Sesame eliciting and safe doses in a large sesame allergic population.

BACKGROUND: Sesame is a significant food allergen causing severe and even fatal reactions. Given its increasing prevalence in western diet, sesame is listed as an allergenic food requiring labeling in the United States and EU. However, data on the population reaction doses to sesame are limited. METHODS: All sesame oral food challenges (OFCs), performed either for diagnosis or for threshold identification before the beginning of sesame oral immunotherapy (OIT) between November 2011 and July 2021 in Shamir medical center were analyzed for reaction threshold distribution. Safe-dose challenges with 90-120 min intervals were also analyzed. RESULTS: Two hundred and fifty patients underwent 338 positive OFCs, and additional 158 safe-dose OFCs were performed. The discrete and cumulative protein amounts estimated to elicit an objective reaction in 1% (ED01) of the entire cohort (n = 250) were 0.8 mg (range 0.3-6.3) and 0.7 mg (range 0.1-7.1), respectively, and those for 5% of the population (ED05) were 3.4 mg (range 1.2-20.6) and 4.5 mg (range 1.2-28.8), respectively. Safe-dose OFCs showed similar values of ED01 (0.8, 0.4-7.5 mg) and ED05 (3.4, 1.2-22.9 mg). While doses of ≤1 mg sesame protein elicited oral pruritus in 11.6% of the patients, no objective reaction was documented to this amount in any of the challenges, including safe-dose OFCs. CONCLUSIONS: This study provides data on sesame reaction threshold distribution in the largest population of allergic patients studied, with no right or left censored data, and with validation using a safe-dose OFC. It further supports the current methods for ED determination as appropriate for establishing safety precautions for the food industry.

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.

Allergen labelling: Current practice and improvement from a communication perspective.

BACKGROUND: Allergen information on product labels is crucial in food allergy management, though inadequacy in current labelling practices is one of the major causes for accidental reactions upon consuming prepacked food products. OBJECTIVE: This study analyses current status of communicating allergen information on food labels and provides practical recommendations for improving the label format based on communication theory. METHODS: Product labels (N 288) of seven food categories from private label products and brands were obtained at three retailers in the Netherlands. Information regarding the 14 EU-regulated allergens was evaluated by the frequency of emphasizing allergens in the ingredient list, use of precautionary allergen labelling (PAL), icons and an allergen information section. Effectiveness of communication was assessed evaluating readability and findability of information on allergens using principles of Gestalt and Cognitive Load theories. RESULTS: As requested by EU regulation 1169/2011, emphasizing allergens in the ingredient list was almost 100%, all other presentations of information on allergens on labels was highly diverse. A separate allergen information section was present on most private label products. This section could, but not necessarily did, repeat allergens from the ingredient list and/or give a PAL. Brands often provided a PAL at the end of the ingredient list. Part of the products displayed an icon at different locations of the label. Label background, a lack of cohesion and variation in location of topics hamper the identification of relevant information on allergens by (allergic) consumers. Recommendations include a standardized order for mandatory and voluntary topics on the label and a separate allergen information section. CONCLUSION AND CLINICAL RELEVANCE: Overall, consumers encounter a wide and inconsistent range in ways of presentation of allergen information on labels. Standardization according to basic design principles can improve usability and support safe food purchases for allergic consumers.

Poor understanding of allergen labelling by allergic and non-allergic consumers.

BACKGROUND: Understanding consumers' interpretation of allergy information is crucial for effective food safety policies. We evaluated consumer understanding of allergy information on foods in controlled, experimental studies. METHOD: Using 18 packaged foods, we evaluated consumer understanding of information about allergens in two experiments: First, a comparison of foods with no stated allergen versus allergen as a stated ingredient versus a precautionary allergen label (PAL); second, a comparison of three common variants of PAL. In each experiment, consumers with and without self-reported food allergy were asked to estimate the risk of allergic reaction and to rate the comprehensibility of the allergen information. In the second experiment, consumers were also asked which form of PAL they preferred. RESULTS: Risk of reaction was assessed as high and low for foods with the allergen stated as ingredient, or without any mention of allergen. However, risk assessment for PAL varied and was judged as higher by non-allergic than allergic participants (82% vs. 58%, p < .001). Understanding of risk associated with PAL also varied by health literacy (p < .001). Both allergic and non-allergic consumers judged all forms of allergy information to be unclear, especially products with no allergy information for non-allergic consumers. Products with a 'Produced in a Factory' PAL were perceived as less risky than 'May contain' or 'Traces of' PALs (p < .001), less than 40% of participants judged PAL information to be comprehensible, and participants preferred 'May contain' over the other PALs. CONCLUSION: Both allergic and non-allergic consumers find allergen information difficult to interpret on packaged foods and misunderstand PAL, incorrectly distinguishing different risk levels for different PAL wording. Clearer allergy information guidelines are called for, and the use of only one PAL wording is recommended.

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.

Potential cofactors in accidental food allergic reactions are frequently present but may not influence severity and occurrence.

BACKGROUND: Cofactors, such as physical exercise and alcohol intake, might be associated with the severity or occurrence of food allergic reactions. OBJECTIVE: To gain insight into the frequency of presence of potential cofactors in accidental food allergic reactions in adults and to what extent these factors influence the severity and occurrence of allergic reactions. METHODS: A prospective cohort study was conducted, with a 1-year follow-up in adult patients with a physician-diagnosed food allergy. Patients were required to fill in a questionnaire after every accidental allergic reactions to food over a 1-year period. The primary outcome measure was the frequency that potential cofactors were present in these allergic reactions. RESULTS: A total of 157 patients were included, of which 46% reported a total of 153 reactions during a 1-year follow-up period. In 74% of the reactions, ≥1 potential cofactor was reported to be present: tiredness (38%), alcohol intake (16%), stress (14%), symptoms of pollinosis (16%), symptoms of asthma (9%), sickness/flu (3%), physical exercise (3%) and use of analgesics (2%). More than one potential cofactor was reported in almost half of all reactions (47%). There was no significant difference in the presence of these factors between mild, moderate and severe reactions (P = 0.522). In the total study population, 9% of the patients used medication that might act as cofactor (antacids, angiotensin receptor blockers [ARBs], beta blockers and angiotensin-converting enzyme inhibitors [ACEIs]) on a daily basis, which however did not influence the occurrence of reactions. Furthermore, 38% daily used allergy-suppressing medication. CONCLUSIONS: Although factors suggested to be cofactors were frequently present during accidental food allergic reactions, we found no evidence for an association between the potential cofactors examined and reaction severity, in a population where most reactions were of mild to moderate severity.

Evidence-based approaches to the application of precautionary allergen labelling: Report from two iFAAM workshops.

Food allergy is a major public health concern with avoidance of the trigger food(s) being central to management by the patient. Food information legislation mandates the declaration of allergenic ingredients; however, the labelling of the unintentional presence of allergens is less defined. Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the risk of reaction from the unintended presence of allergens in foods. In its current form, PAL is counterproductive for consumers with food allergies as there is no standardized approach to applying PAL. Foods with a PAL often do not contain the identified food allergen while some products without a PAL contain quantities of common food allergens that are capable of inducing an allergic reaction. Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM) was an EU-funded project that aimed to improve the management of food allergens by the food industry for the benefit of people with food allergies. Within iFAAM, a clinically validated tiered risk assessment approach for food allergens was developed. Two cross-stakeholder iFAAM workshops were held on 13-14 December 2016 and 19-20 April 2018. One of the objectives of these workshops was to develop a proposal to make PAL effective for consumers. This paper describes the outcomes from these workshops. This provides the basis for the development of more informative and transparent labelling that will ultimately improve management and well-being in consumers with food allergy.

Accidental food allergy reactions: Products and undeclared ingredients.

BACKGROUND: Accidental allergic reactions to food are frequent and can be severe and even fatal. OBJECTIVE: We sought to analyze the culprit food products and levels of unexpected allergens in accidental reactions. METHODS: A prospective cohort study was conducted in adults (n = 157) with a physician-confirmed diagnosis of food allergy. During a 1-year follow-up, 73 patients reported accidental allergic reactions and the culprit food products. Food samples received (n = 51) were analyzed for a wide range of suspected noningredient allergens, and risk was quantified. RESULTS: A very diverse range of food products was responsible for the unexpected allergic reactions. Thirty-seven percent (19/51) of products analyzed had 1 to 4 culprit allergens identified that were not supposed to be present according to the ingredient declaration. Concentrations varied from 1 to 5000 mg of protein of the allergenic food per kilogram of food product and were greatest for peanut, milk, and sesame. Milk proteins posed the highest estimated risk for objective allergic reactions. The intake of culprit allergens by patients varied considerably. For those cases in which culprit allergens were detected, the intake of at least 1 allergen exceeded the reference dose or a culprit allergen with a yet unknown reference dose was present. Both patient neglect of precautionary allergen labeling statements and omission of using a precautionary allergen labeling statement by food manufacturers seem to contribute to accidental reactions. CONCLUSION: A wide range of food products are causing accidental reactions in patients with food allergy. Eight different allergens not declared on the ingredient lists were detected in the culprit food products, all of which were representative of allergens regulated in the European Union.

Component-resolved diagnostics demonstrates that most peanut-allergic individuals could potentially introduce tree nuts to their diet.

BACKGROUND: Nut allergy varies from pollen cross-allergy, to primary severe allergy with life-threatening symptoms. The screening of IgE antibodies to a wide spectrum of allergens, including species-specific and cross-reactive allergens, is made possible via microarray analysis. OBJECTIVE: We sought to study the association of variable IgE sensitization profiles to clinical response in peanut-challenged children and adolescents in a birch-endemic region. In addition, we studied the avoidance of tree nuts and species-specific sensitizations. METHODS: We studied 102 peanut-sensitized patients who underwent a double-blind placebo-controlled challenge to peanut. We analysed ISAC ImmunoCAP microarray to 112 allergens, singleplex ImmunoCAPs for hazelnut Cor a 14 and cashew Ana o 3, and performed skin prick tests to peanut, tree nuts and sesame seed. We surveyed avoidance diets with a questionnaire. RESULTS: Sensitization to PR-10 proteins was frequent (Bet v 1 90%), but equally high in the challenge negatives and positives. IgE to Ara h 2 and Ara h 6 discriminated peanut allergic (n = 69) and tolerant (n = 33) the best. Avoidance of tree nuts was common (52% to 96%), but only 6% to 44% presented species-specific sensitizations to tree nuts, so a great number could potentially introduce these species into their diet. CONCLUSIONS AND CLINICAL RELEVANCE: PR-10-sensitizations were frequent and strong regardless of peanut allergy status. Component-resolved diagnostics can be employed to demonstrate to patients that sensitization to seed storage proteins of tree nuts is uncommon. Several tree nuts could potentially be reintroduced to the diet.

A subset of walnut allergic adults is sensitized to walnut 11S globulin Jug r 4.

BACKGROUND: The role of sensitization to commercially available allergens of English walnut (Juglans regia) Jug r 1, 2 and 3 in walnut allergy has been previously investigated in walnut allergic adults and was unable to explain all cases of walnut allergy. OBJECTIVES: Identify recognized walnut allergens, other than the ones previously investigated (Jug r 1-3), in walnut allergic adults and determine the sensitization frequency and diagnostic value. METHODS: Three different in-house walnut extracts were prepared and analysed on SDS-PAGE blots to identify allergenic walnut proteins. Immunoblots and immunoprecipitation, followed by LC-MS analysis, were performed to screen for, and confirm, IgE binding to walnut allergens in selected walnut allergic adults. In a cohort of 55 walnut challenged adults, including 33 allergic and 22 tolerant, sensitization to native and recombinant walnut allergen Jug r 4 was assessed using immunoblotting and immuno-line blot (EUROLINE), respectively. RESULTS: Screening of sera of 8 walnut allergic adults identified Jug r 4 as an allergen in our population. In the total cohort of 55 subjects, 5 were positive for Jug r 4 on immunoblot and 10 on EUROLINE. All but one EUROLINE positive subject had a positive food challenge (sensitivity 27%, specificity 95%, PPV 90%, NPV 47%). All 5 subjects positive on immunoblot were also positive on EUROLINE. LC-MS analysis showed a lack of Jug r 4 in the ImmunoCAP extract. Co-sensitization to other 11S albumins (eg hazelnut Cor a 9) was common in Jug r 4 sensitized subjects, potentially due to cross-reactivity. CONCLUSIONS: Walnut 11S globulin Jug r 4 is a relevant minor allergen, recognized by 27% of walnut allergic adults. It has a high positive predictive value of 90% for walnut allergy. Specific IgE against Jug r 4 occurred mostly with concomitant sensitization to other walnut components, mainly Jug r 1.

Objective eliciting doses of peanut-allergic adults and children can be combined for risk assessment purposes.

BACKGROUND: To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary. OBJECTIVE: To establish EDs for objective and subjective symptoms and analyse the effect of sensitization levels and other patient characteristics on threshold distribution curves (TDCs). METHODS: Threshold data from 100 adults and 262 children with a positive food challenge were analysed with interval-censoring survival analysis (ICSA) and fitted to a TDC from which EDs could be extracted. Possible influencing factors were analysed as covariates by ICSA. A hazard ratio (HR) was calculated in case of a significant effect. RESULTS: TDCs for both objective and subjective symptoms were significantly different between adults and children (P < 0.001). Objective ED05 values, however, were comparable (2.86 mg peanut protein in adults and 6.38 mg in children). Higher levels of sIgE to Ara h 2 and peanut extract were associated with a larger proportion of patient groups reacting to a dose increase with objective symptoms (adults and children) or subjective symptoms (adults, in children a trend). Age had a similar effect in children (HR 1.05 for objective symptoms and 1.09 for subjective symptoms). Gender had no effect on TDCs. CONCLUSION AND CLINICAL RELEVANCE: Subjective and objective TDCs were different between adults and children, but objective ED05 values were comparable, meaning that threshold data from children and adults can be combined for elaboration of reference doses for risk assessment. Higher sIgE levels to Ara h 2 and peanut extract were associated with a larger proportion of both patient groups to react to a certain dose increase.

Unintended allergens in precautionary labelled and unlabelled products pose significant risks to UK allergic consumers.

BACKGROUND: Allergens in food may pose a risk to allergic consumers. While there is EU regulation for allergens present as an ingredient, this is not the case for unintended allergen presence (UAP). Food companies use precautionary allergen labels to inform allergic individuals of a potential risk from UAPs. This study investigates the risk of an allergic reaction within the milk-, wheat-, hazelnut- and peanut-allergic populations when ingesting UK foods across multiple product categories with and without precautionary allergen labelling. METHODS: Allergen risk assessment using probabilistic techniques enables the estimation of the residual risk after the consumption of a product that unintentionally contains an allergen. RESULTS: Within this selection of UK products, the majority that tested positive for an allergen contained a concentration of allergen predicted to cause a reaction in >1% of the allergic population. The concentrations of allergens measured were greater than the VITAL(®) 2.0 action levels and would trigger precautionary allergen labelling. This was found for products both with and without precautionary allergen labelling. CONCLUSIONS: The results highlight the need for the food industry and regulators to adopt a transparent, risk-based approach for the communication of the risk associated with potential cross-contact that could occur in the processing facility or production chain.

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.

Double-blind placebo-controlled food challenges in children with alleged cow's milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses.

BACKGROUND: Children with cow's milk allergy (CMA) need a cow's milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children. METHODS: All children with suspected CMA under our care (Oct'05-Jun'09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the 'lowest observed adverse effect level' (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child. RESULTS: 116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged ≤ 12 months in our study group have a higher cumulative distribution of MED than older children. CONCLUSIONS: Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers.