Allergen components in diagnosing childhood hazelnut allergy: Systematic literature review and meta-analysis.

C. Nilsson, M. Berthold, B. Mascialino, M. Orme, S. Sjölander, R. Hamilton, 2020. Allergen components in diagnosing childhood hazelnut allergy: Systematic literature review and meta-analysis. Pediatr Allergy Immunol. 31(2):186-196. doi: 10.1111/pai.13110. 

Background:Hazelnut-specific IgE antibodies (sIgEs) in serum support the diagnosis of hazelnut allergy, but extract-based tests have low diagnostic specificity, commonly leading to over-diagnosis. Measuring sensitization to individual allergen components may enhance the diagnosis of hazelnut allergy. We systematically examined data on diagnostic accuracy of sIgE to commercially available hazelnut components to compare their individual contributions in diagnosing hazelnut allergy. Methods:Seven databases were searched for diagnostic studies on patients suspected of having hazelnut allergy. Studies employing component-specific IgE testing on patients whose final diagnosis was determined by oral food challenges were included in the meta-analysis. Study quality was assessed as recommended by Cochrane. Results:Seven cross-sectional studies and one case-control study were identified, seven presenting data on children (N = 635), and one on a mixed age population. Overall, the diagnostic accuracies of sIgE to both Cor a 9 and Cor a 14 were significantly higher than for Cor a 1-sIgE (P < .05). In children, the specificity of Cor a 14-sIgE at 0.35 kUA /L cutoff was 81.7% (95% CI 77.1, 85.6), and 67.3% (60.3, 73.6) for Cor a 9-sIgE. The specificities for Cor a 1-sIgE and hazelnut-sIgE were 22.5% (7.4, 51.2) and 10.8% (3.4, 29.8), respectively. The sensitivity of Cor a 1-sIgE (60.2% [46.9, 72.2]) was lower than for hazelnut extract-sIgE (95.7% [88.7, 98.5]), while their specificities did not differ significantly. Conclusion:sIgE to Cor a 14 and Cor a 9 hazelnut storage proteins increases diagnostic specificity in assessing hazelnut allergy in children. The combined use of hazelnut extract and hazelnut storage proteins may improve diagnostic value.

Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER Study).

Elizur, A., M.Y. Appel, L. Nachshon, M.B. Levy, N. Epstein-Rigbi, B. Pontoppidan, J. Lidholm, M.R. Goldberg, 2020. Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER Study). J Allergy Clin Immunol: In Practice. 8(1):157-165.e2

Background: Diagnostic methods for distinguishing walnut-allergic patients from walnut-sensitized but walnut-tolerant individuals are limited. Furthermore, characteristics of single walnut versus dual walnut-pecan allergy are lacking. Objective: To provide clinical and molecular characteristics of walnut- and pecan-allergic patients. Methods: A prospective cohort study of 76 walnut-sensitized patients was performed. Walnut skin prick test and serum measurements of specific IgE to walnut and its components were performed. Patients were challenged to walnut and pecan unless they regularly consumed walnut and pecan. Results: Of the 76 patients studied, 61 were diagnosed as walnut-allergic and 15 as walnut-tolerant. IgE levels greater than or equal to 0.35 kUA/L to Jug r 1 or 4 provided the best diagnostic method for identifying walnut-allergic patients (accuracy, 0.93). Of the 61 walnut-allergic patients, 49 were pecan-allergic whereas 12 were pecan-tolerant. None of the walnut-tolerant patients was allergic to pecan. Dual allergic patients had significantly lower walnut reaction dose (median, 100 mg vs 1230 mg; P < .001). IgE levels greater than or equal to 0.35 kUA/L to Jug r 4, low-molecular-weight vicilins, or high-molecular-weight vicilins best segregated dual walnut-pecan–allergic patients from single walnut-allergic patients. Inhibition studies demonstrated that walnut pretreatment completely blocked IgE binding to pecan, whereas in some patients, pecan incubation only partially blocked IgE binding to walnut. Conclusions: Walnut components are helpful in diagnosing walnut allergy and in identifying patients with pecan coallergy. Competitive ELISA indicates that pecan comprises a subset of the allergenic determinants of walnut.

Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study.

Brough, H.A., J.-C. Caubet, A. Mazon, D. Haddad, M.M. Bergmann, J. Wassenberg, V. Panetta,  R. Gourgey, S. Radulovic, M. Nieto, A.F. Santos, A. Nieto, G. Lack, P.A. Eigenmann, 2020. Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study. J Allergy Clin Immunol. 145:1231-9.

Background: Peanut, tree nut, and sesame allergies are responsible for most life-threatening food-induced allergic reactions. Rates of coexistent allergy between these foods have been from mostly retrospective studies that include only a limited number of tree nuts or were not based on oral food challenges. Objective: The Pronuts study is a multicenter European study (London, Geneva, and Valencia) assessing the challenge-proven rate of coexistent peanut, tree nut, and/or sesame seed allergy. Methods: Children aged 0 to 16 years with at least 1 confirmed nut or sesame seed allergy underwent sequential diagnostic food challenges to all other nuts and sesame seed. Results: Overall, the rate of coexistent peanut, tree nut, and sesame seed allergy was 60.7% (n 5 74/122; 95% CI, 51.4% to 69.4%). Peanut allergy was more common in London, cashew and pistachio nut allergies were more common in Geneva, and walnut and pecan allergies were more common in Valencia. Strong correlations were found between cashew-pistachio, walnut-pecan, and walnut-pecan-hazelnut-macadamia clusters. Age (>36 months) and center (Valencia > Geneva > London) were associated with an increased odds of multiple nut allergies. By pursuing the diagnostic protocol to demonstrate tolerance to other nuts, participants were able to introduce a median of 9 nuts. Conclusion: We found a higher rate of coexistent nut and sesame seed allergies than previously reported. Performing sequential food challenges was labor intensive and could result in severe allergic reactions; however, it reduced dietary restrictions. Age was a significant predictor of multiple nut allergies, and thus the secondary spread of nut allergies occurred in older children.

Oral immunotherapy for hazelnut allergy: a single-center retrospective study on 100 patients.

Moraly, T., D.P. de Chambure, S. Verdun, C. Preda, M. Seynave, A.C. Vilain, C. Chenivesse, C. Delebarre-Sauvage, 2019. Oral immunotherapy for hazelnut allergy: a single-center retrospective study on 100 patients. J Allergy Clin Immunol Pract.

BACKGROUND: Oral immunotherapy (OIT) protects patients with IgE-mediated food allergies from food-induced allergic reactions due to accidental exposure and may improve their quality of life. This approach has never been evaluated for hazelnut, a major cause of food allergy in Europe. OBJECTIVE: We sought to determine the proportion of hazelnut-desensitized patients after 6 months of OIT and to identify predictors of successful desensitization. METHOD: In a retrospective single-center study, we included patients under 18 years of age who underwent at least 6 months of hazelnut OIT for IgE-mediated allergy, defined by history of hypersensitivity reaction after hazelnut ingestion, positive hazelnut skin prick test (SPT) or specific IgE, and positive double-blind, placebo-controlled food challenge (DBPCFC). Patients able to tolerate 1635 mg of hazelnut protein (approximately 8 hazelnuts) were considered to be hazelnut desensitized. We determined the proportion of desensitized patients after 6 months of OIT, searched for associations between baseline variables and successful desensitization, and estimated the frequency and severity of OIT-related adverse reactions. RESULTS: One hundred patients were included (64% male, median age 5 years). History of severe reactions was noted in 7% of cases. At 6 months, the proportion of desensitized patients was 34% (95%CI: 25-44). The median eliciting dose (defined as the amount of hazelnut protein provoking a hypersensitivity reaction during the DBPCFC) increased from 106 mg [IQR: 51-249] at baseline to 523 mg [IQR: 190-1635] after 6 months of OIT (p<0.0001). With longer therapy, the proportion of desensitized patients increased. Using multivariate analysis, successful desensitization was associated with older age (OR: 1.5, 95%CI: 1.2-2.2), smaller hazelnut SPT wheal diameter (OR: 0.61, 95%CI: 0.4-0.8), lower hazelnut specific IgE level (OR: 0.86, 95%CI: 0.72-0.98), and absence of cashew allergy (OR: 0.42, 95%CI: 0.12-0.64). Adverse reactions occurred in 30% of patients; none were severe. CONCLUSION: In a cohort of 100 patients aged 3-9 years, our results show for the first time that hazelnut OIT is associated with hazelnut desensitization and may be safe in the majority of patients undergoing this therapy.

Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study.

Elizur, A., M.Y. Appel, L. Nachshon, M.B. Levy, N. Epstein-Rigbi, B. Pontoppidan, J. Lidholm, M.R. Goldberg, 2019. Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study. Lancet Child Adolesc Health. 3(5):312-321.

Background: The safety and efficacy of oral immunotherapy for tree nut allergy has not been demonstrated to date, and its effectiveness is complicated by the high prevalence of co-allergies to several nuts. This study aimed to investigate the use of walnut oral immunotherapy in the desensitisation of walnut and additional tree nuts in patients who are co-allergic to several nuts. Methods: In a single-centre, prospective cohort study (the Nut Co-Reactivity ACquiring Knowledge for Elimination Recommendations study) at the Institute of Allergy, Immunology, and Paediatric Pulmonology at the Yitzhak Shamir Medical Centre, we recruited patients aged 4 years or older who were allergic to walnut, with or without co-allergy to pecan, hazelnut, and cashew. The diagnosis of each food allergy was based on a positive skin prick test or specific serum IgE (≥0·35 kUA/L) to the corresponding nut together with a positive oral food challenge, unless an immediate (within 2 h of exposure) reaction in the past year had been documented. Patients with uncontrolled asthma or a medical contraindication to receive adrenaline were excluded. Patients were assigned to walnut oral immunotherapy or the control group (observation and strict dietary exclusion) on the basis of the order of presentation to the clinic. Oral immunotherapy began with a 4-day dose-escalation phase to establish the single highest tolerated dose, which was consumed daily at home for 24 days; subsequent monthly dose escalations were repeated until 4000 mg walnut protein was achieved. Patients who were desensitised to walnut continued to consume 1200 mg walnut protein daily for 6 months as maintenance. The primary outcome was walnut desensitisation (passing an oral food challenge with 4000 mg of walnut protein) at the end of the study, analysed by intention to treat. In patients who were co-allergic to pecan, hazelnut, and cashew, the proportion who achieved cross-desensitisation to these nuts in addition to walnut desensitisation was examined. Findings: 73 patients with a walnut allergy were enrolled between May 15, 2016, and Jan 14, 2018. 49 (89%) of 55 patients in the oral immunotherapy group were desensitised to walnut compared with none of 18 patients in the control group (odds ratio 9·2, 95% CI 4·3-19·5; p<0·0001). Following walnut desensitisation, all patients who were co-allergic to pecan (n=46) were also desensitised to pecan. Additionally, 18 (60%) of 30 patients who were co-allergic to hazelnut or cashew, and 14 (93%) of 15 patients who were co-allergic to hazelnut alone, were either fully desensitised or responded to treatment. 47 (85%) of 55 patients had an adverse reaction (mostly grade 1 or 2) during up-dosing in the clinic; eight patients required intramuscular epinephrine in response to a dose at home. Of 45 patients who had follow-up data for the maintenance phase, all maintained walnut desensitisation and one patient required epinephrine during this period.  Interpretation: Walnut oral immunotherapy can induce desensitisation to walnut as well as cross-desensitisation to pecan and hazelnut in patients who have tree nut co-allergies, with a reasonable safety profile. A low daily dose of the allergen maintains desensitization.

Sensitization profiles to hazelnut allergens across the United States.

Valcour, A., J. Lidholm, M.P. Borres, R.G. Hamilton, 2019. Sensitization profiles to hazelnut allergens across the United States. Ann Allergy Asthma Immunol. 122(1):111-116.

Background: Measurement of IgE antibody to hazelnut components can aid in the prediction of allergic responses to the food. Objective: To investigate the association between patient demographics (age, location) and patterns of allergic sensitization to hazelnut components across the United States and to investigate the degree of correlation between hazelnut sensitization with sensitization to other tree nuts, peanuts, and their components. Methods: Serum samples from 10,503 individuals with hazelnut extract specific IgE (sIgE) levels of 0.35 kUA/L or higher were analyzed for IgE antibodies to Cor a 1, 8, 9, and 14 by ImmunoCAP. A subset of these patients were analyzed for IgE antibodies to peanut, walnut, and cashew nut IgE along with associated components. Results: Among hazelnut sensitized individuals, children (<3 years old) were predominantly sensitized to Cor a 9 and Cor a 14. Conversely, Cor a 1 sIgE sensitization was much higher in adults than children, especially in the Northeastern United States. Cor a 8 sensitization was relatively constant (near 10%) across all ages. Cosensitization of hazelnut with other tree nuts and peanuts was related to correlation of IgE concentrations of individual component families. Conclusion: We conclude that sensitization to individual hazelnut components is highly dependent on age and/or geographic location. Component correlations suggest that cosensitization to hazelnut and walnut may be caused by their pathogenesis-related protein 10 allergens, nonspecific lipid transfer proteins, or seed storage proteins, whereas hazelnut and peanut cosensitization is more often caused by cross-reactivity of pathogenesis-related protein 10 (Cor a 1 and Ara h 8) and nonspecific lipid transfer proteins (Cor a 8 and Ara h 9).

Cashew nut allergy: Clinical relevance and allergen characterisation.

Mendes, C., J. Costa, A.A. Vicente, M.B.P.P. Oliveira, I. Mafra, 2019. Cashew nut allergy: Clinical relevance and allergen characterisation. Clin Rev Allergy Immunol. 57(1):1-22.

Cashew plant (Anacardium occidentale L.) is the most relevant species of the Anacardium genus. It presents high economic value since it is widely used in human nutrition and in several industrial applications. Cashew nut is a well-appreciated food (belongs to the tree nut group), being widely consumed as snacks and in processed foods by the majority of world’s population. However, cashew nut is also classified as a potent allergenic food known to be responsible for triggering severe and systemic immune reactions (e.g. anaphylaxis) in sensitised/allergic individuals that often demand epinephrine treatment and hospitalisation. So far, three groups of allergenic proteins have been identified and characterised in cashew nut: Ana o 1 and Ana o 2 (cupin superfamily) and Ana o 3 (prolamin superfamily), which are all classified as major allergens. The prevalence of cashew nut allergy seems to be rising in industrialised countries with the increasing consumption of this nut. There is still no cure for cashew nut allergy, as well as for other food allergies; thus, the allergic patients are advised to eliminate it from their diets. Accordingly, when carefully choosing processed foods that are commercially available, the allergic consumers have to rely on proper food labelling. In this sense, the control of labelling compliance is much needed, which has prompted the development of proficient analytical methods for allergen analysis. In the recent years, significant research advances in cashew nut allergy have been accomplished, which are highlighted and discussed in this review.

Immunoreactivity of biochemically purified amandin from thermally processed almonds (PrunusdulcisL.).

Zaffran, V.D., S.K. Sathe, 2018. Immunoreactivity of biochemically purified amandin from thermally processed almonds (PrunusdulcisL.). J Food Sci. 83(7):1805-1809.

Almond seeds were subjected to select thermal processing and amandin was purified from processed and unprocessed (control) seeds using cryoprecipitation. Amandin immunoreactivity was assessed using two murine monoclonal antibodies (mAbs)–4C10 and 4F10 detecting human IgE-relevant conformational and linear epitopes, respectively. Overall amandin immunoreactivity following thermal treatment ranged from 64.9% to 277.8% (4C10) and 81.3% to 270.3% (4F10). Except for autoclaving (121°C, 15 psi, 30 min) and roasting (160°C, 30 min), the tested processing conditions resulted in increased immunoreactivity as determined by mAbs 4C10 and 4F10-based enzyme-linked immunosorbent assays (ELISAs). A significant, yet not complete, reduction in immunoreactivity was caused by autoclaving (121°C, 15psi, 30 min) and roasting (160°C, 30 min). Western- and dot-blot immunoassays corroborated the ELISA results, confirming amandin thermal stability.

Food allergen epitope mapping.

Liu, C., S.K. Sathe, 2018. Food allergen epitope mapping. J. Agric. Food Chem. 66:7238−7248.

With the increased global awareness and rise in food allergies, a multifold interest in food allergens is evident. The presence of undeclared food allergens results in expensive food recalls and increased risks of anaphylaxis for the sensitive individuals. Regardless of the allergenic food, the immunogen needs to be identified and detected before making any efforts to inactivate/eliminate it. In type I food allergies, protein immunogen cross-links immunoglobulin E, leading to basophil/mast cell degranulation, resulting in the symptoms that range from mild irritation to anaphylaxis. A portion/part of the protein, known as the epitope, can interact with either antibodies to elicit allergic reactions or T-cell receptors to initiate allergic sensitization. Antibody-recognized epitopes can be either a linear sequence of amino acids (linear epitope) or a three-dimensional motif (conformational epitope), while T-cell-receptor-recognized epitopes are exclusively linear peptides. Identifying and characterizing human-allergy-relevant epitopes are important for allergy diagnosis/prognosis, immunotherapy, and developing food processing methods that can reduce/eliminate immunogencity/immunoreactivity of the allergen.

Almond Allergy: An Overview on Prevalence, Thresholds, Regulations and Allergen Detection.

Mandalari, G., A.R. Mackie, 2018. Almond Allergy: An Overview on Prevalence, Thresholds, Regulations and Allergen Detection. Nutrients. 10(11), 1706;

Food allergy has been on the increase for many years. The prevalence of allergy to different foods varies widely depending on type of food, frequency of consumption and geographic location. Data from the literature suggests that the prevalence of tree nut allergy is of the order of 1% in the general population. Almond is one such tree nut that is frequently eaten in many parts of the world and represents a potential allergenic hazard. Given the need to label products that contain allergens, a number of different methods of direct and indirect detection have been developed. However, in the absence of population-based threshold data, and given that almond allergy is rare, the sensitivity of the required detection is unknown and thus aims as low as possible. Typically, this is less than 1 ppm, which matches the thresholds that have been shown for other allergens. This review highlights the lack of quantitative data on prevalence and thresholds for almonds, which is limiting progress in consumer protection.