Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Accelerating Food Allergy Research: Need for a Data Commons.

Food allergy is a significant health problem affecting approximately 8% of children and 11% of adults in the United States. It exhibits all the characteristics of a "complex" genetic trait; therefore, it is necessary to look at very large numbers of patients, far more than exist at any single organization, to eliminate gaps in the current understanding of this complex chronic disorder. Advances may be achieved by bringing together food allergy data from large numbers of patients into a Data Commons, a secure and efficient platform for researchers, comprising standardized data, available in a common interface for download and/or analysis, in accordance with the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. Prior data commons initiatives indicate that research community consensus and support, formal food allergy ontology, data standards, an accepted platform and data management tools, an agreed upon infrastructure, and trusted governance are the foundation of any successful data commons. In this article, we will present the justification for the creation of a food allergy data commons and describe the core principles that can make it successful and sustainable.

Diagnostic Testing Procedures and Challenges for Primary Immunodeficiencies.

Primary immunodeficiencies are rare but are often on the differential diagnosis list when patients present with recurrent or atypical infections. Patients with primary immunodeficiencies can present with a variety of symptoms and can present providers with diagnostic challenges given this variability, and the severe implications of immunodeficiencies can sometimes lead providers to pursue broad workups that may not be necessary. However, there are certain symptom patterns providers can look out for and diagnostic steps that can be taken to triage these presentations. We have used the practice modeled in the "Five Fingers of the Immune Workup" to outline common laboratory tests for clinicians to order when they are concerned for immunodeficiencies while remembering that these diagnoses are often rare, and true concern for this pathology would warrant referral to a specialist. [Pediatr Ann. 2022;51(12):e480-e484.].

Early Diagnosis of Primary Immunodeficiency Disease Using Clinical Data and Machine Learning.

BACKGROUND: Primary immunodeficiency diseases (PIDD) are a group of immune-related disorders that have a current median delay of diagnosis between 6 and 9 years. Early diagnosis and treatment of PIDD has been associated with improved patient outcomes. OBJECTIVE: To develop a machine learning model using elements within the electronic health record data that are related to prior symptomatic treatment to predict PIDD. METHODS: We conducted a retrospective study of patients with PIDD identified using inclusion criteria of PIDD-related diagnoses, immunodeficiency-specific medications, and low immunoglobulin levels. We constructed a control group of age-, sex-, and race-matched patients with asthma. The primary outcome was the diagnosis of PIDD. We considered comorbidities, laboratory tests, medications, and radiological orders as features, all before diagnosis and indicative of symptom-related treatment. Features were presented sequentially to logistic regression, elastic net, and random forest classifiers, which were trained using a nested cross-validation approach. RESULTS: Our cohort consisted of 6422 patients, of whom 247 (4%) were diagnosed with PIDD. Our logistic regression model with comorbidities demonstrated good discrimination between patients with PIDD and those with asthma (c-statistic: 0.62 [0.58-0.65]). Adding laboratory results, medications, and radiological orders improved discrimination (c-statistic: 0.70 vs 0.62, P < .001), sensitivity, and specificity. Extending to the advanced machine learning models did not improve performance. CONCLUSIONS: We developed a prediction model for early diagnosis of PIDD using historical data that are related to symptomatic care, which has potential to fill an important need in reducing the time to diagnose PIDD, leading to better outcomes for immunodeficient patients.

Eight tips for the implementation of the first licenced peanut allergy oral immunotherapy into clinical practice.

BACKGROUND: Shared learnings from the early use of novel therapies can aid in their optimization. The recent introduction of peanut oral immunotherapy (peanut OIT; Palforzia [Peanut (Arachis hypogaea) Allergen Powder-dnfp]) for peanut allergy addresses a significant unmet need but also highlights the requirement for consideration of several factors by both prescribers and patients. OBJECTIVE: To provide guidance for prescribers of licenced peanut OIT to facilitate treatment delivery and improve outcomes. METHODS: Clinicians with experience of licenced peanut OIT (United States n = 6, United Kingdom n = 1) participated in a series of interviews and group discussions designed to elicit tips for successful implementation. RESULTS: Clinicians identified 8 tips that were considered the most relevant, practical, and impactful for prescribers of Peanut (Arachis hypogaea) Allergen Powder-dnfp: (1) preparing to provide treatment, (2) assessing the medical indication for treatment and (3) shared decision making, (4) staff education, (5) establishing office processes, (6) managing patient expectations and using anticipatory guidance, (7) optimising adherence and (8) maintaining flexibility throughout the treatment process. In addition, a range of supporting materials (e.g., checklists and action plans) are provided. CONCLUSION: The introduction of a novel therapy often requires healthcare providers to modify or adopt practices to effectively employ the treatment. The provision of guidance based upon early real-world experiences of licenced peanut OIT may help inform clinical practice and improve treatment outcomes.

New and emerging concepts and therapies for the treatment of food allergy.

Food allergy is an increasingly common disease that often starts in early childhood and lasts throughout life. Self-reported food allergy has risen at a rate of 1.2% per decade since 1988, and by 2018, the prevalence of food allergy in the United States was estimated to be 8% in children and 11% in adults.- This prevalence has led to an economic burden of almost $25 billion annually. Despite these staggering statistics, as of the time of this writing, the Food and Drug Administration (FDA) has only approved one treatment for food allergy, which is limited to use in children with peanut allergy. Fortunately, a new horizon of therapeutic interventions, in all stages of development, lay ahead and hold promise for the near future.

Development of Food Allergy Data Dictionary: Toward a Food Allergy Data Commons.

BACKGROUND: Food allergy (FA) data lacks a common base of terminology and hinders data exchange among institutions. OBJECTIVE: To examine the current FA concept coverage by clinical terminologies and to develop and evaluate a Food Allergy Data Dictionary (FADD). METHODS: Allergy/immunology templates and patient intake forms from 4 academic medical centers with expertise in FA were systematically reviewed, and in-depth discussions with a panel of FA experts were conducted to identify important FA clinical concepts and data elements. The candidate ontology was iteratively refined through a series of virtual meetings. The concepts were mapped to existing clinical terminologies manually with the ATHENA vocabulary browser. Finally, the revised dictionary document was vetted with experts across 22 academic FA centers and 3 industry partners. RESULTS: A consensus version 1.0 FADD was finalized in November 2020. The FADD v1.0 contained 936 discrete FA concepts that were grouped into 14 categories. The categories included both FA-specific concepts, such as foods triggering reactions, and general health care categories, such as medications. Although many FA concepts are included in existing clinical terminologies, some critical concepts are missing. CONCLUSIONS: The FADD provides a pragmatic tool that can enable improved structured coding of FA data for both research and clinical uses, as well as lay the foundation for the development of standardized FA structured data entry forms.

Early intervention and prevention of allergic diseases.

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well-developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA.

Increase in Epinephrine Administration for Food-Induced Anaphylaxis in Pediatric Emergency Departments From 2007 to 2015.

BACKGROUND: Epinephrine is underused in the treatment of anaphylaxis, despite being the first-line treatment, which reflects the challenges in diagnosing anaphylaxis and understanding the appropriate therapy. OBJECTIVE: To describe trends in epinephrine administration for patients visiting the pediatric emergency department (ED) with food-induced anaphylaxis (FIA) from 2007 to 2015. METHODS: This retrospective cohort study included children 0 to 17 years of age with FIA from 46 children's hospitals in the United States between 2007 and 2015. Multivariable regression was used to identify factors associated with epinephrine administration. RESULTS: A total of 15,318 cases of FIA cases were seen in the pediatric EDs from 2007 to 2015. Among these ED visits, 7,600 (49.6%) had at least 1 dose of epinephrine administered in the ED. Administration of epinephrine for anaphylaxis in the pediatric ED increased by 4% each year (odds ratio [OR] 1.04; 95% CI 1.03-1.05; P < .001). Sensitivity analysis by census region demonstrated that hospitals in the Northeast and the West were associated with an increase in epinephrine administration per year (Northeast OR 1.18, 95% CI 1.13-1.22, P < .001; West OR 1.14, 95% CI 1.10-1.18, P < .001). CONCLUSIONS: Epinephrine administration for FIA in the pediatric ED has increased over time, reflecting the need for continued advocacy for the optimal management of FIA. Further research is warranted to identify optimal strategies for proper recognition and early administration of epinephrine for anaphylaxis.

Food Insecurity in the Food Allergic Population: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee.

Food allergies affect 32 million Americans. Restricted diets due to food allergies can be difficult to maintain especially when the household is food insecure. Food insecurity is defined as the inability to acquire food for household members due to insufficient money or resources for food. The COVID-19 pandemic has caused many people to face food insecurity for the first time with Latinx, Native American, and Black communities disproportionately affected. Because of the increase in food insecurity, this work group developed a survey regarding food insecurity screening. This survey was sent out to a random sample of American Academy of Allergy Asthma & Immunology members to assess food insecurity knowledge and practices. The majority of survey participants did not routinely screen their patients for food insecurity. The biggest barrier identified to screening was lack of knowledge of how to perform a screen and resources available when a patient screened positive. This work group report provides guidance on how to implement and perform a food insecurity screen, including federal resources and assistance programs.

COVID-19-Related Food Insecurity Among Households with Dietary Restrictions: A National Survey.

BACKGROUND: Food insecurity dramatically increased because of the COVID-19 pandemic; however, little is known about pandemic-related food insecurity in households with dietary restrictions. OBJECTIVE: To examine pre-pandemic rates of and pandemic-related change in food insecurity among households with and without dietary restrictions. METHODS: A cross-sectional, panel-based survey of 3200 U.S. women was conducted in April 2020. Pre-pandemic food insecurity and early pandemic-related change in food insecurity were assessed using the adapted Hunger Vital Sign. Weighted, multivariate logistic regression was used to model the odds of pre-pandemic food insecurity and the odds of incident or worsening pandemic-related food insecurity among households with and without dietary restrictions. In models predicting pandemic-related outcomes, interaction effects between race/ethnicity and dietary restrictions were examined. RESULTS: Before the COVID-19 pandemic, households with self-reported food allergy (adjusted odds ratio [aOR]: 1.5, 95% confidence interval [CI]: 1.2-1.9), celiac disease (aOR: 2.3, 95% CI: 1.4-3.5), or both (aOR: 2.1, 95% CI: 1.2-3.6) were significantly more likely to be food insecure than households without restrictions. Households with dietary restrictions were also significantly more likely to experience incident or worsening food insecurity during the early pandemic (food allergy: aOR: 1.6, 95% CI: 1.3-2.1) (celiac disease: aOR: 2.3, 95% CI: 1.5-3.5) (both: aOR: 2.0, 95% CI: 1.2-3.4). Race/ethnicity was not a significant moderator of the relationship between dietary restrictions and pandemic-related food insecurity. CONCLUSION: Households with dietary restrictions were more likely to experience both pre-pandemic and pandemic-related incident or worsening food insecurity than households without restrictions. Clinical care for patients with dietary restrictions requires attention to food insecurity.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Guideline-informed care among Medicaid-enrolled children with food allergy.

OBJECTIVES: To describe food allergy (FA)-related service utilization and identify factors associated with guideline-informed care among Medicaid-enrolled US children with FA. STUDY DESIGN: Retrospective cohort study. METHODS: We used the 2012 Medicaid Analytic eXtract files to identify children with an FA diagnosis. FA-related services including outpatient allergist visits, emergency department (ED) visits, epinephrine autoinjector prescription fills, and diagnostic testing were identified. Factors associated with services were assessed using logistic regression. Kaplan-Meier survival curves evaluated the time to guideline-informed care, and proportional hazard models determined associated socioeconomic characteristics. RESULTS: There were 64,276 Medicaid-enrolled children younger than 20 years who had at least 1 claim with an FA diagnosis in 2012. Minority children and those living in a high-poverty county were less likely to have visited an allergist for FA or received diagnostic testing but more likely to have an FA-related ED visit compared with White children and those not living in a high-poverty county. Survival analyses found that of children seen for FA-related primary care or an ED visit, rates of allergist follow-up visits were 21% and 17%, respectively, and rates of epinephrine autoinjector prescription fills were 39% and 41%. Significant associations with guideline-informed care were found by race/ethnicity, dense population, and high-poverty counties. CONCLUSIONS: Although guideline-informed FA care includes follow-up with an allergist and epinephrine autoinjector prescription, this study finds low probabilities of timely service utilization after medical visits, as well as socioeconomic disparities in care.

Harmonization of Terminology for Tolerated and Reactive Dose in Food Allergy Immunotherapy.

Currently, there is no Food and Drug Administration-approved therapy for food allergy. Several new potential treatments are under investigation, including food allergen immunotherapy via various routes of administration, such as oral immunotherapy, epicutaneous immunotherapy, subcutaneous immunotherapy, and sublingual immunotherapy. The double-blind, placebo-controlled food challenge (DBPCFC) has traditionally been used for diagnostic purposes, but extrapolation of the specific terminology used in food allergy diagnosis to interpretation of efficacy in clinical trials is incongruent and difficult to apply. There is a need for standardization of the terminology used in food allergy clinical trials, because inconsistencies can lead to potential misinterpretation of end points. The reactive dose, previously referred to as the eliciting dose, is defined as the dose given that induces the onset of unequivocal allergic symptoms, or the dose that stops the challenge based on physician discretion. Conversely, the single highest tolerated dose is defined as the highest dose given during a food challenge that elicits either no symptoms or symptoms that do not meet stopping criteria per the study protocol. The evolving field of food allergy provides a novel opportunity to define those end points that are most meaningful for patients, which is fundamental for successful implementation, education, and safety.