Given the potential of exposure to a small amount of allergen to promote tolerance to that allergen and the successful use of immunotherapy for management of venom and pollen allergies, there has been increasing research into the use of immunotherapy to manage common food allergies [12
]. Early use of subcutaneous immunotherapy for food allergy resulted in severe reactions, and so, recent focus has been on oral immunotherapy [37
]. Forms of oral immunotherapy to treat food allergy include specific oral tolerance induction (SOTI) [12
], where the allergen is ingested, or sublingual immunotherapy (SLIT), where a minute amount (picograms) of allergen, in the form of allergen extract or diluted allergen, is placed under the tongue [12
]. Both approaches start with a ‘build up phase’, initially starting with very small, diluted doses of the food protein with the amount of protein included in the dose slowly increased in a stepwise manner. This is followed by a “maintenance phase” with a consistent dose of allergen given at regular intervals. The regimes are followed with a “discontinuation phase” and a “tolerance food challenge” to test the effectiveness of the immunotherapy treatment. The entire process may take 12 months or longer to complete. Adverse events are common during oral immunotherapy—this risk of an adverse event increases with illness, exercise, menses and every time the dose of the food is increased [39
]. If regular consumption of the allergen is discontinued during the maintenance phase, there is a risk that tolerance will be broken, and an allergic reaction may follow exposure [38
]. For food allergy, the endpoint of immunotherapy may not always be tolerance—the therapy may result in desensitization
, an increase in the antigen dose required to elicit symptoms arising from a transient altered immune response and dependent on regular (daily) exposure to the allergen, or the therapy may result in true tolerance
]—the ability to ingest the allergen without any symptoms once regular exposure has ceased, owing to persistent changes in the immune response. Desensitization still has a benefit in that larger doses of the allergen can be tolerated before eliciting a hypersensitivity reaction, thus lessening the potential for an anaphylactic reaction from accidental exposure.
Oral immunotherapy has been attempted for many food proteins, but we have specifically chosen to discuss cow’s milk and egg oral immunotherapy, because of the interest in using baked forms of these foods as a treatment strategy. There is one Cochrane review from 2012 [42
] on oral immunotherapy for cow’s milk allergy, but none for egg. The Cochrane review included 16 studies, representing five trials and concluded that milk oral immunotherapy can lead to desensitization in the majority of individuals, although development of long term-tolerance has not been established.
Key trials reporting cow’s milk oral immunotherapy and egg oral immunotherapy in the last 10 years are summarized in , . Nine studies reported outcomes of cow’s milk oral immunotherapy and also nine for egg oral immunotherapy. These include three randomized controlled trials (RCTs) for cow’s milk SOTI [38
] and three RCTs investigating egg oral immunotherapy [45
], but most of the studies report on open, uncontrolled prospective trials. We have added one trial [38
] that was not included in the cows’ milk immunotherapy Cochrane review. These studies have limitations. The studies utilized highly variable selection criteria, dosing regimens and maintenance doses, making them difficult to compare. The individual studies reported have limited statistical power, as only a small number of children were included in the treatment group.
Summary of key egg-specific oral immunotherapy trials.
Summary of key cow’s milk specific oral immunotherapy trials.
All of the 18 studies reported SOTI, and one study reported results of a SLIT/SOTI combination protocol for cow’s milk immunotherapy. Keet et al
] compared the outcome of children with cow’s milk allergy who were given a SLIT protocol initially and then randomized to a low or high dose SOTI protocol or SLIT alone. More children in the SLIT followed by the high dose SOTI group passed the final oral food challenge after six weeks compared to those in SLIT alone or the lower SOTI dose.
Dosing regimens varied from 15 mL to 200 mL cow’s milk and 0.3 g to 60 g of egg for the maintenance phase. Furthermore the allergen used for the reported regimes varied—for example fresh raw whole egg, fresh raw egg white, pasteurized egg white, pasteurized whole egg, lightly cooked egg have all been used for the egg oral immunotherapy studies. Most of the cow’s milk immunotherapy studies used fresh cow’s milk, but some reported use of dried non fat milk powder. Some of the studies asked participants to consume the maintenance dose on a daily basis, and some required the dose to be consumed every 2–3 days.
Not all of the studies assessed actual tolerance to cow’s milk or egg at the end of the intervention. Some used a double blinded, placebo controlled food challenge, the recognized “gold standard” for diagnosis of food allergy and some of the trials used open oral food challenges. The end point challenges varied in terms of the type of food used for challenge, with some testing the raw cow’s milk or egg and some testing cooked egg for the case of egg immunotherapy. The volume of cow’s milk or egg given in the final challenge varied.
Many children who underwent immune therapy were able to reach tolerance to cow’s milk or egg in these studies however overall there was a high incidence of adverse reactions and a risk of loss of clinical desensitization after small periods off therapy [38
]. Keet et al.
reported loss of tolerance in as little as one week off SOTI [38
]. The longest follow up period after the oral immunotherapy reported was three years for egg allergy [46
] and four years for cow’s milk allergy [56
]. There are no safety data available testing the efficacy of oral immunotherapy beyond this length of time.
Many of the human intervention studies investigating clinical outcomes of individuals undergoing oral immunotherapy to cow’s milk and egg have used skin prick testing as a marker of IgE levels or have measured serum specific IgE / IgG4 levels against the specific allergens to look for changes in the immune system towards tolerance (, ). Only the more recent studies have begun to investigate changes at the cellular level [38
]. Production of cytokines (IL10, TGFß and IFNγ) by T-cells influences the production of protective antibody responses by B cells including secretion of allergen-specific IgG4 and IgA and later inhibition of IgE. Immunotherapy has also been shown to lead to increases in protective IgG (1 and 4) and IgA, a decrease in IgE and a shift in the Th1/Th2 balance towards Th1, along with a decrease in T-cell proliferation and cytokine responses to allergens. Importantly there are increases in regulatory T-cells along with an increased production of IL-10 and TGFß implying that oral tolerance is being established [41
Oral immunotherapy to egg and cow’s milk shows potential as a management strategy for children with cow’s milk and egg allergies and is able to induce desensitization and promote immune changes indicative of moves towards tolerance. However, SOTI carries a risk of adverse events both during the initiation phase and after periods off therapy, and the ideal treatment protocol is still to be identified. For researchers, a strategy that would facilitate this is the development of harmonized protocols, or, at least, harmonization of reporting of studies into SOTI to enable reporting, so that they can be clearly compared.