symptoms only occur with plant-based foods (fruit/vegetables/nuts/cereals/spices)^3,4,5,6 that have similar allergenic epitopes to the sensitizing pollen(s). Symptoms of PFS typically occur within minutes of exposure to the food(s) and can vary in severity.⁵ The most common symptom is pruritus (itching) of the oral and oropharyngeal regions.⁶ Other signs and symptoms include lip, oral and oropharyngeal angioedema (mild, without compromise to airway), tingling, burning and mucosal vesicles/ulcers/blisters.^6,7,8,9 Although PFS is generally thought to produce mild symptoms, more serious systemic symptoms (e.g. gastrointestinal symptoms, respiratory symptoms) can occur, and anaphylaxis is reported in 1.7% of patients.^2,10 The prevalence of PFS varies with geographical location, but is thought to affect 2% of the UK population,³ and is seen particularly in individuals with atopy.¹¹ The allergens involved in PFS are typically heat and acid labile; therefore, symptoms tend to only occur upon direct mucosal contact with the uncooked food(s) in question.³ The prevalence of PFS is thought to be increasing. This may be a consequence of rising levels of pollen and pollution.¹²

Patients with undiagnosed PFS may report their symptoms to dental professionals in the first instance. It is, therefore, important that dental professionals are able to recognize symptoms suggestive of PFS, to identify severe allergic reactions, to give patients advice and to initiate appropriate referrals/investigations.

Using six clinical cases that were referred to our oral medicine department, where a diagnosis of PFS was made, the main learning points that dental professionals should be aware of are summarized. This article is applicable to practitioners working in primary care needing baseline knowledge, and clinicians working in oral medicine and other secondary care units where more in-depth investigations may be initiated.

While oral mucosal lesions, such as vesicles, ulceration and blistering, have been reported in some descriptions of PFS,^6,7,8,9 the pathogenesis and characterization of such mucosal lesions do not appear to have been extensively explored. Five of the cases we describe presented with a history of oral mucosal abnormalities, and four had mucosal abnormalities upon direct clinical examination. These cases provide evidence that such lesions may be a clinical feature of PFS, or occur contemporaneously with PFS.

Food hypersensitivities

In order to fully understand the pathogenesis of PFS, it must be considered in the wider general context of food hypersensitivities.

A type 1 (primary) food allergy (e.g. cow's milk allergy, peanut allergy) is a result of direct sensitization of the food allergen through the gastrointestinal tract.^1,13 These allergens are stable and resistant to breakdown by digestive enzymes, having the ability to cause severe systemic allergic reactions, including anaphylaxis. There is much interest and research in the possibility that food sensitization can also occur through the broken skin barrier (e.g. atopic dermatitis in infants).¹⁴

In contrast, PFS is a type 2 (secondary) food allergy that is the result of primary sensitization through the respiratory tract to pollen, and subsequently clinical cross-reactivity with foods.^1,13 The antigen present in the pollen and food(s) share structural homology at the antibody binding site. When the food antigen makes contact with the oral/oropharyngeal mucosa, the epitope binds to the specific IgE antibodies (previously produced through pollen sensitization) on the surface of mast cells and basophils. This results in release of histamine, and other mediators, by degranulation/exocytosis, triggering an immediate hypersensitivity reaction in the oral and pharyngeal mucosa. In general, the food allergens involved in PFS are broken down by digestive enzymes/acids and therefore symptoms are confined to the point of contact, with systemic reactions occurring rarely.²

While this article focuses on PFS, it is worth noting that there are other cross-reactive plant food allergies affecting the oral mucosa that dental professionals should be aware of. The pathogenic and diagnostic boundaries of each are complex¹⁵ and best understood by considering the variations in pathogenesis.

Lipid transport protein (LTP) food syndrome is a cross-reactive food allergy seen in the UK.¹⁶ LTPs are highly cross-reactive proteins found in multiple plants (e.g. London plane tree, mugwort). There is also evidence that peach can be a primary sensitization agent,^17,18 and this would explain symptoms in patients without pollinosis. LTPs are more stable than the allergens involved in PFS. They are heat and acid resistant and therefore, tend to withstand cooking and processing.^2,16,19 They can be absorbed via the gastrointestinal tract and can elicit more severe systemic reactions²⁰ with a greater risk of anaphylaxis,²¹ especially in the presence of cofactors including exercise and non-steroidal anti-inflammatory drugs (NSAIDs).²² Adrenaline autoinjectors are often prescribed for this group of people.² Owing to the highly cross-reactive nature of LTPs, avoidance of closely related foods may be advocated. There can be a very complex picture in some patients, who have raised specific IgEs to LTPs and to proteins associated with classical PFS.

Latex fruit syndrome is another cross-reactivity reaction where patients are sensitized to proteins in natural rubber latex (NRL) with cross-reactivity to various plant-based foods including kiwi fruit, avocado, banana and peach. Symptoms can range from mild to severe.

Pollen food syndrome in the UK

PFS is a diverse disease and can be caused by sensitization from a number of different pollen antigens, which is largely dictated by area of residence.²³ The most common sensitizing pollen in PFS in central and northern Europe is birch (causing spring allergic rhinitis),²⁴ with 66% of birch-allergic UK adults having PFS, and 48% of birch-allergic children.²⁵ Another common pollen allergy is timothy grass, which causes summer allergic rhinitis. The most common allergens associated with PFS sensitized by birch and timothy grass, respectively, are Bet v1 PR-10 (from the pathogenesis-related protein family) and Phl p12 profilin.²Table 2 shows the related foods that can provoke an allergic reaction in patients sensitized to the protein families to which these allergens belong.

Diagnosis of pollen food syndrome

Clinical history

A good clinical history is key in diagnosing PFS. Listening and appropriately questioning a patient will reveal what oral/oropharyngeal symptoms are present and whether they develop within minutes of ingestion of the specific raw plant-based food in question. The British Society for Allergy and Clinical Immunology (BSACI) recently published a UK guideline for the diagnosis and management of PFS,²⁵ that states that birch-related PFS can be diagnosed by clinical history alone in patients with seasonal allergic rhinitis who report classical mild oral/oropharyngeal symptoms of immediate onset on exposure to typical raw food triggers, including apples, stoned fruits, kiwi fruits, carrots, celery, hazelnuts, almonds, walnuts, soya milk and peanuts.

Allergy testing with or without referral to an immunologist may be needed for those who report one or more of the following:

• Severe and/or atypical symptoms;
• Reacting to processed plant-based foods (e.g. roasted nuts, nuts in composite foods, soya in products other than milk, processed fruit or vegetables, juices/smoothies);
• Reacting to cooked plant-based foods;
• Reacting to foods not associated with PFS (e.g. pistachio nuts, cashew nuts, sesame seeds, beans, lentils and chickpeas);
• Reacting to trace/small amount of peanuts;
• Systemic symptoms (see Table 3) should be noted because these may indicate increased risk of anaphylaxis on subsequent exposure and indicate the need for onward referral.²⁵

Blood tests

When allergy testing is indicated (see above),²⁵ testing for specific IgE to recombinant pollen allergens (e.g. IgE to Bet v1 PR-10 and/or Phl p12 profilin) is undertaken. This is generally performed using the enzyme-linked immunosorbent assay (ELISA), although there are other techniques, such as radioallergosorbent testing (RAST), fluoro-allergosorbent testing (FAST) and immunoassay capture testing.²⁷ Specific IgEs to food allergens can also be carried out. Availability of food allergens can be a limitation, as some have a labile nature (e.g. apple), these may be lost during reagent preparation leading to false negative results.

Skin prick testing

Skin prick testing (or scratch test) is an in vivo test that involves pricking the skin through a drop of allergen extract. The skin is then assessed for any reaction. This can be undertaken with commercial products, fresh fruit juices or by asking the patient to bring samples of the foods in question. Skin prick testing should only be undertaken in a medical secondary care setting by clinicians equipped to manage anaphylaxis.²⁸ Skin prick testing will indicate whether an individual is sensitized to certain pollens and foods, and has better specificity and sensitivity, in most cases,5 than specific IgE testing. Specific IgEs and skin prick testing do not always correlate with clinical history,^11,29,30 making interpretation challenging in some cases.

Other investigations

Oral food challenges (OFC) remain the gold standard for confirming food allergies, but are expensive, time consuming and are rarely used in PFS diagnosis.²⁵ OFC can only be undertaken in a medical secondary care setting by clinicians equipped to manage anaphylaxis.²⁷ An OFC involves giving increasing dosages of the food in question to the patient using a controlled and standardized protocol. Objective signs of an allergic reaction indicate a positive OFC.²²

Treatment of pollen food syndrome

Food trigger avoidance or selecting different methods of cooking/preparation (peeling) is sufficient treatment for most patients with PFS. In some instances, antihistamines may be required. Avoidance of all the foods in the same family known to cross react with the pollen in question is regarded by most as unnecessary. However, patients should be made aware of the potential for such cross reactivity. If systemic symptoms are present, consideration should be given to the provision of an adrenaline autoinjector through the patient's general medical practitioner and referral should be made to an allergist/immunologist for in-depth investigations. For those who present without systemic symptoms, the patient should be made aware of the future possibility of developing a more severe reaction.³¹ In certain circumstances, systemic reactions are more likely (e.g. consuming large quantities of the food trigger or presence of co-factors, including exercise, infection, NSAIDs and alcohol).³² Certain foods can trigger a more severe reaction, for example, consuming large quantities of the allergen (e.g. large handfuls of nuts, smoothies, fresh fruit juice, soya milk/shakes and jackfruit).²⁵

Cases

We present six cases where a diagnosis of PFS was made following referral to our oral medicine department.

Case 1

A 23-year-old female was referred by the emergency dental service with a 9-year history of recurrent oral blistering and ulceration. Each ulcer was approximately 1 cm in greatest diameter, and took 2–3 weeks to heal. Episodes usually consisted of a single ulcer that could arise after eating. The patient also reported oral itchiness immediately after starting to eat raw apples and raw strawberries that settled after about 30 minutes. Medically, the patient had eczema, allergic rhinitis and a history of childhood asthma.

Examination of the oral mucosa revealed non-specific erythema of the palate adjacent to the upper left incisors.

Full blood count, ferritin, B12, folate and IgA tissue transglutaminase antibodies were within normal limits. Specific IgE to grass pollen, birch pollen, rBet v1 PR-10 and apple were increased.

Advice was sought from Immunology who agreed with a diagnosis of PFS. A PFS patient information leaflet was provided detailing advice on avoiding triggering foods. At a review 2 years later, symptoms were well controlled with the patient excluding foods that triggered the PFS. The patient had no recurrence of oral ulceration and was discharged.

Case 2

A 40-year-old female was referred by their general dental practitioner (GDP) with a 1-year history of oral ulceration and painful gums. Approximately five ulcers occurred at a time and took around 3 weeks to heal. The patient also reported a 7-year history of tingling and discomfort affecting the lining of the mouth when eating raw strawberries, apples, apricots and peaches. Antihistamines helped to resolve these symptoms in around 30 minutes. Medical history included allergic rhinitis.

On examination there was an ulcer at the junction of the free and attached oral mucosa in the lower right quadrant.

Full blood count, ferritin, iron studies, B12, folate and IgA tissue transglutaminase antibodies disclosed no abnormalities. Specific IgE to rBet v1 PR-10 and apple were increased.

A diagnosis of PFS with recurrent oral ulceration was made. Lidocaine ointment and betamethasone mouthwash was prescribed and a patient information leaflet given on PFS with advice on dietary exclusion of triggers. The patient continues to be under review.

Case 3

A 56-year-old female was referred by their GDP with haemorrhagic lesions affecting the oral mucosa. The patient reported that her mouth could feel irritated when eating cheese, tomatoes, a buttercream mixture containing vanilla extract and nectarines. The patient was also aware of intermittent blood-filled blisters affecting the lining of the mouth. Medical history included allergic rhinitis for which antihistamines were taken. Recent bloods in Dermatology, on account of the haemorrhagic intra-oral lesions had disclosed increased specific IgE to grass pollen, birch pollen and rBet v1 PR-10. Patch testing revealed positive reactions to palladium and nickel of unclear significance.

On examination, pinpoint erythematous lesions were present affecting the hard palate, and haemorrhagic lesions affecting the lateral borders of the tongue and lingual sulcus were present. Biopsy of the tip of tongue and labial mucosa revealed dilated small blood vessels.

A provisional diagnosis of PFS was made. Trials of a benzoate and a cinnamon-free diet and cetirizine resulted in no significant improvement in symptoms. Symptoms of irritation were controlled with avoidance of nectarines. Haemorrhagic lesions remained unchanged during the 3-year followup period.

Case 4

A 52-year-old female was referred by their GMP with a sore mouth and a bad taste. Her medical history included chronic sinusitis and anxiety. Medications were fexofenadine and citalopram.

On examination, the oral mucosa was healthy.

Trials of Avamys spray (GSK, Middlesex) and omeprazole gave rise to no significant improvement, and thus post-nasal drip and gastric reflux were felt unlikely. A provisional diagnosis of oral dysaesthesia was made.

The patient subsequently reported blistering affecting the inside of her lips when eating raw apples, nectarines and peaches. Full blood count, haematinics, thyroid function, glycosylated haemoglobin and serum zinc disclosed no abnormalities. Specific IgE to grass pollen, birch pollen and rBet v1 PR-10 were increased. An additional diagnosis of PFS was made, and advice on excluding triggers and a patient information leaflet was given. The patient remains under review in the oral medicine department.

Case 5

A 46-year-old female was referred by their GMP with recurrent oral ulceration, reporting recurrent episodes of mucosal blisters that burst and peeled away leaving painful areas of ulceration. Over a 2-year period, the patient reported eight episodes of oropharyngeal irritation when eating, with occasional facial swelling and soreness affecting the throat. Each episode was of sudden onset and took 4–5 weeks to fully resolve. There were no other sites of reported mucosal ulceration. Medically the patient had asthma, irritable bowel disease, allergic rhinitis, allergies to cats and dust mites, as well as reporting cutaneous blistering on contact with citrus fruit, apples and grapes. Medications included cetirizine and a Seretide inhaler (manufacturer, location). There was a family history of atopy.

Examination revealed small areas of superficial ulceration affecting the lateral tongue, buccal mucosa, soft palate and upper and lower labial mucosa (Figure 1). The appearance was not typical of recurrent aphthous stomatitis (RAS).

Full blood count, ferritin, B12, folate and IgA tissue transglutaminase antibodies disclosed no abnormalities. Doxycycline mouthwash was trialled with no significant benefit. Aciclovir 400 mg twice daily was trialled in case this was an unusual presentation of erythema multiforme, with no significant benefit. Further bloods revealed increased specific IgE to birch pollen and rBet v1 PR-10. A referral to Immunology was made where skin prick testing evoked positive reactions to apple, fig and strawberry.

A diagnosis of PFS with recurrent oral ulceration was made. A patient information leaflet was provided on PFS and advice given regarding trigger avoidance.

Case 6

A 62-year-old female was initially referred to special care dentistry for a clearance, but was subsequently referred to oral medicine regarding concerns about denture material allergy (cobalt–chrome). The patient presented with an 8-year history of a burning sensation affecting the tongue, and itchiness affecting the palate when eating fruit, sauces and some spicy foods. This was accompanied occasionally by swelling of the lower lip. There was a history of asthma and a historical diagnosis of PFS. Medications included a salbutamol inhaler and cetirizine. On examination the oral mucosa was healthy.

Bloods revealed increased specific IgE to grass pollen, birch pollen and rBet v1 PR-10. A diagnosis of PFS was made. The patient was also referred to the dermatology department for patch testing to dental materials, but owing to delays associated with the COVID-19 pandemic, these results are still awaited.

Discussion

Each of our patients experienced a different pathway leading to a diagnosis of PFS. The most recent guidance on PFS, published by BSACI, advises that the diagnosis of classical PFS can be made on the basis of clinical history alone. Testing for specific IgEs with or without skin prick testing can be undertaken in certain circumstances.²⁵ This is in accordance with the NICE clinical guideline CG116 for the investigation of IgE-mediated food allergies in the under 19s.²⁷ PFS in the UK is most commonly associated with the rBet v1 PR-10 allergen in birch pollen; this was demonstrated in all of our cases.

Taking into account the new BSACI guidelines,²⁵Figure 2 shows the pathway that suggested within our oral medicine department for the investigation and management of patients with suspected PFS.

Cases 1–4 presented with a clear history of oral mucosal discomfort on eating uncooked fruit/vegetables as described in the case histories. The histories in Cases 5 and 6 were less specific. Interestingly, the majority of our cases (four out of six) also presented with a history of recurrent ulceration/blistering (Cases 1, 2, 4 and 5) and Case 3 presented with a history of occasional blood-filled blisters. Four of our cases (1, 2, 3 and 5) had mucosal abnormalities on direct clinical examination: non-specific palatal erythema; a single ulcer; erythematous haemorrhagic lesions affecting the palate, tongue and lingual sulcus; and multiple ulcers.

Cases 1–5 illustrate oral ulceration/blistering and mucosal abnormalities occurring in the context of PFS that we have been unable to ascribe to any other underlying cause or condition. While the literature suggests that mucosal lesions can be present in PFS,^6–9 there is a lack of clarity and evidence with regards to the type of lesions that can be expected, and their clinical/diagnostic significance. Our cases provide further evidence that such mucosal lesions may be a clinical feature of PFS, or occur contemporaneously with PFS.

Proposed role of general dental practitioners

• Refer all patients reporting symptoms suggestive of PFS or other food hypersensitivity reactions to their GMP for confirmation of the diagnosis and facilitation of allergy testing where required.
• Identify symptoms in the history suggestive of a systemic reaction, and refer these patients urgently to their GMP for provision of an adrenaline autoinjector and onward referral to immunology department.
• In the meantime, give advice about avoiding food triggers.
• Refer to an oral medicine secondary care service if doubt exists about whether PFS can explain oral symptoms or the patient has any associated oral lesions.

Conclusions

General dental practitioners and other dental professionals alike, have a role to play in the identification of patients with signs and symptoms of food hypersensitivities, including PFS, and their onward referral where appropriate. There are suggestions in the literature that PFS can present with oral lesions, and our cases provide evidence that this may indeed be the case.