The natural history of egg allergy

Article Outline

• Abstract
• Methods
  • Statistical analysis
• Results
• Discussion
• Appendix. Supplementary data
• References
• Copyright

Background

Egg allergy is very common, affecting 1% to 2% of children. It is generally thought that the majority of children with egg allergy develop tolerance in early childhood; however, this has not been examined in a large cohort with egg allergy.

Objective

The purpose of the study was to estimate the proportion of children with egg allergy who develop egg tolerance and to identify predictors of tolerance development.

Methods

Retrospective chart review of patients with egg allergy seen in a tertiary referral clinic. Patients were considered to have developed egg tolerance if they tolerated concentrated egg.

Results

Kaplan-Meier analysis predicted resolution in 4% of patients with egg allergy by age 4 years, 12% by age 6 years, 37% by age 10 years, and 68% by age 16 years. Patients with persistent egg allergy had higher egg IgE levels at all ages to age 18 years. A patient's highest recorded egg IgE, presence of other atopic disease, and presence of other food allergy were significantly related to egg allergy persistence.

Conclusion

A majority of patients with egg allergy will develop egg tolerance, although the rate of tolerance development is slower than described previously. Egg IgE is predictive of allergy outcome and should be used in counseling patients on prognosis.

Clinical implications

Most patients with egg allergy are likely to develop egg tolerance by late childhood, with the exception of patients with an egg IgE greater than 50 kU/L, who are unlikely to develop egg tolerance.

Key words: Egg, egg allergy, food allergy, IgE, tolerance, natural history

Abbreviation used: SPT, Skin prick test

Egg allergy is one of the most common food allergies, affecting 1% to 2% of young children.¹, ² It is overall second only to milk allergy in prevalence and in most studies has been shown to be the most common food allergy in children with atopic dermatitis.³, ⁴, ⁵ It can cause severe allergic reactions in sensitized children,⁶ and egg avoidance can cause significant dietary limitations. In addition, early sensitization to egg is a marker of later sensitization to aeroallergens⁷ and the development of asthma.⁸ Egg allergy is also important to the general practitioner in deciding which childhood vaccines are safe to administer.

Three small, prospective studies have attempted to address the natural history of egg allergy.⁹, ¹⁰, ¹¹ Unfortunately, it is difficult to compare results between studies because of different ages at study entry and different follow-up times. On the basis of these studies, parents of children with egg allergy are generally advised that most children will outgrow their allergy by the early school-age years.¹² Clinical and laboratory factors that have been associated with development of tolerance to egg include milder symptoms on egg ingestion,⁹, ¹¹ skin test size,¹¹ earlier age at diagnosis,¹³ egg IgE levels,⁹, ¹⁰ and rate of change of egg IgE levels.¹³

In this study, we evaluated a large population of patients with egg allergy to develop a better understanding of the natural history of egg allergy. The purpose of the study was to determine the rate of development of egg tolerance and to identify clinical and laboratory features that may predict the development of tolerance.

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Methods 

We completed a retrospective chart review of patients from the Johns Hopkins Pediatric Allergy Clinic who were diagnosed with egg allergy. Records were reviewed by a single reviewer (J. H. S.). A total of 4958 charts were reviewed, which yielded 881 patients with egg allergy. The patients were from the practices of 2 attending physicians (R. A. W. and E. C. M.). Patients were included in the chart review if they had a clear clinical history of an IgE-mediated allergic reaction to egg ingestion, or if they had an egg IgE >2 kU/L without known tolerance to egg, typically detected in the evaluation of atopic dermatitis or other food allergies.

The specific data collected included the patient's birth date, sex, age, symptoms at egg allergy diagnosis, presence of other atopic diseases, presence of other food allergies, dietary history, age and symptoms with accidental exposures to egg, egg skin prick test (SPT) results, egg IgE levels, food challenge results, outcome of other food allergies, and egg allergy outcome. Only egg white specific IgE levels were included in this analysis.

The diagnoses of asthma, eczema, allergic rhinitis, and other food allergies were made by the attending physician. Allergy to other foods was defined as having had a clear symptomatic reaction to the food and/or having had a positive food-specific IgE level or SPT without known tolerance to that food. Development of tolerance to foods other than egg was defined as passing a formal food challenge or successful parental introduction of the food at home.

Patients with egg allergy followed in our clinic typically have food-specific IgE levels checked annually using the Pharmacia CAP System FEIA (Phadia, Uppsala, Sweden). CAP IgE values ordered by referring providers were also included in the analysis when these results were available.

The primary endpoint of interest was the development of oral tolerance to egg. Oral egg challenges were generally performed when a patient was considered to have at least a 50% chance of passing the challenge, on the basis of the egg IgE level¹⁴ and/or a history of symptoms with accidental exposure. Food challenges in our clinic typically use concentrated egg (1 whole cooked egg) and follow a protocol described in Perry et al.⁶, ¹⁴ Briefly, patients are offered 5% of a whole cooked egg. If after 15 minutes there are no allergic symptoms, patients are offered more egg in increasing amounts at 15-minute intervals to a maximum dose of 1 whole egg. If at any time allergic symptoms develop, the challenge is stopped and appropriate medications are administered to treat the allergic reaction. Patients who were not likely to have developed egg tolerance did not undergo oral challenges, but continued to be followed.

For this study, 3 definitions of oral tolerance to egg were used that ranged from conservative to inclusive (Table I). Under the most conservative definition (Definition #1), a child was considered to be egg tolerant if they passed a formal food challenge or if they had successful home introduction of concentrated egg. All other patients were considered to have persistent egg allergy. Definition #1 may underestimate the true number of patients who achieved tolerance because it ignores those lost to follow-up, some of whom may have developed tolerance. Therefore, we created 2 more inclusive definitions of oral tolerance. According to Definition #2, a child was considered to have developed egg tolerance if they passed a formal egg challenge, if they had successful home introduction of concentrated egg, or if their last recorded egg IgE was <2 kU/L and they had no recorded reaction with egg exposure in the last 12 months. The most inclusive definition (Definition #3) is identical except that it includes those children with a last recorded egg IgE <6 kU/L. The IgE cutoffs of 2 kU/L and 6 kU/L were chosen because they have been shown to have 90% and 95% positive predictive value in diagnosing egg allergy, respectively.¹⁵, ¹⁶

Table I. Criteria for clinical tolerance

Statistical analysis 

All analyses were performed with StataSE 8.0 (StataCorp, College Station, Tex). Egg IgE levels were recorded as <0.35 kU/L or >100 kU/L, or if between those values, the specific value was recorded. For purposes of statistical analysis, negative egg IgE results (<0.35 kU/L) were assigned a value of 0.18 kU/L, and values of >100 kU/L were assigned a value of 101 kU/L. The highest egg IgE recorded for each patient was considered their peak level. Peak egg IgE levels were stratified into 6 categories: <2 kU/L, 2 to 4.9 kU/L, 5 to 9.9 kU/L, 10 to 19.9 kU/L, 20 to 49.9 kU/L, and ≥50 kU/L. Kaplan-Meier curves were generated to depict the development of tolerance to egg over time for each of the 3 definitions of egg tolerance. Kaplan-Meier curves were also generated to depict the development of tolerance for the group that had had an allergic reaction to egg and the group that was diagnosed with egg allergy on the basis of elevated egg IgE alone. The Mann-Whitney U test was used to compare median egg IgE levels between the group with persistent allergy and the group that went on to develop tolerance. The log-rank test was used to compare time to development of tolerance between patients with and without a particular clinical characteristic. Nonparametric smoothed curves were generated using the lowess command (bandwidth 0.8) to depict the trend in egg IgE levels over time. For all analyses, egg tolerance definition 1 was used unless specified otherwise.

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Results 

A total of 881 patients were studied and are described in Table II. There were 599 (68%) male subjects and 282 (32%) female subjects. The median age at initial visit was 14 months, the median follow-up time was 4.9 years, and the median number of patient visits was 5. The median initial egg IgE was 7.3 kU/L, and the median peak egg IgE was 9.4 kU/L.

Table II. Patient characteristics

Characteristic	Number
Total no. of patients	881
Age at initial visit, median (interquartile range)	14 mo (10-23)
Duration of follow-up, median (range)	59 mo (5-285)
Follow-up visits, median (range)	5 (1-16)
Sex, n (%)
Male	599 (68)
Female	282 (32)
Other atopic conditions, n (%)
Asthma	474 (54)
Allergic rhinitis	482 (55)
Eczema	711 (81)
Any food allergy besides egg, n (%)	817 (93)
Peanut	656 (74)
Milk	633 (72)
Tree nut	375 (43)
Soy	237 (27)
Wheat	208 (24)
Initial diagnosis made by, n (%)
History of reaction	375 (43)
Positive IgE only	506 (57)
Initial symptoms of egg allergy, n (%)∗
Skin (urticaria, angioedema, rash)	219 (58)
Gastrointestinal	78 (21)
Eczema	69 (18)
Lower respiratory	37 (10)
Upper respiratory	15 (4)
Egg IgE levels (kU/L), median (interquartile range)
Initial	7.3 (2.0-22.2)
Peak	9.4 (3.0-34.0)

The initial diagnosis was made on the basis of convincing history of allergic reaction to egg and evidence of egg sensitization (egg IgE >0.35 kU/L or positive SPT) in 375 (43%) and on the basis of a positive IgE (>2 kU/L) in 506 (57%). Of the 506 patients who were given a diagnosis of egg allergy solely on the basis of an egg IgE >2 kU/L, 161 of them developed symptoms with egg ingestion from a food challenge or accidental exposure during follow-up. Therefore, a total of 536 (61%) patients had a clear history of allergic symptoms on egg ingestion in addition to evidence of egg sensitization. The most common presenting symptoms of egg allergy were skin-related (urticaria, angioedema, noneczematous rash) in 59%, gastrointestinal (vomiting, diarrhea, bloody stool, abdominal pain) in 21%, eczema in 18%, lower respiratory (wheezing, coughing, difficulty breathing) in 10%, and upper respiratory (rhinitis, nasal congestion) in 4%. There were a total of 262 food challenges in 212 patients with a pass rate of 57%.

Most patients had at least 1 other food allergy (93%). The most common other food allergies encountered were peanut (75%), milk (72%), and tree nuts (43%). Asthma was diagnosed in 54%, allergic rhinitis in 55%, and eczema in 81%.

Breast-feeding history was known in 74%, of whom 89% were breast-fed. Breast-feeding duration was available for 416 patients; the median breast-feeding duration was 7 months with a range of 1 to 36 months. Formula history was available for 74%. Of those, 62% received cow's milk formula, 57% received soy formula, 48% received a hydrolyzed formula, and 12% received an amino acid formula.

When tolerance was defined by using the most conservative criteria as tolerating concentrated egg (Definition #1), we found that only 4% outgrew their allergy by age 4 years, 26% by age 8 years, 48% by age 12 years, and 68% by age 16 years. When tolerance was defined as tolerating concentrated egg or an egg IgE <2 kU/L and no reaction in the past 12 months (Definition #2), the rates of resolution were 11% at age 4 years, 41% at age 8 years, 65% at age 12 years, and 82% at age 16 years. With the most inclusive definition, tolerating concentrated egg or an egg IgE <6 kU/L and no reaction in the past 12 months (Definition #3), tolerance rates were 19% by age 4 years, 55% by age 8 years, 76% by age 12 years, and 91% by age 16 years (Table III; Fig 1). Kaplan-Meier curves for patients with a history of symptoms on egg ingestion and those whose egg allergy was diagnosed by elevated egg IgE alone were not significantly different (see this article's Fig E1 in the Online Repository at www.jacionline.org).

Table III. Incidence of egg allergy resolution∗

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• Fig 1. 

  Egg allergy resolution over time. Graphs represent Kaplan-Meier survival curves for development of tolerance to egg over time using 3 definitions for tolerance.

There were 2681 egg IgE levels recorded. Patients with persistent allergy had higher egg IgE levels in the first 2 years of life compared with those who went on to develop egg tolerance (median, 11.2 kU/L vs 3.4 kU/L; P < .001). This difference was maintained through age 18 years (Table IV). Trends in egg IgE levels were also different between groups, with the persistent group gradually declining with age, and the resolved group sharply declining by age 2 years (Fig 2).

Table IV. Egg IgE levels in patients with persistent egg allergy and in patients who went on to develop egg tolerance (resolved)

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• Fig 2. 

  Trend in egg IgE levels over time by final egg allergy status. Scatter plots of all egg IgE levels recorded by age (n = 2681). A, All values in the group with persistent egg allergy (n = 2192). B, All values in the group that eventually resolved egg allergy (n = 489). Nonparametric smoothed curves show the trend in egg IgE levels over time.

We also examined the relationship between the peak egg IgE level and the development of tolerance (Fig 3). The rate of tolerance development was inversely related to the peak egg IgE (P < .0001, log-rank test for trend). Children with a peak egg IgE <2 kU/L had the fastest rate of tolerance development. The children whose peak IgE was between 2 and 49.9 had slower rates of tolerance development. However, most children in the peak IgE groups <2 to 49.9 kU/L did eventually develop tolerance to egg. The group of children with a peak egg IgE ≥50 kU/L had the slowest rate of tolerance development, and most of these children did not develop tolerance before age 18 years, the end of the study period. For example, by age 8 years, 46% with a peak egg IgE <2 kU/L, 32% with a peak level of 2 to 4.9 kU/L, 17% with a peak level of 5 to 9.9 kU/L, 16% with a peak level of 10 to 19.9 kU/L, 14% with a peak level of 20 to 49.9 kU/L, and 11% with a peak level ≥50 kU/L had developed tolerance.

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• Fig 3. 

  Relationship of peak egg IgE level and resolution of egg allergy. Survival curves for each stratum of peak egg IgE level. Number of patients in each stratum: <2 kU/L (n = 155); 2-4.9 (n = 131); 5-9.9 (n = 125); 10-19.9 (n = 118); 20-49.9 (n = 103); 50+ (n = 162). Number of patients remaining at the final time point analyzed for each stratum: <2 kU/L (n = 3); 2-4.9 (n = 3); 5-9.9 (n = 3); 10-19.9 (n = 2); 20-49.9 (n = 1); 50+ (n = 1).

The median time to develop tolerance was consistently greater in children with other atopic disease (Table V). In children with asthma, the median time to develop tolerance was 13.5 years compared with 8.5 years for children without asthma (P < .001). The median time to develop tolerance was 12.6 years for children with allergic rhinitis compared with 11.8 years for children without allergic rhinitis (P < .001). The median time to develop egg tolerance was 12.3 years in children with eczema compared with 11.1 years in children without eczema (P = .055). The median time to develop egg tolerance was also consistently greater in children with other food allergies (Table V). This relationship was statistically significant for peanut, milk, tree nuts, soy, wheat, sesame, and fish.

Table V. Clinical parameters and median time (y) to develop tolerance to egg

Characteristic	Presence (median years to develop egg tolerance)	Absence (median years to develop egg tolerance)	P value∗
Other atopic disease
Asthma	13.5	8.5	<.001
Allergic rhinitis	12.6	11.8	<.001
Eczema	12.3	11.1	.056
Other food allergies
Peanut	12.6	11.1	<.05
Milk	12.6	11.4	<.05
Tree nut	13.1	11.4	<.01
Soy	13.9	11.4	<.005
Wheat	17.7	11.5	<.001
Sesame	13.5	11.9	<.01
Fish	15.2	11.9	<.05
Shellfish	13.9	12.0	.093

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Discussion 

Egg allergy is generally considered to have a good prognosis, and parents are typically counseled that their children will outgrow the allergy by the early school-age years. Our results from this analysis of more than 850 patients with IgE-mediated egg allergy support the idea that the majority of children with egg allergy will develop tolerance over time. However, our data suggest that this does not happen as early as previously thought. Furthermore, we have identified an egg IgE level ≥50 kU/L as a marker of persistent egg allergy.

When egg tolerance was defined by using our strictest definition as being tolerant of concentrated egg (Definition #1), we found that 4% developed tolerance by age 4 years, 12% by age 6 years, 37% by age 10 years, and 68% by age 16 years. The largest and most recent prospective study of the natural history of egg allergy, from a cohort of 58 children, found that 50% of children with egg allergy developed tolerance by age 4 to 4.5 years,¹¹ much earlier than in our study. There are several key differences in the patients followed in that study compared with ours. Their patients were not as highly atopic; for example, only 50% had eczema, compared with 81% in our study. The median egg IgE in that study at entry was 1.98 kU/L, and in our study it was 7.3 kU/L. This difference is likely representative of the fact that our population had all been referred to a tertiary care center for their care.

Our study design had several limitations, and we could have overestimated or underestimated the proportion of children who developed egg tolerance. For example, if children lost to follow-up had tolerated egg in unsupervised home food challenges, our data could underestimate the proportion of children who develop egg tolerance. Conversely, there may have been a lower rate of egg tolerance in those lost to follow-up than in those still followed. Children with elevated egg IgE levels, especially those ≥50 kU/L, may have felt that their prognosis was poor and did not see utility in regular allergy evaluations, excluding them from follow-up visits. For these reasons, we analyzed the data by using 3 definitions of egg tolerance that vary from conservative to inclusive. We feel that our most conservative definition, Definition #1, is most accurate, and we have therefore used it for subsequent analyses.

Another limitation of our study is that many patients were diagnosed with egg allergy on the basis of IgE alone and did not have a history of reaction to egg. This occurred because these children were being evaluated for atopic dermatitis or another food allergy before egg had been introduced into the diet, and then strict egg avoidance was instituted on the basis of the elevated egg IgE. However, the Kaplan-Meier survival curves for egg tolerance development in children with a history of reaction with egg ingestion and children whose egg allergy was diagnosed on the basis of elevated egg IgE alone were similar (data not shown), suggesting that those whose allergy was diagnosed on the basis of elevated IgE did indeed have true egg allergy.

Several clinical and laboratory parameters were related to egg allergy outcome. The presence of other atopic disease was significantly related to the persistence of egg allergy. In addition, allergy to other foods was significantly related to the persistence of egg allergy, although we recognize that our methods to diagnose other food allergies were not exhaustive. We found that children with elevated egg IgE were more likely to have persistent egg allergy. A child with an egg IgE level greater than 50 kU/L was unlikely to develop egg tolerance before the age of 18 years, the end of the period studied.

In conclusion, we have shown that even in a highly atopic population, a majority of patients with egg allergy will eventually develop egg tolerance. The rate of development of tolerance is slower than described previously, and this likely reflects the high degree of atopy in our referral population. Egg IgE is highly predictive of allergy outcome and should be used in counseling patients on prognosis.

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Appendix. Supplementary data 

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