f49 Apple

Apple is one of the most popularly cultivated and consumed fruits globally. It belongs to the family Rosaceae and the genus Malus. Apples are widely cultivated in temperate and cool regions. Fruits from the family Rosaceae are well-known causative agents of foodborne allergies. Symptoms of apple allergy occur on direct consumption of apples or through indirect contact with the fruit, such as eating food containing apples or traces of apples left in unclean utensils, etc. Allergy to apple manifests itself majorly as Oral Allergy Syndrome (OAS) with swelling and itching of oral mucosa in throat, lips, itching in the eyes, etc., as allergic rhinitis and asthma in others, and even as severe systemic symptoms like anaphylaxis in some people.

There are four major apple allergens: Mal d 1, Mal d 2, Mal d 3 and Mal d 4. Allergy to apples shows a close relationship with birch pollinosis since Mal d 1 shows a high-level of cross-reactivity with the major birch pollen allergen, Bet v 1. Mal d 2 shows cross-reactivity with another birch pollen allergen Bet v 2. In Europe, more than 70% of patients allergic to birch pollen show sensitivity to apples. In Mediterranean countries with no birch pollinosis, apple allergy is attributed to Mal d 3. A significant cross-reactivity is seen between apples and other members of the Rosaceae family and also with kiwi, grapes, birch pollen and group 4 grass pollen allergens. Moreover, mature apples are found to be more allergic than freshly picked apples.

Sensitive individuals are advised to avoid high allergenic varieties of apples and should maintain basic hygiene around themselves to prevent the onset of apple allergy symptoms.

Worldwide distribution

Food allergy is a widespread phenomenon, commonly seen in both children and adults. Allergy to various fruits of the family Rosaceae is frequently seen. The very first clinical account of allergy to apples originated from northern and central Europe (9).

In Mediterranean countries, where birch pollinosis doesn’t exist, non-specific Lipid Transfer Proteins (nsLTPs) are responsible for allergy to fruits. Mal d 3 is a well- known nsLTPs in apple and allergy to nsLTPs- containing fruit is prevalent in Mediterranean countries (2, 10).

In the Central region of Spain, allergy to apples is associated with grass pollinosis with 82% of patients showing severe systemic symptoms (11).

In a region-specific study with 1139 patients, with some kind of known food hypersensitivity, from Russia, Lithuania, Estonia, Sweden, and Denmark, almost 40% of patients showed hypersensitivity reactions to apples, with the maximum being from Sweden and Denmark (12).

Allergy to Mal d 2 was found prevalent in 75% apple-allergic population in the US, 15% in Spain and Italy, and 5% in Austria and the Netherlands (13).

Risk factors

Allergy to apples is commonly seen in association with birch pollinosis. More than 70% of individuals with birch pollen sensitivity develop allergic sensitization to apples. 

Various other factors like apples used as an ingredient in eatables coming in contact with fruit indirectly through kissing or using utensils which has traces of apple left in them can cause anaphylactic reactions in such patients. Such ‘hidden’ allergic reactions are less common than consuming the apples directly but have been widely reported (14). 

Pediatric issues

Allergy to apples is very well-studied in pediatric populations.  A study was conducted on  24 children between 3-15 years of age (14 males, 10 females) with bronchial asthma,  to assess the food items that can cause aggravation of asthma and it showed that majority of the children (21 children out of 24 i.e. 88%)  had raised specific IgE titers against apple (15, 16).  Salgado et al. in 2017 studied the reaction of apple-dependent exercise-induced anaphylaxis in the pediatric population.  Even though such food-dependent exercise-induced anaphylaxis is rarely reported in children, they found three such cases with apple (16).

Living environment

Restricted production of apples is seen in tropical regions, semi-arid regions, and regions with inadequate winters, heat stress, and sunburn (1, 5). Short-season apple cultivars are produced well in colder regions, like Canada, while long-season cultivars like grow well in the southern hemisphere with milder climatic conditions (1, 6).

Apple varieties have naturalized globally, and in North America, they are even seen growing in abandoned lands, roadsides, and on wood borders (1, 17).

Worldwide distribution

Apple is one of the most cultivated fruits in Europe (13). The species Malus x domestica is known to have originated in Central Asia, in Almaty, Kazakstan. Twenty-four species of Malus are now distributed in Central and Eastern Asia, North America, and Europe. It was then introduced and naturalized to the West through Persia (3).

The leading producers of apples today include the US, China, India, Turkey, Poland, France, Italy, and Iran. Huge apple production for export to the northern hemisphere is seen in regions of South America like Brazil, Chile, Argentina, Australia, New Zealand, and Africa (1).

Main

Allergic reaction to apples occurs upon direct consumption of the fruit (8).

Secondary

Indirect exposure to apples through kissing, using utensils used for apples, and consuming eatables like ice-cream, desserts, pies that contain apple can manifest an allergic reaction in sensitized individuals (14).

Allergic rhinitis

Many patients with apple allergy exhibit respiratory symptoms like rhinoconjunctivitis, asthma, and dyspnoea (8, 10).

Other diseases

• Oral Allergy Syndrome (OAS)

Cross-reaction hypersensitivity to apples major allergen (Mal d 1) is seen majorly in patients (> 70%) with birch pollen allergy.  Symptoms like itching and swelling of the lips, throat, tongue, also referred to as oral allergy syndrome symptoms, occur within minutes of consuming apples(8). OAS is manifested locally, although can sometimes be systemic when apples come in close contact with the mucosal lining of the sensitive individuals (18).

The first apple allergy was reported in patients with AR complaining of itchiness, swelling, and tingling in of tongue, throat, and lips, wheezing, and irritation in the eyes upon apple consumption (2).

•  Systemic reactions

The most common symptoms reported to Mal d 3 allergy include diarrhea, vomiting, urticaria, hypotension, asthma, and even anaphylaxis (10).

A case of a 12-year old male with itching on the face, erythema, and lesions with wheals extended to the trunk after consuming apples was reported. Two weeks later the patient showed generalized urticaria, persistent cough, and labial angioedema and was diagnosed with hives and dyspnea (19).

Formation of blisters and ulcers was reported in a 48-year old woman with allergic symptoms. She had a history of gingival swelling after the consumption of fresh raw apples. She showed a negative skin prick test (SPT) but a positive oral challenge test to apples and apple was considered to be responsible for this food allergy (20).

Prevention strategies

• Avoidance

Avoidance of high -allergenic risk varieties of apples can prevent severe reactions from allergy. Individuals prone to apple allergy should be aware of the ingredients used in foods they eat, use clean surfaces and utensils every time, and avoid unnecessary human touch (14).

Mal d 1, the major apple allergen responsible for OAS, is heat labile, and hence, patients show better tolerability to cooked than raw forms (2, 21).

Allergenic molecules

Four different allergens have been identified and characterized in apples.

1. Mal d 1: Mal d 1 is the major allergen in apple. It’s a 17.5 kDa protein concentrated more in pulp than peel of the fruit (8). Mal d 1 allergy is mostly seen in central and northern Europe (2).
2. Mal d 2: a 31 kDa, thaumatin-like protein (TLP) homologue, present in 5-18% patients (2, 22).
3. Mal d 3: a 9 kDa, non-specific lipid transfer protein (nsLTPS) and highly stable, more prevalent in Mediterranean regions, restricted to peel (2, 10).
4. Mal d 4: 14kDa profilin, more prevalent in Southern Europe, present in 10-40% allergic patients (2, 22).

An apple allergen of size between 40-45kDa was found in apples, with 71% patients sensitive to it. It was identified as a glyceraldehyde--3-phosphate dehydrogenase, a known potent allergen of wheat flour (23).

The four major allergens (Mal d 1, Mal d 2, Mal d 3, Mal d 4) characterized in apples have been reported in different regions showing variety of clinical symptoms. Mal d 1, the major allergen in apples, is more prevalent in northern and central Europe while Mal d 3 and Mal d 4 are widespread in Mediterranean regions of Southern Europe (2).

Biomarkers of severity

Mal d 1 is the allergenic marker responsible for apple allergy in a patient sensitive to birch pollen (2). Lipid Transfer proteins (LTPs) are allergenic markers to apples and not birch pollen, suggesting that allergens of birch pollen cross-react with apple but not vice-versa and not all patients sensitive to apple allergy are sensitive to birch pollinosis (18). Studies have shown that apple allergy without birch pollinosis results in severe symptoms (11).

Cross-reactivity

Pollen-related food allergy accounts for major allergy cases in Europe. More than 70% patients allergic to birch-pollen exhibit allergy to various birch pollen-related foods, including apples because of high-level cross-reactivity between major birch pollen allergen, Bet v 1 and Mal d 1 in apples (24). Mal d 1 shows 64.5% amino acid sequence identity and 55.6% nucleic acid sequence identity to Bet v 1 (25). Almost 50-75% of patients allergic to birch pollen show oral allergic symptoms after consuming apples (2) and Mal d 1 in apples is responsible for this birch pollen-related food allergies (8).  Mal d 2 shows structural homology with another birch pollen allergen, Bet v 2 (18).

As many as 57% patients with known OAS symptoms due to apple allergy reacted to Bet v 1, about 20% polysensitized patients showed reactivity to Bet v 2, 35% patient showed IgE reaction to both (26).

In a study conducted in Sapporo, Japan, it was found that 61% patients with birch pollinosis showed cross-allergy with fruits and vegetables, out of which apple was the most prevalent one (97%) (27).

Cross-reactivity is also seen between apple allergens and a minor birch pollen allergen, Bet v 6, which shows high similarity to phenylcoumaran benzylic ethyl reductase (28).

Cross-reactivity of group 4 grass pollen allergen, Phl p 4,  was shown in birch pollen, mugwort, apples, carrots, celery root and peanut (29).

Cross-reactivity of apples to kiwi and grapes has also been shown (30, 31). Mal d 2 of apple shows cross-reactivity with Pru av 2 of cherry. A homology of 90% is seen between LTPs of apple and cherry (32). In a  study by Marzban et al. (2006) allergenicity to apples was attributed to the expression of Mal d 1, Mal d 3 and their homologues in the Rosaceae pollen (33).

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Fabio Iachetti

Last reviewed: October  2020