Introduction
Search strategy
Diagnostic procedures are improving through molecular approaches
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Peanut and tree nut allergy - The major peanut allergen components Ara h 1, Ara h 2 and Ara h 3 are storage protein [19]. Ara h 8 is a member of the pathogenesis-related protein family (PR-10), which is relevant to patients with birch pollen allergy [20]. Ara h 9 is a nonspecific lipid transfer protein (nsLTP) and has recently been reported to be an important allergen in the Mediterranean area [21]. Ara h 2 has been highlighted as marker of primary sensitization, persistent allergy and severe reactions [22]. In a study of 181 French children with suspected peanut allergy, Ara h 6 and Ara h 2 were the best predictors of peanut allergy [23]. In a multicentre prospective study of 210 German children with suspected peanut or hazelnut allergy, sIgE to Ara h 2 and Cor a 14 resulted more reliable in predicting outcomes in OFC than sIgE to peanut or hazelnut extracts [24]. Similarly, in a recent Dutch study including 161 hazelnut-sensitized adult and children, sIgE to Cor a 9 and Cor a 14 were strongly associated with OFC-proven hazelnut allergy [25]. Among 123 Spanish children with suspected peanut allergy, the frequencies of sensitization to Ara h 1, Ara h 2, and Ara h 3 were 60.0%, 72.7% and 43.6% respectively, with significantly higher sIgE levels in the allergic group [26]. Among 40 Thai children with peanut sensitization, sIgE to Ara h 2 was a marker of anaphylactic reactions, whereas sIgE to Ara h 9 was unrelated to severe reactions [27]. Among 57 Japanese peanut-sensitized children, sIgE to Ara h 2 (cut-off 0.35 kU/l) could discriminate allergic from tolerant children with a sensitivity of 88% and a specificity of 84% [28].
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Cow’s milk allergy - Several studies have tried to determine the serum level cut-off of sIgE to cow’s milk useful to identify sensitized children who are at risk of developing allergic reactions to cow’s milk [14]. Among 123 Brazilian children with cow’s milk allergy (CMA), testing sIgE to whole cow’s milk extract (cut-off 3.06 kU/l) was more useful to diagnose CMA than testing sIgE to α-lactalbumin, β-lactoglobulin or casein [29]. Finally, SPT with milk protein may be more reliable than sIgE level in predicting outcomes in OFC with baked milk products [30].
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Egg allergy - SPT and sIgE to egg white have been shown to be a poor predictor of clinical phenotypes of egg allergy (EA). Among 154 Spanish egg-sensitized infants with CMA and/or atopic dermatitis without previous egg consumption, an egg white SPT wheal reaction of 8 mm and/or sIgE >8.36 KU/l predicted a positive outcome in OFC of around 94% [31]. Most children with EA seem to tolerate baked egg, but tolerance cannot be predicted with conventional allergy testing. In 186 English children with suspected EA who underwent an OFC, SPT to egg extract was slightly better in predicting a positive outcome than SPT to raw egg [32]. Egg white and yolk contain more than 20 different glycoproteins and measurement of sIgE to egg white subcomponents is considered as a new method for diagnosis [33]. Recently, it has been shown that sIgE to egg component Gal d 1 (i.e. ovomucoid) was more accurate in predicting raw EA compared with sIgE to egg white [34-36]. Moreover Gal d 1 negative children showed high frequency of tolerance to boiled egg [37]. In a prospective study of 143 children with EA, SPT to muffin < 2 mm had a high negative predictive value for baked egg OFC, whereas ovomucoid SPT 11 mm was very likely to predict a reaction to baked egg [38]. In 85 Spanish children sIgG4 to ovoalbumin resulted an independent predictor of tolerance development to uncooked egg [39].
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Wheat allergy - sIgE to wheat has poor diagnostic predictability for wheat allergy. A prospective study reported that wheat sIgE levels required to identify subjects with >95% probability of reacting to a wheat challenge were 80 kUA/L [14]. The association of sensitization to ω-5-gliadin with wheat-dependent exercise-induced anaphylaxis (EIA) is one of the best documented forms of wheat allergy [40]. A recent study of 108 Finnish children with suspected wheat allergy, who underwent open or double-blinded, placebo-controlled oral wheat challenges identified the “dimeric alpha-amylase inhibitors 0.19” as a relevant allergen in clinically reactive participants [41]. Cases of wheat-dependent EIA with positivity to nsLTP in absence of ω-5-gliadin sensitization have been reported [42]; thus, patients with a history consistent with cofactor-enhanced food allergic anaphylaxis should be tested for sIgE to nsLTP (e.g. Tri a 14) and to ω-5-gliadin [43].
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Fish and seafood allergy - The major codfish allergen component, Gad c 1 belongs to a group of Calcium-transporting muscle proteins known as parvalbumins. The variable degrees of clinical cross-reactivity in patients with fish allergy could be explained by the various degrees of amino acid homologies ranging from 60% to 80% shared by parvalbumins [44]. For shellfish allergy, tropomyosin is the major allergen responsible for cross-reactions among different species of the shellfish group. Molecular comparison of tropomyosin from different crustacean species revealed a very high homology of up to 98% [44]. It is well known that crustacean and mollusc allergens do not cross-react with fish allergens. On the other hand, patients with shellfish allergy are frequently reported to have allergic reactions to non-crustacean source, such as house dust mites and cockroaches. This cross-reactivity is probably due to the high amino acid homology of tropomyosins shared by these organisms [45]. Despite CRD revealed to be a useful tool to highlight in vitro-immunologic cross-reactivity in seafood allergy, its use in predicting clinical cross-reactivity is still to be improved.
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Fruit and vegetable allergy - Pru p 3 is an nsLTP and considered a major peach allergen component. In 57 Spanish children suffering from allergic reactions after eating or having contact with peach, sIgE to Pru p 3 was detected in 96% of participants but OFC with peach pulp showed that more than 90% tolerated peeled peach [46]. Allergic reactions to fruits and vegetables can either result from primary sensitization to food or to inhalant allergens. In the latter case triggering foods share similar components with inhalant allergens causing cross-reactions. A study performed on 15 subjects from Belgium with birch pollen allergy and suspected soy allergy, showed that secondary soy allergy may be responsible for chronic allergic symptoms (e.g. chronic severe generalized itching, recurrent urticaria, chronic diarrhea and generalized atopic dermatitis), besides typical immediate manifestations (from oral allergic syndrome up to anaphylaxis). In patients with birch pollen allergy SPT with soy flour and sIgE to soy component Gly m 4 were proposed as valuable tools for the diagnosis of secondary soy allergy [47]. Usually, cross reactivity is attributable to heat-labile allergens (i.e., PR-10 and profilins) and it is associated with mild oral reactions. On the contrary heat and proteolysis-resistant allergens (such as storage proteins and nsLTP) that primary sensitize through the oral route are associated with local and systemic reactions [48].