Egg oral immunotherapy in nonanaphylactic children with egg allergy

Article Outline

• Abstract
• Methods
  • Patient selection
  • OIT protocol
    • Modified rush phase
    • Build-up phase
    • Maintenance phase
    • Follow-up
    • Food challenges
  • Egg-specific IgG and IgE concentrations
  • Data analysis
• Results
  • Subjects
  • Modified rush phase
  • Build-up phase
  • Maintenance phase
  • DBPCFC
  • Egg-specific Ig concentrations
• Discussion
• Appendix. Supplementary data
• References
• Copyright

Background

There is no current active treatment for food allergy. Traditional injection immunotherapy has been proved unsafe, and thus there is a need for other forms of immunotherapy.

Objective

The purpose was to study the safety and immunologic effects of egg oral immunotherapy (OIT). The short-term goal was to desensitize subjects to protect against accidental ingestion reactions. The eventual goal was to induce lasting clinical and immunologic tolerance.

Methods

Subjects with a history of egg allergy but without a history of anaphylaxis to egg underwent a 24-month egg OIT protocol involving modified rush, build-up, and maintenance phases. Double-blind, placebo-controlled food challenges were performed at study conclusion. Egg-specific IgE and IgG concentrations were followed.

Results

Seven subjects completed the protocol. Egg-specific IgG concentrations increased significantly, whereas egg-specific IgE concentrations did not significantly change. Three subjects tolerated known or possible accidental egg ingestions while receiving OIT. During double-blind, placebo-controlled food challenges at study conclusion, all tolerated significantly more egg protein than at study onset and than that found in the typical accidental exposure. Two subjects demonstrated oral tolerance.

Conclusion

This study provides proof of concept that OIT can be safely used for patients with egg allergy without a history of anaphylaxis to egg. Egg OIT does not heighten sensitivity to egg and might protect against reaction on accidental ingestion. Whether OIT will induce clinical oral tolerance cannot be concluded from this initial cohort.

Clinical implications

Use of allergen-specific OIT to protect subjects with food allergy from reaction on accidental ingestion would represent a significant paradigm change in the treatment of food allergy.

Key words: Egg allergy, food allergy, anaphylaxis, allergen immunotherapy, oral immunotherapy

Abbreviations used: DBPCFC, Double-blind, placebo-controlled food challenge, HRQL, Health-related quality of life, OIT, Oral immunotherapy

Food allergy affects up to 3.7% of the overall US population and 6% to 8% of young children.¹ Currently, the standard of care for food allergy includes strict allergen avoidance and ready access to self-injectable epinephrine.² Previous studies measuring health-related quality of life (HRQL) have found significantly reduced HRQL in patients with food allergy and their families,³, ⁴, ⁵ clearly indicating that the effects of food allergy extend beyond typical health-related outcomes, such as number or severity of reactions per year. An important factor behind this negative effect is the fear of unexpected or life-threatening reactions. Food-induced anaphylaxis is the most common single cause of anaphylaxis treated in US emergency departments, especially among younger patients.⁶

Patients with allergic diseases, such as asthma and allergic rhinitis, can choose active forms of treatment either through medications or allergen immunotherapy. The administration of allergen immunotherapy alters the natural history of allergic diseases by inducing tolerance to allergens.⁷, ⁸, ⁹ Unfortunately, no active treatment is available for patients with food allergy. Prior studies of allergen immunotherapy for food allergy have had mixed results,¹⁰, ¹¹, ¹² and although other potential immunomodulatory treatments are on the horizon,¹³ these treatments are either years away from being available for human use or, in the case of anti-IgE therapy, expensive and will not alter the natural history of disease. The best that practitioners can currently offer these patients is the possible hope of outgrowing the allergy while on an avoidance diet and education about emergency measures in case of accidental food ingestion.²

Food allergy is believed to result from a breakdown of normal oral tolerance induction.¹⁴ Although injection immunotherapy has been proved unsafe in food allergy,¹⁰, ¹¹ some investigators have had partial success with oral immunotherapy (OIT).¹⁵, ¹⁶ We performed an open uncontrolled study of egg OIT in children with egg allergy without a history of egg-induced anaphylaxis. In addition to evaluating its safety, the overall goals of this study were to show that children can be protected against adverse reactions to accidental food ingestions and to induce oral tolerance to a specific food allergen. Here we present the results of the first group of children to complete the protocol.

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Methods 

Patient selection 

Children (ages 1-16 years) referred to the Pediatric Allergy and Immunology Clinics at Duke University Medical Center and Arkansas Children's Hospital who were given diagnoses of egg allergy on the basis of serum CAP System fluorescent enzyme immunoassay results of 7 kU/L or greater (2 kU/L or greater for subjects ≤2 years of age) or with a positive allergic reaction to egg within 6 months of beginning the study were recruited. CAP fluorescent enzyme immunoassay levels of greater than the established 95% positive predictive values were considered diagnostic because these would not typically be confirmed with challenge in clinical practice.¹⁷ Subjects must have ingested egg before diagnosis. Exclusion criteria included a history of significant systemic anaphylaxis to egg or a medical history that prevented cooperation with a double-blind, placebo-controlled food challenge (DBPCFC). Before beginning the protocol, subjects were placed on an egg-elimination diet for a minimum of 2 weeks. Ethics approval was obtained through the Institutional Review Boards at Duke University Medical Center and the University of Arkansas for Medical Sciences/Arkansas Children's Hospital. Written informed consent was obtained in accordance with each institution's ethics guidelines for research in children.

OIT protocol 

The goal of the OIT protocol was the ingestion of a maintenance egg protein dose of 300 mg daily, with the expectation that this daily dose would both protect subjects with egg allergy from reaction on accidental ingestion of egg and induce oral tolerance to egg. The protocol consisted of the following phases: modified rush, build-up, and maintenance.

Table I summarizes the modified rush phase, which was undertaken at the General Clinical Research Unit at Duke University and at the Pediatric Clinical Research Unit at Arkansas Children's Hospital. Oral and intravenous doses of diphenhydramine and intramuscular epinephrine were at the bedside at all times. A 10 mg/mL solution of powdered egg white in distilled water was prepared for all egg white doses of less than 25 mg. For doses of 25 mg and greater, powdered egg white was dispensed from individual preweighed containers. All doses were mixed with an acceptable vehicle food chosen by the subject and his or her parent.

Table I. Modified rush phase^∗

After placement of an intravenous catheter, the modified rush day began with a first single dose of 0.1 mg of powdered egg white (Michael Foods, Minnetonka, Minn). After the initial dose, subjects received approximately doubling doses every 30 minutes until the highest tolerated single dose was determined. If the subject had a mild reaction to one of the doses, the previously tolerated dose was repeated before resuming the process. If significant symptoms developed, the modified rush phase was stopped. Subjects were treated for reactions as needed. Subjects were then observed for 2 hours, and if there was no evidence of an allergic reaction, they were discharged home. Self-administered epinephrine was provided to all patients' caregivers, along with instructions and indications for administration and education about the nature of possible reactions to OIT. To ensure there were no ill effects of the daily dosing, each subject returned to the research unit on the second day for an observed administration of the starting daily dose.

Based on the highest tolerated single dose during modified rush (Table I), subjects began daily home dosing with between 25 and 200 mg of powdered egg white in 1 to 2 tablespoons of baby food or other acceptable vehicle food. Home doses were provided in individual preweighed containers, and subjects were instructed to ingest 1 dose daily for 2 weeks. As long as subjects were tolerating current doses, these were increased by 25 mg every 2 weeks until reaching 150 mg and then increased by 50 mg at each visit until reaching maintenance (300 mg). Dose escalations were made at visits in the research unit to ensure that subjects tolerated increases, and subjects were observed for at least 2 hours after increases for signs of clinical reactions.

Once subjects reached the daily dose of 300 mg, they were instructed to take this daily for the length of the study (24 months). The subjects were also instructed to otherwise continue an egg-elimination diet for the duration of the study.

Subjects and families were asked to complete daily home diaries to document that daily doses were taken, as well as to report accidental ingestions, problems with dose administration, or related symptoms. Follow-up visits in addition to or in conjunction with the biweekly visits for dose escalation occurred at 3, 6, 9, 12, 15, 18, 21, and 24 months from enrollment. Each visit involved a medical history and physical examination. Serum egg-specific IgE and IgG concentrations were measured at enrollment and at follow-up visits.

Two years after entering the study, each subject underwent a DBPCFC to determine his or her allergenic reactivity to egg protein. Subjects continued OIT dosing through the day before the challenge. One challenge consisted of 6 doses of powdered egg white given every 10 to 20 minutes in increasing amounts up to a total of 10 g of powdered egg white (8 g of egg protein). The other challenge consisted of placebo given also in 6 doses. All negative challenge results were confirmed by means of open challenge, with one scrambled egg (approximately 6.7 g of egg protein) provided 1 hour after completion of the double-blind portion. Those who passed this challenge continued on an egg-restricted diet and without daily OIT for 3 to 4 months, at which time they underwent a second DBPCFC administered in identical fashion to the first.

Egg-specific IgG and IgE concentrations 

Blood draws occurred at enrollment and at the 3-, 6-, 12-, 18-, and 24-month follow-up visits. Sera were stored at −20°C until analysis. Specific IgE and IgG responses to egg were quantified by using the Unicap100 system (Pharmacia Diagnostics AB, Uppsala, Sweden).

Data analysis 

This protocol was a pilot proof-of-concept study designed to determine the safety of egg OIT, as well as to develop an improved understanding of the immunologic dynamics during this process. Descriptive statistics, including means, SDs, frequencies, proportions, and graphic displays, were computed for all study variables. Plots of the longitudinally measured variables were constructed to capture general trends. For egg-specific IgE and IgG concentrations, absolute differences were calculated by subtracting each follow-up time point value from the baseline value for each subject. One-sample paired t tests were used to determine statistical significance (2-tailed, P < .05). Because of the exploratory nature of this study, there were no plans to adjust the significance level for multiple comparisons.

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Results 

Subjects 

Seven subjects were initially enrolled, and all 7 completed the study, with a median age at enrollment of 48 months and a mean age of 44.7 months (range, 14-84 months). Table II outlines the age at enrollment, history of reaction on prior egg ingestion, and comorbid conditions for each subject. All subjects had atopic dermatitis, and 3 (43%) had asthma. Six (86%) subjects had at least one other food allergy. All subjects had histories of egg-ingestion reactions, and none had a history of anaphylaxis to egg. The most common organ system affected by prior ingestion was the skin (100%), with abdominal symptoms occurring in 2 (29%) subjects.

Table II. Subject demographics at enrollment

AD, Atopic dermatitis.

Modified rush phase 

Symptoms experienced during the modified rush phase were generally mild. For each subject, complete symptom profiles and egg protein dose (single and cumulative) at onset of symptoms are provided in Table III. One subject did not require any treatment. Of the remaining 6 subjects, 5 were treated only with antihistamines. One subject received intravenous fluids as a precautionary measure for mild transient hypotension, and no subjects received epinephrine.

Table III. Modified rush symptoms and associated doses with initial home daily doses

SE, Skin erythema; SP, skin pruritus; E, emesis; S, sneezing; R, rhinorrhea; AP, abdominal pain; NC, nasal congestion; U, urticaria; H, hypotension; OP, oral pruritus; NA, not applicable.

Build-up phase 

Table III also shows the initial home daily dose for each subject. Regardless of the reaction during the modified rush phase, all subjects tolerated all subsequent daily doses without significant difficulty. One subject (subjects 006) experienced a temporary delay in initially advancing his daily dose (from 25 mg to 50 mg) when he experienced abdominal pain, nausea, and diffuse pruritus within minutes of receiving the first dose at the increased amount. He was treated with oral diphenhydramine, with prompt resolution of symptoms. After continuing on 25 mg daily for an additional 2 weeks, he tolerated this and all subsequent biweekly increases. No other subjects experienced clinical reactions during the build-up phase and were able to advance to maintenance according to schedule.

Maintenance phase 

No subjects reported symptoms related to home maintenance dosing during the 2-year OIT treatment. Three subjects (subjects 004, 006, and 007) tolerated possible or known accidental ingestions of egg-containing foods. While receiving a dose of 200 mg, subject 004 ate one bite (approximately 50 mg egg protein) of a processed cake with a warning label stating that it contained egg. On noticing the label, the subject did not ingest any more, and no reaction was noted. Subject 006 had an apparent reaction to an unknown trigger at a fast-food restaurant while receiving a maintenance dose of 300 mg. This subject (also allergic to milk, peanut, and wheat) experienced facial itching and perioral hives that resolved after oral diphenhydramine treatment. Subject 007 experienced 3 known accidental egg exposures, all while at a 300-mg maintenance dose: an egg-containing cupcake (approximately 600 mg of egg protein), one bite of an egg-containing cake (approximately 50 mg of egg protein), and an egg-containing cookie (approximately 300 mg of egg protein). None of the 3 accidental exposures in subject 007 led to any clinical symptoms of a reaction.

DBPCFC 

Table IV summarizes outcomes of challenges at study conclusion. Four subjects (subjects 001, 003, 004, and 005) passed their initial challenges, ingesting 8 g of egg protein in the blinded portion and a scrambled egg (approximately 6.7 g) fed openly. Of the remaining subjects, subject 002 reacted at a cumulative dose of 2 g of egg protein, with a minimal amount of emesis, nasal congestion, and complaints of facial and throat itching; he responded rapidly to oral diphenhydramine. Subject 006 completed the blinded portion of the challenge without symptoms, but after progressing to the open portion, the subject experienced facial, neck, and shoulder hives 20 minutes after ingesting the entire scrambled egg; the subject was treated with oral diphenhydramine without further reaction. The final subject, subject 007, experienced abdominal pain, vomiting, and nasal congestion at the conclusion of the blinded portion; this subject was also treated only with oral diphenhydramine. All subjects tolerated significantly higher doses of egg protein at this challenge than during the modified rush phase. The mean cumulative dose of egg protein associated with symptoms at the beginning of the study was 0.05 g (SD, 0.04 g), which increased to 11.93 g (SD, 5.04 g) by the end; this mean increase was statistically significant (P = .0008).

Table IV. Outcomes of DBPCFCs with cumulative ingested egg protein amount at reaction

NA, Not applicable.

Subjects who passed the first challenge (subjects 001, 003, 004, and 005) underwent a second DBPCFC after a 3- to 4-month interval without OIT, during which they maintained an egg-restricted diet. Subjects 001 and 004 passed their second DBPCFC as well. Subjects 003 and 005 both failed the double-blind portion of this second challenge. Subject 003 reacted after consuming 24 mg of protein with urticaria, abdominal pain, vomiting, throat itching, and hoarseness, whereas subject 005 reacted at a cumulative dose of 2 g with perioral urticaria and upper lip and periorbital edema.

Egg-specific Ig concentrations 

Baseline, 12-month, and 24-month egg-specific IgG and IgE values for each subject are provided in Tables E1 and E2 (see the Online Repository at www.jacionline.org), with mean changes over time depicted in Fig 1. Mean baseline and 24-month IgG levels were 8.24 mg/L (SD, 5.57 mg/L; 95% CI, 3.09-13.39 mg/L) and 38.00 mg/L (SD, 18.92 mg/L; 95% CI, 20.49-55.50 mg/L), respectively. Mean change in egg-specific IgG levels from baseline to 24 months was 29.76 mg/L (95% CI, 16.07-43.46 mg/L), which was statistically significant (P = .002). With respect to egg-specific IgE levels, mean baseline and 24-month levels were 23.75 kU/L (SD, 44.01 kU/L; 95% CI, −16.95 to 64.45 kU/L) and 12.43 kU/L (SD, 18.95 kU/L; 95% CI, −5.09 to 29.95 kU/L), respectively. Five (71%) subjects showed an overall decrease in egg-specific IgE levels, and mean change in specific IgE from baseline was −11.32 kU/L, although this decrease did not reach statistical significance.

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• Fig 1. 

  A, Mean egg-specific IgG levels (in milligrams per liter) over time. B, Mean egg-specific IgE levels (in kilounits per liter) over time.

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Discussion 

The only proven management of patients with food allergy is dietary elimination of the offending allergen,² but accidental ingestion reactions are common among such patients.¹⁸ Elimination diets are often complicated, and difficulties with interpretation of labels¹⁹ and undeclared or hidden allergens²⁰, ²¹ cause restriction diets to adversely affect the HRQL of patients and families.³, ⁴, ⁵, ²² The results of the study presented here suggest that egg OIT might offer a way to help alleviate many of these concerns for patients with egg allergy. The protocol appears to be safe, to be well tolerated, and to offer protection against accidental ingestion reactions.

The study began with a modified rush phase, with the goal of first desensitizing subjects to egg. In allergen desensitization effector cells are rendered less reactive or nonreactive by rapid administration of incremental allergen doses, but once administration of allergen stops, the previous level of reactivity returns.²³ The ultimate goal of allergen immunotherapy is the achievement of clinical tolerance²⁴; this refers to a long-lasting effect that persists even after treatment is stopped.¹⁴ The 2 DBPCFCs at study conclusion (one during OIT and the second after discontinuation) were implemented to help determine whether subjects who passed the first challenge did so because they were desensitized or because tolerance had developed.

A theoretical concern with this protocol is that daily ingestion of a food allergen might increase the subject's tendency to react clinically to that food. Physicians, patients, and families might be justifiably anxious about the risks of home dosing with the food patients have previously been instructed to strictly avoid, but no subject experienced any reaction requiring treatment during 2 years of daily home dosing. After daily ingestion of only 300 mg of egg protein, 4 (57%) of 7 subjects passed both a double-blind and open challenge with 14.7 g. Those who failed did so at cumulative doses ranging from 2 to 14.7 g, well above the amount ingested during an average accidental exposure to egg-containing products (75-150 mg). All subjects were able to ingest higher egg protein doses at study conclusion than during the modified rush phase. Although egg dosing during the modified rush phase was provided in an incremental and open fashion and thus these amounts cannot be compared with complete reliability with the DBPCFC at study conclusion, this is encouraging for physicians and parents concerned about the effects of daily ingestion of a known food allergen. Instead of worsening sensitivity, egg OIT might actually increase the threshold of exposure needed to elicit a reaction. The statistically significant increase in allergen-specific IgG concentrations seen here is similar to that described in injection immunotherapy for inhalant and venom allergies.²⁴

Previous investigators have examined various methods of immunotherapy for food allergy. Traditional subcutaneous immunotherapy has been proved effective in inducing tolerance in various allergic diseases,⁷, ⁸, ⁹ and case reports at the beginning of the last century described its successful use for food allergy as well.²⁵ However, although subsequent studies showed that tolerance was increased, the rate of adverse effects was unacceptably high.¹⁰, ¹¹ Investigations into newer immunomodulatory treatments for food allergy are ongoing,²⁶, ²⁷ yet most of these studies are currently limited to animal models²⁸ and are years away from being available to patients. Although studies with humanized, monoclonal anti-IgE antibody for peanut allergy are promising for at least partial protection against severe reactions, this treatment does not reverse disease,²⁹ is expensive, and must be administered indefinitely.³⁰

We sought to develop a therapy for food allergy that would be safe and immediately available to patients. Noninjection routes of immunotherapy have been shown to be viable and safe alternatives to traditional immunotherapy in treating asthma and allergic rhinitis.³¹, ³², ³³, ³⁴ Studies by Patriarca et al¹⁵ and Meglio et al¹⁶ demonstrated partial success with OIT in subjects with a variety of food allergies. Both groups used protocols that began with a single oral dose of allergen, which was increased daily or weekly until reaching maintenance. The failure of some subjects to advance to maintenance in these studies might have been due to inadequate initial desensitization. Perhaps as a result of the initial modified rush phase, all of the subjects in our study were able to proceed through the subsequent build-up phase with little difficulty.

Although we have demonstrated the safety of OIT for egg allergy, we cannot make any conclusions about the mechanism of action of OIT from this initial small cohort. There are several possible explanations as to why a subject would pass one of the challenges at study conclusion. One is that the subject was in the process of outgrowing the allergy, and the protocol did not affect the natural history; approximately 50% of children with egg allergy will outgrow their sensitivity within 36 months after diagnosis.³⁵ Another is that the OIT protocol desensitized a subject but did not induce tolerance; as mentioned, it was for this reason that a second challenge (off OIT) was performed in subjects who passed the first challenge. Conversely, passing either challenge could be an indication that OIT caused true clinical and immunologic tolerance to develop.

The 300-mg maintenance dose used in our protocol seems to be high enough to protect against reaction on accidental exposure to egg, but higher doses might be required to induce tolerance. The 2 subjects who passed both challenges had the lowest egg-specific IgE levels among the cohort at study conclusion, with levels (0.35 and 0.95 kU/L, respectively) that clinically could have been used to suspect tolerance. In the 2 subjects who passed the first DBPCFC but failed the second, the protocol seems to have led to desensitization only. One of these (subject 005) had the highest egg-specific IgE level in the study at baseline (123 kU/L) and study conclusion (53.8 kU/L), suggesting that a high allergen-specific level does not preclude desensitization.

Several other observations can be made about subject baseline characteristics and reactions to egg exposure during the study. For example, subjects 002, 003, and 005 had the highest initial egg-specific IgE levels (12, 14.7, and 123 kU/L, respectively). Although subject 005 experienced the most severe reactions during the modified rush protocol, these subjects did not experience more severe reactions during maintenance OIT or during the DBPCFC; thus a higher initial egg-specific IgE level does not seem to predict difficulty with completing the protocol. In addition, 3 subjects (subjects 002, 003, and 007) had diagnoses of asthma, yet none experienced lower respiratory tract symptoms in response to OIT or DBPCFC. The lack of wheezing during challenges is perhaps surprising, although consistent with the fact that none had wheezed in response to prior egg exposure. It is encouraging that each was able to increase her or his reaction threshold level over the study and still did not wheeze in response to exposure.

A limitation of this study is its lack of a control group. This study represents an attempt to evaluate a new protocol requiring a very significant commitment on the part of subjects and families, and it was believed to be safest and most feasible to perform this initial assessment in an open and uncontrolled fashion. This cohort also involved subjects without a history of severe clinical reactions to egg ingestion. Our next study will incorporate a double-blind, controlled design with more subjects to make more definitive conclusions about the clinical and immunologic effects of egg OIT. Future studies will include subjects with a more severe history of egg allergy (eg, those with a history of egg-induced anaphylaxis), as well as with larger doses and different food allergens. And although modified rush reactions to the current protocol were generally mild, one subject (subject 005) experienced mild and transient hypotension not treated with epinephrine. Our experience here has shown us that if we limit the highest single dose during the modified rush phase to 50 mg, the chance of a severe reaction to initial desensitization should be markedly decreased. Future laboratory studies will be directed at studying changes in allergen-specific T-cell profiles and in egg-specific IgG subclasses; evaluating changes in IgG4 in particular will allow for comparison with studies of traditional immunotherapy, in which this subclass correlates more specifically with induced clinical tolerance than total allergen-specific IgG levels.²⁴

We have shown that daily ingestion of egg protein through OIT seems to safely offer protection against reaction to accidental ingestion. Although the long-term induction of oral tolerance is the ultimate goal, even without such an effect, the use of OIT might provide a significant paradigm shift in the treatment of food allergy: active therapy instead of recommendations for strict avoidance and a prescription for epinephrine.

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Appendix. Supplementary data 

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