Oral immunotherapy has previously been evaluated for its ability to desensitize persons to foods such as milk, peanuts, and eggs.14–20,26
The current study, unlike previous studies, enrolled a substantial number of children at multiple sites and showed sustained unresponsiveness in a double-blind, randomized, controlled study design with long-term follow-up during ad libitum consumption of the allergen. Two previous studies18,27
evaluating oral immunotherapy for milk and peanut allergies had double-blind, placebo-controlled designs, but they were smaller than the current study and neither involved more than two sites. A third study20
showed desensitization and sustained unresponsiveness after prolonged oral immunotherapy with milk but did not evaluate the ability of the participants to consume milk ad libitum. Desensitization alone is a therapeutically beneficial state because it confers protection against allergic reaction to accidental exposure. However, some participants in oral-immunotherapy studies who had only short-term desensitization subsequently had allergic symptoms after exposure to the suspect food during viral infections or after exercise.28
Sustained unresponsiveness, which occurred in 28% of the children in the current study, appears to be therapeutically more desirable than desensitization, in that the children had a higher threshold to the food allergen than would be expected according to the natural history, successfully incorporated egg into their diet, and were without symptoms at 36 months.
Suppression of mast-cell function, basophil activation, and modulation of lymphocyte responses are critical for the development of immune tolerance in response to allergen immunotherapy (e.g., subcutaneous immunotherapy).6,29,30
In the current study, the suppression of mast cells, as evidenced by decreased wheal size on skin-prick testing, and basophil activation were noted in children receiving oral immunotherapy, as compared with those receiving placebo, through 22 months and correlated with desirable clinical outcomes. Egg-specific IgG4 antibody levels at 10 months were increased by a factor of more than 100 above baseline values and correlated with sustained unresponsiveness. However, we identified no threshold elevations of egg-specific IgG4 antibody above the baseline value that were predictive of sustained unresponsiveness or that could be used as a substitute for the observed results of an oral food challenge to predict clinical outcomes. Increases in specific IgG4 antibody levels, with or without decreases in IgE antibody levels, have been associated with successful immunotherapy31–33
and loss of clinical sensitivity to milk and egg.18,20,34,35
After immunotherapy, the blocking activity present in serum is associated with allergen-specific IgG4 antibody, and it may be responsible for long-term immune tolerance after aeroallergen immunotherapy.36,37
Although the results of the current study are consistent with the induction of sustained unresponsiveness, the data cannot formally exclude other possibilities. First, the children who passed the oral food challenge at 24 months might lose the sustained unresponsiveness if ad libitum egg consumption were discontinued. A more prolonged phase of egg avoidance after oral immunotherapy might have excluded this possibility, but it was considered impractical, owing to the difficulty in achieving compliance with longer-term avoidance of egg. Second, participants in the study might have spontaneously outgrown the egg allergy. This explanation is unlikely, given the inclusion criteria that predicted a low likelihood of outgrowing the egg allergy.21,22
Indeed, none of the children who received placebo passed the oral food challenge at 10 months, one did not pass the challenge at 22 months, and the others had persistently high levels of egg-specific IgE antibody at 22 months. Third, the children who passed the oral food challenge at 24 months might not have avoided consuming egg during the period of 4 to 6 weeks when they were not receiving oral immunotherapy, but we believe this to be unlikely.
In conclusion, we found that oral immunotherapy provides protection in a majority of children with egg allergy by raising the reaction threshold and represents a highly promising therapeutic intervention for food allergy. The approach is relatively safe in that reactions to dosing were mild (grade 1), with less than 1% of reactions scored as moderate (grade 2). However, some allergic reactions were of sufficient clinical significance that approximately 15% of the children who received oral immunotherapy did not complete the therapy, in most cases because of allergic reactions. The mechanisms underlying the success of oral immunotherapy and their relationship to natural immune tolerance are unknown. For oral immunotherapy to be recommended as a standard of care, it will be important to better define the risks of oral immunotherapy versus allergen avoidance, determine the dosing regimens with the most favorable outcomes, identify patients who are most likely to benefit from oral immunotherapy, and develop postdesensitization strategies38
that promote long-term immune tolerance.