Food allergy management: Allergen-specific immunotherapy

INTRODUCTION — Management of immunoglobulin E (IgE) mediated food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Allergies to certain foods, such as hen's egg and cow's milk (CM), tend to be outgrown during childhood, whereas allergies to other foods, such as shellfish and nuts, are much more likely to persist. The ultimate goal of therapeutic approaches to food allergy is to induce permanent tolerance to the food, where allergic reactions will not recur upon reexposure after a period of abstinence (figure 1 and table 1). However, none of the available treatments or those under investigation appear to achieve permanent tolerance in a substantial number of treated patients. Rather, they only temporarily desensitize or protect patients, requiring continued treatment to maintain efficacy. (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)

Oral immunotherapy (OIT), an allergen-specific approach to the treatment of food allergy, is reviewed in this topic [1]. Additional experimental food allergen-specific therapies are reviewed here, and nonspecific therapies for food allergy are reviewed separately. (See "Food allergy management: Allergen-nonspecific therapies".)

OVERVIEW OF OIT — OIT to food is a major focus of investigation in the treatment of food allergy. However, studies have yet to demonstrate the ability to cure food allergy (and induce true tolerance). Furthermore, allergic reactions to OIT are common and occur at higher rates in patients on OIT than those avoiding the food. Many unanswered questions remain, and additional long-term follow-up data are needed to help determine in which patients the benefits may outweigh the risks.

The 2014 Updated Food Allergy Practice Parameter advised against performing OIT in routine clinical practice [2]. The 2017 European Academy of Allergy and Clinical Immunology (EEACI) Task Force on Allergen Immunotherapy and the 2016 guidelines from the Japanese Society of Pediatric Allergy and Clinical Immunology recommended conducting OIT in medical facilities with expertise in allergen immunotherapy and management of anaphylactic shock [3,4]. The Japanese guidelines additionally stated that OIT should not be recommended as standard treatment. The Canadian Society of Allergy and Clinical Immunology (CSACI) proposed comprehensive guidelines for clinical implementation of OIT in 2020 [5]. The US Food and Drug Administration (FDA) approved the first biologic drug for peanut OIT in children 4 to 17 years old in January 2020, with the indication of "the mitigation of allergic reactions, including anaphylaxis that may occur with accidental exposure to peanut." Revised guidelines regarding the use of OIT are anticipated.

Despite these limitations and remaining concerns, OIT is increasingly adapted in clinical practice. Many real-world studies reported favorable results of OIT safety and efficacy for desensitization to various foods using commercial food products. This is driven by the clinical need to provide therapies to patients with multiple food allergies for whom no US FDA-approved drugs are available or those who are outside the age indication for the approved peanut commercial product. In addition, a significant subset of patients may be "high-threshold reactors" who might not need to undergo desensitization over multiple visits since they are already above the maintenance dose of the approved product and would benefit from an alternative approach.

Rationale and mechanisms of action — The rationale for using the oral route to treat food allergy is that ingestion of a food antigen by someone not allergic to that food preferentially results in an active immune system response that does not trigger an allergic reaction towards that antigen (ie, oral tolerance) [6,7]. Oral tolerance is thought to be mediated by induction of regulatory T cells with low-dose antigen exposure or lymphocyte anergy or deletion with high antigen doses (figure 1). (See "Pathogenesis of food allergy", section on 'Factors influencing sensitization or tolerance'.)

The humoral immunologic changes associated with OIT include a gradual increase in serum levels of specific immunoglobulin G4 (IgG4), immunoglobulin A (IgA), and immunoglobulin A2 (IgA2) [8,9]. In addition, an initial increase in serum levels of specific IgE antibodies is seen in the first 12 months, followed by a subsequent decrease. Specific T regulatory cells increase and peak at approximately 12 months, with a subsequent decrease. Increased antigen-induced regulatory T cell function is associated with hypomethylation of forkhead box protein 3 (FOXP3) [10].

Basophil reactivity, skin prick test (SPT) responses, and serum levels of T helper type 2 (Th2) cytokines decrease gradually, whereas interferon (IFN) gamma, macrophage inflammatory protein (MIP) 1 alpha, and monocyte chemotactic protein (MCP) 1 increase over the course of OIT [11-14].

Goals — The ultimate goal of treatment for food allergy is to induce permanent tolerance to the food, such that there can be periods of abstinence that do not lead to a recurrence of clinical reactivity upon reintroduction of the food (table 1) [1,7]. However, because achieving permanent tolerance to the food with OIT has proved elusive in most studies of food allergy treatments, the goal of most available treatments is to increase the amount of food persons with food allergies are able to consume before they experience symptoms. Increasing the allergic threshold may prevent reactions that occur due to accidental exposures to that particular food. Additionally, burdensome lifestyle changes as well as anxiety about the possibility of anaphylaxis and death are some of the main causes of morbidity in food allergy. Important goals for patients and their caregiver(s) are to reduce this anxiety and improve quality of life (QoL) [15]. (See "Food allergy: Impact on health-related quality of life" and "Management of food allergy-related anxiety in children and their parents/caregivers".)

Tolerance versus desensitization — Oral tolerance is a permanent state of antigen nonresponsiveness, even when exposure is infrequent (table 1). However, it is unclear what time period of food allergen elimination followed by subsequent safe reexposure defines permanent tolerance to that food. Thus, the surrogate for permanent tolerance used by many clinical trials is "sustained unresponsiveness" (SU) to the food after an interval of sustained treatment followed by removal of the food from the diet over a defined period of time, typically weeks to months. Desensitization, in contrast, is defined as an increase in reaction threshold to a food allergen while receiving active therapy, similar to that achieved with drug desensitization. The primary outcomes typically measured in OIT studies are desensitization and sometimes SU. Desensitization to an arbitrarily chosen dose of food, ranging from a small portion (eg, 300 mg) to a regular serving size of the food, is tested with an oral food challenge (OFC) while continuing maintenance dosing. SU is tested with an OFC to the food following discontinuation of OIT for a period of time, varying from 2 to 52 weeks (usually 4 to 16 weeks).

Foods studied — Multiple OIT protocols have been reported for peanut, cow's milk (CM), and hen's egg, with more limited studies for wheat [16-21] and sesame [22] and only case reports for other foods such as fish [23,24], apple [23,24], orange [23], and celery [25]. The most extensively studied foods are reviewed in this topic. (See 'Single-food OIT' below.)

General protocol — Patients are typically started on a very small daily dose of the food (eg, 3 to 6 mg of food protein) and advanced periodically (usually every two weeks) to a maintenance dose (eg, 300 mg or, depending on the food and goals, 1 to 2 g of food protein daily) over several months. The initial dose and each dose increase are given under clinical supervision (usually with a 60-minute observation period following the dose administration), whereas the remainder of the daily doses during the dose advancement phase and maintenance therapy are administered at home. OIT doses are typically administered at the same time of the day (evening is preferred for home administration), following a meal or large snack. The food included in OIT is almost always otherwise strictly avoided in the diet for the duration of OIT. Each patient treated with OIT is also prescribed an epinephrine autoinjector, instructed in its use, and given a detailed emergency anaphylaxis treatment plan.

Minimizing risk of systemic reactions — A number of general and specific measures are recommended to minimize the risk of systemic reactions related to OIT dosing. Cofactors that increase the risk of an allergic reaction include exercise or hot water exposure (hypermetabolic state with elevation of body temperature), intercurrent illness (eg, viral infection), fasting or dosing on an empty stomach, menstruation, sleep deprivation, and use of nonsteroidal antiinflammatory drugs (NSAIDs) [26-29]. Timing of dosing is adjusted to avoid these cofactors. Hot showers or baths, for example, should be avoided immediately prior to or within three hours of taking the dose, and physical activity should be restricted for one to two hours after dosing.

If avoidance of any of these cofactors is not possible, the dose is temporarily withheld, as in the case of active illness, or decreased. However, reactions may occur during a prodromal phase of an infection before any symptoms of an illness become apparent. Dosing is also adjusted, or the treatment discontinued, in patients with chronic or recurrent allergic gastrointestinal symptoms or anaphylaxis. Additional indications for discontinuation of therapy include inability to tolerate less than a 3 mg dose, nonadherence with daily dosing, suspected eosinophilic esophagitis (EoE), recurrent asthma exacerbations, or persistent loss of asthma control.

When dosing is temporarily withheld or one or more doses are missed, dosing is either resumed at the same dose at home or under supervision in the office, or the dose is reduced and gradually escalated to pre-illness level, depending upon the number of missed doses.

Efficacy and adverse effects — None of the available evidence shows that OIT can induce permanent tolerance, and, for most allergens, only a minority of children treated with OIT appear to achieve SU (table 1). In addition, most studies have shown no difference in improved health-related quality of life (HRQoL) or only improvement in parental, but not child, HRQoL.

Approximately 40 to 75 percent patients treated with OIT pass a supervised challenge to a larger amount of the food allergen while on maintenance therapy than at baseline and are considered at least partially "desensitized." Desensitization in this setting is defined as a state of temporary food allergen hyporesponsiveness with an increased threshold for reactions compared with the pre-OIT threshold. The cut-off for an increased threshold (eg, percentage or amount tolerated compared with baseline) that defines hyporesponsiveness is not standardized and varies from study to study.

Theoretically, this desensitization should protect against reactions to accidental ingestion of similar or lower amounts of the food that were tolerated in the supervised challenge. However, despite the ability of OIT to induce desensitization, significant acute allergic reactions to the therapy and/or accidental exposures are still common in treated patients and can occur even on maintenance dosing. Higher rates of anaphylaxis and use of epinephrine are consistently seen in the treatment groups compared with avoidance alone [30]. In addition, rates of other types of allergic reactions (eg, gastrointestinal symptoms, angioedema, wheezing, and EoE) are common and are typically higher in patients treated with OIT.

It is possible that OIT does provide some protection against reactions due to accidental ingestion, but the effect may be negated by reactions to daily OIT dosing due to a lowered reaction threshold (eg, illness, exercise) or reactions to larger accidental exposures if avoidance is not as careful due to the perceived protective effect of OIT. In addition, limited long-term follow-up data suggest that desensitization may not be maintained in a number of patients, even with daily exposure.

Most of the above data are from peanut OIT trials, with fewer data for other allergens. OIT outcomes for individual foods are discussed in greater detail below. (See 'Single-food OIT' below.)

SINGLE-FOOD OIT

Peanut — The only US Food and Drug Administration (FDA) approved product for OIT is a specific preparation of peanut allergen oral immunotherapy powder containing consistent quantities of the major peanut (Arachis hypogaea, Ara h) proteins. In the available clinical trials, peanut OIT consistently increased the rate of allergic reactions, including anaphylaxis requiring treatment with epinephrine. This occurred despite OIT increasing supervised food challenge thresholds (ie, inducing at least partial desensitization to peanut) in a clinical setting, a surrogate measure of preventing reactions to accidental exposures in a real-world setting. Many patients are unlikely to be good candidates for peanut OIT, either because they already have a threshold that is high enough to make accidental ingestion reactions unlikely [31] or because the adverse effect profile and daily commitments required for therapy outweigh any potential benefit of increasing the reaction threshold. (See 'Efficacy' below and 'Adverse events' below.)

Despite the increased risk of anaphylaxis and other adverse effects, some patients may be highly motivated to try OIT in the hope that it may alleviate some of the anxiety and fear of experiencing a severe allergic reaction in the event of accidental peanut ingestion. For such patients, it is important to provide accurate information on the anticipated effects of OIT, the logistics, time commitment, lifestyle restrictions, and potential for side effects, including anaphylaxis and gastrointestinal symptoms.

Efficacy — Several randomized trials [32-38] and a number of uncontrolled studies [10,39-44] have demonstrated that peanut OIT is highly effective in inducing desensitization in a clinical setting, but it increases, rather than decreases, the rate of allergic reactions in the real-world setting (see 'Adverse events' below). Short-term sustained unresponsiveness (SU) after discontinuing OIT is much less common than desensitization. Data suggest that the development of SU is dose and duration dependent and may also be influenced by the severity of peanut allergy and how early in life OIT is started [32]. Longer-term SU is even rarer, and data suggest that ongoing exposure is necessary to maintain the protective effect [45]. The available evidence also suggests that peanut OIT does not improve quality of life (QoL) for the patient. In addition, there are considerable burdens and costs associated with peanut OIT.

●Desensitization, sustained unresponsiveness, and quality of life – In a meta-analysis of 12 trials (1041 patients), peanut OIT increased the likelihood of passing an in-clinic food challenge compared with an elimination diet alone (40 versus 3 percent; relative risk [RR] 12.4, 95% CI 6.8-22.6) [30]. However, OIT increased the risk of anaphylaxis during the maintenance phase (22 versus 7 percent; RR 3.1, 95% CI 1.8-5.6), increased need for epinephrine (8.2 versus 3.7 percent; RR 2.2, 95% CI 1.3-3.8), increased the frequency of vomiting and other gastrointestinal symptoms (33 versus 19 percent; RR 1.8, 95% CI 1.4-2.4), and increased other adverse events (see 'Adverse events' below). In the four trials that assessed QoL, parent/caregiver- and patient-reported QoL scores were similar in both groups. The trials included in the meta-analysis varied with respect to the OIT formulation and dosing protocol used. However, in subgroup analysis, the findings were consistent irrespective of OIT protocol and whether or not a proprietary formulation or readily available peanut flour was used.

●US FDA-approved form of peanut OIT – A specific preparation of peanut allergen oral immunotherapy powder containing consistent quantities of the major peanut (Arachis hypogaea, Ara h) proteins (Ara h 1, Ara h 2, and Ara h 6) was approved in 2020 by the US FDA for patients 4 to 17 years of age with a confirmed peanut allergy (patients who start therapy at ≤17 years of age may continue therapy as an adult) [46,47]. US FDA approval was based upon the largest trial of this therapy, which included 499 children aged 4 to 17 years and 56 adults aged 18 to 55 years [36]. This trial was included in the above meta-analysis. Patients were considered to have passed the exit peanut challenge even if they had mild symptoms. Of the children randomly assigned to active treatment (ie, 300 mg/day of peanut protein), 77 percent tolerated the 300 mg dose, and 67 percent were able to ingest ≥600 mg of peanut protein (equivalent to approximately two peanut kernels) with no more than mild symptoms at the exit peanut challenge compared with 4 percent in the placebo group. Nearly all patients reported adverse events during the study. Moderate-to-severe exit challenge-associated symptoms were lower in the treatment group compared with placebo. However, the rate of serious or severe adverse events during the study was higher in the active treatment group compared with placebo (6 versus 2 percent, respectively), as was the rate of epinephrine administration (14 versus 6 percent, respectively). In addition, considerably more patients in the OIT group withdrew from the trial due to adverse events compared with the placebo group (16 versus 2 percent). One patient in the treatment group was diagnosed with eosinophilic esophagitis (EoE). Changes in QoL were not examined.

●Efficacy in younger children – Limited randomized trial and observational data suggest that OIT may be better tolerated and perhaps more effective in young children than it is in older children. As part of a larger trial, 146 children <4 years of age (median age 39.3 months) were randomly assigned to peanut OIT (n = 96; minimum daily maintenance dose target 250 mg, maximum 2000 mg) or placebo (n = 50) [38]. After 104 weeks on maintenance therapy, 68 of 96 (70.8 percent) and 1 of 50 (2 percent) in the peanut OIT and placebo groups, respectively, passed the 5000 mg peanut double-blind, placebo-controlled food challenge (DBPCFC) at week 134 and were considered desensitized (risk difference [RD] 69 percent, 95% CI 59-79 percent). The mean peanut dose tolerated in the DBPCFC was 5005 mg in the peanut OIT group and 5 mg in the placebo group. After 26 weeks of avoidance, 20 children (20.8 percent; 29.4 percent of those desensitized, intention to treat [ITT] analysis) versus 1 child (2 percent; same patient that was desensitized) in the treatment and placebo groups, respectively, passed the DBPCFC and were considered in "remission," the term applied for SU at six months in this study (RD 19 percent, 95% CI 10-28 percent). The median peanut dose tolerated in the DBPCFC was 755 mg in the peanut OIT group and 0 mg in the placebo group. In a prospective study of 40 young children (ages 9 to 36 months) treated with either high- or low-dose peanut OIT (ie, 300 mg or 3000 mg peanut protein), both groups demonstrated high rates of short-term SU (78 percent overall) after four weeks of avoidance following the maintenance dosing phase [32]. Nearly all patients experienced mild or moderate adverse events, but serious adverse events were not reported. Of the 32 children with short-term SU who were instructed to continue peanut in the diet ad libitum, 27 reported continued peanut consumption after a mean follow-up of 65 months since completion of the initial study [48].

●Long-term efficacy – However, the effect of OIT appears to wane once therapy is discontinued (ie, it does not appear to induce long-term SU in most patients). This was demonstrated in the Peanut Oral Immunotherapy Study: Safety, Efficacy, and Discovery (POISED) trial, in which 120 patients with peanut allergy were randomly assigned in a three-way fashion to two years of high-dose peanut OIT (daily dose of 4000 mg) followed by one year of no OIT (group 1, n = 60), two years of high-dose peanut OIT followed by one year of low-dose OIT (daily dose of 300 mg; group 2, n = 35), or three years of placebo (n = 25) [45]. At the two-year mark, 84 percent of patients in the active therapy groups (groups 1 and 2) were able to pass a 4000 mg peanut challenge compared with 4 percent in the placebo group. However, the ability to pass the challenge declined considerably during the final year of the trial after stopping or reducing the dose of OIT. At the three-year mark, the rate of passing the peanut challenge among patients who had stopped taking OIT (group 1) was 13 percent, which was not statistically different than the 4 percent rate in the placebo group. Among patients who continued on low-dose OIT (group 2), 37 percent passed the challenge at the three-year mark.

Adverse events — Despite high rates of desensitization, studies have consistently shown an increased risk of allergic reactions including anaphylaxis in patients on OIT compared with avoidance alone. In patients on OIT, these allergic reactions may occur with OIT dosing (up-dosing and maintenance therapy) or with accidental exposures.

●Anaphylaxis – A systematic review and meta-analysis of peanut OIT that included 12 trials with a total of 1041 patients with peanut allergy found that those on OIT had a higher anaphylaxis risk (RR 3.12, 95% CI 1.76-5.55; RD 15.1 percent), anaphylaxis frequency (incidence rate ratio [IRR] 2.72, 95% CI 1.57-4.72; RD 12.2 percent), and epinephrine use (RR 2.21, 95% CI 1.27-3.83; RD 4.5 percent) than those not on OIT (avoidance/placebo) during both the build-up and maintenance phases of dosing despite having a greater likelihood of passing a supervised challenge (RR 12.42, 95% CI 6.82-22.61) [30]. In a retrospective review of peanut OIT administered at five different sites, reactions treated with epinephrine occurred at a rate of 0.7 per 1000 escalation doses and 0.2 per 1000 maintenance doses [49].

●Nonanaphylactic reactions – Patients on OIT are also at increased risk for nonanaphylactic allergic reactions including vomiting, angioedema, and upper and lower respiratory tract reactions [30]. In addition, there are case reports of patients developing EoE on peanut OIT [50]. No difference in QoL was found between the groups in the meta-analysis (RR 1.21, 95% CI 0.87-1.69) [30].

●Factors associated with reactions – Reactions are more common with the initial escalation and up-dosing but can also occur with home dosing, including maintenance therapy. In one small study, the risk of a reaction with any home dose was 3.5 percent, and treatment was given for 0.7 percent of home doses [40]. Approximately 6 to 16 percent of subjects on peanut OIT withdraw from clinical trials due to allergic symptoms [33,34,40]. Treatment-limiting side effects are especially common with high-dose OIT. This was demonstrated in one trial in which only 21 percent of children treated with peanut OIT reached the target dose of 5000 mg peanut protein, primarily due to a distaste for peanuts and unacceptable adverse events [37]. Anaphylaxis during up-dosing occurred in 19 percent of children, and 24 percent discontinued OIT, mostly due to adverse events.

Safety precautions — If OIT is undertaken, appropriate safety precautions are critical. A Risk Evaluation and Mitigation Strategy (REMS) that includes requirements to assure safe use and minimize risk of anaphylaxis is part of the US FDA approval for a peanut allergen oral immunotherapy powder because of the increased rate of anaphylaxis reported in treated patients in clinical trials. Recommendations include continued avoidance of peanut in the diet, immediate availability of injectable epinephrine at all times, and supervised initial dose escalation and up-dosing in a health care setting with clinicians trained and equipped to manage severe allergic reactions. Both the clinician who prescribes the peanut allergen powder and the health care setting in which it is administered must be certified through the REMS program. OIT with peanut allergen powder is contraindicated in patients with uncontrolled asthma or a history of an eosinophilic gastrointestinal disorder.

Other single-food OIT studied — OIT for other single foods has been studied, but there are no US FDA-approved products available for these foods.

Cow's milk — Milk OIT is similar to peanut OIT in that it is also effective in inducing oral food challenge (OFC) desensitization but increases the risk of allergic reactions, although clinical trial data are more limited and there are no approved formulations. A significant challenge in determining the efficacy of therapies for milk and egg allergies is that the natural rate of resolution of these allergies is much higher than for peanut. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

In a 2012 meta-analysis of five milk OIT trials (218 children), milk OIT increased the likelihood of developing full tolerance to milk by 10-fold (95% CI 4.1-24.2) and partial tolerance by fivefold (95% CI 1.2-24.5) compared with a milk elimination diet alone [51]. However, the risk of an adverse reaction was 34-fold higher (95% CI 4.8-244.7) in children receiving OIT compared with an elimination diet alone, and OIT also increased the likelihood of experiencing laryngospasm (RR 12.9, 95% CI 1.7-99) or wheezing (RR 3.8, 95% CI 2.9-5) and needing epinephrine treatment (RR 5.8, 95% CI 1.6-22) or glucocorticoid therapy (RR 11, 95% CI 2.7-46). A separate 2012 meta-analysis had similar findings and noted that 1 in every 11 patients on milk OIT was treated with epinephrine [52].

There is one case report of life-threatening anaphylaxis in a patient during the dose-escalation phase of milk OIT when dose escalation was continued despite a serious reaction that occurred earlier on the same day [53]. In addition, several patients have developed EoE on milk OIT [54,55]. Furthermore, in one of the few long-term follow-up studies of OIT, only 6 of 32 patients (19 percent) who had successfully completed a milk OIT trial had unlimited intake of milk and other dairy products, and, among those six patients, half reported variable symptoms with ingestion [56].

Hen's egg — Egg OIT, as with OIT for other foods, appears to be effective in desensitizing most patients in a clinical challenge setting [57]. SU is induced less frequently than desensitization but occurs at a higher rate in egg OIT-treated patients than in patients who follow a strict egg elimination diet [58]. Results from one study suggest that longer duration of therapy may increase the rate of SU [59]. However, a significant challenge in determining the efficacy of therapies for milk and egg allergies is that the natural rate of resolution of these allergies is much higher than for peanut. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

In one randomized trial, 55 children aged 5 to 11 years (median age 7 years) received either egg-white powder OIT with a maintenance dose goal of 2 grams (n = 40) or placebo (n = 15) [9]. Egg was otherwise avoided by all subjects. All completed the initial day of dose escalation, but 13 percent withdrew before the maintenance phase (two placebo and five in the OIT group). Twenty-two children (55 percent) in the OIT group passed the challenge (5 grams of egg-white powder, approximately equivalent to one large egg [6 grams of protein]) at 10 months and were considered desensitized compared with none in the placebo group. The rates of adverse events associated with OIT doses were highest during the first 10 months of OIT, occurring with 25 percent of OIT doses compared with 4 percent of placebo doses. Oropharyngeal symptoms occurred in 78 percent of patients on OIT compared with 20 percent in the placebo group. No severe adverse events occurred.

In an unblinded extension of the study, the OIT group continued on maintenance dosing, and the placebo group continued complete egg avoidance until the second challenge with 10 grams of egg-white powder at 22 months. Thirty children (75 percent) in the OIT group passed the 22-month OFC, and the one eligible child in the placebo group (egg white-specific IgE <2 kU/L) failed the challenge. The other children in the placebo group were considered still allergic to egg (egg white-specific IgE ≥2 kU/L). SU after two months of egg avoidance was demonstrated in 11 of 29 patients (27.5 percent of the original 40 on OIT). Egg was introduced into the diet ad libitum in these children, and no adverse events were noted at 30 and 36 months of follow-up. Children who did not achieve SU continued egg OIT with no change in the rate of desensitization noted over time [59]. However, an increase in the rate of SU was seen such that 20 children in total (50 percent of the original 40) developed SU by year 4. This compares with a rate of natural resolution of the allergy of 27 percent (4 of 15) in the placebo group. In year 5, 16 percent (3 of 19) of children who achieved SU reported mild, primarily oral symptoms with concentrated egg ingestion, but none reported symptoms with baked egg ingestion [60]. Similar findings were reported in several observational studies [61-64], although egg OIT was not found to expedite the natural acquisition of tolerance in one randomized but unblinded study [29].

Wheat — Five small pilot studies of wheat OIT in children reported variable success with desensitization and some problems with adherence [16-20]. One potential hurdle with wheat OIT that may affect adherence is the larger volume that patients must consume because of the relatively lower amount of protein in wheat compared with milk, egg, or peanut. A randomized trial using high protein-content vital wheat gluten (VWG) rather than more standard forms of wheat for OIT demonstrated desensitization and SU, although at lower rates than that seen for other foods [21]. However, it is not possible to directly compare the outcomes among clinical trials of food OIT, because of heterogeneity of study design, including the maintenance doses used, duration of treatment, and primary endpoints examined.

In this trial, 46 patients aged 4 to 22 years with wheat allergy confirmed by DBPCFC were randomly assigned to lower-dose VWG OIT (maximum daily dose 1445 mg wheat protein) or placebo [21]. DBPCFC (up to a cumulative dose of 7443 mg wheat protein, equivalent to two to three slices of bread) was performed at the end of year 1. Patients on lower-dose OIT continued dosing for another year, followed by an on-therapy DBPCFC and an off-therapy DBPCFC if they passed the on-therapy challenge. Patients on placebo crossed over to higher-dose VWG OIT (maximum daily dose 2748 mg wheat protein) and underwent DBPCFC at the end of year 2. At the end of the first year, 52 percent of the lower-dose group tolerated at least 4443 mg of wheat protein on DBPCFC compared with no patients in the placebo group. At the end of the second year, 30 percent of the lower-dose OIT group and 57 percent of the crossover higher-dose OIT group tolerated the full dose of 7443 mg wheat protein on DBPCFC, and three patients (13 percent) in the lower-dose group demonstrated SU on DBPCFC 8 to 10 weeks after cessation of therapy. Adverse reactions were three times more common in the lower-dose OIT group than placebo (15.4 versus 5.8 percent). Eleven percent of patients on active therapy withdrew due to dosing-related symptoms (predominantly gastrointestinal), and 0.08 percent of doses resulted in treatment with epinephrine.

Tree nuts — OIT to tree nuts has been mostly reported in the context of multifood OIT, showing safety and efficacy similar to peanut, egg, and milk. The issue especially relevant for tree nut OIT is the potential for cross-desensitization due to the structural homology between the allergens in tree nuts. This was illustrated in a small Israeli study in which 50 children with cashew allergy (median age eight years) were treated with a daily maintenance dose of 1200 mg of cashew protein for six months [65]. Among OIT-treated patients, 44 (88 percent) compared with 0 percent of controls (cashew avoidance) tolerated a dose of 4000 mg cashew protein after six months of cashew OIT (odds ratio [OR] 8.3, 95% CI 3.9-17.7). An additional three patients were desensitized to 1200 mg cashew protein, and three patients stopped treatment. Three patients (6 percent) were treated with injectable epinephrine for home reactions. Desensitized patients had decreased skin prick test (SPT), specific IgE, and basophil reactivity and increased specific IgG4 following treatment. Following cashew desensitization, all patients with pistachio (n = 35) and four of eight with walnut co-allergy were cross-desensitized to the respective nut.

Canadian real-world experience in preschool children indicated similar safety and efficacy to peanut OIT in this age group. Of the 92 patients who started tree nut OIT, 79 (85.9 percent) underwent single-tree nut OIT, and 13 (14.1 percent) underwent multi-tree nut OIT to two (10.8 percent) or three (3.3 percent) tree nuts [66]. Eighty-nine (96.7 percent) patients reached maintenance, and four (4.3 percent) dropped out. Sixty-five (70.7 percent) patients experienced reactions during buildup: 35 (38 percent) grade 1 reactions, 30 (32.6 percent) grade 2 reactions, no grade 3 or 4 reactions, and 2 (2.17 percent) received epinephrine.

Sesame — One study has examined the safety and efficacy of sesame OIT. In this study, 60 patients (median age 7.5 years) with sesame allergy confirmed by OFC underwent sesame OIT (target dose 4000 mg sesame protein, minimum dose 240 mg sesame protein [equivalent to 1 gram of tahini]) [22]. At the end of the build-up phase, patients were switched to a daily maintenance dose of 1200 mg sesame protein, equivalent to 5 grams (1 teaspoon) of tahini, or the highest tolerated amount if <1200 mg. Fifteen sex- and age-matched patients with sesame allergy (positive OFC or history of a recent reaction with positive in vitro testing or SPT) who continued avoidance served as observational controls. The median time to reach the maintenance dose was 6.5 months. Full desensitization to 4000 mg sesame protein was achieved at the end of the build-up phase in 53 patients (88.3 percent), and partial desensitization (≥240 mg but <4000 mg) was achieved in seven patients. Of the fully desensitized patients, all 46 who underwent a follow-up OFC after a median of eight months of maintenance therapy passed the challenge. The other three fully desensitized patients continued OIT but did not undergo an OFC. Of the seven partially desensitized patients, only three continued regular maintenance consumption, while four discontinued OIT (two patients because of daily dosing interfering with their activities and two because of food aversion). During the build-up phase, adverse reactions occurred in 4.7 percent of escalation doses administered in clinic and 2 percent of home doses, with 10 and 5 patients (16.7 and 8.3 percent) receiving treatment with epinephrine for clinic and home doses, respectively. During the maintenance phase, no serious reactions were reported, and only two patients experienced a few mild reactions. No patients in the control group tolerated sesame after a median follow-up of 26.8 months: Two (13 percent) had anaphylactic reactions to accidental exposures to sesame, and nine failed sesame oral challenge.

OTHER OIT PROTOCOLS UNDER INVESTIGATION — While single-food OIT is the most extensively studied, other approaches to OIT under investigation include OIT with multiple foods, OIT with altered allergens, and OIT combined with another therapy that, in theory, may decrease the risk of allergic reactions or improve the chance of development of tolerance.

Multifood OIT — Aeroallergen-specific immunotherapy frequently combines multiple allergens. This multiallergen approach is under investigation for foods because at least one-third of patients with food allergy react to multiple foods. Large and rigorous randomized trials are needed to better assess multifood OIT, specifically the optimal maintenance dose of each allergen, the maximal number of included foods, and whether to start all foods simultaneously or sequentially. Real-world experience indicates significant variability in approaches but overall feasibility, with efficacy and safety similar to single-food OIT [67,68].

A phase I safety study of a multifood OIT was conducted in parallel with peanut OIT in subjects with peanut allergy [67]. Forty subjects reacted at the baseline double-blind, placebo-controlled food challenge (DBPCFC) to a maximum cumulative dose of 182 mg of peanut protein; of those, 25 had additional food allergies (eg, walnut, cashew, pecan, almond, hazelnut, cow's milk [CM], hen's egg, and sesame) confirmed by DBPCFC. Fifteen patients received peanut OIT only. OIT was done with two foods in six participants, three foods in eight, four foods in five, and five foods in six. The protocol had three phases: the initial dose escalation day, home dosing with biweekly up-dosing, and the maintenance phase. The daily maintenance dose was 4000 mg protein of each allergen, with up to 20,000 mg as a cumulative dose for five-food OIT. Rates of reaction per OIT dose were 3.3 percent in multifood OIT and 3.7 percent in the single OIT group. Most reactions were mild, but two severe reactions requiring epinephrine occurred in each group during home maintenance dosing. This study did not include challenges while on maintenance therapy to confirm desensitization, nor did it include evaluation of sustained unresponsiveness (SU).

OIT plus anti-IgE — Combined treatment with anti-immunoglobulin E (anti-IgE) and specific food allergen immunotherapy appears to decrease the life-threatening side effects of allergen immunotherapy and allow for more rapid desensitization. However, serious allergic reactions requiring treatment with epinephrine may still occur during desensitization and are more commonly reported to occur with OIT after discontinuation of omalizumab. In addition, treatment with omalizumab does not appear to decrease the risk of developing eosinophilic esophagitis (EoE) in patients receiving OIT. Safety and feasibility studies of milk, egg, and peanut OIT, as well as multifood OIT, combined with anti-IgE have been reported. Most of the preliminary data on treatment with omalizumab prior to OIT are encouraging. Larger clinical trials underway will help clarify which patients would benefit most from this approach.

●Safety and efficacy of omalizumab pretreatment for single-food OIT – In two small, pilot studies for milk OIT and one for peanut, patients received omalizumab pretreatment prior to OIT [69-71]. These high-risk patients were able to tolerate much higher doses of allergen in much shorter periods of time compared with patients in prior studies of OIT without omalizumab. Nearly all patients tolerated rush desensitization to milk or peanut on the first day of dosing, but one patient required treatment with epinephrine for a reaction. Almost all of the patients (90 to 100 percent) also reached the maximum maintenance dose targeted and were considered desensitized. In two of the studies, all patients who were continued on daily maintenance therapy passed oral challenges 8 to 12 weeks after discontinuation of omalizumab [70,71]. However, 6 of 14 patients (43 percent) in the other study developed anaphylaxis to therapy 2.5 to 4 months after stopping omalizumab [72].

In one small trial of milk OIT plus omalizumab, adverse reactions were lower in the omalizumab group compared with placebo, but there were no significant differences in the percent of patients demonstrating desensitization (89 versus 71 percent) or SU (48 versus 36 percent) [72]. In another small trial of peanut OIT plus omalizumab, there was a significant difference in desensitization rates (79 versus 12 percent for omalizumab versus placebo, respectively), but overall reaction rates were similar in both groups [50].

●Safety and efficacy of omalizumab pretreatment for multifood OIT – Pretreatment with omalizumab combined with multifood OIT is also under investigation. In a pilot study, 25 children who had failed an initial DBPCFC at a protein dose of 100 mg or less for each included food were pretreated with omalizumab for 16 weeks and then treated with rush OIT for multiple foods [73]. Nineteen participants (76 percent) were able to complete all six steps of the initial escalation day (up to 1250 mg of combined food proteins) with minimal or no rescue therapy. All patients reached the maintenance dose of 4000 mg protein per allergen. Participants reported 401 reactions per 7530 home doses (5.3 percent); 94 percent of reactions were mild, but there was one severe reaction.

In a subsequent trial, 48 children aged 4 to 15 years with multiple food allergies (two to five foods, confirmed by failed DBPCFC at a dose of ≤500 mg of food protein) were randomly assigned 3:1 to pretreatment with omalizumab or placebo for eight weeks [74]. Both groups were then treated with multifood OIT from weeks 8 to 36. Omalizumab or placebo was continued for 16 weeks total. A greater percent of patients treated with both omalizumab and OIT demonstrated desensitization (passed 2 g of protein DBPCFCs) to at least two of their offending foods compared with those treated with OIT alone (83 versus 33 percent; odds ratio [OR] 10.0, 95% CI 1.8-58.3). Patients in the omalizumab group also had a lower percentage of OIT doses associated with any adverse events compared with placebo (median per-participant percentage of doses 27 versus 68 percent). No serious adverse events were reported.

An ongoing multicenter, randomized clinical trial in 225 participants 1 to less than 56 years of age who are allergic to peanut and at least two other foods (milk, egg, wheat, cashew, hazelnut, or walnut) is evaluating efficacy of omalizumab as monotherapy or in combination with multifood OIT (NCT03881696). The goals of this complex, multiphase study are to tease out the necessary duration and efficacy of omalizumab as monotherapy and evaluate the efficacy of eight weeks of omalizumab pretreatment prior to starting multifood OIT. Anti-IgE monotherapy for food allergy is discussed in greater detail separately. (See "Food allergy management: Allergen-nonspecific therapies", section on 'Omalizumab (anti-IgE)'.)

●Loss of desensitization – It appears that there is some risk of loss of desensitization after omalizumab is discontinued. In a trial with omalizumab with rapid peanut desensitization, 12 weeks after stopping omalizumab, 6 of 22 omalizumab-treated subjects who passed the 4000 mg food challenge at week 31 had to reduce their peanut dose at some point over the following 21 weeks because of allergic reactions [50]. However, all were then able to safely tolerate a daily maintenance dose of 2000 mg of peanut protein.

OIT plus dupilumab — Dupilumab is a fully human monoclonal antibody directed against the receptors for interleukin (IL) 4 and IL-13, which are involved in allergic inflammation. It has demonstrated good efficacy and safety for the treatment of allergic disorders that are frequently comorbid with food allergy, including atopic dermatitis, persistent asthma, EoE, and chronic rhinosinusitis with nasal polyposis [75]. Dupilumab is also a potential therapeutic agent for food allergy. An ongoing large, multicenter clinical trial (NCT03682770) is evaluating efficacy and safety of dupilumab as an adjunct to peanut OIT in children. The primary objective is to assess whether the addition of dupilumab improves the rate desensitization at the completion of up-dosing compared with OIT alone. Another trial is examining OIT in combination with dupilumab in children and adults (NCT03679676).

OIT plus adjuvant — OIT can lead to desensitization in some patients, but the ability of OIT to induce tolerance to the food is less clear. Longer duration of therapy may be a means to induce SU, as described above (see 'Efficacy and adverse effects' above and 'Single-food OIT' above), but adding an immunostimulatory adjuvant, such as a probiotic or unmethylated CpG motifs, are other options under investigation.

The efficacy and safety of OIT using CpG-coated poly(lactic-co-glycolic acid) nanoparticles containing peanut extract (CpG/PN-NPs) was evaluated in a murine model of peanut allergy [76]. Peanut-allergic mice treated with CpG/PN-NPs, but not vehicle or other treatment components, were significantly protected from anaphylaxis to all five oral peanut challenges. CpG/PN-NP treatment did not cause anaphylactic reactions. These preclinical findings suggest that peanut OIT with CpG/PN-NPs is worth investigating in human subjects.

OIT in combination with a probiotic is also under investigation. In one randomized trial of 62 children (mean age six years) with peanut allergy randomly assigned to probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) or placebo, higher rates of desensitization and SU after two weeks of avoidance were achieved in patients receiving PPOIT (90 and 82 percent, respectively) than placebo (7 and 4 percent, respectively) [77]. However, in a follow-up study four years after cessation of treatment, 23 percent achieved SU after eight weeks of avoidance if all enrolled in the initial trial treatment group are included in the analysis, a rate similar to that seen in previously reported studies of OIT without probiotic adjuvant [78]. In addition, there was no difference in the numbers of serious reactions between the two groups during this follow-up period. Furthermore, there were several other significant flaws in study design that limit the conclusions that can be drawn from these results [79]. In another study of PPOIT in children ages 1 to 10 years assigned at a 2:2:1 ratio to PPOIT (with Lactobacillus rhamnosus ATCC 53103), peanut OIT with placebo probiotic, or placebo OIT-placebo probiotic, respectively, no difference in SU was seen between PPOIT and peanut OIT (46 and 51 percent, respectively) [80].

Abatacept is a selective T cell costimulator inhibitor. It is a fusion protein composed of the Fc region of immunoglobulin IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4Ig). Abatacept binds to CD80 and CD86 and prevents the second signal, without which T cells cannot be activated. It approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis refractory to anti-tumor necrosis factor (TNF) alpha therapy and is under investigation as an adjuvant to peanut OIT to induce remission in a phase IIa, multicenter, randomized trial comparing 24 weeks of abatacept versus placebo used as adjuvant in adolescents and adults with persistent severe peanut allergy (NCT04872218). The primary outcome is the suppression of the initial peanut-specific IgE increase during OIT, used as a proxy outcome of peanut allergy remission. Sustained tolerance to peanut will be assessed at 36 weeks.

OIT with modified allergens — Approximately 60 to 80 percent of persons with milk or egg allergy can tolerate extensively heated or baked forms of these foods. In addition, including extensively heated milk or egg in the diet may accelerate the development of tolerance. Humoral and cellular immunologic changes seen in children with a history of milk and/or egg allergy who passed OFCs to milk and/or egg in baked goods parallel the changes reported in OIT trials [81-84]. This approach, allowing ingestion of extensively heated forms if tolerated, might be conceived as similar to OIT in that the exposure may have an immunotherapeutic effect that could lead to higher thresholds of the foods in forms that are not extensively heated. However, for the 20 to 40 percent who are unable to ingest the baked forms, there are insufficient studies addressing the use of extensively heated milk/egg for escalating doses in desensitization regimens. OIT with extensively heated milk or egg is under investigation, so far with limited success. (See "Egg allergy: Management", section on 'Extensively heated (baked) egg' and "Milk allergy: Management", section on 'Extensively heated (baked) cow's milk'.)

As an example, OIT with baked milk was attempted in 14 patients who failed native milk OIT [85]. Only three patients (21 percent) achieved the full daily dose of baked milk (1.3 g baked milk protein) after 12 months of OIT, whereas eight patients developed frequent, immediate systemic reactions to baked milk OIT. The results of this study confirm prior observations from baked milk trials that patients with a more severe phenotype of milk allergy are likely to react to baked milk. In contrast, 8 of 15 children with IgE-mediated egg allergy (aged 6 to 17 years) in another study responded favorably to gradual home-based introduction of baked egg and tolerated an open OFC to one whole hard-boiled egg after 12 months [86]. These children had not previously failed standard egg OIT. In a small trial of OIT with low allergenic hydrolyzed egg (HydE) in young children, the pass rate on the final OFC to one boiled egg at six months was not significantly different between HydE versus placebo (36 versus 21 percent, respectively) [84].

ADDITIONAL FOOD ALLERGEN-SPECIFIC THERAPIES UNDER INVESTIGATION

Overview of allergen-specific therapy — The aim of allergen-specific immunotherapy is to alter the allergic response to the food allergen so that the patient becomes partially or fully desensitized or, preferably, tolerant to the specific food. Food allergen-specific therapies under investigation include sublingual, epicutaneous, and subcutaneous immunotherapy (SLIT, EPIT, and SCIT). Allergens used for SCIT have been modified to decrease allergenicity while retaining immunogenicity.

Sublingual immunotherapy

Overview of SLIT — One experimental approach to food immunotherapy is SLIT with food extracts. SLIT has been attempted for peanut [87-90], hazelnut [91,92], cow's milk (CM) [93,94], and kiwi [95,96] allergies. Both oral immunotherapy (OIT) and SLIT are expected to be safer than subcutaneous administration, with lower rates of systemic reactions reported for SLIT than OIT [87,91,93,95]. However, most studies report higher efficacy of OIT regarding desensitization and induction of tolerance compared with SLIT, although with higher rates of side effects [88,93]. SLIT is used off label by some as it is felt to be a safer alternative to OIT. However, there are no US Food and Drug Administration (FDA) approved products, and the available commercial SLIT food extracts contain very low doses of food protein, raising questions about the efficacy of treatment.

Mechanisms of action — There are few effector cells, such as mast cells, in the sublingual mucosa [97]. Allergen extracts given sublingually are not systemically absorbed. Rather, they are taken up by dendritic cells in the mucosa and presented to T cells in the draining lymph nodes. Likely mechanisms of action include downregulation of mast cells and activation of T regulatory cells.

Treatment approach in clinical trials — In most clinical trials, patients are started on a very low dose of allergen, and the dose is advanced every week or two to the maintenance dose over several months [87-89,93]. Occasionally, a faster schedule of dose advancement is used (rush schedule) to reach the maintenance dose within a matter of days [91]. The maintenance dose for SLIT is much lower than that used for OIT. As an example, 1.4 to 4 mg versus 2000 mg of peanut protein was used for SLIT and OIT, respectively, in several studies (as a reference, an average-size peanut contains approximately 250 to 280 mg of protein, and 2 tablespoons of peanut butter contains 8 grams) [87-89,98].

Efficacy — In small, randomized trials of SLIT versus placebo, the rate of full desensitization (successfully consumed a normal serving size) ranged from 0 to 42 percent for SLIT compared with approximately 10 percent in the placebo group, and the rate of response (successfully consumed full challenge dose or a 10-fold increase over baseline) ranged from 41 to 70 percent for SLIT compared with 15 percent in the placebo group after four to seven months of maintenance therapy [89-91]. Two peanut SLIT trials reported sustained unresponsiveness (SU) rates of 10 to 21 percent after three to five years of therapy, although 65 percent of the original 40 subjects in one of the trials did not continue therapy during the extended phase of the study [90,99]. A study of peanut OIT reported a modeled median time to loss of clinically significant desensitization (successfully consumed dose >800 mg peanut protein) of 22 weeks [98]. Randomized trials of peanut and CM SLIT versus OIT demonstrated similarly low rates of desensitization (0 to 10 percent) and SU (10 percent) [88,93].

Peanut skin prick test (SPT) wheal, peanut-specific IgE, and basophil activation to peanut decreased significantly compared with baseline values, and peanut-specific IgG4 levels increased significantly [98,99].

SLIT trials have generally used the desensitization endpoints defined as ability to ingest a regular serving of food without an allergic reaction, similarly to the OIT trials. This is in contrast with peanut EPIT trials that defined treatment success as a 10-fold increase in the eliciting dose and/or eliciting dose of 1000 mg or greater of peanut protein. When reanalyzing SLIT results according to the EPIT treatment success criteria, SLIT shows a superior efficacy.

Safety — While allergic symptoms with SLIT occur in 5 to 40 percent of doses, they are primarily isolated to the oropharynx [89,90,92,98,99]. Systemic reactions are rare with SLIT, with only one reported reaction that required treatment with epinephrine. No cases of treatment-associated eosinophilic esophagitis (EoE) have been reported for food SLIT, although it has been reported with aeroallergen SLIT [100].

Epicutaneous immunotherapy

Overview of EPIT — The epicutaneous delivery of protein for immunotherapy is under investigation in patients with IgE-mediated CM and peanut allergies and EoE due to CM allergy [101-105] and is in preclinical studies for hen's egg. The epicutaneous delivery system (EDS) solubilizes the allergen by perspiration and disseminates it into the thickness of the stratum corneum [106]. The patches are applied on the upper back in the interscapular area in children ≤11 years of age, and the site of application is rotated daily. In children >11 years, the patches are applied on the inner surface of the arm. The patches are applied to intact skin (eczematous skin is avoided).

Epicutaneous delivery is less invasive than subcutaneous injection and may have a lower risk for systemic reactions than subcutaneous, oral, or sublingual food allergen delivery. Doses are also lower than those used for OIT or SLIT, 250 mcg versus 2 to 4 mg in SLIT and 300 to 2000 mg in OIT. In addition, there is no dose-escalation phase for EPIT compared with OIT or SLIT; the initial dose is the maintenance dose.

Efficacy — Four trials have demonstrated an at least 10-fold increase in the eliciting dose after treatment with peanut EPIT in 35 to 67 percent of patients compared with 12 to 33 percent in the placebo groups [104,105,107-110]. SU to the eliciting dose after 36 months of therapy was found in 7 to 9 percent of patients in two of the trials [108,111]. Desensitization or SU to ingestion of a regular serving of food has not been studied. This therapy appears to be more effective (higher rates of desensitization) in toddlers and young children (response rate difference 33 and 22 percent, respectively) than in older children and adults (no difference in response rate compared with placebo) [104,105,110].

Increased peanut-specific IgG4 levels and IgG4/IgE ratios were detected in patients treated with peanut EPIT, along with trends toward decreased basophil activation and peanut-specific T helper type 2 (Th2) cytokines [104]. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130 [107].

Safety — Most patients report adverse events, primarily mild local skin reactions including localized erythema, eczema, pruritus, and/or urticaria at the site of application [101-105,109]. Mild-to-moderate anaphylaxis has been reported [109-111]. In the toddler peanut EPIT trial, for example, treatment-related anaphylaxis occurred in four infants (1.6 percent) in the active group, with reactions occurring on the first day of application, compared with no similar events in the placebo group. One subject who received CM EPIT had repeated episodes of diarrhea [101]. Adherence is high, and dropout for adverse events is generally low.

Subcutaneous immunotherapy — Early clinical trials with SCIT demonstrated that immunomodulation can be effectively used to induce oral tolerance to peanut but, at the same time, highlighted the serious side effects associated with food allergen immunotherapy [112,113]. Systemic allergic reactions were common both during the build-up phase and with maintenance injections. Subsequent studies have focused on minimizing adverse side effects that are largely IgE mediated. These investigational therapies have been tested in animal models, but most have not been tested in humans.

Chemically modified, alum-adsorbed immunotherapy — A chemically modified, aluminum hydroxide-adsorbed peanut extract given by weekly subcutaneous administration is under evaluation in subjects 5 to 50 years of age with peanut allergy in a safety and tolerability randomized trial [114]. A phase IIb clinical trial evaluating safety and efficacy of SCIT with alum-adsorbed recombinant fish allergen parvalbumin is completed but not yet published [115,116]. Preliminary results of a small clinical trial evaluating safety and immunomodulation with alum-adsorbed, chemically modified peanut extract found that local and systemic reactions were observed more often in the active group, although no late (more than four hours after therapy) systemic reactions were observed [117].

Peptide immunotherapy — Elimination of IgE binding can be achieved with vaccines consisting of overlapping peptides (protein fragments 10 to 20 amino acids long) that represent the entire sequence of a specific protein. Antigen-presenting cells (APCs) are provided with all possible allergenic epitopes, but mast cells are not activated, because the short peptides are unable to crosslink IgE molecules [118]. Peptide immunotherapy appears to induce T cell unresponsiveness and production of interferon (IFN) gamma in a concentration-dependent manner in human in vitro studies [119].

Although promising in a mouse model of peanut allergy [120], peptide immunotherapy is not a practical option for human therapy, because standardization of a vaccine containing over 100 peptides is extremely difficult. A more refined vaccine containing only the most relevant (tolerogenic) peptides is a more feasible option if these peptides can be determined [121]. A phase-II trial with this type of peptide vaccine for peanut in underway in Australia (NCT05621317).

Intradermal/intramuscular immunotherapy with LAMP-DNA vaccines — A next-generation deoxyribonucleic acid (DNA) vaccine platform has been designed to stimulate an immune response against a particular protein. For food allergy immunotherapy, allergen DNA is combined with the genetic sequences for lysosome-associated membrane proteins (LAMPs) and inserted into plasmid DNA. After vaccine administration, APCs take up the vector, and the DNA is translated into allergen associated with LAMP. This vaccine uses the natural biochemistry of LAMP to intersect with the process that APCs use to internalize, digest, and present exogenously derived antigens to the immune system as part of the lysosomal/major histocompatibility complex (MHC) class II molecules complex and activate CD4+ helper T cells, as well as CD8+ cytotoxic T cells. In a mouse model of cedar allergy, the result was a more complete immune response, including antibody production, cytokine release, and development of critical immunologic memory [122]. This contrasts with the immune response to conventional DNA vaccines, which are processed and primarily presented through MHC I and elicit a cytotoxic CD8+ T cell response. Whether or not these immunologic findings in mice also occur in humans remains to be determined.

A LAMP-DNA vaccine for peanut allergy includes the major peanut allergens, Ara h 1, Ara h 2, and Ara h 3. In peanut-allergic C3H/HeJ mice that were sensitized via oral ingestion of peanut and cholera toxin, intradermal injection of 50 mcg LAMP-peanut vaccine attenuated allergic symptoms during peanut challenge as indicated by lower disease scores and higher body temperature compared with vector control, reduced peanut-specific IgE levels, and increased peanut-specific IgG2a levels. There is an ongoing phase I randomized trial of intradermal or intramuscular administration of this vaccine in adults and adolescents with peanut allergy to evaluate safety, tolerability, and immune response [123].

Immunotherapy with modified proteins and adjuvants — Generation of "hypoallergenic" recombinant proteins that have lost the ability to interact with IgE antibodies directed against native protein (ie, allergenicity) but retain the ability to interact with T cells (ie, immunogenicity) should improve the safety of immunotherapy because these engineered recombinant proteins should not activate mast cells. The two main techniques are site-directed mutagenesis and polymerization. These modified proteins are more potent when applied together with immunomodulatory adjuvants. Bacteria are potent stimulants of T helper type 1 (Th1) immune responses. Modified bacterial products, such as heat-killed bacteria [124-127] or synthetic immunostimulatory sequences (ISS) [128,129], can be used as adjuvants in immunotherapy. There are no ongoing clinical trials with these approaches, in part due to safety concerns.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – The ultimate goal of therapy for food allergy is to be able to consume the food ad libitum without symptoms or fear of a reaction. This requires induction of permanent tolerance to the food, where reactions do not occur upon reexposure to the food after any period of abstinence. However, achieving permanent tolerance to a food with oral immunotherapy (OIT) has proved elusive. Thus, the goal of most available treatments is to increase the reaction threshold, which should, in theory, increase the amount of food persons with food allergies are able to consume before they experience symptoms. Additional goals for patients/caregivers may include reduction in anxiety and improve quality of life (QoL). (See "Management of IgE-mediated food allergy: An overview".)

●Management approach – Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. For most patients with immunoglobulin E (IgE) mediated food allergy, we suggest avoidance alone rather than a combination of avoidance and food-specific OIT (Grade 2B). While peanut OIT is effective at increasing supervised in-clinic food challenge thresholds (ie, desensitization), it increases the risk of anaphylaxis, other allergic reactions, and need for epinephrine. In addition, there are considerable burdens and costs associated with peanut OIT, including clinic visits for supervised dose escalations, an indefinite period of treatment, the continued need to avoid peanut in the diet, costs of the standardized peanut OIT powder, dosing restrictions (eg, timing, type of food it can be ingested with), and the need to avoid potential triggers of an allergic reaction (eg, hot showers). Many patients are unlikely to be good candidates for peanut OIT, either because they already have a threshold that is high enough to make accidental ingestion reactions unlikely or because the adverse effect profile and daily commitments required for therapy outweigh any potential benefit of increasing the reaction threshold. Accumulating evidence suggests that peanut OIT in infants and toddlers may have better efficacy and safety outcomes and improved adherence compared with older children. The only US Food and Drug Administration (FDA) approved product for OIT is a specific preparation of peanut allergen oral immunotherapy powder containing consistent quantities of the major peanut (Arachis hypogaea, Ara h) proteins. (See "Management of IgE-mediated food allergy: An overview" and 'Overview of OIT' above and 'Peanut' above.)

Despite the increased risk of anaphylaxis and other adverse effects, some patients may be motivated to try OIT, rather than continue avoidance alone, in the hope that it may increase the reaction threshold to add a measure of safety in the event of an accidental exposure and to alleviate some of the anxiety and fear of experiencing a severe allergic reaction in the event of accidental peanut ingestion. For such patients, it is important to provide accurate information on the anticipated effects of OIT, particularly that it increases rather than decreases risk of anaphylaxis and that, based upon the available data, it does not appear to improve QoL. If OIT is undertaken, appropriate safety precautions are critical. (See 'Peanut' above and 'General protocol' above and 'Minimizing risk of systemic reactions' above.)

An alternative therapy that can raise the reaction threshold is omalizumab, an anti-IgE monoclonal antibody. Treatment with omalizumab is discussed in greater detail separately. (See "Food allergy management: Allergen-nonspecific therapies", section on 'Omalizumab (anti-IgE)'.)

●Investigational approaches to OIT (multifood OIT or combination therapy) – Most studies of OIT have involved treatment with only a single food. However, many children have multiple food allergies. Thus, researchers are beginning to explore OIT with multiple food allergens. Additional approaches under investigation include OIT with modified food allergens and OIT combined with immunomodulatory biologic agents such as anti-IgE or immunostimulatory adjuvant, such as a probiotic or unmethylated CpG motifs. (See 'Single-food OIT' above and 'Other OIT protocols under investigation' above.)

●Experimental food allergen-specific therapy – Additional therapies under investigation include alternative modes of administration (sublingual or epicutaneous), peptide immunotherapy, and immunotherapy with modified proteins and adjuvants. (See 'Additional food allergen-specific therapies under investigation' above.)