A. Case study
An 11-month-old boy was seen for eczema. Since birth he had been given cow's milk-based formula, until he developed eczema at the age of 3 months. He was put onto a soya formula, and his symptoms resolved. The mother began to give him solid foods at age 5 months. She started him on rice and maize cereals and gradually introduced a variety of fruits and vegetables, as well as rice, potato, chicken and beef. At the age of 9 months, he developed severe eczema again. He was drinking about 800ml of soya formula per day at this stage. The general practitioner requested some blood tests, with the following results (in KU/L):

Total IgE: 300 (High)
Soya: 9.47 (Class 3)
Rice: 0.39 (Class 1)
Maize: <0.35 (Class 0)
Potato: <0.35 (Class 0)
Phadiatop: 0.46 (Class 1)

(This last is a screening test that measures the level of IgE to a combination of the common inhalant allergens. A positive result indicates that the subject is sensitized to 1 or more of these inhalants, but does not indicate which. From there one can test for specific allergens.)

The mother was asked to stop feeding with the soya formula, but the symptoms improved only slightly. (She was, importantly, sent to a dietitian to ensure that the child's diet would be nutritionally adequate.) The mother returned to the doctor when the child was 11 months old. He still had chronic eczema, but he also seemed to have severe "flare-ups" now and again. The mother could not establish what the cause was.

THOUGHT PROCESS:
Apart from reacting to something in his everyday environment or diet that produced constant eczema, the child must have been exposed to something causing the "flare-ups." What were the possibilities?
a. He was reacting to something (environmental or dietary) that he was exposed to only occasionally.
b. He was sometimes being exposed to a higher dose of the allergen (environmental or dietary) that was causing his constant eczema.
c. He was reacting to varying "hidden" sources of cow's milk and/or soya in his diet.
d. In a patient with eczema, one should consider stress and other non-food factors (e.g., exposure to house dust mite, pets, smoke, perfumes and fabric softeners) that could aggravate eczema.

DISCUSSION:
a-b. These will be discussed below.
c. A detailed dietary history was taken to determine whether hidden allergens were present. But because the mother was very careful, she gave only plain food (no processed foods or added flavorants). No hidden allergens could be identified.
d. Even though the serum-specific IgE to Phadiatop was quite low, the child could have been reacting to an environmental allergen not tested for in the Phadiatop mix. No association could, however, be drawn between any environmental allergen and his symptoms. The boy was not exposed to smoke, perfumes or fabric softeners, and stress was not a factor.

THOUGHT PROCESS:
What could be the next step?
a. Do more serum-specific IgE tests to other foods.
b. Ask the mother to keep a food-symptom diary.
c. Do an elimination diet and oral challenges.

DISCUSSION:
a. There was no clear indication of which food could be a cause of the reaction, and it would therefore have been difficult to suggest which foods to test for. But testing for the most common allergens can be helpful in such circumstances, as the chance of a child reacting to one of these is better than to uncommon foods. The tests were done and were negative.
b. The purpose of keeping a diary is to detect a pattern in what is eaten and the development of symptoms. Because the child experienced constant eczema, the diary would probably not have assisted in identifying the general cause; but it was potentially helpful for identifying the allergen causing the "flare-ups." But it was decided to do an elimination diet with challenges, which could be useful in both areas.
c. Because there was no clear indication of which food could be the cause of the reaction, an elimination diet was singled out as an approach. The mother was asked to allow only rice and rice products, maize and maize products, potato (as the IgE levels of all of these were 0 or low), banana, pear and chicken (as these are low-allergenic foods) in her son's diet. The plan was to keep him on this diet until his symptoms disappeared, and then challenge him with the foods that were excluded, to see which provoked a reaction. After 1.5 weeks, the symptoms had not improved. The mother did, however, pick up that her son's symptoms got worse ("flared up") after he ate sweet corn. She was asked to exclude all sources of maize, including the maize cereal, while still following the rest of the elimination diet. This was done, and his symptoms improved dramatically. Upon a rechallenge (with a double-blind method), the symptoms flared again. This supports a recent finding that skin-specific IgE and serum-specific IgE to maize have little, if any, clinical significance for most patients studied (discussed below).

The other foods were put back into his diet without adverse effects.

TIP for Allergy Advisor users: Allergy Advisor contains a guide to elimination diets under the "Assessment" bar, under "Assessment Forms & Guides". It contains examples of few foods diets for different age groups as well as a step-by-step guide to oral challenges. The "Challenge Vehicles" provides ideas for vehicles that can be used to disguise foods during challenges.

B. More information:
Mango is not one of the "big eight" allergens (milk, peanut, wheat, seafood, fish, soya, tree nuts, and egg), and therefore not as much is known about it. But there are compelling reasons to study less common allergens to the extent possible. One is that they may be "emerging" allergens, as mango is (see immediately below). Incidence of an allergy may rise significantly in a short time, leaving many clinicians unprepared. Furthermore, knowledge of less common allergens is important not only in terms of the allergies patients may have, but those they DON'T have. Self-diagnosis is probably more common in allergy than in any other area of healthcare, and patients are certainly not restricted mainly to the "big eight" in their incorrect ideas about adverse reactions they are experiencing. For any reported adverse reaction, a clinician needs both the means to assemble solid evidence about the nature of the reaction, and also a theoretical framework within which to reason. Without, for instance, a range of suspicions of cross-reactions, based on, for example, botanical relationship or the presence or the type of a panallergen, diagnosis and management will be incomplete.

In the recent past, the import and consumption of exotic foods have increased substantially. Parallel to this rise, there has been an increase in the number of persons experiencing adverse reactions to these products.¹ These foods are referred to as "emerging allergens". One of the foods is mango. Adverse reactions to mango have been reported from tropical and subtropical areas throughout the world, including the Philippines, Argentina, the West Indies, the East Indies, India, Japan, and Florida. During mango's fruiting season, it is the most common cause of plant dermatitis in Hawaii.² The frequency of adverse reactions to mango may be underestimated because of the low consumption of this fruit in the Northern Hemisphere. It is likely that, with wider consumption of mango in the West, an increased frequency of reported adverse reactions will be seen.^3,4

Mango's Latin botanical name is Mangifera indica, and it belongs to the Anacardiaceae family, which includes cashew nuts, pistachio nuts, "sweet pepper", hog plum, Jamaican plum, sumac, poison ivy and poison oak.^2,4,5,6 (Mangifera is a combination of the common name "mango" and fero ("to bear" in Latin). Indica means "of India", which is where the mango plant originates.²)

Mango is commonly eaten peeled and raw. Green or unripe mango has many uses in the cuisines of India, Malaysia and Thailand. It is used in various vegetable and lentil dishes, as a meat tenderizer, and in recipes for chutney, pickles and squash.²

During harvesting, stem sap may contaminate the peel, forming bleached, varnished or blackened patches. This occurs because of the self-melanizing urushiol (going black on contact with air), a substance present in members of the Anacardiaceae family.

Sensitization to mango pollen⁷, as well as to mango seed⁸ and mango fruit, has been documented.⁹ Commercial products derived from the mango plant, such as mango wood and sawdust (the timber is used commercially for items such as boats and furniture) are potential causes of dermatitis.²

In some fruits, such as apple, some strains or varieties are more allergenic (e.g., Granny Smith and Golden Delicious) than others (e.g., Jamba, Gloster, Boskop); the latter being tolerated without or with moderate symptoms. World-wide mango is cultivated in approximately 1000 strains even though only a few are sold commercially, of which the Tommy Atkins variety is the most popular. It has, however, been demonstrated that the allergenic potencies of the four most consumed mango strains in Europe are very similar.¹⁰

Adverse reactions to mango fruit Adverse reactions can occur after ingestion of or contact with the fruit. The reactions that have been reported are facial erythema,4 urticaria,2,4,11,12 angioedema,11 periorbital oedema,4 rhinoconjunctivitis,3 nausea, vomiting and abdominal cramps,1 dyspnoea.3,4 cough,3 asthma and rhinitis after eating the fruit2,12 as well as from mango tree pollen,13,14 anaphylaxis,15,16 burning sensation in the mouth,1 swelling of the lips, face and tongue,1 pruritis of the eyes and/or mouth, oral allergy syndrome,3 and contact dermatitis.17 Oral allergy syndrome is an IgE-mediated reaction that occurs to a number of foods that all contain a similar allergen, affecting the oropharyngeal mucosa of sensitized individuals.17 The main symptoms include itchiness (pruritus) and swelling of the lips, tongue, palate and throat.19,20 (Also see the Educational Review of September 2003.)

Mango dermatitis is sometimes limited to vesicles at the angles of the mouth, and/or the buccal mucosa, but it usually affects the entire periorbital region, and eruptions may become generalised.^2,21 Even the ingestion of mango skin has induced erythematous vesicular eruptions of the lips and face, and contact dermatitis has also occurred after climbing mango trees.⁴

An interesting finding regarding sensitisation to mango was that mango dermatitis seems to be more common in visitors to Hawaii, and in those who have moved there from the United States mainland, than in those born locally. A possible explanation is that those born on the islands are immunologically tolerant to urushiol (3'5'-pentadecylcatechol), a substance known to sensitize an individual upon exposure. Urushiol is found in the leaves, bark, stems, tree latex and skin (pericarp) of the mango and also in other plants of the Anacardiaceae family.^{2,3,5,6,22,23} It is proposed that when primary exposure to urushiol is through the skin, allergic contact dermatitis can result, but that when initial exposure occurs through ingestion, the substance is presented to the gut-associated lymphoid tissue, resulting in specific immunological tolerance. Mainland-born people experience primary exposure to urushiol through the skin from contact with poison ivy and poison oak, which induce delayed hypersensitivity. Poison ivy and oak are not found on the Hawaiian Islands. An islander's first contact with the antigen is typically through the ingestion of mango at an early age, which results in the induction of specific immunological tolerance.^2,5,22,24 Mango dermatitis presents as very similar to dermatitis caused by cashew and poison ivy. This is probably due to the urushiol present in these foods. Urushiol dermatitis caused by plants of the Anacardiaceae family is thought to be the most common cause of acute allergic contact dermatitis.^25,26 Immediate hypersensitivity to mango is much less common, though it does occur. It is most commonly found in atopic individuals.^2,5,22,24

What is the mechanism of action?
Adverse reactions to mango are probably IgE-mediated, as positive skin prick tests and IgE RAST tests to mango have been documented. Another possible mechanism of less severe reactions, such as contact urticaria, is an IgG-mediated response.³

Potential cross-reactivity One would expect an extensive cross-reactivity among the different individual species of the genus (e.g., mango, cashew and pistachio nut), but this, in fact, does not occur frequently.27 Cross-reactivity has been found among pistachio nut, cashew nut, and mango seed, but this cross-reactivity did not extend to mango pulp. It is possible that pistachio and cashew nut-sensitive patients may tolerate mango since only the pulp is usually consumed. However, more studies are needed to completely understand the cross-reactivity between mango fruit and nuts of this family.1,8 Mango, like many other foods, contains more than one allergen, some of which have been identified and others not. If an allergen belongs to a panallergen family, there is a higher risk that the mango-allergic individual will react to other foods as well (i.e., the cross-reacting foods). Each panallergen in mango is associated with a different group of foods that mango is likely to cross-react with. Some examples are discussed below. (Panallergens are allergens present in a number of plants, including their pollens. The plants are not necessarily related to each other by family. Each panallergen performs a specific function in the various plants. Many panallergens are defense-related proteins, which provide a plant with resistance to stresses such as infections, harsh growing conditions and exposure to some types of chemicals. Under stress conditions, the defense-related proteins increase.28) An association between the so-called "celery-mugwort-spice syndrome" and allergy to mango fruit has been described in the literature. This syndrome involves cross-reactions among mango fruit, mugwort pollen, birch pollen, celery, and carrot and cannot be explained as a sensitization connected by botanic relation, as these plants belong to different botanical families. It is, however, posited that the association is based on allergens related to Bet v 1 and Art v 1, the major allergens of birch and mugwort pollen respectively.9,29,30 Of birch pollen-allergic individuals, 10-15% may also be allergic to mango and other foods such as litchi, banana, orange, apple, pear and carrot. This can be attributed to an allergen that is common to these foods and birch pollen. This is thought to be a 35kDa minor birch pollen allergen.29 Chitinase is one of the important panallergens that contribute to latex-fruit syndrome. Latex-allergic individuals are at a high risk of having a concominant allergy to foods such as mango, papaya, avocado, banana, chestnut, passion fruit, fig, melon, kiwi, pineapple, peach and tomato.13 An allergy to mango as a result of cross-reactivity to latex has been more frequently reported than an allergy to mango alone.3,4 It has been suggested that putative class I chitinases, specifically, are the proteins responsible for these cross-reactions.31 Chitinases are defense proteins, i.e., they are usually activated by stress to the plant. They break down chitin, the structural components of insect exoskeletons and cell walls of fungi. Considering the high degree of structural similarity among chitinases from different plant species, one would suspect individuals with this syndrome to be sensitized to most foods containing class I chitinases. However, this is not the case for foods such as legumes and cereal flours. They are rarely associated with latex allergy.32 This may be due to the fact that these foods are usually heated before being consumed: it has been found that the allergic activity of class I chitinases is lost by heating (i.e., they are heat-labile).32 There has been a report of an allergy to mango and latex in the same individual, without there being any cross-reactivity. The person was allergic to different allergens present in latex and mango respectively.3 How is mango allergy diagnosed? A diagnosis of mango allergy is normally made quite easily through a dietary history. The fruit is usually eaten on its own and is unlikely to be mistaken for another food. However, skin prick tests have been successfully performed using fresh mango juice4 and fresh mango pulp.3 Accurate skin tests are more frequently performed using the fresh fruit than using extracts, because of the lability of the antigen involved. Also, the fruit pulp is more suitable for skin testing than the peel.1 RAST tests are also available.3 Because the diagnosis is usually quite straightforward, there is generally little need for oral challenges.

Management
Avoiding mango in the diet is usually quite easy, barring a few sources of hidden allergens such as meat tenderizers and some oriental dishes. But mango-allergic individuals should be warned about possible cross-reactivity. They may become sensitized to cross-reacting foods and other substances such as latex.

For more information on this subject and other allergy and intolerance related topics, visit:
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D. References
1. Jansen A, de Lijster de Raadt J, van Toorenenbergen AW, van Wijk RG. Allergy to pistachio nuts. Allergy Proc. 1992;13(5):255-8.
2. McGovern TW, LaWarre S. Botanical briefs: the mango tree--Mangifera indica L. Cutis. 2001;67(5):365-6.
3. Duque S, Fernandez-Pellon L, Rodriguez F. Mango allergy in a latex-sensitized patient. Allergy. 1999;54(9):1004-5.
4. Miell J, Papouchado M, Marshall AJ. Anaphylactic reaction after eating a mango. BMJ. 1988;297(6664):1639-40
5. Geroso AM, Elpern DJ. Some observations on mango and mokihana dermatitis from Hawaii. Contact Dermatitis. 1992;26(5):346-7
6. Garcia F, Moneo I, Fernandez B, Garcia-Menaya JM, Blanco J, Juste S, Gonzalo MA. Allergy to Anacardiaceae: Description of cashew and pistachio nut allergens.
7. Vargas Correa JB, Sanchez Solis L, Farfan Ale JA, Noguchi H, Moguel Banos MT, Vargas de la Pena MI. Allergological study of pollen of mango (Magnifera indica) and cross reactivity with pollen of piru (Schinus molle). [Spanish] Rev Alerg. 1991;38(5):134-8
8. Fernandez C, Fiandor A, Martinez-Garate A, Martinez Quesada J. Allergy to pistachio: crossreactivity between pistachio nut and other Anacardiaceae. Clin Exp Allergy. 1995;25(12):1254-9.
9. Paschke A, Kinder H, Zunker K, Wigotzki M, Steinhart H, Wessbecher R, Vieluf I. Characterization of cross-reacting allergens in mango fruit. Allergy. 2001;56(3):237-42
10. Kinder et al. IgE-Binding Patterns and Allergenicity of Mango Fruit Varieties. Internet Symposium on Food Allergens 1999;1(2):43-49.
11. Goldberg LC. Mango dermatitis. J Am Med Assoc. 1954;156(10):954
12. Kahn IS. Fruit sensitivity. South Med 1942;35:858-859
13. Brehler R, Theissen U, Mohr C, Luger T. "Latex-fruit syndrome": frequency of cross-reacting IgE antibodies. Allergy. 1997;52(4):404-10
14. Pumhirun P, Towiwat P, Mahakit P. Aeroallergen sensitivity of Thai patients with allergic rhinitis. Asian Pac J Allergy Immunol. 1997;15(4):183-5.
15. Dang RW, Bell DB 2nd. Anaphylactic reaction to the ingestion of mango. Case report. Hawaii Med J. 1967;27(2):149-50
16. Rubin J, Shapiro J, Muehlbauer P, Grolnick M. Shock reaction following ingestion of mango. JAMA 1965;193:391-398
17. Lampe KF. Dermatitis-producing Anacardiacea of the Caribbean area. Clin Dermatol 1986;4:171-182
18. Amlot PL, Kemeny DM, Zachary C, Parks P, Lessof MH. Oral allergy syndrome (OAS): symptoms of IgE-mediated hypersensitivity to foods. Clin Allergy 1987; 17:33-38.
19. Ortolani G, Ispano M, Pastorello EA, Ansaloni R, Magri A. Comparison of results of skin prick tests (with fresh foods and commercial extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989; 83: 683-690.
20. Liccardi G, D'Amato M, D'Amato G. Oral allergy syndrome after ingestion of salami in a subject with monosensitization to mite allergens. J Allergy Clin Immunol 1996;98:850-2.
21. Zakon SJ. Contact dermatitis due to mango. JAMA 1939;113:1808
22. Hurtado I. Poisonous Anacardiaceae of South America. Clin Dermatol 1986;4:183-190
23. Folster-Holst R, Hausen BM, Brasch J, Christophers E. Contact allergy caused by poison ivy (Toxicodendron spp.) [German] Hautarzt. 2001;52(2):136-42.
24. Ippen H. Contact allergy to Anacardiaceae. A review and case reports of poison ivy allergy in central Europe. [German] Derm Beruf Umwelt. 1983;31(5):140-8
25. Rosen T, Fordice DB. Cashew nut dermatitis. South Med J 1994;87(4):543-546.
26. Marks JG Jr, DeMelfi T, McCarthy MA, Witte EJ, et al. Dermatitis from cashew nuts. J Am Acad Dermatol 1984;10(4):627-631.
27. Yman L. Botanical relations and immunological cross-reactions in pollen allergy. 2nd ed. Pharmacia Diagnostics AB. Uppsala. Sweden. 1982: ISBN 91-970475-09
28. Yagami T. Allergies to cross-reactive plant proteins. Latex-fruit syndrome is comparable with pollen-food allergy syndrome. Int Arch Allergy Immunol. 2002 Aug;128(4):271-9.
29. 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 Dec;35(4):348-55
30. Wüthrich B, Hofer T. Food allergy: the celery-mugwort-spice syndrome. Association with mango allergy? [German] Dtsch Med Wochenschr. 1984 Jun 22;109(25):981-6
31. Diaz-Perales A, Collada C, Blanco C, Sanchez-Monge R, Carrillo T, Aragoncillo C, Salcedo G. Cross-reactions in the latex-fruit syndrome: A relevant role of chitinases but not of complex asparagine-linked glycans. J Allergy Clin Immunol. 1999;104(3 Pt 1):681-7.
32. Sanchez-Monge R, Blanco C, Perales AD, Collada C, Carrillo T, et al. Class I chitinases, the panallergens responsible for the latex-fruit syndrome, are induced by ethylene treatment and inactivated by heating. J Allergy Clin Immunol 2000;106(1 Pt 1):190-5.

2. True or false: Adverse reactions can occur after ingestion of but not on contact with mango fruit.
(a.) True
(b.) False

3. What type of symptoms have been associated with mango allergy?
(a.) Skin manifestations
(b.) Intestinal symptoms
(c.) Respiratory symptoms
(d.) All of the above

4. What possible explanation is given for mango dermatitis being more common in visitors to Hawaii, and in those that moved there from the United States mainland, than in those born locally?
(a.) The locally born are immunologically tolerant to urushiol.
(b.) The locally born have early contact with poison ivy and poison oak.
(c.) The mainland-born have early oral contact with mango.
(d.) None of the above

5. Which is the proposed mechanism of action of severe mango allergic reactions?
(a.) IgE-mediated reaction
(b.) Non-IgE-mediated reaction
(c.) IgG-mediated reaction
(d.) Intolerance reaction

6. Where symptoms occur after oral ingestion of mango: which of the following groups is mango fruit least likely to cross-react with?
(a.) Cashew and pistachio nuts
(b.) Celery, mugwort and carrot
(c.) Birch pollen, litchi and banana
(d.) Latex, papaya and avocado

7. True or false: An allergy to mango as a result of cross-reactivity to latex has been less frequently reported than an allergy to mango alone.
(a.) True
(b.) False

8. Which of the following is true regarding diagnosis of mango allergy?
(a.) Fresh mango juice and fresh mango pulp can be used in skin prick testing.
(b.) Accurate skin tests are more frequently performed using mango extracts than when using the fresh fruit.
(d.) Mango peel is more suitable for skin testing than mango pulp.
(e.) There is no mango RAST test.