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Background: Food challenges (FCs) form the basis for assessing efficacy outcomes in interventional studies of food allergy; however, different studies have used a variety of similar but not identical criteria to define a challenge reaction, including subjective (nonobjective) symptoms occurring in a single-organ system as dose limiting., Objective: Our aim was to undertake a secondary analysis of 4 interventional studies to assess the impact of using less objective criteria to determine challenge-stop on reaction thresholds and their reproducibility., Methods: We analyzed individual participant data, including individual participant data meta-analysis, by using 3 different published challenge-stop criteria: (1) PRACTALL consesus criteria; (2) Consortium for Food Allergy Research version 3 (CoFAR v3) with at least 1 moderate- or severe-grade symptom; or (3) CoFAR v3 with at least 2 mild symptoms occurring in different organ systems. Reproducibility of challenge threshold was also assessed in participants undergoing subsequent repeat FCs., Results: Four studies, with detailed challenge data from a total of 592 participants, were included. Applying CoFAR v3 definitions for dose-limiting symptoms resulted in an underestimate of reaction thresholds compared with those in PRACTALL (P < .001) that is equivalent to almost a single dosing increment when using a semi-log dosing regimen. Reproducibility was also reduced when applying CoFAR v3 (P < .001 [n = 223]). Using the least conservative interpretation of CoFAR v3 (≥2 mild symptoms occurring in different systems) resulted in a significant overestimate of 15% when assessing oral immunotherapy efficacy. Applying a data-driven minor modification to CoFAR v3 resulted in a new set of challenge-stop criteria with validity similar to that of PRACTALL but one that is simpler to implement and in which significant gastrointestinal discomfort with observable decreased activity remains a dose-limiting symptom., Conclusion: The use of less objective symptoms to define challenge-stop compromises the reproducibility of the FC as a tool to assess efficacy outcomes in interventional studies, and potentially overestimates the efficacy of the intervention tested., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A genetic defect in the epidermal barrier protein filaggrin (FLG) plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in FLG contribute to the development and persistence of food allergies., Objectives: This study tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies., Methods: This study recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the 4 most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as the control population., Results: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy., Conclusions: Using the gold standard for food allergy diagnosis, this study demonstrates that FLG LOF mutations confer a risk of any food allergy independent of eczema. These mutations predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years., Objective: We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment., Methods: Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed., Results: Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n = 853; 90.4%). A total of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis])., Conclusion: The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prognostic stratification of patients with colorectal cancer liver metastasis based solely on tumor-related factors has only moderate discriminatory ability. We hypothesized that the inclusion of nontumor related factors can improve prediction of long-term prognosis of patients with colorectal cancer liver metastasis., Methods: Nontumor related laboratory markers were assessed utilizing a training cohort from 2 U.S. institutions (n = 1,205). Factors independently associated with prognosis were used to develop a nontumor related prognostic score. The discriminatory ability, assessed by Harrell's C-statistics (C-index) and net reclassification improvement, was validated and compared with 3 commonly used tumor-related clinical risk scores: Fong clinical risk scores, m-clinical risk scores, and Genetic and Morphological Evaluation (GAME) score in an external validation cohort from 5 Asian (n = 1,307) and 3 European (n = 1,058) institutions. The discriminatory ability of nontumor related prognostic score combined with each of these 3 tumor-related prognostic scores was also estimated., Results: Alkaline phosphatase (hazard ratio 1.43; 95% confidence interval, 1.11-1.84), albumin (hazard ratio 0.71; 95% confidence interval, 0.57-0.89), and mean corpuscular volume (hazard ratio 19.0, per log unit; 95% confidence interval, 4.79-75.0) were each independently associated with increased risk of death after resection of colorectal cancer liver metastasis (all P < .05). In turn, alkaline phosphatase, albumin, and mean corpuscular volume were combined to form a nontumor related prognostic score (2.942 × mean corpuscular volume + 0.399 × alkaline phosphatase-0.339 × albumin-12) × 10 (median, 16; range, 1-30). The nontumor related prognostic score had good-to-modest discriminatory ability in the external cohort (C-index = 0.58), which was comparable to the 3 established tumor-related prognostic scores (C-index: Fong clinical risk scores, 0.53, m-clinical risk scores, 0.55, GAME, 0.58). The addition of the nontumor related prognostic score to the tumor-related prognostic scores enhanced the discriminatory ability in the entire study cohort (C-index: nontumor related score+Fong, 0.60, nontumor related score+m-clinical risk scores, 0.61, nontumor related score+GAME, 0.64), as well reclassification improvement (42.5, 42.7%, and 21.2%, respectively)., Conclusion: Nontumor related prognostic information may help improve the prognostic stratification of patients after resection of colorectal cancer liver metastasis. The nontumor related prognostic score may be combined with tumor-related prognostic tools to enhance prognostic stratification of patients with colorectal cancer liver metastasis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Tolerance development is an important clinical outcome for infants with cow's milk allergy., Objective: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy., Methods: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set., Results: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036)., Conclusions: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg)., Objective: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study., Methods: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment., Results: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%)., Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Wheat is a common food allergen that can cause anaphylaxis., Objective: We sought to determine the efficacy and safety of vital wheat gluten (VWG) oral immunotherapy (OIT)., Methods: After baseline double-blind, placebo-controlled food challenge (DBPCFC), 46 patients with wheat allergy (median age, 8.7 years; range, 4.2-22.3 years) were randomized 1:1 to low-dose VWG OIT or placebo, with biweekly escalation to 1445 mg of wheat protein (WP). After a year 1 DBPCFC, active subjects continued low-dose VWG OIT for another year and underwent a year 2 DBPCFC and, if passed, a subsequent off-therapy DBPCFC. Placebo-treated subjects crossed over to high-dose VWG OIT (maximum, 2748 mg of WP)., Results: The median baseline successfully consumed dose (SCD) was 43 mg of WP in both groups. At year 1, 12 (52.2%) of 23 low-dose VWG OIT-treated and 0 (0%) of 23 placebo-treated subjects achieved the primary end point of an SCD of 4443 mg of WP or greater (P < .0001); median SCDs were 4443 and 143 mg, respectively. At year 2, 7 (30.4%) of 23 low-dose VWG OIT-treated subjects were desensitized to an SCD of 7443 mg of WP; 3 (13%) achieved sustained unresponsiveness 8 to 10 weeks off therapy. Among placebo-treated subjects who crossed over to high-dose VWG OIT, 12 (57.1%) of 21 were desensitized after 1 year (median SCD, 7443 mg of WP; nonsignificant vs low-dose VWG OIT). At year 1, skin prick test responses and wheat- and omega-5 gliadin-specific IgE levels did not differ between groups; the low-dose VWG OIT median specific IgG 4 level was greater than placebo (wheat, P = .0005; omega-5 gliadin, P = .0001). Year 1 SCDs correlated with wheat-specific (rho = 0.55, P = .0003) and omega-5 gliadin-specific (rho = 0.51, P = .001) IgG 4 levels in all subjects. Among 7822 low-dose VWG OIT doses in year 1, 15.4% were associated with adverse reactions: 0.04% were severe, and 0.08% subjects received epinephrine. Among 7921 placebo doses, 5.8% were associated with adverse reactions; none were severe., Conclusions: Low- and high-dose VWG OIT induced desensitization in about one half of the subjects after 1 year of treatment. Two years of low-dose VWG OIT resulted in 30% desensitization, and 13% had sustained unresponsiveness., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hen's egg is the most common cause of food allergy in early childhood., Objective: We investigated the efficacy and safety of early hen's egg introduction at age 4 to 6 months to prevent hen's egg allergy in the general population., Methods: This randomized, placebo-controlled trial included 4- to 6-month-old infants who were not sensitized against hen's egg, as determined based on specific serum antibodies (IgE). These infants were randomized to receive either verum (egg white powder) or placebo (rice powder) added to the first weaning food 3 times a week under a concurrent egg-free diet from age 4 to 6 until 12 months. The primary outcome was sensitization to hen's egg (increased specific serum IgE levels) by age 12 months. Hen's egg allergy (secondary outcome) was confirmed by double-blind, placebo-controlled food challenges., Results: Among 406 screened infants, 23 (5.7%) had hen's egg-specific IgE before randomization. Seventeen of 23 underwent subsequent double-blind, placebo-controlled food challenges, and 16 were confirmed as allergic, including 11 with anaphylactic reactions. Of the 383 nonsensitized infants (56.7% male), 184 were randomized to verum and 199 to placebo. At 12 months of age, 5.6% of the children in the verum group were hen's egg sensitized versus 2.6% in the placebo group (primary outcome; relative risk, 2.20; 95% CI, 0.68-7.14; P = .24), and 2.1% were confirmed to have hen's egg allergy versus 0.6% in the placebo group (relative risk, 3.30; 95% CI, 0.35-31.32; P = .35)., Conclusion: We found no evidence that consumption of hen's egg starting at 4 to 6 months of age prevents hen's egg sensitization or allergy. In contrast, it might result in frequent allergic reactions in the community considering that many 4- to 6-month-old infants were already allergic to hen's egg., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Specific IgE measurement predicts the outcome of oral food challenges with considerable uncertainty when evaluating food allergy., Objective: Our aim was to assess whether accounting for the ratio of component- or allergen-specific to total IgE can improve this prediction., Methods: This multicenter study collected blood samples from children with suspected peanut or hazelnut allergy referred to allergy specialist clinics for food challenges. Specific IgE to peanuts, hazelnuts, and their components (Ara h 1, Ara h 2, Ara h 3, Ara h 8, Cor a 1, Cor a 8, Cor a 9, and Cor a 14) and total IgE levels were determined by using the ImmunoCAP-FEIA. Specific to total IgE ratios were compared with raw IgE levels in terms of discrimination and prediction., Results: Eighty-eight (43%) of 207 children with suspected peanut allergy and 44 (31%) of 142 children with suspected hazelnut allergy had symptoms during food challenge. Discrimination was similar for raw and ratio measures: areas under the curve of 0.93 for Ara h 2-specific IgE versus 0.92 for the Ara h 2-specific/total IgE ratio and 0.89 for Cor a 14-specific IgE versus 0.87 for the Cor a 14-specific/total IgE ratio. The probability for a positive peanut challenge with 0.35 kU/L Ara h 2-specific IgE was 16% when the total IgE level was greater than 500 kU/L compared with 51%/48% for low/medium total IgE levels (<100/100-500 kU/L). A positive hazelnut challenge with 0.35 kU/L Cor a 14-specific IgE was estimated in 7% when total IgE levels were high compared with 34%/32% with low/medium total IgE levels., Conclusions: Raw Ara h 2- and Cor a 14-specific IgE levels were the best single predictors for pediatric peanut and hazelnut allergies, suggesting the omission of challenges at very high levels. Calculating ratio measures did not improve prediction in this population. However, estimation of individual probabilities for challenge outcomes could be supported by total IgE levels because high levels might indicate lower probabilities at a given component-specific IgE level., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Anaphylaxis in children and adolescents is a potentially life-threatening condition. Its heterogeneous clinical presentation and sudden occurrence in virtually any setting without warning have impeded a comprehensive description., Objective: We sought to characterize severe allergic reactions in terms of elicitors, symptoms, emergency treatment, and long-term management in European children and adolescents., Methods: The European Anaphylaxis Registry recorded details of anaphylaxis after referral for in-depth diagnosis and counseling to 1 of 90 tertiary allergy centers in 10 European countries, aiming to oversample the most severe reactions. Data were retrieved from medical records by using a multilanguage online form., Results: Between July 2007 and March 2015, anaphylaxis was identified in 1970 patients younger than 18 years. Most incidents occurred in private homes (46%) and outdoors (19%). One third of the patients had experienced anaphylaxis previously. Food items were the most frequent trigger (66%), followed by insect venom (19%). Cow's milk and hen's egg were prevalent elicitors in the first 2 years, hazelnut and cashew in preschool-aged children, and peanut at all ages. There was a continuous shift from food- to insect venom- and drug-induced anaphylaxis up to age 10 years, and there were few changes thereafter. Vomiting and cough were prevalent symptoms in the first decade of life, and subjective symptoms (nausea, throat tightness, and dizziness) were prevalent later in life. Thirty percent of cases were lay treated, of which 10% were treated with an epinephrine autoinjector. The fraction of intramuscular epinephrine in professional emergency treatment increased from 12% in 2011 to 25% in 2014. Twenty-six (1.3%) patients were either admitted to the intensive care unit or had grade IV/fatal reactions., Conclusions: The European Anaphylaxis Registry confirmed food as the major elicitor of anaphylaxis in children, specifically hen's egg, cow's milk, and nuts. Reactions to insect venom were seen more in young adulthood. Intensive care unit admissions and grade IV/fatal reactions were rare. The registry will serve as a systematic foundation for a continuous description of this multiform condition., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology, American Academy of Pediatrics, American College of Allergy, Asthma & Immunology, Australasian Society of Clinical Immunology and Allergy, Canadian Society of Allergy and Clinical Immunology, European Academy of Allergy and Clinical Immunology, Israel Association of Allergy and Clinical Immunology, Japanese Society for Allergology, Society for Pediatric Dermatology, and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases-sponsored Working Group and the European Academy of Allergy and Clinical Immunology., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Precautionary labeling is used to warn consumers of the presence of unintended allergens, but the lack of agreed allergen thresholds can result in confusion and risk taking by patients with food allergy. The lack of data on threshold doses below which subjects are unlikely to react is preventing the development of evidence-based allergen management strategies that are understood by clinician and patient alike., Objective: We sought to define threshold dose distributions for 5 major allergenic foods in the European population., Methods: Patients with food allergy were drawn from the EuroPrevall birth cohort, community surveys, and outpatient clinic studies and invited to undergo a food challenge. Low-dose, double-blind, placebo-controlled food challenges were undertaken with commercially available food ingredients (peanut, hazelnut, celery, fish, and shrimp) blinded into common matrices. Dose distributions were modeled by using interval-censoring survival analysis with 3 parametric approaches., Results: Of the 5 foods used for challenge, 4 produced similar dose distributions, with estimated doses eliciting reactions in 10% of the allergic population (ED10), ranging from 1.6 to 10.1 mg of protein for hazelnut, peanut, and celery with overlapping 95% CIs. ED10 values for fish were somewhat higher (27.3 mg of protein), although the CIs were wide and overlapping between fish and plant foods. Shrimp provided radically different dose distributions, with an ED10 value of 2.5 g of protein., Conclusion: This evidence base will contribute to the development of reference doses and action levels for allergens in foods below which only the most sensitive subjects might react., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Threshold levels for peanut allergy determined by using oral challenges are important for the food industry with regard to allergen labeling. Moreover, the utility of biological markers in predicting threshold levels is uncertain., Objective: We sought to use a modified oral food challenge regimen that might determine threshold levels for peanut allergy mimicking a more real-life exposure and to correlate the eliciting dose (ED) and severity of clinical reaction in children with peanut allergy with B-cell, T-cell, and effector cell markers., Methods: A modified food challenge procedure with doses scheduled 2 hours apart was used in 63 children with peanut allergy. All children received a maximum of 8 semi-log increasing titration steps of roasted peanuts ranging from 3 to 4500 mg of peanut protein until objective allergic reactions occurred. Severity of symptoms was graded from I to V. Biological markers were measured before challenge., Results: Forty-five of 63 patients showed objective symptoms after greater than 30 minutes, with a median latency of clinical reaction of 55 minutes. By using a log-normal dose-distribution model, the ED5 was calculated to be 1.95 mg of peanut protein. The ED was significantly and inversely correlated with peanut- and Ara h 2-specific IgE levels, skin prick test responses, basophil activation, and TH2 cytokine production by PBMCs. Symptom severity did not correlate with any of the markers or the ED., Conclusion: This modified food challenge procedure might better reflect threshold levels for peanut allergy than the standard procedure because most of the patients reacted at a time interval of greater than 30 minutes. By using this model, threshold levels, but not severity, could be correlated with biological markers., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Food allergies can result in life-threatening reactions and diminish quality of life. In the last several decades, the prevalence of food allergies has increased in several regions throughout the world. Although more than 170 foods have been identified as being potentially allergenic, a minority of these foods cause the majority of reactions, and common food allergens vary between geographic regions. Treatment of food allergy involves strict avoidance of the trigger food. Medications manage symptoms of disease, but currently, there is no cure for food allergy. In light of the increasing burden of allergic diseases, the American Academy of Allergy, Asthma & Immunology; European Academy of Allergy and Clinical Immunology; World Allergy Organization; and American College of Allergy, Asthma & Immunology have come together to increase the communication of information about allergies and asthma at a global level. Within the framework of this collaboration, termed the International Collaboration in Asthma, Allergy and Immunology, a series of consensus documents called International Consensus ON (ICON) are being developed to serve as an important resource and support physicians in managing different allergic diseases. An author group was formed to describe the natural history, prevalence, diagnosis, and treatment of food allergies in the context of the global community., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

The 2nd Milan Meeting on Adverse Reactions to Bovine Proteins was the venue for the presentation of the first consensus-based approach to the management of cow's milk allergy. It was also the first time that the Grading of Recommendations, Assessments, Development, and Evaluation approach for formulating guidelines and recommendations was applied to the field of food allergy. In this report we present the contributions in allergen science, epidemiology, natural history, evidence-based diagnosis, and therapy synthesized in the World Allergy Organization Diagnosis and Rationale for Action against Cow's Milk Allergy guidelines and presented during the meeting. A consensus emerged between discussants that cow's milk allergy management should reflect not only basic research but also a newer and better appraisal of the literature in the light of the values and preferences shared by patients and their caregivers in partnership. In the field of diagnosis, atopy patch testing and microarray technology have not yet evolved for use outside the research setting. With foreseeable breakthroughs (eg, immunotherapy and molecular diagnosis) in the offing, the step ahead in leadership can only stem from a worldwide organization implementing consensus-based clinical practice guidelines to diffuse and share clinical knowledge., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The only treatment option for peanut allergy is strict avoidance., Objective: To investigate efficacy and safety of oral immunotherapy (OIT) in peanut allergy., Methods: Twenty-three children (age, 3.2-14.3 years) with IgE-mediated peanut allergy confirmed by positive double-blind, placebo-controlled food challenge (DBPCFC) received OIT following a rush protocol with roasted peanut for 7 days. If a protective dose of at least 0.5 g peanut was not achieved, patients continued with a long-term buildup protocol using biweekly dose increases up to at least 0.5 g peanut. A maintenance phase for 8 weeks was followed by 2 weeks of peanut avoidance and a final DBPCFC. Immunologic parameters were determined., Results: After OIT using the rush protocol, patients tolerated a median dose of only 0.15 g peanut. Twenty-two of 23 patients continued with the long-term protocol. After a median of 7 months, 14 patients reached the protective dose. At the final DBPCFC, patients tolerated a median of 1 g (range, 0.25-4 g) in comparison with 0.19 g peanut at the DBPCFC before OIT (range, 0.02-1 g). In 2.6% of 6137 total daily doses, mild to moderate side effects were observed; in 1.3%, symptoms of pulmonary obstruction were detected. OIT was discontinued in 4 of 22 patients because of adverse events. There was a significant increase in peanut-specific serum IgG(4) and a decrease in peanut-specific IL-5, IL-4, and IL-2 production by PBMCs after OIT., Conclusion: Long-term OIT appears to be safe and of some benefit in many patients with peanut allergy. With an increase in threshold levels and a reduction of peanut-specific T(H)2 cytokine production, the induction of tolerance may be feasible in some patients., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Shellfish allergy is a prevalent, long-lasting disorder usually persisting throughout life. Few options are available for treatment, and avoidance is the only therapy recommended., Objective: We sought to identify relevant crustacean allergens for use as diagnostic and safe immunotherapeutic agents for subjects with shellfish allergy., Methods: Thirty-eight patients were selected with immediate allergic reactions to shrimp and increased shrimp-specific serum IgE levels. One-dimensional and 2-dimensional electrophoresis of shrimp extracts were followed by IgE immunoblotting. Protein identification was done with matrix-assisted laser desorption/ionization-mass spectrometry and Edman sequencing. A cDNA library was generated from white pacific shrimp (Litopenaeus vannamei) and screened with primers designed on the basis of internal sequences obtained from 2-dimensional tryptic digests. Full-length cDNA clones were isolated from the library and sequenced. Recombinant protein was expressed and tested with sera from patients with shrimp allergy., Results: Immunoblotting demonstrated IgE binding to a 20-kDa shrimp protein by 21 (55%) of 38 sera. Tryptic digestion of the protein followed by matrix-assisted laser desorption/ionization-mass spectrometric analysis and Edman sequencing identified it as a myosin light chain (MLC). Screening of the shrimp cDNA library resulted in isolation of a novel protein cDNA. Open reading frame translation provided the amino acid sequence of a new allergenic shrimp protein with high similarity to Bla g 8 (cockroach MLC). Recombinant protein was recognized by 17 patients, confirming the allergenicity of shrimp MLC., Conclusions: We have identified and cloned a new major shrimp allergen, Lit v 3.0101, an MLC protein.

Background: There is an increasing need to develop test instruments that make oral food challenges superfluous., Objective: We sought to study the utility of atopy patch tests (APTs) in the diagnostic workup of food allergy., Methods: We investigated 437 children (median age, 13 months; 90% with atopic dermatitis) referred for evaluation of suspected food allergy. Specific serum IgE (sIgE) measurements, skin prick tests (SPTs), APTs, and controlled oral food challenges were performed., Results: We analyzed 873 oral challenges with cow's milk, hen's egg, wheat, and/or soy. One thousand seven hundred single APTs were performed. As a single parameter, the APTs showed the best specificity compared with sIgE measurements, SPTs, or both. Combining the APT with either the SPT or sIgE measurement resulted in improved sensitivity and specificity. Decision points for sIgE measurement and for the SPT showed lower values when combined with a positive APT result. Correctly bypassing an oral food challenge with combined testing, including APTs, only between 0.5% and 7% (99% predicted probability) and between 6% and 14% (using 95% predicted probability) of children would fulfill the criteria for avoiding an oral food challenge., Conclusion: Although the predictive capacity of the APT is improved when combined with sIgE measurement or the SPT, oral food challenges become superfluous in only 0.5% to 14% of study patients. In addition, the APT is time consuming and demands a highly experienced test evaluator., Clinical Implications: For daily clinical practice, the APT adds only a small predictive value to the standard SPT and sIgE measurement in the diagnostic workup of suspected food-related symptoms in our study population.

Background: Cashew nut allergy is the second most commonly reported tree nut allergy in the United States. We have previously cloned and characterized major cashew allergens belonging to the vicilin and legumin families of seed storage proteins., Objective: Here we set out to describe a third major cashew allergen, a 2S albumin., Methods: The recombinant cashew 2S albumin was amplified from a cDNA library by means of PCR, sequenced, and expressed in Escherichia coli. Immunoblotting was used to screen for reactivity with patients' sera, and inhibition immunoblotting was used to identify the corresponding native cashew nut proteins. The mass of affinity-purified native allergen was determined by means of matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy. Patients' sera were used to probe solid-phase 2S albumin peptides to identify linear epitopes., Results: The cloned allergen, designated Ana o 3, was identified as 2S albumin. MALDI-TOF mass spectroscopy of native Ana o 3 yielded a molecular mass of 12,598 d. Immunoblot analysis showed 21 (81%) of 26 sera from patients with cashew allergy were reactive. Three native Ana o 3 large-subunit isoforms with molecular weights ranging from approximately 6 to 10 kd were identified. Probing of overlapping synthetic Ana o 3 peptides with patients' sera identified 16 reactive peptides, 4 of which gave strong signals and one of which positionally overlaps linear epitopes in mustard and walnut allergenic 2S albumins. The overlapping cashew and walnut epitopes also share considerable homology., Conclusions: We conclude that this 2S albumin protein is a major allergen in cashew nut and demonstrates a possible basis for cross-reactivity with walnut 2S albumin.

Background: The majority of children with cow's milk and hen's egg allergy develop clinical tolerance with time. However, there are no good indices to predict when and in whom this occurs., Objective: The aim of this study was to determine if monitoring food specific IgE levels over time could be used as a predictor for determining when patients develop clinical tolerance., Methods: Eighty-eight patients with hen's egg and 49 patients with cow's milk allergy who underwent repeated double-blind, placebo-controlled food challenges were included in the study. Using the Pharmacia CAP-System FEIA, specific IgE (sIgE) levels to cow's milk and hen's egg were retrospectively determined from stored serum samples obtained at the time of the food challenges. Logistic regression was used to evaluate the relationship between tolerance development and the decrease in sIgE levels over a specific time period between the two challenges., Results: Twenty-eight of the 66 egg-allergic and 16 of the 33 milk-allergic patients lost their allergy over time. For egg, the decrease in sIgE levels (P=.0014) was significantly related to the probability of developing clinical tolerance, with the duration between challenges having an influence (P=.06). For milk there also was a significant relationship between the decrease in sIgE levels (P=.0175) and the probability of developing tolerance to milk but no significant contribution with regard to time. Stratification into 2 age groups, those below 4 years of age and those above 4 years of age at time of first challenge, had an effect, with the younger age group being more likely to develop clinical tolerance in relation to the rate of decrease in sIgE. The median food sIgE level at diagnosis was significantly less for the group developing "tolerance" to egg (P <.001), and a similar trend was seen for milk allergy (P=.06). Using these results, we developed a model for predicting the likelihood of developing tolerance in milk and egg allergy based on the decrease in food sIgE over time., Conclusion: We found that the rate of decrease in food sIgE levels over time was predictive for the likelihood of developing tolerance in milk and egg allergy. Using the likelihood estimates from this study could aid clinicians in providing prognostic information and in timing subsequent food challenges, thereby decreasing the number of premature and unnecessary double-blind, placebo-controlled food challenges.

Background: IgE epitope mapping of food allergens is a prerequisite for engineering hypoallergenic immunotherapeutic agents and might reveal basic information regarding a patient's immune response. Mapping of large numbers of epitopes by using individual patient sera has been impractical with current techniques., Objective: We sought to develop a peptide microarray-based immunoassay to map peanut epitopes by using microliter quantities of serum., Methods: A set of 213 overlapping 20-residue peptides was synthesized corresponding to the primary sequences of Ara h 1, Ara h 2, and Ara h 3. These were arrayed in triplicate along with the corresponding recombinant proteins onto glass slides and used for immunolabeling., Results: Seventy-seven patient and 15 control sera were analyzed. The majority of patients (97%) had specific IgE to at least one of the recombinant allergens, and 87% had detectable IgE to sequential epitopes. Microarray mapping correlated well with previous studies. However, the analysis of individual patients revealed remarkable heterogeneity in the number and patterns of epitope recognition. High epitope diversity was found in patients with a history of more severe allergic reactions. Also, sensitization of effector cells with more diverse IgE antibodies conferred greater reactivity to specific allergen., Conclusions: The protein microarray immunoassay confirmed that Ara h 1, Ara h 2, and Ara h 3 are major peanut allergens and allows for parallel epitope analysis. This has led to the discovery of an additional important epitope of Ara h 1 and the recognition of a high degree of patient heterogeneity. This qualitative difference in epitope diversity might provide prognostic information about the patient.

Background: Allergy to cow's milk is common in early childhood, and no therapy other than avoidance exists. In murine models of peanut allergy, immunotherapy with mutated, engineered, proteins appears promising., Objective: We sought to identify the critical amino acids (AAs) for immunoglobulin E (IgE) binding within the major B-cell epitopes of alpha(s1)-casein, a major cow's milk allergen. This will provide the necessary information to alter the cDNA to encode a protein capable of activating milk-specific T cells, but with reduced IgE-binding capacity., Methods: For mutational analysis of the IgE-binding epitopes, peptides of 10-14 AAs in length were synthesized on a derivatized cellulose membrane with single or multiple AA substitutions. Membranes were immunolabeled with pooled sera from 15 cow's-milk-allergic patients and with 8 individual sera., Results: With the pooled sera, substitution of a single AA led to complete abrogation of IgE binding to 2 of 8 peptides and diminished binding in the remainder. Substitution of multiple AAs led to an abrogation of binding in the remaining peptides. In 4 of the 8 peptides, the critical AA identified with pooled sera did not result in significant reduction of IgE binding with 1 or more individual patients. For these patients, other critical AAs were identified, indicating a more heterogeneous pattern in IgE recognition., Conclusion: This study indicates that single or multiple AA substitutions within IgE-binding epitopes result in reduced binding of milk-specific IgE antibodies by patients' sera. However, for future immunotherapeutic interventions with mutated peptides, critical AAs should be evaluated with individual patient sera to determine B-cell-epitope heterogeneity.

Background: Peanut allergy is one of the most common food allergies, often resulting in severe reactions. Diagnostic decision levels of food-specific IgE antibody concentrations have been described. However, many patients still need to undergo oral peanut challenges because their IgE levels are in the nondiagnostic level., Objective: The aim of this study was to determine whether differences exist in IgE-binding epitope recognition between sensitized children with and without symptomatic peanut allergy., Methods: Eight peptides representing the immunodominant sequential epitopes on Ara h 1, 2, and 3 were synthesized on SPOTs membranes. Individual patient labeling was performed with sera from 15 patients with symptomatic peanut allergy and 16 patients who were sensitized but tolerant. Ten of these 16 patients had "outgrown" their allergy., Results: Regardless of their peanut-specific IgE levels, most patients with symptomatic peanut allergy showed IgE binding to the 3 immunodominant epitopes on Ara h 2. In contrast, each of these epitopes was recognized by < 10% of the tolerant patients. In addition, tolerant patients did not recognize 2 immunodominant epitopes on Ara h 1. At least 93% of symptomatic, but only 12.5% of tolerant patients, recognized 1 of these "predictive" epitopes on Ara h 1 or 2. Moreover, the cumulative IgE binding to the peanut peptides was significantly higher in patients with peanut allergy than in tolerant patients. With up to 50% of patients with peanut-specific IgE levels below diagnostic decision levels still being clinically reactive, oral food challenges could be avoided in ~90% of these patients through determination of peptide-specific IgE., Conclusions: Determination of epitope recognition provides an additional tool to diagnose symptomatic peanut allergy, especially in children with peanut-specific IgE below diagnostic decision levels.

Background: Hazelnuts are a common cause of food allergy. Allergic reactions to hazelnuts range from oral allergy syndrome caused by cross-reactivity between tree pollen and hazelnut proteins to severe anaphylactic reactions. Little information is available regarding the identification of pollen-independent hazelnut allergens., Objective: The aim of the study was to identify these pollen-independent allergens in patients with hazelnut allergy with systemic reactions., Methods: Extracted hazelnut proteins were separated by means of 2-dimensional PAGE, and immunolabeling was performed with individual sera from 14 patients with hazelnut-induced systemic reactions. Edman sequencing was performed on a 40-kd protein identified as an allergen. In parallel, RNA isolated from hazelnuts was used to construct a cDNA library. By using the peptide sequence data, oligonucleotide primers were synthesized and used to screen the library. Full-length cDNA clones were isolated, sequenced, expressed, and screened with patient sera., Results: By using 2-dimensional proteomics, a protein fraction at 40 kd was recognized by serum IgE from 86% (12/14) of the patients with hazelnut allergy with systemic reactions. Two internal amino acid sequences were determined by means of Edman sequencing. Screening of the prepared hazelnut cDNA library with oligonucleotides based on these internal peptide sequences resulted in isolation of a novel protein cDNA. The new protein, named Cor a 9, belongs to the 11S globulin seed storage protein family. This family comprises known food allergens in peanut (Ara h 3) and soybean (glycine max). The pairwise homology among these 3 proteins ranges from 45% to 50%. Interestingly, one known IgE-binding epitope of Ara h 3 shares 67% of homologous amino acid residues with the corresponding area of Cor a 9. The amino acids that differ were previously shown not to be critical for IgE binding in Ara h 3., Conclusion: Cor a 9 is the first tree pollen-unrelated hazelnut allergen isolated, sequenced, and cloned. The identification of food allergens is the first step toward generating recombinant allergens for use in future immunotherapeutic approaches. In addition, the detection of conserved IgE epitopes in common food allergens, such as seed storage proteins, might be a useful tool for predicting cross-reactivity to certain foods.

Background: Cow's milk is one of the most common causes of food allergy in the first years of life. We recently defined IgE-binding epitopes of all 6 major cow's milk proteins (alpha(s1)-, alpha(s2)-, beta-, and kappa-casein; alpha-lactalbumin; and beta-lactoglobulin) and had some evidence suggesting that IgE antibodies from patients with persistent cow's milk allergy (CMA) recognize different epitopes on cow's milk proteins than do those from patients who were likely to outgrow their allergy., Objective: In this study we sought to assess whether recognition of IgE antibodies of certain epitopes of cow's milk proteins would clearly separate the patients with life-long CMA from those who will become clinically tolerant to cow's milk., Methods: According to the known IgE-binding regions of cow's milk proteins, 25 decapeptides of alpha(s1)-casein, alpha(s2)-casein, kappa-casein, alpha-lactalbumin, and beta-lactoglobulin, comprising the core epitopes, were synthesized on a cellulose-derivatized membrane. Sera from 10 patients with persistent CMA and 10 patients who subsequently outgrew their milk allergy were used to investigate the differences in epitope recognition., Results: Five IgE-binding epitopes (2 on alpha(s1)-casein, 1 on alpha(s2)-casein, and 2 on kappa-casein) were not recognized by any of the patients with transient CMA but showed binding by the majority of the patients with persistent allergy. The presence of IgE antibodies against at least 1 of 3 epitopes (amino acid [AA] 123-132 on alpha(s1)-casein, AA 171-180 on alpha(s2)-casein, and AA 155-164 on kappa-casein) identified all patients with persistent CMA., Conclusions: The presence of IgE antibodies to distinct allergenic epitopes of cow's milk proteins can be used as a marker of persistent CMA. Prospective studies are needed to investigate the usefulness of these informative epitopes in predicting life-long CMA in young children.

Background: Sesame seed allergy is becoming increasingly prevalent, probably because of its use in international fast-food and bakery products. Despite this fact, few studies have focused on the identification of its major allergenic proteins., Objective: The aim of this study was to identify allergenic proteins of sesame seeds (Sesamum indicum)., Methods: Extracted sesame seed proteins were separated by means of SDS-PAGE and 2-dimensional (2-D) PAGE. Immunolabeling was performed with individual patient sera from 20 patients with sesame seed allergy. Selected proteins were further analyzed by means of Edman sequencing., Results: IgE-binding proteins were identified at 78, 52, 45, 34, 32, 29, 25, 20, 9, and 7 kd. Analyzing internal sequences, the protein at 45 kd, which was recognized by 75% of the patients, was found to be a 7S vicilin-type globulin, a seed storage protein of sesame and named Ses i 3. The protein at 7 kd was found to be a 2S albumin, another seed storage protein of sesame and named Ses i 2. Seed storage proteins are known food allergens in peanut, walnut, Brazil nut, and soybean. Interestingly, one known IgE-binding epitope of the peanut allergen Ara h 1 has 80% homology with the corresponding area of Ses i 3. The different amino acids were previously shown not to be critical for IgE binding in Ara h 1. In addition, the proteins at 78 and 34 kd were found to be homologous to the embryonic abundant protein and the seed maturation protein of soybeans, respectively., Conclusion: The identification of 4 sesame seed allergens is the first step toward generating recombinant allergens for use in future immunotherapeutic approaches. In addition, the detection of conserved IgE binding epitopes in common food allergens might be a useful tool for predicting cross-reactivity to certain foods.

Background: A number of gastrointestinal disorders, including allergic eosinophilic gastroenteritis and food protein-induced enteropathy, have been associated with milk hypersensitivity. The immunologic reactions appear to involve T cells that are activated by specific food proteins., Objective: The present study was performed to examine the cytokine profiles of milk-specific lymphocytes from the duodenal lamina propria from children with milk-induced gastrointestinal diseases., Methods: Duodenal biopsy specimens obtained from 10 patients with allergic eosinophilic gastroenteritis, food protein-induced enteropathy, or both and 12 control subjects were mechanically minced and cultured with either mitogens (i.e., polyclonal T-cell expansion) or milk proteins (i.e., milkspecific T-cell expansion). By using flow cytometry, expanded T cells were phenotyped with anti-CD4, anti-CD8, anti-IL-4, anti-IL-5, and anti-IFN-gamma mAbs. The milk specificity of the lines was evaluated by means of the lymphocyte proliferation assay. In addition, the release of T(H)1, T(H)2, and T(H)3 cytokines was determined after restimulation., Results: In patients and control subjects polyclonal expansion of mucosal lymphocytes resulted in predominantly T(H)1 cells. Milk-specific mucosal T-cell lines could be established in 60% of the patients but in none of the control subjects. In contrast to the polyclonal expansion of T cells, the milk-specific expansion of mucosal T cells showed a clear T(H)2 cytokine profile. On restimulation with milk protein, these cells showed a high proliferative response. They released T(H)2 cytokines, predominately IL-13, but failed to release T(H)3 cytokines important in the development of oral tolerance., Conclusion: The release of T(H)2 cytokines after stimulation of milk-specific mucosal T cells may play a pathogenic role in the inflammatory changes seen in milk-induced gastrointestinal disorders.

Background: Two forms of IgE-mediated skin reactions, atopic dermatitis (AD) and urticaria, have been associated with milk allergy. The reason for these distinct reactions is poorly understood. T cells expressing cutaneous lymphocyte antigen (CLA), a unique skin-homing receptor, are known to play an important role in AD. In contrast, the role of lymphocytes in patients with milk-induced urticaria is unclear., Objective: The expression of the skin-specific homing receptor CLA after in vitro milk protein-specific stimulation was investigated to determine whether T-lymphocyte homing to the skin plays a role in food-induced urticaria., Methods: Fourteen patients with milk-induced urticaria but no evidence of AD were included in the study and compared with 6 children with milk-induced AD, 6 children with milk-induced gastrointestinal diseases, and 6 nonatopic and 6 atopic individuals without milk allergy. PBMCs were cultured in the presence or absence of caseins or tetanus toxoid. T-cell proliferation was determined, and T-cell phenotyping was performed by means of flow cytometry with anti-CD4, anti-CD8, and anti-CLA mAbs., Results: After in vitro stimulation with caseins, PBMCs from patients with milk-induced urticaria and AD had a significantly greater percentage of CD4(+) T cells expressing CLA than patients with milk-induced gastrointestinal symptoms and atopic or nonatopic control subjects. After tetanus stimulation in vitro, no significant difference between the groups was observed. T cells from both patients with milk-induced urticaria and control subjects proliferated well in response to caseins and tetanus., Conclusion: Lymphocytes expressing CLA are selectively activated in patients with milk-induced urticaria and may play an important role in the pathogenesis of this disease. Expression of CLA is not unique to milk-induced inflammation in the skin of patients with AD and milk allergy.