BACKGROUND:The IMPACT trial (NCT01867671) demonstrated strong desensitization and the potential for remission with peanut oral immunotherapy (pnOIT) in 1- to 3-year-olds. Data on long-term outcomes of early intervention oral immunotherapy (OIT) are limited. OBJECTIVE:IMPACT-PLuS sought to assess the long-term efficacy, safety, and mechanistic changes related to early-life pnOIT. METHODS:Participants randomized in IMPACT (n = 146) were recruited. The primary outcome was long-term efficacy, defined as ongoing peanut consumption. Secondary outcomes included safety, peanut serology, and skin prick tests. Participants were categorized according to IMPACT treatment (pnOIT, placebo) and participation in any additional peanut allergy intervention apart from guidance given at the end of the IMPACT trial. Patients were grouped as follows: group A, pnOIT with no subsequent intervention; group B, pnOIT with subsequent intervention; group C, placebo OIT with no subsequent intervention; and group D, placebo OIT with subsequent intervention. RESULTS:Follow-up data were available for 78 of the 146 IMPACT participants (aged 9-14 years; 8-11 years after IMPACT enrollment). Fifty-eight received pnOIT in IMPACT. Overall, 80% (32/40) of group A were eating peanut at follow-up (48/58, 83%, of the entire IMPACT follow-up pnOIT group), with 35% (14/40) eating ≥1000 mg peanut. All 15 subjects from the IMPACT remission group were eating peanut at follow-up. Peanut reactions were reported by 35% (14/40) in group A, with epinephrine therapy received by 5. Compared with group C (placebo), group A had significantly lower levels of peanut and Ara h 2 IgE, and higher peanut and Ara h 2 IgG4. CONCLUSIONS:pnOIT initiated early in life can have long-term, sustainable impact, both clinically and immunologically.

The IMPACT trial (NCT01867671) demonstrated strong desensitization and the potential for remission with peanut oral immunotherapy (OIT) in 1–4-year-olds. Data on long-term outcomes of early intervention OIT are limited. Eligible participants had previously been randomized in IMPACT (n=146). The primary outcome was long-term efficacy, defined as ongoing peanut consumption. Key secondary outcomes include safety and risk perception. Follow-up data was available for 39 participants ages 9-13 years (5-9 years after completion of IMPACT). At study completion, 25/39 were advised to introduce dietary peanut. At follow-up, 22/25 were eating peanut and 3/25 had returned to avoidance. Most reported eating a single type of peanut product, with 17/23 eating ≥ 3 times per week, 11 daily. Ingested peanut amounts varied with a maximum of: > 4000mg (n=4), 1000-4000mg (n=6), 300-1000mg (n=11), and <300 mg (n=1) in one serving. Gaps of 1-60 days (median 8 days) in exposure were reported. Compared to the initial end-of-study recommendations, the amount ingested was the same (n=15), less (n=8), or more (n=2). 9/25 reported ≥1 peanut reaction since the end of the study; 2 reported symptoms with most exposures and 5/9 needed epinephrine at least once. Overall, participants reported less perceived risk since the start of the IMPACT study. Five plus years after completing a peanut OIT trial as a young child, peanut remains in the diet for 88% of those given home recommendations, higher than seen in most prior OIT follow-up studies. Vigilance is still required with 1/3 of children reporting symptoms including those requiring epinephrine.

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, like 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 AD patients, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1 (TRPV1), 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 TCI, along with pioneering trials proposed to change their current use (PACI and SEAL). We provide an overview of the novel therapies that enhance the skin barrier, like probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and IL and JAK inhibitors. Lastly, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy (EPIT) and the experimental use of single-dose of adeno-associated virus (AAV) vector gene immunotherapy.

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IntroductionPeanut oral immunotherapy (pOIT) is the only FDA-approved treatment for food allergy and its adoption amongst allergist immunologists and their patients is growing. pOIT is the subject of numerous clinical trials, however, the focus is often on treatment efficacy, safety, and tolerability, rather than identifying patients most likely to benefit from pOIT. Here, we review existing data on the clinical and immunological outcomes of pOIT that inform best practices for pOIT candidate selection.Areas CoveredIn this review, we describe the natural history of peanut allergy, summarize immunological and clinical outcomes of pOIT at different ages, discuss the optimization of pOIT in key age groups, and finally suggest an ideal age range at which to initiate pOIT for best outcomes.Expert OpinionpOIT is currently underutilized by patients and allergist-immunologists. Developing guidelines for selecting appropriate patients and optimizing treatment may help to increase access to pOIT. Many aspects of pOIT need additional study to further our understanding of the optimal timing to start pOIT, with careful consideration to clinical, immunological, and quality of life outcomes.

IntroductionEpicutaneous immunotherapy (EPIT) has been tested in clinical trials for children with peanut allergy (PA) for its safety and efficacy in inducing desensitization. Aside from peanut avoidance and symptom management, oral immunotherapy (OIT) is another option for PA patients. However, OIT can be associated with adverse events and pose safety concerns to children and their caregivers.MethodsThis study assessed 27 children who successfully completed a peanut EPIT trial. 18 of them transitioned to peanut OIT with starting doses ranging from 10–600 mg of peanut protein. Our aim was to learn more about the EPIT to OIT experience through descriptive survey responses and to gather information that may support the sequential use of the two immunotherapies for safe and positive outcomes that may not be achieved by either alone.ResultsOverall, children and their caregivers had less anxiety about starting OIT after having had peanut exposure through EPIT. Most children who transitioned from EPIT to OIT had no or minor symptoms initially, with symptoms lessening later in OIT. Most were also able to maintain or increase their peanut dose over time, achieving maintenance doses of 60–2,000 mg.DiscussionIn comparison with current literature on OIT for PA in children, the reported symptoms appeared less severe and less prevalent in the EPIT to OIT group. However, there were 3 participants who withdrew from OIT due to the development of intolerable symptoms. This study provides initial data in support of EPIT to OIT, and larger randomized controlled trials assessing effectiveness of the two therapies together are warranted.

The safety and efficacy of food oral immunotherapy (OIT) has been extensively studied, however long-term maintenance OIT studies are limited. To better understand the durability of OIT long-term, larger studies on compliance, quality of life (QOL), and burden of treatment (BOT) are needed. Participants and caregivers who participated in food OIT clinical trials at Stanford University completed three IRB approved surveys: food allergy long-term follow up questionnaire (FALTFU), food allergy quality of life questionnaire (FAQOL), and burden of treatment questionnaire (BOT). FAQOL scores at baseline and study completion were compared using a Wilcoxon signed rank test. BOT was measured on a 1 to 7 scale (1=extremely positive, 7=extremely negative). 186 participants completed FALTFU questionnaires. 120 (69%) were children (0-12 years). Compliance rates were 79% for multi-food OIT (n=77) and 61% for single-food OIT (n=109, p=0.016). Younger children (0-12 years) were more compliant vs older children and adults (80% vs 52%, p<0.001). 104 (65%) continued peanut, 40 (78%) continued cashew, and 36 (69%) continued walnut. Multi-food OIT participants reported worse baseline FAQOL vs single-food OIT participants (p=0.034). Multi-food OIT participants reported significant improvement of FAQOL after study completion (p<0.001) but single-food OIT participants did not (p=0.055). Younger children reported positive or extremely positive more frequently on BOT vs older children and adults (82% vs 57%, p=0.001). This is the largest, long-term OIT follow up study to date to assess compliance, QOL, and BOT. The majority of participants continued OIT long-term. Positive treatment perception and improved QOL were seen among all participants.

The safety of oral immunotherapy (OIT) in treating multi-food allergy remains unclear. We evaluated the difference in OIT-related allergic adverse events (AEs) between home versus clinic dose among participants who received omalizumab in randomized phase 2 studies MAPX and MIMIX. A total of 108 participants with multi-food allergy were included. Ninety-six participants (89%) received omalizumab (38% from MAPX and 62% from MIMIX). Omalizumab dose was weight based for MAPX participants. All participants in MIMIX received 150 mg omalizumab. The per-person AE rate was calculated by dividing the number of dose-related allergic AEs per location by the number of doses taken at each location during OIT up-dosing and maintenance phase. Differences in median AE rates between groups of interest were evaluated using Kruskal-Wallis rank sum test. P values were adjusted for multiple testing using Benjamini-Hochberg procedure (Q value). All participants reported mild or moderate AEs. In MAPX, there was no difference between AE rate in clinic vs home in omalizumab group. In MIMIX, higher mild and moderate AE rates were reported in clinic dose compared to home dose within 1200 vs 300 mg OIT groups (1200 mg: mild: 0.5 vs 0.012, Q<0.001; moderate 0.38 vs 0.04, Q<0.001; 300 mg: mild: 0.39 vs 0.17, Q=0.006; moderate: 0.33 vs 0.04, Q=0.006). No difference in AE rate between clinic vs home dose was found among non-omalizumab group. Participants who received fixed omalizumab dose showed greater differences in AE rates between clinic and home dose compared to those with weight based omalizumab or without omalizumab.

The intent of this research is to better understand the role of mucosal and gut proteins with respect to total IgE levels in atopic diseases and determine if these peptides could be potential blood-based biomarkers.

While food allergy oral immunotherapy (OIT) can provide safe and effective desensitization (DS), the immune mechanisms underlying development of sustained unresponsiveness (SU) following a period of avoidance are largely unknown. Here, we compare high dimensional phenotypes of innate and adaptive immune cell subsets of participants in a previously reported, phase 2 randomized, controlled, peanut OIT trial who achieved SU vs. DS (no vs. with allergic reactions upon food challenge after a withdrawal period; n = 21 vs. 30 respectively among total 120 intent-to-treat participants). Lower frequencies of naïve CD8 + T cells and terminally differentiated CD57 + CD8 + T cell subsets at baseline (pre-OIT) are associated with SU. Frequency of naïve CD8 + T cells shows a significant positive correlation with peanut-specific and Ara h 2-specific IgE levels at baseline. Higher frequencies of IL-4 + and IFNγ + CD4 + T cells post-OIT are negatively correlated with SU. Our findings provide evidence that an immune signature consisting of certain CD8 + T cell subset frequencies is potentially predictive of SU following OIT.

Determining strong candidates for Multi-food oral immunotherapy (OIT) could mitigate the risk of severe reactions, such as anaphylaxis. The intent of this research is to investigate predictors of successful desensitization early in the clinical trial. Data was obtained through MAPX, a randomized, double-blind, placebo-controlled phase two clinical trial (NCT02643862) conducted at Stanford University. Allergens were administered every two weeks with an increasing dose in addition to omalizumab. Successful desensitization to an allergen was defined as tolerance to at least 2g of that allergen at week 36 of the trial. Analyses were conducted on a multiracial group of 42 participants between the ages 4-15. Logistic regression was used to estimate the association between desensitization to a specific individual allergen and week 12 dose, allergen type, age, or sex respectively (n=137). Four participants achieved no desensitization, eight participants achieved desensitization to at least one allergen, and 30 participants achieved desensitization to all of their allergens. Week 12 dose, sex and allergen type were poor predictors of successful desensitization. Instead, increased age was significantly associated with successful desensitization (OR: 1.214, 95% CI: 1.039, 1.442; p = 0.020). Children between the ages of eight and 15 were 4.048 (95% CI: 1.757, 9.741; p = 0.0013) times more likely to achieve desensitization than children under the age of eight. Many studies advocate for desensitization to allergens in early childhood; however, these findings suggest that successful desensitization can continue to be achieved later in childhood and early adolescence.

More objective measurements for eczema diagnosis and severity are needed. Nevisense Go (NG; SciBase, Sweden) is a portable non-invasive hand-held device that can objectively and consistently provide measurements to assess skin barrier dysfunction.

Food insecurity (FI) is an important social determinant of health associated with greater physical and psychosocial disease burden. During the COVID pandemic, FI has increased substantially, adversely impacting many families managing food allergy and already experiencing challenges accessing safe food. In collaboration with a non-profit food pantry, Food Equality Initiative, we are piloting a 6-month program that provides free monthly direct shipments of self-selected allergen-safe foods to food-allergic children at risk of food insecurity. Additionally, we provide fresh produce as well as management/food preparation resources.

Multifood oral immunotherapy (mOIT) with adjunctive anti‐IgE (omalizumab, XOLAIR®) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated.

DNA methylation (DNAm) has been shown to play a role in mediating food allergy; however, the mechanism by which it does so is poorly understood. In this study, we used targeted next-generation bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) versus nonallergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 potentially novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity), as well as DNAm signature combinations with superior diagnostic potential compared with serum peanut–specific IgE for PA versus NA. Furthermore, we found that, following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared with NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than those in randomly paired genetically unrelated individuals, suggesting that PA-related DNAm signatures may be associated with genetic factors.