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Laury Masthoff

Friday 20 December 2013

Hazelnut allergy in children and adults diagnosis and underlying mechanisms

Promotor: Prof. dr. C.A.F.M. Bruijnzeel-Koomen
Defence: 20 December 2013

Hazelnut is a frequently consumed tree nut, because of the taste and price. Unfortunately, allergic symptoms to hazelnut are common, especially in adults from Northern Europe. Allergic symptoms to hazelnut are highly variable from mild symptoms limited to the oral cavity to severe and even anaphylactic reactions. The frequency of severity of a hazelnut allergy shows differences between children and adults, as described in Chapter 3. A hazelnut allergy in adults is generally limited to mild and local symptoms in the oral cavity and associated with birch pollen allergy. In children, a hazelnut allergy is more severe and often accompanied by atopic dermatitis. Frequently reported allergic symptoms in children are angio-edema, urticaria and dyspnoea. The diagnosis of a food allergy has a great impact on daily life, because allergic individuals are continuously confronted with the risk of unexpected allergic reactions. This influences not only the life of the allergic individuals and their parents, but also their environment (friends, school etcetera). Therefore, a correct diagnosis is important, so that appropriate advise on dietary restrictions and emergency medication can be given. To diagnose a hazelnut allergy in adults, a history with only oral symptoms to hazelnut in combination with birch pollinosis is generally convincing to diagnose a hazelnut allergy, without the need to perform additional tests. In other cases, additional tests, including a DBPCFC, are often needed for a correct diagnosis. Chapter 2 describes the diagnostic value of hazelnut allergy tests in children. A history of allergic reactions with previous ingestion of hazelnut is often unknown in children, because many children have an elimination diet solely based on sensitization. Therefore, the diagnosis of a hazelnut allergy in children strongly relies on diagnostic tests. The skin prick test (SPT) with hazelnut extract is a better predictor of a hazelnut allergy in children than specific IgE to hazelnut. The SPT with hazelnut extract can reduce the number of double-blind placebo-controlled food challenges (DBPCFCs) in less than 30% of the children, but a DBPCFC remains necessary in many children to diagnose a hazelnut allergy. Chapter 4 shows the value of IgE to specific hazelnut components in the diagnostic work-up of a severe hazelnut allergy. IgE to hazelnut seed storage proteins Cor a 9 and Cor a 14 was highly specific for a severe hazelnut allergy in children and adults. Determination of IgE to these components may identify almost all children and half of the adults with a severe hazelnut allergy. In children, this may reduce the number of DBPCFCs considerably. Chapter 7 shows the potency of the major hazelnut allergen in basophil activation in comparison to the peanut allergens. Cor a 14 is the most potent hazelnut allergen in basophil activation, comparable to the 2S albumins in peanut (Ara h 2 and Ara h 6) which are most potent. This fits with the observation that IgE to Cor a 14 is highly specific for severe allergic reactions. Chapter 4 also showed that some children and half of the adults with a severe hazelnut allergy have an isolated Cor a 1 sensitization. This may suggest that Cor a 1 can be involved in severe symptoms to hazelnut in some individuals. In line with this, chapter 7 showed a large variation in basophil activation with Cor a 1 among different individuals.
The amount of hazelnut needed to elicit symptoms in hazelnut allergic children and adults was studied in chapter 5. The thresholds for objective symptoms to hazelnut (considered as a severe hazelnut allergy in this thesis) were comparable between children and adults. Several patient characteristics like age, SPT to hazelnut extract and IgE to Cor a 9 and Cor a 14 influenced the threshold distribution curve (TDC) to hazelnut. The obtained eliciting dose values from this chapter may improve the food labeling. The product choice of hazelnut allergic individuals is strongly reduced, because an increasing number of products may contain hazelnut. Labeling information based on eliciting doses may improve the product choice of hazelnut allergic individuals. Hazelnut can be consumed after processing which is generally the case in industrially prepared food, but raw consumption directly from the tree is increasingly popular. Chapter 8 is a systematic review of the literature about the influence of processing on the allergenicity of tree nuts, including hazelnut. Roasting reduces the allergenicity of the PR-10 protein Cor a 1 in hazelnut. Sensitization to Cor a 1 is frequently observed in individuals with a hazelnut and birch pollen allergy, as a cross-reactive response after primary sensitization to Bet v 1 from birch pollen. Clinical studies with DBPCFCs have confirmed the reduced allergenicity of hazelnut after roasting in individuals with a hazelnut and birch pollen allergy. Still, the allergic symptoms were not absent in all individuals after roasting of hazelnuts, which suggests that other allergens are involved in the allergic reaction in these patients. The in vitro heat lability of the birch pollen related hazelnut allergen and the reduced in vivo allergenicity indicate that raw hazelnut is more allergenic than roasted hazelnut in individuals with a birch pollen related tree nut allergy. The heat lability of the PR-10 proteins in hazelnut has important implications for source material used for IgE testing, SPT and DBPCFCs and diet advises. Allergens not related to birch pollen, the lipid transfer proteins and seed storage proteins, present in different tree nuts (hazelnut, cashew, walnut etcetera), are generally heat stable, which suggests that processing may not influence their allergenicity.
Allergy to peanut, which is a legume and not a tree nut, is common in individuals with a hazelnut allergy as shown in chapter 6. The severity of the hazelnut allergy was not predictive for the presence and severity of the peanut allergy. Almost half of the children and adults with a sensitization to hazelnut seed storage proteins were also sensitized to their homologous proteins in peanut. ImmunoCAP inhibition experiments showed that the peanut allergy was not the result of IgE cross-reactivity to hazelnut seed storage proteins. These data may imply that IgE to Cor a 14 and Ara h 2 are useful markers of primary sensitization to hazelnut and peanut respectively.
Chapter 7 shows the T cell responses to major hazelnut and peanut allergens. A high molecular weight molecule in hazelnut, possibly Cor a 11 was the strongest inducer of T cell proliferation of hazelnut specific T cell lines. At T cell level, cross-reactivity between hazelnut and peanut major allergens was observed. This suggests that the cross-reactivity may be induced at T cell level and is not always accompanied by cross-reactive IgE antibodies. The observed cross-reactivity at T cell level may in part explain the frequently observed concomitant hazelnut and peanut allergy.
In conclusion, our data show clinical aspects of a hazelnut allergy in children and adults. New diagnostic tests may improve the diagnosis of a severe hazelnut allergy, which may result in a reduction of the number of DBPCFCs and unnecessary elimination diets. The underlying mechanism leading to a concomitant hazelnut and peanut allergy was further studied, which may provide a basis for the development of preventative and therapeutic strategies.