Route Of Exposure

Allergen Exposure

Oranges, with orange-coloured peels and juicy fruit in separable quarter-moon-shaped sections, come from an evergreen tree growing up to 9 m tall. Oranges are the most important commercial citrus fruit. They were cultivated over 3 000 years ago in China. They now thrive around the world in warm-climate areas, including Portugal, Spain, North Africa and the south of the United States (the world's largest producer). Spain and Israel are leaders in orange exports. The many varieties (Mandarin, tangerine, blood orange, etc.) fall under the basic categories of loose-skinned and tight-skinned, and sweet and bitter (the latter not eaten raw or on its own, but used as a flavouring in processed foods).

The fruit is often eaten fresh and raw. The juice is also extracted and sold fresh and as frozen concentrate, or employed as flavouring in jellies, ice cream, etc. The rind serves as flavouring in cakes, marmalade and other sweets. The flowers are cooked as a vegetable or made into a tea. Oranges are high in vitamin C and flavanoids. They contain thiamin, folate and pectin, which may lower blood cholesterol levels. The fruit, juice and rind are folk remedies for many ailments.

An essential oil from the peel is used as a food flavouring and also in perfumery and medicines. One of the plant’s more recent applications is as a source of antioxidants and chemical exfoliants in specialised cosmetics.

Clinical Relevance

Allergen Description

A number of proteins of various sizes have been isolated, and a number characterised. Furthermore, a 30 kDa protein, found in orange tree pollen, orange fruit and Mandarin extract, but absent in lemon extract, has been identified. This allergen is involved in patients with primary sensitisation to orange tree pollen from occupational exposure.

The following allergens have been characterised:

Cit s 1 was previously known as Cit s 5; Cit s 2 as Cit s 4, and Cit s 3 as Cit s 6.

Cit s 1 has been isolated from orange peel and pulp. Specific IgE to Cit s 1 was detected in 62% of 29 individual sera from Spanish orange-allergic patients, whereas positive skin-prick test responses to the purified allergen were obtained in only 10% of such patients. A major IgE-binding protein band from orange extract, later identified as Cit s 1, was recognised by all of 5 sera from children allergic to oranges. A number of children were also sensitised to a lipid transfer protein, now known as Cit s 3.

Cit s 2, a profilin, has been identified as a major orange allergen. In 23 Spanish Orange-allergic patients, skin-specific IgE reactivity to Cit s 2 was found in 78%, and 87% in serum-specific IgE tests. Authors have suggested that sensitisation to orange profilin is associated with underlying pollen allergy (mainly grass and olive pollen) and that oral allergy syndrome is its principal clinical manifestation.

In a study of 56 subjects with self-reported reactions to orange, 23 were orange-allergic, expressing mainly oral allergy syndrome. Of the 23 subjects, 22 were sensitised to profilin Cit s 2. Of the allergic patients, 78% were also sensitised to Cit s 1. Both allergens retained IgE reactivity in heat-processed orange juice. Interestingly, subjects with and without clinical allergy showed a comparable sensitisation profile. Subjects without symptoms were predominantly sensitised to both allergens.

Cit s 3, a lipid transfer protein (LTP), is associated with systemic and severe symptoms. The LTP allergen family is particularly relevant in the Mediterranean area but shows very limited effects in central and northern Europe. Cit r 3, a Mandarin lipid transfer protein that is similar to Cit s 3, has been shown to be present in both the peel and pulp of Mandarin.

In a study of 27 orange-allergic Spanish patients, manifesting mainly oral allergy syndrome, specific IgE to purified orange allergens was found in 54% for nCit l 3, 48% for nCit s 3, 46% for rCit s 3, and 37% for rPru p 3. Positive skin-prick test responses were obtained in 7 out of 26 patients tested for nCit s 3, 3 out of 8 tested for nCit l 3, and 10 out of 26 tested for nPru p 3. ELISA inhibition assays showed an equivalent IgE-binding pattern for the natural and recombinant orange LTPs, and provided evidence for IgE cross-reactivity among the purified orange, lemon and peach LTP allergens. The study concluded that members of the LTP allergen family are involved in allergy to oranges. Both orange and lemon allergens show cross-reactivity with the major peach allergen Pru p 3.

A Bet v 6-related allergen, a phenylcoumaran benzylic ether reductase, has been detected in orange.

An early study suggested that the major allergenic components of orange reside in orange seeds instead of orange juice/pulp, and that orange seed contains highly potent allergens, which may induce symptoms after careless chewing. More recently, citrus seed extracts were shown to have protein bands between 9 and 61 kDa, with strong bands at 9, 14, 15, and 27 kDa. The proteins present between 9 and 15 kDa were thought to represent profilin and lipid transfer protein. A 51 kDa protein was thought to represent citrin, and the 22 and 33 kDa proteins were thought to represent citrin subunits. It is therefore possible that individuals may react to allergens in orange seed.

Potential Cross Reactivity

Extensive cross-reactivity between the different individual species of the genus could be expected.

The presence of a profilin in orange, Cit s 2, may result in cross-reactivity with other foods containing profilin, and the profilin is a common cause of OAS. In a study of 200 consecutive patients with pollen allergy who were subjected to skin-prick tests with purified natural date palm profilin, 30% were positive. All were sensitised to grass pollen, and most of them reacted to birch, mugwort, ragweed and plantain pollen as well. Thirty-four of 60 (57%) profilin reactors had food allergy; 21 of these were monosensitised to profilin, 11 were sensitised to both profilin and Bet v 1-homologous protein, 1 was sensitised to both profilin and LTP, and 1 was sensitised to all of the 3 allergens. The large majority of profilin-allergic patients reported oral allergy syndrome as the only food-induced symptom, and were able to tolerate the offending foods if they were cooked or otherwise processed. Rosaceae foods, tree nuts, melon and watermelon, tomato, pineapple, citrus fruit and banana were the more frequently offending foods. The authors suggested that allergy to melon, watermelon, tomato, banana, pineapple or orange may be considered to be a marker of profilin hypersensitivity.

Orange contains a lipid transfer protein, Cit s 3, which may result in cross-reactivity with other lipid transfer protein-containing foods. Orange and lemon lipid transfer proteins have been shown to be cross-reactive with the major peach allergen Pru p 3 and with other lipid transfer protein-containing foods.

A 35 kDa birch pollen protein, which results in sensitisation in approximately 10-15% of birch pollen-allergic individuals, has been demonstrated to have cross-reactivity with proteins of comparable size from litchi, mango, banana, orange, apple, pear and carrot. This allergen may be the birch pollen allergen Bet v 6, which in a later study was found to be a plant defence mechanism protein ­– named phenylcoumaran benzylic ether reductase (PCBER) – and was also found to be present in many foods such as apple, peach, orange, litchi, strawberry, persimmon, zucchini, and carrot. The cross-reactivity of this allergen among foods was not thought to correlate with the development of clinical food allergy.

An association between grass pollinosis and sensitisation to tomato, potato, green pea, peanut, watermelon, melon, apple, orange or kiwi has been reported.

When peanut allergy coexists with citrus seed allergy, IgE cross-reactivity between peanut and citrus seed proteins can be demonstrated, suggesting a basis for this co-sensitivity.

Clinical Experience

IgE-mediated reactions

Orange may induce symptoms of food allergy in sensitised individuals, and earlier studies reported orange to be among the top 10 food allergens resulting in adverse effects in children. Symptoms reported included nausea, pruritis, abdominal cramping, abdominal pain, vomiting, diarrhoea, oral itching, angioedema, dyspnoea, bronchospasm, rhinitis, laryngeal oedema, urticaria, hypotension and anaphylaxis. Oral allergy syndrome (OAS) is common, this last study concluding that childhood OAS may have different mechanisms from adulthood OAS, which is almost always accompanied by pollinosis or latex allergy. Orange may also contribute to multi-food allergy, such as reported in a 4-year-old child. Sensitisation to orange has also been reported to occur in the elderly, as reported in a study examining the prevalence and risk factors for sensitisations in 109 people with a mean age of 77 years living in a geriatric nursing home. Specific IgE to orange was detected in 5 of 109 subjects.

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 questionnaires completed by food-allergic individuals concerning 86 foods, that the foods most often reported as eliciting symptoms in Russia, Estonia, and Lithuania were citrus fruits, chocolate, honey, apple, hazelnut, strawberry, fish, tomato, egg, and milk; but in Sweden and Denmark, birch pollen-related foods such as nuts, apple, pear, kiwi, stone fruits, and carrot were the most common 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, orange was the 3rd-most-reported food allergen, resulting in adverse effects in 36%.

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

Approximately 3% of children aged 3 years were reported to be allergic to citrus fruit. In a study of 1 419 patients aged 1 year to 18 years of age, fish, milk, seafood, soya, orange, onion, tomato, chicken, nuts, lettuce and strawberry were responsible for 58% of the total allergic reactions. Fish, milk, seafood, soya and orange had the highest frequency (39%). An early study also reported orange to be a common allergenic fruit in China, inducing severe food allergy in sensitive individuals. Among 26 orange-sensitive patients, intradermal specific IgE determination with extracts of orange juice and seeds was performed in 16. The authors suggested that the major allergenic components of orange reside in orange seed and not orange juice. Systemic reactions developed in 5 patients after intradermal tests with orange seed extracts. The authors conclude that orange seed contains highly potent allergens, which may induce orange sensitivity due to careless chewing.

In an Indian study of 24 children with documented deterioration in the control of their perennial asthma, specific IgE against orange was determined in 17%.

In a study of 27 orange-allergic Spanish patients, mainly with oral allergy syndrome, approximately 50% were sensitised to a lipid transfer protein. In a European study of 56 subjects with self-reported reactions to orange, 23 were classified as orange-allergic, for the most part experiencing oral allergy syndrome. Of 23 subjects classified as orange-allergic, 22 were sensitised to profilin. The authors suggested that a high frequency of clinically insignificant sensitisation may occur in the population.

However, other symptoms have been reported, as illustrated by a study of 29 orange-allergic patients, aged 6 months to 29 years, mainly with symptoms of OAS, but also with eyelid oedema, sneezing, epigastralgia, vomiting, generalised urticaria, throat swelling, atopic dermatitis and chest tightness. Specific IgE to Cit s 1 was detected in 62% of 29 individual sera from these patients, whereas positive skin-prick tests to the purified allergen were obtained in only 10% of the patients. The authors suggested that false positive diagnosis could occur if the diagnosis of allergy to orange is based mainly on in vitro specific IgE determination.

Other case reports have detailed the complexity of orange allergy. Orange allergy was diagnosed in 6 patients following adverse reactions after ingestion of orange juice and a positive skin-prick test on at least 2 occasions. The dose eliciting symptoms was between 20 and 100 g. Three patients tolerated small quantities of lemon juice. One patient tolerated tangerine, but 2 patients had oral allergy syndrome to this fruit. Skin-prick tests were positive to both pulp and peel of tangerine. OAS was reported in all patients. One reported OAS, atopic dermatitis and general discomfort, and another reported OAS and generalised urticaria. Serum-specific IgE was raised in all, ranging from 0.76 to 6.04 kU/L. Specific IgE was raised for tangerine in 5 patients (highest 6.04) and for lemon in 6 patients, ranging from 0.67 to 5.37 kU/L, and for grapefruit in 5. Bet v 2 was raised in 4 patients (8.81 to 39.2). These 4 patients experienced symptoms with pollen, but the 2 with values of <0.35 kU/L for Bet v 2 did not. Cross-reactivity with other foods and pollens was not evaluated for.

Anaphylaxis to orange may occur uncommonly. Food-dependent, exercise-induced anaphylaxis has been described in a 12-year-old boy. Angioedema was the main symptom and was ascribed to the ingestion of an orange prior to exercise. Food-dependent exercise-induced anaphylaxis due to ingestion of orange has been described in an 18-year-old Japanese woman. She had a history of recurrent redness and swelling of the face, with irritation accompanied by dyspnoea and abdominal distress, but she had been able to ingest citrus fruit without symptoms; however, after ingesting orange and then exercising, she developed redness and swelling on her face, and mild dyspnoea and abdominal distress; this was 30 minutes after the onset of exercise. Serum-specific IgE for orange was 0.83 U/ml.

A Spanish study reports that the most common food allergens found to be associated with recurrent otitis media with ear effusion were milk, egg, bean, citrus, and tomato, and that elimination of the offending food from the diet led to a significant amelioration of the otitis in the majority of patients.

Orange has also been reported to result in contact dermatitis and atopic dermatitis in children. Orange has been reported to be a frequent cause of the exacerbation of atopic dermatitis. Occupational dermatitis in farmers and workers in the food industry who come into contact with orange has been reported. Many cases of dermatitis seen in the industry are due to contact with the peel and oil of orange, and not with the juice.

There have been some conflicting studies. A study reported that ingestion of fresh orange juice per se did not heighten non-specific bronchial hyperreactivity. The number of patients was low, and they were stable asthmatics. The results may also indicate that processing influences the allergenicity of orange. A second study evaluated for the presence of specific IgE and IgG antibodies to the oranges Citrus aurantium sinensis and Citrus silension in 41 atopic and 20 non-atopic children aged 8-12 years. The 41 atopic patients were selected as a result of an acute episode of hives and/or sneezing following a provocation test with 150ml orange juice. Skin-prick tests, serum-specific IgE and IgG RAST were performed on both groups. Thirty-six of the 41 patients were skin-prick test-positive to orange. RAST was positive in 34 of the 41. A citrus fruit exclusion diet was maintained for 180 days. No significant changes in these tests occurred before or after the diet: a slight increase was recorded after.

In a study aimed at characterising allergens from raspberry, sera from 8 female patients were assessed. Three were described as having allergy to orange. A 26-year-old experienced severe OAS from orange, asparagus, banana, and melon, with mild OAS from apple, peach, carrot, and kiwi. Prick-to-prick was positive to peach, banana, melon, cucumber, orange, asparagus, tomato, and potato. A 20-year-old reported erythema and pruritus to peach, kiwi, orange, mite, and Alternaria. Prick-to-prick was not determined. The third, a 25-year-old with periorbital edema and rhinitis from lemon and other citrus fruits, was shown to be prick-to-prick positive to peach, lemon, sweet lime, orange, banana, blueberry, tomato, grape and bell pepper. (51

Other reactions

An unusual report describes a 38-year-old woman who presented with a 10-year history of painful ulcerations on her tongue and who drank large quantities of diet cola and some orange juice daily. Patch testing elicited positive reactions to Balsam of Peru, with a resultant diagnosis of allergic contact dermatitis. She was put on a restricted diet and a fragrance-free regimen, and her condition resolved. The authors state that this is a fragrance as well as a flavouring agent put in cola drinks, which cross-reacts with orange juice.

True allergic reactions that appear to result from contact with orange may be due to environmental exposure to spider mites. This may occur in farmers and orange orchard workers as well as in children and adolescents living in environments leading to sensitisation and to the clinical manifestation of asthma and rhinitis.

Non-allergic reactions may occur to other substances in orange, e.g. aromatic substances and tyramine. Orange has been reported to be one of the most common food causes of migraine. Gustatory sweating due to orange juice has been reported. Phytophotodermatitis may result from coumarins such as bergapten contained in the orange skin. Bergapten is sometimes added to tanning preparations, since it promotes pigmentation in the skin.

d-Limonene, obtained from the citrus juice industry as a by-product, was introduced to the market as a more environmentally friendly de-fatting and cleaning agent than the organic solvents traditionally used. Autoxidation of d-limonene occurs readily, and yields a variety of oxygenated monocyclic terpenes that are strong contact allergens. Increased use of d-limonene in industry, where high concentrations are used, as well as in domestic settings, might result in contact sensitisation and dermatitis.