Evaluation of clinical outcomes of efficacy in food allergen immunotherapy trials, COFAITH EAACI task force.

Food allergy is a global public health problem that until recent years lacked any aetiological treatment supported by academy, industry and regulators. Food immunotherapy (AIT) is an evolving treatment option, supported by clinical practice and industry trial data. Recent AIT meta-analyses have highlighted the difficulty in pooling safety and efficacy data from AIT trials, due to secondary heterogeneity in the study. An EAACI task force (CO-FAITH) initiated by the Paediatric Section was created to focus on AIT efficacy outcomes for milk, egg and peanut allergy rather than in trial results. A systematic search and a narrative review of AIT controlled clinical trials and large case series was conducted. A total of 63 manuscripts met inclusion criteria, corresponding to 23, 21 and 22 studies of milk, egg and peanut AIT, respectively. The most common AIT efficacy outcome was desensitization, mostly defined as tolerating a maintenance phase dose, or reaching a particular dose upon successful exit oral food challenge (OFC). However, a large degree of heterogeneity was identified regarding the dose quantity defining this outcome. Sustained unresponsiveness and patient-reported outcomes (e.g. quality of life) were explored less frequently, and to date have been most rigorously described for peanut AIT versus other allergens. Change in allergen threshold assessed by OFC remains the most common efficacy measure, but OFC methods suffer from heterogeneity and methodological disparity. This review has identified multiple heterogeneous outcomes related to measuring the efficacy of AIT. Efforts to better standardize and harmonize which outcomes, and how to measure them must be carried out to help in the clinical development of safe and efficacious food allergy treatments.

Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis.

BACKGROUND: Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds. OBJECTIVE: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. METHODS: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. RESULTS: Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. CONCLUSIONS: About 5% of CM-allergic individuals reacting to ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

Using data from food challenges to inform management of consumers with food allergy: A systematic review with individual participant data meta-analysis.

BACKGROUND: Eliciting doses (EDs) (eg, ED01 or ED05 values, which are the amounts of allergen expected to cause objective symptoms in 1% and 5% of the population with an allergy, respectively) are increasingly being used to inform allergen labeling and clinical management. These values are generated from food challenge, but the frequency of anaphylaxis in response to these low levels of allergen exposure and their reproducibility are unknown. OBJECTIVE: Our aim was to determine (1) the rate of anaphylaxis in response to low-level peanut exposure and (2) the reproducibility of reaction thresholds (and anaphylaxis) at food challenge. METHODS: We conducted a systematic review and individual participant data meta-analysis of studies that reported at least 50 individuals with peanut allergy reacting to peanut at double-blind, placebo-controlled food challenge (DBPCFC) and were published between January 2010 and September 2020. Risk of bias was assessed by using National Institute for Clinical Excellence methodologic checklists. RESULTS: A total of 19 studies were included (covering a total of 3151 participants, 534 of whom subsequently underwent further peanut challenge). At individual participant data meta-analysis, 4.5% (95% CI, 1.9% to 10.1%) of individuals reacted to 5 mg or less of peanut protein with anaphylaxis (moderate heterogeneity [I2 = 57%]). Intraindividual thresholds varied by up to 3 logs, although this variation was limited to a half-log change in 71.2% (95% CI, 56.2% to 82.6%) of individuals. In all, 2.4% (95% CI, 1.1% to 5.0%) of patients initially tolerated 5 mg of peanut protein but then reacted to this dose at subsequent challenge (low heterogeneity [I2 = 16%]); none developed anaphylaxis. CONCLUSION: Around 5% of individuals reacting to an ED01 or ED05 level of exposure to peanut might develop anaphylaxis in response to that dose. This equates to 1 and 6 anaphylaxis events per 2500 patients exposed to an ED01 or ED05 dose, respectively, in the broader population of individuals with peanut allergy.

Addressing risk management difficulties in children with food allergies.

Risk is a concept inherent in every medical procedure. It can be defined as the probability of an adverse event in a defined population over a specified period of time. In the frame of food allergy management, it might be related to a diagnostic procedure, a treatment, or the consumption of foods. The risk of an adverse event can also be augmented by individual factors. This rostrum article discusses various aspects faced by children with food allergies in the light of risk, and their practical implications. Identifying personal risks for severe reaction, such as unstable asthma, and correcting them whenever possible also contribute to a reduction of the risk inherent to food allergy. Among the facets discussed, oral food challenges (OFC) are the most common diagnostic procedures implying an inherent risk. The risk of OFCs can be minimized by correct indication and timing of the test, a safe setting, as well as by ensuring that the patient is otherwise well without potential stressor potentially increasing the risk of a more severe reaction. Oral immunotherapy (OIT) has been studied as a potential treatment for increasing the threshold dose for reaction, and thus reducing the risk of accidental reaction. Nevertheless, the procedure is not devoid of risk as the patients may and do often react during the course of the procedure. Ingestion of trace amounts in processed foods, mainly in community settings such as restaurants, schools, or day care, represents a potential risk of reactions, although for a minority of patients. Precautionary allergen labeling (PAL) is a widespread strategy to reduce the potential risk of reactions due to traces. However, PAL is currently inefficient due to inconsistent labeling, also not indicating a clear maximum amount possibly present in the manufactured food. Finally, cost-effectiveness needs to be considered in risk management, as many risk reduction procedures are clearly not cost-effective.

Bayesian Stacked Parametric Survival with Frailty Components and Interval-Censored Failure Times: An Application to Food Allergy Risk.

To better understand the risk of exposure to food allergens, food challenge studies are designed to slowly increase the dose of an allergen delivered to allergic individuals until an objective reaction occurs. These dose-to-failure studies are used to determine acceptable intake levels and are analyzed using parametric failure time models. Though these models can provide estimates of the survival curve and risk, their parametric form may misrepresent the survival function for doses of interest. Different models that describe the data similarly may produce different dose-to-failure estimates. Motivated by predictive inference, we developed a Bayesian approach to combine survival estimates based on posterior predictive stacking, where the weights are formed to maximize posterior predictive accuracy. The approach defines a model space that is much larger than traditional parametric failure time modeling approaches. In our case, we use the approach to include random effects accounting for frailty components. The methodology is investigated in simulation, and is used to estimate allergic population eliciting doses for multiple food allergens.

Risk of shared equipment in restaurants for consumers with peanut allergy: a simulation for preparing Asian foods: A simulation for preparing Asian foods.

BACKGROUND: Allergic reactions to meals consumed outside the home are common and can be severe and sometimes fatal. OBJECTIVE: To quantify the risk reduction potentially achieved by increasing an individual's threshold sensitivity to peanut (such as by means of immunotherapy) in scenarios of peanut exposure through shared kitchen materials in a restaurant setting. METHODS: Three versions of popular peanut-containing sauces were selected to represent common ingredients used in Asian cooking. Different combinations of utensils, equipment, sauces, and test conditions were prepared by a professional chef, with or without common cleaning procedures, to represent normal daily practice. Residue amounts of peanut-containing material on kitchen equipment and utensils were measured and used for quantitative risk assessment to model the risk reduction associated with increasing an individual's threshold. RESULTS: Shared utensils had mean residue amounts of 23 to 1519 mg peanut protein (no cleaning) and 3 to 82 mg peanut protein (after water rinse). Shared woks and pans had up to 20 mg peanut protein after rinsing. Individuals who reach a threshold of 300 mg peanut protein have a predicted relative risk reduction of 94.9% to greater than 99.99% with brief cleaning. With no cleaning, relative risk reductions were 63.5% to 91.1% for individuals with a baseline threshold of less than or equal to 100 mg peanut protein who reach a threshold of 300 mg peanut protein, increasing to 91% to 99.7% when reaching a threshold value of 1000 mg peanut protein. CONCLUSION: In all shared kitchen material scenarios that we studied, achieving an eliciting dose of 300 or 1000 mg peanut protein seems clinically relevant for the peanut-allergic population.

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.

Estimated risk reduction to packaged food reactions by epicutaneous immunotherapy (EPIT) for peanut allergy.

BACKGROUND: Peanut allergy is a generally persistent, sometimes life-threatening food allergy. With no treatments demonstrating the ability to cure a food allergy, the focus of drugs in development has been on providing a level of protection against accidental exposure reactions. However, no study has estimated the relative risk reduction of a food-allergic population receiving a specific immunotherapeutic treatment for their allergies. OBJECTIVE: To estimate the relative risk reduction when consuming peanut-contaminated packaged food products in a double-blind, placebo-controlled Phase 3 study population of children treated with epicutaneous immunotherapy (EPIT) for 12 months with either a patch containing 250 µg peanut protein (250-µg patch) or a placebo patch. METHODS: The probability of an allergic reaction due to the unintended presence of peanut protein in packaged food products was modeled per study group and food category combination using Monte Carlo simulations. Risks per eating occasion of a contaminated packaged food product and the number of individuals per study population predicted to react on a yearly basis were investigated. RESULTS: The population treated with the 250-µg patch demonstrated a significantly increased dose-response distribution after 12 months of treatment, which resulted in a relative risk reduction of 73.2% to 78.4% when consuming peanut-contaminated packaged food products. In contrast, no statistically significant change was observed for the placebo group at the 12-month point. CONCLUSION: Our study estimates a substantial relative risk reduction for allergic reactions among peanut-allergic children after 12 months of EPIT with the 250-µg patch, supporting the potential real-world clinical relevance of this investigational immunotherapy and its possible role as a future therapy for peanut-allergic children. ClinicalTrials.gov Identifier: NCT02636699.

Quantitative risk reduction through peanut immunotherapy: Safety benefits of an increased threshold in Europe.

BACKGROUND: The clinical relevance of increasing an allergic individual's peanut sensitivity threshold by immunotherapy, that is, eliciting dose (ED) to 300 or 1000 mg peanut protein, has not been previously characterized in a European population. In this study, we quantify the clinical benefits of an increased threshold of reaction following immunotherapy for the peanut-allergic individual. METHODS: Quantitative risk assessments incorporated numerous inputs to predict the risk of an allergic reaction after exposure to residual peanut protein in packaged foods. The three primary inputs for the risk assessment were the peanut-allergic individual's clinical threshold value, the amount of food consumed per eating occasion of selected packaged foods, and the concentration of peanut protein in the consumed product. Individual risk reductions were calculated for both children and adolescents-adults. RESULTS: Using available consumption and packaged food contamination data, children reaching an ED of 300 mg (if initial ED ≤ 100 mg) or 1000 mg (if initial ED 300 mg) achieved >99.99% risk reduction. Adolescents-adults also achieved >99.99% risk reduction in all cases but one. Adolescents-adults who reached an ED of 300 mg (if initial ED ≤ 100 mg) achieved 99.3%-99.9% risk reduction when consuming ice cream. CONCLUSIONS: It is concluded that an increase in threshold following immunotherapy which achieves an eliciting dose of 300 or 1000 mg peanut protein is clinically relevant for the European peanut-allergic population. Benefits of an increased threshold include a significant reduction in risk due to traces of peanut protein.

Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications.

BACKGROUND: There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in a significant reduction in choice of potentially safe foods for allergic consumers. OBJECTIVES: We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data. METHODS: Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used. RESULTS: The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.03 mg for egg, and 0.1 mg for hazelnut. CONCLUSIONS: These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety.

Updated full range of Eliciting Dose values for Cow's milk for use in food allergen risk assessment.

Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow's milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally.

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.