Peanut Can Be Used as a Reference Allergen for Hazard Characterization in Food Allergen Risk Management: A Rapid Evidence Assessment and Meta-Analysis

Regional and national legislation mandates the disclosure of “priority” allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen (“may contain”) labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed “reference doses,” below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure. Resumen: La legislación regional y nacional exige la divulgación de alérgenos "prioritarios" cuando están presentes como ingrediente en los alimentos, pero esto no se extiende a la presencia involuntaria de alérgenos debido a instalaciones de producción compartidas. Esto ha dado lugar a una proliferación de etiquetas de precaución para alérgenos ("pueden contener") (PAL) que los consumidores alérgicos a los alimentos suelen ignorar. Se han hecho intentos para mejorar la gestión del riesgo de alérgenos para informar mejor el uso de PAL, pero la falta de consenso ha llevado a una variedad de enfoques regulatorios y a la falta de uniformidad en el uso de PAL por parte de las empresas alimentarias. Una posible solución sería establecer “dosis de referencia” acordadas internacionalmente, por debajo de las cuales no se necesitaría PAL. Sin embargo, si se van a utilizar dosis de referencia para informar la necesidad de PAL, entonces es esencial caracterizar el peligro asociado con estas exposiciones de bajo nivel. Para el maní, ahora hay datos publicados relacionados con más de 3000 desafíos doble ciego controlados por placebo en individuos alérgicos, pero falta un nivel similar de evidencia para otros alérgenos prioritarios. Presentamos los resultados de una evaluación rápida de la evidencia y un metanálisis del riesgo deanafilaxia a una exposición a alérgenos de bajo nivel para alérgenos prioritarios. Sobre la base de este análisis, proponemos que el cacahuete puede y debe considerarse un alérgeno ejemplar para la caracterización del peligro en una exposición a un alérgeno de bajo nivel.Instituto de Investigación de Tecnología de AlimentosFil: Turner, Paul J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Patel, Nandinee. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Clínica de Dermatología y Alergología. Kantonsspital; Suiza.Fil: Baumert, Joe L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Blom, W. Marty. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brooke-Taylor, Simon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. King's College London. Departamento de Alergia Pediátrica; Reino Unido.Fil: Campbell, Dianne E. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Campbell, Dianne E. Tecnologías DBV. Montrouge; Francia.Fil: Chen, Hongbing. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Chinthrajah, R. Sharon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Crevel, René W.R. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Dubois, Anthony E.J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ebisawa, Motohiro. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Universidad de Tel Aviv. Facultad de Medicina Sackler. Departamento de Pediatría; Israel.Fil: Gerdts, Jennifer D. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Gowland, M. Hazel. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Houben, Geert F. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Hourihane, Jonathan O.B. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Knulst, André C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: La Vieille, Sébastien. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: López, María Cristina. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Mills, E.N. Clare. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Polenta, Gustavo Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Polenta, Gustavo Alberto. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Purington, Natasha. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Said, María. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Escuela de Medicina Icahn. División de Alergia e Inmunología Pediátricasen. Nueva York. Estados Unidos de América.Fil: Schnadt, Sabine. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. ThermoFisher Scientific; Suecia.Fil: Taylor, Stephen L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Grupo BV. Consultoría Remington; Holanda

Thresholds of allergenic proteins in foods

Threshold doses or Estimated Eliciting Doses (EEDs) represent an important new field of research in food allergy. Clinicians and regulators have embraced some toxicological concepts such as LOAEL and NOAEL and applied them to an area of significant clinical uncertainty and interest. The impact of intrinsic human factors (e.g., asthma and exercise) and extrinsic event factors (e.g., season, location and especially dose of allergen) on a future allergic reaction in the community needs to be considered carefully when interpreting results of clinical and research low-dose food challenges. The ongoing cooperation of food allergy research groups in medicine, food science and government will surely deliver results of the highest importance to the wider communities of allergology, food science and technology and the increasing number of allergic consumers

Translating reference doses into allergen management practice: Challenges for stakeholders

Risk assessment describes the impact of a particular hazard as a function of dose and exposure. It forms the foundation of risk management and contributes to the overall decision-making process, but is not its endpoint. This paper outlines a risk analysis framework to underpin decision-making in the area of allergen cross-contact. Specifically, it identifies challenges relevant to each component of the risk analysis: risk assessment (data gaps and output interpretation); risk management (clear and realistic objectives); and risk communication (clear articulation of risk and benefit). Translation of the outputs from risk assessment models into risk management measures must be informed by a clear understanding of the model outputs and their limitations. This will lead to feasible and achievable risk management objectives, grounded in a level of risk accepted by the different stakeholders, thereby avoiding potential unintended detrimental consequences. Clear, consistent and trustworthy communications actively involving all stakeholders underpin these objectives. The conclusions, integrating the perspectives of different stakeholders, offer a vision where clear, science-based benchmarks form the basis of allergen management and labelling, cutting through the current confusion and uncertainty. Finally, the paper recognises that the proposed framework must be adaptable to new and emerging evidence

Translating reference doses into allergen management practice: Challenges for stakeholders

Risk assessment describes the impact of a particular hazard as a function of dose and exposure. It forms the foundation of risk management and contributes to the overall decision-making process, but is not its endpoint. This paper outlines a risk analysis framework to underpin decision-making in the area of allergen cross-contact. Specifically, it identifies challenges relevant to each component of the risk analysis: risk assessment (data gaps and output interpretation); risk management (clear and realistic objectives); and risk communication (clear articulation of risk and benefit). Translation of the outputs from risk assessment models into risk management measures must be informed by a clear understanding of the model outputs and their limitations. This will lead to feasible and achievable risk management objectives, grounded in a level of risk accepted by the different stakeholders, thereby avoiding potential unintended detrimental consequences. Clear, consistent and trustworthy communications actively involving all stakeholders underpin these objectives. The conclusions, integrating the perspectives of different stakeholders, offer a vision where clear, science-based benchmarks form the basis of allergen management and labelling, cutting through the current confusion and uncertainty. Finally, the paper recognises that the proposed framework must be adaptable to new and emerging evidence

Psychometric parameters of food allergy quality of life during an allergen immunotherapy trial

BACKGROUND: The Food Allergy Quality of Life Questionnaire–Parent Form (FAQLQ‐PF) is a commonly used patient‐reported outcome measure in food allergy (FA) research. It was developed before FA treatment clinical trials were commonplace and is used as a secondary outcome measure in pivotal FA treatment trials. We examined the psychometric properties of the FAQLQ‐PF and its relevance to children with peanut allergy engaged in an epicutaneous immunotherapy (EPIT) clinical trial. METHODS: Analysis was performed on 26 universally answered items of the FAQLQ‐PF, from assessments undertaken during the phase 3 PEPITES study (baseline, Month 12), which examined the safety and efficacy of EPIT for children with peanut allergy aged 4–11 years. Item response theory (IRT) was used to assess psychometric parameters of the FAQLQ‐PF (i.e., discrimination, difficulty, and information). Confirmatory factor analysis was also employed; reliability was assessed using McDonald's omega (ω) and Cronbach's alpha (α). RESULTS: A total of 23 of 26 items presented very high discrimination levels (>1.7), and all 26 fell within the recommended difficulty threshold (between −1.5 and 1.5). The items contributed a reasonable information level for their respective factors/subdomains. The measure also presented a marginally acceptable model fit for the 3‐factor structure (e.g., comparative fit index = 0.88, Tucker–Lewis index = 0.87) and good reliability levels across time points (ω and α > 0.90). CONCLUSIONS: Herein, we present a novel reanalysis of the FAQLQ‐PF items using IRT. The longitudinal performance of individual items and subscales was corroborated, and items with the highest discrimination were identified, showing that the tool is suitable for longitudinal measurements in FA treatment trials

Physician's appraisal vs documented signs and symptoms in the interpretation of food challenge tests:The EuroPrevall birth cohort

Background. Blinded food challenges are considered the current gold standard for the diagnosis of food allergies. We used data from a pan-European multicentre project to assess differences between study centres, aiming to identify the impact of subjective aspects for the interpretation of oral food challenges. Methods: Nine study centres of the EuroPrevall birth cohort study on food allergy recruited 12,049 newborns and followed them for up to 30 months in regular intervals. Intensive training was conducted and every centre visited to ensure similar handling of the protocols. Suspected food allergy was clinically evaluated by double-blind, placebocontrolled food challenges using a nine dose escalation protocol. The primary challenge outcomes based on physician’s appraisal were compared to documented signs and symptoms. Results: Of 839 challenges conducted, study centres confirmed food allergy in 15.6% to 53.6% of locally conducted challenges. Centres reported 0 to 16 positive placebo challenges. Worsening of eczema was the most common sign when challenged with placebo. Agreement between documented objective signs and the challenge outcome assigned by the physician was heterogeneous, with Cohen’s kappa spanning from 0.42 to 0.84. Conclusions: These differences suggest that the comparison of food challenge outcomes between centres is difficult despite common protocols and training. We recommend detailed symptom assessment and documentation as well as objective sign-based challenge outcome algorithms to assur

Deriving individual threshold doses from clinical food challenge data for population risk assessment of food allergens

Background: Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. Objective: We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. Methods: Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. Results: In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. Conclusion: With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption