Eliciting Dose and Safety Outcomes From a Large Dataset of Standardized Multiple Food Challenges

Background: Food allergy prevalence has continued to rise over the past decade. While studies have reported threshold doses for multiple foods, large-scale multi-food allergen studies are lacking. Our goal was to identify threshold dose distributions and predictors of severe reactions during blinded oral food challenges (OFCs) in multi-food allergic patients.Methods: A retrospective chart review was performed on all Stanford-initiated clinical protocols involving standardized screening OFCs to any of 11 food allergens at 7 sites. Interval-censoring survival analysis was used to calculate eliciting dose (ED) curves for each food. Changes in severity and ED were also analyzed among participants who had repeated challenges to the same food.Results: Of 428 participants, 410 (96%) had at least one positive challenge (1445 standardized OFCs with 1054 total positive challenges). Participants undergoing peanut challenges had the highest ED50 (29.9 mg), while those challenged with egg or pistachio had the lowest (7.07 or 1.7 mg, respectively). The most common adverse event was skin related (54%), followed by gastrointestinal (GI) events (33%). A history of asthma was associated with a significantly higher risk of a severe reaction (hazard ratio [HR]: 2.37, 95% confidence interval [CI]: 1.36, 4.13). Higher values of allergen-specific IgE (sIgE) and sIgE to total IgE ratio (sIgEr) were also associated with higher risk of a severe reaction (1.49 [1.19, 1.85] and 1.84 [1.30, 2.59], respectively). Participants undergoing cashew, peanut, pecan, sesame, and walnut challenges had more severe reactions as ED increased. In participants who underwent repeat challenges, the ED did not change (p = 0.66), but reactions were more severe (p = 0.02).Conclusions: Participants with a history of asthma, high sIgEr, and/or high values of sIgE were found to be at higher risk for severe reactions during food challenges. These findings may help to optimize food challenge dosing schemes in multi-food allergic, atopic patients, specifically at lower doses where the majority of reactions occur.Trials Registration Number: ClinicalTrials. gov number NCT03539692; https://clinicaltrials.gov/ct2/show/NCT03539692

Analysis of a Large Standardized Food Challenge Data Set to Determine Predictors of Positive Outcome Across Multiple Allergens

Background: Double-blind placebo-controlled food challenges (DBPCFCs) remain the gold standard for the diagnosis of food allergy; however, challenges require significant time and resources and place the patient at an increased risk for severe allergic adverse events. There have been continued efforts to identify alternative diagnostic methods to replace or minimize the need for oral food challenges (OFCs) in the diagnosis of food allergy.Methods: Data was extracted for all IRB-approved, Stanford-initiated clinical protocols involving standardized screening OFCs to a cumulative dose of 500 mg protein to any of 11 food allergens in participants with elevated skin prick test (SPT) and/or specific IgE (sIgE) values to the challenged food across 7 sites. Baseline population characteristics, biomarkers, and challenge outcomes were analyzed to develop diagnostic criteria predictive of positive OFCs across multiple allergens in our multi-allergic cohorts.Results: A total of 1247 OFCs completed by 427 participants were analyzed in this cohort. Eighty-five percent of all OFCs had positive challenges. A history of atopic dermatitis and multiple food allergies were significantly associated with a higher risk of positive OFCs. The majority of food-specific SPT, sIgE, and sIgE/total IgE (tIgE) thresholds calculated from cumulative tolerated dose (CTD)-dependent receiver operator curves (ROC) had high discrimination of OFC outcome (area under the curves > 0.75). Participants with values above the thresholds were more likely to have positive challenges.Conclusions: This is the first study, to our knowledge, to not only adjust for tolerated allergen dose in predicting OFC outcome, but to also use this method to establish biomarker thresholds. The presented findings suggest that readily obtainable biomarker values and patient demographics may be of use in the prediction of OFC outcome and food allergy. In the subset of patients with SPT or sIgE values above the thresholds, values appear highly predictive of a positive OFC and true food allergy. While these values are relatively high, they may serve as an appropriate substitute for food challenges in clinical and research settings

IgE and IgG4 epitopes of the peanut allergens shift following oral immunotherapy

Background Oral immunotherapy (OIT) with peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Aimmune Therapeutics) is an FDA-approved treatment to desensitize peanut allergic participants. Objective Here we assessed shifts in IgE and IgG4 binding to peanut allergens and their epitopes recognized by United States (US) peanut allergic participants (n = 20) enrolled in phase 3 PTAH OIT clinical trials. Methods Pre- and post- trial participant sera were collected approximately 12 months apart and tested for IgE binding to intact peanut proteins via ImmunoCAP ISAC immunoassays. IgE and IgG4 linear epitopes were identified based on binding to synthetic overlapping 15-mer linear peptides of 10 peanut allergens (Ara h 1-11) synthesized on microarray slides. Results Statistically significant decreases in IgE binding were identified for intact Ara h 2, 3, and 6, and known and newly identified IgE epitopes were shown to exhibit shifts towards IgG4 binding post-OIT, with most linear peptides having increased IgG4 binding after treatment with PTAH. While PTAH does not seem to alter the actual peptide binding patterns significantly after one year of treatment, the IgE and IgG4 binding ratios and intensity are altered. Conclusion At a population level, the linear IgE and IgG4 epitopes of 10 peanut allergens overlap and that increase in IgG4 with OIT results in displacement of IgE binding to both conformational and linear epitopes. Furthermore, it appears as though the increase in IgG4 is more important to achieve desensitization at the 12-month timepoint than the decrease in IgE. This type of knowledge can be useful in the identification of IgE and IgG4-binding allergen and peptide biomarkers that may indicate desensitization or sustained unresponsiveness of allergic individuals to peanut

The importance of allergic disease in public health: an iCAALL statement

Allergic diseases constitute a significant cause of morbidity worldwide and a considerable burden on the health and medical systems of both developed and emerging economies. Allergies and related diseases including asthma, rhinosinusitis, atopic dermatitis and life threatening food, drug, and stinging insect allergies affect at least 30% of the population and nearly 80% of families. According to recent studies, their prevalence is increasing globally [1–4]. Medical services providing expert allergy care are lacking in many countries; therefore, the major organizations devoted to the field of allergy (American Academy of Allergy, Asthma and Immunology, AAAAI; American College of Allergy, Asthma, and Immunology, ACAAI; European Academy of Allergy, Asthma and Clinical Immunology, EAACI; and the World Allergy Organization, WAO), strongly feel that education of health professionals and the public on the importance and impact of allergic diseases as a public health concern should be encouraged. The International Collaboration in Allergy, Asthma, and Immunology (iCAALL), a partnership constituted by AAAAI, ACAAI, EAACI, and WAO, have recommended publishing an advocacy statement with the purpose of calling to the attention of the medical community, health authorities and the public in general, the major impact and relevance of the allergy specialists as key groups of professionals specifically trained for the adequate diagnosis, treatment, and prevention of allergic diseases

The diagnosis and management of anaphylaxis practice parameter: 2010 Update

These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing “The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, or the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion

Qualitative interviews to understand health care providers experiences of prescribing licensed peanut oral immunotherapy.

OBJECTIVE: This research sought to explore health care providers (HCPs) experiences of delivering the first US Food and Drug Administration (FDA) and European Commission (EC) approved peanut oral immunotherapy (peanut OIT; Palforzia). Semi-structured qualitative interviews with HCPs who had initiated treatment with ≥ 3 patients in the first nine months following FDA approval sought to identify challenges faced and successful implementation strategies. RESULTS: Eight allergists and three nurse practitioners from eight sites based in the United States participated. The HCPs included in this research were motivated to implement this novel treatment, however, entered the process with some reservations. HCPs described how successful implementation of peanut OIT requires them to be thoughtful about their clinics abilities to integrate complex, time-consuming treatments into their daily practice. Prior experience of OIT was deemed beneficial, but not essential for implementation and learning from others experience was suggested as a way of helping new prescribers overcome perceived and actual implementation challenges. Delivering licensed peanut OIT during the COVID-19 pandemic posed both challenges and unexpected opportunities for implementation. The experiences described have the potential to benefit the wider allergy community by providing practical solutions, successful implementation strategies and opportunities to enhance training and resources

A study to assess current approaches of allergists in European countries diagnosing and managing children and adolescents with peanut allergy.

RationaleFood allergy is documented to result in considerable morbidity, negative impact on quality of life, and substantial medical care costs. Although anecdotal data suggest widely varying practices in the diagnosis and management of food allergies, the diversity and relative frequency of these practices have not been documented.MethodsA questionnaire was developed evaluating allergists' management approaches of individuals with peanut allergy (PA) in Germany (DE), France (FR), and the United Kingdom (UK).ResultsHere, we report the survey results from a total of 109 allergists from DE, FR and the UK. They reported to confirm PA at initial diagnosis using skin prick test (≥60%), while allergists from DE and FR reported using allergen-specific IgE testing more (>86%) compared to the UK (75%). Half of the responders reported assessing the patient's quality of life. 63% allergists reported retesting for PA resolution at a later date, with 45% allergists indicated to recommend ingestion of a normal serving of peanut regularly upon resolution. Lack of effective PA treatment was reported to be a 'very significant' barrier for optimal PA treatment, with allergists being less than 'moderately familiar' with data from clinical trials testing new treatments options for PA. Lastly, allergists stated that the severity of patient's PA ranked as the most important factor in their decision to recommend oral immunotherapy for PA treatment.ConclusionsThis survey provides essential insights into the practice of allergists and highlights some areas that would inform strategies for education and improving PA healthcare