Bollemeijer, Juliette F.

Ehlers, Anna M.

Kallen, Emily J.J.

Knulst, André C.

Le, Thuy My

van Ree, Ronald

Welsing, Paco M.J.

Utrecht University Repository

880  |    Clin Exp Allergy. 2023;53:880–882.wileyonlinelibrary.com/journal/ceaReceived: 25 January 2023  | Revised: 23 March 2023  | Accepted: 31 March 2023DOI: 10.1111/cea.14331  R E S E A R C H  L E T T E RComponent Ana o 3 versus extract for cashew nut allergy: A diagnostic test accuracy study in adultsTo the Editor,Cashew nut allergy is a common tree nut allergy.1,2 In children, pre-vious studies showed that IgE against the cashew nut component Ana o 3 has a better diagnostic value for cashew nut allergy than IgE against cashew nut extract.3– 7 In adults, studies are lacking. Therefore, the aim of this study was to determine the diagnostic value of IgE against cashew nut extract and Ana o 3 in adults sus-pected of cashew nut allergy. In addition, the association between severity and IgE levels against cashew nut extract and Ana o 3 was assessed.Adult patients (≥18 years) who visited the Department of Dermatology and Allergology of the University Medical Center Utrecht (UMCU), the Netherlands, with a clear history of anaphy-laxis to cashew nut and patients with a suspected cashew nut allergy who underwent an open food challenge (OFC) were included. The reasons for a suspected cashew nut allergy were for example a past history of symptoms to cashew nut, positive provocation at earlier age or symptoms to a meal containing cashew nut. Patients were excluded from analyses if the time between IgE measurement and OFC was more than 2 years and/or if they had missing data on sIgE and insufficient serum available to determine sIgE results. This study was approved by the local ethical committee (protocol number 13- 272). All patients provided informed consent.Data on patient demographics (age, sex), allergic comorbidities (allergic rhinitis, asthma, atopic dermatitis), OFC results and serum IgE levels against cashew nut extract and Ana o 3 were retrospec-tively collected from patients' medical files. Anaphylaxis was diag-nosed according to the Anaphylaxis guideline of the EAACI.8 IgE levels against cashew nut extract and Ana o 3 were determined using the ImmunoCAP platform (ThermoFisher Scientific). In pa-tients without historic sIgE results, sIgE levels were obtained using leftover serum stored in our biobank. If possible, serum from the same timepoint was used to measure both IgE levels. Otherwise, available serum closest to the first measurement was used with a maximum of 2 years between measurements. Sensitization was de-fined as positive when sIgE levels were ≥0.35 kU/L. Typically, IgE measurements were performed prior to OFC and doctors and pa-tients were aware of the results.Analyses were performed using IBM SPSS Statistics (ver-sion 26.0.0.1) and RStudio (version 1.3.1093). The characteristics between patients with cashew nut allergy and those without ca-shew nut allergy were described and compared statistically. P values ≤.05 were considered statistically significant. The correlation among IgE levels against cashew nut extract and Ana o 3 was calculated using Spearman's rho coefficients. The diagnostic value of IgE levels against cashew nut extract and Ana o 3 was assessed by the area under the curve (AUC) of the receiver operating characteristic (ROC) analysis. DeLong's test was used to statistically compare the AUCs.9 Sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were calculated for the clinically used cutoff point and the calculated optimal cutoff point. Cutoff points above which the PPV was 100% and below which the NPV was 100% were determined in our sample. If the cutoff point for the 100% NPV was below 0.10 kU/L (the detection limit for accurately measuring IgE levels) the NPV corresponding to 0.10 kU/L was used.The severity of cashew nut allergy was dichotomized into mild to moderate cashew nut allergy (i.e. oFASS- 3 grade 1 and 2) versus severe cashew nut allergy (i.e. oFASS- 3 grade 3). Differences in IgE levels between tolerant patients, patients with mild/moderate and severe symptoms were tested using Kruskal- Wallis tests. AUC was used to further explore differences in IgE levels against cashew nut extract and Ana o 3 between patients with mild/moderate versus severe symptoms.A total of 52 patients underwent an OFC for suspected cashew nut allergy after which nine patients were excluded from analyses due to insufficient serum volume availability and two due to exceeding the maximum amount of time between IgE measurement and OFC. Two patients were included based on a clear history of anaphylaxis to cashew nut. There was no significant difference in age, sex, atopic background and severity of allergic reaction during OFC between included and excluded patients. In total, 43 patients were included in this study. Of the 43 included patients, 18 (42%) were allergic to cashew nut. Of the 18 allergic patients, 16 underwent an OFC and 2 had an anaphylactic history to cashew nut. Of all allergic patients, 16 (89%) experienced objective symptoms and 2 (11%) only subjective symptoms. When classifying the allergic patients according to the oFASS- 3 classification, none of the patients experienced a mild reac-tion, 12 (67%) had a moderate reaction and 6 (33%) a severe reaction.IgE levels against cashew nut extract and Ana o 3 were signifi-cantly higher in the allergic group (sIgE against cashew nut extract This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.    |  881RESEARCH LETTER2.57 kUa/L and Ana o 3 2.65 kUa/L) than in the tolerant group (sIgE against cashew nut extract 0.05 kUa/L and Ana o 3 0.01 kUa/L; both p < .001). The correlation between IgE against cashew nut extract and Ana o 3 was strong (Spearman's rho: 0.92).IgE against Ana o 3 was slightly better at distinguishing between cashew nut allergic and tolerant patients (AUC of 0.95 [95% CI: 0.90– 1.00]) than IgE against cashew nut extract (AUC of 0.90 [95% CI: 0.80– 0.99]); p- value for comparison AUC– ROC = .05 (Figure 1). The lowest cutoff value above which PPV was 100% was 1.27 kUa/L for IgE against Ana o 3. Twenty- six percent (11/43) of the patients had an IgE level against Ana o 3 above this cutoff value. A value of <0.10 kUa/L for IgE against Ana o 3 resulted in a NPV of 91%, and identified 47% (20/43) of patients correctly as tolerant. When these values were combined, 72% of the patients could be diagnosed as cashew nut allergic or tolerant. When we combined the 100% PPV (cutoff value IgE > 5.82) and 94% NPV (cutoff value IgE < 0.10) val-ues for IgE against cashew nut extract, 49% (21/43) of the patients could be diagnosed as cashew nut tolerant or allergic. Measuring IgE against cashew nut extract had no added value when Ana o 3 had already been measured.The median IgE levels of cashew nut extract and Ana o 3 were significantly higher in the mild/moderate and severe allergic patients compared to the tolerant patients (all p- values <.001). Patients with a severe cashew nut allergy tended to have higher median IgE lev-els against both cashew nut extract and Ana o 3 than patients with mild to moderate cashew nut allergy, but this was not statistically significant (p = .43 vs. p = .42, respectively; Figure 2). The AUCs of IgE levels against Ana o 3 and cashew nut extract in predicting se-verity were 0.69 [95% CI: 0.43– 0.96] and 0.68 [95% CI: 0.41– 0.94], respectively.This is the first study that investigated the diagnostic value of Ana o 3 versus cashew nut extract in adults. IgE against Ana o 3 was found to be superior to IgE against cashew nut extract in the predic-tion of cashew nut allergy which is in line with previous studies in children (AUCs IgE against Ana o 3: 0.90– 0.99; IgE against cashew nut extract: 0.78– 0.89).3– 7 When combining the cutoff value for 100% PPV (1.27 kUa/L) and 91% NPV (<0.10 kUa/L) for IgE against Ana o 3, a total of 72% of patients were diagnosed as either cashew nut allergic or tolerant. Only for patients with an IgE level against Ana o 3 between 0.10 and 1.27 kUa/L (28%) an OFC be needed. As PPV and NPV of diagnostic tools are dependent on the prevalence of cashew nut allergy in the population examined and our patient Key messages• We undertook a diagnostic test accuracy study in 43 adults with a suspected cashew nut allergy.• We found that specific IgE to Ana o 3 had a slightly bet-ter diagnostic performance than cashew nut extract.• Both specific IgE to Ana o 3 and cashew nut extract did not reliably predict reaction severity.F I G U R E  1  ROC- curves of IgE against cashew nut extract and Ana o 3 to predict cashew nut allergy. Abbreviations: AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristics.F I G U R E  2  Level of IgE against cashew nut extract and Ana o 3 in tolerant patients, patients with mild to moderate symptoms (oFASS- 1/2) and those with severe symptoms (oFASS- 3). Abbreviations: kUa/L = kilo units of antibody per litre.Tolerant oFASS-1/2 oFASS-305101520IgEagainstcashewnutextract(kUa/L)p < 0.001p = 0.428p < 0.001Tolerant oFASS-1/2 oFASS-305101520IgEagainstAnao3(kUa/L)p < 0.001p < 0.001p = 0.418 13652222, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.14331 by Cochrane Netherlands, Wiley Online Library on [12/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License882  |    RESEARCH LETTERsample was relatively small, generalizability of these cutoff values to other populations is unclear, stressing the importance of validation in other datasets.In relation to severity of cashew nut allergy, the median IgE val-ues against cashew nut extract and Ana o 3 were significantly higher in the allergic patients with mild/moderate and severe symptoms compared to the cashew nut tolerant patients. Although levels of IgE against cashew nut extract and against Ana o 3 tended to be higher in patients with severe reactions compared to patients with mild to moderate reactions, this was not statistically significant. This might be due to the small number of cashew nut allergic patients (12 patients with moderate vs 6 patients with severe allergic reactions). An earlier Dutch study (n = 173) obtained comparable results in chil-dren and found a significant difference in IgE levels against cashew nut extract and against Ana o 3 between the tolerant and cashew nut allergic group (p < .001), and no significant difference in both IgE levels between patients with mild symptoms and anaphylaxis (p = .916).7In conclusion, this study showed that IgE against Ana o 3 is a very good predictor of cashew nut allergy in adults, correctly categoriz-ing 72% of patients as allergic or tolerant in our study population. Although an association with symptom severity was observed, IgE against Ana o 3 and against cashew nut extract were not able to predict severity of cashew nut allergy.AUTHOR CONTRIBUTIONSAll authors have made substantial contributions to conception and design of this study and have been involved in drafting or revising the manuscript. All authors have given final approval of the ver-sion to be published and agreed to be accountable for all aspects of the work. E. Kallen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. This research did not receive any specific grant from funding agencies in the public, commercial, or not- for- profit sectors.KE Y WORDSAna o 3, cashew nut allergy, cashew nut extract, diagnostic value, severityCONFLIC T OF INTERE S T S TATEMENTEmily Kallen, Juliette Bollemeijer and André Knulst have noth-ing to disclose. Anna Ehlers has received research support from EUROIMMUN. Paco Welsing has nothing to disclose. Ronald van Ree has stock options in Angany Inc; is a consultant and/or speaker for HAL Allergy, Citeq BV, Angany Inc., Reacta Healthcare Ltd., Mission MightyMe, AB Enzymes, ALK and Thermo Fisher Scientific. Thuy- My Le is a speaker for and/or received research support from Novartis, Thermo Fisher Scientific and AbbVie.DATA AVAIL ABILIT Y S TATEMENTThe data that support the findings of this study are available from the corresponding author upon reasonable request.Emily J. J. Kallen1Juliette F. Bollemeijer1André C. Knulst1Anna M. Ehlers2Paco M. J. Welsing1Ronald van Ree3Thuy- My Le11Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands2Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands3Departments of Experimental Immunology and Otorhinolaryngology, Amsterdam University Medical Center, Amsterdam, The NetherlandsCorrespondenceEmily J. J. Kallen, Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.Email: e.j.j.kallen@umcutrecht.nlORCIDEmily J. J. Kallen  https://orcid.org/0000-0001-5711-5552 Juliette F. Bollemeijer  https://orcid.org/0000-0002-2350-9526 André C. Knulst  https://orcid.org/0000-0002-1056-3179 Anna M. Ehlers  https://orcid.org/0000-0001-7833-2900 Paco M. J. Welsing  https://orcid.org/0000-0003-2361-2803 Ronald van Ree  https://orcid.org/0000-0003-0767-0894 Thuy- My Le  https://orcid.org/0000-0001-6571-220X R E FE R E N C E S 1. McWilliam V, Koplin J, Lodge C, Tang M, Dharmage S, Allen K. The prevalence of tree nut allergy: a systematic review. Curr Allergy Asthma Rep. 2015;15:15- 13. doi:10.1007/s11882-015-0555-8 2. McWilliam VL, Perrett KP, Dang T, Peters RL. Prevalence and natural history of tree nut allergy. Ann Allergy Asthma Immunol. 2020;124:466- 472. doi:10.1016/j.anai.2020.01.024 3. Lange L, Lasota L, Finger A, et al. Ana o 3- specific IgE is a good predictor for clinically relevant cashew allergy in children. Allergy. 2017;72:598- 603. 4. Röntynen P, Kukkonen K, Savinko T, Mäkelä MJ. Optimizing tools for evaluating challenge outcomes in children with cashew nut al-lergy. Ann Allergy Asthma Immunol. 2022;128:270- 278. 5. Sato S, Movérare R, Ohya Y, et al. Ana o 3– specific IgE is a pre-dictive marker for cashew oral food challenge failure. J Allergy Clin Immunol. 2019;7:2909- 2911.e4. 6. Dang TD, Peters R, Neeland MR, et al. Ana o 3 sIgE testing increases the accuracy of cashew allergy diagnosis using a two- step model. Pediatr Allergy. 2022;33:e13705. doi:10.1111/pai.13705 7. van der Valk JPM, Gerth van Wijk R, Vergouwe Y, et al. sIgE Ana o 1, 2 and 3 accurately distinguish tolerant from allergic children sensitized to cashew nuts. Clin Exp Allergy. 2017;47:113- 120. 8. Muraro A, Worm M, Alviani C, et al. EAACI guidelines: anaphylaxis (2021 update). Allergy. 2022;77:357- 377. 9. DeLong ER, DeLong DM, Clarke- Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837- 845. 13652222, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cea.14331 by Cochrane Netherlands, Wiley Online Library on [12/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Component Ana o 3 versus extract for cashew nut allergy: A diagnostic test accuracy study in adults

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Component Ana o 3 versus extract for cashew nut allergy: A diagnostic test accuracy study in adults

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