Mount Sinai School of Medicine; Jaffe Food Allergy Institute
Food allergy has become a major health problem in westernized countries, now affecting approximately 3.5% of the U.S. population, or about 12 million Americans, and is the leading single cause of anaphylaxis treated in U.S. emergency departments. The standard of care for dealing with food allergies has been to educate patients and their families how to avoid allergenic foods and to recognize and treat allergic reactions if they have an accidental ingestion. In the past 5 years, there has been a growing interest in oral immunotherapy (OIT) for treating food allergy, a practice that was first reported in The Lancet over 100 years ago in an article called “A case of egg poisoning” [Lancet 1908; 1:716]. Considerably more recently, several small clinical trials of OIT for milk, egg and peanut allergies have yielded some promising results, and some practicing allergists have even begun using OIT to treat food-allergic patients.
I certainly can’t fault the desire of patients and patients’ parents to seek relief from the difficulty of managing a severe food allergy (and who pay for these treatments out of pocket). However, I wish to caution that widespread adoption of any OIT methods is premature, and may lead to crushing the hopes of patients, and worse.
Three carefully conducted scientific reviews* of trials have raised serious questions about OIT’s effectiveness, safety and long-term benefits, with the most recent concluding that “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.” In other words, we can’t judge on the basis of these trials whether it’s really working or not, or whether some researchers are getting the results they want instead of what the data really shows.
Our understanding of the underlying immunologic changes brought about by OIT is very limited and published reports provide inconsistent results. OIT appears to induce “desensitization,” or a clinical state in which the quantity of food required to trigger an allergic reaction is raised while on therapy, in most patients. “Tolerance,” or the long-term loss of allergic reactivity following the discontinuation of therapy, i.e. “a cure,” has been reported in some OIT trials, but most of these trials lack the appropriate controls. Different treatments follow different protocols, creating apples-and-oranges comparisons. In some cases, we can’t distinguish whether improvements with milk are the result of the therapy or whether a child is merely outgrowing the problem, as happens with milk allergies about 80% of the time. In fact, the only OIT trial to date stringently controlling for the natural development of tolerance in food-allergic children failed to find a difference in outcome between treated and control subjects.
In spite of the reservations my colleagues and I have, there are many instances of what we might call “retail OIT” being offered by some practicing allergists. The history of medicine is replete with examples of how premature adoption of new techniques can go wrong. Drugs and technologies that showed “no harm” in trials have often proven to be problematic as they made their way into wider use. We are nowhere near that regulatory threshold with OIT.
Furthermore, administering an experimental therapy creates management problems. Even in a research setting, patients must endure much of the discomfort and reactions that make food allergies a problem to begin with, necessitating a good deal of after-hours support and encouragement; do OIT doctors provide that? And while I trust my fellow allergists to treat emergencies, proliferation of unproven therapies creates more and more probability of mishaps. How long before a patient who believes himself “cured” suffers because he has ignored elementary precautions?
At this time, oral immunotherapy should be considered a promising experimental treatment for food allergy, but proper well-controlled trials are needed to demonstrate that it is safe and effective before the FDA will approve it for general use by practicing allergists.
* [(1)Brozek JL, Terracciano L, Hsu J, Kreis J, Compalati E, Santesso N et al. Oral immunotherapy for IgE-mediated cow’s milk allergy: a systematic review and meta-analysis. Clin Exp Allergy 2012; 42(3):363-74;
(2) 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(1):41-9; and
(3) Fisher HR, Du TG, Lack G. Specific oral tolerance induction in food allergic children: is oral desensitisation more effective than allergen avoidance?: a meta-analysis of published RCTs. Arch Dis Child 2011; 96(3):259-64]
Of note is this comment from Dr. Wayne Shreffler on the Allergies Asthma Children website:
I’m glad to see this being publicly debated. I’m not a parent of a food allergic child, but I have, like Drs. Sampson, Nash and others had the privilege of specializing in their care for more than a decade now.
I don’t believe there is any valid reason to doubt that physicians on either side of this question are equally well-intentioned. I am the principal investigator of an active peanut OIT trial and two more, funded by the NIH, due to start this year. I did my fellowship training with Dr. Sampson at Mount Sinai from 2000-03 and was on faculty there until 2009 when I moved to Boston. So you would be correct if you guessed that my opinion is that OIT still belongs in the research setting, and not something available as a fee for service.
But I think that some may be wrong about why I have that opinion. I hold that opinion primarily because I am biased to believe that oral immunotherapy IS effective. It is precisely because of this desire I have to find that OIT is an effective therapy — the same bias that every parent, private practitioner AND researcher currently has — that it is absolutely necessary to conduct impartial and rigorous studies.
Almost everything that has been published on OIT to date consists of case series reports, not randomized clinical trials. The overall numbers are still small and the patient selection highly subject to bias. We do not know that the benefits of OIT outweigh the risks, who is most likely to benefit, who will fail or develop chronic allergic inflammation while taking it, or who would have outgrown the allergy without it but now never will. No scientific review conducted or expert panel convened has concluded that OIT should yet be offered outside of a trial.
I have no doubt that practitioners among us who are offering OIT are setting out to do good. But the data are not yet sufficient to conclude that they will be. Until we have that data, in my opinion nobody should be laying down money for this treatment.
I believe that I understand the desire parents have to do something proactive about as well as anyone who is not personally affected can. My practice and my research are very much informed by that desire. But not only is OIT not ready for prime time, its proliferation outside of the research setting may well undermine our collective capacity to ever determine its efficacy.
Read the full article on OneSpot Allergy: http://blog.onespotallergy.com/2012/05/oral-immunotherapy-for-food-allergy-not-ready-for-prime-time/
REBUTTAL ARTICLE by Dr. Jeffrey Factor et al, July 2012
“Although we agree with Dr Sampson’s comments that the long term implication of oral immunotherapy to foods is yet to be determined, we disagree with the conclusions and recommendations about the current use of oral immunotherapy. At a dedicated food allergy treatment center, we have been treating patients having peanut allergy using oral desensitization for 18 months and we have enrolled over 160 patients to date. We believe this is the largest single series of patients receiving oral immunotherapy to peanut.Additionally, we have participated in an IRB approved study on the safety and efficacy of our treatment and have presented data on method, results, and improvement in food-specific quality of life in patients receiving oral immunotherapy to peanut. The quality of life data is now in press.
The protocol we have used is very similar to those studied by researchers at Duke University (Burks et al.) and the University of Arkansas (Jones et al.) that are part of the NIH food consortium. We defined as our goal to reduce anxiety of patients as a result of consuming foods containing a small amount of peanut, such as accidental ingestions and contamination. We felt that allowing the patients to eat the equivalent of three peanut M&M’s would accomplish our goal. Based on the published data, our goal has been to ‘desensitize’ and not inducing ‘tolerance’ (attempt to cure) these patients since the results have not been very convincing in this regard. Our experience with peanut desensitization by board certified allergists at a clinical center devoted to this treatment alone has been very convincing regarding the safety and effectiveness of our treatment.
The protocols we have followed are not without adverse effects. In fact, gastrointestinal symptoms during the build-up phase of our treatment are relatively common. These symptoms are managed by dosing reduction and/or modification. The great majority of these patients have had a resolution of symptoms and are able to achieve the maintenance dose. None of our patients have experienced anaphylactic reactions requiring epinephrine during the build up to maintenance. We have observed more significant reactions requiring epinephrine in 12 cases/76,000 total maintenance doses administered (an incidence of 0.03%). These reactions were associated with specific circumstances such exercising too soon after receiving oral maintenance dose, menses, viral or febrile illnesses. This experience has helped us better manage our patients on maintenance therapy, and hopefully add to the literature in safely treating peanut allergic patients receiving oral desensitization.
The positive effects on perceived and real quality of life have been clinically and statistically significant, for children, adolescents as well as parent perceptions of their children’s experience. There are countless examples of patients’ testimonials who have commented how oral desensitization to peanut has ‘changed their life.’ These experiences are real and poignant, and patients have not had any regret in participating in this treatment. We also know that many patients with peanut allergy suffer from significant psychosocial impairment as a result of this diagnosis. This is of great concern. The positive effects of peanut oral immunotherapy may mitigate these effects.
Any new therapy raises a lot of issues especially in the context of limited controlled clinical studies. This does not mean, however, that a modality of such benefit be set aside until all the requisite assessments are completed. There a many examples of treatment that have not been examined extensively by researchers yet are accepted forms of treatment. Even in our field, treatment such as inhalant immunotherapy and drug desensitization, are examples of this. Furthermore, full understanding of the ‘immunologic changes brought about’ by these treatments has not precluded their effective and accepted use.
I am somewhat taken aback by Dr Sampson’s reference to ‘retail oral immunotherapy’ as if the treating patients with oral immunotherapy as being motivated by some degree of recklessness and greed. This discounts the fact that we truly believe what we are doing is the right thing for our food allergic patients. In the absence of grants or other institutional sources of funding it is necessary to seek payment or reimbursement. It should be noted that the five board certified Allergist who are conducting this study are receiving no monetary remuneration. We assume that Dr. Sampson and his colleagues do receive compensation.
Concerning his comments about management problems and after hours support and encouragement, we are all private practitioners and we are very used to providing this for our patients. We don’t have study coordinators or fellows handling these problems. We are available 24 hours a day. In addition all the nurses in our center have children with food allergies and therefore can relate very well to our patients. Concerning the management of severe allergic reactions, I feel that we are just as competent in recognizing and treating mishaps as Dr.Sampson and his colleagues. We too, are working to get a better understanding of these reactions, and how they can be prevented.We have been doing food challenges, antibiotic challenges and drug desensitization for years. One of our physicians made a significant contribution to the field of penicillin allergy by demonstrating that patients could be tested for penicillin allergy electively, in spite of the recommendations of those in academia that it should not have been done. When he embarked on this venture he was seriously criticized by the experts in the field. Today his approach is the standard of care in the evaluation of this condition.
Although as Dr Sampson points out that ‘the history of medicine is replete with how premature adoption of new techniques can go wrong’ where is the evidence for that thus far? Treatment of food allergies by OIT is still ongoing in much the same way at research centers. It is also true that those who push forward with newer therapies open the door for those who otherwise have limited options.As Emerson stated, “Do not go where the path may lead, go instead where there is no path and leave a trail”. We believe oral immunotherapy has shown more than just promise in our patients and advocate its ongoing use in clinical practice.”
Jeffrey M Factor MD, Louis M Mendelson MD, Mitchell R Lester MD, Joseph Sproviero MD PhD, Jason O Lee MD
