Summary

Soybean, a legume species native to East Asia, is a rich and inexpensive source of proteins for both human and animal foods.

Soy is one of the “big eight”, a group of eight allergens responsible for 90% of all allergic reactions to foods. Processed food is an important source of hidden soy allergens, due to wide use for soy as a food additive. Fermented soy products such as soy sauce and miso are much less allergenic compared with tofu and soymilk.

Prevalence assessments of soy allergy applying measurements of objective clinical symptoms by double blind placebo controlled oral food challenge are rare. Studies on the worldwide prevalence of soy allergy have been summarized in a systematic review, concluding that 0.27% of the general population and 2.7% of atopic children are soy allergic if assessed by oral food challenge. Allergy with soy as the primary sensitizer is more common in children than in adults and by the age of 10 years approximately 70% of allergic children will outgrow their allergy. In adults, the most common cause of reaction to soy is cross-reactivity between Bet v 1 and the homolog in soy, Gly m 4. There is also cross reactivity between soy and other legumes, for example peanut.

Soy allergy can be diagnosed with the help of in vitro testing to allergen specific IgE, skin prick test and oral food challenge. Component testing can aid in determining if the reaction is due to a primary sensitization to soy or due to a cross reactivity.

The most common treatment of soy allergy is avoidance of soy products. The avoidance strategy should depend on the severity of the reaction and the reaction-eliciting dose.

Epidemiology

Worldwide distribution

Soy is one of the “big eight”, the eight allergens that are believed to cause 90% of all allergic reactions to food. Soy is consumed around the world and it is widely used as additive in processed foods, making these foodstuffs a common source of hidden soy allergen. Products such as soy milk and tofu have been shown to be more allergenic compared to fermented soy products like miso and soy sauce.

The exact prevalence of soy allergy is not known, because multiple factors such as allergy definitions, study populations, methodologies, geographic variation, ages, dietary exposure, and other factors influence the estimates. A comprehensive review of 40 papers published on soy allergy in children reports an oral food challenge proven prevalence of between 0 and 0,5% (0,27%) in the general population, between 0,4 and 3,1% (1,9%) in the population referred to the allergy clinic for evaluating food related problems and between 0 and 12,9% (2,7%) in atopic children. Another study reports an estimated rate in the USA of 0.4% in children and 0.3% in adults. IgE testing in a large cohort of approximately 13,000 German children (3 – 17 years) found allergen-specific IgE to soybean extract in 6.3% of the cohort and when sensitization in approximately 7,000 German adults was measured, a sensitization rate of 3.7% to soybean extract and 10.3% to the soybean allergen Gly m 4 was found.

Sensitization rates derived from IgE extract measurements may suffer from inaccuracies due to underrepresentation of the labile soybean allergens Gly m 4 in diagnostic soybean extracts. Hence, molecular diagnosis of soy allergy may give rise to other sensitization rates compared with extract testing.

Risk factors

The widespread cultivation, processing and consumption of soybeans in forms ranging from unprocessed to highly processed means that many individuals, from infants to adults, are exposed to some level of soy allergens.

Sensitization to soy frequently occurs in infants, and eczema is a major risk factor for food allergies.

In patients with birch pollen allergy sensitized to the PR-10 protein Bet v 1, more than 70% have variable degree pf cross-reactivity towards Gly m 4, the soybean PR-10 protein. Allergic symptoms after consumption of soy products occurs in about 10% of birch pollen sensitized patients.

Individuals such as freight or harbor workers involved in handling large quantities of unprocessed soybeans are at risk of heavy exposure to very large quantities of allergen. Inhalation of soybean dust under these special circumstances has been linked to epidemic outbreaks of inhalant allergies Occupational exposure to soy in the form of flour has also been shown to be a risk for asthma in bakers.

The soy-sensitized population at large is at risk of insidious exposure to soy components used as labeled or unlabeled ingredients/additives in food, pharmaceutical, cosmeceutical or other industrial products

Pediatric Issues

Soy allergy is one of the most common food allergies in children, although the precise prevalence of soy allergy in different populations is unclear, as different studies have used different measures of allergy.

Soy formula is one alternative formula used for infants with cow´s milk allergy. There is a concern for increased sensitization and soy allergy in infants fed with soy formula. In the EAACI Food and allergy and Anaphylaxis Guideline: diagnosis and management of food allergy from 2014, soy formulas are not recommended before 6 months of age. However, according to Katz et al. the prevalence of soy allergy after soy formula consumption is less than reported and therefore there is no use not to use soy formulas in infants under the age of 6 months with cow´s milk allergy.

A substantial proportion of children will outgrow their soy allergy. In a study by Savage, 69% of children had outgrown their soy allergy at the age of 10.

Route Of Exposure

Main

In infants, sensitization to the stable soy allergens Gly m 5, Gly m 6 and Gly m 8 may occur through oral exposure, or via the percutaneous route. Percutaneous sensitization is most likely to occur in children with atopic dermatitis where the skin barrier is compromised. Once sensitized, these individuals may experience allergic symptoms in multiple organ systems upon oral exposure to small quantities of the sensitizing allergen. These reactions can be severe, including anaphylaxis

Birch pollen sensitized individuals may experience oropharyngeal and mild to severe systemic symptoms after ingestion of partially processed soy products retaining significant quantities of intact Gly m 4 because of cross-reactivity with the birch pollen component Bet v 1. This is the most common type of soy allergy in the northern hemisphere, particularly in regions with relevant birch pollen exposure.

Secondary

Exposure to soy allergens via the respiratory route may also occur. This exposure can cause asthma in populations exposed to high levels of airborne soybean hull allergens in soybean dust or in bakers exposed to soybean flour.

Clinical Relevance

Allergic symptoms to soy can vary greatly from one individual to another and a single individual may also experience different symptoms from one exposure to another. Symptoms range from mild oral reactions or atopic dermatitis to severe respiratory and even cardiovascular symptoms. There are three main types of soy allergy described with different routes of sensitization and varied, partly overlapping symptoms.

In children, the most common type is soy allergy where sensitization occurs via the gastrointestinal (or percutaneous) route. Many different soy products, both processed and unprocessed can cause symptoms and the symptoms can be severe, including anaphylaxis. In a study by Savage (2010), the most frequent presenting symptoms of soy allergy in children was gastrointestinal (vomiting, diarrhea, bloody stool, and abdominal pain) in 40%, skin related (urticaria, angioedema, and noneczematous rash) in 28%, eczema in 11%, lower respiratory tract (wheezing, coughing, and difficulty breathing) in 5%, and upper respiratory tract (rhinitis and nasal congestion) in 4% of cases.

In adults, soy allergy due to cross reactivity with the soy protein Gly m 4 and birch pollen allergen Bet v 1 is the most common type. Consumption of especially unprocessed or mildly processed soy products give rise to reactions that are often mild mucosal symptoms. However, in some patients the reactions can be severe and include anaphylaxis. The third main type of soy allergy described involves asthma or rhinoconjunctivitis and occurs after inhalation of dust from whole unprocessed soya beans. Besides the three main types there is also occupational asthma in bakers after inhalation of soybean flour, so called bakers asthma, reported

Diagnostics

Environmental Source

The increasing use of soy flour and soy protein as food additives means that vigilance is increasingly necessary to prevent unintentional contamination of foods with soybean allergens.

Main Methods

The detection of soy protein in food is commonly performed using enzyme-linked immunosorbent assays (ELISAs). Currently commercially available soy ELISA kits use antibodies that detect one of three soybean proteins: trypsin inhibitor (Gly m TI) or the abundant storage proteins conglycinin (Gly m 5) and glycinin (Gly m 6), with Gly m 8 being proposed as an alternative highly stable and relevant alternative.

The clinical diagnosis of soy allergy involves taking an accurate clinical history, interpretation of sensitization tests in the context of the history, and if appropriate, challenges with the offending food. A diagnostic workup for soy allergy can be found in.

In vitro Diagnostics

During the diagnostic workup of a patient with suspected soy allergy, total IgE levels as well as allergen specific IgE to soy extract and soy components are appropriate to test.

Allergen-specific IgE to soy extract can show sensitization to soy, but there is a risk of false negative results in patients cross-reactive to birch pollen, since the extract may contain low amounts of the labile Bet v 1 homolog Gly m 4.

To distinguish primary sensitization from cross reactivity, specific IgE to soy components can be measured. Sensitization to Gly m 5, Gly m 6 and Gly m 8 is common in patients primary sensitized to soy while sensitization to Gly m 4 and/or Bet v 1 occurs in patients primary sensitized to birch pollen and cross-reactive to soy.

Skin prick tests

Skin prick tests may be performed using commercial soy extract, but there is a risk of false negative results due to low amounts of Gly m 4 present in the extract.

Prick to prick test with the reaction-eliciting product can also be performed.

For patients with severe reactions to soy, the soy product may be diluted before used in prick to prick testing. An alternative is to first perform in vitro allergen specific IgE-test.

Food challenge tests

If there is doubt whether soy is the reaction-causing agent, an oral food challenge test can be performed. The test can be performed with the offending product or with another soy product with similar level of processing of soy protein content.

Prevention And Therapy

Prevention Stratergies

Avoidance of soy-containing products is the treatment option for soy allergic patients since there at present is no immunotherapy for soy available.

Avoidance strategy should be dependent on the type of soy allergy (see section 6 Clinical relevance above) and the symptom-elicited dose. Patients with a primary soy allergy should avoid all soy food items, also small amounts, especially in cases with severe reactions after a small dose ingested. Soy sauce, miso and other fermented soy products are much less allergenic than for example soymilk and tofu.

In patients with Bet v 1 associated soy allergy, larger amounts of soy products should be avoided. Products that have been heated are generally tolerated (because of the heat labile symptom causing allergens).

In case of asthma induced by dust from unprocessed soy, dust containing unprocessed soy proteins should be avoided.

Cross-Reactivity

Cross-reactivity between Gly m 4 and the birch pollen allergens Bet v 1 is responsible for soy allergy in the majority of adults in areas where exposure to birch pollen is ubiquitous.

Clinically relevant IgE cross-reactivity between soybean and other legumes, notably peanut, has been demonstrated as well.