Route Of Exposure

Allergen Exposure

The wild cherry or sweet cherry (Prunus avium) is a species of cherry native to Europe, north-west Africa, and western Asia.

Botanically, cherries are more closely related to plums than to peaches or apricots. Europe leads the world in production. The cultivated varieties have large red, purple or yellow berries.

The deciduous tree grows 4.5-10 m tall, with a trunk up to 1.5 m in diameter. The bark is smooth and purplish-brown with prominent horizontal grey-brown lenticels showing on young trees, becoming thick, dark, blackish-brown and fissured on old trees. The leaves are alternate, simple ovoid-acute, 7-14 cm long and 4-7 cm broad, glabrous matt or sub-shiny green above, variably finely downy beneath, and with a serrated margin and an acuminate tip; the green or reddish petiole is 2-3.5 cm long and bears 2 to 5 small red glands. The tip of each serrated edge of a leaf also bears small red glands.

In autumn, the leaves turn orange, pink or red before falling. The flowers are produced in early spring at the same time as the new leaves, borne in corymbs of 2 to 6 together, each flower pendent on a 2-5 cm peduncle, 2.5-3.5 cm diameter, and with 5 pure white petals, yellowish stamens, and a superior ovary; they are hermaphroditic, and pollinated by bees. The fruit is a drupe 1-2 cm in diameter (larger in some cultivated selections), bright red to dark purple when mature in midsummer, edible, variably sweet to somewhat astringent and bitter when eaten fresh; it contains a single hard-shelled stone 8-12 mm long, 7-10 mm wide and 6-8 mm thick, grooved along the flattest edge; the seed (kernel) inside the stone is 6-8 mm long.

Sweet cherry and its ancestor, the wild cherry, supply most of the world's commercial cultivars of edible cherry (the other source being the sour cherry, Prunus cerasus, the varieties of which are used mainly for cooking). A great many various cherry cultivars are now grown worldwide, wherever the climate is suitable. The species has also escaped from cultivation and become naturalised in some temperate regions.

Clinical Relevance

Allergen Description

The following allergens have been characterised:

A beta-glucosidase (68 kDa) was isolated from ripe fruits of sweet cherry. (Its allergenicity was not assessed, but beta-glucosidase is an allergen in other fruit.)

Pru av 1 was previously known as Pru a 1.

A heterogeneous sensitisation to cherry allergens occurs, and is influenced by geographic location. For example, Pru av 3, an LTP, has been identified as a major allergen in Mediterranean patients allergic to cherry, but was shown to be of minor clinical relevance in central and northern Europe, where birch trees are abundant. Patients with birch pollen-related cherry allergy are predominantly sensitised to the Bet v 1-homologous allergen Pru av 1. Nonspecific LTPs are predominantly Rosaceae fruit allergens in the Mediterranean population, and sensitisation to these allergens occurs independently from allergy to birch pollen. Whereas symptoms to pollen-related food allergens in fruits typically cause only oral allergy syndrome (OAS), symptoms (in addition to OAS) of LTP-sensitised subjects are frequently systemic, including anaphylactic reactions. IgE reactivity to pollen-related food allergens is a consequence of primary sensitisation to inhalant allergens (commonly birch pollen), and of IgE cross-reactivity with homologous food allergens. In contrast, LTPs are probably capable of sensitising by the ingestion route.

In a study of 101 cherry-allergic German and Italian patients, IgE prevalence was as follows: LTP (Pru av 3), 3 of 101 (3%); rPru av 1, 97 of 101 (96.0%); rPru av 4, 16 of 101 (16.2%); and cherry extract, 98 of 101 (97%). All 7 Italian patients had IgE against the cherry LTP. In a study evaluating a panel of recombinant allergens for use in component-resolved in vivo diagnosis, with cherry as a model food, 79 subjects were included in the study: 24 Swiss patients (group 1) with a positive double-blind placebo-controlled food challenge result to cherry; 23 Swiss patients with birch pollen allergy but without cherry allergy (group 2); 23 non-atopic Swiss subjects (group 3); and 9 Spanish patients with a history of cherry allergy (group 4). SPT responses with rPru av 1, rPru av 4, and rPru av 3 were positive in 92%, 17%, and 4%, respectively, of the patients in group 1; in 74%, 30%, and 0% of the patients in group 2; in 0%, 22%, and 89% of the patients in group 4; and negative for all non-atopic subjects (group 3).

In a study of 186 cherry-allergic subjects from central Europe and Spain, serum IgE was analysed with serum IgE tests carrying rPru av 1, 3 and 4, combined and separately, and cherry extract. Consistent with previous reports, major geographic differences in sensitisation patterns and prevalence of systemic reactions were found. A significantly higher rate of systemic reactions was found in Spanish patients sensitised to Pru av 3, whereas German patients sensitised to LTP had only oral allergy syndrome.

Cherry Pru av 2, a thaumatin-like protein, is the most abundant soluble protein in ripe cherry; accumulation of this protein begins at the onset of ripening as the fruit turns from yellow to red. Pru av 2 was recognised by the majority of cherry-allergic patients in a study, binding IgE of 50% of cherry-allergic patients.

Cherry LTP Pru av 3 has been shown to have a high degree of resistance to digestion, and immunologically active Pru av 3 was detectable after 2 hours of digestion by pepsin, whereas IgE reactivity of Pru av 1 and Pru av 4 was eliminated within less than 60 minutes. Pru av 3 is also heat-stable. There were no marked differences between the LTP of 6 cherry cultivars. LTP is found mainly in the peel, and chemical peeling has been shown to successfully remove Pru av 3.

Cross Reactivity

Extensive cross-reactivity among the different individual species of the family could be expected.

Like other Prunus fruits, cherry contains a variety of allergenic proteins, including 2 birch tree pollen-homologous allergens, Bet v 1 and Bet v 2 (a profilin). Both Bet v 1 homologues and profilin may result in mild symptoms such as oral allergy syndrome, although sensitisation to profilin is commonly associated with more generalised symptoms, in particular urticaria and angioedema. Lipid transfer protein may also be responsible for OAS in patients without pollen allergy, though adverse reactions are typically more severe. This is exemplified by a study of 14 subjects with Pru av 3 (LTP) sensitisation experiencing OAS, which was associated in some of the patients with gastrointestinal, respiratory or cardio-vascular symptoms.

The relationship between pollen allergy and OAS to fruits and vegetables was evaluated in Sapporo, Japan, and it was found that out of 843 patients with birch-pollen allergy, 378 (37%) had episodes of OAS. The most frequent foods causing OAS were apple, peach and cherry, followed by kiwi, pear, plum and melon. In an earlier study of 87 patients, in 61% of patients with birch allergy, apple (97%) was the most prevalent allergen resulting in OAS, followed by peach (67%), cherry (58%), pear (40%), plum (40%) and melon (33%). In a European study, hazelnut (53%) was shown to be the most common food allergen associated with OAS in 380 birch pollen-allergic patients. Approximately 33% of these patients were also hypersensitive to almond and cherry, as reported on questionnaires.

Pru av 1, a Bet v 1-homologous panallergen, has a 67% homology to Bet v 1. Cloned cherry allergen has a 59.1% identity to Bet v 1. Some authors have described Pru av 1 as nearly identical with Bet v 1. This cross-reactive panallergen is found in (among other substances) cherry (Pru a 1), apple (Mal d 1), pear (Pyr c 1), celery (Api g 1), peach (Pru p 1) and carrot (Dau c 1). Bet v 1 homologues mainly cause mild symptoms such as oral allergy syndrome (OAS). Other Bet v 1 homologues are found in soya bean (Gly m 4) and peanut (Ara h 8).

Pru av 2, a thaumatin-like protein (TLP), is a panallergen found in cherry and other foods. The amino acid sequence of cherry TLP has been shown to be highly homologous to grape and apple thaumatins.

Pru av 3, a lipid transfer protein (LTP), is found in cherry. Pru av 3 shows high amino acid sequence identity with LTPs from peach (Pru p 3, 88%), apricot (Pru ar 3, 86%), and maize (Zea m 14, 59%), and no IgE cross-reactivity with birch pollen. LTPs have also been shown to be present in walnut and peanut, mugwort and chestnut, Vit v 1 from grape, Cor a 8 from hazelnut, Mal d 3 from apple, and Lac s 1 from lettuce. Vit v 1, the LTP from grape, was shown to completely inhibit cherry LTP Pru av 3. Hazelnut LTP has an amino acid identity of 59% with cherry LTP. LTPs are also found in blueberry, raspberry, hazelnut, barley, asparagus, and carrot. However, there is no firm correlation between sequence identity and clinical cross-reactivity, and therefore the degree of cross-reactivity resulting from LTPs varies among foods containing this panallergen. Lipid transfer proteins of Rosaceae fruits, including cherry, represent major allergens for atopic Mediterranean populations.

Pru av 4, a profilin and panallergen, is recognised in about 20% of pollen-allergic patients from central Europe. However, sensitisation depends on the geographic area: in Swedish and Finnish patients, approximately 5-7% are sensitised to birch profilin, compared to 20-38% in central and southern Europe. Approximately 20% of Spanish patients allergic to Bermuda grass were found to be sensitised to profilin, and about 42% of celery-allergic individuals to celery-profilin. Sensitisation to profilin may result in cross-reactivity between cherry and other profilin-containing foods; although the cross-reactivity is quite variable, especially as profilin is heat-labile. Other foods containing profilin include tomato (Lyc e 1), celery (Api g 4), pineapple (Ana c 1), banana (Mus xp 1), carrot (Dau c 4) and pear (Pyr c 4).

Pear (Pyr c 4) and Pru av 4 from cherry showed high amino acid sequence identity with birch pollen profilin, Bet v 2 (76-83%). Forty-three of 49 patients (88%) preselected for an IgE reactivity with Bet v 2 showed specific IgE antibodies to recombinant pear profilin, 92% to recombinant cherry profilin, and 80% to celery profilin. Profilins of peanut, cherry, pear, celery and birch have been shown to have marked differences in their IgE binding capacity. IgE binding profiles indicate the presence of epitope differences among the related profilins, suggesting that cross-reactivity among related profilins may explain pollen-related allergy to food in a minority of patients.

In a study of 61 patients with a documented history of IgE-mediated reactions to grapes or their products (wine, juice, and wine vinegar), 81.9% were co-sensitised to apple, 70.5% to peach, 47.5% to cherry, 32.8% to strawberry, 49.2% to peanut, 42.6% to walnut, 31.1% to hazelnut, 26.2% to almond, and 29.5% to pistachio. The high prevalence of concomitant reactivity to other fruits elicits an interest in the clinical relevance of these findings for the grape-allergic population. In 11 Greek patients studied for IgE-mediated reactions to grapes, wine, or other grape products, other foods that induced anaphylaxis were apple (54.5%), cherry (18.6%), peach (18.6%), and banana (9.3%). Panallergens were not tested for.

Clinical Experience

IgE-mediated reactions

Cherry may commonly induce symptoms of food allergy in sensitised individuals. Adverse reactions may range from mild oral allergy syndrome (OAS) to nausea, vomiting, diarrhoea, cough, dysphagia, rhinitis, conjunctivitis, angioedema, urticaria, laryngeal oedema, and severe anaphylaxis following ingestion of cherry.

As mentioned above, symptoms of cherry allergy are dependent on geographic location and predominant sensitization, whether to Pru av 1 or Pru av 3. Severe reactions, including anaphylaxis, are often associated with sensitisation to Pru av 3, a lipid transfer protein, but sensitisation to this allergen may manifest as OAS alone, or as OAS associated with gastrointestinal, respiratory or cardiovascular symptoms. This is exemplified by a study of 186 cherry-allergic subjects from central Europe and Spain, where the most frequently reported symptoms to cherry were OAS and dyspnoea. OAS was found in 68% and dyspnoea in 13% of the entire cherry-allergic group. None of the other recorded symptoms (angioedema, urticaria, rhinitis, flush, conjunctivitis, larynx oedema, cough, dysphagia, nausea, emesis, diarrhoea and cardiovascular reactions) were reported in more than 5% of the subjects. However, the subjects from central Europe and Spain showed marked differences in the frequency of specific symptoms. Ninety-three per cent (113/121) of the central European study population reported OAS and other mild symptoms, with 1.7% (2/121) having urticaria and 0.8% (1/121) having angioedema, after ingestion of cherry. The same symptoms were reported by 64%, 27% and 27% of the Spanish subjects, respectively. Further, episodes of anaphylactic reactions upon consumption of cherry were reported by 3 of the Spanish but none of the central European subjects. An unusual observation was that 1 Swiss subject – who displayed symptoms upon cherry ingestion that were unusually severe (urticaria, severe angioedema, cough, dyspnoea and gastrointestinal symptoms) compared with other central European subjects – in fact originated from the Mediterranean area, and allergy to cherry first occurred when the subject had already been living in Switzerland for a couple of years.

Allergy to Rosaceae fruits in patients without a related pollen allergy is also a severe clinical entity. Profilin- and Bet v 1-related structures are not involved.

A cross-sectional, descriptive, questionnaire-based survey was conducted in Toulouse (France) schools to determine the prevalence of food allergies among schoolchildren. Of 2 716 questionnaires returned, 192 questionnaires reported a food allergy. One reported allergy to cherry.

A study was conducted at 17 clinics in 15 European cities to evaluate the differences between some Northern countries regarding what foods, according to the patients, elicit hypersensitivity symptoms. It was reported (the informants being food-allergic individuals responding to questionnaires concerning 86 different foods) that the foods eliciting symptoms in Russia, Estonia, and Lithuania were citrus fruits, chocolate, honey, apple, hazelnut, strawberry, fish, tomato, egg, and milk, which differed from the situation in Sweden and Denmark, where birch pollen-related foods such as nuts, apple, pear, kiwi, stone fruits and carrot were the most common reported causes. The most common symptoms reported were oral allergy syndrome and urticaria. Birch pollen-related foods dominate in Scandinavia, whereas some mugwort-related foods were of more importance in Russia and the Baltic states. Among 1 139 individuals, cherry was the 23 (rd)-most-reported culprit food, resulting in adverse effects in 19%.

A 24-year-old with allergy to grape also reported experiencing oropharyngeal pruritus after eating cherry. Skin-prick tests with commercial food extracts were positive for cherry and plum.

Anaphylaxis (vomiting, dyspnoea, itching, and generalised oedema) following ingestion of cherry has been described. This patient had previously tolerated other fruit from the same family (apple, plum and peach).

A 4-year-old child was described with allergy to multiple foods. Symptoms of urticaria and asthma were clearly associated with ingestion of hen’s egg at the age of 2. He subsequently developed rhinitis, angioedema, headache, and gastroenteritis, symptoms variously associated and started between a few minutes and 2 hours after the ingestion of numerous foods. Skin-prick tests with fresh food were positive for fig, asparagus, cherry, walnut, medlar, orange, chicory, strawberry, fish, peanut, peach and egg. Serum-specific IgE was detected for hen’s egg, fish, peanuts, walnut, fig, orange, strawberry, peach and cherry. DBPCFC was positive to various degrees for all the skin-prick test-positive foods.

Other reaction

Respiratory allergy to pollen from cherry tree has been reported.