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Food allergy is an important medical problem with increasing prevalence throughout the world. Different approaches of food immunotherapy are being investigated including oral, epicutaneous and sublingual routes. Sublingual immunotherapy (SLIT) for food allergy involves placement of glycerinated allergen under the tongue daily to achieve allergen-specific desensitization. SLIT has been studied in the treatment of hazelnut, peach, apple, milk and peanut allergies with substantial focus on the treatment of peanut allergy. Phase II studies have shown SLIT for treatment of peanut allergy increases the tolerated dose of peanut by a substantial margin with fewer and less severe side effects than other modalities. This review discusses the mechanisms of SLIT, early studies of its use in food allergy and larger randomized controlled trials for treatment of peanut allergy. Future directions using the mechanisms involved in SLIT include oral mucosal immunotherapy for peanut allergy.

Food allergies can pose significant risks and profoundly impact the quality of life of children and their families, making them a major public health concern. Allergen avoidance has been the traditional mainstay of treatment; however, recent research has focused on various approaches to food allergen immunotherapy. This review summarizes the recent advancements in oral, sublingual, and epicutaneous immunotherapies, highlighting their respective advantages and disadvantages. The ultimate goal of food allergen immunotherapy is to maximize efficacy while minimizing risks, leading to the exploration of strategies such as low-dose immunotherapy and the use of biologics. When selecting candidates for immunotherapy among patients with food allergies, factors such as allergen characteristics, the likelihood of natural resolution, age, symptom severity, and impact on quality of life require consideration, and an individualized approach should be adopted to determine the most suitable treatment method.

For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8–44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61–80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59–79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755–5005) for peanut oral immunotherapy versus 5 mg (0–105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13–30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05–11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10–28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0–2755) for peanut oral immunotherapy and 0 mg (0–55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

Purpose of ReviewThe aim of this review is to highlight key published oral immunotherapy (OIT) protocols and post-desensitization strategies for the major food allergens and to cover important concepts to consider when evaluating OIT for food-allergic patients. Shared decision-making should help identify patient and family values which will help influence the type of evidence-based protocol and maintenance strategy to use.Recent FindingsWith food OIT emerging as a treatment option, there is a pressing need for patients, physicians, and other providers to have a nuanced understanding of the management choices available to them. There are now randomized controlled trials (RCT) of OIT for peanut, egg, milk, and wheat, and reports of cohorts of patients who have undergone OIT for tree nuts and sesame clinically. The current published protocols contain significant diversity in terms of starting dose, build-up schedule, maintenance dose, and even the product used for desensitization. Emerging data can help direct the long-term maintenance strategy for patients on OIT.SummaryBased on patient and family values elicited through the shared decision-making process, an OIT protocol may be selected that balances the level of desensitization, potential side effects, frequency of clinic visits, and potential to induce sustained unresponsiveness, among other factors. Once maintenance dosing is reached, most patients will need to maintain regular exposure to the food allergen to remain desensitized. The option to transition to commercial food products with equivalent amounts of food protein as the OIT maintenance dose would simplify the dosing process and perhaps improve palatability as well. Less frequent or decreased OIT dosing can provide practical benefits but may affect the level of desensitization and safety for some patients.

Opinion statement Purpose of review The recent approval of the first commercial peanut oral immunotherapy formulation ushered a new era of clinical food allergy treatment. With different options for peanut immunotherapy available, it is important review the evidence of efficacy, risks, and unique considerations for the individual modalities. Recent findings Oral immunotherapy (OIT), epicutaneous immunotherapy (EPIT), and sublingual immunotherapy (SLIT) for peanut allergy have risen as possible treatments for peanut allergy. Numerous studies indicate that OIT effectively desensitizes by increasing the amount of peanut protein than can be consumed without symptoms. While this desensitization is to increased amounts of peanut protein when compared to SLIT or EPIT, OIT appears to have greater risk for anaphylaxis and other adverse events. EPIT has the unique benefit of a single-dose patch without the need for in-clinic visits for dose escalation, and it bypasses the oral route which may be advantageous in certain patients. The impact of peanut immunotherapy on health-related quality of life is not well studied and current data is conflicting, but suggests that improvement in certain domains of QOL, especially for caregivers of children with peanut allergy, may be an important target for immunotherapy. Summary This review focuses on the data for efficacy, safety, and tolerability of OIT, SLIT, and EPIT with the aim of presenting information that will assist allergy practitioners in choosing an immunotherapy modality when indicated.

In the last decade, there has been increasing research dedicated to food immunotherapy to induce clinical desensitization and provide protection by increasing clinical reaction thresholds. Results from recent food immunotherapy studies with differing routes of administration (oral, sublingual, and epicutaneous) suggest that food immunotherapy can induce clinical desensitization with varying levels of safety, however lasting tolerance has not been demonstrated. Furthermore, treatment side effects and dosing logistics may make the therapies difficult for some supporting the need for alternative treatment approaches. Peptide immunotherapy and DNA vaccine approaches should in theory allow for safer administration by decreasing allergenicity but proof of their clinical efficacy and immunogenicity remains to be proven. Biologic agents may allow for increased safety and rapid up-dosing of immunotherapy with the added benefit of treating multiple allergens simultaneously.

The proportional hazards (PH) model is arguably one of the most popular models used to analyze time to event data arising from clinical trials and longitudinal studies. In many such studies, the event time is not directly observed but is known relative to periodic examination times; i.e., practitioners observe either current status or interval-censored data. The analysis of data of this structure is often fraught with many difficulties since the event time of interest is unobserved. Further exacerbating this issue, in some such studies the observed data also consists of instantaneous failures; i.e., the event times for several study units coincide exactly with the time at which the study begins. In light of these difficulties, this work focuses on developing a mixture model, under the PH assumptions, which can be used to analyze interval-censored data subject to instantaneous failures. To allow for modeling flexibility, two methods of estimating the unknown cumulative baseline hazard function are proposed; a fully parametric and a monotone spline representation are considered. Through a novel data augmentation procedure involving latent Poisson random variables, an expectation–maximization (EM) algorithm is developed to complete model fitting. The resulting EM algorithm is easy to implement and is computationally efficient. Moreover, through extensive simulation studies the proposed approach is shown to provide both reliable estimation and inference. The motivation for this work arises from a randomized clinical trial aimed at assessing the effectiveness of a new peanut allergen treatment in attaining sustained unresponsiveness in children.

Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Opinion statement Subcutaneous immunotherapy is the only disease-modifying treatment for allergic rhinitis and asthma. Unfortunately, it is not accessible or appropriate for all patients, for reasons such as the risks of treatment, time commitment and cost involved, poor access to subspecialty care, and even the fear of injections. In the case of food allergy, treatments are inaccessible simply because they do not exist. Oral and sublingual immunotherapies offer superior safety when compared to allergy shots. The ease of administration, in particular with sublingual immunotherapy, and the ability to dose at home make these modalities very attractive. Aeroallergen sublingual immunotherapy has been used extensively in Europe for more than 10 years, but is not approved in the United States, despite various studies demonstrating its safety and efficacy. Recent studies have focused on addressing continuing concerns, such as determining the ideal dose and protocol, the therapy’s effect in polysensitized patients, its safety in more severe patients, and its long-term effects. As each of these concerns is addressed, it seems more likely that sublingual immunotherapy will be added to the arsenal of treatments available to US allergists. Both oral and sublingual immunotherapies have been studied for food allergy, with preliminary evidence suggesting the ability of these treatments to induce desensitization. Recent studies, including the Burks study reviewed in this manuscript, suggest the potential for tolerance induction. However, there has been ongoing debate on how tolerance should be defined and measured. In addition, questions remain about the short-term and long-term safety of the treatment. Until these questions can be addressed with larger controlled studies, these oral and sublingual immunotherapies should not be considered ready for clinical use for food allergy.

\"Pediatricians should also discuss with families the situations when epinephrine would be needed, provide written emergency plans and address any concerns families may have related to identifying symptoms and use of medications to empower families to initiate prompt treatment for allergic reactions.\" - by Katherine Bortz ? PERSPECTIVE These findings highlight some key deficiencies in our current care model. Expert guidelines on anaphylaxis (ie, from the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network), while statistically accurate, can be difficult even for medical providers to follow and are thus unusable for most laypeople. Edwin H. Kim, MD Assistant professor of medicine UNC division of rheumatology, allergy and immunology Director, UNC Allergy and Immunology Clinic Director, UNC allergy and immunology fellowship training program Disclosure: Kim reports receiving honorarium for consultation from Aimmune Therapeutics and DBV Technologies.