Food allergy is a potentially life-threatening adverse immunologic response that occurs reproducibly to a food allergen. Food allergy has been estimated to affect an estimated 8% of children.1 Food allergy is not only a widespread problem, but also the prevalence has been increasing in recent decades.2 Of the most common food allergens that cause reactions in children, cow’s milk (CM), egg, wheat, and soy allergies are commonly outgrown, whereas allergies to peanut, tree nuts, fish, and shellfish often persist into adulthood. Unfortunately, as the prevalence of food allergies has increased, treatment options have remained limited.
Over the years, the standard of care for food allergies has largely remained education about strict allergen avoidance and treatment with emergency medications in the case of accidental ingestions. Not only does allergen avoidance lead to difficult dietary restrictions, it can be challenging as accidental ingestions commonly occur.3 The severity of food allergic reactions is unpredictable, and reactions can be fatal.4,5
In recent years there have been many reports of promising food allergy therapies. We will discuss a number of therapies, both allergen-specific and allergen-nonspecific, that are currently being investigated.
Allergen-specific immunotherapy entails exposure to the allergen, whether it be through the subcutaneous, oral, or sublingual route, and is intended to alter the allergic response so that the patient becomes desensitized (requires continued treatment to maintain efficacy) or, preferably, tolerant of the allergen (no reaction to a food allergen will occur, even if ingested after a period of abstinence). Most immunotherapy protocols involve an initial “build-up” phase in which the allergen is increased from a miniscule, easily tolerated amount, typically on a weekly or biweekly basis, up to a target dose of allergen. Many protocols begin with an accelerated build-up known as a “rush protocol” phase, where a patient will have the allergen dose increased more rapidly, with the target dose reached within a few days. During the “maintenance” phase, this goal dose is repeated on a daily, weekly, or monthly basis.
Long used as a treatment for allergic rhinitis and allergic asthma, a number of reports came out in the 1990s exploring subcutaneous immunotherapy (SCIT) as a food allergy remedy. Although multiple studies have demonstrated that SCIT can be an effective method of desensitization in peanut allergy, the rates of systemic reactions in these trials have been unacceptably high.6,7 In 2 trials of SCIT for treatment of peanut allergy, all participants had some level of decreased sensitivity compared with participants in the placebo group. Although somewhat effective, the systemic reaction rate with a rush protocol in one of these studies was 13.3%, whereas in the other it was 23% in an initial rush protocol and 39% with maintenance injections.6,7 In addition to the high rate of adverse reactions with SCIT, there are no long-term studies examining whether the decreased reactivity persists after treatment is discontinued.
One of the most promising and widely studied therapies for food allergy is oral immunotherapy (OIT). A successful case of oral immunotherapy in a child with egg-induced anaphylaxis was first published in 1908,8 although only scattered case reports were seen until the 1990s. Although OIT to a variety of foods has been reported, we will focus on several recent studies for CM, egg, and peanut, as these foods have been the most extensively studied.
Cow’s Milk Allergy
In 2008, Skripak et al9 reported the first double-blind, placebo-controlled OIT study for CM allergy in children. Twenty children were randomized to receive CM OIT or placebo. The dosing protocol included an initial build-up to 40 mg of milk protein, daily home doses with weekly dose escalation under observation for 8 weeks (maximum 500 mg), and then daily home maintenance for 3 to 4 months. All children in the active OIT group had an increased threshold for reaction to CM at the post-treatment challenge (median 5,140 mg versus median 40 mg at baseline double-blind, placebo-controlled food challenge [DBPCFC]). Although the increased threshold was encouraging, the majority of participants experienced reactions during the post-treatment CM challenge, demonstrating that complete protection from allergic reactions due to CM was not achieved. Furthermore, adverse reactions to OIT doses were common and unpredictable.
Several other studies have similarly demonstrated that milk OIT can result in increased thresholds of reaction to milk, even for highly milk-allergic children.10,11 However, the majority of participants experienced adverse reactions, with some requiring epinephrine to treat severe reactions. A recent Cochrane review of milk OIT found that studies to date have involved small numbers of patients and the quality of evidence is generally low.12 Although milk OIT can lead to desensitization in the majority of individuals with CM allergy, adverse effects are frequent, and the use of epinephrine to treat reactions is not infrequent. Furthermore, the possibility of long-term tolerance has not been established, and standardization of protocols and guidelines are required before milk OIT can be used in clinical practice.
Studies of egg OIT have shown that this therapy not only results in desensitization, but also is effective in the induction of tolerance for some individuals. In 1 study, 7 participants who completed a 24-month egg OIT protocol were able to tolerate significantly higher doses of egg protein than at baseline.13 Of 4 patients who did not react at the 24-month DBPCFC, 2 did not react during DBPCFC after a 3- to 4-month period of egg avoidance, indicating that tolerance was achieved. Another open-label clinical trial for egg allergy used individualized OIT protocols in 8 children.14 OIT continued until the subject’s egg white–specific immunoglobulin E (IgE) level was < 2 kU/L. Six of the 8 children completed the study, and these 6 children developed clinical tolerance to egg. These participants were also found to have decreased skin prick test responses, decreased egg-specific IgE levels, and increased egg-specific IgG4 levels, all of which are favorable immunologic indicators for tolerance.
In a recent multicenter, double-blind, randomized, placebo-controlled study, 40 children received egg OIT while 15 received placebo.15 After a build-up to a maximum of 2 g of egg white powder daily (about one-third of an egg), participants underwent an oral food challenge (OFC) at 10 months to assess for desensitization. Those on active treatment underwent a second OFC at 22 months. Those who did not react at this challenge discontinued OIT and avoided all egg consumption for 4 to 6 weeks before undergoing a repeat OFC to assess for tolerance. OIT resulted in desensitization for 55% at 10 months and 75% at 22 months.
At the 24-month challenge, only 28% achieved tolerance to egg. At 30 and 36 months, all children who achieved tolerance were consuming egg ad lib without reactions. Consistent with other OIT trials, adverse events were not infrequent, though they were generally mild. It should be noted that 15% of the children who were randomized to OIT did not finish the therapy, in most cases due to allergic reactions.
In 2009, a study demonstrated that desensitization could be achieved for peanut as well. Participants underwent an initial day escalation, build-up and maintenance phases (ranging from 4 to 22 months), followed by an OFC.16 Twenty-nine of 39 participants completed the protocol, with 27 able to ingest 3.9 g of peanut protein during OFC. Most symptoms that occurred during OIT resolved spontaneously or with antihistamines. More recently, the results of the first randomized, double-blind, placebo-controlled trial of peanut OIT were published.17 Twenty-eight peanut-allergic children were enrolled, 19 on peanut OIT and 9 on placebo.
Of those receiving peanut OIT, 3 withdrew early due to allergic side effects. The remaining 16 who completed the protocol were able to ingest 5 g of peanut protein (approximately 20 peanuts) at DBPCFC performed after 1 year of treatment, which was significantly higher than those in the placebo group (median cumulative dose of 280 mg). Those in the peanut OIT group also showed reductions in skin prick size, reductions in allergic cytokines (IL-4 and IL-13), and increases in peanut-specific IgG4, changes not seen in the placebo group.
A meta-analysis assessing the effectiveness and safety of peanut OIT was recently published by the Cochrane Collaboration.18 Of all the randomized controlled, quasi-randomized controlled, and case-controlled trials of peanut OIT published from 1990 through January 2012, only 1 study17 fulfilled the inclusion criteria and was considered to be at low risk of bias in all domains.
Other studies were excluded because they were case series or open trials without a control group, small case reports, or did not report either of their primary outcomes (desensitization or tolerance). The group concluded that although peanut OIT is promising, it cannot be recommended for routine use at this time, and that additional larger studies investigating safer OIT regimens and establishing the long-term effectiveness of OIT are necessary.
In summary, the preliminary evidence for OIT for foods is encouraging, although a lack of standardized protocols, frequent adverse effects (acute reactions from dosing as well more chronic illnesses such as eosinophilic esophagitis),19,20 potential bias from studies reported to date, and a lack of knowledge regarding whether these interventions achieve tolerance in addition to desensitization, leave experts concluding that OIT is not yet ready for routine clinical use.
The sublingual administration of small amounts of allergen is another approach to immunotherapy. Sublingual immunotherapy (SLIT) has been more extensively investigated for allergic rhinitis, but early studies using SLIT for kiwi, peach, and hazelnut allergies suggested that it could be a fruitful option for food allergy as well.21–23 In a double-blind, placebo-controlled study of peanut SLIT, participants underwent 6 months of build-up and 6 months of maintenance dosing, followed by a DBPCFC.24 After the 12 months of therapy, the SLIT groups were desensitized and were able to ingest about 20 times more peanut protein than the placebo group. This treatment was well tolerated, with less than 0.3% of doses requiring treatment with either an antihistamine or albuterol.
Recently, the Consortium of Food Allergy Research (CoFAR) conducted a multicenter, randomized, double-blind, placebo-controlled investigation of SLIT for peanut allergy.25 Following a baseline DBPCFC, 40 participants were randomized in a 1:1 fashion to daily peanut or placebo SLIT. After 44 weeks of therapy, a 5-g DBPCFC was performed. Participants were then unblinded, and the placebo-treated participants were given higher-dose peanut SLIT for 44 weeks, followed by DBPCFC.
Peanut SLIT was found to induce a modest level of desensitization in a majority of participants compared with placebo. Longer duration of therapy showed statistically significant increases in the amount of peanut tolerated. There was a high symptom rate in this study (41.1% of 5,825 peanut SLIT doses), as well as a high drop-out rate (25%).
A recent study compared milk SLIT alone and in combination with milk OIT.26 Thirty children were randomized to SLIT only or SLIT followed by OIT. Fifteen months of maintenance OIT (1 g or 2 g) was found to be more efficacious than SLIT (7 mg) at desensitizing to milk, with 70% of the OIT group passing the 15-month challenge compared with only 10% of the SLIT group. After a brief avoidance period, 40% of participants regained reactivity to milk. This study raises the important point that although most children can be desensitized using OIT, desensitization can be lost rather quickly. Of note, the participants in the OIT group did have more frequent and serious side effects than those who received SLIT alone.
These studies suggest that SLIT is less effective than OIT; however, further studies optimizing the SLIT protocols and examining the safety of SLIT are still necessary.
Oral Immunotherapy with Heat-Denatured Proteins
Recent studies have shown that a majority of children with milk and egg allergy can tolerate extensively heated milk and egg.27–29 Participants with transient milk allergy produce IgE antibodies primarily directed at conformational epitopes (amino acids brought into close proximity through protein folding) as opposed to sequential epitopes (contiguous amino acids). High temperatures break down conformational epitopes of milk and egg proteins, thus reducing the allergenicity of these foods for many individuals.
The introduction of the extensively heated milk and egg into the diet not only has quality of life benefits, but also has therapeutic potential. Kim et al28 reported that those who were able to tolerate baked milk products and incorporated them into the diet were significantly more likely to become tolerant to unheated milk within 60 months than the comparison group that maintained milk avoidance. The addition of baked milk products into the diets of these children had no adverse effects on growth or intestinal permeability. Similar results were seen in a study with baked egg.29 Participants in the active group who were incorporating baked egg into their diets on a regular basis were 14.6 times more likely to develop tolerance to regular egg than participants in the comparison group who continued strict egg avoidance.
Unfortunately, the reduction in allergenicity induced by heating seen with milk and egg is not universal to all foods. For some foods, heating has actually been reported to increase allergenicity. This has been seen both in peanut (dry roasting) and shrimp (boiling).30,31
Allergen Non-Specific Therapies
Recombinant monoclonal humanized anti-IgE is currently used for the treatment of environmental allergies associated with asthma. This medication reduces circulating free IgE, thus preventing the initiation of effector cell (such as mast cell or basophil) degranulation, inhibiting the early and late phase allergic response, suppressing inflammation, and improving control of allergic symptoms.
In one multicenter, double-blind, randomized, dose-ranging trial, 84 peanut-allergic patients were treated with either 1 of 3 doses of an anti-IgE antibody (TNX-901; 150 mg, 300 mg, or 450 mg) or placebo every 4 weeks for 4 months.32 DBPCFC was performed within 2 to 4 weeks after the fourth dose. Participants who received the 450-mg monthly dose had a significant decrease in symptoms with peanut OFC compared with the placebo group. The median threshold of sensitivity to peanut increased from 178 mg of peanut protein (the equivalent of 1 peanut) to 2.8 g (almost 9 peanuts). Notably, whereas 25% of patients were able to tolerate more than 20 peanuts following therapy, another 25% failed to develop any improvement in tolerance to peanut following treatment.
Ongoing trials are examining whether anti-IgE therapy used in conjunction with OIT may allow more rapid and higher dosing of OIT, while leading to fewer and less severe side effects during treatment. In a small study of omalizumab in combination with relatively rapid milk OIT in 11 children with CM allergy, combination therapy permitted rapid milk-dose escalation in the majority of participants, with 9 of 11 participants desensitized to a dose of 2,000 mg/day within 7 to 11 weeks.33
Traditional Chinese Medicine
In recent years, traditional Chinese medicine (TCM) has garnered attention in Western countries as a possible therapy for food allergies. TCM has been used for thousands of years to treat a wide range of diseases. The Food Allergy Herbal Formula-2 (FAHF-2), a combination of 9 herbs, completely blocks anaphylaxis in peanut-sensitized mice after peanut challenge.34 This effect persisted up to 6 months post-therapy, which is about 25% of the life span of the mouse.35 FAHF-2 has been shown to be safe and well tolerated by food-allergic patients in a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.36 Currently, a multicenter, double-blind, placebo-controlled phase 2 study is under way to evaluate the efficacy of this remedy and to further establish its safety.
Food allergy is an increasingly common problem seen by both pediatricians and allergists. Unfortunately, as the prevalence of food allergy has grown, there has been little in the advancement of therapy. We have described several promising approaches that are currently under investigation (see Table), and researchers around the world are working meticulously to improve the safety and efficacy of these therapies so that, either alone or in combination, they may provide long-term treatment options or even a cure for food allergy.
Table. Potential Therapies for Food Allergies
- Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9–17.
- Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549–1555.
- Fleischer DM, Perry TT, Atkins D, et al. Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. Pediatrics. 2012;130(1):e25–32.
- Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327(6):380–384.
- Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107(1):191–193.
- Oppenheimer JJ, Nelson HS, Bock SA, et al. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol. 1992;90(2):256–262.
- Nelson HS, Lahr J, Rule R, et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol. 1997;99(6):744–751.
- Schofield AT. A case of egg poisoning. Lancet. 1908;1:716.
- Skripak JM, Nash SD, Rowley H, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol. 2008;122(6):1154–1160.
- Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with very severe cow’s milk-induced reactions. J Allergy Clin Immunol. 2008;121(2):343–347.
- Pajno GB, Caminiti L, Ruggeri P, et al. Oral immunotherapy for cow’s milk allergy with weekly up-dosing regimen: a randomized single-blind controlled study. Ann Allergy Asthma Immunol. 2010;105(5):376–381.
- Yeung JP, Kloda LA, McDevitt J, et al. Oral immunotherapy for milk allergy. Cochrane Database Syst Rev. 2012;11:CD009542.
- Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol. 2007;119(1):199–205.
- Vickery BP, Pons L, Kulis M, et al. Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance. Ann Allergy Asthma Immunol. 2010;105(6):444–450.
- Burks AW, Jones SM, Wood RA, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012;367(3):233–243.
- Jones SM, Pons L, Roberts JL, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009;124(2):292–300.
- Varshney P, Steele PH, Vickery BP, et al. Adverse reactions during peanut oral immunotherapy home dosing. J Allergy Clin Immunol. 2009;124(6):1351–1352.
- Nurmatov U, Venderbosch I, Devereux G, et al. Allergen-specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev. 2012;9:CD009014.
- Ridolo E, De Angelis GL, Dall’aglio P. Eosinophilic esophagitis after specific oral tolerance induction for egg protein. Ann Allergy Asthma Immunol. 2011;106(1):73–74.
- Sanchez-Garcia S, Rodriguez Del Rio P, Escudero C, et al. Possible eosinophilic esophagitis induced my milk oral immunotherapy. J Allergy Clin Immunol. 2012;129(4):1155–1157.
- Mempel M, Rakoski J, Ring J, Ollert M. Severe anaphylaxis to kiwi fruit: immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol. 2003;111(6):1406–1409.
- Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, et al. Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy. 2009;64(6):876–883.
- Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116(5):1073–1079.
- Kim EH, Bird JA, Kulis M, et al. Sublingual immunotherapy for peanut allergy: Clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2011;127(3):640–646.
- Fleischer DM, Burks AW, Vicker BP, et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol. 2013;131(1):119–127.
- Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2012;129(2):448–455.
- Nowak-Wegrzyn A, Bloom KA, Sicherer SH, et al. Tolerance to extensively heated milk in children with cow’s milk allergy. J Allergy Clin Immunol. 2008;122(2):342–347.
- Kim JS, Nowak-Wegrzyn A, Sicherer SH, et al. Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol. 2011;128(1):125–131.
- Leonard SA, Sampson HA, Sicherer SH, et al. Dietary baked egg accelerates resolution of egg allergy in children. J Allergy Clin Immunol. 2012;130(2):473–480.
- Beyer K, Morrow E, Li XM, et al. Effects of cooking methods on peanut allergenicity. J Allergy Clin Immunol. 2001;107(6):1077–1081.
- Carnes J, Ferrer A, Huertas AJ, et al. The use of raw or boiled crustacean extracts for the diagnosis of seafood allergic individuals. Ann Allergy Asthma Immunol. 2007;98:349–354.
- Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. 2003;348(11):986–993.
- Nadeau KC, Schneider LC, Hoyte L, et al. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol. 2011;127(6):1622–1623.
- Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol. 2005;115(1):171–178.
- Srivastava KD, Zhang T, Qu C, et al. Silencing peanut allergy: A Chinese Herbal Formula, Fahf-2, completely blocks peanut-induced anaphylaxis for up to 6 months following therapy in a murine model of peanut allergy. J Allergy Clin Immunol. 2006;117:S328.
- Wang J, Patil SP, Yang N, et al. Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study. Ann Allergy Asthma Immunol. 2010;105(1):75–84.
Potential Therapies for Food Allergies
|Subcutaneous immunotherapy (SCIT)
||An accepted treatment for allergic rhinitis, SCIT involves subcutaneous injections of increasing amounts of allergen to desensitize or induce tolerance in a patient. Rates of systemic reactions to this therapy in food allergy trials have been unacceptably high.
|Oral immunotherapy (OIT) with natural proteins
||Widely studied as a food allergy therapy, OIT involves ingesting increasing amounts of a food allergen. Although promising, further studies are needed to standardize protocols, optimize safety, and determine whether the intervention achieves tolerance in addition to desensitization.
|Oral immunotherapy with heat-denatured proteins
||Extensively heated forms of milk or egg are often tolerated in children with these food allergies. When tolerated and regularly incorporated into the diet, patients are more likely to become tolerant to unheated forms of these foods. No reduction in allergenicity has been seen in other foods with heating.
|Sublingual immunotherapy (SLIT)
||SLIT involves small amounts of allergen extracts administered under the tongue. Several studies suggest that SLIT is less effective at desensitization than OIT, although further studies optimizing the SLIT protocols are necessary.
|Anti-immunoglobulin E treatment
||Infusions of this humanized, monoclonal antibody are used to treat environmental allergies associated with asthma, as they inhibit the allergic response. Investigations are under way to see if it can decrease adverse events related to OIT, although it is generally not viewed as a potential stand-alone therapy for food allergy.
|Traditional Chinese medicine
||Administration of the herbal formula Food Allergy Herbal Formula-2 has been effective at preventing anaphylaxis in mouse models of peanut allergy, and studies are ongoing to determine its efficacy in humans.