Food Challenge Outcomes Research Articles

A Streamlined Strategy for Basophil Activation Testing in a Multicenter Phase III Clinical Trial

BackgroundThe basophil activation test (BAT) has been limited to research settings due to technical issues. Novel approaches using dry, ready-to-use reagents and streamlined protocols offer greater flexibility and may open opportunities for easier implementation in clinical research. ObjectiveUsing a streamlined BAT (sBAT) strategy and the settings of the baseline study of the EPITOPE trial of EPicutaneous ImmunoTherapy (EPIT™) for peanut allergy, we aimed to assess the feasibility of implementing BAT in a multicenter trial and to evaluate its utility in predicting the outcomes of peanut double-blind placebo-controlled food challenge (DBPCFC). MethodsWhole blood samples were collected from subjects aged 1-3 years (n=241) undergoing baseline eligibility DBPCFC in the EPITOPE study across 15 clinical sites in North America. After preparation with sBAT reagents, processed samples were analyzed in a single central laboratory within 5 days of collection and preparation. The eliciting dose (ED) at DBPCFC was determined using PRACTALL criteria. Using a machine learning (ML) approach which incorporated BAT-derived features, clinical characteristics, and peanut-specific IgE, the ability to predict outcomes of interest (ED [<300 mg or >300 mg] and use of epinephrine) was assessed using data randomly split into training (n=182) and validation (n=59) subsets. ResultsThe expression of basophil activation markers CD203c and CD63 correlated with ED and severity outcomes of DBPCFC. Most informative concentrations of peanut extract in the sBAT assay for these associations were 1 and 10 ng/ml. Using ML to assess the ability to predict the outcomes of DBPCFC, the best models using only the BAT-derived features provided relatively high sensitivities of 0.86 and 0.85 for predicting eliciting dose and epinephrine use, respectively, while specificities were lower, ranging from 0.60 to 0.80. While including specific IgE and SPT data in addition to those from sBAT did not improve the ability to identify individuals most at risk for severe reactions, it did improve the ability to identify patients with an eliciting dose above 300 mg. ConclusionIn addition to facilitating implementation in multicenter trials, sBAT retains the potential of BAT to characterize allergic patients and confirms its potential to contribute to predicting the outcome of oral food challenges.

Role of serum-specific immunoglobulin E in egg allergy: a comprehensive study of Portuguese pediatric patients.

Food allergies represent a growing public health concern, particularly among children. This study aims to examine egg allergy in pediatric patients and analyze the value of serum-specific immunoglobulin E (sIgE) levels as predictive biomarkers for oral food challenge (OFC) outcomes. Retrospective study, involving pediatric patients with suspected IgE-mediated egg allergy, conducted at a tertiary hospital. Data from 176 pediatric patients were analyzed, revealing a higher male prevalence (59.1%). Most cases (40.3%) presented symptoms in the first year of life, predominantly mucocutaneous symptoms (46%). OFC results varied across various forms of egg presentation, with cooked egg being the most frequently tested food. Positive OFCs were observed in 14.6% (n = 36) of cases. The study identified specific egg protein biomarkers for positive OFC, with ovalbumin for raw egg (sIgE > 1.28 KUA/L; area under the curve [AUC] = 0.917; sensitivity [S] 100%; and specificity [Sp] 92%), ovomucoid for cooked egg (sIgE > 0.99 KUA/L; AUC = 0.788, 95%; S: 79%; and Sp: 74%), and ovomucoid for baked egg (sIgE> 4.63 KUA/L; AUC = 0.870; S: 80%; and Sp: 85%) showing predictive capacities. The findings underscore the importance of considering various forms of egg presentation in the diagnosis and management of egg allergy. The findings highlight the valuable discriminatory capacity and provided reliable biomarkers, such as ovalbumin for raw egg and ovomucoid for cooked and baked egg in risk assessment, aiding in predicting OFC outcomes and helping clinicians to make informed decisions in diagnosing and managing egg allergies, thus improving patient care and quality of life.

Prediction of pediatric peanut oral food challenge outcomes using machine learning

Clinical testing, including food-specific skin and serum IgE level tests, provides limited accuracy to predict food allergy. Confirmatory oral food challenges (OFCs) are often required, but the associated risks, cost, and logistic difficulties comprise a barrier to proper diagnosis. We sought to utilize advanced machine learning methodologies to integrate clinical variables associated with peanut allergy to create a predictive model for OFCs to improve predictive performance over that of purely statistical methods. Machine learning was applied to the Learning Early about Peanut Allergy (LEAP) study of 463 peanut OFCs and associated clinical variables. Patient-wise cross-validation was used to create ensemble models that were evaluated on holdout test sets. These models were further evaluated by using 2 additional peanut allergy OFC cohorts: the IMPACT study cohort and a local University of Michigan cohort. In the LEAP data set, the ensemble models achieved a maximum mean area under the curve of 0.997, with a sensitivity and specificity of 0.994 and 1.00, respectively. In the combined validation data sets, the top ensemble model achieved a maximum area under the curve of 0.871, with a sensitivity and specificity of 0.763 and 0.980, respectively. Machine learning models for predicting peanut OFC results have the potential to accurately predict OFC outcomes, potentially minimizing the need for OFCs while increasing confidence in food allergy diagnoses.

Descriptive analysis of oral food challenge outcomes from a multicentre cohort study

Descriptive analysis of oral food challenge outcomes from a multicentre cohort study

Predicting the Outcome of Pediatric Oral Food Challenges for Determining Tolerance Development.

Despite the risk of anaphylaxis, oral food challenges (OFCs) are performed clinically for various indications, particularly to confirm tolerance development. This study aimed to assess OFCs by relevant indications and build an outcome prediction model to help determine when to perform OFCs in children who are likely to have developed immune tolerance. In total, 432 pediatric OFCs were retrospectively analyzed according to indications. Clinical characteristics, serum total immunoglobulin (Ig) E, blood eosinophils, and specific IgE and IgG4 levels for food allergens were noted and compared. Machine learning was utilized to select the most important variables in determining the passage of the OFCs, and prediction models were constructed using the selected variables. OFCs were most commonly performed to confirm tolerance development (number, %; 267, 61.8%). The most common food allergens tested were egg (191, 44.2%) and milk (135, 31.3%). Children who passed the egg challenges for confirming tolerance acquisition had significantly lower egg white-specific IgE level (P = 0.008). Similarly, those who passed milk challenges had significantly lower cow's milk-specific IgE (P = 0.002) and casein-specific IgE levels (P = 0.005). We developed a nomogram to predict the outcome of OFCs to determine the tolerance acquisition with the selected variables; lower food-specific IgE, higher total IgE, and younger age indicated a higher probability of passage. The area under the curve (95% confidence interval) was 0.623 (0.503-0.743) for egg and 0.734 (0.628-0.840) for milk. Serum total IgE and food-specific IgE combined with age showed trends toward passing OFCs for confirming tolerance development. The constructed model may be used by clinicians as a practical guide for minimizing the risks of OFCs and a timely reintroduction for children with food allergies.

Partial Egg Consumption Modifies the Diagnostic Performance of Allergy Tests to Predict Outcome of Double-Blind Placebo-Controlled Food Challenges to Egg

Many children are consuming some egg when they are diagnosed with egg allergy. We hypothesized that egg consumption could modify the diagnostic performance of allergy tests. To stratify diagnostic performance of tests according to egg consumption status. The BAT2 study (NCT03309488) participants underwent oral food challenge (OFC), food-frequency questionnaires, skin prick test (SPT), specific immunoglobulin E (sIgE) and specific immunoglobulin G4 (sIgG4) and basophil activation test (BAT). At study entry, 45% of participants reported partial egg consumption ("consumers") and 55% were avoiding egg strictly ("avoiders"). Avoiders had larger SPT (P < .001), higher BAT to egg (P < .001), sIgE to egg white (EW; P= .001) and to ovalbumin (OVA; P= .001), but not to ovomucoid (P= .231). Consumers had higher levels of sIgG4 to all egg allergens (P < .001) than avoiders. In consumers, the test with the best diagnostic performance was BAT (area under the curve [AUC]= .912) followed by SPT to raw egg (AUC= 0.805), EW-sIgE (AUC= 0.738), and OVA-sIgE (AUC= 0.732). In avoiders, the best tests were BAT (AUC= 0.834) and EW-sIgE (AUC= 0.833) followed by OVA-sIgE (AUC= 0.793) and SPT to EW (AUC=0.789). Using 100% sensitivity and 100% specificity cut-offs, the proportion of patients requiring OFC were 33% for BAT, 53% for SPT to raw egg, 61% for OVA-sIgE, and 73% for EW-sIgE for consumers; and 73% for BAT, 79% for EW-sIgE, and 93% for SPT to EW for avoiders. The diagnostic performance of tests is influenced by the immunomodulatory effect of egg consumption. BAT is the most reliable test and reduced the need for OFC, particularly in partial egg consumers.

Predictors of oral food challenge outcome in young children.

Predictors of oral food challenge outcome in young children.

Transepidermal water loss rises before food anaphylaxis and predicts food challenge outcomes.

Food allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes during an OFC could predict anaphylaxis onset. Physicians and nurses blind to TEWL results conducted and adjudicated the results of all 209 OFCs in this study. A study coordinator measured TEWL throughout the OFC and had no input on OFC conduct. TEWL was measured two ways in two separate groups. First, TEWL was measured using static, discrete measurements. Second, TEWL was measured using continuous monitoring. Participants who consented gave blood before and after OFCs for biomarker analyses. TEWL rose significantly (2.93 g/m2/h) during reactions and did not rise during non-reacting OFCs (-1.00 g/m2/h). Systemic increases in tryptase and interleukin-3 were also detected during reactions, providing supporting biochemical evidence of anaphylaxis. The TEWL rise occurred 48 minutes earlier than clinically evident anaphylaxis. Continuous monitoring detected a significant rise in TEWL that presaged positive OFCs, but no rise was seen in OFCs with no reaction, providing high predictive specificity (96%) for anaphylaxis against non-reactions 38 minutes prior to anaphylaxis. During OFCs, a TEWL rise anticipates a positive clinical challenge. TEWL presents a novel monitoring modality that may predict food anaphylaxis and facilitate improvements in OFC safety and tolerability.

Outcomes of oral food challenges in a real-world setting, with predictors of outcomes

BackgroundOral food challenge (OFC) remains the reference standard for food allergy (FA) diagnosis. ObjectiveThis study reports a single-center observational experience with all OFCs conducted over 3 years. MethodsAll OFCs performed at an outpatient office were tracked. The OFCs were conducted without strict prespecified inclusion or exclusion criteria. Demographic information along with results of diagnostic testing and results of the OFCs were recorded. ResultsA total of 1132 OFCs were performed, with a median age of 4 years (interquartile range = 2.0-10.0). Of the 1132 OFCs, 862 (76.1%) tolerated the food, whereas 232 (20.5%) experienced a reaction, and 38 (3.4%) did not complete the OFC because of food refusal. The highest percentage of tolerated food was shellfish (91.1%), with the lowest percentage of tolerated food being baked egg (66.1%). There were 66 (5.8%) OFCs that were deemed to be high risk, of which 35 (53.0%) tolerated the food. More than 50% of reactions occurred on the first or second dose, with the most common clinical symptom being urticaria or angioedema, with 29.2% of reactions treated with epinephrine. There were several factors that predicted tolerating an OFC, including the food challenge, the reason for food avoidance, older age at the time of OFC and less reactive skin prick testing, and lower food-specific immunoglobulin E levels. ConclusionCertain factors can predict tolerating an OFC, and even those considered to be high risk can be safely completed in an outpatient setting, with most tolerating the food, and most reactions not requiring treatment with epinephrine.

The Combination of Binding Avidity of Ovomucoid-Specific IgE Antibody and Specific IgG4 Antibody Can Predict Positive Outcomes of Oral Food Challenges during Stepwise Slow Oral Immunotherapy in Children with Hen's Egg Allergy.

To increase the prediction accuracy of positive oral food challenge (OFC) outcomes during stepwise slow oral immunotherapy (SS-OIT) in children with a hen's egg (HE) allergy, we evaluated the predictive value of the combination of antigen-specific IgE (sIgE) with antigen binding avidity and sIgG4 values. Sixty-three children with HE allergy undergoing SS-OIT were subjected to repeated OFCs with HE. We measured the ovomucoid (OVM)-sIgE by ImmunoCAP or densely carboxylated protein (DCP) microarray, sIgG4 by DCP microarray, and the binding avidity of OVM-sIgE defined as the level of 1/IC50 (nM) measured by competitive binding inhibition assays. The OFC was positive in 37 (59%) patients undergoing SS-OIT. Significant differences in DCP-OVM-sIgE, CAP-OVM-sIgE, I/IC50, DCP-OVM-sIgG4, the multiplication products of DCP-OVM-sIgE, and the binding avidity of DCP-OVM-sIgE (DCP-OVM-sIgE/IC50) and DCP-OVM-sIgE/sIgG4 were compared between the negative and positive groups (p < 0.01). Among them, the variable with the greatest area under the receiver operating characteristic curve was DCP-OVM-sIgE/IC50 (0.84), followed by DCP-OVM-sIgE/sIgG4 (0.81). DCP-OVM-sIgE/IC50 and DCP-OVM-sIgE/sIgG4 are potentially useful markers for the prediction of positive OFCs during HE-SS-OIT and may allow proper evaluation of the current allergic status in the healing process during HE-SS-OIT.

Previous test food intake and different allergenic food modified outcomes of oral food challenges

Previous test food intake and different allergenic food modified outcomes of oral food challenges

IgE-mediated cow’s milk allergy in Brazilian children: Outcomes of oral food challenge

BackgroundOral food challenge (OFC) is useful for diagnosing food allergies and assessing tolerance, but severe reactions may occur during the procedure. ObjectiveTo characterize the frequency and severity of reactions during cow's milk (CM) OFCs. MethodsA cross-sectional study was conducted to analyze the outcome of cow's milk oral food challenges (CMOFCs) performed to confirm IgE-mediated CM allergy or to assess food tolerance. CM was given first as baked milk (BM), followed by whole CM if there was no prior reaction to BM. An OFC was considered positive if IgE-mediated symptoms developed up to 2 h after ingestion. Symptoms were described and variables including age at OFC, prior anaphylaxis, other atopic diseases, and skin test results were compared according to the OFC outcomes. ResultsA total of 266 CMOFCs were performed, including 159 patients with a median age of 6.3 years old. One hundred thirty-six tests were positive and 62 resulted in anaphylaxis. Thirty-nine anaphylactic reactions were observed up to 30 min after the first dose. Severe anaphylaxis (cardiovascular and/or neurological involvement) was reported in 5 tests. A second dose of epinephrine was required in 3 tests, and 1 presented a biphasic response. Younger patients had a higher risk of anaphylaxis during baked milk oral food challenge (BMOFC) (p = 0.009). The frequency of anaphylaxis was higher in patients submitted to BM (p = 0.009). ConclusionsAnaphylaxis is a known complication of CMOFCs even when there is no prior anaphylaxis or when conducted with baked products. This study reinforces the importance of conducting OFC in appropriate settings with a well-trained team.

Oral food challenge outcomes in children and adolescents in a tertiary centre: A 5-year experience.

Oral food challenges (OFC) are an important tool in the assessment of food allergy. We sought to identify factors available at initial assessment visit which were associated with successful outcome or challenge failure in Australian children. We conducted a retrospective review of all paediatric patients who underwent OFC in our allergy service over a 5-year period. Clinical data comprising patient demographics, co-morbidities, skin prick test (SPT) results, nature of previous reactions, elapsed time since previous reactions and outcome at OFC were recorded. Four hundred and fifty-six OFCs were conducted, with 56 cases (12.3%) resulting in a reaction. Likelihood of reaction at OFC was significantly increased for patients with atopic dermatitis (odds ratio 1.99). When stratified by food substance, atopic dermatitis had the strongest association with reaction within the peanut group (odds ratio 3.2), and no association was demonstrated for soy or prawn. Increasing SPT wheal size (P < 0.001) and previous history of anaphylaxis to the challenge food (P < 0.001) correlated with failure at OFC. A low-risk group was identified, of patients with no clear history of prior reaction to the challenge food, and SPT result <3 mm. Factors identified at assessment visit which correlated with reaction at OFC are atopic dermatitis, prior history of anaphylaxis, and increasing SPT wheal size. Domiciliary OFC could be considered in a select low-risk group of patients undergoing food challenge. This study was performed at a single centre with limited sample size, further large-scale and multicentre study verification of our data will provide more accurate representation of the Australian demographic.

Retrospective Review of Adult Oral Food Challenge Outcomes in a Military Medical Center

Oral food challenges (OFCs) are the gold standard for diagnosis of food allergies. Limited data exists comparing adult OFCs in the military's health care system. The purpose of this study is to characterize adult OFC outcomes in one military medical center.

Systemic Reactions in Infants and Toddlers: A Prospective Study of Oral Food Challenge Outcomes

Systemic Reactions in Infants and Toddlers: A Prospective Study of Oral Food Challenge Outcomes

Cow’s milk allergy skin tests: fresh milk, commercial extracts, or both?

BackgroundThe diagnosis of food allergy is based on a history of immediate allergic reaction following food ingestion, and skin prick test (SPT) demonstrating sensitization with commercial extracts (CE) or fresh food (FF). For most food allergens, the SPT with FF is considered more accurate and predictive. Regarding cow’s milk, the results are inconclusive. This retrospective study aimed to evaluate the accuracy of SPT with fresh milk compared to CE (cow’s milk and casein) for evaluation of cow’s milk allergy (CMA).MethodsThis study summarized the medical records of children, diagnosed with CMA. The data include demographics, skin tests and oral food challenge results, as well as atopic comorbidities.ResultsRecords of 698 patients with the diagnosis of CMA were reviewed, 388 fulfilled the inclusion criteria. Overall, 134 patients (34.54%) had an additional atopic disease. The SPT wheal size with fresh milk was significantly larger than with CE (cow's milk and casein) at first evaluation or before oral food challenge (OFC). Combination of SPT results (CE and FF) gave the maximal odds ratio for reaction during OFC and SPT with fresh milk alone gave the minimal OR (34.18 and 4.74, respectively).ConclusionsSPT with CE for CMA evaluation is more reliable than SPT performed with fresh milk. In patients suspected of having IgE-mediated CMA, before deciding on performing OFC, it is advised to perform SPT with at least two different extracts, and always include casein. Fresh milk can serve as a backup if commercial extracts are not available. In cases that the SPT with fresh milk is 3 mm or less, there is 93.3% chance that the OFC will pass without reaction.Trial registration This study protocol was reviewed and approved by the Ethics Committee of Meir Medical Center, IRB Number 0083-18 MMC.

Prediction of oral food challenge outcomes via ensemble learning

Oral Food Challenges (OFCs) are essential to accurately diagnosing food allergy due to the limitations of existing clinical testing. However, some patients are hesitant to undergo OFCs, while those willing suffer from limited access to allergists in rural/community healthcare settings. Despite its success in predicting patient outcomes in other clinical settings, few applications of machine learning to food allergy have been developed. Thus, in this study, we seek to leverage machine learning methodologies for OFC outcome prediction. Retrospective data was gathered from 1,112 patients who collectively underwent a total of 1,284 OFCs, and consisted of clinical factors including serum-specific Immunoglobulin E (IgE), total IgE, skin prick tests (SPTs), comorbidities, sex, and age. Using these features, multiple machine learning models were constructed to predict OFC outcomes for three common allergens: peanut, egg, and milk. The best performing model for each allergen was an ensemble of random forest (egg) or Learning Using Concave and Convex Kernels (LUCCK) (peanut, milk) models, which achieved an Area under the Curve (AUC) of 0.91, 0.96, and 0.94, in predicting OFC outcomes for peanut, egg, and milk, respectively. Moreover, all such models had sensitivity and specificity values ≥89%. Model interpretation via SHapley Additive exPlanations (SHAP) indicates that specific IgE, along with wheal and flare values from SPTs, are highly predictive of OFC outcomes. The results of this analysis suggest that ensemble learning has the potential to predict OFC outcomes and reveal relevant clinical factors for further study.

CHARACTERISTICS OF PEDIATRIC PATIENTS WITH IGE-MEDIATED ALLERGY TO GREEN PEA

<h3>Introduction</h3> There are few published studies describing clinical characteristics of pediatric patients with IgE-mediated allergy to green pea (GP). Additionally, studies correlating skin prick testing (SPT) and sIgE testing with oral food challenge (OFC) outcomes to GP are lacking. <h3>Methods</h3> Retrospective review of patients evaluated for IgE-mediated GP allergy at a pediatric tertiary care center over a 10-year period was conducted. Wilcoxon signed-rank test was developed to compare SPT and sIgE values for patients who tolerated and those who reacted during an OFC. <h3>Results</h3> One hundred eighty-nine patients with GP allergy met inclusion criteria. Among included GP-allergic patients, 62% had documented peanut allergy, 79% had other documented IgE-mediated food allergy, and 53% had asthma. Seventeen patients underwent OFC to GP, with an OFC tolerance rate of 76%. Median SPT and sIgE values were significantly higher for those who did not tolerate OFC to GP (p = 0.023 and p = 0.027, respectively). <h3>Conclusion</h3> The majority of patients with GP allergy also had allergy to other foods. SPT and sIgE values were significantly higher in patients who reacted than those who tolerated OFC to GP. Further studies with larger sample sizes are indicated to establish diagnostic cutoff values to aid in prediction of OFC outcome to GP.

IL-4 receptor alpha signaling alters oral food challenge and immunotherapy outcomes in mice

Food allergy diagnosis and management causes a number of social and emotional challenges for individuals with food allergies and their caregivers. This has led to increased interest in developing approaches to accurately predict food allergy diagnosis, severity of food allergic reactions, and treatment outcomes. However, the utility of these approaches is somewhat conflicting. We sought to develop and utilize a murine model that mimics the disease course of food allergy diagnosis and treatment in humans and to identify biomarkers that predict reactivity during food challenge (FC) and responsiveness during oral immunotherapy (OIT) and how these outcomes are modified by genetics. Skin-sensitized intestinal IL-9 transgenic (IL9Tg) and IL9Tg mice backcrossed onto the IL-4RαY709F background received a single intragastric exposure of egg antigen (ovalbumin), underwent oral FC and OIT; food allergy severity, mast cell activation, and ovalbumin-specific IgE levels were examined to determine the predictability of these outcomes in determining reactivity and treatment outcomes. Subcutaneous sensitization and a single intragastric allergen challenge of egg antigen to BALB/c IL9Tg mice and Il4raY709F IL9Tg induced a food allergic reaction. Enhanced IL-4Rα signaling altered the symptoms induced by the first oral exposure, decreased the cumulative antigen dose, increased the severity of reaction during oral FC, and altered the frequency of adverse events and OIT outcomes. Biomarkers after first oral exposure indicated that only the severity of the initial reaction significantly correlated with cumulative dose of oral FC. Collectively, these data indicate that single nucleotide polymorphisms in IL-4Rα can alter clinical symptoms of food allergic reactions, severity, and reactive dose during FC and OIT, and that severity of first reaction can predict the likelihood of reaction during FC in mice with IL-4Rα gain of function.

Predictors of initial oral food challenge outcome in food protein-induced enterocolitis syndrome.

There is a paucity of data on predictors of clinical history in oral food challenge (OFC) outcome for the initial diagnosis of food protein-induced enterocolitis syndrome (FPIES). This study aimed to identify predictors for the diagnosis of FPIES. The study included patients who underwent OFC to diagnose FPIES from 2010 to 2021. Patients with a positive OFC result were classified as belonging to the FPIES group, and those with negative OFC result within 120 days from the last symptomatic episode were classified as belonging to the no-allergy (NA) group. Background factors were analyzed in the groups. A total of 50 OFCs to 12 different foods were conducted in 50 patients. Of those 50 patients, 30 were classified as belonging to the FPIES group. No significant difference was observed between the FPIES and NA groups with respect to background factors, including the features of symptomatic episodes and examinations of immediate-type allergy. Ahistory of asymptomatic ingestion was observed in 23 of 24 and 13 of 19 patients in the FPIES and NA groups, respectively; thus, it was significantly more common in patients with FPIES. The diagnostic rate of patients with fewer than 3 symptomatic episodes was 52%, and that of patients with 3 episodes or more was 75%, not considering a patient without available data. A definite diagnosis of FPIES should be based on OFC, as there are no predictors for OFC positivity other than a history of asymptomatic ingestion. The absence of asymptomatic ingestion history was a negative predictor for the diagnosis of FPIES.