Apple

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Code: f49
Latin name: Malus x domestica
Source material: Peel from green Apple
Family: Rosaceae
Common names: Apple, Cultivated apple, Crabapple

Synonyms: M. domestica, M. communis, M. pumila, M. sylvestris

Food

A food, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Apples are among the most widely grown fruits in the Western Hemisphere.

The apple is the pomaceous fruit of the apple tree, species Malus domestica, in the Rosaceae (Rose) family. It is among the most widely cultivated tree fruits. The tree is small and deciduous, reaching 5 to 12 metres tall, with a broad, often densely twiggy crown. The leaves are alternately arranged simple ovals, 5 to 12 cm long and 3 to 6 cm broad, on a 2 to 5 cm petiole with an acute tip, serrated margin and a slightly downy underside. Flowers are produced in spring, simultaneously with the budding of the leaves. The flowers are white with a pink tinge that gradually fades, 5-petaled, and 2.5 to 3.5 cm in diameter. The fruit matures in autumn and is typically 5 to 9 cm in diameter. The centre of the fruit contains 5 carpels arranged in a 5-point star, each carpel containing 1 to 3 seeds. (1)

The tree originated from Central Asia, where its wild ancestor is still found today. Early cultivation probably predates written history, and over 7 500 known cultivars exist. Different cultivars are available for temperate and subtropical climates. Most of these cultivars are bred for eating fresh (dessert apples), though some are cultivated specifically for cooking (cooking apples) or producing cider. Cider apples are typically too tart and astringent to eat fresh, but they give the beverage a rich flavour that dessert apples cannot. Old cultivars are often oddly shaped and russeted, and have a variety of textures and colours. (1)

Apples may be classified into 4 main groups: dessert, culinary, cider and ornamental. Varieties are also often grouped into ‘summer’ and ‘late autumn’, according to the time of maturity. Apples are grown in temperate zones throughout the world. They are relatively easy to transport and store, and so are readily available throughout the year. Commercially, apples can be stored for some months in controlled-atmosphere chambers to delay the ethylene-induced onset of ripening. Ripening begins when the fruit is removed.

Readily edible varieties are all cultivated. Apples are most valued as a fresh dessert fruit, but may also be made into jams, jellies, vinegars, fresh juice, a purée called applesauce, a preserve called apple butter, wines, ciders, brandies and pastries. They may also be baked, fried, stewed, dried, spiced, candied, or used in mincemeat or chutney. The fruit is a source of pectin. Pectin is a thickener in jams, etc., and a culture medium in laboratories. Apple can also be dried, in which case it may contain the preservative sulphur dioxide, or another preservative, sulphite, which also prevents browning. An edible oil (that is also used for illumination) can be obtained from the seed.

Apple is also regarded as bactericide, astringent, carminative, cyanogenetic, depurative, diuretic, emollient, hypnotic, refrigerant, sedative, and tonic. Apple is used as a folk remedy for a number of medical conditions. The tree root and bark are considered anthelmintic, hypnotic, and refrigerant. Apple leaves contain an antibacterial substance called phloretin, which is active in doses as low as 30 ppm.

Apple contains over 266 volatile components that include alcohol, esters, aldehydes, ketones, ethers, acids, bases, acetals, and hydrocarbons. (2)

The hard wood is used for turnery, canes, tool handles, pipes and fuel.

Allergen Description

Early studies reported the presence of a number of allergenic proteins in apple extracts: they were of 18, 31, 50, 38, 16, 14, and 13 kDa. (3) An allergen of approximately 60 kDa has been isolated, cross-reacting with the major mugwort pollen allergen Art v 1, along with birch pollen, Timothy grass pollen, peanuts, and celery. The allergen appeared to be distinct from Bet v 1 and profilin and was thought to represent a novel cross-reactive allergen involved in oral allergy syndrome. (4)

An allergen present in apple was reported as being similar in size to a 35 kDa protein isolated from birch pollen, a minor allergen to which 10 to15% of birch pollen-allergic individuals are sensitised. Cross-reactivity was demonstrated with proteins of comparable size from litchi, mango, banana, orange, pear and carrot. The 35 kDa protein was immunologically independent from the major birch pollen allergen Bet v 1. (5)

The following allergens have been characterised:

  • Mal d 1, a 18 kDa heat-labile protein, a major allergen, a Bet v 1 homologue (PR 10) protein family member. (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)
  • Mal d 2, a 31 kDa thaumatin-like protein. (6, 15, 18, 19, 22, 25, 31, 32, 33, 34)
  • Mal d 3, a 9 kDa lipid transfer protein, a minor allergen. (6, 15, 19, 22, 24, 25, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)
  • Mal d 4, a 14 kDa protein, a profilin and a major allergen. (6, 15, 19, 22, 24, 33, 51, 52, 53, 54)
  • A Bet v 6-related food allergen, a PCBER (Phenylcoumaran benzylic ether reductase). (55, 56)

An isoflavone reductase (IFR) allergen has been described. (57)

A novel putative allergen, a glyceraldehyde-3-phosphate dehydrogenase, has been detected; of 7 apple-allergic patients, 71% reacted to this protein. (58)

As in the case of other allergens, sensitisation to apple allergens follows a heterogenous pattern: for example, in a study to determine the pattern of recognition of individual major and minor allergens among subjects with a positive in vitro diagnosis for apple allergy, the following frequencies were found: nMal d1 (87%), rMal d2 (57%), nMal d3 (31%), nMal d4 (29%). (59)

The peel of apple and other Rosaceae fruits has been reported to have a clinically-relevant higher allergenicity than the pulp. (60) The 18 and 31 kDa allergens, which are heat-labile and unstable in solution, experience almost complete elimination of allergenic potency with short heating. (61) Mal d 1 and Mal d 2 are distributed throughout apple pulp and peel, while Mal d 3 is restricted to the peel. Different apple cultivars show markedly different expression of major allergens. (25) Interestingly, Mal d 1 and Mal d 3 and their homologues have been detected in Rosaceae pollen. Although the pollen load of Rosaceae is rather low as a rule, there is confirmed evidence for temporary peaks, indicating that allergen exposure for sensitised individuals is likely. (62)

Anecdotal reports from Apple-allergic patients hold that some apple strains tend to be highly allergenic (Granny Smith, Golden Delicious), whereas others (Jamba, Gloster, Boskop) are tolerated without any symptoms or with moderate symptoms. (63) This may be true: the level of allergenic protein varies with the species of apple and its ripeness; the IgE-binding potency depends on the 18-kDa allergen. (63) The Mal d 1 content of Golden Delicious apples was shown to rise considerably during maturation and storage. (64) Golden Delicious apples had the most 18 kDa allergen (compared with Macintosh, Red Delicious, and Granny Smith). The 18 kDa allergen was found at levels in this order: Golden Delicious > Boskoop > Jamba. This would explain the different results to skin-specific IgE determination to allergens from different apple extracts. (65) Mal d 1 content ranged from 0.84 to 33.17 [mu]g/g fresh weight in 39 selected cultivars. (25) Other factors may influence the protein content or allergenicity of apple. Apples in stores have been shown to have higher levels of allergens than freshly picked fruit. The amount of the 18 kDa allergen (Mal d 1) increased significantly when apples were stored at 4 degrees C, but not under controlled exposure to oxygen and carbon dioxide. (3)

Whether apple cultivars containing low amounts of Mal d 1 are better tolerated by apple-allergic patients was assessed: 3 different apple cultivars induced wheals of similar size in most patients, but 2 cultivars induced significantly more severe symptoms in 2 out of 7 cases each, suggesting that allergy to Mal d 1 is characterised by significant inter-patient variability as well as marked inter-apple and intra-apple variability. (20)

Further, different Mal d 1 isoforms can be present within a single cultivar. (6) The divergent allergenicity of apple strains appears to depend on different expression levels of the major allergen. The introduction of a proline residue in position 111 of Mal d 1 and in position 112 of Bet v 1 of birch-tree pollen resulted in a drastic reduction of allergenicity of both the pollen and the food allergen, obviously having altered the cross-reactive epitope. (6) Also, it was demonstrated that although Mal d 1 did not induce basophil activation after gastrointestinal digestion, digested Mal d 1 (and Hazelnut Cor a 1.04) still activated Bet v 1-specific T cells, suggesting that gastrointestinal degradation of Bet v 1-related food allergens destroys their histamine-releasing – but not T cell-activating – property. This data emphasises that birch pollen-related foods are relevant activators of pollen-specific T cells. (66)

On the basis of band intensity in SDS-PAGE studies, the mean amount of Mal d 1 present in mature Golden Delicious apples has been estimated to be 1 to 5 mg per 100 g fresh weight. A bite of apple of approximately 10 g, which is able to elicit symptoms in apple-allergic patients, represents 0.1-0.5 mg of the ingested major allergen. (63)

Mal d 2, a thaumatin-like protein, shows high stability to proteolysis and heat treatment and remains intact after 2 hours each of gastric and subsequent duodenal digestion, retaining its full IgE-binding capacity. Mal d 2, although detected by an anti-TLP antibody in cloudy apple juice, did not bind the IgE of a serum pool of apple-allergic patients. These findings suggest that Mal d 2 maintains its structure in the gastrointestinal tract, a feature essential for sensitising the mucosal immune system and provoking allergic reactions. (32)

Mal d 3, a lipid transfer protein, was assessed in 53 apple cultivars grown in Italy and 35 grown in the Netherlands, in order to determine whether levels of LTP varied among cultivars. Differences of around 100-fold in LTP levels existed between certain apple cultivars. The authors suggested that whether the lowest observed levels of LTP warrant designation as hypo-allergenic required more extensive confirmation by oral challenge. (44, 67) Furthermore, LTP levels are greatly dependent on the position of the fruit growing on the tree, maturity, storage conditions, and cultivar. The highest LTP levels are found in mature, freshly-picked fruits, whereas LTP levels decrease during storage (with the greatest decrease happening under controlled atmosphere conditions). (46, 67) Most LTP concentrates in the pericarp (skin) of the fruit, whereas the pulp contains lower amounts of the allergen. (45)

Potential Cross-Reactivity

An extensive cross-reactivity among the different individual species of the Rosaceae family could be expected, and in fact does occur frequently. (68) For example, in a DBPCFC study, reactions to peach occurred in 22 patients, to apple in 6 and to apricot in 5. The authors conclude that a positive skin- or serum-specific IgE test should not be taken as the only guide for multi-species dietary restrictions, but that nevertheless, the potential for clinical allergy to other Rosaceae should not be neglected. (69)

Early studies reported cross-reactivity between birch pollen and a number of foods, e.g. apple, pear, celery, carrot and potato. (70) Subsequently, a number of allergens or panallergens have been identified, and this has shed light on the causes and patterns. (71)

Birch pollen is a significant cause of allergy in temperate climates, affecting 5-54% of the population in Western Europe. Patients allergic to birch pollen are more often allergic to fresh fruits and vegetables than are patients allergic to other pollens. (72) About 40-70% of birch pollen-allergic patients show allergic symptoms after ingesting or handling raw fruits, especially apple, due to cross-reactivity between an allergen present in the food and Bet v 1, the major birch pollen allergen. (73, 74, 75, 76, 77, 78, 79)

Type I allergic symptoms in the oropharyngeal mucosa, upon contact with plant-derived food in patients with pollen allergies, have been termed oral allergy syndrome (OAS). IgE cross-reactivity between pollen – in particular birch pollen – and food allergens is the molecular basis for this phenomenon. No single allergen in a single source can of course be responsible, but rather one or a number of cross-reacting allergens in multiple sources. For example, in a study of patients with a history of oral allergy syndrome after eating apple, 16 of 28 (57%) reacted to Bet v 1; among 20 polysensitised subjects presenting oral allergy syndrome after consumption of apple, 4 reacted to Bet v 2 (20%). Among patients with IgE against both recombinant allergens, 6 (35.30%) presented symptoms of allergy after eating apples. (80)

In a Japanese study of oral allergy syndrome and pollen allergy, in 101 patients the most common allergen was birch-tree pollen. In 61% of birch-allergic patients, a concomitant allergy to fruit or vegetable was reported. Apple was the most prevalent allergen (97%), followed by peach (67%), cherry (58%), pear (40%), plum (40%) and melon (33%). (81) Similar results were reported from a study in Hokkaido. In patients with birch-pollen allergy, the higher the serum-specific IgE to birch pollen, the higher was the incidence of hypersensitivity to apple pulp. (82)

Laboratory evidence has demonstrated that the major cause of cross-reactivity between birch pollen and apple is biochemical and immunological similarity between the major allergens, Bet v 1 and Mal d 1, as shown by serological and cellular immunoassays. (6, 11, 83, 84) Mal d 1 (the major apple allergen) has been shown through sequence comparison to Bet v 1 (the major Birch pollen allergen) to have a 64.5% identity on the amino acid level and a 55.6% identity on the nucleic acid level. (12)

Clinical and laboratory evidence is supported by research demonstrating that patients who are birch pollen- and apple-allergic improve if desensitised to birch pollen; (85) and by research showing a marked reduction or total disappearance of apple-induced oral allergy syndrome after injection immunotherapy with birch pollen extracts. (86) These recent studies contradict an earlier study that reported a poorer response. (85)

Allergy to apple is commonly associated with birch pollinosis because the 2 share homologous allergens. However, some patients have apple allergy but no allergy to birch pollen, suggesting that there are allergens in apple that do not cross-react with birch. (39) Serum IgE antibodies to apple allergens were detected in 90% of patients with clinical apple allergy, with similar allergens being demonstrated in 44% of patients with clinical birch pollen allergy, and in 5-10% of patients with other atopic allergies. RAST inhibition studies confirmed that apple and birch pollen allergens cross-react. (87) In other words, Bet v 1 has all the allergenic epitopes of Mal d 1, but Mal d 1 is only a weak inhibitor of IgE reactivity with the major birch pollen allergen, probably due to the absence of some Bet v 1 epitopes on the fruit allergen. Other reasons for the latter observation have been proposed: there may be a lower association constant of Bet v 1-specific IgE to Mal d 1 epitopes; or Mal d 1 may represent most of the allergenicity of apple fruit; or the high lability of allergens during extraction or processing of apple is probably not due to destruction of discontinuous epitopes, but to interactions with compounds from the fruit tissue, and most of these reactions are catalysed by enzymes. (9) Cross-inhibition assays have also demonstrated the existence of common B-cell epitopes present on Dau c 1 in carrot and Api g 1 in celery, as well as on Bet v 1. (88)

In Mediterranean areas, oral allergy syndrome occurs without birch pollen allergy, and on occasion may present with no other associated pollen allergy. In a study to assess the possible association of OAS with London plane tree (Platanus acerifolia) pollen allergy, 720 patients were selected on the basis of seasonal or perennial rhinitis, or asthma, or both; 61 (8.48%) were found to be sensitised to P. acerifolia pollen; and a food allergy was observed in 32 (52.45%). Food allergens most frequently implicated included hazelnut, peach, and apple. (89)

Allergy to Rosaceae fruits in patients without a related pollen allergy has been reported to result in a severe clinical entity; it was also reported that profilin- and Bet v 1-related structures are not involved in Rosaceae fruit allergy without pollinosis. (90)

Other allergens or panallergens may also contribute to cross-reactivity between birch pollen and apple allergy.

A minor allergen present in birch pollen and a similar protein present in Timothy pollen were shown to have common epitopes with antigens in apple, carrot and celery tuber. (91) This may have been the minor birch pollen allergen Bet v 6 (phenylcoumaran benzylic ether reductase [PCBER]), which occurs in many foods, including apple, peach, orange, litchi, strawberry, persimmon, zucchini, and carrot. (57, 76) This allergen may also have been the 35 kDa protein isolated from birch pollen, a minor allergen immunologically independent of the major birch pollen allergen Bet v 1, to which 10 -15% of birch pollen-allergic individuals are sensitised, and for which cross-reactivity was demonstrated with proteins of comparable size from apple, litchi, mango, banana, orange, pear and carrot. (5)

Lipid transfer proteins (LTPs) have been reported to be important, clinically relevant panallergens. One has been characterised in apple, and named Mal d 3. LTP from Artemisia pollen and chestnut has been demonstrated to cross-react with allergens of Rosaceae fruits, but significant differences in specific IgE-binding capacities were observed among members of the plant LTP family. (36, 38, 41) Similarly, the LTP present in peach and beer may cross-react with LTP from several other plant-derived foods. (36, 92)

Although cross-reactivity has been clearly established between apple and birch tree pollen, cross-reactivity may occur between apple and other pollens as well. In a study of cross-allergenicity between apple pulp and 5 pollen species (birch, Japanese cedar, orchard grass, mugwort and ragweed) investigated by RAST inhibition, it was demonstrated that apple pulp extract effectively inhibited RASTs to all the pollens except Japanese cedar pollen. (93) Similarly, a study reported an association between grass pollen allergy and sensitisation to tomato, potato, green pea, peanut, watermelon, melon, apple, orange and kiwi. (94) This may be a result of a Group 4 grass pollen allergen, a 60 kDa glycoprotein, which is recognised by 70% of patients sensitive to these pollens and is found in Timothy grass, mugwort and birch pollen, and in peanut, apple, celery root, and carrot. Group 4-related allergens thus occur in pollens of unrelated plants and plant foods, and may therefore contribute to cross-reactivity in patients allergic to various pollens and plant food. (95)

Some patients with grass allergy show polysensitisation against other pollens and plant-derived foods. In these patients, oral allergic syndrome (OAS) is frequently found. This is a result of cross-reactive Bet v 1- and Bet v 2-like allergens. The most common foods implicated are hazelnut, peanut, kiwi, apple and walnut. Specific IgE for Bet v 1 is associated more with nuts and legumes, while Bet v 2 is more often related to fresh fruit and vegetables. (96)

Allergy to apple has been associated with kiwi-allergic individuals. (97) Individuals with allergy to grape or related products are often co-sensitised to apple. (98, 99)

Sensitisation to profilin and/or bromelain-type cross-reacting carbohydrate determinants (CCD) – caused by pollen (Timothy grass, mugwort) or Hymenoptera venom allergens – can elicit false-positive IgE antibodies against natural rubber latex and apple. (100)

Minor allergenic determinants cross-reactive with apple and birch pollen epitopes have also been isolated in the pollen of the apple tree. (101) Apple-seed allergens have been reported to cross-react with birch pollen allergen(s). (102)

Clinical Experience

IgE-mediated reactions

Allergy to apple has been documented for over 3 decades, and may frequently induce symptoms of food allergy in sensitised individuals, in particular oral allergy syndrome. (51, 87, 103, 104, 105, 106, 107, 108, 109, 110 111) Itching, tingling and other mild reactions on the oropharyngeal mucosa are the most common complaints after eating raw apple; angioedema, urticaria and shock are less common. Other symptoms may include rhinoconjunctivitis, asthma, laryngeal oedema, abdominal effects, pruritis and hand dermatitis. (112) Individuals may be highly allergic to apple, with symptoms being elicited even from kissing, resulting in local or regional, mild, moderate or severe symptoms, including angioedema, bronchospasm, acute respiratory distress and anaphylaxis. (113, 114)

In a Japanese study of sera of 4.8 million patients collected in laboratories during 1994-1998, evaluation of specific IgE values of greater than 0.70 UA/ml showed that among food allergens, apple had the highest response. (115) Similarly, in a food hypersensitivity study of Finnish university students, among 172 subjects, apple was a frequent (29.1%) cause of symptoms. (116) Approximately 2% of the Northern and Central European population is allergic to apple. (117) A study was conducted at 17 clinics in 15 European cities to describe the differences among some Northern countries regarding what foods (according to the patients) elicit hypersensitivity symptoms, and it was found that apple was responsible in 45% of 1 139 participants. (111)

However, symptoms of apple allergy may show a geographically skewed distribution. In Northern and Central Europe, where birch trees predominate, symptoms tend to be mild, whereas in Southern Europe and the Mediterranean, symptoms are more likely to be severe. This is illustrated by a study that sought to investigate the primary sensitisers in apple allergy across Europe, the individual allergens involved, and whether these differences determine the clinical presentation. Results from 389 patients with apple allergy (case histories and positive skin-prick test) showed that in the Netherlands, Austria, and Italy, apple allergy was mild (>90% isolated oral symptoms) and related to birch-pollen allergy and sensitisation to Bet v 1 and its apple homologue, Mal d 1. In Spain, apple allergy was severe (>35% systemic reactions) and related to peach allergy and sensitisation to Mal d 3 (lipid transfer protein). (22) A study of an unselected Danish population of children and adults reported that 17% of pollen-sensitised adults were allergic to apple. (118) In an Indian study of 24 children aged 3 to 15 years, with documented deterioration in control of their perennial asthma, the presence of serum-specific IgE to apple was found in 21 (88%). (119)

‘Apple contact urticaria syndrome’ and rhinitis are relevant phenomena. However, itching and tingling and other mild reactions on the oropharyngeal mucosa were reported in early studies to be the most common complaints after eating raw apple. (120) These became known as oral allergy syndrome, and apple is the most frequently reported offending food in birch pollen-sensitive patients with OAS. (65, 82, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130) Up to 70% of patients with birch pollen allergy exhibit this syndrome. The most frequent and therefore best characterised pollen-fruit syndrome combines apple allergy and tree pollen-induced allergy. Some studies have reported an extremely close association: for example, in 196 birch pollen-hypersensitive patients with oral allergy syndrome caused by various vegetable foods, 195 patients had apple and/or hazelnut allergy. (131)

Oral allergy syndrome may occur following low-dose exposure to apple, as demonstrated in a report of a 24-year-old-woman who experienced acute oedema of the lips with itching in the mouth after a kiss from her boyfriend, who had just eaten a green apple. (132) Because of symptoms of oral allergy syndrome, many individuals avoid eating fresh apples. A study demonstrated that the allergens responsible vary between cultivars: out of 15 apple-allergic individuals who underwent an open oral challenge with 3 different apple cultivars – Santana, Golden Delicious, and Topaz – during the birch-pollen season, 8 of the participants (53%) developed no symptoms following challenge with Santana apple, compared with the Topaz apple (1 participant) and Golden Delicious apple (1 participant). (117) Apple allergy confined to the gingival tissues was reported in a 48-year-old woman. Serum- and skin-specific IgE detection with commercial extract of apple was negative, whereas the oral challenge test resulted in blister and ulcer formation. (133)

Among 1 129 adult patients with bronchial asthma and/or allergic rhinitis responding to a questionnaire regarding food sensitivity, 276 (24%) reported allergic symptoms on eating or handling various foods, of which hazelnut, apple and shellfish were the most often named. (134)

The prevalence of atopy caused by apple, peach, and hazelnut in patients with tree pollen allergy was evaluated. Skin-prick tests for apple, peach, and hazelnut were positive in 51 (64.6%), 61 (77.2%), and 71 (89.9%) patients respectively. Granny Smith showed more positive skin reactions and a better agreement with clinical history than did Golden Delicious. RAST for Apple, Peach, and Hazelnut was positive in 53 (68.8%), 13 (16.9%), and 31 (40.3%) patients, respectively. (65)

Although not as common as allergy to apple associated with pollen allergy, allergy to Rosaceae fruits in patients without a related pollen allergy is reported to be a severe clinical entity. Profilin- and Bet v 1-related structures are not involved. (51, 135)

Anaphylaxis to apple has been reported, including that of a 23-year-old woman and a 14-year-old girl with 3-year and 7-year histories, respectively, of anaphylactic reactions to apple pulp. In the first patient, eating raw apples immediately elicited itching and tingling of the lips and mouth, with severe oedema of the lips and tongue, irritation of the throat, and slight colic in the upper abdomen. In the second, nausea and vomiting occurred after ingestion of apples. (93) Anaphylaxis may occur in association with other allergic manifestations such as contact urticaria. (136) Anaphylaxis may be precipitated by apple in association with exercise: this is food-dependent exercise-induced anaphylaxis (FDEIA). (137, 138, 139, 140, 141, 142, 143) FDEIA as a result of apple has been described in a 14-year-old Japanese male who experienced repeated episodes of generalised urticaria and dyspnoea after ingesting apple, followed by exercise. (143)

In a study of 99 children with atopic dermatitis, hen’s egg was the most common food allergen in children under 1 year of age. After that age, apple, carrot, pea, and soya bean elicited positive reactions as often as hen’s egg. (144)

Contact urticaria, although uncommon, can occur following contact with apple. (145)

Apple may present as a ‘hidden allergen’. (146)

The authors of one study reported that oral challenge tests indicated an increase in clinical reactivity to apples during the birch-pollen season in birch pollen-allergic individuals. (147)

Other reactions

All members of this genus contain the toxin hydrogen cyanide in their seeds and possibly also in their leaves, but almost never in their fruits. Hydrogen cyanide is the substance that gives almonds their characteristic taste, but it should be consumed only in very small quantities. Apple seeds do not normally contain very high quantities of hydrogen cyanide, but even so they should not be consumed in large quantities. In small quantities, hydrogen cyanide has been shown to stimulate respiration and improve digestion; it is also claimed (probably not accurately) to be of benefit in the treatment of cancer. In excess, however, it can cause respiratory failure and even death.

An anaphylactic reaction has been recorded to apple juice containing acerola, the allergy reaction being to the acerola. (148)

The acidity of apple juice may result in bronchoconstriction in some individuals. (149)

Auriculotemporal syndrome (Frey’s syndrome, gustatory flushing) has occurred within minutes of eating apple. (150)

Compiled by Dr Harris Steinman, harris@allergyadvisor.com 

Updated*: 30/10/2012

References

  1. Wikipedia contributors, ‘Apple’, Wikipedia, The Free Encyclopedia, http://en.wikipedia.org/wiki/Apple (accessed 30 September 2012).
  2. Dimick PS, Hoskin JC. Review of apple flavor--state of the art. Crit Rev Food Sci Nutr 1983;18(4):387-409.
  3. Hsieh LS, Moos M Jr, Lin Y. Characterization of apple 18 and 31 kd allergens by microsequencing and evaluation of their content during storage and ripening. J Allergy Clin Immunol 1995;96(6 Pt 1): 960-70.
  4. Heiss S, Fischer S, Muller WD, Weber B, Hirschwehr R, Spitzauer S, Kraft D, Valenta R. Identification of a 60 kd cross-reactive allergen in pollen and plant-derived food. J Allergy Clin Immunol 1996;98(5 Pt 1):938-47.
  5. Wellhausen A, Schoning B, Petersen A, Vieths S. IgE binding to a new cross-reactive structure:a 35 kDa protein in birch pollen, exotic fruit and other plant foods. Z Ernahrungswiss 1996;35(4):348-55.
  6. International Union of Immunological Societies Allergen Nomenclature: IUIS official list http://www.allergen.org/ (accessed October 2012).
  7. Son DY, Scheurer S, Hoffmann A, Haustein D, Vieths S. Pollen-related food allergy: cloning and immunological analysis of isoforms and mutants of Mal d 1, the major apple allergen, and Bet v 1, the major birch pollen allergen. Eur J Nutr 1999;38(4):201-15.
  8. Hoffmann-Sommergruber K, Vanek-Krebitz M, Ferris R, O'Riordain G, Susani M, Hirschwehr R, Ebner C, Ahorn H, Kraft D, Scheiner O, Breiteneder H. Isolation and cloning of Bet v 1-homologous food allergens from celeriac (Api g1) and apple (Mal d1). Adv Exp Med Biol 1996;409:219-24.
  9. Vieths S, Schoning B. Characterization of Mal d 1, the 18-kD major apple allergen, at the molecular level. Monogr Allergy 1996;32:63-72.
  10. Puehringer HM, Zinoecker I, Marzban G, Katinger H, Laimer M. MdAP, a novel protein in apple, is associated with the major allergen Mal d 1. Gene 2003;321:173-83.
  11. Holm J, Baerentzen G, Gajhede M, Ipsen H, Larsen JN, Lowenstein H, Wissenbach M, Spangfort MD. Molecular basis of allergic cross-reactivity between group 1 major allergens from birch and apple. J Chromatogr B Biomed Sci Appl. 2001;756(1-2):307-13.
  12. Vanek-Krebitz M, Hoffmann-Sommergruber K, Laimer da Camara Machado M, Susani M, Ebner C, Kraft D, Scheiner O, Breiteneder H. Cloning and sequencing of Mal d 1, the major allergen from apple (Malus domestica), and its immunological relationship to Bet v 1, the major birch pollen allergen. Biochem Biophys Res Commun 1995;214(2):538-51.
  13. Vieths S, Janek K, Aulepp H, Petersen A. Isolation and characterization of the 18-kDa major apple allergen and comparison with the major birch pollen allergen (Bet v I). Allergy 1995;50(5):421-30.
  14. Vieths S, Schoning B, Petersen A. Characterization of the 18-kDa apple allergen by two-dimensional immunoblotting and microsequencing. Int Arch Allergy Immunol 1994;104(4):399-404.
  15. Oberhuber C, Ma Y, Marsh J, Rigby N, Smole U, Radauer C, Alessandri S, Briza P, Zuidmeer L, Maderegger B, Himly M, Sancho AI, van Ree R, Knulst A, Ebner C, Shewry P, Mills EN, Wellner K, Breiteneder H, Hoffmann-Sommergruber K, Bublin M. Purification and characterisation of relevant natural and recombinant apple allergens. Mol Nutr Food Res 2008;52 Suppl 2:S208-19.
  16. Botton A, Lezzer P, Dorigoni A, Barcaccia G, Ruperti B, Ramina A. Genetic and environmental factors affecting allergen-related gene expression in apple fruit (Malus domestica L. Borkh). J Agric Food Chem 2008;56(15):6707-16.
  17. Marañon MJ, Banik U, Rouhani R, Poladian M, Drummond A, Lopez M, Jaggi K, Davoudzadeh D, Scala E, Zaffiro A, Mari A, Hovanec-Burns D. Response to Recombinant PR-10 Allergens rMal d 1 and rPru av 1 in a Specific IgE Assay in Patients with Allergy to Rosaceae. (Poster) 2nd Int Symp Molecular Allergol, Rome, Italy 2007;22-24 April.
  18. Guarino C, Arena S, De Simone L, D'Ambrosio C, Santoro S, Rocco M, Scaloni A, Marra M. Proteomic analysis of the major soluble components in Annurca apple flesh. Mol Nutr Food Res 2007;51(2):255-62.
  19. Herndl A, Marzban G, Kolarich D, Hahn R, Boscia D, Hemmer W, Maghuly F, Stoyanova E, Katinger H, Laimer M. Mapping of Malus domestica allergens by 2-D electrophoresis and IgE-reactivity. Electrophoresis 2007;28(3):437-48.
  20. Asero R, Marzban G, Martinelli A, Zaccarini M, Machado ML. Search for low allergenic apple cultivars for birch pollen-allergic patients: is there a correlation between in vitro assays and patient response? Allerg Immunol (Paris) 2006;38(3):94-8.
  21. Ma Y, Gadermaier G, Bohle B, Bolhaar S, Knulst A, Markovic-Housley Z, Breiteneder H, Briza P, Hoffmann-Sommergruber K, Ferreira F. Mutational analysis of amino acid positions crucial for IgE-binding epitopes of the major apple (Malus domestica) allergen, Mal d 1. Int Arch Allergy Immunol 2006;139(1):53-62.
  22. Fernández-Rivas M, Bolhaar S, González-Mancebo E, Asero R, van Leeuwen A, Bohle B, Ma Y, Ebner C, Rigby N, Sancho AI, Miles S, Zuidmeer L, Knulst A, Breiteneder H, Mills C, Hoffmann-Sommergruber K, van Ree R. Apple allergy across Europe: how allergen sensitization profiles determine the clinical expression of allergies to plant foods. J Allergy Clin Immunol 2006;118(2):481-8.
  23. Sancho AI, Foxall R, Browne T, Dey R, Zuidmeer L, Marzban G, Waldron KW, van Ree R, Hoffmann-Sommergruber K, Laimer M, Mills EN. Effect of postharvest storage on the expression of the apple allergen Mal d 1. J Agric Food Chem 2006;54(16):5917-23.
  24. Zuidmeer L, van Leeuwen WA, Kleine Budde I, Breiteneder H, Ma Y, Mills C, Sancho AI, Meulenbroek EJ, van de Weg E, Gilissen L, Ferreira F, Hoffmann-Sommergruber K, van Ree R. Allergenicity assessment of apple cultivars: hurdles in quantifying labile fruit allergens. Int Arch Allergy Immunol 2006;141(3):230-40.
  25. Marzban G, Puehringer H, Dey R, Brynda S, Ma Y, Martinelli A, Zaccarini M, van der Weg E, Housley Z, Kolarich D. Localisation and distribution of the major allergens in apple fruits. Plant Sci 2005;169(2):387-94.
  26. Gilissen LJ, Bolhaar ST, Matos CI, Rouwendal GJ, Boone MJ, Krens FA, Zuidmeer L, Van Leeuwen A, Akkerdaas J, Hoffmann-Sommergruber K, Knulst AC, Bosch D, Van de Weg WE, Van Ree R. Silencing the major apple allergen Mal d 1 by using the RNA interference approach. J Allergy Clin Immunol 2005;115(2):364-9.
  27. Bolhaar ST, Zuidmeer L, Ma Y, Ferreira F, Bruijnzeel-Koomen CA, Hoffmann-Sommergruber K, van RR, Knulst AC. A mutant of the major apple allergen, Mal d 1, demonstrating hypo-allergenicity in the target organ by double-blind placebo-controlled food challenge. Clin Exp Allergy 2005;35(12):1638-44.
  28. Beuning L, Bowen J, Persson H, Barraclough D, Bulley S, Macrae E. Characterisation of Mal d 1-related genes in Malus. Plant Mol Biol 2004;55(3):369-88.
  29. Son DY, Vieths S. Three monoclonal antibodies against the major apple allergen Mal d 1 have different binding characteristics. AAAAI 56th Annual Meeting 2000;3-8 March.
  30. Schöning B, Ziegler WH, Vieths S, Baltes W. Apple allergy: The cDNA sequence of the major allergen of apple, determined by performing PCR with a primer based on the N-terminal amino acid sequence, is highly homologous to the sequence of the major birch pollen allergen. J Science Food Agricul 1999;71(4):475-82.
  31. Krebitz M, Wagner B, Ferreira F, Peterbauer C, Campillo N, Witty M, Kolarich D, Steinkellner H, Scheiner O, Breiteneder H. Plant-based heterologous expression of Mal d 2, a thaumatin-like protein and allergen of apple (Malus domestica), and its characterization as an antifungal protein. J Mol Biol 2003;329(4):721-30.
  32. Smole U, Bublin M, Radauer C, Ebner C, Breiteneder H. Mal d 2, the Thaumatin-like allergen from apple, is highly resistant to gastrointestinal digestion and thermal processing. Int Arch Allergy Immunol 2008;147(4):289-98.
  33. Gao ZS, Weg WE, Schaart JG, Arkel G, Breiteneder H, Hoffmann-Sommergruber K, Gilissen LJ. Genomic characterization and linkage mapping of the apple allergen genes Mal d 2 (thaumatin-like protein) and Mal d 4 (profilin). Theor Appl Genet 2005;111(6):1087-97.
  34. Menu-Bouaouiche L, Vriet C, Peumans WJ, Barre A, Van Damme EJ, Rouge P. A molecular basis for the endo-beta 1,3-glucanase activity of the thaumatin-like proteins from edible fruits. Biochimie 2003;85(1-2):123-31.
  35. García-Sellés FJ, Díaz-Perales A, Sánchez-Monge R, Alcántara M, Lombardero M, Barber D, Salcedo G, Fernández-Rivas M. Patterns of reactivity to lipid transfer proteins of plant foods and Artemisia pollen: an in vivo study. Int Arch Allergy Immunol 2002;128(2):115-22.
  36. Diaz-Perales A, Garcia-Casado G, Sanchez-Monge R, Garcia-Selles FJ, Barber D, Salcedo G. cDNA cloning and heterologous expression of the major allergens from peach and apple belonging to the lipid-transfer protein family. Clin Exp Allergy 2002;32(1):87-92.
  37. Pastorello EA, Pompei C, Pravettoni V, Brenna O, Farioli L, Trambaioli C, Conti A. Lipid transfer proteins and 2S albumins as allergens. Allergy 2001;56 Suppl 67:45-7.
  38. Asero R, Mistrello G, Roncarolo D, de Vries SC, Gautier MF, Ciurana CL, Verbeek E, Mohammadi T, Knul-Brettlova V, Akkerdaas JH, Bulder I, Aalberse RC, van Ree R. Lipid transfer protein:a pan-allergen in plant-derived foods that is highly resistant to pepsin digestion. Int Arch Allergy Immunol 2000;122(1):20-32.
  39. Pastorello EA, Pravettoni V, Farioli L, Ispano M, Fortunato D, Monza M, Giuffrida MG, Rivolta F, Scibola E, Ansaloni R, Incorvaia C, Conti A, Ortolani C. Clinical role of a lipid transfer protein that acts as a new apple-specific allergen. J Allergy Clin Immunol 1999;104(5):1099-106.
  40. Sanchez-Monge R, Lombardero M, Garcia-Selles FJ, Barber D, Salcedo G. Lipid-transfer proteins are relevant allergens in fruit allergy. J Allergy Clin Immunol 1999;103(3 Pt 1):514-9.
  41. Díaz-Perales A, Lombardero M, Sánchez-Monge R, García-Selles FJ, Pernas M, Fernández-Rivas M, Barber D, Salcedo G. Lipid-transfer proteins as potential plant panallergens: cross-reactivity among proteins of Artemisia pollen, Castanea nut and Rosaceae fruits, with different IgE-binding capacities. Clin Exp Allergy 2000;30(10):1403-10.
  42. Asero R, Mistrello G, Roncarolo D, Amato S, Falagiani P. Analysis of the heat stability of lipid transfer protein from apple. J Allergy Clin Immunol 2003;112(5):1009-11.
  43. Borges JP, Barre A, Culerrier R, Granier C, Didier A, Rougé P. Lipid transfer proteins from Rosaceae fruits share consensus epitopes responsible for their IgE-binding cross-reactivity. Biochem Biophys Res Commun 2008;365(4):685-90.
  44. Sancho AI, van Ree R, van Leeuwen A, Meulenbroek BJ, van de Weg EW, Gilissen LJ, Puehringer H, Laimer M, Martinelli A, Zaccharini M, Vazquez-Cortés S, Fernandez-Rivas M, Hoffmann-Sommergruber K, Mills EN, Zuidmeer L. Measurement of Lipid Transfer Protein in 88 Apple Cultivars. Int Arch Allergy Immunol 2007;146(1):19-26.
  45. Borges JP, Jauneau A, Brulé C, Culerrier R, Barre A, Didier A, Rougé P. The lipid transfer proteins (LTP) essentially concentrate in the skin of Rosaceae fruits as cell surface exposed allergens. Plant Physiol Biochem 2006;44(10):535-42.
  46. Sancho AI, Foxall R, Rigby NM, Browne T, Zuidmeer L, van Ree R, Waldron KW, Mills EN. Maturity and storage influence on the apple (Malus domestica) allergen Mal d 3, a nonspecific lipid transfer protein. J Agric Food Chem 2006;54(14):5098-104.
  47. Carnés J, Ferrer A, Fernández-Caldas E. Allergenicity of 10 different apple varieties. Ann Allergy Asthma Immunol 2006;96(4):564-70.
  48. Sancho AI, Rigby NM, Zuidmeer L, Asero R, Mistrello G, Amato S, González-Mancebo E, Fernández-Rivas M, van Ree R, Mills EN. The effect of thermal processing on the IgE reactivity of the non-specific lipid transfer protein from apple, Mal d 3. Allergy 2005;60(10):1262-8.
  49. Zuidmeer L, van Leeuwen WA, Budde IK, Cornelissen J, Bulder I, Rafalska I, Besolí NT, Akkerdaas JH, Asero R, Fernandez Rivas M, Gonzalez Mancebo E, van Ree R. Lipid transfer proteins from fruit: cloning, expression and quantification. Int Arch Allergy Immunol 2005;137(4):273-81.
  50. Gao ZS, van de Weg WE, Schaart JG, van der Meer I, Kodde L, Laimer M, Breiteneder H, Hoffmann-Sommergruber K, Gilissen LJ. Linkage map positions and allelic diversity of two Mal d 3 (non-specific lipid transfer protein) genes in the cultivated apple (Malus domestica). Theor Appl Genet 2005;110(3):479-91.
  51. van Ree R, Fernández-Rivas M, Cuevas M, van Wijngaarden M, Aalberse RC. Pollen-related allergy to peach and apple: an important role for profilin. J Allergy Clin Immunol 1995;95(3):726-34.
  52. Ma Y, Zuidmeer L, Bohle B, Bolhaar ST, Gadermaier G, Gonzalez-Mancebo E, Fernandez-Rivas M, Knulst AC, Himly M, Asero R, Ebner C, van Ree R, Ferreira F, Breiteneder H, Hoffmann-Sommergruber K. Characterization of recombinant Mal d 4 and its application for component-resolved diagnosis of apple allergy. Clin Exp Allergy 2006;36(8):1087-96.
  53. Ma Y, Breiteneder H, Ebner C, Hoffmann-Sommergruber K. Characterization of apple profilins as members of the profilin allergen family. [Poster: XXI Congress of EAACI] Allergy 2002;57 Suppl 73:79-84.
  54. van Ree R, Voitenko V, van Leeuwen WA, Aalberse RC. Profilin is a cross-reactive allergen in pollen and vegetable foods. Int Arch Allergy Immunol 1992;98(2):97-104.
  55. Karamloo F, Schmitz N, Scheurer S, Foetisch K, Hoffmann A, Haustein D, Vieths S. Molecular cloning and characterization of a birch pollen minor allergen, Bet v 5, belonging to a family of isoflavone reductase-related proteins. J Allergy Clin Immunol 1999;104:991-9.
  56. Wellhausen A, Schoning B, Petersen A, Vieths S. IgE binding to a new cross-reactive structure:a 35 kDa protein in birch pollen, exotic fruit and other plant foods. Z Ernahrungswiss 1996;35(4):348-55.
  57. Karamloo F, Wangorsch A, Kasahara H, Davin LB, Haustein D, Lewis NG, Vieths S. Phenylcoumaran benzylic ether and isoflavonoid reductases are a new class of cross-reactive allergens in birch pollen, fruits and vegetables. Eur J Biochem. 2001;268(20):5310-20.
  58. Herndl A, Marzban G, Kolarich D, Hahn R, Hemmer W, Maghuly F, Stoyanova E, Katinger H, Laimer M. Mapping of Malus domestica allergens by 2-D electrophoresis and IgE-reactivity. (Poster) 2nd Int Symp Molecular Allergol, Rome, Italy 2007;22-24 April.
  59. Zuidmeer L, Leeuwen A, Krebitz M, Hoffman-Sommergruber K, Breiteneder H, Van Ree R. IgE responses to individual purified apple allergens. [Poster: XXI Congress of EAACI] Allergy 2002;57(Suppl 73):85-105.
  60. Fernandez-Rivas M, Cuevas M. Peels of Rosaceae fruits have a higher allergenicity than pulps. Clin Exp Allergy 1999;29(9):1239-47.
  61. Paschke A, Wigotzki M, Steinhart H. Alterations of allergenicity of fruits and vegetables during technological processing. [Abstract] 8th International Symposium on Problems of Food Allergy, Venice, Italy, 2001. 11-13 March.
  62. Marzban G, Mansfeld A, Herndl A, Jager S, Stoyanova M, Hemmer W, Katinger H, Laimer M. Direct evidence for the presence of allergens in Rosaceae fruit tree pollen. Aerobiologia 2006;22(3):237-45.
  63. Vieths S, Jankiewicz A, Schöning B, Aulepp H. Apple allergy: the IgE-binding potency of apple strains is related to the occurrence of the 18-kDa allergen. Allergy 1994;49(4):262-71.
  64. Vieths S, Schöning B, Jankiewicz A. Occurrence of IgE binding allergens during ripening of apple fruits. Food Agric Immunol 1993;5:93-105.
  65. de Groot H, de Jong NW, Vuijk MH, Gerth van Wijk R. Birch pollinosis and atopy caused by apple, peach, and hazelnut; comparison of three extraction procedures with two apple strains. Allergy 1996;51(10):712-8.
  66. Schimek EM, Zwölfer B, Briza P, Jahn-Schmid B, Vogel L, Vieths S, Ebner C, Bohle B. Gastrointestinal digestion of Bet v 1-homologous food allergens destroys their mediator-releasing, but not T cell-activating, capacity. J Allergy Clin Immunol 2005 Dec;116(6):1327-33.
  67. Zuidmeer L, van Ree RR. Lipid transfer protein allergy: primary food allergy or pollen/food syndrome in some cases. Curr Opin Allergy Clin Immunol 2007;7(3):269-73.
  68. Yman L. Botanical relations and immunological cross-reactions in pollen allergy. 2nd ed. Pharmacia Diagnostics AB. Uppsala. Sweden. 1982: ISBN 91-970475-09.
  69. Rodriguez J, Crespo JF, Lopez-Rubio A, De La Cruz-Bertolo J, Ferrando-Vivas P, Vives R, Daroca P. Clinical cross-reactivity among foods of the Rosaceae family. J Allergy Clin Immunol 2000;106(1 Pt 1):183-9.
  70. Dreborg S, Foucard T. Allergy to apple, carrot and potato in children with birch pollen allergy. Allergy 1983;38(3):167-72.
  71. Grote M. Binding of antibodies against birch pollen antigens/allergens to various parts of apples as studied by immuno-gold electron microscopy. Immunobiology 1988;176(3):290-300.
  72. Osterballe M, Scheller R, Stahl Skov P, Andersen KE, Bindslev-Jensen C. Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple. Allergy 2003;58(9):950-3.
  73. Jeep S, Pilz B, Baisch A, Kleine-Tebbe J, Ohnemus U, Kunkel G. Immunoblot studies in birch pollen-allergic patients with and without fruit hypersensitivity: part I: antibody pattern for birch pollen extract. J Investig Allergol Clin Immunol 2001;11(4):255-63.
  74. Asero R, Mistrello G, Roncarolo D, Amato S, Zanoni D, Barocci F, Caldironi G. Detection of clinical markers of sensitization to profilin in patients allergic to plant-derived foods. J Allergy Clin Immunol 2003;112(2):427-32.
  75. Jeep S, Pilz B, Baisch A, Kleine-Tebbe J, Ohnemus U, Kunkel G. Immunoblot studies in birch pollen-allergic patients with and without fruit hypersensitivity:part II:antibody pattern for fruit extracts. J Investig Allergol Clin Immunol 2001;11(4):264-70.
  76. Vieths S, Scheurer S, Ballmer-Weber B. Current understanding of cross-reactivity of food allergens and pollen. Ann N Y Acad Sci 2002;964:47-68.
  77. Kleine-Tebbe J, Galleani M, Jeep S, Pilz B, Baisch A, Kunkel G. Basophil histamine release in patients with birch pollen hypersensitivity with and without allergic symptoms to fruits. Allergy 1992;47(6):618-23.
  78. Wensing M, Akkerdaas JH, van Leeuwen WA, Stapel SO, Bruijnzeel-Koomen CA, Aalberse RC, Bast BJ, Knulst AC, van Ree R. IgE to Bet v 1 and profilin: cross-reactivity patterns and clinical relevance. J Allergy Clin Immunol 2002;110(3):435-42.
  79. Yamamoto T, Asakura K, Shirasaki H, Himi T, Ogasawara H, Narita S, Kataura A. Relationship between pollen allergy and oral allergy syndrome. Nippon Jibiinkoka Gakkai Kaiho 2005;108(10):971-9.
  80. Rossi RE, Monasterolo G, Operti D, Corsi M. Evaluation of recombinant allergens Bet v 1 and Bet v 2 (profilin) by Pharmacia CAP system in patients with pollen-related allergy to birch and apple. Allergy 1996;51(12):940-5.
  81. Gotoda H, Maguchi S, Kawahara H, Terayama Y, Fukuda S. Springtime pollinosis and oral allergy syndrome in Sapporo. Auris Nasus Larynx 2001;28 Suppl:S49-52.
  82. Yamamoto T, Asakura K, Kataura A. Hypersensitivity to apple pulp among patients with birch pollinosis in Hokkaido. [Japanese] Arerugi 1993;42(11):1701-6.
  83. Ebner C, Hirschwehr R, Bauer L, Breiteneder H, Valenta R, Ebner H, Kraft D, Scheiner O. Identification of allergens in fruits and vegetables: IgE cross-reactivities with the important birch pollen allergens Bet v 1 and Bet v 2 (birch profilin). J Allergy Clin Immunol 1995;95(5 Pt 1):962-9.
  84. Fritsch R, Bohle B, Vollmann U, Wiedermann U, Jahn-Schmid B, Krebitz M, Breiteneder H, Kraft D, Ebner C. Bet v 1, the major birch pollen allergen, and Mal d 1, the major apple allergen, cross-react at the level of allergen-specific T helper cells. J Allergy Clin Immunol 1998;102(4 Pt 1):679-86.
  85. Herrmann D, Henzgen M, Frank E, Rudeschko O, Jäger L. Effect of hyposensitization for tree pollinosis on associated apple allergy. J Investig Allergol Clin Immunol 1995;5(5):259-67.
  86. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients. Clin Exp Allergy 1998;28(11):1368-73.
  87. Bjorksten F, Halmepuro L, Hannuksela M, Lahti A. Extraction and properties of apple allergens. Allergy 1980;35(8):671-7.
  88. Hoffmann-Sommergruber K, O'Riordain G, Ahorn H, Ebner C, Laimer Da Camara Machado M, Puhringer H, Scheiner O, Breiteneder H. Molecular characterization of Dau c 1, the Bet v 1 homologous protein from carrot and its cross-reactivity with Bet v 1 and Api g 1. Clin Exp Allergy 1999;29(6):840-7.
  89. Enrique E, Cistero-Bahima A, Bartolome B, Alonso R, San Miguel-Moncin MM, Bartra J, Martinez A. Platanus acerifolia pollinosis and food allergy. Allergy 2002;57(4):351-6.
  90. Fernandez-Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol 1997;100(6 Pt 1):728-33.
  91. Halmepuro L, Lowenstein H. Immunological investigation of possible structural similarities between pollen antigens and antigens in apple, carrot and celery tuber. Allergy 1985;40(4):264-72.
  92. Asero R, Mistrello G, Roncarolo D, Amato S, van Ree R. A case of allergy to beer showing cross-reactivity between lipid transfer proteins. Ann Allergy Asthma Immunol 2001;87(1):65-7.
  93. Sakamoto T, Hayashi Y, Yamada M, Torii S, Urisu A. A clinical study of two cases with immediate hypersensitivity to apple-pulp and an investigation of cross-allergenicity between apple-pulp allergen and some other pollen allergens. [Japanese] Arerugi 1989;38(7):573-9.
  94. Caballero T, Martin-Esteban M. Association between pollen hypersensitivity and edible vegetable allergy: a review. J Investig Allergol Clin Immunol 1998;8(1):6-16.
  95. Grote M, Stumvoll S, Reichelt R, Lidholm J, Rudolf V. Identification of an allergen related to Phl p 4, a major timothy grass pollen allergen, in pollens, vegetables, and fruits by immunogold electron microscopy. Biol Chem 2002; 383(9):1441-5.
  96. Ricci G, Righetti F, Menna G, Bellini F, Miniaci A, Masi M. Relationship between Bet v 1 and Bet v 2 specific IgE and food allergy in children with grass pollen respiratory allergy. Mol Immunol 2005 Jun;42(10):1251-7.
  97. Gall H, Kalveram KJ, Forck G, Sterry W. Kiwi fruit allergy: a new birch pollen-associated food allergy. J Allergy Clin Immunol 1994;94(1):70-6.
  98. Kalogeromitros DC, Makris MP, Gregoriou SG, Katoulis AC, Straurianeas NG. Sensitization to other foods in subjects with reported allergy to grapes. Allergy Asthma Proc 2006;27(1):68-71.
  99. Sbornik M, Rakoski J, Mempel M, Ollert M, Ring J. IgE-mediated type-I-allergy against red wine and grapes. Allergy 2007;62(11):1339-40.
  100. Ebo D, Hagendorens M, Bridts C, De Clerck L, Stevens W. Sensitization to cross-reactive carbohydrate determinants and the ubiquitous protein profilin: mimickers of allergy. Clin Exp Allergy 2004;34(1):137-44.
  101. Berrens L, van Dijk AG, Houben GF, Hagemans ML, Koers WJ. Cross-reactivity among the pollen proteins of birch and apple trees. Allerg Immunol (Leipz) 1990;36(3):147-56.
  102. Lahti A, Bjorksten F, Hannuksela M. Allergy to birch pollen and apple, and cross-reactivity of the allergens studied with the RAST. Allergy 1980;35(4):297-300.
  103. Besler M, Ortolani C, Vieths S. Apple (Malus domestica) Internet Symposium on Food Allergens 2000;2(4):1-23.
  104. Johnstone IL. Apple allergy. Br Med J 1972;4(840):613.
  105. Lahti A, Hannuksela M. Hypersensitivity to apple and carrot can be reliably detected with fresh material. Allergy 1978;33(3):143-6.
  106. Kennedy P. Acute reaction to apple-eating. Br Med J. 1978;2(6150):1501-2.
  107. Skamstrup Hansen K, Vestergaard H, Stahl Skov P, Sondergaard Khinchi M, Vieths S, Poulsen LK, Bindslev-Jensen C. Double-blind, placebo-controlled food challenge with apple. Allergy 2001;56(2):109-17.
  108. Kalyoncu AF, Demir AU, Kisacik G, Karakoca Y, Iskandarani A, Coplu L, Sahin AA, Baris YI. Birch pollen related food hypersensitivity: as a para-occupational syndrome. Allergol Immunopathol (Madr) 1995;23(2):94-5.
  109. Roehr CC, Edenharter G, Reimann S, Ehlers I, Worm M, Zuberbier T, Niggemann B. Food allergy and non-allergic food hypersensitivity in children and adolescents. Clin Exp Allergy 2004;34(10):1534-41.
  110. Zuidmeer L, Goldhahn K, Rona RJ, Gislason D, Madsen C, Summers C, Sodergren E, Dahlstrom J, Lindner T, Sigurdardottir ST, McBride D, Keil T. The prevalence of plant food allergies: a systematic review. J Allergy Clin Immunol 2008;121(5):1210-8.
  111. Eriksson NE, Moller C, Werner S, Magnusson J, Bengtsson U, Zolubas M. Self-reported food hypersensitivity in Sweden, Denmark, Estonia, Lithuania, and Russia. J Investig Allergol Clin Immunol 2004;14(1):70-9.
  112. Hannuksela M, Lahti A. Immediate reactions to fruits and vegetables. Contact Dermatitis 1977;3(2):79-84.
  113. Dutau G, Rancé F. Le syndrome des allergies induites par le baiser / Kiss-induced allergy. Revue francaise d allergologie 2006;46(2):80-4.
  114. Saraswat A, Kumar B. Anaphylactic reaction to apple, banana and lychee: what is common between botanically disparate plant families? Int J Dermatol 2005;44(12):996-8.
  115. Kimura S. Positive ratio of allergen specific IgE antibodies in serum, from a large scale study. [Japanese] Rinsho Byori 2001;49(4):376-80.
  116. Mattila L, Kilpelainen M, Terho EO, Koskenvuo M, Helenius H, Kalimo K. Food hypersensitivity among Finnish university students: association with atopic diseases. Clin Exp Allergy 2003;33(5):600-6.
  117. Kootstra HS, Vlieg-Boerstra BJ, Dubois AE. Assessment of the reduced allergenic properties of the Santana apple. Ann Allergy Asthma Immunol 2007;99(6):522-5.
  118. Osterballe M, Hansen TK, Mortz CG, Host A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. Pediatr Allergy Immunol 2005;16(7):567-73.
  119. Agarkhedkar SR, Bapat HB, Bapat BN. Avoidance of food allergens in childhood asthma. Indian Pediatr 2005;42(4):362-6.
  120. Kremser M, Lindemayr W. Frequency of the so-called "apple allergy" ("apple contact urticaria syndrome") in patients with birch pollinosis. [German] Z Hautkr 1983;58(8):543-52.
  121. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral allergy syndrome. Ann Allergy 1988;61(6 Pt 2):47-52.
  122. Halmepuro L, Vuontela K, Kalimo K, Bjorksten F. Cross-reactivity of IgE antibodies with allergens in birch pollen, fruits and vegetables. Int Arch Allergy Appl Immunol 1984;74(3):235-40.
  123. Helbling A Important cross-reactive allergens. [German] Schweiz Med Wochenschr 1997;127(10):382-9.
  124. Hernandez J, Garcia Selles FJ, Pagan JA, Negro JM. Immediate hypersensitivity to fruits and vegetables and pollenosis. [Spanish] Allergol Immunopathol (Madr) 1985;13(3):197-211.
  125. Ishida T, Murai K, Yasuda T, Satou T, Sejima T, Kitamura K. Oral allergy syndrome in patients with Japanese cedar pollinosis. [Japanese] Nippon Jibiinkoka Gakkai Kaiho 2000;103(3):199-205.
  126. Asero R, Mistrello G, Roncarolo D, Casarini M, Falagiani P. Allergy to nonspecific lipid transfer proteins in Rosaceae:a comparative study of different in vivo diagnostic methods. Ann Allergy Asthma Immunol 2001;87(1):68-71.
  127. Asero R. Detection and clinical characterization of patients with oral allergy syndrome caused by stable allergens in Rosaceae and nuts. Ann Allergy Asthma Immunol 1999;83(5):377-83.
  128. Wuthrich B, Borga A, Yman L. Oral allergy syndrome to a jackfruit (Artocarpus integrifolia). Allergy 1997;52(4):428-31.
  129. Kazemi-Shirazi L, Pauli G, Purohit A, Spitzauer S, Froschl R, Hoffmann-Sommergruber K, Breiteneder H, Scheiner O, Kraft D, Valenta R. Quantitative IgE inhibition experiments with purified recombinant allergens indicate pollen-derived allergens as the sensitizing agents responsible for many forms of plant food allergy. J Allergy Clin Immunol 2000;105(1 Pt 1):116-25.
  130. Pastorello EA, Pravettoni V, Bigi A, Qualizza R, Vassellatti D, Schilke ML, Stocchi L, Tedeschi A, Ansaloni R, Zanussi C. IgE-mediated food allergy. Ann Allergy 1987;59(5 Pt 2):82-9.
  131. Asero R. Relevance of pollen-specific IgE levels to the development of Apiaceae hypersensitivity in patients with birch pollen allergy. Allergy 1997;52(5):560-4.
  132. Wuthrich B. Oral allergy syndrome to apple after a lover's kiss. Allergy 1997;52(2):235-6.
  133. Ozcelik O, Haytac MC. Oral challenge test for the diagnosis of gingival hypersensitivity to apple: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101(3):317-21.
  134. Eriksson NE. Food sensitivity reported by patients with asthma and hay fever. A relationship between food sensitivity and birch pollen-allergy and between food sensitivity and acetylsalicylic acid intolerance. Allergy 1978;33(4):189-96.
  135. Fernandez Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol 1997;100(6 Pt 1):728-33.
  136. Pigatto PD, Riva F, Altomare GF, Parotelli R. Short-term anaphylactic antibodies in contact urticaria and generalized anaphylaxis to apple. Contact Dermatitis. 1983;9(6):511.
  137. Añíbarro B, Domínguez C, Díaz JM, Martín MF, García-Ara MC, Boyano MT, Ojeda JA. Apple-dependent exercise-induced anaphylaxis. Allergy 1994;49:481-2.
  138. Guinnepain MT, Eloit C, Raffard M, Brunet-Moret MJ, Rassemont R, Laurent J. Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy 1996;77(6):491-6.
  139. Anaut A, Iglesias A, Zapatero L, AranzabaI A, Gil P, Martinez Molero MI. Exercise-induced anaphylactic reaction to apple. Allergy 1994;49:67.
  140. Mathelier-Fusade P, Vermeulen C, Leynadier F. Responsibility of food in exercise-induced anaphylaxis:7 cases. [French] Ann Dermatol Venereol 2002;129(5 Pt 1):694-7.
  141. Sanchez-Morillas L, Iglesias Cadarso A, Zapatero Remon L, Reano Martos M, Rodriguez Mosquera M, Martinez Molero MI. Exercise-induced anaphylaxis after apple intake. [Spanish] Allergol Immunopathol (Madr) 2003;31(4):240-3.
  142. Anibarro B, Dominguez C, Diaz JM, Martin MF, Garcia-Ara MC, Boyano MT, Ojeda JA. Apple-dependent exercise-induced anaphylaxis. Allergy 1994;49(6):481-2.
  143. Morimoto K, Sanada S, Hara T, Hide M. Two cases of food-dependent exercise-induced anaphylaxis difficult to evoke symptoms by provocation test. [Japanese] Arerugi 2006;55(11):1433-6.
  144. Hannuksela M. Diagnosis of dermatologic food allergy. Ann Allergy 1987;59(5 Pt 2):153-6.
  145. Meynadier J, Meynadier JM, Guilhou JJ. Contact urticaria in atopic patients. Apropos of 2 cases. [French] Ann Dermatol Venereol 1982;109(10):871-4.
  146. Anibarro B, Seoane FJ, Mugica MV. Involvement of hidden allergens in food allergic reactions. J Investig Allergol Clin Immunol 2007;17(3):168-72.
  147. Skamstrup Hansen K, Vieths S, Vestergaard H, Skov PS, Bindslev-Jensen C, Poulsen LK. Seasonal variation in food allergy to apple. J Chromatogr B Biomed Sci Appl 2001;756(1-2):19-32.
  148. Raulf-Heimsoth M, Stark R, Sander I, Maryska S, Rihs HP, Bruning T, Voshaar T. Anaphylactic reaction to apple juice containing acerola: cross-reactivity to latex due to prohevein. J Allergy Clin Immunol 2002;109(4):715-6.
  149. Santucci TF Jr, Rourk MH Jr, Spock A. Apple juice challenge-pulmonary function test: a simple method to identify an acid-sensitive esophagus inducing bronchoconstriction. Ann Allergy 1990;64(2Pt1):135-42.
  150. Zacharisen MC, George RA. Recurrent rash associated with food ingestion in a 5-year-old child. Ann Allergy Asthma Immunol 2003;90(6):599-603.

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.