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Hazelnut anaphylaxis: The usefulness of molecular-based allergy diagnostics
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ScienceDirect www.sciencedirect.com Revue française d’allergologie 55 (2015) 100–102
Letter to the editor Hazelnut anaphylaxis: The usefulness of molecularbased allergy diagnostics Anaphylaxie à la noisette : utilité diagnostique des allergènes moléculaires
Keywords: Hazelnut; Anaphylaxis; Food allergy; Diagnosis; Molecular allergens Mots clés : Noisette ; Anaphylaxie ; Allergie alimentaire ; Diagnostic ; Allergènes moléculaires
To the Editor, The hazelnut is the fruit of the hazel tree (Corylus avellana) belonging to the Corylaceae family. Its seed is commonly eaten dried, roasted or heated. Hazelnut may be a hidden allergen as contained in pastries, cookies, and chocolate. Hazelnut allergy (HA) accounts for a serious cause of food allergy [1]. In fact, the clinical presentation of HA may be particularly variable: ranging from mild subjective symptoms up to severe and fatal anaphylaxis. Usually, severe and systemic reactions are more frequent in childhood than in adulthood [2]. The HA prevalence is about 0.2% in children [3]. However, it is up to 4.5% among adults in regions with heavy exposure to Betulaceae and/or Corylaceae tree species [4]. Moreover, primary sensitization to hazelnut is more common in children than in adults [5]. These clinical and immunological differences might depend on different sensitization profile to the hazelnut allergen proteins. In this regard, at least 15 hazelnut allergen proteins have been identified. Cor a 1 is a PR-10 protein with high homology with the major birch allergen Bet v 1, as both display extensive cross-reactivity. Cor a 1 is heat- and digestion-labile: for this reason is primarily associated with local reaction: the so-called Oral Allergic Syndrome. Patients sensitized to Cor a 1 usually tolerate roasted hazelnuts. Cor a 8 is a lipid transfer protein (LTP), its sensitization is often associated with symptoms to other LTP-containing food, such as peach, lettuce, peanut, walnut, and cherry [6]. Cor a 8 is heat- and digestion-stable so is associated with local as well as systemic reactions. Cor a 9 and Cor a 14 are hazelnut storage proteins (the former is a 11S globulin; the last is a 2S albumin). Cor a 9 and 14 sensitization can occur early in life [7]. They are heat- and digestion-stable, are abundant in hazelnut, and associated with systemic reactions [2,5,8]. Recently, Masthoff et al. reported that sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective http://dx.doi.org/10.1016/j.reval.2014.09.005 1877-0320/© 2015 Elsevier Masson SAS. All rights reserved.
symptoms after oral challenge and both may be a marker for a more severe hazelnut allergic phenotype [5]. In addition, a recent Italian study reported a wide heterogeneity in molecular pattern of sensitization in allergic patients to hazelnut [9]. The HA diagnostic work-up is typically based on history, detection of allergen-specific IgE by skin prick test and/or serum assessment, and oral challenge. Prick by prick with hazelnut may be also performed. Oral food challenge represents the mainstay for food allergy as it allows of clarifying accurately the causality of the specific allergen. On the other hand, challenge is very dangerous in patients with anaphylaxis. Thus, serum allergenspecific IgE assessment could support the HA diagnosis. The raw allergen extract is available since long time. However, molecular-based allergy diagnostics have been recently available in the clinical practice [10]. This method allows to define and to characterize the sensitization profile, so identifying potential dangerous proteins and suggesting a more precise prognosis and improving management. HA presents relevant geographic differences both concerning severity and molecular pattern. In this regard, a recent study investigated a population of Dutch children selected on the presence of sensitization to hazelnut (> 0.35 kUA/L) and subdivided on the basis of symptoms severity (subjective or objective). However, reported anaphylaxis was not considered. Therefore, we retrospectively considered a group of children with HA visited in the last year at the Istituto Giannina Gaslini (a third level children hospital in the Northern Italy), subdivided in two groups: • children with history of anaphylaxis after ingestion of hazelnut and; • children with diagnosed HA. Diagnosis of hazelnut anaphylaxis was based on validated criteria, such as: • suggestive clinical history (such as clinical presentation suggesting severe allergic reaction, including vomiting and/or diarrhea, dyspnea, hypotension, orticaria/angioedema); • allergen-specific IgE detection for suspected food and; • symptoms consistent with sensitization, i.e. the demonstration of a cause/effect dependence between hazelnut ingestion and occurrence of anaphylaxis clinical features.
Letter to the editor / Revue française d’allergologie 55 (2015) 100–102
101
Table 1 Demographic and immunological characteristics of the studied subjects.
Age [yrs, mean (SD)] Males [No. of subjects (%)] Total IgE (kU/L) Specific IgE to raw hazelnut (kUA/L) Positive pts. to specific IgE (> 0.35 kUA/L) [n (%)] Specific IgE to Cor a 1 (ISU-E) Positive pts. to Cor a 1 (> 0.3 ISU-E) [n (%)] Specific IgE to Cor a 8 (ISU-E) Positive pts. to Cor a 8 (> 0.3 ISU-E) [n (%)] Specific IgE to Cor a 9 (ISU-E) Positive pts. to Cor a 9 (> 0.3 ISU-E) [n (%)]
Hazelnut anaphylaxis(n = 16)
Hazelnut allergy (n = 33)
P**
9.05 (4.01) 11 (68.75) 1312.50 (688.00–2024.00) 11.62 (2.34–63.30) 16 (100) 0.795 (0.29–6.80) 8 (50) 0.29 (0.29–0.90) 5 (31.2) 0.29 (0.29–1.60) 7 (43.7)
9.45 (4.45) 20 (60.61) 462.00 (230.00–897.00) 1.47 (0.52–9.78) 26 (78.8) 0.29 (0.29–5.6) 15 (45.4) 0.29 (0.29–0.60) 10 (30.3) 0.29 (0.29–0.29) 1 (3)
0.68* 0.58 0.07 0.0045 0.28 0.83 0.76 0.97 0.95 0.0184 0.0009
Unless otherwise specified, all data are reported as median with lower and upper quartiles in parentheses. *P value refers to the unpaired t-test; ISU-E: ISAC Standardized Units. ** P values refer to the Mann-Whitney U test unless otherwise specified. Table 2 Sensitivity, specificity, positive and negative predictive values for each test used to predict anaphylaxis.
Total IgE levels (kU/L) Raw hazelnut levels (kU/L) Cor a 1 levels (ISU-E) Cor a 9 levels (ISU-E)
Cut-offa
AUC (IC95%)
Sens %
Spec %
PPV
NPV
532 19.2 0.7 0.29
0.718 (0.513–0.872) 0.775 (0.608–0.895) 0.526 (0.373–0.665) 0.708 (0.561–0.829)
88.89 42.86 50.00 43.75
58.82 100.00 63.64 96.97
53.33 100.00 40.00 87.50
90.91 74.19 74.21 78.05
AUC: area under the curve; Sens: sensitivity; Spec: specificity; PPV: positive predictive value; NPV: negative predictive value; ROC: receiver operating characteristic. a Cut-off values were determined by means of the ROC curve analysis.
HA diagnosis was performed on: • suggestive history (such as clinical presentation suggesting mild allergic reaction, including oral allergic syndrome); • documented hazelnut sensitization and; • positive oral challenge test. Specific IgE to raw hazelnut allergen was measured by ImmunoCAP method (Thermo Fisher Italy). Specific IgE to molecular components of hazelnut, such as Cor a 1, Cor a 8, and Cor a 9, were assayed by the semi-quantitative ISAC method (Thermo Fisher Italy). Globally, 49 patients were seen: 16 with severe anaphylaxis and 33 with HA. The Table 1 shows clinical and immunologic characteristics of the two groups. Allergen-specific IgE levels to raw hazelnut were significantly higher in anaphylaxis group. Children with anaphylaxis had higher IgE levels to Cor a 9: 7 subjects had positive values, whereas only 1 child with HA (it is to note that this patient had anaphylaxis to walnut). Receiver operating characteristic analysis showed that raw hazelnut (ImmunoCAP) cut-off > 19.2 kUA/L and Cor a 9 (ISAC) cut-off >0.29 ISU (such as the positivity) had fair reliability (area under the curve 0.77 and 0.71 respectively) (Table 2). These findings support the concept that both specific IgE to raw extract and to molecular allergens could be useful and should be integrated for an optimal diagnosis. Therefore, we believe that molecular-based allergy diagnostic should be performed in children with HA, mainly with anaphylaxis, for better defining the sensitization profile and improve the prognosis
and the management of HA children. In fact, molecular-based diagnosis allows to: • distinguish between allergy due to cross-reactivity (Cor a 1 and Cor a 8) and primary hazelnut allergy (Cor a 9); • improve the risk assessment (Cor a 9 defines severe phenotype); • enhance management as children sensitized to Cor a 9 should avoid hazelnut ingestion in any form, whereas monosensitization to Cor a 1 is associated with tolerance of roasted/heated hazelnuts [11], and children sensitized to Cor a 9 should be investigated for allergy to other nuts as poly-allergy may exist [12]. On the other hand, an important and clinically relevant issue is the choice between multiplex (microarray) and singleplex molecular allergen testing. In fact, 3/4 hazelnut allergens (such as Cor a 1, 8, 9) are spotted on the ISAC microarray, whereas 4/4 hazelnut allergens (such as Cor a1, 8, 9, 14) are available as singleplex reagents, thus singleplex determination offers a more complete protein assessment. Moreover, the singleplex determination offers reliable detection and accurate quantitation, while the ISAC microarray is a semi-quantitative assay and its sensitivity is questioned for the detection of conformational allergens such as storage proteins and LTP. The price of microarray vs singleplex is not the same and medical insurance systems may not offer payback for the former. However, microarray offers the possibility of having a wide spectrum of proteins, particularly useful in poly-sensitized patients.
102
Letter to the editor / Revue française d’allergologie 55 (2015) 100–102
In conclusion, high levels of IgE to raw hazelnut and positivity to Cor a 9 may be considered marker of severe HA and adequate counselling should be adopted. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Funding: Partially funded by Ricerca Corrente - Italian Ministry of Health. References [1] Flinterman AE, Akkerdaas JH, Knulst AC, van Ree R, Pasmans SG. Hazelnut allergy: from pollen-associated mild allergy to severe anaphylactic reactions. Curr Opin Allergy Clin Immunol 2008;8:261–5. [2] De Knop KJ, Verweij MM, Grimmelikhuijsen M, Philipse E, Hagendorens MM, Bridts CH, et al. Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region. Ped Allergy Immunol 2011;22:139–49. [3] Sicherer SH, Mu˜noz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1077–83. [4] Osterballe M, Hansen TK, Mortz CG, Høst A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. Ped Allergy Immunol 2005;16:567–73. [5] Mastoff LJN, Mattsson L, Zuidmeer-Jongejan L, Lidholm J, Andersson K, Akkerdaas JH, et al. Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. J Allergy Clin Immunol 2013;132:393–9. [6] Schocker F, Lüttkopf D, Scheurer S, Petersen A, Cisteró-Bahima A, Enrique E, et al. Recombinant lipid transfer protein Cor a 8 fro hazelnut: a new tool for in vitro diagnosis of potentially severe hazelnut allergy. J Allergy Clin Immunol 2004;113:141–7. [7] Verweij MM, Hagendorens MM, De Knop KJ, Bridts CH, De Clerck LS, Stevens WJ, et al. Young infants with atopic dermatitis can display sensitization to Cor a 9. Ped Allergy Immunol 2011;22:196–201.
[8] Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. J Allergy Clin Immunol 2002;110: 517–23. [9] Asero R, Arena A, Cervone M, Crivellaro M, Lodi Rizzini F, Lomgo R, et al. Heterogeneity of IgE response to walnut and hazelnut in Italian allergic patients. Eur Ann Allergy Clin Immunol 2013;45:160–6. [10] Canonica GW, Ansotegui IJ, Pawankar R, Schmid-Grendelmeier P, van Hage M, Baena-Cagnani CE, et al. A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics. WAO J 2013; 6:17. [11] Hansen KS, Ballmer-Weber BK, Lüttkopf D, Skov PS, Wüthrich B, Bindslev-Jensen C, et al. Roasted hazelnuts-allergenic activity evaluated by double-blind, placebo-controlled food challenge. Allergy 2003;58: 132–8. [12] Asero R, Mistrello G, Roncarolo D, Amato S. Walnut-induced anaphylaxis with cross-reactivity to hazelnut and Brazil nut. J Allergy Clin Immunol 2004;113:358–60.
G. Ciprandi a,∗ A. Pistorio b M. Silvestri c G.A. Rossi c M.A. Tosca c a Medicine Department, IRCCS - Azienda Ospedaliera Universitaria San Martino, Genoa, Italy b Epidemiology and Biostatistics Service, Istituto Giannina Gaslini, Genoa, Italy c Pulmonary Disease and Allergy Unit, Istituto Giannina Gaslini, Genoa, Italy ∗ Corresponding
author. Viale Benedetto XV 6, 16132 Genoa, Italy. E-mail address: [email protected] (G. Ciprandi) Received 27 May 2014 Accepted 25 September 2014 Available online 27 January 2015
ScienceDirect www.sciencedirect.com Revue française d’allergologie 55 (2015) 100–102
Letter to the editor Hazelnut anaphylaxis: The usefulness of molecularbased allergy diagnostics Anaphylaxie à la noisette : utilité diagnostique des allergènes moléculaires
Keywords: Hazelnut; Anaphylaxis; Food allergy; Diagnosis; Molecular allergens Mots clés : Noisette ; Anaphylaxie ; Allergie alimentaire ; Diagnostic ; Allergènes moléculaires
To the Editor, The hazelnut is the fruit of the hazel tree (Corylus avellana) belonging to the Corylaceae family. Its seed is commonly eaten dried, roasted or heated. Hazelnut may be a hidden allergen as contained in pastries, cookies, and chocolate. Hazelnut allergy (HA) accounts for a serious cause of food allergy [1]. In fact, the clinical presentation of HA may be particularly variable: ranging from mild subjective symptoms up to severe and fatal anaphylaxis. Usually, severe and systemic reactions are more frequent in childhood than in adulthood [2]. The HA prevalence is about 0.2% in children [3]. However, it is up to 4.5% among adults in regions with heavy exposure to Betulaceae and/or Corylaceae tree species [4]. Moreover, primary sensitization to hazelnut is more common in children than in adults [5]. These clinical and immunological differences might depend on different sensitization profile to the hazelnut allergen proteins. In this regard, at least 15 hazelnut allergen proteins have been identified. Cor a 1 is a PR-10 protein with high homology with the major birch allergen Bet v 1, as both display extensive cross-reactivity. Cor a 1 is heat- and digestion-labile: for this reason is primarily associated with local reaction: the so-called Oral Allergic Syndrome. Patients sensitized to Cor a 1 usually tolerate roasted hazelnuts. Cor a 8 is a lipid transfer protein (LTP), its sensitization is often associated with symptoms to other LTP-containing food, such as peach, lettuce, peanut, walnut, and cherry [6]. Cor a 8 is heat- and digestion-stable so is associated with local as well as systemic reactions. Cor a 9 and Cor a 14 are hazelnut storage proteins (the former is a 11S globulin; the last is a 2S albumin). Cor a 9 and 14 sensitization can occur early in life [7]. They are heat- and digestion-stable, are abundant in hazelnut, and associated with systemic reactions [2,5,8]. Recently, Masthoff et al. reported that sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective http://dx.doi.org/10.1016/j.reval.2014.09.005 1877-0320/© 2015 Elsevier Masson SAS. All rights reserved.
symptoms after oral challenge and both may be a marker for a more severe hazelnut allergic phenotype [5]. In addition, a recent Italian study reported a wide heterogeneity in molecular pattern of sensitization in allergic patients to hazelnut [9]. The HA diagnostic work-up is typically based on history, detection of allergen-specific IgE by skin prick test and/or serum assessment, and oral challenge. Prick by prick with hazelnut may be also performed. Oral food challenge represents the mainstay for food allergy as it allows of clarifying accurately the causality of the specific allergen. On the other hand, challenge is very dangerous in patients with anaphylaxis. Thus, serum allergenspecific IgE assessment could support the HA diagnosis. The raw allergen extract is available since long time. However, molecular-based allergy diagnostics have been recently available in the clinical practice [10]. This method allows to define and to characterize the sensitization profile, so identifying potential dangerous proteins and suggesting a more precise prognosis and improving management. HA presents relevant geographic differences both concerning severity and molecular pattern. In this regard, a recent study investigated a population of Dutch children selected on the presence of sensitization to hazelnut (> 0.35 kUA/L) and subdivided on the basis of symptoms severity (subjective or objective). However, reported anaphylaxis was not considered. Therefore, we retrospectively considered a group of children with HA visited in the last year at the Istituto Giannina Gaslini (a third level children hospital in the Northern Italy), subdivided in two groups: • children with history of anaphylaxis after ingestion of hazelnut and; • children with diagnosed HA. Diagnosis of hazelnut anaphylaxis was based on validated criteria, such as: • suggestive clinical history (such as clinical presentation suggesting severe allergic reaction, including vomiting and/or diarrhea, dyspnea, hypotension, orticaria/angioedema); • allergen-specific IgE detection for suspected food and; • symptoms consistent with sensitization, i.e. the demonstration of a cause/effect dependence between hazelnut ingestion and occurrence of anaphylaxis clinical features.
Letter to the editor / Revue française d’allergologie 55 (2015) 100–102
101
Table 1 Demographic and immunological characteristics of the studied subjects.
Age [yrs, mean (SD)] Males [No. of subjects (%)] Total IgE (kU/L) Specific IgE to raw hazelnut (kUA/L) Positive pts. to specific IgE (> 0.35 kUA/L) [n (%)] Specific IgE to Cor a 1 (ISU-E) Positive pts. to Cor a 1 (> 0.3 ISU-E) [n (%)] Specific IgE to Cor a 8 (ISU-E) Positive pts. to Cor a 8 (> 0.3 ISU-E) [n (%)] Specific IgE to Cor a 9 (ISU-E) Positive pts. to Cor a 9 (> 0.3 ISU-E) [n (%)]
Hazelnut anaphylaxis(n = 16)
Hazelnut allergy (n = 33)
P**
9.05 (4.01) 11 (68.75) 1312.50 (688.00–2024.00) 11.62 (2.34–63.30) 16 (100) 0.795 (0.29–6.80) 8 (50) 0.29 (0.29–0.90) 5 (31.2) 0.29 (0.29–1.60) 7 (43.7)
9.45 (4.45) 20 (60.61) 462.00 (230.00–897.00) 1.47 (0.52–9.78) 26 (78.8) 0.29 (0.29–5.6) 15 (45.4) 0.29 (0.29–0.60) 10 (30.3) 0.29 (0.29–0.29) 1 (3)
0.68* 0.58 0.07 0.0045 0.28 0.83 0.76 0.97 0.95 0.0184 0.0009
Unless otherwise specified, all data are reported as median with lower and upper quartiles in parentheses. *P value refers to the unpaired t-test; ISU-E: ISAC Standardized Units. ** P values refer to the Mann-Whitney U test unless otherwise specified. Table 2 Sensitivity, specificity, positive and negative predictive values for each test used to predict anaphylaxis.
Total IgE levels (kU/L) Raw hazelnut levels (kU/L) Cor a 1 levels (ISU-E) Cor a 9 levels (ISU-E)
Cut-offa
AUC (IC95%)
Sens %
Spec %
PPV
NPV
532 19.2 0.7 0.29
0.718 (0.513–0.872) 0.775 (0.608–0.895) 0.526 (0.373–0.665) 0.708 (0.561–0.829)
88.89 42.86 50.00 43.75
58.82 100.00 63.64 96.97
53.33 100.00 40.00 87.50
90.91 74.19 74.21 78.05
AUC: area under the curve; Sens: sensitivity; Spec: specificity; PPV: positive predictive value; NPV: negative predictive value; ROC: receiver operating characteristic. a Cut-off values were determined by means of the ROC curve analysis.
HA diagnosis was performed on: • suggestive history (such as clinical presentation suggesting mild allergic reaction, including oral allergic syndrome); • documented hazelnut sensitization and; • positive oral challenge test. Specific IgE to raw hazelnut allergen was measured by ImmunoCAP method (Thermo Fisher Italy). Specific IgE to molecular components of hazelnut, such as Cor a 1, Cor a 8, and Cor a 9, were assayed by the semi-quantitative ISAC method (Thermo Fisher Italy). Globally, 49 patients were seen: 16 with severe anaphylaxis and 33 with HA. The Table 1 shows clinical and immunologic characteristics of the two groups. Allergen-specific IgE levels to raw hazelnut were significantly higher in anaphylaxis group. Children with anaphylaxis had higher IgE levels to Cor a 9: 7 subjects had positive values, whereas only 1 child with HA (it is to note that this patient had anaphylaxis to walnut). Receiver operating characteristic analysis showed that raw hazelnut (ImmunoCAP) cut-off > 19.2 kUA/L and Cor a 9 (ISAC) cut-off >0.29 ISU (such as the positivity) had fair reliability (area under the curve 0.77 and 0.71 respectively) (Table 2). These findings support the concept that both specific IgE to raw extract and to molecular allergens could be useful and should be integrated for an optimal diagnosis. Therefore, we believe that molecular-based allergy diagnostic should be performed in children with HA, mainly with anaphylaxis, for better defining the sensitization profile and improve the prognosis
and the management of HA children. In fact, molecular-based diagnosis allows to: • distinguish between allergy due to cross-reactivity (Cor a 1 and Cor a 8) and primary hazelnut allergy (Cor a 9); • improve the risk assessment (Cor a 9 defines severe phenotype); • enhance management as children sensitized to Cor a 9 should avoid hazelnut ingestion in any form, whereas monosensitization to Cor a 1 is associated with tolerance of roasted/heated hazelnuts [11], and children sensitized to Cor a 9 should be investigated for allergy to other nuts as poly-allergy may exist [12]. On the other hand, an important and clinically relevant issue is the choice between multiplex (microarray) and singleplex molecular allergen testing. In fact, 3/4 hazelnut allergens (such as Cor a 1, 8, 9) are spotted on the ISAC microarray, whereas 4/4 hazelnut allergens (such as Cor a1, 8, 9, 14) are available as singleplex reagents, thus singleplex determination offers a more complete protein assessment. Moreover, the singleplex determination offers reliable detection and accurate quantitation, while the ISAC microarray is a semi-quantitative assay and its sensitivity is questioned for the detection of conformational allergens such as storage proteins and LTP. The price of microarray vs singleplex is not the same and medical insurance systems may not offer payback for the former. However, microarray offers the possibility of having a wide spectrum of proteins, particularly useful in poly-sensitized patients.
102
Letter to the editor / Revue française d’allergologie 55 (2015) 100–102
In conclusion, high levels of IgE to raw hazelnut and positivity to Cor a 9 may be considered marker of severe HA and adequate counselling should be adopted. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Funding: Partially funded by Ricerca Corrente - Italian Ministry of Health. References [1] Flinterman AE, Akkerdaas JH, Knulst AC, van Ree R, Pasmans SG. Hazelnut allergy: from pollen-associated mild allergy to severe anaphylactic reactions. Curr Opin Allergy Clin Immunol 2008;8:261–5. [2] De Knop KJ, Verweij MM, Grimmelikhuijsen M, Philipse E, Hagendorens MM, Bridts CH, et al. Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region. Ped Allergy Immunol 2011;22:139–49. [3] Sicherer SH, Mu˜noz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1077–83. [4] Osterballe M, Hansen TK, Mortz CG, Høst A, Bindslev-Jensen C. The prevalence of food hypersensitivity in an unselected population of children and adults. Ped Allergy Immunol 2005;16:567–73. [5] Mastoff LJN, Mattsson L, Zuidmeer-Jongejan L, Lidholm J, Andersson K, Akkerdaas JH, et al. Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. J Allergy Clin Immunol 2013;132:393–9. [6] Schocker F, Lüttkopf D, Scheurer S, Petersen A, Cisteró-Bahima A, Enrique E, et al. Recombinant lipid transfer protein Cor a 8 fro hazelnut: a new tool for in vitro diagnosis of potentially severe hazelnut allergy. J Allergy Clin Immunol 2004;113:141–7. [7] Verweij MM, Hagendorens MM, De Knop KJ, Bridts CH, De Clerck LS, Stevens WJ, et al. Young infants with atopic dermatitis can display sensitization to Cor a 9. Ped Allergy Immunol 2011;22:196–201.
[8] Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. J Allergy Clin Immunol 2002;110: 517–23. [9] Asero R, Arena A, Cervone M, Crivellaro M, Lodi Rizzini F, Lomgo R, et al. Heterogeneity of IgE response to walnut and hazelnut in Italian allergic patients. Eur Ann Allergy Clin Immunol 2013;45:160–6. [10] Canonica GW, Ansotegui IJ, Pawankar R, Schmid-Grendelmeier P, van Hage M, Baena-Cagnani CE, et al. A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics. WAO J 2013; 6:17. [11] Hansen KS, Ballmer-Weber BK, Lüttkopf D, Skov PS, Wüthrich B, Bindslev-Jensen C, et al. Roasted hazelnuts-allergenic activity evaluated by double-blind, placebo-controlled food challenge. Allergy 2003;58: 132–8. [12] Asero R, Mistrello G, Roncarolo D, Amato S. Walnut-induced anaphylaxis with cross-reactivity to hazelnut and Brazil nut. J Allergy Clin Immunol 2004;113:358–60.
G. Ciprandi a,∗ A. Pistorio b M. Silvestri c G.A. Rossi c M.A. Tosca c a Medicine Department, IRCCS - Azienda Ospedaliera Universitaria San Martino, Genoa, Italy b Epidemiology and Biostatistics Service, Istituto Giannina Gaslini, Genoa, Italy c Pulmonary Disease and Allergy Unit, Istituto Giannina Gaslini, Genoa, Italy ∗ Corresponding
author. Viale Benedetto XV 6, 16132 Genoa, Italy. E-mail address: [email protected] (G. Ciprandi) Received 27 May 2014 Accepted 25 September 2014 Available online 27 January 2015