Could oral immunotherapy be the first treatment for food allergy?

Eventually, yes. But we need more data first.

The current standard of clinical care for food-allergic patients involves careful dietary avoidance and ready access to emergency medications. In general, resolution of allergy to egg, milk, wheat, and soy can be expected, although sensitivity may persist into the second decade of life, longer than previously appreciated. In contrast, most patients allergic to peanut, tree nuts, and seafood will not outgrow their disease and must maintain strict elimination diets. And little is known about the natural history of emerging allergens such as sesame. In addition, standard diagnostic testing cannot predict which patients are at risk for anaphylaxis, and exactly how much exposure might be harmful. Because milligram quantities of allergen are sufficient to produce anaphylaxis in some patients, great vigilance is required. Yet despite appropriate precautions, accidental ingestions frequently occur due to mislabeling, contamination events, or risk-taking behavior among adolescents. Indeed, food allergy is the leading cause of anaphylaxis among children treated in U.S. emergency departments. Fortunately fatalities are rare, but they do continue to occur.

Thus, parents often maintain reasonable concerns about the security of social and educational environments for their children, and typical childhood activities such as parties, camp, travel, sleepovers, etc. are frequently disrupted. These limitations, and more importantly their inability to completely eliminate the possibility of accidents, are great sources of stress on affected families. Over time, health-related quality of life is adversely affected, to a greater degree than seen in other serious chronic diseases of childhood such as type 1 diabetes or ventilator-dependent chronic respiratory failure. There is clearly a great clinical need to modify the natural history of food allergy, and many investigators are currently testing a variety of approaches to develop interventional therapies.

Of these, the most promising approach is oral immunotherapy (OIT), which involves the careful daily administration of gradually increasing doses of allergen. OIT takes advantage of the mucosal immune system of the gut, in which multiple redundant and overlapping immunologic pathways actively suppress reactivity to foreign antigens. Over time, OIT modifies the allergic immune response, and the amount of allergen required to cause a reaction is increased to levels well above those which would be expected in an accidental ingestion. This is referred to as desensitization, which implies a transient effect requiring continued dosing, and can be thought of as analogous to drug desensitization. Although most early OIT studies were uncontrolled, the weight of evidence from studies in the U.S. and Europe suggests that desensitization to allergens such as milk, egg, and peanut is achievable in most patients. Trials utilizing randomized, double-blinded, placebo-controlled designs are currently underway and should definitively address efficacy. Among the advantages of OIT are its simplicity and relatively low cost, which should allow it to be widely and readily implemented. In fact, it has been reported that some U.S. allergists are already offering OIT in their clinics.

Brian Vickery

Until more is known, however, OIT should remain an experimental therapy offered only by experienced researchers in IRB- and FDA-approved settings. The cumulative sample size of all OIT trials published to date is only several hundred patients, and as mentioned, most of these studies were uncontrolled. Safety concerns are paramount, and the rate of both short and long-term OIT-related adverse effects remain poorly understood. Although 15-20% of subjects in OIT trials are unable to continue therapy due to persistent allergic side effects, strict inclusion criteria and the bias inherent in recruiting study volunteers suggest that this proportion could be significantly higher in practice. And though the long term scientific goal remains the development of bona fide immunologic tolerance, a permanent state allowing discontinuation of therapy, it is entirely unclear if this is possible with OIT.

Still, millions of families in the U.S. and worldwide continue their daily struggles with food allergy, and their numbers are increasing. Although little is formally known about the impact of OIT on quality of life, our anecdotal experience is that parents generally express significant relief that a daily treatment may provide even partial benefit. And while researchers continue the pursuit of immunologic tolerance, families clamor for the incremental protection offered by desensitization. For them, the first step towards a definitive treatment for food allergy will be literally life-changing. As physicians and investigators, we must be careful to balance these great clinical demands with good science. I believe OIT will be the first clinically available treatment for food allergy – but practice should not be changed unless and until high-quality evidence supports that belief.

Brian P. Vickery, MD, is an instructor for the department of pediatrics in the divison of pediatric allergy and immunology at Duke University School of Medicine .

Oral immunotherapy (OIT) to food represents a potential future therapy for food allergy, but not a present reality. Several studies, including a limited number of randomized, controlled trials, have shown that a portion of highly-selected participants can gain a temporary desensitization (or increase in threshold to reaction) after undergoing a gradual build-up protocol involving home dosing. However, despite limited success, too many unresolved questions remain for this to be a recommended therapy as part of the new NIH food allergy practice guidelines.

Of foremost concern, the process has not been shown to be completely safe, though severe reactions have been limited. Many patients undergoing their build-up have suffered reactions, the majority of which were mild, but some required epinephrine (including in the home dosing phase). Some reactions have been severe enough to precipitate disenrollment in the protocol. Though the various investigators involved have concluded their studies were safe, reactions have been shown as a function of number of total doses, as opposed to reporting the number of reactions per person. This may obscure the fact that a large percentage of participants suffer some reaction, which may factor into a parent’s decision to allow their child to participate. Furthermore, there has been at least one case of a food allergic child developing symptoms consistent with eosinophilic esophagitis during the protocol, which is a frightening development that bears further investigation.

Beyond safety concerns, efficacy concerns also linger. While it has been shown that many patients can increase their reaction threshold dose (or in some cases actually ingest large, liberalized quantities of the particular food to which they are allergic), the overall efficacy of the procedure is still unknown. It is not known if patients achieve a desensitized state or actually regain tolerance. Understandably, this is a major concern, and to date, only one study has shown that patients can withstand even a temporary 2-week discontinuation of maintenance therapy and still retain tolerance. Obviously the nature of the effect must be well understood before OIT becomes a routine therapy, and it must be known if the effect will persist despite discontinuation of therapy. No clear pattern has emerged to predict which patients will tolerate more allergen than other patients despite having similar reaction thresholds. Most studies have involved patients without a history of severe past reactions, and have not included children under the age of 5 or 6. Both these factors limit the ability to fully generalize any findings, though such exclusions are understandable in this initial phase of investigation. However, these both must be studied before the therapy becomes “mainstream.” Lastly, there is no consensus on how a protocol should be structured. Both slow buildup with prolonged maintenance phases at home versus rapid inpatient desensitization have been performed. One European study even performed inpatient rush desensitization and maintenance continuation with patients on 1 mg/kg of an antihistamine. To date, however, no single method has proven to be superior.

Matthew Greenhawt

On an immunologic level, investigators have been trying to demonstrate a cellular effect that explains the clinical change of becoming desensitized or regaining tolerance. Across the foods that have been studied, allergen specific IgG4 has increased through the maintenance phase, similar to what occurs in inhalant and venom subcutaneous immunotherapy. Skin test wheal size has been shown to decrease from baseline during therapy as well. However, allergen specific IgE has been shown to have increased in some studies, decreased in others, and remain largely unchanged in other studies. Cell cultures, incubated with allergen extracts to measure cytokine levels in the supernatants, have also shown varying levels across several studies. In some studies, there have been diminished levels of IL-2, IL-4, IL-5 after undergoing OIT, which may suggest a dimming of the factors that promote allergy, but other studies have shown increases in IL-5. Therefore, the immunologic nature of the effect is entirely unclear at present.

Food OIT represents an important, exciting approach to the treatment of food allergy. These are some of the most important food allergy studies being conducted presently. However, OIT’s potential as a current therapy is limited by a paucity of studies, an unknown duration and nature of the effect, safety issues, patient selection issues, and lack of clear consensus on a protocol to be followed. Several of the investigators involved in these trials recently wrote an editorial urging caution and restraint in marketing OIT as a market-ready clinical therapy given it is still highly experimental and poorly understood. Therefore, food OIT may represent an important future therapy, but at present it is well beyond the scope of present-day therapy for recommendation by the expert panel NIH Food Allergy Practice Guidelines, and is inappropriate for use outside the research setting.

Matthew Greenhawt, MD, MBA, is a clinical lecturer at the University of Michigan Medical School and practices in the division of allergy and immunology of the University of Michigan Health Systems.