INTRODUCTION — Food allergy encompasses a variety of immune-mediated adverse reactions to foods that occur in genetically predisposed individuals [1]. Management of 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. Several approaches are under investigation for the treatment of food allergy. (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)
Novel therapeutic approaches to food allergy can be classified as food allergen specific (eg, immunotherapy with native or modified recombinant allergens, or oral desensitization) or food allergen nonspecific (eg, anti-immunoglobulin E [IgE], traditional Chinese medicine [TCM]) (table 1) [2]. The ultimate goal of therapy is to induce permanent tolerance to the food, where the allergy will not recur upon reexposure after a period of abstinence (figure 1 and table 2). However, some therapies in development appear to only temporarily desensitize or protect patients, requiring continued treatment to maintain efficacy. Before these new approaches are applied in clinical practice, they must be carefully evaluated for side effects, such as acute adverse reactions, toxicity, and overstimulation of T helper type 1 (Th1) immune responses that could prime for autoimmunity.
Oral immunotherapy (OIT) for food allergy is reviewed separately. Other food-specific therapies, as well as nonspecific therapies, are reviewed here. (See "Oral immunotherapy for food allergy".)
GOALS OF TREATMENT FOR FOOD ALLERGY — The ultimate goal of treatment for food allergy is to induce permanent tolerance to the food, which means that there is no recurrence of clinical reactivity upon reintroduction of the food after a period of abstinence (table 2). Important goals for patients and their parents/caregivers are reduction of anxiety related to food allergies and improvement in quality of life. These goals may be accomplished even if the patient does not develop permanent tolerance but rather a temporary state of desensitization or protection. They may also be accomplished even if dietary restrictions are not lifted by increasing the eliciting dose and thereby reducing the risk of reactions to the food. (See "Management of food allergy-related anxiety in children and their parents/caregivers".)
FOOD ALLERGEN-SPECIFIC THERAPY — The aim of allergen-specific immunotherapy is to alter the allergic response to the food allergen so that the patient becomes desensitized or, preferably, tolerant to the specific food. Some patients may not be fully desensitized in that they cannot tolerate ingestion of a normal serving size of the allergenic food. These patients nevertheless may benefit from an increase in the threshold dose of food required to cause an allergic reaction as they have some protection from accidental exposures. This enhanced safety often also improves quality of life. Partial reintroduction of the food may have some nutritional value as well.
Food allergen-specific therapies under investigation include oral, sublingual, epicutaneous, and subcutaneous immunotherapy (OIT, SLIT, EPIT, and SCIT). Allergens used for SCIT have been modified to decrease allergenicity while retaining immunogenicity. OIT for food allergy is discussed in detail separately. (See "Oral immunotherapy for food allergy".)
Sublingual immunotherapy — One approach to food immunotherapy is SLIT with food extracts. There are few effector cells, such as mast cells, in the sublingual mucosa [3]. 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. SLIT has been attempted for peanut [4-7], hazelnut [8,9], cow's milk (CM) [10,11], and kiwi [12,13] allergies.
Both OIT and SLIT are expected to be safer than subcutaneous administration, with lower rates of systemic reactions reported for SLIT than OIT [4,8,10,12]. However, most studies report higher efficacy of OIT regarding desensitization and induction of tolerance compared with SLIT, although with higher rates of side effects [5,10]. (See "Oral immunotherapy for food allergy".)
As with OIT, 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 [4-6,10]. Occasionally, a faster schedule of dose advancement is used (rush schedule) to reach the maintenance dose within a matter of days [8]. The maintenance dose for SLIT is much lower than that used for OIT. As an example, 1.4 to 3.7 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) [4-6].
Various measures have been used to determine efficacy of SLIT, including an increase in the median cumulative challenge dose tolerated, the rate of response (includes both subjects who are able to ingest the full challenge dose and those who are able to ingest a 10-fold-higher dose than they could at baseline), the rate of full desensitization (tolerate ingestion of the full challenge dose, which ranged from 5 to 20 g for peanut studies), and the rate of sustained unresponsiveness (SU; tolerate ingestion of the full challenge dose after avoiding the food for four to eight weeks after discontinuation of therapy). In small, randomized trials of SLIT versus placebo, the rate of desensitization ranged from 0 to 42 percent for SLIT compared with approximately 10 percent in the placebo group, and the rate of response ranged from 41 to 70 percent for SLIT compared with 15 percent in the placebo group after four to seven months of maintenance therapy [6-8]. One peanut SLIT study found an SU rate of 10 percent after three years of therapy, although 65 percent of the original 40 subjects did not continue therapy during the extended phase of this study [7]. Randomized trials of peanut and CM SLIT versus OIT demonstrated similarly low rates of desensitization (0 to 10 percent) and SU (10 percent) [5,10].
A single-center study of 48 participants (median age 6.5 years) with history of clinical reaction to peanut and peanut-specific IgE of ≥7 kU/L at study entry who received extended (up to five years) peanut SLIT treatment with daily maintenance dose 2 mg peanut protein reported a 23 percent study withdrawal rate but excellent adherence in the remaining 37 patients [14]. In the intention-to-treat analyses, 32 participants (66.7 percent) successfully consumed dose of ≥750 mg during exit double-blind, placebo-controlled food challenge (DBPCFC), while 12 (25 percent) tolerated the 5000 mg oral food challenge (OFC), with 10 (20.8 percent) demonstrating SU at four weeks. Peanut skin prick test (SPT) wheal, peanut-specific-IgE, and basophil activation to peanut decreased significantly compared with baseline values. Peanut SLIT was safe, with 4.8 percent of doses having associated symptoms (transient oropharyngeal pruritus); only 0.21 percent of doses were treated with oral antihistamines, no epinephrine was administered, and no eosinophilic esophagitis (EoE) was reported. This study suggests that extended peanut SLIT therapy is safe and provides clinically meaningful desensitization in the majority of peanut-allergic children and can provide SU in a subset of them.
It should be noted that 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 epicutaneous immunotherapy (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. A clinical trial of SLIT using peanut extract adjuvanted with glucopyranosyl lipid A (GLA) in adults and adolescents with peanut allergy was terminated prematurely [15].
While allergic symptoms are common with SLIT, occurring in 33 to 40 percent of doses, they are primarily isolated to the oropharynx [6,7,9]. Systemic reactions are rare with SLIT, with only one reported reaction that required treatment with epinephrine.
Epicutaneous immunotherapy — The epicutaneous delivery of protein for immunotherapy (EPIT) is under investigation in patients with IgE-mediated CM and peanut allergies and EoE due to CM allergy [16-20] 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 [21]. 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 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. Preliminary reports suggest that the epicutaneous antigen delivery for food allergy immunotherapy can lead to desensitization to a higher eliciting dose and may result in SU to this eliciting dose in a small proportion of patients. Desensitization or SU to ingestion of a regular serving of food has not been studied. This therapy appears to be more effective in children 6 to 11 years old than in older children and adults [19,20]. The most frequent adverse events are localized erythema, eczema, pruritus, and/or urticaria at the site of application [16-19,22]. Mild-to-moderate anaphylaxis has been reported, and one subject who received CM EPIT had repeated episodes of diarrhea. Adherence is high, and dropout for adverse events is generally low. An ongoing multicenter clinical trial in infants one to three years of age will provide additional data regarding safety and efficacy of peanut EPIT in infants and young children (NCT03211247, NCT03859700).
Two trials have demonstrated an increase in the eliciting dose after treatment with peanut EPIT. In the multicenter United States trial conducted by the Consortium for Food Allergy Research (CoFAR), 74 peanut-allergic individuals (ages 4 to 25 years) were randomly assigned to peanut EPIT (100 or 250 mcg) or placebo [19]. The primary outcome was treatment success defined as passing a 5044 mg protein OFC or achieving at least a 10-fold increase in the eliciting dose from baseline to week 52. Treatment success was achieved in 3 (12 percent) placebo-treated participants, 11 (46 percent) EPIT 100 mcg participants, and 12 (48 percent) EPIT 250 mcg participants, with median changes in eliciting doses of 0, 43, and 130 mg of peanut protein in the same groups, respectively. Treatment success was higher among children younger than 11 years at enrollment. Overall, 14 percent of placebo doses and 80 percent of peanut EPIT doses resulted in reactions, predominantly local patch-site and mild reactions. Increased peanut-specific immunoglobulin G4 (IgG4) levels and IgG4/IgE ratios were detected in peanut EPIT-treated participants, along with trends toward decreased basophil activation and peanut-specific T helper type 2 (Th2) cytokines. Long-term follow-up over 130 weeks showed that desensitization success was achieved in 9 of 25 (36 percent) participants receiving 250 mcg peanut EPIT, with median successfully consumed dose change from baseline of 400 mg [23]. Adherence was 96 percent. Adverse reactions were predominantly local patch-site reactions. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130. By a post-hoc analysis, there were no statistically significant increases from week 52 to week 130 in either desensitization success or successfully consumed dose. Younger age at initiation of EPIT was a predictor of success.
In the second trial, conducted at multiple centers in North America and Europe, 221 patients aged 6 to 55 years with peanut allergy were randomly assigned to peanut EPIT (50, 100, or 250 mcg) or placebo for 12 months [20]. The primary outcome was treatment success defined as the eliciting dose during the posttreatment food challenge equal or greater than 1000 mg of peanut protein and/or 10 times or more greater than the eliciting dose prior to treatment. Treatment success was achieved in 14 (25 percent) placebo-treated patients, 24 (45 percent) EPIT 50 mcg participants, 23 (41 percent) EPIT 100 mcg participants, and 28 (50 percent) EPIT 250 mcg participants. However, only the 250 mcg EPIT was significantly different than placebo (absolute difference 25 percent; 95% CI 7.7-42.3 percent). When stratified by age, a significant difference remained for the 6-to-11-year-old group (absolute difference 34.2 percent; 95% CI 11.1-57.3 percent) but not the adolescents/adults. The mean eliciting dose at month 12 was greater for the 250 mcg patch (1117.8 mg) than for the placebo patch (469.3 mg) overall (least squares [LS] mean difference 336.2, 95% CI 110.9-739.7) and for the children stratum (250 mcg patch: 1211.9 mg; placebo patch: 239.1 mg; LS mean difference 333.7, 95% CI 92.5-887.6). Nearly all patients had reported adverse events, primarily local skin reactions. No dose-related serious adverse events were reported. The long-term, open-label extension study enrolled 221 subjects who received 250 mcg peanut EPIT daily. Following a total of 36-month study duration, 124 subjects underwent a DBPCFC, of which 29 (23 percent) had no objective symptoms to a cumulative dose of 1440 mg of peanut protein. Of these 29 subjects, 25 elected to undergo the prespecified SU assessment, and 20 (80 percent) remained desensitized to at least 1440 mg cumulative dose after two months of EPIT discontinuation [24].
A third randomized trial had a slightly different primary outcome of the percentage difference in responders between peanut and placebo EPIT. In this trial, 356 children aged 4 to 11 years who developed objective symptoms to ≤300 mg peanut protein on a baseline DBPCFC but did not have a history of severe anaphylaxis to peanut were randomly assigned to peanut EPIT 250 mcg or placebo for 12 months [22]. Patients with a baseline eliciting dose of ≤10 mg or >10 to 300 mg were classified as responders if the posttreatment eliciting dose was ≥300 mg or ≥1000 mg, respectively. The trial was considered positive if the prespecified threshold on the lower bound of the 95% CI for responder rate difference was ≥15 percent. The responder rate was 35.3 percent for peanut EPIT compared with 13.6 percent for placebo (difference 21.7 percent; 95% CI 12.4-29.8 percent). As with the other trials, nearly all patients had reported adverse events, primarily local skin reactions. Treatment-related mild-to-moderate anaphylaxis was reported in 3.4 percent of the peanut EPIT group compared with 0.8 percent in the placebo group. This is the first documentation of the potential for peanut EPIT to trigger systemic reactions. Of the 213 eligible patients on peanut EPIT during the trial, 93 percent (n = 198) continued with an open-label extension of this study, and 141 had an assessable DBPCFC at 36 months [25]. An eliciting dose of ≥1000 mg was reached in 51.8 percent at month 36 compared with 40.4 percent at month 12, and 13.5 percent tolerated the full dose of 5444 mg of peanut protein. Fourteen of 18 patients who opted for assessment of SU maintained an eliciting dose of ≥1000 mg at week 38 after two months of peanut avoidance. One patient during the two years of continued therapy had a mild anaphylactic reaction possibly related to EPIT that resolved without treatment. No treatment-related epinephrine use was reported. In a post-hoc analysis, actively treated subjects experienced milder reactions during the 12-month study challenge than at baseline challenge compared with placebo-treated subjects [26].
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 [27,28]. 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 [29]. A phase-IIb clinical trial evaluating safety and efficacy of SCIT with alum-adsorbed, recombinant fish allergen parvalbumin is completed but not yet published [30,31]. 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 [32].
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 [33]. Peptide immunotherapy appears to induce T cell unresponsiveness and production of interferon (IFN) gamma in a concentration-dependent manner in human in vitro studies [34].
Major peanut protein Ara h 2 peptide mixture was evaluated in a mouse model of peanut allergy. Pretreatment with two doses of the major peanut protein Ara h 2 peptide mixture prior to peanut challenge prevented anaphylactic reactions, lowered plasma histamine levels, and increased IFN-gamma production in peanut-sensitized mice compared with controls [35]. No in vivo human studies have been performed.
Although promising, 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 [36].
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 [37]. 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 [38].
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 or synthetic immunostimulatory sequences (ISS), can be used as adjuvants in immunotherapy.
Rectal immunotherapy with heat-killed bacteria and modified protein — Initial studies using a mixture of heat-killed Listeria monocytogenes (HKLM) and allergen in animal models of food allergy were successful [39,40]. However, safety concerns about subcutaneous administration of potentially pathogenic bacteria (HKLM) in humans resulted in the switch to a nonpathogenic strain of heat killed Escherichia coli (HKE) as a bacterial adjuvant [41]. Further studies focused on vaccine administered per rectum. It was felt that rectal delivery would provide superior safety regarding possible infectious complications since nonpathogenic E. coli bacteria reside in the colon and would be associated with lower rates of severe adverse reactions. In addition, the rectal route was somewhat less invasive and could be safely used in young children, the primary target group for this vaccine.
In a phase-I trial of rectally administered recombinant Ara h 1, 2, and 3 encapsulated in heat/phenol-killed E. coli, 5 of 10 patients with peanut allergy had adverse reactions (including anaphylaxis) that were significant enough to prevent completion of dosing [42]. Subjects who reacted did not have IgE antibodies that bound modified or unmodified epitopes differently than the five subjects who experienced no symptoms, so the cause of their adverse allergic reactions is not clear. This raised serious safety concerns, and the vaccine is undergoing reevaluation for possible reformulation for future studies.
Intradermal immunotherapy with immunostimulatory sequences — Synthetic immunostimulatory oligodeoxynucleotides containing unmethylated CpG (cytosine and guanine nucleotides linked by a single phosphate) motifs (also called ISSs) are thought to potentiate Th1 responses. Antigen-ISS immunization may have a prophylactic effect against allergy. However, the ability of this therapy to reverse established food allergy is unknown. Peanut-allergic mice were immunized intradermally with ISS-linked Ara h 2 or ISS-linked Amb a 1 (major ragweed allergen) as a control [43]. ISS-Ara h 2-treated mice did not develop symptoms of anaphylaxis and had significantly lower plasma histamine levels following oral peanut challenge compared with the control mice. In another mouse study, intradermal immunization with a mixture of ISS and beta-galactosidase (beta-gal), but not with either alone, provided protection against fatal anaphylaxis induced by intraperitoneal beta-gal sensitization and challenge [44].
NONSPECIFIC THERAPY — The aim of nonspecific therapies for food allergy is primarily to downregulate the allergic immune response [45]. Some therapies in development have only a transient effect, but others may be curative. Allergen-nonspecific therapies include monoclonal antibodies against IgE (anti-IgE), traditional Chinese medicine (TCM), and blockade of vasoactive mediators (eg, leukotrienes, prostaglandins, bradykinin). Other potential biologic treatments for food allergy include monoclonal antibodies against alarmins (anti-interleukin [IL] 33, anti-thymic stromal lymphopoietin [TSLP]), Bruton tyrosine kinase inhibitor (ibrutinib), and Janus kinase inhibitors. Additional novel approaches include use of a Toll-like receptor 9 (TLR9) agonist to decrease T helper type 2 (Th2) responses and induce T helper type 1 (Th1) responses [46] and blockade of vasoactive mediators such as platelet-activating factor (PAF) from mast cells and basophils [47].
Anti-IgE — Allergen-specific immunoglobulin E (IgE) antibodies play an important role in the pathophysiology of food allergy. IgE antibodies bind to high-affinity receptors (Fc-epsilon-RI) on the surface of mast cells and basophils. Crosslinking of IgE molecules on the surface of mast cells by allergen leads to the release of preformed mast cell mediators (the early phase of an allergic reaction) as well as synthesis of proinflammatory cytokines and chemokines that result in late-phase reaction [48]. Humanized monoclonal anti-IgE antibodies (anti-IgE) bind to IgE molecules, preventing them from binding to IgE receptors; downregulate the expression of the high-affinity IgE receptor on mast cells; and decrease basophil histamine release [49]. Evidence from the studies on three different anti-IgE molecules (omalizumab, ligelizumab, and quilizumab) showed differential activity in various diseases and suggested that combination therapies may be needed to effectively address IgE blockade through suppression of de novo IgE production as well as neutralization of the previously released IgE molecules. Anti-IgE therapy alone is not a cure, and protection requires administration at regular intervals indefinitely. However, its appeal is that it should be effective for allergy to any food. It may have a role in pretreatment before oral immunotherapy (OIT) and has been shown to decrease the rate of adverse events during single and multifood OIT. Prior to clinical application, further studies are necessary to confirm and optimize the protective effect of anti-IgE against food allergy, establish a safety profile in young children, and identify markers for selecting patients who are most likely to benefit from anti-IgE therapy. (See "The biology of IgE" and "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE' and "Anti-IgE therapy".)
One clinical trial has reported the results of using anti-IgE antibody as monotherapy for peanut allergy. This multicenter, randomized trial evaluated humanized monoclonal anti-IgE mouse IgG1 antibody (talizumab) in 84 patients with challenge-confirmed immediate hypersensitivity to peanut [50]. Patients were randomly assigned to receive either talizumab (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. Patients underwent a second oral peanut challenge within two to four weeks after the fourth dose. The mean baseline threshold of sensitivity increased in all groups with an apparent dose response that was only significant in the 450 mg group (increased from 178 to 2805 mg, or half a peanut to nearly nine peanuts, an effect that should provide protection against most accidental ingestion). However, even at the highest dose of talizumab, approximately 25 percent were not protected. A controlled trial of different anti-IgE humanized IgG1 antibody (omalizumab) in children older than six years with peanut anaphylaxis showed a significant increase in the threshold dose for peanut in the anti-IgE group compared with placebo in participants who completed the study [51]. However, the trial was discontinued prematurely because of safety issues related to anaphylactic reactions during baseline food challenges. The studies suggest that anti-IgE can alter the threshold for many treated patients, but more studies on safety and efficacy are needed. Cost may also be an issue since long-term monotherapy would be required.
In a real-life study, 15 children allergic to 37 foods were treated with omalizumab for severe asthma [52]. Omalizumab therapy was associated with increased threshold for cow's milk (CM), hen's egg, wheat, and hazelnut from a mean (standard deviation [SD]) 1012.6±1464.5 mg protein to 8727±6463.3 eliciting dose. A total of 70.4 percent of subjects tolerated the oral food challenge (OFC) with a regular serving of the food after four months of treatment with omalizumab. These foods were reintroduced in the patients' diet without the need for any OIT procedures. The remaining foods were partially tolerated. This uncontrolled study supports the potential of anti-IgE as a monotherapy for a subset of patients with food allergy. Another approach to omalizumab is using it as a pretreatment or concomitant treatment with OIT. 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 (CM, hen's egg, wheat, cashew, hazelnut, or walnut) is evaluating efficacy of omalizumab as monotherapy or in combination with multifood OIT (NCT03881696).
A different humanized IgG1 anti-IgE molecule, ligelizumab, has significantly higher potency of binding to the high-affinity IgE type I receptor (Fc-epsilon-RI) on the surface of basophils and mast cells, but not to low-affinity IgE receptor type II (Fc-epsilon-RII, CD23), compared with omalizumab. Ligelizumab is more efficacious versus omalizumab in chronic spontaneous urticaria but less efficacious in asthma [53]. Assessment of ligelizumab safety and clinical efficacy in 486 participants ages 6 to 55 years with peanut allergy is underway in a multicenter phase-III clinical trial (NCT04984876).
Quilizumab is the third anti-IgE monoclonal humanized IgG1 molecule targeting specifically the M1 prime epitope of cell membrane-bound IgE. In randomized trials for allergic asthma and chronic spontaneous urticaria, it was found to decrease IgE levels but did not improve clinical parameters [54,55]. It has not been studied for the treatment of food allergy.
Anti-IL-4 — Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor and inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in atopic diseases. It is indicated for the treatment of patients older than 12 years with moderate-to-severe atopic dermatitis and moderate-to-severe asthma with eosinophilic phenotype, as well as chronic rhinosinusitis with nasal polyposis in patients older than 18 years. It is also in phase-II trials for eosinophilic esophagitis (EoE). Ongoing clinical trials are evaluating efficacy and safety of dupilumab as monotherapy and combined with peanut OIT for children with IgE-mediated peanut allergy [56]. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)
Anti-IL-33 — Etokimab is a monoclonal antibody against the alarmin interleukin (IL) 33 (anti-IL-33). It was evaluated in a six-week placebo-controlled phase-IIa study in adults with peanut allergy, with inconclusive results [57]. Participants received either a single dose of etokimab (n = 15) or placebo (n = 5). At the day 15 food challenge, there was a significant difference in tolerating a cumulative 275 mg of peanut protein on food challenge in the treatment versus placebo group (11 of 15 versus 0 of 5, respectively), but there was not a significant difference in passing a 375 mg peanut challenge, nor was there any difference in passing a peanut challenge at either dose level at day 45. The etokimab group had fewer adverse events compared with placebo. The study had a very high dropout rate (11 out of 20 by day 45).
Traditional Chinese medicine — Herbs have been successfully used in Asia for centuries for treatment of various ailments, including asthma and environmental allergies. TCM is attracting increasing interest because of its reported effectiveness, favorable safety profile, and low cost [58,59]. The mechanism of action of TCM is largely unknown in spite of extensive clinical experience with TCM in Asia. In addition, TCM has not been rigorously evaluated in randomized clinical trials. The use of Chinese herbs for the treatment of food allergy is discussed in greater detail separately. (See "Chinese herbal medicine for the treatment of allergic diseases".)
SUMMARY
●Overview – Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Novel therapeutic approaches to food allergy can be classified as food allergen specific or food allergen nonspecific (table 1). 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. However, a reduction in the risk of allergic reactions, even if the food cannot be fully reintroduced into the diet, may be a sufficient outcome for many patients. (See 'Introduction' above.)
●Oral immunotherapy (OIT) – Patients have been successfully desensitized with this approach, but a smaller percentage achieves oral tolerance (or at least sustained unresponsiveness [SU]). The rate of serious allergic reactions is low, and home administration is possible. (See "Oral immunotherapy for food allergy".)
●Sublingual immunotherapy (SLIT) – Most patients are at least partially desensitized, but persistent tolerance after discontinuation of therapy is uncommon. Systemic reactions are rare and generally mild. (See 'Sublingual immunotherapy' above.)
●Epicutaneous immunotherapy (EPIT) – EPIT is safe and well tolerated, induces modest desensitization, and may be more efficacious when initiated in younger children.
●Peptide immunotherapy – This approach minimizes the risk of immunoglobulin E (IgE) mediated reactions because the peptides are too small to bind to and crosslink IgE. Standardization issues make this option less viable. There are no human studies in food allergy. (See 'Peptide immunotherapy' above.)
●Lysosome-associated membrane protein (LAMP) deoxyribonucleic acid (DNA) vaccines – This next-generation plasmid DNA vaccine results in a more complete immune response in animal models than conventional DNA vaccines and is under investigation for the treatment of peanut allergy.
●Immunotherapy with modified proteins and adjuvants – Modified bacterial products, such as heat-killed Escherichia coli (HKE), are used as immunomodulatory adjuvants. A human trial with rectally administered HKE producing recombinant hypoallergenic peanut proteins was unsuccessful. (See 'Immunotherapy with modified proteins and adjuvants' above.)
●Anti-IgE – Anti-IgE monoclonal antibody (anti-IgE) can be used for any food allergen, but it is not curative, and protection is not uniform. Anti-IgE monotherapy is being studied in conjunction with OIT. (See 'Anti-IgE' above and "Oral immunotherapy for food allergy", section on 'OIT plus anti-IgE'.)
●Anti-interleukin (IL) 4/IL-13 – Anti-IL-4/IL-13 receptor monoclonal antibody is under investigation for the treatment of eosinophilic esophagitis (EoE) and for IgE-mediated peanut allergy as monotherapy and as adjunctive therapy to peanut OIT. (See 'Anti-IL-4' above.)
●Traditional Chinese medicine (TCM) – The exact mechanism(s) of this herbal therapy is unclear. Preclinical studies in a murine model of peanut-induced anaphylaxis demonstrate a protective effect that may be prolonged. Human safety and efficacy trials are underway. (See 'Traditional Chinese medicine' above and "Chinese herbal medicine for the treatment of allergic diseases".)
