Ann Allergy Asthma Immunol 117 (2016) 476e478
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Mini-Symposium - International Food Allergy Symposium
The latest on food allergy immunotherapy Jeffrey M. Chambliss, MD; A. Wesley Burks, MD Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina
A R T I C L E
I N F O
Article history: Received for publication March 31, 2016. Received in revised form May 25, 2016. Accepted for publication July 19, 2016.
Introduction Food allergies are becoming increasingly common and have a signiﬁcant effect on patients and families. In 2007 the estimated prevalence of food allergies among school-aged children was approximately 3.9%, an 18% increase since 1997, with other studies estimating up to 8% of children affected (and 5% of adults).1,2 However, exposures and symptoms may occur well before children enter school. When egg allergy was speciﬁcally looked at, the cumulative prevalence was estimated at 2.6% by 2.5 years old.3 There is an incomplete understanding of why food allergies are increasing. One theory related to the hygiene hypothesis is that less exposure to certain microorganisms that we have an “evolved dependence” for may lead to immune dysregulation and an increasing prevalence of autoinﬂammatory conditions, including food allergies.4 This is unlikely the only cause of increasing food allergies. Other factors, such as changes in gut ﬂora with obesity and diet, vitamin D deﬁciency, and route of exposure, are possibly implicated.2 Some food allergies are more likely to be transient, such as milk and egg, and resolve with time regardless of exposure. Others, such as peanut, tree nut, ﬁsh, and shellﬁsh allergies, more frequently have life-long effects. In IgE sensitized individuals, exposure to an allergen can result in symptoms that range from urticaria to anaphylaxis. The current management involves strict avoidance with reactionary treatment to ingestions by antihistamines or intramuscular epinephrine. This leaves affected individuals at risk and with a significant unmet need for the development of a proactive treatment. Food Allergy Immunotherapy Within the last few years, research and clinical trials have been under way to evaluate the safety and efﬁcacy of immunotherapy to
treat food allergies. Targeted immunotherapy seems to be an increasingly possible strategy, driven by several concerns. One is what patients and parents want and fear the most, including lifethreatening or life-ending allergic reactions and the possibility of children being away from parents when the allergic reaction occurs. Another factor to consider for the future of immunotherapy is what physicians and investigators see as best interventions. Whether one has a therapy aimed to prevent signiﬁcant unintentional ingestion allergic reactions or to ameliorate the disease, the accepted treatment may look different, with varying ﬁnancial effects on patients and the health care society. There have been several approaches to food allergy immunotherapy. Allergen-speciﬁc therapies with both native and nonnative food allergens and allergen nonspeciﬁc approaches, such as with Chinese herbals, have been used.5 Each strategy and modality have certain strengths and weaknesses to be kept in mind when considering the goals of therapy. Desensitization appears achievable with regard to food immunotherapy and indicates the ability to tolerate more allergen quantity during a food challenge while continuing with the treatment. This goal is an improvement if it provides protection against an unintentional ingestion but could still leave patients at risk because it falls short of tolerance of that food added into the diet. Clinical tolerance or sustained unresponsiveness would be a true lack of reactivity after the treatment is stopped with or without ongoing allergen exposure.6 In the following discussion, some of the evidence around egg and peanut oral immunotherapy (OIT), peanut sublingual immunotherapy (SLIT), and peanut epicutaneous immunotherapy (EPIT) is reviewed. These examples represent a sample, illustrative of many more studies.7 Egg and Peanut OIT
Reprints: A. Wesley Burks, MD, University of North Carolina School of Medicine, 4030 Bondurant Hall, Campus Box 7000, Chapel Hill, NC 27599; E-mail: wesley. [email protected]
Disclosures: Dr Burks reported having research interests at the National Institutes of Health and Food Allergy Research and Education (FARE), working as an independent contractor for PPD Development LP, working as a consultant for ActoGeniX, Adept Field Solutions, Aimmune Therapeutics Inc, Genetech, GLG Research, Insys Therapeutics, Sanoﬁ US Services, SRA International, and Valeant Pharmaceuticals America LLC; and serving as an advisory board member for Epiva Biosciences Inc and Murdoch Children’s Research Institute.
OIT involves the daily ingestion of food to which the patient is allergic, which may be in pill or powder form, although generally it is given in powder form within food. Escalating doses are often consumed in a controlled setting, with stable dosing completed at home. In a double-blind, randomized, placebo-controlled study of 55 patients aged 5 to 11 years with an egg allergy by Burks et al, 40 children received OIT and 15 received placebo.8 Patients underwent dose-escalation, build-up, and maintenance phases before an oral
http://dx.doi.org/10.1016/j.anai.2016.07.027 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
J.M. Chambliss and A.W. Burks / Ann Allergy Asthma Immunol 117 (2016) 476e478
food challenge (OFC) with egg-white powder. After 10 months of therapy, patients underwent a 5-g OFC in which 22 of 40 patients (55%) treated with OIT passed and none of those treated with placebo passed. Then at 22 months patients underwent a 10-g OFC in which 30 of 40 patients (75%) receiving OIT passed and none receiving placebo passed. For those who passed, OIT was stopped and avoidance undertaken before an OFC at 24 months, with 11 of 40 (27.5%) passing. These patients were considered to have sustained unresponsiveness and allowed ad libitum egg consumption in their diet. Long-term follow-up was completed for those now consuming ad libitum as well as those who failed the 22-month OFC who continued to receive OIT.9 At 36 and 48 months, OFC indicated that 18 of 40 (45%) and 20 of 40 (50%), respectively, of the patients who had OIT were able to tolerate 10 g of egg-white powder and then had sustained unresponsiveness. This sample included 41% of the 22 patients receiving OIT after 24 months. Further evidence of OIT came when Varshney et al10 evaluated peanut OIT in a double-blinded, placebo-controlled study. Again, escalation, build-up, and maintenance phases were completed before a double-blind, placebo-controlled food challenge (DBPCFC) after 1 year. The 16 patients who received peanut OIT were all able to tolerate the maximum dose of 5,000 mg of peanut protein, whereas the placebo group of 9 tolerated a median cumulative dose of 280 mg. Similarly, Anagnostou et al11 evaluated OIT in a randomized, controlled, crossover trial with patients aged 7 to 16 years. A total of 39 patients were enrolled in the active group, with 84% tolerating ingestion of 800 mg of peanut protein daily before a DBPCFC at 6 months. From this group, 24 of 39 (62%) passed this 1,400-mg protein challenge compared with 0 of 46 in the control group. This active group also had increase in peanut threshold. After the second phase during which the initial control group underwent OIT, 91% were able to tolerate daily dosing, with 54% passing the 1,400-mg challenge. Gastrointestinal symptoms, such as nausea and vomiting, were most common. Peanut SLIT SLIT is a treatment where allergen extracts are taken by mouth, held underneath the tongue for up to several minutes, and then spit out or swallowed. Fleischer et al12 studied 40 patients aged 12 to 37 years with a peanut allergy treated with peanut SLIT. A baseline OFC was completed with a median dose consumed of 46 mg. Patients were randomized to placebo or peanut SLIT before another food challenge at 44 weeks, during which 70% of those treated were able to tolerate 5 g or a 10-fold increase from the baseline OFC compared with 15% of the placebo group. The placebo group was then crossed to a treatment arm and retested after 44 weeks of SLIT, with 7 of 16 (44%) passing the challenge. During a food challenge at 68 weeks of therapy, the successfully consumed dose increased from 496 to 996 mg among the SLIT responders. Even stronger evidence for SLIT was obtained by Kim et al13 in a pediatric population with a group of 18 children aged 1 to 11 years who underwent 6 months of escalation and 6 months of maintenance dosing with peanut SLIT before a DBPCFC. After 12 months of therapy, the treatment group was able to safely tolerate 20 times more peanut protein, a median dose of 1,710 mg compared with 85 mg in the placebo group in the DBPCFC. In addition, skin prick test wheal sizes were decreased among the treatment group, and immunologic changes were seen, such as speciﬁc IgE levels decreasing during the ﬁnal 8 months of therapy and IgG4 levels increasing. Peanut EPIT EPIT involves daily administration to the skin surface of a patch that contains the allergen. Last year, information about Viaskin (a peanut EPIT product) was presented from a phase IIb study of 221 patients aged 6 to 55 years who underwent 12 months of EPIT.14 Participants were treated with placebo or 1 of 3 doses of EPIT (50
mg, 100 mg, 250 mg) for the duration of the study. Children aged 6 to 11 years in particular had increases in the cumulative reactive dose at the 12-month DBPCFC of 62.8 mg increase among the placebo group, 471.2 mg in the 50-mg patch treatment arm, 617.5 mg in the 100-mg treatment arm, and 1,121 mg in the 250-mg treatment arm. They also had signiﬁcant immunologic responses, including peanut speciﬁc IgE increasing during the ﬁrst 3 months (median increase, 50 kUA/L for the 250-mg patch) before returning to baseline near 12 months and IgG4 increasing dose dependently at 12 months. Desensitization vs Tolerance Studies have consistently found that clinical desensitization with food immunotherapy is possible. That is, when being treated with immunotherapy, the tolerated dose for an individual patient is increased. Not all patients are able to complete dosing protocols because of allergic adverse effects or adherence issues. In fact, with OIT, 10% to 20% of patients do not reach maintenance dosing because of adverse reactions.5,15 However, after stopping treatment, the question remains whether tolerance or sustained unresponsiveness to a food allergen can be achieved. What period after immunotherapy is completed represents sustained unresponsiveness and not desensitization? A previously mentioned study regarding egg OIT found that 50% of the patients treated had sustained unresponsiveness to egg in their diet after treatment.9 Among 24 patients with a peanut allergy who completed OIT for a range of 33 to 70 months and then an OFC 4 weeks after stopping therapy, 12 passed the challenge and achieved sustained unresponsiveness.16 Vickery et al17 recently presented data investigating early intervention OIT for peanut allergic patients aged 9 to 36 months. Forty patients were enrolled, either allergic by sensitization and history of exposure with reaction or sensitization alone (peanut speciﬁc IgE, 5 kUA/L). After reacting to baseline OFC, groups were randomized to receive maintenance therapy of 300 or 3,000 mg/d of peanut protein. After a minimum of 12 months or a maximum of 36 months of OIT, participants underwent DBPCFC 1 month after stopping therapy, with 26 of 37 (70%) passing this challenge. This success with early intervention OIT had not previously been seen, and further information will come when the study is completed. Limitations and Knowledge Gaps Desensitization appears to occur within days to months of starting treatment, allowing the reactive dose threshold to increase among all forms of food immunotherapy.8,18 The results depend on both daily and total dose of immunotherapy, the length of treatment, and when the OFC is completed with baseline food challenges important for analyzing responses. Although protocols in general follow similar formats with initial escalation, build-up, and maintenance dosing, there is a lack of uniformity among them. OIT appears more efﬁcacious in achieving a greater amount of desensitization than SLIT19 and SLIT greater than EPIT. However, the allergic adverse effects also appear in this order. With OIT, the most common adverse effects are gastrointestinal symptoms, particularly signiﬁcant abdominal pain and vomiting, which can limit patients’ ability to continue with therapy.15 More signiﬁcant reactions that require epinephrine are rare. In addition, eosinophilic esophagitis has been reported to occur in up to 2.7%.20 Even with stable dosing, reaction thresholds may be decreased intermittently by viral infections or exercise.21 SLIT may be less efﬁcacious but perhaps offers a cleaner adverse effect proﬁle. It exhibits primarily oropharyngeal adverse effects, with systemic reactions being rare.19 EPIT does not cause systemic reactions, but difﬁculties remain with keeping a daily patch in place, and large local reactions along with pruritus are common.22 However, further knowledge is needed to understand the mechanisms of inducing desensitization and tolerance. Studies will need to focus on changes speciﬁc to the form of immunotherapy, dosing, length of treatment, and interval after
J.M. Chambliss and A.W. Burks / Ann Allergy Asthma Immunol 117 (2016) 476e478
stopping therapy. With the existing data, there is an equipoise between avoiding food allergens and actively intervening in an attempt to treat them. More information is needed to guarantee the safety of immunotherapy before its use in clinical practice. At this time, it remains investigational. Ultimately, there are suggestions that tolerance or sustained unresponsiveness can be achieved, but there are no long-term blinded studies to conﬁrm this. References  Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124:1549e1555.  Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133:291e307.  Eggesbø M, Botten G, Halvorsen R, Magnus P. The prevalence of allergy to egg: a population-based study in young children. Allergy. 2001;56:403e411.  Rook GA. 99th Dahlem Conference on Infection, Inﬂammation and Chronic Inﬂammatory Disorders: Darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol. 2010;160:70e79.  Nowak-We˛ grzyn A, Sampson HA. Future therapies for food allergies. J Allergy Clin Immunol. 2011;127:558e573.  Moran TP, Burks AW. Is clinical tolerance possible after allergen immunotherapy? Curr Allergy Asthma Rep. 2015;15:23.  Jones SM, Burks AW, Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous. J Allergy Clin Immunol. 2014;133: 318e323.  Burks AW, Jones SM, Wood R, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012;367:233e243.  Jones SM, Burks AW, Keet C, et al. Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy. J Allergy Clin Immunol. 2016;137:1117e1127.  Varshney P, Jones SM, Scurlock AM, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127:654e660.
 Anagnostou K, Islam S, King Y, et al. Assessing the efﬁcacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial. Lancet. 2014;383:1297e1304.  Fleischer DM, Burks AW, Vickery BP, et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol. 2013;131:119e127.e7.  Kim EH, Bird JA, Kulis M, et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2011;127:640e646.e1.  Sampson HA, Agbotounou W, Thébault C, et al. Epicutaneous immunotherapy (EPIT) is effective and safe to treat peanut allergy: a multi-national doubleblind placebo-controlled randomized phase IIb trial [abstract]. J Allergy Clin Immunol. 2015;135:AB390.  Vickery BP, Scurlock AM, Steele P, et al. Early and persistent gastrointestinal side effects predict withdrawal from peanut oral immunotherapy (OIT) [abstract]. J Allergy Clin Immunol. 2011;127:AB87.  Vickery BP, Scurlock AM, Kulis M, et al. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol. 2014;133(2):468e475.  Vickery BP, Beavers A, Berglund J, et al. High rate of sustained unresponsiveness with early-intervention peanut oral immunotherapy [abstract]. J Allergy Clin Immunol. 2015;135:AB155.  Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG. A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy. 2004;59:980e987.  Keet CA, Frischmeyer-Gerrerio PA, Thyagarajan A, et al. The safety and efﬁcacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2012;129:448e455. 455.e1-5.  Lucendo AJ, Arias A, Tenias JM. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2014;113:624e629.  Varshney P, Steele PH, Vickery BP, et al. Adverse reactions during peanut oral immunotherapy home dosing. J Allergy Clin Immunol. 2009;124:1351e1352.  Agbotounoi W, Martin L, Dupont B, Pascal I, Vauléon C, Benhamou PH. Epicutaneous immunotherapy (EPIT) is safe for the treatment of peanut allergy in allergic patients [abstract]. J Allergy Clin Immunol. 2013;131:AB91.