Table of Contents

Whole Allergen

f202 Cashew nut

f202 Cashew nut Scientific Information

Type:

Whole Allergen

Display Name:

Cashew nut

Route of Exposure:

Ingestion

Family:

Anacardiaceae

Species:

Anacardium occidentale

Latin Name:

Anacardium occidentale

Other Names:

Cashew

Summary

Cashew is a tropical, evergreen tree that belongs to Anacardiaceae family. It is a very versalile crop that grows commercially in many parts of the world. The unique features of this tree are its fruits that consists of a pseudofruit (cashew apple), which develops as a yellowish-red swollen peduncle and a true fruit, that evolves enclosing a kidney-shaped nut inside a double hard shell, growing at the end of the apple. This hard shell consists of toxic oily fluid, containing allergenic phenolic molecules inside it, however the kernels/nuts are protected from this toxic oil by a film. Cashew nuts are consumed, either in raw or roasted form, as snacks or used in butter, sweets, confectionery items, chocolates, and ice-creams. Cashews are salt-loving species, that prefer growing in warm and humid climate with optimum temperature ranging from 22 to 32℃. Oral ingestion or direct contact with skin/mucosa are the two routes of cashew nut exposure causing allergic reactions in individuals. These allergic reactions include skin lesions (urticaria and angioedema), gastrointestinal symptoms (abdominal pain and vomiting) and even anaphylaxis. Furthermore, atopic conditions, like asthma, allergic rhinitis, rhino-conjunctivitis and atopic dermatitis may also be observed. Importantly, the major food allergens found in cashew nuts are Ana o 1, Ana o 2 and Ana o 3. Extensive cross-reactivity has been reported between cashew nuts and pistachio, and to some extent with other tree nuts, such as hazelnut, walnut and peanut, and also with citrus seeds.

Allergen

Nature

Anacardium occidentale, also referred to as cashew, is a tropical, evergreen, large tree that belongs to the family Anacardiaceae (1). This tree grows to a height of about 5 to 14 m, with the canopy as wide as 20 m. The trunk is usually short with branches close to the ground and having 3 to 14 leaves, that are spirally arranged on each stem. The leaves are elliptical-to-oblong in shape with smooth margins. The root system (taproots and lateral roots) is deep and can spread laterally for up to 300 cm and vertically about 100 cm. The male or hermaphrodite flowers are usually in clusters, with about 200-1600 flowers in one panicle. Flowers appear at the end of the offshoots, during the vegetative flush period (30-60 days) near the margin of canopies (2).

The fruits of this tree are unique as it consists of an accessory fruit or pseudofruit (cashew apple) and a true fruit (drupe containing cashew nut) (2). The cashew apple (pear or oval shape) develops as a yellow or red swollen peduncle (5-11 cm in length) with a juicy pulp having a sweet fragrance. The true fruit evolves enclosing a kidney-shaped nut (actually a seed) inside a double hard shell, growing at the end of the apple (1, 2). This shell consists of an outer leathery epicarp enclosing spongy, honeycombed mesocarp, which is filled with toxic oily fluid (cashew nut shell liquid) containing allergenic phenolic molecules, like anacardic acid, cardol or methyl cardiol (1-4). This oily liquid is used in several industries to produce different resins, paints, adhesives, polymers, brake liners, surface coatings as well as insecticides, fungicides or pesticides (5). The nut/seed/kernel/almond grown inside the hard shell is protected from the toxic oil by a film. (3).

The cashew nuts are highly consumed globally, either in raw or roasted form, as snacks or added in different kinds of butter, sweets, confectionery items, chocolates, and ice-creams. They are widely used in Indian, Chinese as well as in Thai cuisines (1, 6). Furthermore, these nuts are also used in medicines, while the cashew tree wood is used for firewood (5).

Habitat

Cashew nut is a versatile crop that grows commercially in many parts of the world. (5). The tree can grow in a variety of soils; however, it favors fertile soil that is well-drained, deep, sandy, laterite/rocky-textured, containing large amounts of organic content. The optimal pH of the soil required for the growth of the tree ranges between 4.5 to 7.3, with sensitivity towards variation in temperature (7).

Cashew is a salt-loving plant species, that prefers growing in a warm and humid climate with optimum temperature ranging from 22 to 32℃ (3). The annual rainfall requirement ranges between 1000 and 3000 mm. The specialty of the plant is that, with very minimum care required, it produces about 50-75 kgs of cashew apples and nuts, every year (per tree). The life of cashew trees is around 50 to 60 years and usually begin to bear fruits within 3 to 5 years (5).

Taxonomy

The genus Anacardium consists of nine species, with A. occidentale being one of the most important ones. All the nine species are native to South America and produce edible nuts with some cross-reactivity among themselves. These are A. occidentale (A. microcarpum), A. giganteum (wild cashew), A. humile (A. pumilum), A. excelsum (A. rhinocarpus), A. othonianum, A. spruceanum, A. corymbosum, A. negrense and A. nanum. The most closely-related species to A. occidentale are A. giganteum and A. humile with some degree of cross-reactivity among its allergens (1).

Taxonomic tree of cashew nut (8)
Domain	Eukaryota
Kingdom	Plantae
Phylum	Spermatophyta
Subphylum	Angiospermae
Class	Dicotyledonae
Order	Sapindales
Family	Anacardiaceae
Genus	Anacardium
Species	Anacardium occidentale

Tissue

Cashew nuts have been found to produce severe allergic reactions on ingestion and three of its proteins, namely Ana o 1, Ana o 2 and Ana o 3 have been identified as having allergenic potential (1).

Epidemiology

Worldwide distribution

Allergy to cashew nuts (Anacardium occidentale) is a typical Immunoglobulin (Ig) E-mediated allergic disorder being reported from the United States, Australia, and Europe, and sparsely from Asia and Africa (1).

The Pronuts study was a multicenter, European study (London, Geneva, and Valencia) that reported the cashew nut allergy in 34.4% (42 of 122) of nut-allergic individuals, with significantly varying prevalence in all three centers (p<0.001). Also, it was considered to be an index nut among the allergic children included in the study (9). Besides, cashew nut-induced allergy was reported in 42.3% of East Mediterranean children with tree-nut/peanut allergy (96 out of 227) (10).

In a 10-year study conducted in Sweden, the prevalence of allergic reactions caused by cashew nut was reported to be 6% (20 out of 352 cases) (11). In a study conducted in Finland, the results revealed the prevalence of cashew sensitization in tree-nut-allergic subjects, with and without birch sensitization to be 28% (n=842) and 12% (n=909), respectively (12). In addition to this, reports are available from Asian countries as well. A prospective, cohort study conducted in Israel reported clinical allergy to cashew nut in 65.6% of cashew-nut-sensitized allergic individuals (40 out of 61) (13), while a study from Taiwan reported 18.9% cases of sensitization to cashew nut among 339 food-sensitized cases (14).

In two studies conducted in the Netherlands, one study showed positive double-blind placebo-controlled food challenge (DBPCFC) test in 76.5% of cashew-sensitized children (137 out of 179) (15), while in the other study, positive DBPCFC to cashew was reported in 17.3% of food-allergic children (n=734) (16). Furthermore, a study conducted in Japan showed 18.2% of cashew-sensitized children having positive results towards oral food challenge (OFC) to cashews (17).

Recently, OFC-confirmed cashew nut allergy was also reported by two studies from Australia. The first, HealthNuts study performed in 3232 children (6 years), reported the prevalence of challenge-confirmed cashew nut allergy to be 2.7% (18), while the second study reported positive cashew OFC in 62% of the community cohort (n=145) and 20% of clinic cohort (n=386) in Australia (19).

Interestingly, in a prospective study conducted in Leicester (United Kingdom), cashew nut allergy was reported to be 27.4% in South Asian and 10.6% in the White (European origin) population. The study demonstrated that the Asian population was more sensitized towards cashews as compared to the Europeans (20). Further, in a retrospective study conducted in Turkish children, cashew was considered as an allergen in 13.5% of subjects with food allergy (123 out of 912) and 8% of patients with atopic dermatitis (AD) (n=1140) (21). Studies from China also reported cashew as an ingested allergen in 17.8% of patients with allergic rhinitis (AR) and asthma (55 out of 309) (22) and 8.1% of patients with urticaria (88 out of 1091) (23).

A retrospective study conducted in South Korea reported that the prevalence of cashew nut allergy was found to be 4.8% in pediatric patients with anaphylaxis induced due to peanuts, tree nuts and seeds (6 out of 126) (24). Furthermore, cashew was found as one of the important allergens (23%) that could be responsible for food-anaphylactic reactions in a study involving preschool children in France (n=325) (25).

Furthermore, significantly higher sensitization to cashew nuts in males than in females (p<0.01) and in adults (>18 years) than in children (p<0.01) was observed in a study conducted in China, where specific-IgE to cashew nut was found in 8.5% (1320 of 15,534) of patients with suspected allergic diseases (26).

Environmental Characteristics

Worldwide distribution

The discovery of cashew nut in Brazil dates back to the sixteenth century, which was then introduced into India as well as Africa (5). Furthermore, the major continents involved in the production of cashew nuts, across the globe are Asia, Africa and South America. Cashew nuts have reportedly been produced in large quantities in many countries of these continents, including India, Vietnam, Tanzania, Indonesia, Nigeria, Cote d'Ivoire, Mali, Philippines, Guinea Bissau, Benin, Burkina Faso, Ghana, Mozambique and Brazil (1, 5). Currently, India (671000 tons), Vietnam (1,221,070 tons), Nigeria (958,860 tons) and Cote d’Ivoire (607,300 tons) have the major contribution of cashew nuts (3).

Route of Exposure

Main

Oral ingestion of cashew nuts may induce severe allergic reactions, including skin lesions (urticaria and angioedema), gastrointestinal symptoms (vomiting and pain in the abdomen), and even anaphylaxis (1). Furthermore, atopic conditions, such as asthma, allergic rhino-conjunctivitis as well as atopic dermatitis may also be observed on cashew nut ingestion (27).

Secondary

Direct contact with skin or mucosa could be another route of cashew nut exposure causing allergic reactions in individuals. This was found in a study conducted on 55 cashew-allergic patients, which reported 18% (10 of 55) of patients showing allergic reactions by cashew exposure through skin or mucosa (28).

Clinical Relevance

Severe allergic reactions and Anaphylaxis

Cashew nuts allergy are generally associated with severe reactions, i.e. initially manifested as skin reactions, which are followed by respiratory, gastrointestinal, and even systemic allergic reactions, such as anaphylaxis (1).

In a study conducted in The Netherlands among 137 suspected cashew-allergic children, positive to DBPCFC test, the majority of them reported gastrointestinal symptoms (72%), followed by oral allergy (64%), skin (urticaria: 21%, angioedema: 27%) and respiratory symptoms (upper airway: 15%, lower airway: 7%) (15). In a study conducted in Sweden among 46 cashew-allergic patients confirmed by DBPCFC, allergic reactions such as skin, gastrointestinal and respiratory reactions were reported in 91%, 61% and 11% of patients, respectively (29).

A retrospective analysis conducted on 52 cashew nut-allergic patients in Singapore reported severe allergic reactions, with cutaneous being the most prominent (71.2%), followed by gastrointestinal and respiratory reactions in 44.2% and 30.8%, respectively. Anaphylaxis was also reported in 3.8% of patients (30). Furthermore, in a study conducted in Japan, the challenge-positive cashew-allergic children (n=12) reported gastrointestinal symptoms as the most common allergic symptoms (91.7%), followed by skin (58.3%), respiratory (50%), neurological (25%) and cardiovascular symptoms (8.3%). In this study, anaphylaxis was also reported in 41.7% of children (17).

A study conducted in Australia among 90 children with positive cashew-OFC, reported angioedema in 61.1%, skin reactions in 60%, oropharyngeal symptoms in 48.9%, respiratory reactions in 13.3% and gastrointestinal symptoms in 35.6% of children (19).

In the European Anaphylaxis Registry that compiled data of 1970 patients (<18 years) between the year from 2007 to 2015, cashew nut was found to be an elicitor in 7.1% (78 out of 1092) of patients with anaphylaxis due to food. Furthermore, based on age group, cashew was found as an important elicitor of anaphylaxis in pre-school children (<6 years) (58 out of 78; 74.3%) when compared to other age groups (6 to 12 years: 21.7% and 13 to 17 years: 3.8% ) (31). Similarly, a retrospective study reported cashew to be responsible for 44% of tree-nut-induced anaphylaxis in preschool children (11 out of 25) (32).

Allergic rhinitis

In a prospective cohort study involving 112 children with a history of pistachio and/or cashew nut allergy, AR was reported in 13.3% of children with a history of cashew allergy (4 out of 30) (27). Furthermore, in a retrospective study conducted on 55 cashew nut-allergic Irish patients, AR was reported in 65% of patients (28), whereas it was reported to be 42.2% in 64 cashew-sensitized patients in another retrospective study conducted in Taiwan (14).

Asthma

In a study conducted in the Netherlands, asthma was reported to be 31% in cashew nut-sensitized children (55 out of 179) (15). In two studies conducted in France among 52 and 51 cashew nut-allergic children, asthma was reported in 44.2% and 41.2% of children, respectively (33, 34). Furthermore, in a retrospective study conducted in Ireland among 55 cashew nut-allergic patients, asthma was reported in 44% of patients (28), while it was reported to be 12.5% in 64 cashew-sensitized cases, in another retrospective study conducted in Taiwan (14).

In a study conducted in Japan among 66 cashew-sensitized children, 45.5% of patients were reported having bronchial asthma (17). Furthermore, asthma was reported in 46.7 % of children with a history of cashew allergy (14 out of 30) in a prospective study conducted in Turkey (27).

Atopic Dermatitis

In a study conducted in the Netherlands, AD was reported to be 39% in cashew nut-sensitized children (70 out of 179) (15). Two studies conducted in France showed AD in 73.1% (n=52) and 60.8% (n=51) of cashew nut-allergic children (33, 34).

In a study conducted in Ireland among 55 cashew nut-allergic patients, AD was found in 76% of patients (28). Furthermore, in a prospective study conducted in Turkey, AD was reported in 56.3% of children with a history of cashew allergy (9 out of 16) (27). In another study conducted in Japan among 66 cashew-sensitized children, 75.8% of children reported AD (17).

Furthermore, contact dermatitis has been observed in cashew-nut workers who may have been sensitized to cardol present in cashew nut shell liquid. It has been reported that these workers might have come in contact with the nut shells before heating and would have developed irritant reactions (35). This was further observed in 294 patients with contact dermatitis, where a positive reaction to cardol patch test was observed in 8.3% of patients in Brazil (36).

Rhino-conjunctivitis

In two studies conducted in France among 52 and 51 cashew nut-allergic children, rhino-conjunctivitis was reported in 32.7% and 33.3% of children, respectively (33, 34). While in a study conducted in Japan among 66 cashew-sensitized children, 22.5% of children reported allergic conjunctivitis (17).

Diagnostics Sensitization

Challenge test

Oral food challenge (especially double-blind placebo-controlled food challenge test) may be considered as a gold standard for diagnosing allergy related to cashew nut. However, it is very time-consuming, expensive and generally associated with the risk of developing severe reactions (6).

Prevention and Therapy

Allergen immunotherapy

A randomized, controlled, Phase 2 trial evaluating oral immunotherapy with cashew among 34 patients, demonstrated desensitization among all the patients with a tolerance of a dose of ≥1 g at the end of Week 30 (37). This desensitization was found to be associated with the IgG4 reactivity towards the cashew allergens in the patients (38).

Prevention strategies

Avoidance

Allergies to tree nuts are commonly being observed, that may become severe in certain individuals, hence it is generally advised to avoid consumption of tree nuts or the food products containing them (39). Furthermore, it has been suggested to avoid consumption of pistachios in individuals with allergy to cashew nuts as they are botanically closely-related foods and exhibit extensive cross-reactivity (1, 6)

Molecular Aspects

Allergenic molecules

To date, 3 allergenic molecules have been identified, characterized and published officially by the World Health Organization (WHO) and International Union of Immunological Studies (IUIS) Allergen Nomenclature Sub-Committee for cashew nut. Among the three cashew nut allergenic proteins, Ana o 1 and 2 are the seed-storage proteins that belong to the cupin superfamily, whereas Ana o 3 belongs to the prolamin superfamily (1, 40). The table below provides detailed information on each of the allergenic protein identified by WHO/IUIS as of 26 January 2021:

Name of allergen	Isoallergen	Biochemical name	Molecular weight (kDa)	Allergenicity
Ana o 1	Ana o 1.0101	7S Vicilin-like protein	50	Major allergen (1). Immunoblot assay showed 50% of patients having IgE binding to rAna o 1 (10 out of 20) (41). Ana o 1 was able to inhibit the IgE-binding to Ana o 3 (minor cross-reactivity) (1).
Ana o 1	Ana o 1.0102	7S Vicilin-like protein	50
Ana o 2	Ana o 2.01	11S Legumin-like protein	55	Major allergen (1). On immunoblot, 62% of cashew-allergic sera were found reactive (13 out of 21) (42).
Ana o 3	Ana o 3.01	2S albumin	14	Major allergen (1). On immunoblot, 81% of cashew-allergic sera were found reactive (21 of 26) (43).

kDa: kilodaltons, IgE: Immunoglobulin E

It has been reported that different processing techniques, such as g-irradiation and frying, blanching, microwave and autoclaving, may not be able to produce any effect on the allergenicity of the three allergens. However, it has been found that roasting at 200℃ for about 15 mins could slightly reduce the allergenicity of Ana o 1 and Ana o 3, while could increase the allergenicity of Ana o 2. Furthermore, sodium sulfate treatments have been shown to damage the Ana o 3 secondary structure (44).

Biomarkers of severity

According to a study conducted among 52 cashew nut-allergic children in France, it was reported that even a low dose of cashew exposure could elicit severe reactions, independent of age or prior history (33).

Cross-reactivity

Among various nut allergies, a high correlation has been reported between cashew and pistachio, both serologically as well as clinically (9, 15). This strong association between them was further confirmed by positive DBPCFC to pistachio in 42 out of 46 patients (29). Further, cross-desensitization to pistachio was also shown in individuals with dual allergies through cashew oral immunotherapy (37, 45). The amino-acid sequence identity between cashew and pistachio nut allergens: Ana o 1 with Pis v 3, Ana o 2 with Pis v 2, and Ana o 3 with Pis v 1 has been found to be 78%, 80% and 70%, respectively (46).

Mango, sumac and pink peppercorn belong to the same family Anacardiaceae, as cashew and hence may likely carry the risk of potential cross-reactivity (46). However, sensitization to mango was found only in 21% of cashew-sensitized children in a study conducted in the Netherlands (15), while no cross-reactivity was reported in another study conducted in Spain (47). Furthermore, cross-sensitization between pink peppercorn, cashew and pistachio has been demonstrated in 76.2% (16 out of 21) of individuals by skin prick tests (48), while cross-reactivity was confirmed in two cases by serum-IgE analysis (49).

In a study conducted among 96 Turkish cashew-allergic children, the co-allergy rates of cashew with pistachio, walnut, hazelnut, almond and peanut were reported to be 82.3%, 44.8%, 64.6%, 15.6% and 28.1%, respectively (10). Similarly, in another study conducted on 40 cashew-allergic patients in Israel, the co-allergy rates of cashew with pistachio, walnut, hazelnut and pecan were found to be 65%, 50%, 15% and 35% respectively (13). A study conducted on 52 cashew nut-allergic patients in Singapore, reported 51.9% and 53.8% of patients to be either allergic or sensitized to pistachio and peanuts, respectively (30). Furthermore, the HealthNuts study performed in Australia reported co-allergy rates of cashew with pistachio, peanut, walnut, hazelnut, almond, macadamia, pecan, and Brazil nut to be 36.3%, 35.5% 14.5%, 22.6%, 8.9%, 5.6%, 3.2%, 2.4% and 35.5%, respectively (18). As per a study, cashew nuts were serologically cross-reactive with peanuts, however, 51.6% of peanut-allergic individuals consumed cashews (50).

Citrus seeds, such as lemon and orange seeds belong to the family Rutaceae, which are botanically related to the family of Anacardiaceae. Serological cross-reactivity among related proteins from citrus seeds and cashew has been found, however, the fruits do not cause allergic reactions in cashew-allergic patients, unless the citrus seeds are consumed (51). Another study conducted in Turkey demonstrated co-sensitization of cashew with citrus seeds, quince seeds, pomegranate, and apple as well as with raw potato in 42 cashew-allergic children (52). In a retrospective analysis, 52% of co-sensitization was reported between cashew and coconut, however, this co-sensitization was not significantly associated (p=0.02) (53).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Fabio Iachetti

Last reviewed: February 2021

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