Route Of Exposure

Allergen Exposure

Vitis vinifera is one of the oldest cultivated plants. It grows in temperate and subtropical climates, especially around the Mediterranean, and its fruit, the grape, is consumed either directly or as juice or wine. Western Europe is the world’s biggest producer of grapes. France, Italy, and Spain are the major producers of wine that is sold and drunk throughout the world, though grapes are grown on nearly all continents.

Grapes belong to the Vitis vinifera species, subfamily Ampelideae, of the Vitiaceae family. The only species grown around the Mediterranean is Vitis vinifera, and the composition of the pulp of the ripe fruit varies widely, depending on the variety of vine, the climate, the physicochemical characteristics of the soil, and the agricultural methods employed (fertilisation, irrigation, etc.).

Grapes are widely consumed as fresh fruit, juice, and wine, and the boiled vine leaves are used for the preparation of stuffed vine leaves, so-called ‘dolmades’.

Clinical Relevance

Allergen Description

Assessing grape allergens is hampered by the low protein and high tannin and pectin concentrations of grape. A number of allergenic proteins have been isolated, but few have been characterised. In a Spanish study of sera of 5 of 14 children who had suffered allergic reactions involving fresh grapes or grape juice, an IgE-binding grape protein of 94 kDa was recognised in 1 patient; proteins of 100, 60, 34, 28, 24 and 17 kDa in a second; a 31 and a 24 kDa protein in a third patient; a 34 kDa protein in a fourth; and a 17 kDa band in a fifth, indicating heterogenous sensitisation to a variety of allergenic proteins. Other studies have reported similar- and different-sized allergenic proteins. A 5-year-old child with oral allergy syndrome and lip angioedema after eating grape was shown to be sensitised to a 94 kDa antigenic protein. An 18-year-old woman experienced anaphylaxis to grape only when concomitantly ingesting champagne, and 2 patients with allergic reactions to grape tolerated alcoholic drinks. Grape serum-specific IgE was detected only in the latter 2, although skin-specific IgE was demonstrated in all 3. IgE binding was reported to proteins of 28 kDa, 30.6 kDa, 43 kDa and 56 kDa in case 1, to proteins of 28 kDa, 30.6 kDa, 43 kDa, 56 kDa, and 75 kDa in case 2, and to none in case 3.

In a 33-year-old woman with exercise-induced anaphylaxis to grape and allergic symptoms after drinking white or red wine, no grape-specific IgE could be demonstrated in the serum by RAST, but serum IgE reactivity was shown to a protein band at about 67 kDa, and to another between 25 and 35 kDa. In a study of 3 patients with anaphylaxis to grape, a protein of approximately 30 kDa bound IgE antibodies from all 3. In a patient with food-dependent, exercise-induced anaphylaxis to wine, IgE directed against a 13 kDa protein was demonstrated. Further evidence of the allergens involved in grape allergy derives from a study of 11 patients with severe allergic reactions to grape, and 3 with anaphylactic reactions to wine. IgE binding of proteins of 30 kDa in 79%, 9 kDa in 71%, and 24 kDa in 21% was demonstrated. The major allergens were identified as an endochitinase and a lipid-transfer protein (LTP). The 24 kDa protein, a thaumatin-like allergen, was a minor allergen.

Significantly, grape allergy may be specific to a certain grape variety while there is tolerance to others, as demonstrated in a patient who had experienced several anaphylactic reactions to grape and who was selectively sensitised to the Americana grape (Vitis labrusca). Some patients may be allergic to grape but not wine, whereas others might not tolerate grape, wine or raisins.

The following allergen(s) have been characterised:

Vit v 1, a 15 kDa lipid transfer protein.

Vit v 4, a profilin.

Vit v 5, a 30 kDa chitinase-like protein.

Vit v Thaumatin, a 24 kDa thaumatin-like protein.

Vit v Glucanase, a 39 kDa beta-1,3-glucanase protein.

Grape chitinases account for 50% of the soluble proteins of grape and persist through the process of vinification. The lipid transfer protein Vit v 1 is a major allergen and may sensitise between 70% and 100% of grape-allergic individuals. The beta-1,3-glucanase and thaumatin-like protein are minor allergens. Some authors regard the endochitinases as minor allergens and other authors the opposite. Severe grape allergy has been linked to lipid transfer protein (LTP) sensitisation. Grape LTP is resistant to gastric digestion. Grape LTP is highly homologous to peach LTP (80%).

Potential Cross Reactivity

Cross-reactivity between grapes and Rosaceae fruits is suspected.

A Bet v 1 homologue from Melon, Cuc m 3, shares more than 60% sequence identity with PR-1 proteins from grape and cucumber.

Grape contains a thaumatin, a protein analogous to the cherry thaumatin-like allergen, which may result in cross-reactivity with other foods containing this panallergen. However, the protein is a minor allergen in grape.

Grape contains a lipid transfer protein, which may result in cross-reactivity with other lipid transfer protein-containing foods such as peach and cherry. Lipid transfer protein is a widely cross-reacting plant panallergen found in Rosaceae, tree nuts, peanut, beer, maize, mustard, asparagus, grape, mulberry, cabbage, date, orange, fig, kiwi, lupin, fennel, celery, tomato, eggplant, lettuce, chestnut and pineapple. However, the degree of homology and other factors may result in tolerance of certain LTP-containing foods, as demonstrated in an Italian study that concluded that carrot, potato, banana and melon seemed safe for LTP-allergic patients.

However, as grape contains a number of allergens, of which some act as panallergens, cross-reactivity expression may be more complex. This is illustrated in a study of 11 patients with severe allergic reactions to grape and 3 with anaphylactic reactions to wine, among whom IgE binding to an endochitinase occurred in 79%, to an LTP in 71%, and to a thaumatin in 21%. The endochitinase was the likely allergen in vino novello and in vino Fragolino; V labrusca, which is used to make Fragolino wine, has 4 times the chitinase activity of V vinifera, which may explain why certain patients reacted more strongly to this kind of wine than to others. The authors suggested that, given LTP as a factor, the primary sensitisation is to peach LTP, which would influence the sensitisation to grape LTP, but that only a few IgE epitopes of peach LTP are present on grape LTP. They also reported that the complete inhibition of IgE binding to a 20 kDa band of latex, probably representing prohevein, demonstrated the existence of the hypothesised cross-reactivity between latex and grape, but that the cross-reactivity may not be clinically expressed. This is illustrated by a report that identified cross-reactivity between latex and grape; however, in a study of 2 children with latex hypersensitivity, skin-prick tests with banana, kiwi, pineapple, apricot, avocado, and grape were positive, but children presented no symptoms after ingestion of these fruits.

Cross-reactivity has been reported to occur among apricot, avocado, banana, cherry, chestnut, grape, kiwi, papaya, passion fruit, peach and pineapple. Cross-reactivity has been reported between grape and peach, and between grape and cherry.

Cross-reactivity has also been reported to occur between allergens in vine pollen and grape fruit, and also among botanically-unrelated pollens. An 18-year-old female with seasonal rhinoconjunctivitis who was sensitised to pollens from vine, and also sensitised to grass, Olive tree, and Chenopodiaceae plants, described episodes of itching, maculopapular rash, and facial angioedema after eating Grape.

In a Japanese study of 272 patients and reciprocal relationships between foods causing OAS in patients with birch-pollen allergy, it was reported that kiwi, melon, persimmon, tomato, grape, watermelon, mango, and banana made a large cluster and were partly associated with each other.

In a study of 61 Greek patients with IgE-mediated reactions to grape or its 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.

Clinical Experience

IgE-mediated reactions

Grape has been reported to cause oral allergy syndrome, generalised urticaria, asthma, atopic dermatitis, angioedema, gastro-intestinal symptoms, hypotension, rhinitis, and exercised-induced asthma and anaphylaxis. The aetiology has been confirmed with skin-prick testing, specific IgE and challenge tests. Oral allergy to grape is a common adverse effect. Importantly, patients may subsequently experience anaphylactic shock or exercise-induced anaphylaxis. Patients might not tolerate any grape species, wine or raisins. Adverse reactions to wine may be caused by allergic reactions to grape, but may also be the result of the presence of other components such as sulphites (sulphur dioxide), histamine or alcohol. Patients who complain of symptoms suggesting anaphylaxis should be tested for allergy to grape.

Initially few reports of adverse reactions to grape were reported in the literature, but recently a number of reports have highlighted the relevance of Grape allergy, and its characteristics. Grape allergy is not common, but the prevalence of allergy to grape has been highlighted by studies such as the following:

In a study of food allergy in 674 allergic Spanish patients, food allergy was found in 106, but allergy to Grape in only 1. In a cross-sectional, descriptive, questionnaire-based survey conducted in Toulouse schools to determine the prevalence of food allergies among schoolchildren, 2 716 questionnaires were returned, and 192 reported a food allergy. In 2 cases, grape was reported to be the responsible allergen. In an Indian study of 24 children aged 3 to 15 years with documented deterioration in control of their perennial asthma, the purpose of which study was to evaluate any effect of a specific elimination diet on symptoms, 21 (88%) were sensitised to grape. Allergy to grape was not confirmed. In a Turkish study of 4 331 students, none reported allergy to grape.

A number of studies and case reports have illustrated the complexity of allergy to grape.

Thirty-seven patients with reported severe allergic reactions to grape were described. Symptoms included generalised urticaria, asthma, atopic dermatitis, angioedema, gastro-intestinal symptoms, hypotension, rhinitis, and oral allergy symptoms. All subjects were poly-allergic, both sensitised and reactive to several additional foods and pollen. All the patients were sensitised to grape LTP, although other minor grape allergens were identified, including a 28 kDa expansin, a polygalacturonase-inhibiting protein, a beta-1,3-glucanase, and an unidentified 60 kDa protein.

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, based on a questionnaire concerning 86 different foods, that among 1 139 individuals, grape was the 28th-most-reported food allergen, resulting in adverse effects in 18%.

Sixty-one Greek patients, aged 14-52 years and with documented histories of IgE-mediated reactions to grape or its products (wine, juice, and wine vinegar), were evaluated. The patients each reported 1-15 allergic episodes after consumption of grape or grape products. Seventy-seven per cent of the patients presented with OAS after eating grape before the first reported reaction. The time for the onset of symptoms was between 4 and 160 minutes. Seventy-two per cent of patients reported more than 1 reaction. Skin was involved in 93.4% of patients; the respiratory system in 75.4%; the cardiovascular system in 44.3%; and the gastrointestinal tract in 39.3%. Co-sensitisations identified by skin-prick tests were mainly to apple (81.9%), peach (70.5%), cherry (47.5%), strawberry (32.8%), peanut (49.2%), walnuts (42.6%), hazelnut (31.1%), almond (26.2%), and pistachio (29.5%).

In a study of 11 Greek patients, aged 16-44 years and with documented histories of IgE-mediated reactions to grape, wine, or other grape products, 35 grape-induced anaphylaxis episodes ranging from moderate to severe were reported. Causative agents were identified: wine 10/35 (28.6%); red grapes 9/35 (25.7%); stuffed vine leaves 8/35 (22.9%); raisins 3/35 (8.6%); white grapes 2/35 (5.7%); wine vinegar 2/35 (5. 7%); and grape juice 1/35 (2.9%). Other foods that induced anaphylaxis were apple (54.5%), cherry (18.6%), peach (18.6%), and banana (9.3%).

In a Spanish study of 14 children aged 4-16 who had suffered allergic reactions involving fresh grape or grape juice, OAS was reported in 6, angioedema in 2, urticaria in 1, angioedema-urticaria in 1, and anaphylaxis in 3. A wide range of allergic proteins was isolated, with little commonality between individual patients.

In an Italian study of 14 patients aged 23-47 years with documented histories of severe allergic reactions to grape (11 patients) or wine (3 patients), some patients reacted after drinking 2 particular kinds of red wine, namely Fragolino and young wine, or vino novello. The severity of the reactions precluded food challenges in all cases. Three patients with wine allergy experienced repeated reactions because they initially did not identify the relationship between symptoms and drinking young, new wine or Fragolino wine; they had not shown intolerance to other kinds of wine. A patient with OAS to fresh grape, peach, and cherry had experienced anaphylaxis 3 times after drinking young wine; and another, twice after drinking a glass of Fragolino. One patient experienced OAS to grape and young wine for 1 year and then suddenly experienced severe laryngeal oedema after drinking a single glass of Fragolino. Skin-prick tests with fresh grape were positive to both varieties in all 3 patients, although the patients reacted more strongly to the V. labrusca grape. One patient had 3 episodes of exercise-induced anaphylaxis after eating large amounts of grape before going dancing or swimming. He could tolerate traditionally-prepared red wines, and the reactions started after a generalised reaction to acetylsalicylic acid. Another patient developed severe asthma after eating grape. Six other patients reported many years of OAS to grape that had abruptly changed, causing laryngeal oedema. Many of these patients reported previous allergic reactions to peach, cherry, or tree nuts. Only a single patient, a nurse, reported severe cutaneous and respiratory reactions to latex gloves.

Allergy to grape in individuals with adverse reactions to wine may be influenced by a number of factors. The composition of red wines is affected by both the active wine-making process and aging. Vini novelli (vins nouveaux, or young red wines) have become popular in recent years; in these wines, the grapes are processed by means of carbonic maceration. The wines are intended to be drunk within a short time, so that polymerisation of the polyphenols present in red wines cannot occur; the result is that any proteins remain in solution. Polymerisation of polyphenols causes the tiny residual proteinaceous material in red wines to coalesce, so that it can be filtered off once the wine has aged, thus theoretically explaining why patients tolerated older wine. Fragolino wine, obtained from a blue V. labrusca grape, is also drunk young. Furthermore, authors have reported that RAST results were positive only when the polyphenols were chemically removed from the grape, since they can affect diagnostic results. Plant cells contain the enzyme polyphenoloxidase, which accelerates the oxidation of phenols to quinones; these react in various ways with proteins, leading to the formation of polymers that interfere with allergenic reactivity. Therefore, for a reliable extract, compounds such as PVPP are employed to eliminate the polyphenols.

A 24-year-old man with seasonal spring oculorhinitis described how, 6 years earlier, 15 minutes after drinking white wine, he had experienced flushing of the face and neck, followed by local itchy skin rash, itching and oedema of the oral and perioral mucosa, and moderate dyspnoea. Subsequently, similar reactions occurred every time he drank red or white wine. Similarly, flushing of the face and neck with itchy skin rash, oedema of the oral and perioral mucosa, and dyspnoea occurred 10 min after ingesting fresh grape. He had experienced similar reactions 30 minutes after eating a confection containing sultanas. He also reported oropharyngeal pruritus after eating cherry. The prick-by-prick test was positive for grape, cherry and plum. Serum-specific IgE was 2.88 for grape. However, the RAST result was positive only when the polyphenols were chemically removed from the grapes, since these substances can affect diagnostic results.

Oral allergy syndrome to grape was described in a 4-year-old boy. The diagnosis was confirmed by a positive labial test to a fresh grape, in addition to a positive prick test and specific IgE. He was also allergic to house dust mites, grass pollen, egg, fish, coconut, kiwi, almond and latex.

A thirty-one year old Catholic priest presented with sneezing, nasal obstruction, and perennial rhinitis. Attacks occurred at any time. Skin tests were negative for the common inhalants and foods except for Timothy grass. A very restricted diet was instituted for a period of three weeks. During this period, he continued saying Mass, which involved taking small quantities of wheat, and grape wine. Although symptoms were neither exacerbated nor ameliorated, the pattern of reaction changed. Symptoms all occurred simultaneously and were worse each morning, about ten minutes after Mass. The grape wine fell under suspicion. Skin testing for grape and raisin resulted in very positive reactions. Two weeks later, within ten minutes after drinking two ounces of wine, he experienced a violent reaction, with injected conjunctivae, sneezing, rhinitis, cough, wheeze, and generalised angio-oedema and urticaria. A grain alcohol challenge two weeks later was negative. Beer and whiskey caused no symptoms. Following cessation of saying Mass, all symptoms cleared within fifty-six hours. On one occasion, the ingestion of wine resulted in the onset of symptoms within fifteen minutes, and lasted three days. Limiting the wine to 5 drops, to which was added one drop of water, once daily, resulted in symptoms that were milder, but were otherwise continuously present.

A number of reports have described anaphylaxis to grape. A total of 107 allergy cases was reported to the French Allergy Vigilance Network in 2002, of which 59.8% involved anaphylactic shock, 18.7% systemic reactions, 15.9% laryngeal angioedema, and 5.6% serious acute asthma;, but only a single adverse reaction to grape was reported. In an Italian study of 11 patients presenting with anaphylactic reactions following grape ingestion, anaphylactic shock was reported in 4 cases, of which 2 followed grape ingestion and 2 followed young wine consumption; there was severe asthma in 1 case, glottic oedema and angioedema in 4 cases, glottic oedema and urticaria in 2 cases, and gastrointestinal symptoms and hypotension in 1 case. In 2 cases, symptoms followed exercise.

Anaphylaxis was described in 3 patients following ingestion of fresh grape. Grape-specific IgE was detected by skin and serum tests. An unidentified protein of approximately 30 kDa bound serum IgE from all 3.

A 28-year-old woman experienced generalised urticaria, facial/oropharyngeal angioedema, and dizziness after eating a bunch of white grapes. She became dyspnoeic and hypotensive. Skin-prick tests were strongly positive. Grape-specific serum IgE was weakly positive according to a modified RAST, and negative according to a commercial assay.

Importantly, grape-allergic patients with symptoms of OAS may in future develop anaphylaxis and/or exercise-induced anaphylaxis to grape. Furthermore, anaphylactic reactions may occur in patients selectively sensitised to a specific grape cultivar, as described in an individual who experienced anaphylaxis to Americana grape (Vitis labrusca) specifically.

Food-dependent, exercise-induced anaphylaxis to grape has been reported. This is well-illustrated by a report of a 33-year-old woman, with allergic rhinoconjunctivitis due to Parietaria and mugwort, who reported facial flushing, oedema of the lips, and dyspnoea after drinking white or red wine. She could eat fresh grapes. One month before, after she ate white grapes and exercised, urticaria, facial, pharyngeal oedema, abdominal pain, and dyspnoea appeared and rapidly worsened, followed by profound hypotension. Prick-to-prick tests with white and red grape juice were positive. No grape-specific IgE could be demonstrated in the patient's serum by commercial assays, but IgE reactivity of serum against grape extract was positive.

A number of individual case reports also illustrate the varieties of grape allergy.

A 5-year-old child experienced oral allergy syndrome and lip angioedema after eating grape. A prick test with commercial grape extract and a prick-by-prick test with pulp and peel of fresh white grape (Moscatel variety) and with pulp and peel of blue grape were all positive. An non-blinded lip challenge was positive.

A 38-year-old latex-allergic individual developed an itchy nose and palate while eating a bowl of Raisin Bran cereal. He developed repeated bouts of sneezing, facial flushing, and periorbital angioedema. A skin test to commercial grape extract was positive.

A 39-year-old female described the onset of acute urticaria, angioedema, shortness of breath, wheezing and dry cough after eating mulberry for the first time. Previously, reactions had occurred after eating white grape, and on another occasion, white grape and apricot. The reaction appeared immediately after eating mulberry, and within 2 hours after the other foods. The reactions were life-threatening, requiring emergency-room visits. Serum-specific IgE was 1.15 for grape.

A 66-year-old man developed anaphylaxis with swelling of the tongue and respiratory distress, 2 hours after consuming red wine. He had previously tolerated red wine and grape. Prick-to-prick was positive for red wine, white wine and grape. Specific IgE reactivity to 3 allergens in grape and red wine was demonstrated; and endochitinase, a thaumatin-like protein and a lipid transfer protein were identified.

An 18-year-old woman was described who had anaphylaxis to grape only when concomitantly ingesting champagne; and a further 2 patients with allergic reactions to grape who tolerated grape-based alcoholic drinks. Grape serum-specific IgE was detected only in the latter 2, although skin-specific IgE was demonstrated in all 3.

Anaphylaxis to wine was reported in a 27-year-old German woman. She described several episodes of palmoplantar pruritus, angioedema of the lips, eyelids and tongue, dyspnoea, dysphagia and tachycardia 20–60 minutes after drinking red wine and champagne or eating fresh White grapes and raisins. Prick-to-prick tests were positive to fresh and cooked white and blue grapes, to raisins, to white and red wine, and to grape extract. Grape-specific IgE was 2.43 kU/l. A lipid transfer protein was identified as the responsible allergen. The authors pointed out that the study shows that sensitisation to lipid transfer protein can occur outside the Mediterranean area, resulting in severe fruit allergy without association with pollen allergy.

A 28-year-old woman had 2 episodes of systemic allergic reactions after eating white grapes. The anaphylactic symptoms included generalised pruritus, acute generalised urticaria, facial swelling, lip and oropharyngeal angioedema, and dysphagia. Skin-prick tests with a commercial extract of grape were negative, while prick-by-prick testing with white grapes and white grape juice was positive. Grape-specific serum IgE was confirmed. The authors highlight that in the diagnosis of grape allergy, commercial extracts might not be completely reliable, so the prick-by-prick procedure with fresh Grape should be performed.

An 18-year-old female student suffered from seasonal rhinoconjunctivitis, with sensitisation to pollens from vine and also from grass, olive, and Chenopodiaceae plants. She had recently developed episodes of itching, maculopapular rash, and facial angioedema after eating grapes. Testing revealed positive reactions to vine pollen and grapes, and specific IgE was found for both allergens. Immunoblotting and inhibition assays revealed cross-reactivity between the allergenic structures of vine pollen and grape fruit,and also among botanically unrelated pollens.

Grape workers have been reported to have developed occupational contact dermatitis and lichenified hand dermatitis. Authors have suggested that, as asymptomatic sensitisation to grape was detected only in workers handling the grape, sensitisation may be more likely to occur through cutaneous exposure and/or minor wounding than through the gastrointestinal tract.

Other reactions

Some patients complain of abdominal distension and excessive flatus after ingesting grape. This has been attributed to the presence of fructose in grape.

After wine consumption, symptoms such as flush, rhinitis, asthma, and migraine are not rare. Such symptoms could be caused by an immediate-type reaction to grape or moulds, as well as by intolerance reactions to histamine and sulphite. Sulphite preservatives (sulphite, metabisulphite and sulphur dioxide) are not only found in wine but are also used to prevent spoilage of fresh grape. Sulphite preservatives may precipitate asthma. The likelihood of a reaction is dependent on the nature of the food, the level of residual sulphite, the sensitivity of the patient; and perhaps on the form of residual sulphite and the mechanism of the sulphite-induced reaction.

Vine pollen could be the cause of rhinoconjunctivitis and asthma in allergic individuals living in areas with a high density of vineyards. Grape farmers have been shown to have a high prevalence of allergic rhinitis and work-related respiratory symptoms as a result of Grape pollen exposure, compared to control subjects. However, other factors, such as pesticides and the two-spotted spider mite (Tetranychus urticae), may be causal or contributory factors. Wall rocket is a common Crucifera plant that grows in European and American vineyards and olive groves. A study reports on 2 farmers working in vine plantations who experienced asthma and rhinitis after exposure to this plant.