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.).

Food insecurity and allergic diseases: A call to collective action.

Food security encompassess the concept of access by all people at all times to enough food for an active, healthy life. Conversely, food insecurity (FI) refers to household-level economic and social conditions of limited or uncertain access to adequate food. FI is a key social determinant of health that can negatively affect nutrition and health outcomes, as it is estimated that 10.2% of the US population meets criteria for FI. Recognizing the impact of FI on our patients and families is critical to promote health equity and optimize health outcomes. This review focuses on FI and allergic disease from the perspective of key multisector stakeholders within the field of allergy and immunology as well as from the larger health care arena, highlighting key resources and initiatives important to patients. Collectively, as specialists in allergy and immunology, and within the medical field more broadly, we must leverage our unique roles as we interface with patients and families and serve as committed advocates for change. Developing innovative strategies to promote health equity can provide a pathway forward for all children, adults, and families to gain access to healthy, nutritious food as part of their routine lifestyle. This is a call to action.

A penicillin allergy stewardship team to address unconfirmed pediatric penicillin allergies in Houston, Texas.

BACKGROUND: Penicillin (PCN) allergy labels are the most common drug allergy label and limit use of first-line antibiotics for many pediatric bacterial infections. Improving access to PCN allergy evaluations is a priority for allergy and immunology (A&I) and infectious diseases (ID) programs. OBJECTIVE: To increase the number of completed PCN allergy evaluations from 6 to 24 per month from January 2022 to December 2023. METHODS: A collaborative PCN allergy stewardship team was established in the A&I and ID divisions at Texas Children's Hospital. Telemedicine evaluations and, when clinically indicated, in-person PCN allergy evaluations were conducted from January 2022 to December 2023. Plan-do-study-act cycles were conducted to increase awareness about the clinics. The primary outcome measure was the average number of monthly completed PCN allergy evaluations. RESULTS: The average number of completed PCN allergy evaluations increased from 6 to 19 per month. Children were seen rapidly in the ID telemedicine clinic (20 vs 62 days, P < .001), and 428 of 627 (68%) children who required in-person challenge were scheduled for their in-person evaluation. Among the 211 children delabeled, 71 (33.6%) were subsequently diagnosed with a bacterial infection requiring PCN during the study period. CONCLUSION: A collaborative PCN allergy stewardship team consisting of ID and A&I specialists increased the number of completed PCN allergy evaluations 3-fold. ID telemedicine services allowed prompt access to care, and most children were delabeled and subsequently able to receive PCN antibiotics for bacterial respiratory tract infections. Future work should explore ways to minimize barriers to PCN allergy evaluations and further expand testing services in other settings.

Current and future perspectives on the consensus guideline for food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy presenting with delayed onset of projectile vomiting in the absence of cutaneous and respiratory symptoms. The pathophysiology of FPIES remains poorly characterized. The first international consensus guidelines for FPIES were published in 2017 and provided clinicians with parameters on the diagnosis and treatment of FPIES. The guidelines have served as a resource in the recognition and management of FPIES, contributing to an increased awareness of FPIES. Since then, new evidence has emerged, shedding light on adult-onset FPIES, the different phenotypes of FPIES, the recognition of new food triggers, center-specific food challenge protocols and management of acute FPIES. Emerging evidence indicates that FPIES impacts both pediatric and adult population. As a result, there is growing need to tailor the consensus guidelines to capture diagnoses in both patient groups. Furthermore, it is crucial to provide food challenge protocols that meet the needs of both pediatric and adult FPIES patients, as well as the subset of patients with atypical FPIES. This review highlights the evolving clinical evidence relating to FPIES diagnosis and management published since the 2017 International FPIES Guidelines. We will focus on areas where recent published evidence may support evolution or revision of the guidelines.

Pediatric Eosinophilia: A Review and Multiyear Investigation into Etiologies.

OBJECTIVES: To identify the etiology of peripheral eosinophilia in a large pediatric population and to develop a diagnostic algorithm to help guide diagnosis and management of peripheral eosinophilia in the outpatient pediatric population. STUDY DESIGN: We performed a retrospective chart review of children presenting to Texas Children's Hospital in Houston with peripheral eosinophilia between January 1, 2011 and December 31, 2019. Eosinophilia was classified as mild (absolute eosinophil count [AEC] >500 and <1500 cells/µL), moderate (AEC >1500 and <4500 cells/µL), or severe (AEC >4500 cells/µL). Demographic information and diagnostic workup data were collected. RESULTS: A total of 771 patients aged <18 years were evaluated. The most common cause of eosinophilia was allergy (n = 357; 46%), with atopy (n = 296) and drug reaction (n = 54) the most common subcauses. This was followed by unknown etiology (n = 274; 36%), infectious causes (n = 72; 9%), and eosinophilic disorders (n = 47; 6%). Many patients with an unknown cause (n = 202; 74%) had limited or no follow-up testing. CONCLUSIONS: More information on the etiology of pediatric eosinophilia and workup data could help identify the causes. This study provides important information on the evaluation of eosinophilia in the US pediatric population, including a diagnostic algorithm to guide primary care pediatricians.

Updates in food allergen immunotherapy.

PURPOSE OF REVIEW: Food allergies are on the rise. Though allergen avoidance and management of acute reactions have been the backbone of therapy, complete avoidance and timely acute care is often not feasible. Food allergen immunotherapy (FAIT) is a novel and evolving treatment option intended to induce desensitization and potential sustained unresponsiveness (SU) to food allergens. This review addresses the methods, mechanisms, efficacy, and adverse effects of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) for food allergens in the published literature. RECENT FINDINGS: Single FAIT has been most extensively studied in peanut, milk, and hen's egg allergic patients and has been successful in achieving desensitization in treated individuals through various modalities. Long-term data regarding SU is limited; however, current data suggests subsets of patients may be more likely to achieve SU compared to others. Other studies are actively assessing multifood AIT and novel FAIT protocols with adjunctive therapies. SUMMARY: Food allergy constitutes a prevalent problem with far-reaching consequences. The emergence of FAIT may mitigate the burden of food allergy. Current evidence is promising for specific allergens and pediatric patient populations. Future studies are needed to further assess efficacy between different modalities of immunotherapy for food allergens across an age continuum.

Memory and naïve gamma delta regulatory T-cell gene expression in the first 24-weeks of peanut oral immunotherapy.

BACKGROUND: Peanut oral immunotherapy (POIT) has provided desensitization to peanut allergic individuals. Limited immunological evaluation exists during the first 24-weeks of POIT. OBJECTIVE: Regulatory T-cells (Tregs) are antigen induced immunosuppressive T-cells important in establishing tolerance. Delineation of early immunologic changes contributing to the development of peanut desensitization would help clarify the mechanism of action in POIT. We performed single-cell RNA sequencing (scRNAseq) on Tregs in pediatric subjects undergoing POIT during the first 24-weeks of therapy to evaluate early immunological changes induced by POIT. METHODS: PBMC samples from peanut allergic subjects between 5 and 12 years of age enrolled in a Phase 1/2a POIT study were collected and analyzed at 0, 6, and 24-weeks after POIT initiation and samples were compared to healthy non-peanut allergic controls. Tregs were enriched from PBMCs and scRNAseq analysis performed. Cell Ranger 3.1.0 (10× Genomics) was utilized to identify cell clusters and differentially expressed genes, and results were analyzed with Seurat suite version 3.0.0. RESULTS: Gene analysis revealed 10 major clusters corresponding to different cell types observed to change during POIT when compared to the healthy, non-peanut-allergic state. scRNAseq analysis of Tregs revealed strong CD3G expression correlating with gdTregs. scRNAseq analysis of gdTregs revealed dynamic changes occurring within the first 6-weeks of treatment and cell frequencies of naïve and memory gdTregs at 24-weeks of treatment reducing to levels similar to healthy controls. Analysis of transcriptomic cell identity analysis using SingleR showed gene expression in gdTregs similar to healthy control after 24-weeks of POIT treatment. scRNAseq analysis revealed alterations in gene expression for memory and naïve gdTregs during this timeframe. Specifically, expression of OX40R (TNFRSF4), GITR (TNFRSF18), TGFB1, CTLA4, ISG20, CD69 were upregulated in memory gdTregs compared to naive gdTregs by 24-weeks of POIT, while IL7R and SELL were downregulated in memory gdTregs compared to naïve gdTregs. CONCLUSIONS: There are specific expression profiles of peripheral naïve and mature gdTreg cells in peanut allergic patients undergoing POIT in the first 24-weeks of treatment implicating pathways involved in maintenance of immune homeostasis. gdTreg cells may contribute to the tolerogenic effect of POIT within the first 24-weeks of POIT treatment. These findings suggest that gdTregs cells may be an early marker of desensitization in subjects undergoing POIT.

Unconfirmed penicillin allergy labels in the paediatric outpatient setting: A call for research and quality improvement initiatives.

Over the last 10 years, the electronic medical record has redefined medical documentation, and physicians rely on accurate records to make clinical decisions. Penicillin allergy labels (PALs) are important pieces of the medical history that guide physicians in selecting specific antibiotic classes for the treatment of infectious diseases. However, most children labelled as penicillin-allergic do not have an IgE-mediated (immediate) allergic reaction to penicillin or its derivatives. In the absence of confirmatory penicillin allergy testing or additional history, these children receive alternative, often broad-spectrum and second-line, antibiotics. Addressing unconfirmed PALs requires an understanding of how and why labels get added to the electronic medical record. This viewpoint highlights the knowledge gaps in paediatric outpatient penicillin allergy labelling and proposes an acronym ('LABEL') that primary care providers and antimicrobial stewards can utilise when designing initiatives to address unconfirmed PALs in the community.

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

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.

Quality of life in food allergic children: Results from 174 quality-of-life patient questionnaires.

BACKGROUND: Food allergies are becoming a global concern and pose a significant burden on allergic children and their family, with reported physical and emotional effects. OBJECTIVE: To investigate the effect of food allergy on patients' quality of life (QoL), to identify any characteristics associated with worse QoL, and to directly compare the effect of food allergies on the QoL of adolescents vs younger children. METHODS: Children 0 to 17 years old with a physician-confirmed food allergy diagnosis were invited to participate by completing the validated Food Allergy Quality of Life Questionnaire (FAQLQ). The FAQLQ form for children 10 to 12 years old was completed by the parent (proxy report), whereas the FAQLQ form for adolescents was completed by the adolescent (self-report). Scores were compared using the Wilcoxon rank sum test. Independent median regressions were used to test association between potential risk factors and QoL outcomes. RESULTS: In our cohort, the median FAQLQ score was significantly higher (reflecting lower QoL) in adolescents compared with children (4.7 vs 3.5, P = .007). The median social and dietary limitations score (5.2 vs 4, P = .002) and the median emotional impact score (3.8 vs 3.1, P = .02) were also higher in adolescents. Limitations in family activities because of food allergy had a negative effect on QoL. CONCLUSION: Food allergic adolescents are affected more than younger children (based on parental report) in terms of QoL, with a direct reflection on all areas of their daily life (emotional, dietary, and social). In addition, limitations in family activities because of the child's food allergy significantly worsen the QoL and well being of all family members.

The clinical and immune outcomes after food allergen immunotherapy emphasizing the development of tolerance.

PURPOSE OF REVIEW: The present review serves to outline the direction of food allergy immunotherapy research with an emphasis on clinical and immunologic outcomes. It helps to delineate sustained unresponsiveness achieved from food immunotherapy as the clinical outcome most similar to immune tolerance. RECENT FINDINGS: We will discuss the difference between immune tolerance, desensitization, and sustained unresponsiveness in relation to food immunotherapy by discussing the clinical and immunologic changes which have been recently discovered. SUMMARY: Research has recently shown that oral immunotherapy is most efficacious clinically at achieving desensitization to a food and sustained unresponsiveness.

Emerging triggers of food protein-induced enterocolitis syndrome: Lessons from a pediatric cohort of 74 children in the United States.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is an infrequent non-IgE-mediated gastrointestinal allergic disorder that occurs mostly in infants and young children. FPIES food triggers vary among different geographic locations, and the condition is still underdiagnosed and underrecognized. OBJECTIVE: To identify the triggers, characteristics, and management of FPIES in a pediatric US population of 74 children presenting to a tertiary center during a 3-year period. METHODS: We performed a retrospective electronic record review of all pediatric patients with a diagnosis of FPIES who presented to Texas Children's Hospital emergency centers and clinics. RESULTS: Most of our patients were white, and 65% had a positive family history of atopy. The median age at the first FPIES episode was 5 months (interquartile range, 4-6 months), and the median age at diagnosis was 11 months (interquartile range, 7-16 months). Grains (88%), cow's milk (49%), and vegetables (43%) were the most common food triggers in our cohort. Of the fruits, banana (24%) and avocado (16%) were predominantly reported. More than half of our patients experienced FPIES to multiple food triggers. CONCLUSION: In our cohort, rice (53%) was the most common individual food trigger, surpassing cow's milk and soybean, previously reported as the most prevalent FPIES triggers in the United States. Banana (24%) and avocado (16%) rates were also much higher than in other studied populations, likely a reflection of different dietary and weaning habits in our area. Time from disease presentation to diagnosis was delayed, potentially because of difficulties in disease recognition. We noted a significant percentage of multiple-food FPIES in contrast to other populations.

Improved diagnostic clarity in shrimp allergic non-dust-mite sensitized patients.

BACKGROUND: Allergen specific immunoglobulin E (sIgE) levels predictive of shrimp allergy have not been identified, but these may be helpful in identifying patients at risk for shrimp-induced allergic reactions. OBJECTIVE: This study sought to identify component resolved diagnostic tests useful for diagnosis of shrimp allergy in patients with or without house-dust mite (HDM) sensitization to the major allergen cysteine protease (Der p 1). METHODS: Patients with positive skin-prick test (SPT) results and/or sIgE values were recruited. Shrimp allergy was classified by oral food challenge (OFC) or by a clear history of anaphylaxis after shrimp ingestion. Patients with shrimp allergy and patients who were tolerant were further classified based on HDM sensitivity (Der p 1 > 0.35 kUA/L). Testing for sIgE to total shrimp, and shrimp and HDM components was performed. The Fisher exact test, Wilcoxon sum rank test, and receiver operating characteristics analyses were used to compare sIgE levels in patients with allergy and patients who were tolerant. RESULTS: Of 79 patients recruited, 12 patients with shrimp allergy (7 with positive OFC results and 5 with a history of anaphylaxis) and 18 patients who were shrimp tolerant were enrolled. Of the patients not HDM sensitized, sIgE levels to shrimp (10.5 kUA/L, p = 0.012) and Der p 10 (4.09 kUA/L, p = 0.035) were higher in patients with shrimp allergy. Shrimp sIgE of ≥3.55 kUA/L had 100% diagnostic sensitivity and 85.7% specificity (receiver operating characteristic 0.94 [0.81, 1.0] 95% CI) and Der p 10 sIgE levels of ≥3.98 kUA/L had a diagnostic sensitivity of 80% and specificity of 100% (receiver operating characteristic 0.86 [0.57, 1.0] 95% CI) for prediction of clinical reactivity. CONCLUSION: HDM sensitization influences shrimp and HDM component sIgE levels and, consequently, their diagnostic accuracy in shrimp allergy. In our series, in the patients who were non-HDM sensitized, a shrimp sIgE level of >3.55 kUA/L showed 100% sensitivity and, Der p 10 sIgE of >3.98 kUA/L showed 100% specificity for the diagnosis of shrimp allergy. These levels may not be applicable to every patient and, therefore, may not obviate the need for OFC.

The role of intravenous access during oral food challenges in food protein-induced enterocolitis syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E mediated food hypersensitivity syndrome characterized by profuse vomiting and diarrhea, which leads to lethargy, dehydration, and hypotension. Given the potential severity of reactions, resolution of FPIES is confirmed via oral food challenge (OFC) during which intravenous (IV) access is recommended to facilitate IV fluids (IVF) and steroid therapy. Risk factors for IV treatment are not well characterized. OBJECTIVES: The objectives of this study were to analyze predictors for IV treatment during OFC in patients with FPIES. METHODS: A retrospective chart review was conducted of patients with The International Classification of Diseases, Ninth Revision codes 558.3 and 558.9, and with OFC who were seen in an allergy and immunology clinic from January 2000 to October 2015. OFC reaction severity was scored (1, mild; 2, moderate; 3, severe), and demographics, IV treatment frequency, and OFC outcomes were evaluated. The Fisher exact test and Wilcoxon rank sum test statistical analyses were performed. RESULTS: Of 184 patients, 28 met inclusion criteria, with 39 OFCs performed. The median age of onset of FPIES was 6 months. The median age at OFC was 2.6 years. This was 2.2 years (range, 0.3-8.5 years) from symptom onset. Of 39 OFCs, IV treatment, including IVF and/or steroids, was required in only 7.7%. Thirty-eight OFCs (97.4%) were of equal or lesser severity than historical reactions. The median severity of presenting reaction (3[IV+]:1[IV-]; p = 0.05) was greater in those who required IV treatment. OFCs with IV treatment were in younger patients (15 months [IV+]:32 months [IV-]; p = 0.039) who underwent OFCs earlier relative to the time of diagnosis (8 months [IV+]:28 months [IV-]); p = 0.018). CONCLUSION: Although FPIES can potentially elicit severe symptomatology, the patients most commonly experienced only vomiting and diarrhea, which often resolved with minimal treatment. Reactions generally did not worsen over time. Fewer than 10% of the patients challenged required IV treatment, all were young and with severe FPIES. It is reasonable to consider age and length of time from historical reactions when evaluating the necessity of IV placement in patients undergoing FPIES OFC.