Cor a 14
Summary
Cor a 14 is a water-soluble, thermoresistant, 2S albumin storage protein found in hazelnuts (Corylus avellana). It is a 147 amino-acid protein with a molecular weight of 15-16 kDa. Cor a 14 sensitization among hazelnut-sensitized individuals has been found in Central, Southern and North-western Europe as well as in the United States. Also, age-related variations in prevalence, with greater IgE-reactivity towards Cor a 14 in children than in adults, are also reported. Cor a 14 possesses two important features: its ability to induce direct (primary) sensitization to hazelnut, as opposed to pollen-related sensitization, and its association with more severe clinical reactions (skin, respiratory, gastrointestinal, or even anaphylaxis). Determination of specific immunoglobulin E (sIgE) for Cor a 14 can serve as a predictive marker for clinical allergy to hazelnut with moderate-to-severe symptoms and could differentiate between sensitization and clinical allergy. However, the predictive ability of Cor a 14-sIgE could be enhanced by combining it with Cor a 9-sIgE and thus alleviate the risk of misclassifying patients. Moreover, Cor a 14-sIgE determination could predict the oral food challenge (OFC) outcomes better than other allergens (Cor a 1, Cor a 8 and Cor a 9) and could thus reduce the number of OFC to be conducted. Furthermore, even though clinical cross-reactivity among 2S albumins is variable, significant sequence homology and identity of Cor a 14 has been reported with Jug r 1 (walnut), Car i 1 (pecan) and Ana o 3 (cashew nut).
Epidemiology
Worldwide distribution
Hazelnut allergy (Corylus avellana) is the most common tree nut allergy in Europe. According to a systematic review, this allergy accounts for about 17-100% of the total tree nut allergies in Europe. Further, hazelnut allergy as well as sensitization is also frequent outside Europe, in countries such as India, Russia, Israel, Australia, Mexico and South Africa.
Cor a 14 is a storage protein of the 2S albumin family. In the EuroPrevall study conducted from 2005 to 2010 among 731 hazelnut-sensitized individuals in 12 European centers (central, eastern, north-western and southern countries), sensitization to Cor a 14 exhibited an overall prevalence of 5.9%. The highest prevalence was noted (18.2%-27.3%) in some cities of Central Europe (Prague [Czech Republic], Utrecht [The Netherlands], and Manchester [United Kingdom], Southern Europe (Madrid [Spain]) and North-western Europe (Reykjavik [Iceland]), while the prevalence in other cities of Central and Southern Europe was found to be <7%.
In the Netherlands, sensitization to Cor a 14 was found to be 34% (55 out of 161) in hazelnut-sensitized patients (81 children and 80 adults), while in Sweden among 220 hazelnut-allergic and asthmatic children (10-≤18 years) and young adults (>18-35 years), sensitization to Cor a 14 was 10.4% (23 out of 220). On the other hand, a study conducted in Turkey reported 66.7% prevalence of Cor a 14 sensitization, among hazelnut-sensitized children having a median age of 3.4 years (34 out of 51).
Similarly, the prevalence of Cor a 14 among hazelnut-sensitized patients ranged from 26% to 32% in different regions of United States (US). It was further noted that the prevalence rates decreased with an increasing age.
Age-related variations in prevalence, with greater IgE-reactivity towards Cor a 14 in children than in adults, was reported in a few studies. In Belgium, sensitization to Cor a 14 was reported to be 90% in preschool children, 80% in school-age children and 29% in adults. Furthermore, 21% of infants with atopic dermatitis were found to be sensitized to Cor a 14. A similar pattern was reported in a study conducted in Dutch children and adults, where sensitization to Cor a 14 was reported to be higher in children (70%) than in adults (39%) with objective symptoms (allergic symptoms seen on food challenge) or convincing history of hazelnut allergy.
Clinical Relevance
Disease severity
Similar to other nut storage proteins, Cor a 14 possesses two important features: its ability to induce direct (primary) sensitization to hazelnut, as opposed to pollen-related sensitization, and its association with more severe clinical reactions (skin, respiratory, gastrointestinal [GI], or even anaphylaxis). As an example, the Europrevall study conducted among 731 hazelnut-sensitized individuals demonstrated a statistically significant association of Cor a 14 sensitization (p=0.006) with the prevalence of moderate-to-severe clinical presentations. In this study, Cor a 14 sensitization was present in 15.2% of patients with severe symptoms, 5.6% with moderate symptoms, and 3.7% with OAS. Similar data were collected in a study conducted in Belgium among 119 hazelnut-sensitized patients, with Cor a 14 sensitization significantly more prevalent in patients with generalized reactions (erythema, urticaria, angioedema, GI symptoms, and respiratory symptoms) as compared to patients with OAS (76% vs. 5%, p<0.05). Also, in another study involving 220 hazelnut-allergic asthmatic patients, individuals displaying positive specific immunoglobulin E (sIgE) to Cor a 14 or Cor a 9 were found to report more generalized reactions, like GI symptoms or anaphylaxis as compared to ones without Cor a 14 or Cor a 9 sensitization.
Further, sensitization to Cor a 14 was found to be associated with the presence of clinical allergy to hazelnut. This could be seen from two studies conducted in Belgium (n=15) and the Netherlands (n= 38), which showed no sensitization to Cor a 14 in each of the hazelnut-tolerant individuals.
Cross-reactive molecules
Clinical cross-reactivity among 2S albumins is variable. However, co-sensitization of Cor a 14 with Jug r 1 (walnut) or Ana o 3 (cashew nut) may be present as observed in a study conducted among 10,503 hazelnut-sensitized individuals in the US. Strong co-sensitization was reported between Cor a 14 and Jug r 1 of walnut (correlation coefficient=0.7), with the co-sensitization being comparatively lower between Cor a 14 and Ana o 3 of cashew nut (correlation coefficient=0.43).
A study conducted on 13 walnut and/or hazelnut-allergic patients sensitized to both nuts revealed strong cross-inhibition between the extracts and Cor a 14 or Jug r 1, indicating strong biological cross-reactivity and suggesting a potential risk of clinically relevant cross-reactivity.
Cor a 14 and peanut 2S albumin Ara h 2 are not found to be cross-reactive, as demonstrated in a study investigating peanut and hazelnut molecular profiles in 114 hazelnut-allergic patients, of whom 48% were also confirmed as peanut-allergic. Co-sensitization between Cor a 14 and Ara h 2 was virtually absent in hazelnut-allergic patients without peanut allergy, however reached up to 20% in peanut-allergic patients, with no hazelnut allergy, and to even 40% in patients with both hazelnut- and peanut-allergy.
Diagnostics
Disease Severity
Determination of sIgE for Cor a 14 can serve as a prediction marker for clinical allergy to hazelnut with moderate-to-severe symptoms which holds true even in regions with less birch pollen-sensitization as reported by a study conducted on 82 individuals in Finland.
This predictive ability was best observed at a cut-off value of 0.35 kUA/L as reported in a meta-analysis involving 8 studies. However, it was suggested that rather than an independent test, the predictive ability of Cor a 14-sIgE could be enhanced by combining it with Cor a 9-sIgE and thus alleviate the risk of misclassifying patients. Furthermore, the predictive capacity of Cor a 14 determination by both sIgE antibodies and basophil activation, was confirmed by double-blind, placebo-controlled, food challenge (DBPCFC) test conducted on 8 children. The specificity of these tests (IgE antibodies and basophil activation) was found to be >97% and >94%, respectively with the sensitivity being 100%. Hence, Cor a 14 determination could differentiate between sensitization and clinical allergy. This was also shown in two studies conducted in Italy (n=36) and Denmark (n=155), wherein Cor a 14-sIgE determination could detect true hazelnut-allergic patients in 94% and 87% of overall patient population respectively.
Based on the above studies, Cor a 14-sIgE determination could predict the oral food challenge (OFC) outcomes better than other allergens (Cor a 1, Cor a 8 and Cor a 9) and could thus reduce the number of OFC to be conducted. This was evidenced from several studies which confirmed the ability of Cor a 14-sIgE in differentiating positive and negative outcomes after OFC. Cor a 14-sIgE was detected in 96.2% reactive vs. 36% non-reactive patients in the study conducted among 64 hazelnut-sensitized patients in Turkey. Similarly, in a US study, it was detectable in 85% and 35% of reactive and non-reactive patients, respectively. In addition, two studies conducted on 161 and 147 Dutch hazelnut-sensitized individuals, also confirmed higher levels of Cor a 14-sIgE in patients with objective symptoms (allergic symptoms seen on food challenge or convincing history of hazelnut allergy).
Cross-Reactivity
Cor a 14 is a marker of primary sensitization to hazelnut; its cross-reactivity is limited to Jug r 1 from walnut and Car i 1 from pecan.
Exposure
The main route of exposure is through ingestion.
Cross-Reactivity
As a rule, cross-reactivity among 2S albumins is variable; however, Cor a 14 shares significant sequence homology, ≥ 60%, with Jug r 1 (63%) and Car i 1 (62%), the walnut and pecan 2S albumins, allowing clinical cross-reactivity.
Furthermore, the sequence identity of Cor a 14 with the 2S albumins of cashew nut (Ana o 3) was reported to be 43% and with 2S albumin of peanut (Ara h 2) was reported to be 29%.
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