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Abstract

In the opening paragraph, Wasserman et al1Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.The real world is not standardized.J Allergy Clin Immunol Pract. 2019; 7: 2098-2099Abstract Full Text Full Text PDF Scopus (3) Google Scholar state that my editorial “criticizes the report for not being the randomized, controlled trial that it was never intended to be.” I am surprised that they interpreted the editorial to be a criticism as I simply pointed out that “the authors acknowledge certain limitations given the retrospective nature of their data,”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar which is a reiteration of Wasserman et al's3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar own words in the discussion of their original report, “As a retrospective study, there are potential biases.” As the authors already present their report as being from real-world practice, the editorial serves to point out to readers the similarities and differences, as well as advantages and limitations, when examining different approaches to peanut oral immunotherapy. The correspondence takes issue with my statement about the lack of food challenges, which simply stated: “The authors acknowledge certain limitations…For example, baseline food challenges were not performed so the magnitude of efficacy remains uncertain.”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar The authors themselves state in their original article that “clinicians modified patient treatment according to their judgment” and specifically say that “because all patients were not challenged before beginning POIT, we cannot be certain that they were all peanut allergic.”3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Therefore, it is merely a statement of fact on my part that baseline food challenges were not performed for the patients in their cohort, and not an implication of inferiority. However, I would not agree with Wasserman et al's conclusion that “the only bias was the choice parents made in seeking care for their children” when we are discussing a retrospective review of an open treatment. Wasserman et al1Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.The real world is not standardized.J Allergy Clin Immunol Pract. 2019; 7: 2098-2099Abstract Full Text Full Text PDF Scopus (3) Google Scholar further question “would it have been ethical to challenge patients with known peanut allergy?” Although it is understandable why this “real-world” study decided not to routinely perform food challenges, I take issue with the comment that doing so is unethical. There are dozens of completed and ongoing clinical trials of peanut allergy that are sponsored by the National Institutes of Health, investigator-initiated or pharmaceutical trials that include baseline food challenges for patients with known peanut allergy. These studies have all undergone review and received approval by different institutional review boards and Data Safety Monitoring Boards. The mandate of institutional review boards is to provide ethical and regulatory oversight of research that involves human subjects. Therefore, challenging patients with known peanut allergy has repeatedly been found to be an acceptable procedure to be included in peanut allergy studies. Wasserman et al allege that the editorial is promoting a specific product. First, there is no mention of any specific product anywhere in the editorial.2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar Second, the word “product” is used as a generic term throughout the editorial, defined as “something that is marketed or sold as a commodity.”4Merriam-Webster. Dictionary by Merriam-Webster: America's most trusted online dictionary. Available from: https://www.merriam-webster.com/. Accessed March 20, 2019.Google Scholar This term was chosen because there are different sources of peanut protein available (including peanut, peanut butter, peanut flour) that have been used for peanut oral immunotherapy (OIT). The authors also mistakenly interpret the editorial statement on allergic reactions due to OIT, erroneously assuming that it refers only to the use of nonstandardized peanut. The editorial notes that Wasserman et al's report is in fact similar to other published reports in finding that allergic symptoms to OIT are common. The references I cite included 4 different studies that used different peanut sources/products, 3 of which used nonstandardized products (Blumchen et al5Blumchen K. Ulbricht H. Staden U. Dobberstein K. Beschorner J. de Oliveira L.C. et al.Oral peanut immunotherapy in children with peanut anaphylaxis.J Allergy Clin Immunol. 2010; 126: 83-91.e1Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar used crushed roasted peanut and Anagnostou et al6Anagnostou K. Islam S. King Y. Foley L. Pasea L. Bond S. 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: 1297-1304Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar and Varshney et al7Varshney P. Jones S.M. Scurlock A.M. Perry T.T. Kemper A. Steele P. et al.A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.J Allergy Clin Immunol. 2011; 127: 654-660Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar used lightly roasted flour). Another point related to safety brought up in the editorial to which Wasserman et al take offense is that switching between peanut protein sources during OIT could pose a potential safety concern. This concern was raised on the basis of data published by Filep et al8Filep S. Block D.S. Smith B.R.E. King E.M. Commins S. Kulis M. et al.Specific allergen profiles of peanut foods and diagnostic or therapeutic allergenic products.J Allergy Clin Immunol. 2018; 141: 626-631.e7Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar and Hindley et al,9Hindley J.P. Filep S. Block D.S. King E.M. Chapman M.D. Dose of allergens in a peanut snack (Bamba) associated with prevention of peanut allergy.J Allergy Clin Immunol. 2018; 141: 780-782Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar which demonstrate variability in peanut protein content across different peanut foods. Following Wasserman et al's suggestion to compare peanut OIT to subcutaneous immunotherapy for environmental allergies, I would point out that the practice parameter on allergen immunotherapy10Cox L. Nelson H. Lockey R. Calabria C. Chacko T. Finegold I. et al.Allergen immunotherapy: a practice parameter third update.J Allergy Clin Immunol. 2011; 127: S1-S55Abstract Full Text Full Text PDF PubMed Scopus (857) Google Scholar specifically states that:“[A]n allergen immunotherapy extract must be considered different from a clinical standpoint if there is any change in the constituents of the allergen immunotherapy extract. These include changes in the lot, manufacturer, extract type (eg, aqueous, glycerinated, standardized, and nonstandardized), and component allergens and their respective concentrations in the allergen immunotherapy extract. There is potentially an increased risk of a systemic reaction if the allergen immunotherapy extract is changed and the patient's dose is not modified.” As such, an analogous approach should not be unexpected for peanut OIT in that caution would be warranted when switching between peanut protein sources from different manufacturers, both standardized and nonstandardized. Although Wasserman et al3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar did not report any problems when their patients switched between peanut products, these data from a single cohort are insufficient to deem this concern to be irrelevant, such that no caution is warranted for any patient. Wasserman et al also take offense to the points made in my editorial about reasons why practices may find implementing OIT to be challenging. The reasons listed for physician concern are taken directly from the study by Greenhawt and Vickery11Greenhawt M.J. Vickery B.P. Allergist-reported trends in the practice of food allergen oral immunotherapy.J Allergy Clin Immunol Pract. 2015; 3: 33-38Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar who conducted a survey of American Academy of Allergy, Asthma & Immunology membership that included 442 respondents, of which 75.9% self-identified they were in private practice and 13.8% reported they were “providing OIT as a service or were studying OIT under a research protocol.” In this study, 381 providers who were not using OIT currently were asked to rate the relative importance of factors that would specifically motivate them to offer OIT in the future—91.9% stated availability of a standardized product and 86% would like a current procedural terminology (CPT) billing code. The report indicates that 74.3% are awaiting Food and Drug Administration approval before offering this therapy, and 4.5% identify that they did not have the resources at present to offer OIT. Thus, the reasons brought forth as challenging regarding OIT implementation are not a single person's opinion, but rather the opinions of American Academy of Allergy, Asthma & Immunology members taking the survey. In fact, another one of Wasserman et al's12Wasserman R.L. Jones D.H. Windom H.H. Oral immunotherapy for food allergy: the FAST perspective.Ann Allergy Asthma Immunol. 2018; 121: 272-275Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar publications specifically states that:“[B]ecause FOIT [oral immunotherapy for food allergy] is not yet the standard of care, discussions about the process, the risks, and potential benefits are time consuming. Sourcing and preparing foods requires staff training. Food allergy patients may require 1 or more food challenges before FOIT. Only those allergy practices with extensive experience in performing food challenges should consider offering FOIT. Although all allergy offices should be prepared to manage anaphylaxis, this capability is especially important to an FOIT program.” This direct quote from Wasserman et al's first author publication clearly asserts that resources (including people and time) are required for practices choosing to provide OIT. There is no implication in the editorial “that it is not possible to have a guideline or billing code without a commercial product” as the authors contend.1Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.The real world is not standardized.J Allergy Clin Immunol Pract. 2019; 7: 2098-2099Abstract Full Text Full Text PDF Scopus (3) Google Scholar Wasserman et al misconstrue the statement, “the medicolegal implications associated with off-label OIT, a treatment that is currently not recommended by evidence-based guidelines, as well as lack of Current Procedural Terminology (CPT) billing code and insurance coverage are additional concerns for widespread adoption of OIT,”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar which, again, are concerns brought forth by the results of Greenhawt and Vickery's11Greenhawt M.J. Vickery B.P. Allergist-reported trends in the practice of food allergen oral immunotherapy.J Allergy Clin Immunol Pract. 2015; 3: 33-38Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar survey. The editorial is simply stating the facts that OIT is not currently recommended by evidence-based US guidelines and there is currently no CPT billing code available. Wasserman et al1Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.The real world is not standardized.J Allergy Clin Immunol Pract. 2019; 7: 2098-2099Abstract Full Text Full Text PDF Scopus (3) Google Scholar raise the point that Bamba and peanut butters are included in prevention guidelines and suggest that use of such commercial peanut food products for OIT would be comparable with regard to treatment guidelines and billing codes. However, it is important to remember that early introduction of peanut into an infant's diet is intended for those who are NOT allergic. Therefore, the discussion of foods used in infant feeding should not be conflated with discussions on products or protein sources to be used as medical therapy for treatment of patients who are known to be allergic and are at risk for reactions, including severe ones, with allergen exposure. Wasserman et al claim that the editorial promotes a single pathway for OIT product development, which is a gross misinterpretation. The intention of the statement that “development of well-characterized products from GMP facilities [NOTE: the plural of “product” is used, indicating that this is not a promotion for a single product. Also, these words were specifically chosen to not only refer to a pharmaceutical product, but also OIT products that are manufactured at different GMP facilities in academic centers or other locations] is ultimately worthwhile to allow more patients and practices to have access to this therapeutic approach”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar is to leave open room for different OIT products to be used to increase access of this therapeutic option to more patients. I hope that Wasserman et al can agree that I never criticized the report “for not being …[a] randomized, controlled trial.” In fact, I emphasized the value of the information obtainable from this large “real-world” study in my editorial. But, I am confident Wasserman et al and others recognize the advantages of controlled trials. Wasserman et al3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar state in their original article, “no study has yet demonstrated the ideal or even preferred food allergy immunotherapy algorithm,” indicating the need for further investigations to fully understand safety, efficacy, and how treatment should be provided. Under the principles of beneficence and nonmaleficience in medical ethics, a benefit-risk analysis is important before starting a medical therapy. As Wasserman et al3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar also point out in their original report, there was an “apparently high frequency of epinephrine use” and a “rate of ELORS [eosinophilic esophagitis-like oral immunotherapy-related syndrome] within a range seen in other POIT reports.” These data support the need for assessments of risk and burden of treatment such as those discussed in the recent review by Soller et al13Soller L. Abrams E.M. Chan E.S. An update on the controversy around offering oral immunotherapy to peanut-allergic children outside of research.Ann Allergy Asthma Immunol. 2019; 122: 559-562Abstract Full Text Full Text PDF Scopus (11) Google Scholar that compare the rates of epinephrine administration using studies of peanut avoidance, peanut OIT in research, and peanut OIT in clinical practice. Soller et al point out that among those practicing peanut avoidance, there is a 10% annual rate of accidental reactions, with 1% to 2% requiring epinephrine or emergency department visits. This rate is lower than reported rates of epinephrine use in peanut OIT in research, which ranges up to 14%,14Vickery B.P. Vereda A. Casale T.B. Beyer K. du Toit G. Hourihane J.O. et al.AR101 Oral immunotherapy for peanut allergy.N Engl J Med. 2018; 379: 1991-2001Crossref PubMed Scopus (349) Google Scholar and peanut OIT in clinical practice, which was reported to be 10%.15Wasserman R.L. Factor J.M. Baker J.W. Mansfield L.E. Katz Y. Hague A.R. et al.Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions.J Allergy Clin Immunol Pract. 2014; 2: 91-96Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar To fully evaluate the risk/benefit, in this area that we agree remains in equipoise, I would argue in fact that randomized, placebo-controlled trials have a clear advantage in allowing us to compare the benefit of OIT versus allergen avoidance. The concluding paragraph of my editorials states that “advancing OIT into routine clinical practice will require a balance between rigorous placebo-controlled studies and large retrospective studies of this kind,”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar which in fact reads no different than Wasserman et al's3Wasserman R.L. Hague A.R. Pence D.M. Sugerman R.W. Silvers S.K. Rolen J.G. et al.Real world experience with peanut oral immunotherapy: lessons learned from 270 patients.J Allergy Clin Immunol Pract. 2019; 7: 418-426.e4Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar original conclusion that “careful observations of clinical experiences can supplement information from controlled clinical trials to improve the treatment of peanut allergic patients.” As in other areas of medicine, there will be a place for various approaches to treatment and as we move the field forward, it “will be essential to weigh the benefits versus risks of this therapy in a precision medicine approach.”2Wang J. Peanut oral immunotherapy: data from a real-world clinical practice.J Allergy Clin Immunol Pract. 2019; 7: 427-428Abstract Full Text Full Text PDF Scopus (3) Google Scholar The real world is not standardizedThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 6PreviewThe editorial by Wang1 that accompanied the article on peanut oral immunotherapy (OIT) in clinical practice2 notes the size of the reported cohort and the duration of observations of our clinical practice. However, the editorial criticizes the report for not being the randomized, controlled trial that it was never intended to be. Baseline food challenges were not performed in patients with a history of an IgE-mediated reaction within 2 years of starting OIT. Would it have been ethical to challenge patients with known peanut allergy? As we note in our article, no patient was excluded from OIT because of the severity of reaction history or the magnitude of peanut specific IgE. Full-Text PDF