Prevalence of tree nut allergy in Europe: A systematic review and meta-analysis.

In 2014, the European Academy of Allergy and Clinical Immunology (EAACI) published the first systematic review that summarized the prevalence of food allergy (FA) and food sensitization in Europe for studies published 2000-2012. However, only summary estimates for tree nut allergy (TNA) were feasible in that work. In the current update of that systematic review, we summarized the prevalence of tree nut allergy/sensitization to individual tree nuts. Six databases were searched for relevant papers published 2012-2021 and 17 eligible studies were added to the 15 studies already identified between 2000 and 2012, giving a total of 32 studies. Of the investigated tree nuts, meta-analysis was possible for hazelnut, walnut, almond, and in few cases, for cashew, and Brazil nut. The lifetime self-reported prevalence was 0.8% (95% CI 0.5-1.1) for hazelnut and 0.4% (0.2-0.9) for walnut. The point self-reported prevalence was 4.0% (2.9-5.2) for hazelnut, 3.4% (2.0-4.9) for Brazil nut, 2.0% (1.1-2.9) for almond, and 1.8% (1.1-2.5) for walnut. Point prevalence of food challenge-confirmed TNA was 0.04% (0.0-0.1) for hazelnut and 0.02% (0.01-0.1) for walnut. Due to paucity of data, we could not identify any meaningful and consistent differences across age groups and European regions.

The Severity and Frequency of Systemic Reactions to Hazelnut Are Significantly Higher in Hazelnut Allergic Patients Monosensitized to Cor a 8 than in Patients Polysensitized to Cor a 1, Cor a 8, and Cor a 9.

INTRODUCTION: Hazelnuts are a leading trigger of food allergy. To date, several molecular components of hazelnut are available for component-resolved diagnosis. However, little is known about how simultaneous sensitization to multiple allergens affects the severity of the hazelnut-induced reaction. In a previous study, our group demonstrated a lower risk of systemic reactions to peach in patients sensitized to both Pru p 3 and Pru p 1 than in the patient monosensitized to peach LTP. We aimed to assess whether this was also true in hazelnut allergy in a cohort of adult patients. METHODS: Patients were selected based on a history of symptoms such as urticaria, vomiting, diarrhea, asthma, and anaphylaxis indicative of hazelnut IgE-mediated food allergy and graded according to a clinical severity scale. For all patients, specific IgE was determined for Cor a 1 and Cor a 8 and, for most patients, also Cor a 9. Patients were offered an oral food challenge in open format (OFC) with a cocoa-based roasted hazelnut spread on a voluntary basis in order to prescribe an appropriate diet. RESULTS: A total of two hundred and fourteen patients were recruited. Among these, 43 patients were monosensitized to Cor a 8. One hundred and seventy-one patients were sensitized to Cor a 1 (79.9%), and, among them, 48/171 (28.1%) were also Cor a 8 positive. Cor a 9 was evaluated in 124/214 patients, testing positive in 21/124 (16.9%). Patients monosensitized to Cor a 8 experienced systemic reactions more frequently than those sensitized to Cor a 1 ± Cor a 8 (p < 0.00001), with significantly more severe reactions (p < 0.0005) and testing more frequently positive at OFC (p < 0.0001). Regarding Cor a 9, the sensitized patients were significantly younger (p = 0.0013) and showed reactions of similar severity to patients who tested Cor a 9 negative, and these reactions were milder than in patients monosensitized only to Cor a 8. DISCUSSION/CONCLUSION: Sensitization to Cor a 1 seems to protect from the development of the severe systemic reactions induced by Cor a 8 sensitization, Cor a 9 does not influence the severity of symptoms in adult patients. The OFC with roasted hazelnut may help in dietary guidance.

Moldy Hazelnut Husk and Shell Related Hypersensitivity Pneumonitis: A Possible Novel Occupational Causative Agent.

Hypersensitivity pneumonitis (HP) is a complex immune-mediated interstitial lung disease (ILD) triggered by inhalation exposure to environmental or occupational antigens in genetically susceptible individuals. Novel exposure sources and antigens are frequently identified. However, the causative agent remains unidentified in nearly half of HP cases. Early diagnosis for nonfibrotic-HP and quitting the exposure may prevent the disease progression to fibrotic forms and related complications. Here, we present two cases of HP associated with mold exposure in hazelnut husks, leaves, and shells in hazelnut agriculture.

Measurement of IgE to hazelnut allergen components cannot replace hazelnut challenge in Dutch adults.

BACKGROUND: Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults. METHODS: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis. RESULTS: Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kUA /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively. CONCLUSIONS: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country.

Multiplex component-based allergen macroarray test is useful to predict clinical reactivity to tree nuts in children.

BACKGROUND: In tree nut (TN) allergy, singleplex tests showed the diagnostic utility of rAna o 3, rCor a 14/nCor a 9, and nJug r 1/nJug r 4 for cashew/pistachio, hazelnut, and walnut allergies, respectively. However, disadvantages of the tests include high costs and excessive blood sampling in multi-sensitized patients, and a limited number of components. We investigated the utility of a multiplex macroarray (i.e., the ALEX2 test) in TN allergy. METHODS: In 169 children, skin prick test, the component- and extract-specific IgEs of TNs were investigated for clinical reactivity and tolerance. RESULTS: The predictors (AUC = 0.962-0.749) of clinical reactivity to cashew, pistachio, hazelnut, and walnut were rPis v 1/rAna o 3, rPis v 1/rAna o 3/nPis v 2/nPis v 3, rCor a 14/nCor a 11/nCor a 9, and nJug r 1/nJug r 2/nJug r 6/nJug r 4, respectively. More than 93% of the patients with clinical reactivity to pistachio/cashew, hazelnut and walnut had positivity of (≥0.3 kUA/L) rPis v 1/rAna o 3, rCor a 14 and nJug r 1/nJug r 2, respectively. The highest accuracies of clinical reactivity to culprit nut were obtained with combination of rPis v 1, sIgE and SPT positivities for cashew/pistachio, rPis v 1 ≥ 1.0 kUA/L for pistachio, rCor a 14 ≥ 1.0 kUA/L for hazelnut and combination of nJug r 1 and nJug r 2 positivities for walnut, respectively. Also, higher concentrations of rPis v 1 (≥15.0 kUA/L), rCor a 14 (≥5.0 kUA/L) and nJug r 1/nJug r 2 (≥15.0 kUA/L) had %100 specificity and PPV in predicting clinical reactivity to cashew, hazelnut and walnut, respectively. CONCLUSIONS: Multiplex macroarray test is useful and reliable in the diagnosis of TN allergy in children, confirms and expands existing knowledge, and can be used as a stand-alone tool in the bottom-up diagnostic approach.

Evidence of Cross-Reactivity between Different Seed Storage Proteins from Hazelnut (Corylus avellana) and Walnut (Juglans regia) Using Recombinant Allergen Proteins.

Seed storage proteins are extremely stable allergens in nuts, seeds, and legumes and are responsible for the most severe allergic reactions to these foods. The cross-reactivity between seed storage proteins from different sources has not been studied at a molecular level so far. This study aimed to ascertain the cross-reactivity between walnut and hazelnut seed storage proteins using recombinant allergens. Sera from 13 consecutive patients with severe primary walnut and/or hazelnut allergy and hypersensitive to both nuts were studied. IgE specific for rCor a 9, rCor a 14, and rJug r 1 was measured, and inhibition experiments were carried out by measuring IgE reactivity after absorption of patients' sera with freshly prepared walnut extract. All 13 sera showed strong IgE reactivity against walnut 2S albumin, Jug r 1, 12 reacted to hazelnut 2S albumin, Cor a 14, and 8 to the hazelnut legumin, Cor a 9. In inhibition experiments, absorption of sera with whole walnut extract led to the complete disappearance of IgE reactivity to Jug r 1 in 12/13 cases, as expected, but also to the complete disappearance of specific IgE to Cor a 14 in 9/12 sera, and of IgE reactivity to Cor a 9 in 7/8. In the remaining cases a dramatic drop in IgE reactivity was observed. The study shows that patients primarily allergic to either walnut or hazelnut showing a skin or serological reactivity to the other nut also are potentially at risk of severe allergic reactions caused by cross-reactivity between 2S albumins and legumins.

Low-Dose Oral Food Challenge with Hazelnut: Efficacy and Tolerability in Children.

BACKGROUND: Hazelnut allergy (HA) is one of the more common food allergies (FAs) in Europe with a prevalence of 0.2%. The gold standard for diagnosing FA is oral food challenge (OFC) with the culprit food. Another purpose of OFC is to identify the "threshold level" of food as the dose that elicits symptoms. In this way it is possible to avoid a strict elimination diet and to determine the minimal quantity of the culprit food tolerated by the patient. OBJECTIVE: The aim of our study was to assess the efficacy and tolerability of hazelnut low-dose OFC (H-LDOFC) in children with HA. METHODS: From January 2015 to December 2016, we retrospectively analyzed the charts of patients referred to Allergy Unit of Meyer Children's Hospital, Florence, Italy for a history of HA. Prick by prick (PbP) and specific serum IgE (s-IgE) to hazelnut were performed. We proposed conducting an H-LDOFC to parents of children with HA. The H-LDOFC was considered completed when a cumulative dose of 2.5 g of hazelnut was reached. We divided the patients who underwent the H-LDOFC into an asymptomatic and a symptomatic group. For statistics we used SPSS for Windows version 16.0 and conducted a t test for comparing the averages, considering a p value of < 0.05 significant. RESULTS: Forty-three out of 70 patients (61.4%) with HA underwent an H-LDOFC. The PbP to hazelnut (mean ± SD) was 7.2 ± 2.9 mm and the s-IgE to hazelnut 25.3 ± 32.5 kU/L. Twenty-eight out of the 43 patients (65.1%) who underwent H-LDOFC reached the cumulative dose of 2.5 g of hazelnut. During the H-LDOFC, 20/43 patients (46.5%) had no reactions and 23/43 patients had a total of 55 reactions: 34 (61.8%) oral allergy syndrome, 8 (14.5%) rash, 6 (10.9%) abdominal pain, 2 (3.6%) urticaria, 2 (3.6%) angioedema, and 3 (5.4%) dyspnea. Atopic dermatitis was found to present the only statistically significant difference (p = 0.002) in patients with symptoms compared to asymptomatic patients during H-LDOFC. CONCLUSIONS: To our knowledge, this was the first study to assess the efficacy and tolerability of H-LDOFC in a pediatric population. Our study suggests that in children with HA, H-LDOFC is well accepted and safe because adverse reactions are mild and the majority are represented by localized symptoms (oral allergy syndrome) and efficient, especially in terms of improvement of quality of life. For these reasons it could be more extensively used in the treatment of HA.

Diagnostic accuracy, risk assessment, and cost-effectiveness of component-resolved diagnostics for food allergy: A systematic review.

BACKGROUND: Component-resolved diagnostics (CRD) are promising tools for diagnosing food allergy, offering the potential to determine specific phenotypes and to develop patient-tailored risk profiles. Nevertheless, the diagnostic accuracy of these tests varies across studies; thus, their clinical utility remains unclear. Therefore, we synthesized the evidence from studies investigating the diagnostic accuracy, risk assessment ability, and cost-effectiveness of CRD for food allergy. METHODS: We systematically searched 10 electronic databases and four clinical trial registries for studies published from January 2000 to February 2017. The quality of included studies was assessed using QUADAS-2. Due to heterogeneity, we narratively synthesized the evidence. RESULTS: Eleven studies met inclusion criteria, altogether recruiting 1098 participants. The food allergies investigated were cow's milk, hen's egg, peanut, hazelnut, and shrimp. The components with the highest diagnostic accuracy for each allergen, along with their sensitivity-specificity pairs, were as follows: Bos d 4 for cow's milk (62.0% and 87.5%), Gal d 1 for hen's egg (84.2% and 89.8% for heated egg, and 60.6% and 97.1% for raw egg), Ara h 6 for peanut (94.9% and 95.1%), Cor a 14 for hazelnut (100% and 93.8%), and Lit v 1 for shrimp (82.8% and 56.3%) allergy. CONCLUSION: Selected components of cow's milk, hen's egg, peanut, hazelnut, and shrimp allergen showed high specificity, but lower sensitivity. However, few studies exist for each component, and studies vary widely regarding the cutoff values used, making it challenging to synthesize findings across studies. Further research is needed to determine clinically appropriate cutoff values, risk assessment abilities, and cost-effectiveness of CRD approaches.

Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children.

BACKGROUND: Severe allergic reactions, including anaphylaxis, occur during oral food challenges (OFCs) and the first-line treatment of anaphylaxis is epinephrine. OBJECTIVE: To evaluate the percentage of anaphylactic reactions treated with epinephrine during OFCs and to identify associated factors for the administration of epinephrine. METHODS: Children who underwent an OFC with peanut, hazelnut, cow's milk, hen's egg, or cashew nut from 2005 through 2015 in the Netherlands were evaluated. Children with reactions meeting the criteria for anaphylaxis according to the European Academy of Allergy and Clinical Immunology guidelines for food allergy and anaphylaxis were included. Children with an anaphylactic reaction treated with vs without epinephrine were compared. Possible factors associated with the administration of epinephrine, such as age, sex, symptoms consistent with asthma, history of an allergic reaction to the tested allergen, and symptom types during the anaphylactic reaction, were evaluated using logistic regression analysis. RESULTS: Eighty-three children in clinical and research settings (43% boys; median age, 7 years; range, 1-17) who met the criteria for anaphylaxis were included in this study. Thirty-two of 83 children (39%) with anaphylaxis were treated with epinephrine. Respiratory symptoms during the OFC were treated significantly more often with epinephrine than gastrointestinal symptoms (P = .01). CONCLUSION: Only 39% of children with anaphylaxis, according to the guideline criteria, were treated with epinephrine during the OFC and most of these children had respiratory symptoms. There is need for an easy-to-use international guideline for the treatment of allergic symptoms during OFCs.

Bortezomib treatment diminishes hazelnut-induced intestinal anaphylaxis in mice.

Food allergy is a common health problem and can cause anaphylaxis. Avoidance of the offending food allergen is still the mainstay therapeutic approach. In this study, we investigated the role of plasma cell reduction by proteasome inhibition in a murine model of food allergy and examined the impact of this treatment on the systemic and local immune response. For this purpose, intestinal anaphylaxis was induced in BALB/c mice with the food allergen hazelnut, in conjunction with different adjuvants (alum and Staphylococcal enterotoxin B SEB) and different administration routes (oral and intraperitoneal). In both models, allergy symptoms were observed, but the clinical severity was more pronounced in the hazelnut-alum model than in the hazelnut-SEB model. Accordingly, allergen-specific immunoglobulin E (IgE) against hazelnut was detectable, and mast cell protease-1 in serum was increased after allergen provocation. Treatment with the proteasome inhibitor bortezomib reduced plasma cells and resulted in an abolishment of hazelnut allergen-specific IgE, which was associated with amelioration of clinical symptoms as well as a significant decrease in both CD19(+) and follicular B lymphocytes. Our data demonstrate the importance of allergen-specific IgE in food allergy and point to B cells as potential therapeutic targets for its treatment.

Validation of Recipes for Double-Blind Placebo-Controlled Challenges With Milk, Egg White, and Hazelnut.

BACKGROUND: The double-blind, placebo-controlled food challenge (DBPCFC) is considered the definitive diagnostic test for food allergy. Nevertheless, validated recipes for masking the foods are scarce, have not been standardized, and differ between centers. Sensory evaluation techniques such as the triangle test are necessary to validate the recipes used for DBPCFC. METHODS: We developed 3 recipes for use in DBPCFC with milk, egg white, and hazelnut and used the triangle test to validate them in a 2-phase study in which 197 volunteers participated. In each phase, participants tried 3 samples (2 active-1 placebo or 2 placebo-1 active) and had to identify the odd one. In phase 1, the 3 samples were given simultaneously, whereas in phase 2, the 3 samples of foods that failed validation in phase 1 were given sequentially. A visual analog scale (VAS) ranging from 1 to 10 was used to evaluate how much participants liked the recipes. RESULTS: In phase 1, the egg white recipe was validated (n=89 volunteers, 38.9% found the odd sample, P=.16). Milk and hazelnut recipes were validated in phase 2 (for both foods, n=30 participants, 36.7% found the odd sample, P=.36). Median VAS scores for the 3 recipes ranged from 6.6 to 9.7. CONCLUSIONS: We used sensory testing to validate milk, egg white, and hazelnut recipes for use in DBPCFC. The validated recipes are easy to prepare in a clinical setting, provide the equivalent of 1 serving dose, and were liked by most participants.

The component-specific to total IgE ratios do not improve peanut and hazelnut allergy diagnoses.

BACKGROUND: Specific IgE measurement predicts the outcome of oral food challenges with considerable uncertainty when evaluating food allergy. OBJECTIVE: Our aim was to assess whether accounting for the ratio of component- or allergen-specific to total IgE can improve this prediction. METHODS: This multicenter study collected blood samples from children with suspected peanut or hazelnut allergy referred to allergy specialist clinics for food challenges. Specific IgE to peanuts, hazelnuts, and their components (Ara h 1, Ara h 2, Ara h 3, Ara h 8, Cor a 1, Cor a 8, Cor a 9, and Cor a 14) and total IgE levels were determined by using the ImmunoCAP-FEIA. Specific to total IgE ratios were compared with raw IgE levels in terms of discrimination and prediction. RESULTS: Eighty-eight (43%) of 207 children with suspected peanut allergy and 44 (31%) of 142 children with suspected hazelnut allergy had symptoms during food challenge. Discrimination was similar for raw and ratio measures: areas under the curve of 0.93 for Ara h 2-specific IgE versus 0.92 for the Ara h 2-specific/total IgE ratio and 0.89 for Cor a 14-specific IgE versus 0.87 for the Cor a 14-specific/total IgE ratio. The probability for a positive peanut challenge with 0.35 kU/L Ara h 2-specific IgE was 16% when the total IgE level was greater than 500 kU/L compared with 51%/48% for low/medium total IgE levels (<100/100-500 kU/L). A positive hazelnut challenge with 0.35 kU/L Cor a 14-specific IgE was estimated in 7% when total IgE levels were high compared with 34%/32% with low/medium total IgE levels. CONCLUSIONS: Raw Ara h 2- and Cor a 14-specific IgE levels were the best single predictors for pediatric peanut and hazelnut allergies, suggesting the omission of challenges at very high levels. Calculating ratio measures did not improve prediction in this population. However, estimation of individual probabilities for challenge outcomes could be supported by total IgE levels because high levels might indicate lower probabilities at a given component-specific IgE level.

Cor a 14 is the superior serological marker for hazelnut allergy in children, independent of concomitant peanut allergy.

BACKGROUND: Hazelnut is the most frequent cause of tree nut allergy, but up to half of all children with hazelnut allergy additionally suffer from peanut allergy. Our aim was to identify diagnostic values of the most promising serological markers (Cor a 9 and Cor a 14) and to address the influence of concomitant peanut allergy and PR10 sensitization. METHOD: We included 155 children suspected of hazelnut allergy and challenged according to the guidelines. Concomitant allergy to peanuts was verified or ruled out by challenge. Skin prick test, s-IgE and CRD to hazelnut, peanut, PR10 and LPT protein families were measured using ImmunoCAP. RESULTS: Sixty-five children had a positive hazelnut challenge, and 60% of these also had a concomitant peanut allergy. Children allergic to hazelnut were sensitized to Cor a 9 and Cor a 14; peanut-allergic children were sensitized to Ara h 2. Sensitization to PR10 protein components was seen in 45% of all included children, irrelevant to allergy to peanut or hazelnut. A cut-off >0.72 kU/L of IgE towards Cor a 14 diagnosed 87% correctly, making Cor a 14 the superior serology marker. However, nine hazelnut-allergic children were primarily sensitized to Cor a 9. CONCLUSION: Concomitant peanut allergy is common in hazelnut-allergic children, but decision points as well as diagnostic values for Cor a 14 are not affected. We found three independent and well-characterized serotypes; hazelnut-allergic children were sensitized to Cor a 14, peanut-allergic children were sensitized to Ara h 2, and independently of this were children sensitized to birch pollen (Bet v 1).

Cross-sensitization profiles of edible nuts in a birch-endemic area.

BACKGROUND: Sensitization to birch pollen causes cross-sensitization to nuts, but rarely leads to clinical nut allergy. The aim was to study sensitizations to nuts in individuals sensitized to birch pollen and examine cross-reactivities between birch and nut species. METHODS: All subjects with skin prick tests (SPTs) for birch pollen conducted during 1997-2013 in the Skin and Allergy Hospital in Helsinki (n = 114 572) and their available SPTs for nuts (n = 50 604) were included. Nut sensitizations were analyzed both with and without cosensitization to birch and stratified into age-categories. Cross-reactivities were analyzed with hierarchical clustering. One group of 1589 patients was surveyed for symptoms. Data were gathered also from Lapland to examine sensitizations in an area with less birch-pollen exposure. RESULTS: Of subjects with birch sensitization, 84% were cosensitized to hazelnut, 71% to almond, and 60% to peanut. In a subgroup without birch sensitization, young children (<5 years) were most commonly nut-sensitized (8-40%); and this prevalence decreased in adolescents and further in adults (4-12%). Cashew and pistachio (ρ = 0.66; P < 0.001) and pecan and walnut (ρ = 0.65; P < 0.001) correlated the strongest. The majority of nut-sensitized patients (71% hazelnut, 83% almond, 73% peanut) reported no or mild symptoms. Cosensitizations between nuts and birch were similar in Lapland with its lower birch-pollen exposure. CONCLUSION: Birch-sensitized individuals are frequently cosensitized to hazelnut, almond, and peanut. Among the birch-negatives, prevalences of nut sensitizations decrease from early childhood to adolescence. Cashew and pistachio, and pecan and walnut cross-react the most.

Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.

BACKGROUND: Oral challenges are the gold standard in food allergy diagnostic, but time-consuming. Aim of the study was to investigate the role of peanut- and hazelnut-component-specific IgE in the diagnostics of peanut and hazelnut allergy and to identify cutoff levels to make some challenges superfluous. METHODS: In a prospective and multicenter study, children with suspected peanut or hazelnut allergy underwent oral challenges. Specific IgE to peanut, hazelnut, and their components (Ara h 1, Ara h 2, Ara h 3, and Ara h 8, Cor a 1, Cor a 8, Cor a 9, and Cor a 14) were determined by ImmunoCAP-FEIA. RESULTS: A total of 210 children were challenged orally with peanut and 143 with hazelnut. 43% of the patients had a positive peanut and 31% a positive hazelnut challenge. With an area under the curve of 0.92 and 0.89, respectively, Ara h 2 and Cor a 14-specific IgE discriminated between allergic and tolerant children better than peanut- or hazelnut-specific IgE. For the first time, probability curves for peanut and hazelnut components have been calculated. A 90% probability for a positive peanut or hazelnut challenge was estimated for Ara h 2-specific IgE at 14.4 kU/l and for Cor a 14-specific IgE at 47.8 kU/l. A 95% probability could only be estimated for Ara h 2 at 42.2 kU/l. CONCLUSIONS: Ara h 2- and Cor a 14-specific IgE are useful to estimate the probability for a positive challenge outcome in the diagnostic work-up of peanut or hazelnut allergy making some food challenges superfluous.

Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity.

BACKGROUND: Hazelnut and peanut are botanically unrelated foods, but patients are often sensitized and allergic to both, for reasons that are not well understood. METHODS: To investigate molecular cosensitization and cross-reactivity to peanut in hazelnut-sensitized individuals, children (n = 81) and adults (n = 80) were retrospectively selected based on sensitization to hazelnut. IgE to hazelnut extract, Cor a 1, 8, 9 and 14, to peanut extract, Ara h 1, 2, 3, 8 and 9, and to Bet v 1 was determined by ImmunoCAP. Allergy to hazelnut and peanut was established by DBPCFC and/or detailed clinical history. Patients were either tolerant or displayed subjective or objective symptoms to either food. IgE cross-reactivity between hazelnut and peanut storage proteins was assessed by reciprocal ImmunoCAP inhibition experiments. RESULTS: Of the 161 hazelnut-sensitized subjects, 109 (68%) were also sensitized to peanut, and 73 (45%) had clinical expression of allergy to peanut that was not associated with the presence or severity of hazelnut allergy. Instead, it was associated with IgE reactivity to peanut storage proteins, in particular Ara h 2. No cross-reactivity could be detected between Ara h 2 and Cor a 14, and 2 of 13 subjects displayed extensive cross-reactivity between 11S globulins; in plasma of both individuals, Ara h 3 almost completely inhibited IgE binding to Cor a 9. CONCLUSIONS: Peanut allergy is not primarily the result of IgE cross-reactivity to hazelnut storage proteins. IgE to Cor a 14 and Ara h 2 may serve as useful markers of primary sensitization to hazelnut and peanut, respectively.

Failure of introduction of food allergens after negative oral food challenge tests in children.

UNLABELLED: One of the purposes to perform an oral food challenge (FC) test is to avoid unnecessary elimination of food allergens. In case of a negative FC test result, the food can be introduced. It is, however, unknown if patients act according to the outcome of the test. This study evaluates the rate of introduction of peanut, hazelnut, cow's milk or hen's egg allergens after a negative FC test. We investigated the introduction rate of children (0-18 years) with a negative FC test visiting the Department of Allergology, Erasmus Medical Centre Rotterdam from 2008 till 2013 and the factors that influence the rate of introduction. Patients were asked to complete a comprehensive questionnaire about their FC test. In total, 157 (38% girls, mean age during challenge 6.9 years) participated in the study. Of these FC tests, 104 (56%) were followed by a successful introduction, 30 (16%) by a partly introduction (traces or processed foods) and 52 (28%) by a failed introduction. Peanut and hazelnut showed a statistically significant lower successful introduction rate. Age, gender, symptoms during FC test, dietary advice and time period to introduction significantly influenced the rate of introduction. One fourth of the children with failure of introducing foods experienced symptoms during the introduction. CONCLUSION: More than one quarter of all children with a negative FC test result did not introduce the food. The FC test in its current form does not achieve its objective for this group of children.

Hazelnut allergy differs between children and adults in frequency of severity, aetiology and relevance of diagnostic parameters.

BACKGROUND: Hazelnut allergy in adults is often birch pollen related, whereas in children, non-pollen-related hazelnut allergy is more frequent. OBJECTIVE: To compare the differences in hazelnut allergy between children and adults with regard to severity, aetiology and diagnostic value of routinely available data. METHODS: Adults (n = 120) who underwent a double-blind placebo-controlled food challenge (DBPCFC) for hazelnut were selected and compared to 151 hazelnut-challenged children from a previous study. Univariate and multivariate logistic regression analyses were performed to build a prediction model. The area under the curve (AUC) of the ROC curve was determined for level of hazelnut-specific IgE, skin prick test (SPT) and the prediction model. RESULTS: Hazelnut allergy was confirmed by DBPCFC in 95/120 (79%) adults, 77% had only subjective and 23% objective symptoms, whereas in children, 63% had objective symptoms to hazelnut. Within the group of children, the frequency of severe hazelnut allergy was higher in younger than in older children. A concomitant birch pollen allergy was more common in adults (82%) than in children (39%) with a hazelnut allergy. A detailed history with allergic symptoms to previous ingestion of hazelnut had the highest diagnostic value in adults, while in children, SPT to hazelnut extract showed the highest level of discrimination between clinical reactivity and tolerance to hazelnut. CONCLUSIONS AND CLINICAL RELEVANCE: Hazelnut allergy differs between children and adults with respect to frequency of severity, aetiology and relevance of diagnostic parameters. Therefore, age has to be taken into account in the diagnostic work-up of a hazelnut allergy.

Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.

BACKGROUND: Component-resolved diagnosis has been shown to improve the diagnosis of food allergy. OBJECTIVE: We sought to evaluate whether component-resolved diagnosis might help to identify patients at risk of objective allergic reactions to hazelnut. METHOD: A total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms on double-blind, placebo-controlled food challenges (DBPCFCs) and 24 adults with a convincing objective history were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP. RESULTS: IgE levels to hazelnut extract were significantly higher in children with objective than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitization to rCor a 1.04 was observed and not to other water-soluble allergens. Sensitization to rCor a 8 was rare, which is in contrast to rCor a 1. Sensitization to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. By using adapted cutoff levels, a diagnostic discrimination between severity groups was obtained. IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 5 kUA/L or greater (children) and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults) had a specificity of greater than 90% and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms. CONCLUSION: Sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective symptoms in DBPCFCs as a marker for a more severe hazelnut allergic phenotype.

Threshold dose distributions for 5 major allergenic foods in children.

BACKGROUND: For most allergenic foods, insufficient threshold dose information within the population restricts the advice on levels of unintended allergenic foods which should trigger precautionary labeling on prepackaged foods. OBJECTIVE: We wanted to derive threshold dose distributions for major allergenic foods and to elaborate the protein doses at which a proportion of the allergic population is likely to respond. METHODS: For 7 allergenic foods double-blind, placebo-controlled food challenges (DBPCFCs) with a positive outcome for allergic reactions were selected from the clinical database of children routinely tested to diagnose food allergy at the University Medical Center Groningen. For each allergen 2 population threshold distributions were determined with the individual minimal eliciting dose and the preceding dose of each DBPCFC for objective symptoms and any symptom (either subjective or objective). RESULTS: Individual positive DBPCFCs were available for peanut (n = 135), cow's milk (n = 93), hen's egg (n = 53), hazelnut (n = 28), and cashew nut (n = 31). Fewer children were challenged with soy (n = 10) or walnut (n = 13). Threshold dose distributions showed a good statistical and visual fit. The protein dose at which 5% of the allergic population is likely to respond with objective reactions was 1.6 mg for peanut, 1.1 mg for cow's milk, 1.5 mg for hen's egg, 7.4 mg for cashew nut, and 0.29 mg for hazelnut. Thresholds for any symptom were on average 2 to 6 times lower than for objective symptoms. The 95% upper and lower confidence intervals of the threshold distributions were overlapping. The peanut threshold distribution on objective symptoms was similar to the distribution of another European center. CONCLUSIONS: Threshold distribution curves and eliciting doses are a powerful tool to compare different allergenic foods and for informing policy on precautionary labeling.