P o t e n t i a l Trea t m e n t s f o r Food Allergy Stephanie Albin,
MD
a
, Anna Nowak-We˛grzyn,
MD
b,
*
KEYWORDS Food allergy Food immunotherapy Desensitization Tolerance Omalizumab KEY POINTS There is currently no cure for food allergy, and standard of care remains strict avoidance of foods to which a patient is allergic. Immunotherapy is based on established protocols for desensitization, and it involves administering increasing doses of an allergenic food over a period of several months to increase tolerance. Goals of ongoing immunotherapy trials are to achieve sustained unresponsiveness and permanent tolerance, although this has not yet been consistently established. The oral route appears to be the preferred method of food allergen delivery, but immunotherapy is also being studied through sublingual and epicutaneous routes. Improvements in immunotherapy safety and outcomes may come with antiimmunoglobulin E monoclonal antibody adjuncts, modified food antigens, and recombinant vaccines. Allergen nonspecific treatments could potentially be used to treat various and multiple food allergies.
INTRODUCTION
Food allergy has been a subject of increasing research interest in the past decade. Data from multiple centers and various study designs indicate that there is a potential to effectively treat food allergy with immunomodulating therapies in both allergenspecific and nonspecific ways. This review serves to highlight the major therapeutics under investigation for food allergy, and the treatments discussed herein are summarized in Fig. 1.
Funding Sources: No funding for this article. Conflict of Interest: No conflicts of interest for this article. a Division of Allergy and Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA; b Division of Allergy and Immunology, Department of Pediatrics, Kravis Children’s Hospital, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA * Corresponding author. E-mail address: [email protected] Immunol Allergy Clin N Am 35 (2015) 77–100 http://dx.doi.org/10.1016/j.iac.2014.09.011 immunology.theclinics.com 0889-8561/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Fig. 1. Food allergy therapy. IT, immunotherapy.
Current Standard of Care for Food Allergy
Currently, there is no cure for food allergy, and standard of care hinges on strict avoidance of those foods to which a patient is allergic. The National Institute of Allergy and Infectious Diseases has put forth guidelines for the management of food allergy in the United States, which emphasizes the importance of food avoidance and labelreading, nutritional guidance and growth monitoring, and regular follow-up with an allergist.1 An international consensus document endorses similar strategies, but concedes that no randomized clinical studies have proven the superiority of allergen avoidance or whether food allergen avoidance diminishes nutritional status.2 Avoidance is difficult in many situations, and as such, management always also necessitates education on timely and appropriate treatment of accidental exposures.3 In the registry of fatal food-induced anaphylaxis, most fatal reactions were reported in the subjects who unknowingly ingested an offending food, thus highlighting the need for a more definitive approach to food allergy management.4 POTENTIAL ALLERGEN-SPECIFIC TREATMENTS FOR FOOD ALLERGY Concept of Immunotherapy
Given that there is currently no cure for food allergy, there is great interest in researching methods of tolerance induction, particularly food-specific immunotherapy. Food immunotherapy is based on established protocols for drug desensitization and aeroallergen/venom immunotherapy, and it involves administering increasing doses of an allergenic food over a period of several months.5 For example, in oral immunotherapy (OIT), typically there is an initial rapid dose escalation, followed by further dose
Potential Treatments for Food Allergy
escalation on a biweekly schedule in a controlled clinical setting until maintenance dose is achieved. Daily ingestion of tolerated doses during the build-up and maintenance phases occurs at home. The oral route appears to be the preferred method of food allergen delivery, but immunotherapy is also being studied through sublingual and epicutaneous routes. Of note, subcutaneous immunotherapy for food allergy was abandoned following early pilot studies, demonstrating serious side effects during all phases of treatment.6,7 Mechanism of Oral Immunotherapy
The exact mechanism of desensitization in food immunotherapy is not known, but associated immunologic changes include decreased reactivity of mast cells and basophils, increased food-specific serum immunoglobulin (Ig) G4 antibodies, and initially increased but eventually decreased serum food-specific IgE antibodies.8 Specific regulatory T cells (Tregs) increase and peak at around 12 months, with a subsequent decrease over time.9 Increased antigen-induced Treg function is associated with hypomethylation of forkhead box protein 3.10 Desensitization Versus Sustained Unresponsiveness
Early clinical trials in immunotherapy aimed to safely desensitize subjects to a maintenance dose equivalent to a small serving of allergenic food, to protect allergic subjects from accidental exposures.11–15 Current, more rigorous clinical trials are aiming for a sustained protective effect (sustained unresponsiveness), whereby subjects have a prolonged ability to ingest large amounts of allergenic food without the continuation of scheduled immunotherapy. Although consistent methods and mechanisms for induction of permanent tolerance have not yet been demonstrated, clinical trials have shown that OIT can “successfully desensitize a large number of individuals without major morbidity or mortality; at the end of the all of the studies, the greater part of patients can tolerate more of the food than at the start.”16 Two studies provide insight into sustained unresponsiveness following peanut OIT. In a study by Vickery and colleagues,17 24 subjects were treated up to 5 years with peanut OIT, with a maintenance daily dose of 4000 mg peanut protein and a mean duration of 3.98 years (SD, 1.8 years). Twelve (50%) of 24 passed a peanut challenge to 5000 mg of peanut protein 1 month after stopping OIT, were considered to have achieved sustained unresponsiveness, and added unrestricted peanut to their diet. At baseline and at the time of the final peanut challenge, subjects who achieved sustained unresponsiveness had smaller skin test results, lower serum peanut-specific IgE antibody levels for peanut, Ara h 1, Ara h 2, and lower ratios of peanut-specific IgE/total IgE compared with subjects who did not achieve achieved sustained unresponsiveness. Syed and colleagues10 showed that with a shorter duration of peanut OIT (24 months of daily dosing with 4000 mg of peanut protein), 20 of 24 (83%) treated subjects became desensitized, as determined by a peanut challenge while on OIT. However, after 3 months of strict peanut elimination, only 7 of 24 (29%) subjects passed the peanut challenge with 4000 mg of peanut protein. Following an additional 3 months of peanut avoidance (a total of 6 months after discontinuation of peanut OIT), 3 of those 7 subjects (12.5% of original treatment group) remained tolerant to peanut during a final peanut challenge. These observations suggest that sustained responsiveness to peanut following peanut OIT is likely dose-dependent and duration-dependent.
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Effect of Oral Immunotherapy on Quality of Life
Studies looking at quality of life in the setting of food immunotherapy have identified improvement in domains, including dietary and social limitations, risk of accidental exposure, and anxiety after immunotherapy.18,19 Oral Immunotherapy
Clinical trials have been undertaken to study the effect of OIT in the context of peanut, milk, and egg allergy.20 Peanut oral immunotherapy
In 2010, Blumchen and colleagues21 investigated the efficacy and safety of OIT in patients with peanut allergy. Of 22 subjects who completed a rush protocol followed by 8 weeks of OIT, only 14 (64%) reached a goal maintenance dose of 500 mg of peanut. At the final double-blind, placebo-controlled food challenge (DBPCFC) however, subjects tolerated a median of 1000 mg (range, 250–4000 mg) in comparison with 190 mg peanut at the DBPCFC before OIT. The authors concluded that peanut OIT appeared to be safe and of some benefit in patients with peanut allergy, as the intervention increased threshold levels of ingestion. In 2011, Varshney and colleagues9 reported the results of the first randomized, double-blind, placebo-controlled trial evaluating peanut OIT that proved effective desensitization. After 1 year of treatment, those who completed a peanut OIT protocol ingested the maximum cumulative dose of 5000 mg of peanuts, whereas placebo subjects ingested a median cumulative dose of 280 mg (range, 0–1900 mg). In 2013, Vickery and colleagues17 went on to demonstrate sustained unresponsiveness after stopping peanut OIT. Of 24 subjects who completed up to 5 years of peanut OIT, 12 (50%) successfully passed a 5000mg challenge 1 month after stopping OIT and introduced peanut into their diet. Most recently, in 2014, Anagnostou and colleagues22 published a randomized controlled trial showing an estimate of the effect size, benefits, and risks of desensitization with peanut OIT. In this study group, desensitization (defined as passing a 1400 mg [roughly 10 peanuts] DBPCFC) was achieved for 24 of 49 (62%) subjects receiving peanut OIT for 6 months, and for none of the control group abiding by strict peanut avoidance. There was an increase in median peanut threshold after OIT to 1345 mg (range, 45–1400 mg). Quality-of-life scores improved in the group receiving OIT, and side effects were mild in most participants. Although these studies are promising, a meta-analysis of published peanut OIT trials concluded that only one small randomized controlled trial demonstrated that peanut OIT can result in desensitization with immune modulation.23 They went on to point out that this study (as with most OIT studies) was associated with a substantial risk of adverse events, although most were mild. The meta-analysis, as well as other expert opinion, supports that peanut OIT cannot be currently recommended as a treatment for management of IgE-mediated peanut allergy, and larger randomized control trials are needed.24 Milk/egg oral immunotherapy
In 2007, Staden and colleagues25 sought to examine the efficacy of milk and egg OIT as compared with strict avoidance. Subjects had immunotherapy maintenance doses increased (according to individual tolerance) to a maximum dose of 8250 mg of cow’s milk or 2800 mg hen’s egg protein, with a minimum dose of 3300 mg cow’s milk or 1600 mg hen’s egg protein. Of the 25 subjects randomized to OIT, 16 (64%) were able to integrate the food allergen into their diet in some form: 9 subjects (36%) receiving OIT showed sustained unresponsiveness after a secondary 2-month
Potential Treatments for Food Allergy
elimination diet; 3 subjects (12%) showed tolerance with regular intake; and 4 subjects (16%) were partial responders who did not meet the planned, full maintenance dose. In contrast, only 7 of 20 control subjects (35%) developed natural tolerance during the elimination diet, as evidenced by passing a DBPCFC (cumulative goal dose of cow’s milk protein 4770 mg, cumulative goal dose of hen’s egg protein 6200 mg) after a median interval of 21 months. Skripak and colleagues26 went on to publish the first randomized, double-blind, placebo-controlled study of milk OIT in 2008, showing efficacy in the treatment group with an increase in the median threshold of ingested milk protein from 40 mg to 5140 mg (without a change in the placebo group). A follow-up, open-label study in 2009 showed that after 13 to 75 weeks of open-label dosing (median dose 7000 mg), 6 of 13 subjects (46%) tolerated 16,000 mg milk protein without reaction and 7 subjects reacted at doses 3000 to 16,000 mg.27 Most recently, the clinical status of 32 subjects from 2 of this group’s study protocols26,28 evaluated the long-term outcomes of milk immunotherapy.29 Sixteen subjects were followed up after a median of 4.5 years (range, 1.3–5.3 years)26 and 16 were followed up after a median of 3.2 years (range, 2.6–3.4 years)28 from the end of dose escalation. Twenty-five of 32 subjects (78%) were ingesting some amount of uncooked milk, although only 6 (19%) reported unlimited milk consumption. Two subjects (6%) were ingesting trace or baked milk products, and 5 subjects (16%) reported no milk consumption. Most worrisome, the authors reported that some subjects who initially did well and passed interim oral food challenges (OFCs) subsequently had increased symptoms (including severe symptoms), which led to the restriction of cow’s milk. Other studies have focused on dosing schedules of milk OIT in consideration of feasibility and compliance. Pajno and colleagues30 found that after achieving desensitization to cow’s milk with OIT, a maintenance regimen with milk given twice weekly was as effective as daily maintenance. However, in terms of “clinical readiness,” a systematic review of randomized controlled trials for milk OIT concluded the overall low quality of evidence “leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes.[there were] frequent and sometimes serious adverse effects.and additional, larger [trials] measuring all patientimportant outcomes are still needed.”31 There have been relatively fewer trials for egg immunotherapy. Small pilot and proof-of-concept studies have shown feasibility and safety of egg OIT,11–13,32,33 and, in 2012, Burks and colleagues34 published the first randomized, double-blind, placebo-controlled trial for egg OIT. Forty subjects received egg OIT with a goal maintenance dose of 2000 mg egg protein daily, and 15 subjects received placebo. At a 10month desensitization challenge, 22 of 40 OIT subjects (55%) tolerated 5000 mg of egg protein, as compared with none of the placebo group. At a 22-month desensitization challenge, 30 of 40 OIT subjects (75%) tolerated 5000 mg of egg protein. However, at a 24-month tolerance challenge after 6 to 8 weeks off of OIT, only 11 of 29 subjects (28%) tolerated 5000 mg of egg protein, raising concerns about the longterm protection afforded by the protocol. In keeping with meta-analyses of specific food OIT, a meta-analysis of general food OIT concluded that it cannot yet be recommended in routine practice as a means to induce tolerance in children with IgEmediated food allergy.35 Safety of Oral Immunotherapy
OIT is associated with adverse effects in virtually all published trials, although side effects are often mild and localized to the oropharynx. A study looking at safety in the
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different phases of OIT showed that reactions were most frequent during the initial escalation day when subjects underwent oral desensitization, and doses were better tolerated during the buildup phase and home dosing.36 Factors such as febrile illness, exercise, and menstruation can reduce tolerated threshold doses.37 The predominance of gastrointestinal symptoms merits a thoughtful consideration regarding eosinophilic esophagitis (EoE), as the risk is estimated to be about 10% to 20% in those treated with OIT.38,39 Oral Immunotherapy with Anti-Immunoglobulin E
An anti-IgE agent, omalizumab, is currently approved for moderate-to-severe allergic asthma. It functions by depleting free IgE and downregulating FcεRI on effector cells, such as mast cells and basophils, and on antigen-presenting cells, such as dendritic cells and B cells.40 Omalizumab may also have a role to play in food allergy immunotherapy, as it minimizes IgE-mediated side effects and may contribute to mechanisms of tolerance. Pretreatment with omalizumab for 9 to 12 weeks before starting OIT and combined treatment during the build-up phase of OIT appears to reduce side effects and accelerate buildup dosing. Preliminary studies evaluating safety of omalizumab in combination with milk, peanut, and multifood OIT have been published (Table 1).41–43 Sublingual and Epicutaneous Immunotherapy
In sublingual immunotherapy (SLIT), a food allergen extract is kept in the mouth for 2 to 3 minutes and then spit out or swallowed. It is generally better tolerated and uses significantly lower doses than OIT, but appears to have inferior clinical effects of desensitization.44 Clinical trials of food SLIT have been reported for milk, peanut, hazelnut, and peach extracts (Table 2).28,44–50 Epicutaneous immunotherapy (EPIT) uses a skin patch containing soluble allergen that is absorbed into intact stratum corneum. It is an attractive approach to noninvasive immunotherapy with minimal side effects, and studies have demonstrated that EPIT commonly causes local reactions but almost never induces serious systemic adverse events.51 Pilot trials are currently underway for milk and peanut (see Table 2).51,52 Role for Aeroallergen Immunotherapy for Pollen Cross-Reactive Foods
Pollen immunotherapy has typically been considered a therapeutic option for patients with allergic rhinitis and asthma, but studies have also shown an effect on symptoms of pollen food syndrome (PFS). In PFS, cross-reactive IgE antibodies recognize homologous allergens in pollen and raw fruits, vegetables, and nuts. These allergens are typically broken down during the process of digestion, but patients with pollen allergies can develop oropharyngeal symptoms (commonly pruritus or swelling of the mouth, face, lip, tongue, and throat) with ingestion of various plant-based foods. Multiple studies have successfully used subcutaneous birch pollen immunotherapy to treat apple allergy in this context.53–57 Birch-pollen immunotherapy has been demonstrated to decrease skin prick test (SPT) reactivity for recombinant Bet v 1 (major birch allergen) and recombinant Mal d 1 (major apple allergen), induce IgG4 antibodies against Bet v 1 (which display cross-reactivity to Mal d 1), and increase the amount of fresh apple ingested at a DBPCFC after 1 year.56 In addition, the beneficial effects of immunotherapy on PFS appear to be long lasting after treatment, despite a propensity for apple resensitization over time.54 Immunotherapy with Modified Food Antigens
Recently, there has been a movement toward modifying food antigens to create more effective and safe immunotherapeutic materials. One of the most commonly used
Potential Treatments for Food Allergy
approaches to immunomodulation with modified food antigens is the incorporation of extensively heated egg and milk products into the diet of selected allergic patients. Certain egg and milk conformational epitopes are destroyed by high temperatures, making it possible for some allergic patients to consume small amounts of these foods in the baked form.58 Most patients with cow’s milk and egg allergy tolerate extensively heated products, and the addition of baked milk and baked egg to the diet of children tolerating such foods appears to accelerate the development of unheated milk and egg tolerance compared with strict avoidance.59,60 Immunologic changes induced by a diet containing baked milk and egg are similar to changes that have been observed during OIT trials, although individuals who are tolerant to heated milk products may represent a milder milk allergy phenotype with evidence of greater immune regulation, such as lower specific IgE, higher specific IgG4, lower basophil reactivity to milk proteins, and a higher frequency of milk-specific Tregs.61–63 Additional immunotherapy with modified food antigens includes peptide immunotherapy and mannose-conjugated food allergen immunotherapy, which are both currently under investigation in preclinical studies (Table 3).64–68 Immunotherapy with Recombinant Peanut Rectal Vaccine
In another model of modification, Bannon and colleagues69 have successfully developed and characterized cDNA clones for 3 major peanut allergens, Ara h 1, Ara h 2, and Ara h 3. The group substituted amino acids through site-directed mutagenesis of the cDNA clones and performed recombinant production of the modified allergens. In a murine model of peanut allergy using the heat-killed Escherichia coli producing mutated Ara h 1, 2, and 3 (HKE-MP123), mice had reduced symptom scores on challenge, lower IgE levels, and decreased Th2 cytokines/increased Th1 cytokines from peanut-stimulated splenocytes in vitro.70 Most recently, a phase I safety study was undertaken, giving 5 healthy adult controls and 10 peanut-allergic adult subjects weekly dose escalations of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2, and Ara h 3.71 There were no significant effects on the healthy controls, but there were severe allergic reactions in 20% of the peanut-allergic subjects, and the authors concluded that “future studies with this product, if any, will require alterations in the dosing scheme and/or route of delivery.”71 POTENTIAL ALLERGEN NON-SPECIFIC TREATMENTS FOR FOOD ALLERGY
Although significant resources are being put toward allergen-specific immunotherapy, there is a parallel effort toward developing nonspecific treatments that could potentially be used to treat various and multiple food allergies. One promising example of this is Chinese herbal formulas, and others include probiotics/prebiotics, helminths, monoclonal antibodies, and toll-like receptor (TLR) agonists. Chinese Herbal Formulas
Chinese herbal medicine studies in the setting of food allergy were initially done using food allergy herbal formula-1 (FAHF-1), an 11-herb formula containing the classical Wu-Mei Wan (a combination of 10 herbs previously used for intestinal parasitic infection, gastroenteritis, and asthma) and Ling Shi (an additional herb with purported antiinflammatory properties).72 The herbs Xi-Xin and Zhi-Fu-Zi were removed from the formula for safety concerns, and the resultant 9-herb formula, FAHF-2, has been used in both murine research and early clinical trials (Table 4).73–76 These herbal formulas are thought to have synergistic anti-inflammatory effects, with reduced side effects in formulation as compared with individual herbs.72 In general, results from
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Study/Subjects
Success Rate
Immunologic Changes
Side Effects/Comments
Nadeau et al,41 2011 n 5 11; age 7–17 y Pilot phase I study using omalizumab in combination with oral milk desensitization (desensitization performed 9 wk after start of omalizumab treatment) Goal maintenance dose: 2000 mg milk protein/d
The mean frequency for total reactions reported by week 24 was 1.6% (32 reactions of 2199 doses total for all 11 subjects). All subjects experienced some adverse events, though most reactions were defined as mild and needed no treatment. One dose of epinephrine was given during rush desensitization, and 2 subjects received epinephrine at home during the maintenance phase. Nine of the 11 subjects tolerated desensitization to a dose of 2000 mg milk within a period of 7–11 wk.
Within a week of treatment, the CD41 T-cell response to milk was nearly eliminated. Over the following 3 mo, the CD41 T-cell response returned, characterized by a shift from IL-4 to IFN-g. MilkIgE decreased, and milk-IgG4 increased 15-fold.
This was a phase I study, and the primary objectives were to examine the safety of this approach and to determine whether subjects could be dosed up to 2000 mg milk within 7–11 wk of initiating desensitization.
Schneider et al,42 2013 n 5 13; age 8–16 y Pilot study using omalizumab in combination with oral peanut desensitization (desensitization performed 12 wk after start of omalizumab treatment) Goal maintenance dose: 4000 mg peanut protein/d
All 13 subjects (100%) reached the 500 mg peanut desensitization dose on the first day (cumulative dose, 992 mg), which was the primary outcome of the study, with minimal or no symptoms. Twelve of the 13 subjects (92%) reached the 4000 mg maintenance dose, which was a secondary outcome of the study, requiring median time of 8 wk. Twelve weeks after stopping omalizumab (week 32), 12 subjects underwent a DBPCFC (cumulative dose, 8000 mg peanut). Eleven of the subjects (85%) tolerated this challenge, and the twelfth subject later passed an open challenge of 8000 mg peanut. Therefore, 12 of the 13 subjects (92%) tolerated an 8000-mg dose of peanut.
Not reported
There were a total of 72 reactions during the study (2% of the 3502 total peanut doses ingested). During the study, 6 of the 13 subjects experienced mild or no allergic reactions; 5 subjects had grade 2 reactions, and 2 subjects had grade 3 reactions, all of which responded rapidly to treatment.
Albin & Nowak-We˛grzyn
Table 1 Oral immunotherapy and anti-IgE safety studies
Be´gin et al,43 2014 n 5 25; age 4–15 y Phase I study using up to 5 different food allergens rush OIT simultaneously with omalizumab (omalizumab was administered for 8 wk before and 8 wk following the initiation of rush OIT) Goal maintenance dose: 4000 mg protein per allergen
The median time to reach maintenance dose (4000 mg per allergen) was 18 wk (range, 7–36 wk) with all subjects able to reach this dose by 9 mo. All subjects had reached a dose equivalent to a 10-fold increase of all their allergens by 2 mo of therapy. Over the study period, there were 3 withdrawals because of noncompliance with study medication.
Peanut-specific IgG4 levels increased and peanut SPT decreased. Peanut-specific IgE did not change significantly.
This was a proof of concept study and evaluated subjects for desensitization. Thirteen subjects (52%) experienced some symptoms on their initial dose escalation day. With home dosing, 401 of the 7530 doses (5.3%) triggered reactions, and most home reactions occurred in the first months of therapy. Most (94%) allergic reactions were mild. One severe reaction requiring epinephrine occurred shortly after a subject reached maintenance phase (16,000 mg).
Potential Treatments for Food Allergy 85
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Study/Subjects
Success Rate
Immunologic Changes
Side Effects/Comments
Milk Keet et al,28 2012 n 5 30; age 6–17 y Randomized clinical trial comparing milk OIT and SLIT with challenge performed after 12 and 60 wk Goal maintenance dose: SLIT: 7 mg daily Low-dose OIT: 1000 mg High-dose OIT: 2000 mg
One of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/lowdose OIT group, and 8 of 10 subjects in the SLIT/high-dose OIT group passed the 8 g milk protein challenge (P 5 .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 subjects in each OIT group) regained reactivity, 2 after only 1 wk off therapy.
Titrated milk SPT wheal diameter and basophil activity decreased in all groups. Milk-specific IgG4 increased in all groups. Milk-specific IgE and spontaneous histamine release decreased in only the OIT group.
OIT was more efficacious for desensitization than SLIT alone, but was accompanied by more systemic side effects. There were symptoms with 1802 (29%) of 6246 SLIT doses and 2402 (23%) of 10,645 OIT doses. However, OIT had significantly more multisystem, upper respiratory tract, gastrointestinal, and lower respiratory tract symptoms than SLIT.
Peanut Fleischer et al,50 2013 n 5 40; age 12–37 y Randomized, double-blind, placebo-controlled multicenter trial comparing peanut SLIT and placebo after 44 wk; placebotreated patients were unblinded, then crossed over into a higher dose peanut SLIT for 44 wk Goal maintenance dose: minimum dose of 165 mg and maximum dose of 1386 mg daily Crossover group: maximum maintenance dose of 3696 mg daily
After 44 wk of SLIT, 14 of 20 subjects receiving peanut SLIT passed a 5 g peanut powder challenge (or ingested at least 10-fold more peanut powder than the baseline OFC), compared with 3 of 20 subjects receiving placebo (P
MD
a
, Anna Nowak-We˛grzyn,
MD
b,
*
KEYWORDS Food allergy Food immunotherapy Desensitization Tolerance Omalizumab KEY POINTS There is currently no cure for food allergy, and standard of care remains strict avoidance of foods to which a patient is allergic. Immunotherapy is based on established protocols for desensitization, and it involves administering increasing doses of an allergenic food over a period of several months to increase tolerance. Goals of ongoing immunotherapy trials are to achieve sustained unresponsiveness and permanent tolerance, although this has not yet been consistently established. The oral route appears to be the preferred method of food allergen delivery, but immunotherapy is also being studied through sublingual and epicutaneous routes. Improvements in immunotherapy safety and outcomes may come with antiimmunoglobulin E monoclonal antibody adjuncts, modified food antigens, and recombinant vaccines. Allergen nonspecific treatments could potentially be used to treat various and multiple food allergies.
INTRODUCTION
Food allergy has been a subject of increasing research interest in the past decade. Data from multiple centers and various study designs indicate that there is a potential to effectively treat food allergy with immunomodulating therapies in both allergenspecific and nonspecific ways. This review serves to highlight the major therapeutics under investigation for food allergy, and the treatments discussed herein are summarized in Fig. 1.
Funding Sources: No funding for this article. Conflict of Interest: No conflicts of interest for this article. a Division of Allergy and Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA; b Division of Allergy and Immunology, Department of Pediatrics, Kravis Children’s Hospital, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA * Corresponding author. E-mail address: [email protected] Immunol Allergy Clin N Am 35 (2015) 77–100 http://dx.doi.org/10.1016/j.iac.2014.09.011 immunology.theclinics.com 0889-8561/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
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Fig. 1. Food allergy therapy. IT, immunotherapy.
Current Standard of Care for Food Allergy
Currently, there is no cure for food allergy, and standard of care hinges on strict avoidance of those foods to which a patient is allergic. The National Institute of Allergy and Infectious Diseases has put forth guidelines for the management of food allergy in the United States, which emphasizes the importance of food avoidance and labelreading, nutritional guidance and growth monitoring, and regular follow-up with an allergist.1 An international consensus document endorses similar strategies, but concedes that no randomized clinical studies have proven the superiority of allergen avoidance or whether food allergen avoidance diminishes nutritional status.2 Avoidance is difficult in many situations, and as such, management always also necessitates education on timely and appropriate treatment of accidental exposures.3 In the registry of fatal food-induced anaphylaxis, most fatal reactions were reported in the subjects who unknowingly ingested an offending food, thus highlighting the need for a more definitive approach to food allergy management.4 POTENTIAL ALLERGEN-SPECIFIC TREATMENTS FOR FOOD ALLERGY Concept of Immunotherapy
Given that there is currently no cure for food allergy, there is great interest in researching methods of tolerance induction, particularly food-specific immunotherapy. Food immunotherapy is based on established protocols for drug desensitization and aeroallergen/venom immunotherapy, and it involves administering increasing doses of an allergenic food over a period of several months.5 For example, in oral immunotherapy (OIT), typically there is an initial rapid dose escalation, followed by further dose
Potential Treatments for Food Allergy
escalation on a biweekly schedule in a controlled clinical setting until maintenance dose is achieved. Daily ingestion of tolerated doses during the build-up and maintenance phases occurs at home. The oral route appears to be the preferred method of food allergen delivery, but immunotherapy is also being studied through sublingual and epicutaneous routes. Of note, subcutaneous immunotherapy for food allergy was abandoned following early pilot studies, demonstrating serious side effects during all phases of treatment.6,7 Mechanism of Oral Immunotherapy
The exact mechanism of desensitization in food immunotherapy is not known, but associated immunologic changes include decreased reactivity of mast cells and basophils, increased food-specific serum immunoglobulin (Ig) G4 antibodies, and initially increased but eventually decreased serum food-specific IgE antibodies.8 Specific regulatory T cells (Tregs) increase and peak at around 12 months, with a subsequent decrease over time.9 Increased antigen-induced Treg function is associated with hypomethylation of forkhead box protein 3.10 Desensitization Versus Sustained Unresponsiveness
Early clinical trials in immunotherapy aimed to safely desensitize subjects to a maintenance dose equivalent to a small serving of allergenic food, to protect allergic subjects from accidental exposures.11–15 Current, more rigorous clinical trials are aiming for a sustained protective effect (sustained unresponsiveness), whereby subjects have a prolonged ability to ingest large amounts of allergenic food without the continuation of scheduled immunotherapy. Although consistent methods and mechanisms for induction of permanent tolerance have not yet been demonstrated, clinical trials have shown that OIT can “successfully desensitize a large number of individuals without major morbidity or mortality; at the end of the all of the studies, the greater part of patients can tolerate more of the food than at the start.”16 Two studies provide insight into sustained unresponsiveness following peanut OIT. In a study by Vickery and colleagues,17 24 subjects were treated up to 5 years with peanut OIT, with a maintenance daily dose of 4000 mg peanut protein and a mean duration of 3.98 years (SD, 1.8 years). Twelve (50%) of 24 passed a peanut challenge to 5000 mg of peanut protein 1 month after stopping OIT, were considered to have achieved sustained unresponsiveness, and added unrestricted peanut to their diet. At baseline and at the time of the final peanut challenge, subjects who achieved sustained unresponsiveness had smaller skin test results, lower serum peanut-specific IgE antibody levels for peanut, Ara h 1, Ara h 2, and lower ratios of peanut-specific IgE/total IgE compared with subjects who did not achieve achieved sustained unresponsiveness. Syed and colleagues10 showed that with a shorter duration of peanut OIT (24 months of daily dosing with 4000 mg of peanut protein), 20 of 24 (83%) treated subjects became desensitized, as determined by a peanut challenge while on OIT. However, after 3 months of strict peanut elimination, only 7 of 24 (29%) subjects passed the peanut challenge with 4000 mg of peanut protein. Following an additional 3 months of peanut avoidance (a total of 6 months after discontinuation of peanut OIT), 3 of those 7 subjects (12.5% of original treatment group) remained tolerant to peanut during a final peanut challenge. These observations suggest that sustained responsiveness to peanut following peanut OIT is likely dose-dependent and duration-dependent.
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Effect of Oral Immunotherapy on Quality of Life
Studies looking at quality of life in the setting of food immunotherapy have identified improvement in domains, including dietary and social limitations, risk of accidental exposure, and anxiety after immunotherapy.18,19 Oral Immunotherapy
Clinical trials have been undertaken to study the effect of OIT in the context of peanut, milk, and egg allergy.20 Peanut oral immunotherapy
In 2010, Blumchen and colleagues21 investigated the efficacy and safety of OIT in patients with peanut allergy. Of 22 subjects who completed a rush protocol followed by 8 weeks of OIT, only 14 (64%) reached a goal maintenance dose of 500 mg of peanut. At the final double-blind, placebo-controlled food challenge (DBPCFC) however, subjects tolerated a median of 1000 mg (range, 250–4000 mg) in comparison with 190 mg peanut at the DBPCFC before OIT. The authors concluded that peanut OIT appeared to be safe and of some benefit in patients with peanut allergy, as the intervention increased threshold levels of ingestion. In 2011, Varshney and colleagues9 reported the results of the first randomized, double-blind, placebo-controlled trial evaluating peanut OIT that proved effective desensitization. After 1 year of treatment, those who completed a peanut OIT protocol ingested the maximum cumulative dose of 5000 mg of peanuts, whereas placebo subjects ingested a median cumulative dose of 280 mg (range, 0–1900 mg). In 2013, Vickery and colleagues17 went on to demonstrate sustained unresponsiveness after stopping peanut OIT. Of 24 subjects who completed up to 5 years of peanut OIT, 12 (50%) successfully passed a 5000mg challenge 1 month after stopping OIT and introduced peanut into their diet. Most recently, in 2014, Anagnostou and colleagues22 published a randomized controlled trial showing an estimate of the effect size, benefits, and risks of desensitization with peanut OIT. In this study group, desensitization (defined as passing a 1400 mg [roughly 10 peanuts] DBPCFC) was achieved for 24 of 49 (62%) subjects receiving peanut OIT for 6 months, and for none of the control group abiding by strict peanut avoidance. There was an increase in median peanut threshold after OIT to 1345 mg (range, 45–1400 mg). Quality-of-life scores improved in the group receiving OIT, and side effects were mild in most participants. Although these studies are promising, a meta-analysis of published peanut OIT trials concluded that only one small randomized controlled trial demonstrated that peanut OIT can result in desensitization with immune modulation.23 They went on to point out that this study (as with most OIT studies) was associated with a substantial risk of adverse events, although most were mild. The meta-analysis, as well as other expert opinion, supports that peanut OIT cannot be currently recommended as a treatment for management of IgE-mediated peanut allergy, and larger randomized control trials are needed.24 Milk/egg oral immunotherapy
In 2007, Staden and colleagues25 sought to examine the efficacy of milk and egg OIT as compared with strict avoidance. Subjects had immunotherapy maintenance doses increased (according to individual tolerance) to a maximum dose of 8250 mg of cow’s milk or 2800 mg hen’s egg protein, with a minimum dose of 3300 mg cow’s milk or 1600 mg hen’s egg protein. Of the 25 subjects randomized to OIT, 16 (64%) were able to integrate the food allergen into their diet in some form: 9 subjects (36%) receiving OIT showed sustained unresponsiveness after a secondary 2-month
Potential Treatments for Food Allergy
elimination diet; 3 subjects (12%) showed tolerance with regular intake; and 4 subjects (16%) were partial responders who did not meet the planned, full maintenance dose. In contrast, only 7 of 20 control subjects (35%) developed natural tolerance during the elimination diet, as evidenced by passing a DBPCFC (cumulative goal dose of cow’s milk protein 4770 mg, cumulative goal dose of hen’s egg protein 6200 mg) after a median interval of 21 months. Skripak and colleagues26 went on to publish the first randomized, double-blind, placebo-controlled study of milk OIT in 2008, showing efficacy in the treatment group with an increase in the median threshold of ingested milk protein from 40 mg to 5140 mg (without a change in the placebo group). A follow-up, open-label study in 2009 showed that after 13 to 75 weeks of open-label dosing (median dose 7000 mg), 6 of 13 subjects (46%) tolerated 16,000 mg milk protein without reaction and 7 subjects reacted at doses 3000 to 16,000 mg.27 Most recently, the clinical status of 32 subjects from 2 of this group’s study protocols26,28 evaluated the long-term outcomes of milk immunotherapy.29 Sixteen subjects were followed up after a median of 4.5 years (range, 1.3–5.3 years)26 and 16 were followed up after a median of 3.2 years (range, 2.6–3.4 years)28 from the end of dose escalation. Twenty-five of 32 subjects (78%) were ingesting some amount of uncooked milk, although only 6 (19%) reported unlimited milk consumption. Two subjects (6%) were ingesting trace or baked milk products, and 5 subjects (16%) reported no milk consumption. Most worrisome, the authors reported that some subjects who initially did well and passed interim oral food challenges (OFCs) subsequently had increased symptoms (including severe symptoms), which led to the restriction of cow’s milk. Other studies have focused on dosing schedules of milk OIT in consideration of feasibility and compliance. Pajno and colleagues30 found that after achieving desensitization to cow’s milk with OIT, a maintenance regimen with milk given twice weekly was as effective as daily maintenance. However, in terms of “clinical readiness,” a systematic review of randomized controlled trials for milk OIT concluded the overall low quality of evidence “leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes.[there were] frequent and sometimes serious adverse effects.and additional, larger [trials] measuring all patientimportant outcomes are still needed.”31 There have been relatively fewer trials for egg immunotherapy. Small pilot and proof-of-concept studies have shown feasibility and safety of egg OIT,11–13,32,33 and, in 2012, Burks and colleagues34 published the first randomized, double-blind, placebo-controlled trial for egg OIT. Forty subjects received egg OIT with a goal maintenance dose of 2000 mg egg protein daily, and 15 subjects received placebo. At a 10month desensitization challenge, 22 of 40 OIT subjects (55%) tolerated 5000 mg of egg protein, as compared with none of the placebo group. At a 22-month desensitization challenge, 30 of 40 OIT subjects (75%) tolerated 5000 mg of egg protein. However, at a 24-month tolerance challenge after 6 to 8 weeks off of OIT, only 11 of 29 subjects (28%) tolerated 5000 mg of egg protein, raising concerns about the longterm protection afforded by the protocol. In keeping with meta-analyses of specific food OIT, a meta-analysis of general food OIT concluded that it cannot yet be recommended in routine practice as a means to induce tolerance in children with IgEmediated food allergy.35 Safety of Oral Immunotherapy
OIT is associated with adverse effects in virtually all published trials, although side effects are often mild and localized to the oropharynx. A study looking at safety in the
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different phases of OIT showed that reactions were most frequent during the initial escalation day when subjects underwent oral desensitization, and doses were better tolerated during the buildup phase and home dosing.36 Factors such as febrile illness, exercise, and menstruation can reduce tolerated threshold doses.37 The predominance of gastrointestinal symptoms merits a thoughtful consideration regarding eosinophilic esophagitis (EoE), as the risk is estimated to be about 10% to 20% in those treated with OIT.38,39 Oral Immunotherapy with Anti-Immunoglobulin E
An anti-IgE agent, omalizumab, is currently approved for moderate-to-severe allergic asthma. It functions by depleting free IgE and downregulating FcεRI on effector cells, such as mast cells and basophils, and on antigen-presenting cells, such as dendritic cells and B cells.40 Omalizumab may also have a role to play in food allergy immunotherapy, as it minimizes IgE-mediated side effects and may contribute to mechanisms of tolerance. Pretreatment with omalizumab for 9 to 12 weeks before starting OIT and combined treatment during the build-up phase of OIT appears to reduce side effects and accelerate buildup dosing. Preliminary studies evaluating safety of omalizumab in combination with milk, peanut, and multifood OIT have been published (Table 1).41–43 Sublingual and Epicutaneous Immunotherapy
In sublingual immunotherapy (SLIT), a food allergen extract is kept in the mouth for 2 to 3 minutes and then spit out or swallowed. It is generally better tolerated and uses significantly lower doses than OIT, but appears to have inferior clinical effects of desensitization.44 Clinical trials of food SLIT have been reported for milk, peanut, hazelnut, and peach extracts (Table 2).28,44–50 Epicutaneous immunotherapy (EPIT) uses a skin patch containing soluble allergen that is absorbed into intact stratum corneum. It is an attractive approach to noninvasive immunotherapy with minimal side effects, and studies have demonstrated that EPIT commonly causes local reactions but almost never induces serious systemic adverse events.51 Pilot trials are currently underway for milk and peanut (see Table 2).51,52 Role for Aeroallergen Immunotherapy for Pollen Cross-Reactive Foods
Pollen immunotherapy has typically been considered a therapeutic option for patients with allergic rhinitis and asthma, but studies have also shown an effect on symptoms of pollen food syndrome (PFS). In PFS, cross-reactive IgE antibodies recognize homologous allergens in pollen and raw fruits, vegetables, and nuts. These allergens are typically broken down during the process of digestion, but patients with pollen allergies can develop oropharyngeal symptoms (commonly pruritus or swelling of the mouth, face, lip, tongue, and throat) with ingestion of various plant-based foods. Multiple studies have successfully used subcutaneous birch pollen immunotherapy to treat apple allergy in this context.53–57 Birch-pollen immunotherapy has been demonstrated to decrease skin prick test (SPT) reactivity for recombinant Bet v 1 (major birch allergen) and recombinant Mal d 1 (major apple allergen), induce IgG4 antibodies against Bet v 1 (which display cross-reactivity to Mal d 1), and increase the amount of fresh apple ingested at a DBPCFC after 1 year.56 In addition, the beneficial effects of immunotherapy on PFS appear to be long lasting after treatment, despite a propensity for apple resensitization over time.54 Immunotherapy with Modified Food Antigens
Recently, there has been a movement toward modifying food antigens to create more effective and safe immunotherapeutic materials. One of the most commonly used
Potential Treatments for Food Allergy
approaches to immunomodulation with modified food antigens is the incorporation of extensively heated egg and milk products into the diet of selected allergic patients. Certain egg and milk conformational epitopes are destroyed by high temperatures, making it possible for some allergic patients to consume small amounts of these foods in the baked form.58 Most patients with cow’s milk and egg allergy tolerate extensively heated products, and the addition of baked milk and baked egg to the diet of children tolerating such foods appears to accelerate the development of unheated milk and egg tolerance compared with strict avoidance.59,60 Immunologic changes induced by a diet containing baked milk and egg are similar to changes that have been observed during OIT trials, although individuals who are tolerant to heated milk products may represent a milder milk allergy phenotype with evidence of greater immune regulation, such as lower specific IgE, higher specific IgG4, lower basophil reactivity to milk proteins, and a higher frequency of milk-specific Tregs.61–63 Additional immunotherapy with modified food antigens includes peptide immunotherapy and mannose-conjugated food allergen immunotherapy, which are both currently under investigation in preclinical studies (Table 3).64–68 Immunotherapy with Recombinant Peanut Rectal Vaccine
In another model of modification, Bannon and colleagues69 have successfully developed and characterized cDNA clones for 3 major peanut allergens, Ara h 1, Ara h 2, and Ara h 3. The group substituted amino acids through site-directed mutagenesis of the cDNA clones and performed recombinant production of the modified allergens. In a murine model of peanut allergy using the heat-killed Escherichia coli producing mutated Ara h 1, 2, and 3 (HKE-MP123), mice had reduced symptom scores on challenge, lower IgE levels, and decreased Th2 cytokines/increased Th1 cytokines from peanut-stimulated splenocytes in vitro.70 Most recently, a phase I safety study was undertaken, giving 5 healthy adult controls and 10 peanut-allergic adult subjects weekly dose escalations of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2, and Ara h 3.71 There were no significant effects on the healthy controls, but there were severe allergic reactions in 20% of the peanut-allergic subjects, and the authors concluded that “future studies with this product, if any, will require alterations in the dosing scheme and/or route of delivery.”71 POTENTIAL ALLERGEN NON-SPECIFIC TREATMENTS FOR FOOD ALLERGY
Although significant resources are being put toward allergen-specific immunotherapy, there is a parallel effort toward developing nonspecific treatments that could potentially be used to treat various and multiple food allergies. One promising example of this is Chinese herbal formulas, and others include probiotics/prebiotics, helminths, monoclonal antibodies, and toll-like receptor (TLR) agonists. Chinese Herbal Formulas
Chinese herbal medicine studies in the setting of food allergy were initially done using food allergy herbal formula-1 (FAHF-1), an 11-herb formula containing the classical Wu-Mei Wan (a combination of 10 herbs previously used for intestinal parasitic infection, gastroenteritis, and asthma) and Ling Shi (an additional herb with purported antiinflammatory properties).72 The herbs Xi-Xin and Zhi-Fu-Zi were removed from the formula for safety concerns, and the resultant 9-herb formula, FAHF-2, has been used in both murine research and early clinical trials (Table 4).73–76 These herbal formulas are thought to have synergistic anti-inflammatory effects, with reduced side effects in formulation as compared with individual herbs.72 In general, results from
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Success Rate
Immunologic Changes
Side Effects/Comments
Nadeau et al,41 2011 n 5 11; age 7–17 y Pilot phase I study using omalizumab in combination with oral milk desensitization (desensitization performed 9 wk after start of omalizumab treatment) Goal maintenance dose: 2000 mg milk protein/d
The mean frequency for total reactions reported by week 24 was 1.6% (32 reactions of 2199 doses total for all 11 subjects). All subjects experienced some adverse events, though most reactions were defined as mild and needed no treatment. One dose of epinephrine was given during rush desensitization, and 2 subjects received epinephrine at home during the maintenance phase. Nine of the 11 subjects tolerated desensitization to a dose of 2000 mg milk within a period of 7–11 wk.
Within a week of treatment, the CD41 T-cell response to milk was nearly eliminated. Over the following 3 mo, the CD41 T-cell response returned, characterized by a shift from IL-4 to IFN-g. MilkIgE decreased, and milk-IgG4 increased 15-fold.
This was a phase I study, and the primary objectives were to examine the safety of this approach and to determine whether subjects could be dosed up to 2000 mg milk within 7–11 wk of initiating desensitization.
Schneider et al,42 2013 n 5 13; age 8–16 y Pilot study using omalizumab in combination with oral peanut desensitization (desensitization performed 12 wk after start of omalizumab treatment) Goal maintenance dose: 4000 mg peanut protein/d
All 13 subjects (100%) reached the 500 mg peanut desensitization dose on the first day (cumulative dose, 992 mg), which was the primary outcome of the study, with minimal or no symptoms. Twelve of the 13 subjects (92%) reached the 4000 mg maintenance dose, which was a secondary outcome of the study, requiring median time of 8 wk. Twelve weeks after stopping omalizumab (week 32), 12 subjects underwent a DBPCFC (cumulative dose, 8000 mg peanut). Eleven of the subjects (85%) tolerated this challenge, and the twelfth subject later passed an open challenge of 8000 mg peanut. Therefore, 12 of the 13 subjects (92%) tolerated an 8000-mg dose of peanut.
Not reported
There were a total of 72 reactions during the study (2% of the 3502 total peanut doses ingested). During the study, 6 of the 13 subjects experienced mild or no allergic reactions; 5 subjects had grade 2 reactions, and 2 subjects had grade 3 reactions, all of which responded rapidly to treatment.
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Table 1 Oral immunotherapy and anti-IgE safety studies
Be´gin et al,43 2014 n 5 25; age 4–15 y Phase I study using up to 5 different food allergens rush OIT simultaneously with omalizumab (omalizumab was administered for 8 wk before and 8 wk following the initiation of rush OIT) Goal maintenance dose: 4000 mg protein per allergen
The median time to reach maintenance dose (4000 mg per allergen) was 18 wk (range, 7–36 wk) with all subjects able to reach this dose by 9 mo. All subjects had reached a dose equivalent to a 10-fold increase of all their allergens by 2 mo of therapy. Over the study period, there were 3 withdrawals because of noncompliance with study medication.
Peanut-specific IgG4 levels increased and peanut SPT decreased. Peanut-specific IgE did not change significantly.
This was a proof of concept study and evaluated subjects for desensitization. Thirteen subjects (52%) experienced some symptoms on their initial dose escalation day. With home dosing, 401 of the 7530 doses (5.3%) triggered reactions, and most home reactions occurred in the first months of therapy. Most (94%) allergic reactions were mild. One severe reaction requiring epinephrine occurred shortly after a subject reached maintenance phase (16,000 mg).
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Immunologic Changes
Side Effects/Comments
Milk Keet et al,28 2012 n 5 30; age 6–17 y Randomized clinical trial comparing milk OIT and SLIT with challenge performed after 12 and 60 wk Goal maintenance dose: SLIT: 7 mg daily Low-dose OIT: 1000 mg High-dose OIT: 2000 mg
One of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/lowdose OIT group, and 8 of 10 subjects in the SLIT/high-dose OIT group passed the 8 g milk protein challenge (P 5 .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 subjects in each OIT group) regained reactivity, 2 after only 1 wk off therapy.
Titrated milk SPT wheal diameter and basophil activity decreased in all groups. Milk-specific IgG4 increased in all groups. Milk-specific IgE and spontaneous histamine release decreased in only the OIT group.
OIT was more efficacious for desensitization than SLIT alone, but was accompanied by more systemic side effects. There were symptoms with 1802 (29%) of 6246 SLIT doses and 2402 (23%) of 10,645 OIT doses. However, OIT had significantly more multisystem, upper respiratory tract, gastrointestinal, and lower respiratory tract symptoms than SLIT.
Peanut Fleischer et al,50 2013 n 5 40; age 12–37 y Randomized, double-blind, placebo-controlled multicenter trial comparing peanut SLIT and placebo after 44 wk; placebotreated patients were unblinded, then crossed over into a higher dose peanut SLIT for 44 wk Goal maintenance dose: minimum dose of 165 mg and maximum dose of 1386 mg daily Crossover group: maximum maintenance dose of 3696 mg daily
After 44 wk of SLIT, 14 of 20 subjects receiving peanut SLIT passed a 5 g peanut powder challenge (or ingested at least 10-fold more peanut powder than the baseline OFC), compared with 3 of 20 subjects receiving placebo (P
