Summary

The hazel plant (Corylus avellana) is a native species of Europe and Western Asia which majorly contributes to the global production of hazelnuts. Upon ingestion, hazelnut may induce allergic reactions in two ways: as primary immunoglobulin E (IgE)-mediated food allergy or as oral allergy syndrome (OAS) associated with pollen allergy. It is the most common tree nut allergy in Europe. However, the prevalence of hazelnut allergy differs as a function of climate and age. Hazelnut allergy is considered as birch pollen-related in North-Western Europe, while it is considered to be pollen-unrelated allergy in Southern Europe. Primary sensitization to hazelnut occurs more often in children (<5 years) than in adults and predisposes to severe reactions, including anaphylaxis. As of February 9, 2021, 11 allergenic molecules have been identified, characterized and published officially by WHO/IUIS Allergen Nomenclature Sub-Committee for hazelnut. Among these 11 allergens, some are present in both hazel pollen and hazelnut (Cor a 1, Cor a 2, Cor a 6), some are present only in hazelnut (Cor a 8, Cor a 9, Cor a 11, Cor a 12, Cor a 13, Cor a 14, Cor a 15), and Cor a 10 is only found in hazel pollen. The OAS due to hazelnuts is mainly attributed to cross-reactivity between homologous allergens of hazelnut and birch pollens (Cor a 1 and Bet v 1, Cor a 2 and Bet v 2), while primary hazelnut allergy (gastrointestinal, respiratory or cardiovascular reactions, bronchospasms or even anaphylaxis) is attributed to thermostable allergens and storage proteins, such as Cor a 8, Cor a 9, Cor a 11 and Cor a 14. Furthermore, Cor a 14-IgE, followed by Cor a 9-IgE, serve as excellent diagnostic markers for identifying true hazelnut allergy and are often associated with severe symptoms. Hazelnut allergy may occur in association with other tree nut allergies, like peanut, walnuts, pecan, almond, cashew nuts, pistachio, macadamia, and Brazil nut.

Epidemiology

Worldwide distribution

Hazelnut allergy can occur in two ways: as primary immunoglobulin E (IgE)-mediated food allergy or as oral allergy syndrome (OAS) associated with pollen allergy (pollen-food allergy syndrome, PFAS). It is the most common tree nut allergy in Europe. According to a systematic review, hazelnut allergy accounts for 17-100% of the total tree nut allergies in Europe. In a Europrevall study conducted in 6069 school children enrolled in birth cohorts from 8 European countries among, the overall prevalence of doctor-diagnosed hazelnut allergy was 1%. The Pronuts study, a prospective, multicenter, European study in London, Geneva and Valencia, reported hazelnut allergy in 32% of nut-allergic individuals (n=122).

However, the prevalence of hazelnut allergy differs as a function of climate and age. Hazelnut allergy is considered as birch pollen-related in North-Western Europe (Sweden, Germany, the Netherlands and Switzerland), while it is considered to be pollen-unrelated, mostly lipid transfer protein (LTP)-driven allergy in Southern Europe. A study conducted to assess the cross-sensitization profiles of tree nuts in birch-endemic areas in Finland found that the prevalence of hazelnut allergy among tree nut-allergic subjects, with and without birch sensitization, was 84% and 5%, respectively.

Furthermore, a prevalence study of probable food allergy (individuals having symptoms plus IgE sensitization) to 24 Europrevall priority foods in adults (20-54 years) and school-age children (7-10 years) across Europe was conducted. Probable hazelnut allergy, defined as the association of symptoms and confirmed sensitization, was markedly more common among adults and school children in Central and Northern countries (Zurich [Switzerland], Lodz [Poland], Utrecht [The Netherlands] and Vilnius [Lithuania]) than in Mediterranean countries (Madrid [Spain] and Athens [Greece]). However, in Central and Northern Europe adults were more often affected than children. The highest prevalence in adults was found in Zurich (2.57%), while that in school-age children was found in Vilnius (2.15%). Additionally, self-reported hazelnut allergy was present in 8.9% of adults from the Swedish general population in a cross-sectional survey (n=1042), and 5.3% exhibited both symptoms and hazelnut sensitzation.

The Danish Calmette study conducted on 1066 infants aged 13 months reported hazelnut sensitization in 1.2%, usually without associated symptoms. In Dutch patients displaying IgE to hazelnut, roughly 50% were confirmed as allergic (40/81 children and 39/80 adults). A study conducted in 227 East Mediterranean children with tree nut/peanut allergy showed hazelnut to be the cause of allergy in 63.9% of children. Besides, hazelnut was responsible for allergic reactions in 22.4% of children with food allergy (n=912) and 14% of children with atopic dermatitis (n=1140) in a retrospective study conducted in Turkey. Hazelnut has been considered as a common nut allergy, ranking third among food allergies in Turkey.

Outside Europe and Mediterranean regions, hazelnut sensitization and allergy are also frequent. Two studies in the framework of Europrevall project reported the prevalence of hazelnut sensitization in 7.3% of patients in South India (n=588) and the prevalence of hazelnut allergy in 0.09% of children in Tomsk, Russia (n=652). A prospective, single-center cohort study in Israel reported clinical allergy to hazelnut in 23% of tree nut-suspected allergic individuals (n=83). The HealthNuts study performed in 3232 children (6 years) in Australia reported a prevalence of 0.9% for challenge-confirmed hazelnut allergy. In a cross-sectional, retrospective study conducted in Mexico, 49% of food-allergic individuals were found to be sensitized to hazelnut, a high prevalence attributed to oak tree pollen cross-sensitization (n=2633). Another study conducted in 137 food-sensitized children from urban Cape Town, South Africa, found a 1.1% prevalence of hazelnut sensitization, however, none of the children were diagnosed with hazelnut allergy based on oral food challenge (OFC).

Risk factors

Birch, hazel or alder pollinosis is associated with a higher risk of developing pollen-related hazelnut allergy. Further, individuals with filaggrin gene mutations are usually at higher risk of developing hazelnut allergy. Such individuals are predisposed to atopic dermatitis and may develop severe allergy due to early sensitization to the food allergen.

Pediatric issues

Primary sensitization to hazelnut occurs more often in children (<5 years) than in adults, and predisposes to severe reactions, including anaphylaxis.

Route Of Exposure

Main

Oral ingestion of hazelnuts can trigger allergic reactions, with symptoms ranging from mild oral symptoms to very severe symptoms like bronchospasm or even anaphylaxis.

Secondary

In addition to ingestion, skin contact can also be a route of exposure, especially in atopic children, since hazelnut oil is used in several cosmetic products, like cream or bath oil.

Clinical Relevance

Oral allergy symptoms and Anaphylaxis

Hazelnut allergy is mainly IgE-mediated, however, it is manifested in two ways: primary hazelnut allergy and OAS related to pollens. Birch pollen-related hazelnut allergy is mainly observed in adults, manifesting mainly as OAS (symptoms limited to the oropharyngeal cavity), although systemic symptoms and even anaphylaxis have been infrequently reported. It is mainly attributed to cross-reactivity between homologous allergens of hazelnut and birch pollens (PR-10 proteins Cor a 1 and Bet v 1, profilins Cor a 2 and Bet v 2). Primary hazelnut allergy, however, is usually manifested as generalized symptoms (gastrointestinal, respiratory or cardiovascular reactions), which could be severe, leading to bronchospasm or even anaphylaxis. These reactions are attributed to thermostable allergens: the LTP Cor a 8 and the storage proteins Cor a 9, Cor a 11 and Cor a 14.

Oral Allergy Syndrome (OAS) is very commonly observed in hazelnut-allergic patients with different rates of severity. This was observed in a study conducted on 731 patients from 12 European centers. Mild, moderate and severe allergic reactions were reported in 47.9%, 36% and 15.9% of patients, respectively. Furthermore, anaphylaxis was observed in 3% of patients.

A study was conducted on 24 Eastern Mediterranean hazelnut-allergic children who were confirmed as allergic based on a double-blind placebo-controlled food challenge (DBPCFC). The results reported allergic reactions, such as cutaneous, gastrointestinal, and respiratory reactions in 87.5%, 29.2% and 33.3% of patients, respectively. Anaphylactic reactions were observed in 41.6% of children.

Further, a retrospective study conducted in Japan on 91 hazelnut-sensitized school children confirmed clinical allergy in 9 patients. The symptoms reported were skin and respiratory reactions in 44% of patients and gastrointestinal reactions in 100% of the allergic patients, while anaphylaxis was reported in 33%.

In the European Anaphylaxis Registry, which compiled the data of 1970 patients (<18 years), between the years 2007 to 2015, anaphylaxis due to hazelnut was reported in 76 patients, suspected in ten more, and was associated with 2 out of 17 most severe reactions, defined as grade III or higher.

Allergic rhinitis (AR) and allergic rhino-conjunctivitis (ARC)

Allergic rhinitis is not induced by hazelnut but can be associated with reactions to it. Allergic rhinitis was reported in 2 of 9 Japanese pediatric patients with challenge-confirmed allergy to hazelnut.

In a retrospective study conducted in the Netherlands, rhino-conjunctivitis was reported in 6% of adults during a DBPCFC conducted for hazelnut. In another retrospective study conducted in Japan, allergic conjunctivitis was reported in 22% of hazelnut-allergic patients.

Asthma

Bronchial asthma was reported in 33% of patients who reported clinical allergy to hazelnut in a study conducted in Japan.

Atopic Dermatitis

Atopic dermatitis was frequently reported in a survey conducted on 731 hazelnut-allergic patients from 12 European centers. It was observed to be 20% in mild patients, 34% in moderate patients and 37% in severe patients. The Danish Calmette study conducted in Denmark reported atopic dermatitis in 61.5% of hazelnut-allergic infants (n=13). Further, in a retrospective study conducted in Japan, atopic dermatitis was found to be 56% in patients who reported clinical allergy to hazelnuts.

Diagnostics

Challenge test

Oral food challenge, especially DBPCFC, is considered as a gold standard for diagnosing allergy related to hazelnut. However, it is very time-consuming, expensive and related with risk of developing severe reactions.

A study has documented that low-dose OFC in hazelnut-allergic children could be safe and effective, as it leads to only mild and localized allergic symptoms. In addition, specific-IgE reactivity to Cor a 9 and Cor a 14 may also be useful in predicting the challenge outcomes. It is shown in a study that hazelnut-allergic patients (children as well as adults) with high specific-IgE levels to Cor a 9 and Cor a 14 have lower clinical thresholds to hazelnut and thus at more risk of developing severe reactions on a challenge.

Prevention And Therapy

Allergen immunotherapy

Sublingual immunotherapy for hazelnut results in decreased sensitization in skin prick test (SPT) with higher levels of IgG4 and less systemic reactions. However, there is a paucity of evidence for its long-term safety and tolerability. A study was conducted to evaluate the efficacy and safety of low-dose hazelnut OFC in 43 patients with hazelnut allergy. The procedure showed 66% success rate and was observed to be effective in terms of improvement in the quality of life.

A retrospective single-center study evaluating 6-month oral allergen immunotherapy in 100 hazelnut-allergic children (<18 years), showed one-third of patients to be desensitized to hazelnut with adverse reaction reported in 30%. Whole hazelnut-IgE levels, small wheal diameter on SPT, absence of allergy to cashew and older age were strongly correlated with the efficiency of oral allergen immunotherapy.