Among young children, CMA is the most common food allergy, occurring in as many as 2% to 3%.18-21
Although the prognosis for CMA resolution had been considered good, with up to 85% tolerating dairy by the age of 3 years,18,19
more recent studies show less optimistic outcomes.22-26
Given that milk allergy is extremely prevalent, might be exhibiting an increasing tendency to persist, is exceedingly difficult to avoid, and has the potential to result in severe and even fatal reactions,5-8
it is highly desirable to have some form of therapy to treat this condition.
In this study milk OIT was effective in increasing the threshold for reactions to milk in all treated children. This study is the first done in a double-blind, placebo-controlled fashion in children. before treatment, nearly all individuals had symptoms after the first 40-mg dose at the baseline food challenge, whereas after therapy, the average cumulative dose causing a reaction was 5140 mg. The lowest dose causing a reaction in any participant was 1340 mg, which still is likely to be protective against the overwhelming majority of accidental exposures. However, it is also important to note that after completion of active treatment, despite an increased threshold, 14 of 18 still exhibited a reaction at the post-OIT food challenge. And even in those who did not react to the post-OIT challenge, it is not clear whether they are fully tolerant or rather transiently desensitized and thus still at risk of future reactions.
Establishing whether patients are desensitized or tolerized through OIT is extremely important. Desensitization should be defined as the ability to tolerate more of an allergenic substance after treatment. The state of desensitization likely requires ongoing exposure to be maintained, and it is completely unclear how long it would take before lack of continued exposure would result in loss of desensitization. Tolerance should be defined as a permanent loss of reactivity to a previously allergenic substance. This can only be proved by completely removing the relevant allergen from an individual’s diet for a period of time.
Buchanan et al9
treated 7 patients with 300 mg of egg protein for 24 months. After treatment, 4 of 7 passed an egg challenge. These 4 then restricted egg from their diet for 3 to 4 months and were then rechallenged. Two of the 4 again passed the challenges, but the other 2 were again reactive and at fairly low amounts of egg. Whether this represents inadequate therapy or a subset of patients who will not be capable of tolerance induction remains to be determined. Our current study does not address this issue because all successfully desensitized participants are continuing with daily consumption of dairy as instructed.
With regard to other outcomes, although there were many actively treated participants with large changes in the end-point titration SPT threshold, the median change was not statistically different than that with placebo. It did appear that larger fold changes were associated with higher milk dose thresholds, but this could not be confirmed statistically in this small group. Milk-specific IgE antibody levels remained unchanged, on average, after 3 or 6 months of treatment. In previous studies, significant decreases in food-specific IgE levels have been reported at time points ranging from 6 to 24 months of therapy.9,11,14,17
It is possible that the duration of treatment in our study was not long enough to see a decrease in serum IgE antibody levels. It appeared that higher baseline milk-specific IgE levels were associated with lower post-OIT milk dose thresholds, as well as with greater difficulty in tolerating milk OIT doses, but like the SPT results, this could not be confirmed statistically in this small group.
Milk-specific IgG4 antibody levels exhibited a large increase by the 3-month time point in the actively treated group. Possibly because of sample size, there was no apparent association between the degree of increase in milk-specific IgG4 level and the observed clinical outcome. However, there was large individual variability such that large increases in milk-specific IgG4 antibody levels did not guarantee significantly higher milk thresholds and smaller increases did not exclude higher thresholds.
There are a number of recent reports in the literature of food-specific OIT, including that to milk, egg, peanut, hazelnut, and fish.10-17
However, these reports have varied widely using different modes of delivery (sublingual versus oral/swallowed), widely differing dosing regimens, and variable criteria to define outcomes. In a recent study of OIT by Longo et al,11
children with severe milk allergy were gradually escalated to a goal of 5 ounces of milk. After 1 year, one third could tolerate this amount or more, one half tolerated between 1 teaspoon and 5 ounces, and 10% discontinued treatment because of side effects.
In contrast, Enrique et al10
reported on the use of hazelnut sublingual immunotherapy. These patients were escalated to a maintenance dose in 4 days and treated for 5 months. There was a highly significant increase in hazelnut tolerance in the actively treated group. Five of 11 in the active group compared with 1 of 11 in the placebo group were able to tolerate the entire 20 g of hazelnut at the posttreatment challenge. However, approximately half of the active-treated participants had a history described as only oral allergy syndrome. Minimal dose-related systemic side effects were reported, and there were no dropouts. The studies by Longo et al11
and Enrique et al10
are representative of the variability in study populations and methodologies used in oral food-specific immunotherapy protocols.
In our study adverse reactions were common, but the risk of a severe reaction fell within the range that we would consider acceptable. Despite the relatively high frequency of reactions of any type (45% of active doses), nearly 90% were transient reactions that required no treatment. Approximately 1 in 100 active doses resulted in a multisystem reaction, and 1 in 600 resulted in a reaction requiring treatment with epinephrine. Although the ideal for any therapy is no serious reactions, when dealing with highly allergic children, some level of reaction is almost inevitable. It is essential that families considering OIT trials be made aware of these risks, that emergency medications are always available, and that physician coverage be available at all times. Families contemplating such therapy will need to consider whether the benefit of increased, but not necessarily complete, tolerance is worth these risks compared with the alternative of strict avoidance. The majority of prior studies involving orally administered immunotherapy reported less frequent reactions either of a mild or more serious nature.10,12-17
Only Longo et al11
reported the need for intramuscular epinephrine, and this was only with in-hospital rapid build-up. This contrasts with our experience, in which local symptoms were common in most individuals. Although there was a tendency for symptoms to be more common during build-up, they were still observed during maintenance, even including 1 reaction requiring epinephrine. Possible explanations for these discrepancies could be that our study population was on average more severely allergic, that our subjects were more diligent in reporting symptoms, that we did not require maintenance oral antihistamines as has been done in some other studies,11,12
and/or that our dosing protocol was not optimal.
Another issue regarding safety is what appear to be factors associated with a lower threshold for reaction to OIT. This concept was previously raised by Staden et al,17
who referred to ‘‘augmentation factors.’’ Although we did not formally study this, it is our impression from this study that both exercise and infectious illnesses can potentially contribute to a reaction at a previously well-tolerated OIT dose.
Future studies should be aimed at improving both the safety and efficacy of this form of treatment. It is possible that smaller incremental increases in doses might lessen reaction frequency or severity. However, because there was no clear preponderance of reactions at or shortly after dose increases, this might not be the case. It is also possible that treatment through the sublingual route, which might allow for much lower doses, would be better tolerated. Having all participants take a daily long-acting antihistamine might help to reduce mild symptoms.
In conclusion, this study provides evidence that orally administered immunotherapy can result in a significant degree of desensitization to a given food in most allergic patients. Although allergic reactions to OIT doses were common, the majority did not require treatment, and reactions that did require treatment responded well to medications administered by parents. Future studies should aim to establish optimal doses, length of therapy, and route of therapy (oral/swallowed vs sublingual) required to obtain maximal desensitization. Once this is established, further investigation of whether this treatment can induce long-term tolerance or just temporary desensitization will be essential. Finally, given the current uncertainty regarding both safety and efficacy, it is essential that these clinical trials be completed before anyone considers the use of OIT in clinical practice.