Sustained Unresponsiveness Research Articles

Baseline Epitope-Specific IgE Profiles are Predictive of Sustained Unresponsiveness or High Threshold One-Year Post OIT in the POISED Trial

BackgroundResults from the POISED trial suggest that discontinuation of peanut oral immunotherapy can increase the risk of regaining clinical reactivity to peanut. ObjectiveWe sought to determine whether those who achieved sustained unresponsiveness (SU) or sustained high threshold (SHT) have different baseline sequential epitope-specific (es-) IgE profiles than those who achieved transient desensitization (TD). MethodsSubjects in the POISED trial (NCT02103270) were randomized to peanut (n=95) or placebo (n=25) for 24 months. OIT-desensitized subjects were then assigned to no peanut (PN-0, n=51) or 300mg (PN-300, n=30) for 12 months. SU and SHT were determined by those in PN-0 and PN-300, respectively, passing 4000mg peanut oral challenge. Specific IgE and IgG4 levels to peanut, Ara h 1-3 proteins and 64 allergenic epitopes were measured. We developed machine learning glmnet models with bootstrap simulations using baseline data to predict SU/SHT. ResultsEighty (84%) subjects were desensitized to peanut. Of those, 13% (n=8) and 37% (n=13) achieved SU/SHT in PN-0 and PN-300. Decreases in epitope-and protein-specific IgE levels and increases in IgG4 levels were observed during 2 years of OIT. At baseline, patients with SU in Peanut-0 but not Peanut-300 had lower es-IgE and protein-sIgE levels compared to the TD group. A machine-learning model with 12 baseline es-IgEs and age could predict SU/SHT with an accuracy of 94%, AUC 0.97, Sensitivity 1.00, Specificity 0.91. ConclusionsPatients who achieved SU/SHT have different baseline protein-and epitope-specific IgE profiles than those with TD. These profiles may help identify patients with an increased likelihood of achieving SU/SHT.

Immunomodulatory metabolites in IgE-mediated food allergy and oral immunotherapy outcomes based on metabolomic profiling.

The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multiethnic cohorts and responses to OIT. Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N = 384), a Costa Rican cohort of children with asthma (N = 1040), and a peanut OIT trial (N = 20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterward). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q = 2.4 × 10-20) and linoleic acid derivatives (q = 3.8 × 10-5) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q = 4.1 × 10-8), eicosanoids (q = 7.9 × 10-7), and histidine pathways (q = .015). In particular, the bile acid lithocholate (4.97 [1.93, 16.14], p = .0027), the eicosanoid leukotriene B4 (3.21 [1.38, 8.38], p = .01), and the histidine metabolite urocanic acid (22.13 [3.98, 194.67], p = .0015) were higher in SU. We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Long-term efficacy and safety of cow’s milk anaphylaxis specific immunotherapy: Allergen unresponsiveness via the Tolerance Induction Program

Tolerance Induction Program (TIP) immunotherapy applies machine learning contextualized on immunologic and food protein data sets. TIP has established efficacy toward peanut allergy. This form of treatment demonstrates equal efficacy toward cow's milk anaphylaxis. TIP maintains remission outcomes defined as a minimum of 7 days of allergen unresponsiveness to high-dose protein exposures. Furthermore, remission patients openly consume unrestricted amounts of dairy protein. We sought to assess the rate of decline in specific IgE specific whole and component-resolved diagnostics following 1 year of TIP milk immunotherapy. The study comprised 214 cow milk anaphylactic children who underwent TIP at the Translational Pulmonary & Immunology Research Center/Food Allergy Institute. Postintervention changes in cow milk specific IgE, component-resolved diagnostics, and specific IgG4 were assessed. After 1 year of 10-g dairy protein weekly sustained unresponsiveness, eosinophil count decreased from 558.38 to 409.26 cells/μL, the mean cow milk IgE decreased from 16.91 to 9.10 kU/L, the mean boiled cow milk IgE decreased from 12.89 to 6.03 kU/L, the mean Bos D4 decreased from 7.38 to 3.52 kU/L, the mean Bos D5 decreased from 6.79 to 3.16 kU/L, and the mean Bos D8 decreased from 13.55 to 6.62 kU/L. Adverse events were rare. TIP cow milk immunotherapy significantly reduced cow milk specific IgE and component-resolved diagnostics while increasing specific IgG4 in cow milk anaphylactic children. TIP demonstrates safety and clinical efficacy in cow milk anaphylaxis treatment.

Transcriptomic changes associated with oral immunotherapy for food allergy.

This review summarizes recent advances in characterizing the transcriptional pathways associated with outcomes following Oral Immunotherapy. Recent technological advances including single-cell sequencing are transforming the ways in which the transcriptional landscape is understood. The application of these technologies is still in its infancy in food allergy but here we summarize current understanding of gene expression changes following oral immunotherapy for food allergy and specific signatures underpinning the different clinical outcomes of desensitization and remission (sustained unresponsiveness). T helper 2A cells have been identified as a cell type which correlates with disease activity and is modified by treatment. Molecular features at study entry may differentiate individuals who achieve more positive outcomes during OIT. Recent findings point to T cell anergy and Type 1 interferon pathways as potential mechanisms supporting redirection of the allergen-specific immune response away from allergy towards remission. Despite these developments in our understanding of immune mechanisms following OIT, there are still significant gaps. Additional studies examining immune signatures associated with long term and well-defined clinical outcomes are required to gain a more complete understanding of the pathways leading to remission of allergy, in order to optimize treatments and gain improved outcomes for patients.

The future of cow's milk allergy - milk ladders in IgE-mediated food allergy.

Cow's milk allergy (CMA) is one of the most common and complex presentations of allergy in early childhood. CMA can present as IgE and non-IgE mediated forms of food allergy. Non-IgE mediated CMA includes food protein-induced enterocolitis syndrome (FPIES), eosinophilic gastrointestinal disorders (EGIDs), and food protein-induced proctocolitis (FPIAP). There are recent guidelines addressing CMA diagnosis, management, and treatment. Each of these guidelines have their own strengths and limitations. To best manage CMA, individualized avoidance advice should be given. Cow's milk (CM) can be replaced in the diet by using hypoallergenic formulas or plant-based milk, depending on factors such as the child's age and their current food intake. Oral and epicutaneous immunotherapy is used to increase tolerance in children with CMA but is not without risk, and the long-term outcome of sustained unresponsiveness is still unclear. The allergenicity of CM proteins are affected differently by different forms of heating, leading to the use of baked milk or milk ladders in the management of CMA, most likely the most promising option for future management and treatment of CMA. Future management of children with CMA will also include discussion around the immunomodulatory potential of the child's dietary intake.

Evaluation of clinical outcomes of efficacy in food allergen immunotherapy trials, COFAITH EAACI task force.

Food allergy is a global public health problem that until recent years lacked any aetiological treatment supported by academy, industry and regulators. Food immunotherapy (AIT) is an evolving treatment option, supported by clinical practice and industry trial data. Recent AIT meta-analyses have highlighted the difficulty in pooling safety and efficacy data from AIT trials, due to secondary heterogeneity in the study. An EAACI task force (CO-FAITH) initiated by the Paediatric Section was created to focus on AIT efficacy outcomes for milk, egg and peanut allergy rather than in trial results. A systematic search and a narrative review of AIT controlled clinical trials and large case series was conducted. A total of 63 manuscripts met inclusion criteria, corresponding to 23, 21 and 22 studies of milk, egg and peanut AIT, respectively. The most common AIT efficacy outcome was desensitization, mostly defined as tolerating a maintenance phase dose, or reaching a particular dose upon successful exit oral food challenge (OFC). However, a large degree of heterogeneity was identified regarding the dose quantity defining this outcome. Sustained unresponsiveness and patient-reported outcomes (e.g. quality of life) were explored less frequently, and to date have been most rigorously described for peanut AIT versus other allergens. Change in allergen threshold assessed by OFC remains the most common efficacy measure, but OFC methods suffer from heterogeneity and methodological disparity. This review has identified multiple heterogeneous outcomes related to measuring the efficacy of AIT. Efforts to better standardize and harmonize which outcomes, and how to measure them must be carried out to help in the clinical development of safe and efficacious food allergy treatments.

Probiotics and other adjuvants in allergen-specific immunotherapy for food allergy: a comprehensive review.

This review delves into the potential of manipulating the microbiome to enhance oral tolerance in food allergy, focusing on food allergen-specific immunotherapy (FA-AIT) and the use of adjuvants, with a significant emphasis on probiotics. FA-AIT, including oral (OIT), sublingual (SLIT), and epicutaneous (EPIT) immunotherapy, has shown efficacy in desensitizing patients and achieving sustained unresponsiveness (SU). However, the long-term effectiveness and safety of FA-AIT are still under investigation. Probiotics, particularly strains of Lactobacillus, play a crucial role in enhancing immune tolerance by promoting regulatory T cells (Tregs) and modulating cytokine profiles. These probiotics can induce semi-mature dendritic cells, enhance CD40 expression, inhibit IL-4 and IL-5, and promote IL-10 and TGF-β, thus contributing to mucosal defense and immunological tolerance. Clinical trials combining probiotics with FA-AIT have demonstrated improved desensitization rates and immune tolerance in food-allergic patients. For example, the combination of Lactobacillus rhamnosus with peanut OIT resulted in a significantly higher rate of SU compared to the placebo group, along with notable immune changes such as reduced peanut-specific IgE and increased IgG4 levels. The review also explores other adjuvants in FA-AIT, such as biologic drugs, which target specific immune pathways to improve treatment outcomes. Additionally, nanoparticles and herbal therapies like food allergy herbal formula 2 (FAHF-2) are discussed for their potential to enhance allergen delivery and immunogenicity, reduce adverse events, and improve desensitization. In conclusion, integrating probiotics and other adjuvants into FA-AIT protocols could significantly enhance the safety and efficacy of FA-AIT, leading to better patient outcomes and quality of life.

Cost-effectiveness analysis of probiotic peanut oral immunotherapy (PPOIT) versus placebo in Australian children with peanut allergy alongside a randomised trial

ObjectiveTo compared the cost-effectiveness of coadministration of a probiotic adjuvant with peanut oral immunotherapy (PPOIT) with placebo (no treatment) in children with peanut allergy.DesignProspectively planned cost-effectiveness analysis alongside a randomised...

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

BackgroundOral immunotherapy (OIT) with peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Aimmune Therapeutics) is an FDA-approved treatment to desensitize peanut allergic participants.ObjectiveHere 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.MethodsPre- 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.ResultsStatistically 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.ConclusionAt 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.

Gut microbiota and fecal metabolites in sustained unresponsiveness by oral immunotherapy in school-age children with cow's milk allergy

BackgroundOral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. MethodsWe conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. ResultsDuring OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41–0.93 and 0.42–0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10–2.03), and these associations were observed until the end of OIT. ConclusionsIn this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Oral immunotherapy as a curative treatment for food-allergic preschool children: Current evidence and potential underlying mechanisms.

The worldwide rising prevalence of food allergy is a major public health concern. Standard care consists of allergen avoidance and rescue medication upon accidental exposure. Oral immunotherapy (OIT) is increasingly being studied as a treatment option. Although desensitization (an increased reaction threshold) is often achieved during OIT, sustained unresponsiveness (SU; clinical nonreactivity after finishing OIT) is not achieved in most patients. A few studies have investigated the effectiveness of OIT in children younger than 4 years of age (early = e-OIT) and have shown a much more favorable outcome in terms of SU development. Together with food allergy prevention studies, which have demonstrated high efficacy of early oral allergen exposure, the outcomes of e-OIT studies indicate an early-life window of opportunity to achieve SU, allowing unrestricted dietary intake. However, the underlying mechanism of the high effectiveness of e-OIT is not understood yet. Both cohort and OIT studies indicate early-life immune plasticity. An immature food-allergic response in the first years of life seems to be a major driver of this immune plasticity, along with a higher tolerogenic immunological state. Allergy maturation can likely be disrupted effectively by early intervention, preventing the development of persistent food allergy. Upcoming studies will provide important additional data on the safety, feasibility, and effectiveness of e-OIT. Combined with immune mechanistic studies, this should inform the implementation of e-OIT.

Long-term follow-up of children who achieved sustained unresponsiveness after peanut oral immunotherapy

Long-term follow-up of children who achieved sustained unresponsiveness after peanut oral immunotherapy

Immune signatures predicting the clinical outcome of peanut oral immunotherapy: where we stand.

Peanut allergy is a growing health concern that can cause mild to severe anaphylaxis as well as reduced quality of life in patients and their families. Oral immunotherapy is an important therapeutic intervention that aims to reshape the immune system toward a higher threshold dose reactivity and sustained unresponsiveness in some patients. From an immunological point of view, young patients, especially those under 3 years old, seem to have the best chance for therapy success. To date, surrogate markers for therapy duration and response are evasive. We provide a comprehensive overview of the current literature state regarding immune signatures evolving over the course of oral immunotherapy as well as baseline immune conditions prior to the initiation of treatment. Although research comparing clinical and immune traits in the first years of life vs. later stages across different age groups is limited, promising insights are available on immunological endotypes among peanut-allergic patients. The available data call for continued research to fill in gaps in knowledge, possibly in an integrated manner, to design novel precision health approaches for advanced therapeutic interventions in peanut allergy.

Animal Models in the Study of Food Allergens: Long-Term Maintenance of Allergic Reactivity in Mouse Models of Food Allergy.

Multiple mouse models have been used to characterize mechanisms of allergic sensitization and anaphylaxis and are widely used for preclinical development of novel therapeutics. However, the majority of published works with mouse models of food allergy have very short intervals between the time of sensitization and the end of the study, and the duration of maintenance of reactivity has not been widely reported. This chapter focuses on two of the most commonly used mouse models with sensitization to peanut or ovalbumin, with the focus on the long-term durability of sensitization to allow for longer therapeutic protocols and assessment of sustained unresponsiveness.

Combination of omalizumab with allergen immunotherapy versus immunotherapy alone for allergic diseases: A meta-analysis of randomized controlled trials.

Allergen immunotherapy (AIT)-associated adverse events (AEs) limit its usage in the management of allergic diseases. The monoclonal anti-IgE antibody (omalizumab) and AIT have complementary actions. However, no consensus has been reached on whether their combination could exert superior efficacy and safety. To evaluate whether the combination of AIT with omalizumab is superior to AIT alone in treating allergic diseases. The MEDLINE/PubMed, Embase, Scopus and Cochrane Library databases were searched to identify randomized control trials (RCTs) reporting the outcomes of omalizumab combined with AIT (omalizumab + AIT) versus AIT alone. A random-effect model was established to estimate outcomes with a 95% confidence interval (CI). A total of 11 eligible RCTs (involving 901 patients) were screened out for the meta-analysis. According to a pooled analysis, omalizumab + AIT significantly increased the number of patients achieving the target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergens (odds ratio [OR]=2.43; 95% CI: 1.33-4.44; p=0.004; I2=35%, and OR=6.77; 95% CI: 2.10-21.80; p=0.001; I2=36%, respectively). Similarly, individuals receiving the combination therapy reported significantly fewer episodes of severe systemic AEs than AIT alone (OR=0.32; 95% CI: 0.18-0.59; p=0.0003; I2=0%). Meanwhile, the improvements in symptom severity score (mean difference [MD]=-0.26), rescue medication daily means score (MD=-0.14), and number of patients consuming epinephrine in AIT (OR=0.20) were all more evident than those in AIT alone. Omalizumab + AIT can significantly enhance the efficacy and safety of AIT by increasing TMD and SU to allergens, while decreasing severe systemic AEs.

Optimal period for achieving sustained unresponsiveness in peanut oral immunotherapy.

Oral immunotherapy (OIT) can help children with persistent food allergies achieve sustained unresponsiveness (SU). However, the optimal therapeutic period for obtaining SU remains unclear. We aimed to retrospectively investigate the association between the OIT treatment period and achievement of SU. We enrolled patients who received OIT for peanut allergy between January 1, 2018 and December 31, 2022. OIT comprised the build-up phase, maintenance phase, complete avoidance, and an oral food challenge (OFC) for confirming SU. The peanut dose in the OFC was gradually increased to 3,000 mg (peanut protein: 795 mg), which was subsequently maintained for ≥5 months. SU was defined as a negative response to 795 mg of peanut protein after ≥2 weeks of complete avoidance. We evaluated the therapeutic OIT period for achieving SU using Kaplan-Meier analysis. Forty-eight patients underwent peanut OIT. The starting age at OIT initiation was 8 (interquartile range [IQR], 7-10) years. Forty-one (85%) patients had a history of anaphylaxis. The median specific immunoglobulin E concentration to peanut and Ara h 2 at OIT initiation was 85.3 (IQR, 33.7-100) and 57.6 (IQR, 21.9-100) UA/mL, respectively. The median observational period was 2.1 (IQR, 1.6-3.0) person-years (PY). Thirty-four (71%) patients achieved SU, with the rate of SU achievement gradually increasing with the therapeutic period. The median period until SU achievement was 2.1 (95% confidence interval, 1.6-2.5) PY. The rate of SU achievement slowed down after 2.7 PY. OIT for at least 2.7 PY can increase the rate of SU achievement. The protocol No. 3107.

Updates in food allergen immunotherapy.

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. 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. 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.

Sustained unresponsiveness development in wheat oral immunotherapy: predictive factors and flexible regimen in the maintenance phase.

Background and aim. Immunotherapy may induce sustained unresponsiveness (SU) in which the patient can tolerate the allergen without any severe symptoms after discontinuing immunotherapy. The present study evaluated serum and cutaneous markers for predicting SU in patients with wheat anaphylaxis who underwent oral immunotherapy. Moreover, we investigated the effectiveness of a flexible regimen of 5 to 10 g wheat protein (WP) in the maintenance phase of oral immunotherapy (OIT). Methods. This study was conducted on 19 patients with wheat anaphylaxis who underwent OIT. The result of the skin prick test (SPT), besides specific serum IgE (sIgE) and IgG4 (sIgG4) to WP, were evaluated before the desensitization. The maintenance dose started from the preferred dose of 5 to 10 g WP after the build-up phase, if the patient could tolerate it. All patients were recruited 7 to 9 months after undergoing this flexible regimen, and the results of SPT and sIgE, and sIgG4 levels were obtained once more. The patients underwent oral food challenge (OFC) after a 3-4-week avoidance to evaluate SU. Results. There was an association between mean IgE reduction and SU (p less than 0.0006), while no association was observed between the mean increase in specific IgG4 (p = 0.1) and the mean wheal diameter decrease (p = 0.29). In the present study, a 50% reduction in sIgE was associated with SU. Thirteen patients were considered to have a SU. Moreover, there was no association between the flexible regimen and the desensitization rate. Conclusions. The results revealed that the reduction of 50% sIgE is a predictive factor for SU in patients with IgE-mediated wheat allergy.