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Oral Immunotherapy for the Treatment of Peanut Allergy: Is It Ready for Prime Time?
Editorial
Oral Immunotherapy for the Treatment of Peanut Allergy: Is It Ready for Prime Time? Robert A. Wood, MDa, and Hugh A. Sampson, MDb
Baltimore, Md; and New York, NY
Results of recent studies that suggest that immunotherapy for food allergy may be possible represent one of the most exciting areas of research in our specialty. However, although studies on this topic have certainly provided many encouraging results, we and others have expressed concern that further studies are needed to answer questions regarding both safety and long-term efficacy before bringing these treatments into clinical practice.1-3 It is clear, however, that many do not agree with this conservative viewpoint and, in this issue of the journal, Wasserman et al4 report their experience on the use of peanut oral immunotherapy (OIT) in practice settings and in providing this treatment as a clinical tool rather than as a research procedure. In brief, they summarize the results of a retrospective chart review of 352 patients treated with peanut OIT in 5 different practices: 4 office-based practices in the United States and 1 hospital-based practice in Israel. Although the selection criteria for enrolling patients are not given and OIT methods used in each site varied considerably, the investigators provide overall outcomes from the cumulative experience of these 5 practices. Their report emerges with 2 main messages. First is that they had a success rate of 85% based on the number of patients who reached the targeted maintenance dose and, second, that reactions to dosing that required epinephrine were relatively uncommon, which occurred in 0.7 of 1000 doses during dose escalation and in 0.2 of 1000 doses during maintenance. With regard to these outcomes, we believe that it is important to consider several additional perspectives. Although achieving
a
Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md b Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY No funding was received for this work. Conflicts of interest: R. A. Wood has received consultancy fees from the Asthma and Allergy Foundation of America; is employed by Johns Hopkins University; has received research support from the National Institutes of Health (NIH); and receives royalties from UpToDate. H. A. Sampson has received research support from the National Institute of Allergy and Infectious Diseases, NIH (Consortium of Food Allergy Research); has received funding supporting clinical trials in milk and wheat allergy from the Food Allergy Research Education; has received travel support as chair of PhARF Award Review Committee; has received consultancy fees from Allertein Therapeutics and Regeneron; has received lecture fees from ThermoFisher Scientific, UCB, and Pfizer. Received for publication November 7, 2013; accepted for publication November 21, 2013. Corresponding author: Robert A. Wood, MD, Division of Allergy and immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md. E-mail: [email protected]. J Allergy Clin Immunol Pract 2014;2:97-8. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.11.010
maintenance is a reasonable outcome, it is important to note that this, in fact, could range among the sites from 415 to 8000 mg of peanut protein. Given this enormous range, with approximately one-third of the results based on the lowest maintenance dose, it is very difficult to understand what this outcome really means and hard to justify it as a definition of success. It would be far preferable to have a well-defined outcome, such as a challenge threshold before and after treatment, although we recognize that this may not be possible in practice settings. In addition, they report that an additional 5% of patients dropped out while on maintenance and, far more importantly, that the maintenance period only lasted for “a few weeks” in some patients. The second outcome, based on the rate of reactions that required epinephrine, is also problematic. The investigators do provide an estimate that compared their rate of epinephrine use with epinephrine use in untreated patients and state that treated patients have an approximately 2-fold increased chance of a reaction that requires epinephrine compared with untreated patients. This outcome would likely be acceptable if the treatment resulted in a significant long-term reduction in reactions from accidental exposures. However, such long-term results are currently unknown. In addition, their assessment of this risk was based on data from a single study that may not accurately represent the true risk of anaphylaxis in patients with untreated peanut allergy.5 Although the study that they quoted reported a risk of accidental peanut reactions as occurring in 11.9% of patients each year, in fact, only 20% of those reactions were treated with epinephrine. Furthermore, this rate of reaction is far higher than that of a recent large US study that reported a rate of accidental exposures with severe reactions of 1.6% per year and of reactions treated with epinephrine of 1.1% per year.6 Based on our review of all available data, as well as our cumulative clinical experience, we estimate that the risk of reactions of all types, including severe anaphylaxis, is far higher in patients being treated with OIT than in patients who practice avoidance. In addition, it is important to recognize that the risk if OIT extends far beyond the use of epinephrine. Because adverse events were not systematically collected for these patients, we do not have any idea about the rate of less-severe reactions, the number of reactions that required treatment with other medications or that resulted in emergency department visits or even severe reactions for which epinephrine was not administered. Information also was not provided on the development of eosinophilic esophagitis, which had previously been reported by one of these practices to occur in at least 10% of their patients treated with peanut OIT.7 Because this was not a clinical trial, institutional review board and/or US Food and Drug Administration approval was not necessarily required. Although 2 sites did have institutional review board approval for OIT treatment, the other 3 only had 97
98
WOOD AND SAMPSON
approval for retrospective chart reviews. The investigators state that all the patients and their parents were provided detailed information, including discussions about “the unproven nature of the treatment,” and that a consent was signed by all the participants. However, we are concerned that the information provided may not have been completely unbiased, in that a brief look at the Web sites of these practices revealed statements such as OIT “is a safe and effective treatment to desensitize patients with peanut allergy,” and that it “can provide a long-term solution for patients with peanut, egg, milk, or other food allergies. At the end of this 3-6 month program, patients should be able to consume these foods with no allergic reactions.” We believe that such claims are potentially misleading and certainly not justified by the current state of research in this field, including the report of Wasserman et al4 itself. We strongly recommend that these experimental treatments still be provided only under the oversight of institutional review boards and the US Food and Drug Administration. In addition to risk-benefit considerations, it also is important to consider cost in the development of new treatments for any condition. Because we do not know how patients included in the report by Wasserman et al4 were billed for their treatments, we are not able to provide a clear assessment in this regard. It is clear, however, that this treatment requires frequent, time-consuming office visits, and, in some cases, the costs for provision of the treatment materials. Without treatment, we would expect that most patients with peanut allergy would require only an annual office visit and a rare emergency department visit. Because costs for epinephrine or other medications are not reduced by this treatment, it would appear that the overall cost of care would increase dramatically with treatment compared with the current standard of care. It may well be that the long-term outcomes of treatment will clearly justify these costs, but this will not be known until the appropriate clinical trials have been conducted. Furthermore, we would presume that the cost for this treatment currently represents an out-of-pocket expense for most patients, although the Web site of one of the investigators does state that “most insurance policies cover this treatment.” In the highlights of this report, the investigators conclude that “this study suggests that some allergists may be able to offer oral immunotherapy for peanut allergy.” In fact, there are a variety of unproven therapies that we could offer but that does not necessarily mean that it is the right thing to do. Furthermore, very few, if any, of other unproven treatments for food allergy carry the risk of anaphylaxis. Even more importantly, this treatment is not only unproven in the short term, it is completely unproven with regard to longer-term results. This concern was clearly evidenced in the recent study by Keet et al8 on the long-term outcomes of milk OIT, in which they found that many patients regained significant reactivity, sometimes with very severe reactions, after having an apparent short-term treatment success. In our estimation, these
J ALLERGY CLIN IMMUNOL PRACT JANUARY/FEBRUARY 2014
long-term concerns are far more worrisome than the short-term concerns related simply to the risk of reactions while on treatment. The greatest risks of OIT may not be apparent until after treatment, when the patients may be at true risk of anaphylaxis but living with a false sense of security and potentially without epinephrine. These concerns are further magnified by studies demonstrating that protection after OIT may be lost with even brief periods of avoidance.9 We remain convinced that food OIT is not ready for clinical practice, and we are not at all comforted by the report of Wasserman et al.4 This opinion is completely consistent with the results of several recent systematic reviews and meta-analyses,10,11 the most recent of which still concluded that “peanut OIT represents a promising, potentially disease-modifying therapeutic approach for the management of IgE-mediated peanut allergy. However, currently, there is insufficient evidence in terms of longterm effectiveness, safety, and cost-effectiveness of peanut OIT to recommend its routine use in clinical practice.”11 If we believe that our specialty should remain grounded in science and evidencebased medicine, then it is clear that food OIT remains in a state of equipoise and is not ready for routine clinical use. REFERENCES 1. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010;126(Suppl):S1-58. 2. Sampson HA. Peanut oral immunotherapy: is it ready for clinical practice? J Allergy Clin Immunol Pract 2013;1:15-21. 3. Thyagarajan A, Varshney P, Jones SM, Sicherer SH, Wood RA, Vickery BP, et al. Peanut oral immunotherapy is not ready for clinical use. J Allergy Clin Immunol 2010;126:31-2. 4. Wasserman RL, Factor JM, Baker JW, Mansfield LE, Katz Y, Hague AR, et al. Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions. J Allergy Clin Immunol Pract 2014;2:91-6. 5. Nguyen-Luu NU, Ben-Shoshan M, Alizadehfar R, Joseph L, Harada L, Allen M, et al. Inadvertent exposures in children with peanut allergy. Pediatr Allergy Immunol 2012;23:133-9. 6. Neuman-Sunshine DL, Eckman JA, Keet CA, Matsui EC, Peng RD, Lenehan P, et al. The natural history of persistent peanut allergy. Ann Allergy Asthma Immunol 2012;108:326-31. 7. Wasserman RL, Sugerman RW, Mireku-Akomeah AR, Gallucci A, Pence D, Long NA. Peanut oral immunotherapy (OIT) of food allergy (FA) carries a significant risk of eosinophilic esophagitis (EoE). J Allergy Clin Immunol 2011; 127:AB28. 8. Keet CA, Seopaul S, Knorr S, Narisety S, Skripak J, Wood RA. Long-term follow-up of oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol 2013;132:737-9. 9. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton T, Steele P, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 2012;129:448-55. 10. Sheikh A, Nurmatov U, Venderbosch I, Bischoff E. Oral immunotherapy for the treatment of peanut allergy: systematic review of six case series studies. Prim Care Respir J 2012;21:41-9. 11. Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A. Allergen specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev 2012;9:CD009014.
Oral Immunotherapy for the Treatment of Peanut Allergy: Is It Ready for Prime Time? Robert A. Wood, MDa, and Hugh A. Sampson, MDb
Baltimore, Md; and New York, NY
Results of recent studies that suggest that immunotherapy for food allergy may be possible represent one of the most exciting areas of research in our specialty. However, although studies on this topic have certainly provided many encouraging results, we and others have expressed concern that further studies are needed to answer questions regarding both safety and long-term efficacy before bringing these treatments into clinical practice.1-3 It is clear, however, that many do not agree with this conservative viewpoint and, in this issue of the journal, Wasserman et al4 report their experience on the use of peanut oral immunotherapy (OIT) in practice settings and in providing this treatment as a clinical tool rather than as a research procedure. In brief, they summarize the results of a retrospective chart review of 352 patients treated with peanut OIT in 5 different practices: 4 office-based practices in the United States and 1 hospital-based practice in Israel. Although the selection criteria for enrolling patients are not given and OIT methods used in each site varied considerably, the investigators provide overall outcomes from the cumulative experience of these 5 practices. Their report emerges with 2 main messages. First is that they had a success rate of 85% based on the number of patients who reached the targeted maintenance dose and, second, that reactions to dosing that required epinephrine were relatively uncommon, which occurred in 0.7 of 1000 doses during dose escalation and in 0.2 of 1000 doses during maintenance. With regard to these outcomes, we believe that it is important to consider several additional perspectives. Although achieving
a
Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md b Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY No funding was received for this work. Conflicts of interest: R. A. Wood has received consultancy fees from the Asthma and Allergy Foundation of America; is employed by Johns Hopkins University; has received research support from the National Institutes of Health (NIH); and receives royalties from UpToDate. H. A. Sampson has received research support from the National Institute of Allergy and Infectious Diseases, NIH (Consortium of Food Allergy Research); has received funding supporting clinical trials in milk and wheat allergy from the Food Allergy Research Education; has received travel support as chair of PhARF Award Review Committee; has received consultancy fees from Allertein Therapeutics and Regeneron; has received lecture fees from ThermoFisher Scientific, UCB, and Pfizer. Received for publication November 7, 2013; accepted for publication November 21, 2013. Corresponding author: Robert A. Wood, MD, Division of Allergy and immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md. E-mail: [email protected]. J Allergy Clin Immunol Pract 2014;2:97-8. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.11.010
maintenance is a reasonable outcome, it is important to note that this, in fact, could range among the sites from 415 to 8000 mg of peanut protein. Given this enormous range, with approximately one-third of the results based on the lowest maintenance dose, it is very difficult to understand what this outcome really means and hard to justify it as a definition of success. It would be far preferable to have a well-defined outcome, such as a challenge threshold before and after treatment, although we recognize that this may not be possible in practice settings. In addition, they report that an additional 5% of patients dropped out while on maintenance and, far more importantly, that the maintenance period only lasted for “a few weeks” in some patients. The second outcome, based on the rate of reactions that required epinephrine, is also problematic. The investigators do provide an estimate that compared their rate of epinephrine use with epinephrine use in untreated patients and state that treated patients have an approximately 2-fold increased chance of a reaction that requires epinephrine compared with untreated patients. This outcome would likely be acceptable if the treatment resulted in a significant long-term reduction in reactions from accidental exposures. However, such long-term results are currently unknown. In addition, their assessment of this risk was based on data from a single study that may not accurately represent the true risk of anaphylaxis in patients with untreated peanut allergy.5 Although the study that they quoted reported a risk of accidental peanut reactions as occurring in 11.9% of patients each year, in fact, only 20% of those reactions were treated with epinephrine. Furthermore, this rate of reaction is far higher than that of a recent large US study that reported a rate of accidental exposures with severe reactions of 1.6% per year and of reactions treated with epinephrine of 1.1% per year.6 Based on our review of all available data, as well as our cumulative clinical experience, we estimate that the risk of reactions of all types, including severe anaphylaxis, is far higher in patients being treated with OIT than in patients who practice avoidance. In addition, it is important to recognize that the risk if OIT extends far beyond the use of epinephrine. Because adverse events were not systematically collected for these patients, we do not have any idea about the rate of less-severe reactions, the number of reactions that required treatment with other medications or that resulted in emergency department visits or even severe reactions for which epinephrine was not administered. Information also was not provided on the development of eosinophilic esophagitis, which had previously been reported by one of these practices to occur in at least 10% of their patients treated with peanut OIT.7 Because this was not a clinical trial, institutional review board and/or US Food and Drug Administration approval was not necessarily required. Although 2 sites did have institutional review board approval for OIT treatment, the other 3 only had 97
98
WOOD AND SAMPSON
approval for retrospective chart reviews. The investigators state that all the patients and their parents were provided detailed information, including discussions about “the unproven nature of the treatment,” and that a consent was signed by all the participants. However, we are concerned that the information provided may not have been completely unbiased, in that a brief look at the Web sites of these practices revealed statements such as OIT “is a safe and effective treatment to desensitize patients with peanut allergy,” and that it “can provide a long-term solution for patients with peanut, egg, milk, or other food allergies. At the end of this 3-6 month program, patients should be able to consume these foods with no allergic reactions.” We believe that such claims are potentially misleading and certainly not justified by the current state of research in this field, including the report of Wasserman et al4 itself. We strongly recommend that these experimental treatments still be provided only under the oversight of institutional review boards and the US Food and Drug Administration. In addition to risk-benefit considerations, it also is important to consider cost in the development of new treatments for any condition. Because we do not know how patients included in the report by Wasserman et al4 were billed for their treatments, we are not able to provide a clear assessment in this regard. It is clear, however, that this treatment requires frequent, time-consuming office visits, and, in some cases, the costs for provision of the treatment materials. Without treatment, we would expect that most patients with peanut allergy would require only an annual office visit and a rare emergency department visit. Because costs for epinephrine or other medications are not reduced by this treatment, it would appear that the overall cost of care would increase dramatically with treatment compared with the current standard of care. It may well be that the long-term outcomes of treatment will clearly justify these costs, but this will not be known until the appropriate clinical trials have been conducted. Furthermore, we would presume that the cost for this treatment currently represents an out-of-pocket expense for most patients, although the Web site of one of the investigators does state that “most insurance policies cover this treatment.” In the highlights of this report, the investigators conclude that “this study suggests that some allergists may be able to offer oral immunotherapy for peanut allergy.” In fact, there are a variety of unproven therapies that we could offer but that does not necessarily mean that it is the right thing to do. Furthermore, very few, if any, of other unproven treatments for food allergy carry the risk of anaphylaxis. Even more importantly, this treatment is not only unproven in the short term, it is completely unproven with regard to longer-term results. This concern was clearly evidenced in the recent study by Keet et al8 on the long-term outcomes of milk OIT, in which they found that many patients regained significant reactivity, sometimes with very severe reactions, after having an apparent short-term treatment success. In our estimation, these
J ALLERGY CLIN IMMUNOL PRACT JANUARY/FEBRUARY 2014
long-term concerns are far more worrisome than the short-term concerns related simply to the risk of reactions while on treatment. The greatest risks of OIT may not be apparent until after treatment, when the patients may be at true risk of anaphylaxis but living with a false sense of security and potentially without epinephrine. These concerns are further magnified by studies demonstrating that protection after OIT may be lost with even brief periods of avoidance.9 We remain convinced that food OIT is not ready for clinical practice, and we are not at all comforted by the report of Wasserman et al.4 This opinion is completely consistent with the results of several recent systematic reviews and meta-analyses,10,11 the most recent of which still concluded that “peanut OIT represents a promising, potentially disease-modifying therapeutic approach for the management of IgE-mediated peanut allergy. However, currently, there is insufficient evidence in terms of longterm effectiveness, safety, and cost-effectiveness of peanut OIT to recommend its routine use in clinical practice.”11 If we believe that our specialty should remain grounded in science and evidencebased medicine, then it is clear that food OIT remains in a state of equipoise and is not ready for routine clinical use. REFERENCES 1. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010;126(Suppl):S1-58. 2. Sampson HA. Peanut oral immunotherapy: is it ready for clinical practice? J Allergy Clin Immunol Pract 2013;1:15-21. 3. Thyagarajan A, Varshney P, Jones SM, Sicherer SH, Wood RA, Vickery BP, et al. Peanut oral immunotherapy is not ready for clinical use. J Allergy Clin Immunol 2010;126:31-2. 4. Wasserman RL, Factor JM, Baker JW, Mansfield LE, Katz Y, Hague AR, et al. Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions. J Allergy Clin Immunol Pract 2014;2:91-6. 5. Nguyen-Luu NU, Ben-Shoshan M, Alizadehfar R, Joseph L, Harada L, Allen M, et al. Inadvertent exposures in children with peanut allergy. Pediatr Allergy Immunol 2012;23:133-9. 6. Neuman-Sunshine DL, Eckman JA, Keet CA, Matsui EC, Peng RD, Lenehan P, et al. The natural history of persistent peanut allergy. Ann Allergy Asthma Immunol 2012;108:326-31. 7. Wasserman RL, Sugerman RW, Mireku-Akomeah AR, Gallucci A, Pence D, Long NA. Peanut oral immunotherapy (OIT) of food allergy (FA) carries a significant risk of eosinophilic esophagitis (EoE). J Allergy Clin Immunol 2011; 127:AB28. 8. Keet CA, Seopaul S, Knorr S, Narisety S, Skripak J, Wood RA. Long-term follow-up of oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol 2013;132:737-9. 9. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton T, Steele P, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 2012;129:448-55. 10. Sheikh A, Nurmatov U, Venderbosch I, Bischoff E. Oral immunotherapy for the treatment of peanut allergy: systematic review of six case series studies. Prim Care Respir J 2012;21:41-9. 11. Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A. Allergen specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev 2012;9:CD009014.