Summary

Peanuts are consumed across the world, however, the form they are consumed in varies geographically and this can impact their allergenicity. Currently, 17 peanut allergens have been identified and the seed storage proteins being stable to cooking and digestion. Ara h 1, 2, 3 and 6 are considered to be the major peanut allergens and it is estimated that 97% of peanut allergy patients are sensitized to at least one of the allergens Ara h 1, 2 and 3. Peanut allergens belong to diverse protein families leading to immunochemical IgE-mediated cross-reactions among different members of the legume families, other plant foods such as tree nuts and also pollen. Peanut allergy usually begins in childhood and persists throughout the affected individual’s lifetime, however, approximately 20% of young children develop tolerance. Typical clinical symptoms of peanut allergy range from angioedema, urticaria, nausea, abdominal pain, vomiting, wheezing, and breathlessness which usually occur soon after peanut ingestion. A significant proportion of sensitized individuals do not show clinical signs of peanut allergy. Sensitization to the storage proteins, Ara h 1, 2, 3, 6, and 7, carries an increased risk for more severe symptoms and anaphylactic reactions. Individuals with peanut allergy are of elevated risk of anaphylaxis compared to other food allergies, with over 90% of food-induced anaphylaxis-related fatalities occurring in peanut sensitized individuals. There are several prevention strategies including introducing peanuts to infants at an early stage, avoidance and ‘peanut-free’ schools have been proposed. However, the Food and Drug Administration (FDA) approved an oral immunotherapy for clinical use in the USA in 2020 which may be more widely available in the future.

Allergen

Summary

Peanuts are consumed across the world, however, the form they are consumed in varies geographically and this can impact their allergenicity. Currently, 17 peanut allergens have been identified and the seed storage proteins being stable to cooking and digestion. Ara h 1, 2, 3 and 6 are considered to be the major peanut allergens and it is estimated that 97% of peanut allergy patients are sensitized to at least one of the allergens Ara h 1, 2 and 3. Peanut allergens belong to diverse protein families leading to immunochemical IgE-mediated cross-reactions among different members of the legume families, other plant foods such as tree nuts and also pollen. Peanut allergy usually begins in childhood and persists throughout the affected individual’s lifetime however, approximately 20% of young children develop tolerance. Typical clinical symptoms of peanut allergy range from angioedema, urticaria, nausea, abdominal pain, vomiting, wheezing, and breathlessness which usually occur soon after peanut ingestion. A significant proportion of sensitized individuals do not show clinical signs of peanut allergy. Sensitization to the storage proteins, Ara h 1, 2, 3, 6, and 7, carries an increased risk for more severe symptoms and anaphylactic reactions. Individuals with peanut allergy are of elevated risk of anaphylaxis compared to other food allergies, with over 90% of food-induced anaphylaxis-related fatalities occurring in peanut sensitized individuals. There are several prevention strategies including introducing peanuts to infants at an early stage, avoidance and ‘peanut-free’ schools have been proposed. However, the Food and Drug Administration (FDA) approved an oral immunotherapy for clinical use in the USA in 2020 which may be more widely available in the future.

Epidemiology

Worldwide distribution

Studies have typically reported peanut allergy prevalence rates between 1-2% in Western nations. Peanut allergy appears to be less common in Asia and other global areas, although epidemiological studies in non-Western regions have been sparse. Peanut allergy usually begins in childhood and persists throughout the affected individual’s lifetime however, approximately 20% of young children develop tolerance.

In 2002, the results from a USA survey indicated that about 0.8% of children had an allergy to peanuts with the prevalence estimated to be 1.4% in 2008. The prevalence of peanut allergy in a study of 7768 primary school children in Montreal, Canada, was 1.50%. When data concerning the peanut allergy status of non-responders were also included, the estimated prevalence was 1.34%.

According to a population-based study of children aged three to four years old in the United Kingdom, the prevalence of sensitization to peanuts increased three-fold from 1.1% in 1989 to 3.3% in 1994 to 1996. However, of 41 sensitized children in the study, 10 reported a convincing clinical reaction to peanut, and eight had positive oral challenge results, giving an overall estimate of peanut allergy of 1.5% (18/1246). Similarly, the population-based study in Australia, HealthNuts, reported a challenge-confirmed peanut allergy prevalence of 1.9% in children aged four years. In European school children aged six to 10 years previously involved in the EuroPrevall cohort (except for the centers in Italy), three of 2097 children had positive double-blind, placebo-controlled oral food challenges (DBPCFC) to peanut equating to a prevalence of 0.1%. The EuroPrevall-INCO prevalence of ‘probable’ peanut allergy (defined as allergic symptoms within two hours of ingestion and positive IgE and/or skin prick test result) in Hong Kong, Guangzhou and Shaoguan (China), Tomsk (Russia) and India were, 0.10, 0.00, 0.00, 0.08 and 0.03%, respectively.

Risk factors (WESTERN)

First sensitization has been attributed to the presence of peanut allergen in breast milk. In a study involving eight infants with immediate hypersensitivity reactions to foods, including peanut, occurring at the first-known exposure, the most likely route of sensitization was thought to be breast milk, and reactions were thought to be dose-dependent.

Differences in the way peanuts are prepared may contribute to the variations in the prevalence of peanut allergy in different parts of the world. Frying or boiling peanuts, commonly used in China, appears to reduce the allergenicity of peanuts compared with dry roasting, widely used in the US, which has shown to increase allergenicity. This could help to explain why despite a higher rate of peanut consumption in China, peanut allergy is lower than the United States.

A factor postulated to have contributed to peanut allergy in the UK is the cutaneous exposure to ultra-low doses of peanut antigens in peanut oil found in diaper rash emollients, which are applied to the skin of infants with eczema or diaper rash.

Peanut allergy has been reported to have been transferred through a combined liver and kidney transplant, bone marrow and peripheral blood stem cell transplantations.

There is evidence demonstrating that minute quantities of ingested peanut can cause allergic reactions, including fatal and very severe reactions, for example when ingesting undeclared peanut flour which was used in a food product as a flavoring. There are also reports highlighting that peanut-sensitive people can experience allergic reactions when in close proximity to peanuts.

Pediatric issues

Infants have reacted adversely to breast feeds after maternal consumption of peanut. Sensitization has been reported with use of products containing peanut oil such as vitamins and infant milk formula, and also topically in creams and lotions.

Casual exposure to peanut butter (skin contact and inhalation of fumes) is unlikely to cause significant allergic reactions. Although the authors warn that the results cannot be generalized to larger exposures or to contact with peanut in other forms (flour and roasted peanuts). However, the authors who published a series of five case reports concluded that severe food allergic reactions can occur from exposure to small amounts of allergens via skin contact or inhalation. Examples include a nine-month-old male who developed generalized urticaria after his brother ate a peanut butter sandwich and touched his bare leg. Similarly, a child developed wheezing when entering the classroom of a teacher who had just eaten peanuts. Although causal exposure (proximity to peanut/’airborne’ exposure, skin contact, kissing) poses a minimal risk, unintended ingestion could lead to a reaction.

Peanut allergy usually begins in childhood and persists throughout the affected individual’s lifetime however, approximately 20% of young children develop tolerance. Higher peanut-specific IgE levels are associated with both persistence of peanut allergy and more severe allergic reactions when peanuts are consumed.

Route Of Exposure

Main

The main route of exposure is through consumption of peanuts or products containing peanuts and there is evidence that roasting increases the allergenicity of peanuts. In fact, extracts of roasted peanuts where shown to bind to serum IgE from allergic people at approximately 90-fold higher levels compared to raw peanuts. The protein concentration is higher in raw peanuts (approx. 16.6 g per 100 g) than in roasted peanuts (approx. 2.6 g per 100 g), and the histamine concentration is higher in roasted peanuts. It has been suggested that an increased amount of histamine in roasted peanuts could worsen IgE-related allergies.

Frying or boiling peanuts, commonly used in China, appears to reduce the allergenicity of peanuts compared with dry roasting which has shown to increase the allergenicity of peanuts, widely used in the United States. This could help to explain why despite a higher rate of peanut consumption in China, peanut allergy is lower than that in the United States.

Secondary

A series of five case reports concluded that severe food allergic reactions can occur from exposure to small amounts of allergens via skin contact or inhalation. However, causal exposure (proximity to peanut/’airborne’ exposure, skin contact, kissing) poses a minimal risk of an allergic reaction but if unintended ingestion occurs, this could lead to an allergic reaction. A major concern has been exposure to peanut within airplanes and many airlines have decided to ban peanuts onboard because of risk of airborne exposure. Peanut proteins have been found in the ventilation filters of airplanes, however, these results have not been replicated. Peanut proteins have recently been detected on seat and tray tables of commercial irrespective of whether peanuts were served during the flight. The sample with the highest amount of peanut protein was taken after two bags of roasted peanuts were consumed and small peanut particles were present on the filter. Currently, the clinical relevance of these results are unknown.

Other topics

Peanut allergens have been shown in breast milk and may sensitize infants. In a study of 23 lactating women given 50 g of dry roasted peanuts to eat, peanut protein was detected in the breast milk of 11. It was detected in 10 participants within two hours of ingestion and in one participant within six hours. The median peak peanut protein concentration in breast milk was 200 ng/ml (range, 120-430 ng/ml). Both of the major peanut allergens, Ara h 1 and Ara h 2, were detected. Although peanut allergens in breast milk decline over time, a study showed the Ara h6 allergen was detected in breast milk 26 hours after ingestion.

Clinical Relevance

Typical clinical symptoms of peanut allergy range from angioedema, urticaria, nausea, abdominal pain, vomiting, wheezing, and breathlessness which usually occur soon after peanut ingestion. A significant proportion of sensitized individuals (have specific IgE) do not show clinical signs of peanut allergy.

Cutaneous

The most frequently encountered clinical signs of peanut allergy at initial presentation are cutaneous and typically involve urticaria, erythema and angioedema. The cutaneous clinical signs associated with peanut allergy are considered to be mild to moderate.

Respiratory

The second most frequently experienced clinical signs of peanut allergy at initial presentation involve the respiratory system. Patients can experience wheezing, stridor, coughing, dyspnea, tightness in the throat and/or chest, vocal changes and nasal congestion which are indicative of a more severe reaction to peanuts.

Gastrointestinal

Vomiting, diarrhea and abdominal pain are estimated to be experienced by approximately a quarter of peanut-allergic patients on first presentation. In terms of severity, the GI signs are usually mild to moderate.

Anaphylaxis

Peanut allergy is of elevated risk compared to other food allergies, with over 90% of food-induced anaphylaxis-related fatalities occurring in peanut sensitized individuals. Asthma is a key risk factor for fatal and near-fatal food induced anaphylaxis with evidence to show that children over three years old with peanut allergy have a 2.3 times greater risk of hospitalization for asthma. A study on peanut or tree nut allergies demonstrated that patients with a history of severe asthma were at increased risk of life-threatening bronchospasm occurring after consuming nuts. In a study of children with peanut allergy, 9% (4/46) died from an exacerbation of asthma that indicating a higher fatality rate for people with asthma.

Atopic Dermatitis

Studies have shown that the prevalence of food allergy in patients with atopic dermatitis ranges from 20% to 80%. Peanuts are considered to be a common food trigger of atopic dermatitis and research has demonstrated that food allergy plays a major role in exacerbating symptoms of atopic dermatitis and diet exclusion will decrease the severity. In an Australian study it has been shown that infants with atopic dermatitis were 11-times more likely to develop peanut allergy than infants without atopic dermatitis.

Other diseases

Peanuts are also one of the foods most commonly involved in food-dependent exercise-induced anaphylaxis. In addition, the association of food allergies and otitis media with effusion (OME) was investigated. One study reported that 78% of 104 children with recurrent OME were sensitized to one or more food allergens and 86% saw an improvement in clinical signs of OME when the suspected food was eliminated from the diet.

Rhinitis is not typically associated with food-induced allergic reactions. However, peanut was found to be one of the most prevalent food allergies in adults with allergic rhinitis.

Diagnostics

The gold standard test for diagnosing peanut allergy and other food allergies is using an oral food challenge. However, it poses a risk of severe reactions and is time consuming.

Prevention And Therapy

Allergen immunotherapy

In a multicenter, phase three, double-blind, placebo-controlled food challenge, participants with peanut allergy were randomized in a 3:1 ratio to receive a peanut-derived investigational biologic oral immunotherapy drug, AR101 or placebo in an increasing-dose protocol. The primary endpoint was the proportion of participants aged four to 17 who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. Of the 496 participants who were four to 17 years old, 250 of 372 participants (67%) who received active treatment, as compared with five of 124 participants (4%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). In 2020, oral immunotherapy for peanut allergy was approved by the Food and Drug Administration (FDA) for clinical use in the USA. The treatment will most likely be available within EU during 2021.

Prevention strategies

Introducing peanuts to infants early, significantly decreased the occurrence of the development of peanut allergy among children at increased risk for peanut allergy and modulated immune responses to peanuts. Egg allergy and/or severe eczema appear to be useful criteria for identifying high-risk infants. Avoiding and minimizing symptoms of food allergies are focused on avoidance and prompt emergency management (including the use of self-administered epinephrine). Since individuals with peanut allergy can have serious reactions, banning peanut consumption within school premises has been suggested. Studies from different countries have evaluated ‘peanut-free’ schools as a possible prevention strategy although further research is required to evaluate the effect of allergen-restrictive policies on improving safety for students with food allergy.

Cross-Reactivity

Peanut and tree nut show cross reactivity in 25 to 50% of peanut-allergic patients because Ara h 2 shares IgE-binding epitopes with almond and Brazil nut allergens. However, despite 2S seed albumin allergens sharing structural similarities, a major peanut allergen, Ara h 2, showed no structural homology with the corresponding regions of Walnut Jug r 1, Pecan Car i 1 or Brazil nut Ber e 1. Although there is a theory of cross reactivity being dependent on allergens sharing a similar sequence and/or structure, there is experimental data highlighting a lack of relationship between the percentage of shared identity and the ability to bind IgE. Similarities in physicochemical properties to known IgE epitopes of 2S albumins could account for clinically observed cross-sensitivity between peanuts and tree nuts.

Patients with peanut allergy may demonstrate sensitization to other legumes, for example soybean, lupin, lentil or pea, although currently limited data are available. Cross-reactivity exists among legumes because they have structurally homologous proteins and share common epitopes. However, peanut allergy associated with other legumes is less frequently reported compared to the cross-reactivity demonstrated for other types of legumes Clinically, peanut allergen cross-reactivity can be relevant but in some cases, irrelevant with approximately half of patients having positive SPTs to other legumes, however, less than 5% show clinical signs when consuming them.

The Bet v 1 homologous peanut allergen Ara h 8, is thought to be involved in the cross reactivity of peanut allergy patients. Twenty patients with peanut and birch pollen allergy, and a positive double-blind, placebo-controlled food challenge result to peanut, all experienced symptoms in the oral cavity, progressing to more severe symptoms in 40% of patients. Recombinant Ara h 8-specific IgE was demonstrated in 85%, IgE binding to Ara h 8 was inhibited by Bet v 1 and recombinant Ara h 8 inhibited IgE binding to peanut in four of seven tested patient sera. The study concludes that peanut allergy might be mediated in a subgroup of the patients by cross-reactivity of Bet v 1 with the homologous peanut allergen Ara h 8. Similarly, examination of the sera of five patients in relation to four recombinant allergens led to the conclusion that IgE cross-reactivity existed between Bet v 1 (birch pollen) and its homologues Gly m 4 from soybean, Ara h 8, and Pru av 1 from Cherry but variation in IgE specificity between patients was observed. In addition, Ara h 8 is involved in grass pollen-associated food allergy.

Lupins are an emerging cause of food allergy because of recent large-scale introduction as an additive to wheat flour or the use of lupin flour in processed foods and is frequently used in Europe and Australia. They are legumes of the Fabaceae family with PR-10 white lupin sharing significant sequence homology and molecular similarity between the peanut allergen Ara h 8. Sanz et al. (2010) explained that in patients with clinical sensitization to a legume, particularly peanut, greater caution is required depending on the population with lupin cross-reactivity of approximately 5% in British and Norwegian populations, 17% to 68% for French and Belgian populations, and 32% for Danish populations.