Total serum IgE levels as predictor of the acquisition of tolerance in children with food allergy: Findings from a pilot study

Introduction

Cow’s milk is the most common and clinically important food allergen in children, likely because it is an important nutrient source in early childhood (1). However, the diagnosis of milk allergy is often difficult, with symptoms consistent with other conditions, including lactose intolerance and protein-induced enterocolitic syndrome. Nevertheless, growing up, many children acquire tolerance towards milk and they should be assessed for reintroduction (2). Egg allergy is the second most common food allergy (FA) in childhood, affecting 0.5%–8.9% of the pediatric population (3). Although the majority of children have outgrown their egg allergy by the age of 16, only 12%–50% reach the tolerance between the ages of 6 to 11 (4). Given the acquisition of tolerance over time in both egg and milk allergy, we decided to focalize our study on this topic and only consider patients affected by food allergy mediated by IgE-mediated mechanisms.

Oral food challenge (OFC) is considered the gold standard to diagnose FA and to assess the attained tolerance (5), but it is time-consuming, difficult to perform and related to the risk of severe allergic reactions. Therefore, easier, and less invasive laboratory methods have been evaluated to avoid the severe allergic reactions caused by OFC. The relationship between food-specific IgE levels and outcome of OFC was firstly investigated in a prospective study including 100 children with FA by Sampson et al. (6). The authors showed that the evaluation of food-specific IgE was useful for the diagnosis of symptomatic FA and for avoiding the need OFC in a considerable number of allergic children. For example, Komata et al. (7) found that specific IgE levels above 25.5 kUA/L for egg and 50.9 kUA/L for milk indicated a 95% risk of reaction to OFC. Specific IgE levels ≤2 kUA/L to milk, egg, or peanut (or ≤5 kUA/L to peanut without history of previous reaction) 41 were associated with 50% likelihood of negative OFC. Therefore, children with these specific IgE cut-offs were appropriate candidates for OFC to investigate the acquisition of tolerance (8). Further prospective studies developed significant FA probability curves to predict OFC test failure (9, 10). Mehl et al. (11) retrospectively analyzed 992 OFCs performed in 501 children with median age of 13 months, showing a significant correlation between the specific IgE/total IgE ratio and the outcome of OFCs for milk, egg, and wheat, although without benefit compared with the specific IgE alone. However, the correlations between specific IgE and total IgE levels are not linear, given that total IgE level usually follows a lognormal distribution while the specific IgE level does not, therefore the calculation of the ratio might be too simple to accurately reflect the true relationship between the two factors. Horimukai et al. (5) examined retrospectively the medical records of 337 and 266 patients who underwent OFCs for 3.5 g boiled hen's egg white and 3.1 ml raw cow's milk, respectively. The authors found that children with higher total IgE levels were significantly less responsive during OFC; indeed, they explained that nonspecific IgE could suppress specific IgE-mediated activation of basophils in vitro (12), affecting the clinical severity of patients with food, drug and Hymenoptera venom allergies (13, 14). The previous findings identified clinical and laboratory factors that could predict the negativity of the OFCs reducing the number of unnecessary tests. Differently, in our study we decided to evaluate whether total IgE levels could be considered as a marker of the acquisition of tolerance after an elimination period of the causal allergen in children with milk or egg allergy.

The main aim of this pilot study was to assess the association between total IgE levels at the diagnosis of FA and the duration of the causal food elimination diet in order to establish the best timing to perform an OFC without severe allergic reactions.

Methods

We carried out a retrospective study to investigate the clinical and laboratory parameters in milk and egg allergic children. The inclusion criteria were:

• children diagnosed with IgE-mediated allergy to milk (group 1) or egg (group 2) who were on a specific food elimination diet; the diagnosis was based on clinical history and positive food-specific IgE values;

• OFC test performed to assess for tolerance acquisition, in the Pediatric Allergy and Respiratory Unit of the University of Chieti from January 2018 to December 2020;

• available total IgE values at the diagnosis (time 0), specific IgE for egg and milk and recombinant milk allergens (lactalbumin, lactoglobulin and casein recombinant allergens) at the diagnosis (time 0) and at the time of OFC (time 1).

An accurate family and personal medical history was collected by the parental interview and by consulting medical records. Symptoms of allergy at the onset and children age at the onset of FA, at the beginning of food elimination diet and of food reintroduction were obtained. To better describe our study population, symptoms at the allergy onset were classified as localized (cutaneous, gastrointestinal, upper respiratory) or systemic (anaphylaxis) and characterized according to the severity of symptoms (15). The definition of anaphylaxis is the one of WHO 2020 (16).

(1) Mild (grade 1): isolated local reactions of the skin or mucous membranes in the site of contact with the allergen.

(2) Moderate (grade 2): allergic reactions involving skin areas away from the site of contact with the allergen, the upper airways, and/or the gastrointestinal tract.

(3) Severe (grade 3): severe allergic reactions, potentially at risk of life, which include signs which include cardiovascular, neurological, bronchial and/or laryngeal signs and symptoms.

All the patients involved in the study were selected to perform OFC when their food-specific IgE results fell below 15 KUA/L that we usually use as a cut-off; furthermore, none of them presented recent clinical reactions to accidentally administered causal food in the previous twelve months. In our center, we usually visit allergic patients annually and perform food-specific IgE dosages each time (17).

Primary outcome was to investigate the association between total IgE levels at baseline and the duration of elimination diet (years).

Secondary outcomes were:

- to assess the difference between food-specific IgE levels (milk or egg) at the diagnosis of FA and at the time of food re-introduction;

- to assess the association of different recombinant milk allergens with the severity of the clinical manifestations at the diagnosis.

Written informed consent was obtained from parents or legal representatives of all children. The study was approved by the local Ethical Committee of the University of Chieti, and it was conducted in compliance with ethical principles based on the Declaration of Helsinki.

Statistical analysis

Continuous data were presented as mean and standard deviation (SD) or median and range 5%–95%. Categorical data were presented as absolute numbers and percentages. Shapiro-Wilk test was used to investigate the normality of the distribution of all variables. Given the non-normal distribution of total IgE, the logarithmic transformation has been applied to normalize this variable. Nonparametric tests, such as Wilcoxon test or Mann-Whitney test, were used for continuous variables, while the χ² test for categorical variables. Pearson's correlation was used to assess the correlation between total IgE levels and duration of elimination diet.

In addition, a multivariate linear regression model was performed to investigate the association between total IgE and duration of elimination diet after adjusting for potential confounding factors, such as sex, age at the diagnosis and type of allergy. Spearman's correlation was performed to assess the correlation of different recombinant milk allergens (lactalbumin, lactoglobulin and casein IgE values) with the severity of symptoms at the diagnosis. P-value <0.05 was considered for the significance of our statistical reports.

Statistical analysis was conducted using Stata 15 Software for Statistics and Data Science for Windows

Results

We enrolled 40 patients: 14 (35.0%) were on milk elimination diet and underwent milk OFC, while 26 (65.0%) were on egg elimination diet and performed egg OFC. Clinical and laboratory characteristics of our population were reported in Table 1.

TABLE 1

Table 1. Clinical and laboratory characteristics of our population.

Clinical manifestations at the onset occurred at the median age of 9 months in the group 1. Symptoms described by parents were skin reactions in 7/14 (50.0%) patients, gastrointestinal disorders in 7/14 (50.0%) patients, upper respiratory involvement in 1/14 (7.1%) patients, anaphylaxis in 2/14 (14.3%) patients. Symptoms were mild in 2/14 (14.3%), moderate in 8/14 (57.1%) and severe in 4/14 (28.6%) children.

Clinical manifestations at the onset occurred at the median age of 12 months in the group 2. Symptoms reported by parents were skin reactions in 12/26 (46.2%) patients, gastrointestinal disorders in 8/26 (30.8%) patients, bronchial involvement 3/26 (11.5%) patients, anaphylaxis in 3/26 (11.5%) patients. Symptoms were mild in 10/26 (38.5%), moderate in 12/26 (46.15%) and severe in 4/26 (15.4%) children.

One of 14 (7.1%) milk OFC resulted positive; therefore, 13 children in the group 1 (92.9%) reached the tolerance and started a free diet. Three of 26 (11.5%) egg OFCs were positive; therefore, 23 children in the group 2 (88.5%) reached the tolerance and started a free diet.

The median duration of food allergy (from onset of symptoms to reintroduction of food) was 4.3 years in patients with milk allergy and 5.7 years in patients with egg allergy. We obtained a positive association between total IgE levels and duration of the elimination diet, after adjusting for age, sex, and type of allergy as well (β = 0.153; CI, 95% 0.04–0.27).

Additionally, we confirmed the linear correlation between total IgE levels at the diagnosis (expressed in logarithmic scale) and the duration of the elimination diet in the study population by using Pearson's correlation (r = 0.41; p-value = 0.007) (Figure 1).

FIGURE 1

Figure 1. Correlation between total serum IgE and diet duration.

As regards the secondary outcomes, we also found a significant difference among specific IgE values for casein, α-lactalbumin and β- lactoglobulin at the diagnosis and those obtained at the time of OFC (p = 0.008; p = 0.02; p = 0.03; respectively). We also found a significant difference among specific IgE values for egg white and yolk at the diagnosis and those obtained at the time of OFC (p < 0.001; p < 0.001; respectively). Supplementary Tables S1 and S2 reported these data.

In addition, we observed a significant correlation between specific IgE values for casein at the diagnosis and the severity of symptoms at the onset of FA (Rho = 0.66; p-value 0.009). On the contrary, no correlation of specific IgE for α-lactalbumin and β-lactoglobulin with severity of symptoms at the onset of allergy was found.

Discussion

In the literature, cow's milk allergy appears during early infancy since the first two months of life (18, 19). Egg allergy generally appears with the first intake of food in the second half of the first year of life, at about 1 year of age (20). In our study population, the median age of onset was 9 months for cow's milk allergy and 12 months for egg allergy, comparable to literature findings.

In group 1, 50.0% of milk allergic patients presented cutaneous manifestation, whereas the percentage of cutaneous manifestation reported in the literature is higher. For example, Martorell et al. (21) found the most frequent clinical signs were cutaneous in 94% of milk allergy cases. In agreement with the literature (22), in group 2 the symptoms at the onset were more commonly cutaneous (42.3% of children showed erythema, itching, hives and angioedema), while the gastrointestinal disorders such as vomiting, diarrhea and abdominal pain were less frequent (30.8% of cases), as well as upper respiratory (7.7% of cases) and systemic involvement (anaphylaxis in 11.5% of children).

The median duration of milk allergy in our sample was 4.3 years. This finding differs slightly from the data in the literature, which reported an allergy resolution rate of 45%–50% within the first year of life, 60%–75% within 2 years, and 85%–90% within the third year of life (23). The median duration of egg allergy in our sample was 5.7 years. In children, the prognosis of egg allergy is generally good (20). In previous studies Boyano et al. (24) reported a clinical resolution in 50% of cases within 3 years of age, and in 66% of cases within five years (25). More recently, Clark et al. (25) found that nearly 1/3 of their patients had resolved allergy to well-cooked egg at 3 years and 2/3 at 6 years. Having discussed the results concerning the characteristics of the population, we now focus on the objectives of our study. In this study, in fact, we assessed total IgE at the time of diagnosis as a predictor of the time required for acquiring the tolerance for the causal food allergen.

To date, OFC remains the gold standard to diagnose FA as indicated by EAACI food allergy and anaphylaxis guidelines (26). However, in clinical practice easier and less invasive laboratory methods would be useful in the follow up of allergic patients. Sampson (6) and Komata (7) separately confirmed that quantification of food-specific IgE could avoid probably positive OFC tests thus reducing adverse reactions. At the same time, children with specific IgE ≤ 2 kUA/L to milk, egg, or peanut (or ≤5 kUA/L to peanut without history of previous reaction) were appropriate candidates for OFC to investigate the resolution of FA, because these specific IgE cut-offs were associated with 50% likelihood of negative OFC (7). As in the literature there are several reports about specific IgE role in assessment of acquisition of tolerance (6, 7), we hypothesized we could find a relationship also between total IgE values and acquired tolerance. With this aim, we analyzed the medical records of milk and egg allergic patients who underwent OFC in our center and found an association between total IgE values and diet duration.

Currently, the evaluation of total IgE is only considered a supplemental diagnostic measure for allergic diseases, because of the relatively low sensitivity and specificity and the undefined cost-effectiveness (15). In the literature, we found little evidence to support our result.

Conversely, Beigelman et al. (8) found that higher total IgE levels were associated with an increased likelihood of negative oral milk challenge test, but the authors did not provide an explanation. Al Mughales et al. (27) stated that total IgE evaluation was not efficient as a diagnostic test, especially in food allergies. More recently, an observational retrospective study included 253 children with median age of 8 years affected by milk or egg allergy who underwent OFCs. The authors concluded that total IgE measurement was not recommended because the ratio specific/total IgE was not a better predictor of the outcome of OFCs than food-specific IgEs alone (28). Furthermore, we know that total IgE levels naturally tend to increase over time (29), often coinciding with the acquisition of tolerance. Regarding the previous data and the seeming contradiction with our results, we noted that we performed total IgE dosage at the diagnosis of FA while in the previous studies it was performed at the moment of OFC and also that our sample size is smaller than that of the other studies and this fact could affected the obtained results.

We also found a substantial reduction of specific IgE values from diagnosis to the execution of OFC. It is well known that the greater the serum IgEs level, the greater the probability of allergic reactions (6, 7). In 2018 in their systematic review Calvani et al. (30) suggested that raw egg allergy seems very likely if food-specific IgEis ≥ 1.7 kUA/L in children aged <2 years, while in children 2 years or older the suggested cut-off is ≥7.3 kUA/L (30). For example, Dang et al. found that an egg white food-specific IgE cut-off of 11.0 kUA/L had a specificity of 95% and a sensitivity of 45%, to predict 50% of probability of acquired tolerance (31). Therefore, specific IgE are commonly used in the follow161 up of a child's elimination diet, and their values associate with the likelihood of severe allergic reactions during OFC (32, 33). However, a standardized threshold value of food-specific IgEs to predict the outcome of OFC and the acquisition of tolerance was not definitely established yet. Additionally, the cut-off points predictive of clinical reactivity change over time and depend on the moment of follow-up (34). Briefly, with our results we support the fact that the decrease of specific IgE values in the allergic patient's follow-up could guide the physician in the timing of the food reintroduction, as well as described in the literature.

As a last point, we found a significant correlation between specific IgE for casein and the severity of the symptoms at the onset of FA. Casein is the main protein allergen in cow's milk (34) and several studies have recognized specific IgE for casein as the best predictive factor of positive OFC (34–37). Martorell et al. (34) in a prospective 4-year follow-up study including 170 cow’s milk allergic patients, described that specific IgE levels to casein 0.97 kUA/L at 12 months, 1.22 kUA/L at 18 months, 3 kUA/L at 24 months, 2.39 kUA/L at 36 months, 2.73 kUA/L at 48 months predicted the clinical reactivity, respectively.

This is the first study which examined the association between total serum IgE at baseline, and the duration of elimination diet in milk and egg allergic children. However, some methodological limitations should be discussed. Firstly, a retrospective study design could lead to bias related to the type of study. However, we considered several measures to minimize bias and to increase the validity of our findings. To minimize potential selection bias, we fixed clearly defined inclusion/exclusion criteria identifying the population of interest. To minimize potential measurement bias, data were collected by a trained research pediatrician using a predefined questionnaire. Secondly, the small sample size could have affected the power of the study. Lastly, although we adjusted for several confounders, we might not have had information on all possible confounding factors. Therefore, our findings should be confirmed in observational prospective studies with a large sample of allergic children rightly selected who underwent double-blind placebo controlled OFCs.

In conclusion, we would suggest that total IgE values could be useful in managing children with FA. Particularly, this simple and cheap test should be considered to guide the decision of the duration of the elimination diet and the timing for food reintroduction. We also confirmed the utility of specific IgE for casein to predict the severity of the clinical manifestations. In clinical practice, the allergy tests commonly used to support food allergy diagnosis are skin prick test and specific IgE levels, with total IgE levels, which can also be used to monitor the spontaneous resolution of food allergy over time.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by Comitato Etico dell'Università di Chieti-Pescara. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Author contributions

MA, PDF and SDP conceived the idea. GD worked for data collection. MA, GD reviewed the database. MA analyzed the database. MA, PDF and GD wrote the first draft of the paper. All author contributed in data interpretation and reviewed the manuscript. MA, FC and SDP revised critically the manuscript for important intellectual content. All author approved the final manuscript.

Acknowledgments

The authors would like to thank the investigators and patients at the investigative sites for their support of this study and all the nurses of the Department of Pediatrics, University of Chieti, in particular Romina Capuzzi and Cecilia Finamore for their daily support in clinical research and care of children.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2022.1013807/full#supplementary-material.

Abbreviations

FA, food allergy; OFC, oral food challenge; IgE, immunoglobulin E; SD, standard deviation

References

1. Mousan G, Kamat D. Cow’s milk protein allergy. Clin Pediatr (Phila). (2016) 55(11):1054–63. doi: 10.1177/0009922816664512

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Luyt D, Ball H, Makwana N, Green MR, Bravin K, Nasser SM, et al.  BSACI guideline for the diagnosis and management of cow’s milk allergy. Clin Exp Allergy. (2014) 44(5):642–72. doi: 10.1111/cea.12302

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol. (2011) 127(3):668–76.e1-2. doi: 10.1016/j.jaci.2011.01.039

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Sicherer SH, Wood RA, Vickery BP, Jones SM, Liu AH, Fleischer DM, et al. The natural history of egg allergy in an observational cohort. J Allergy Clin Immunol. (2014) 133(2):492–9. doi: 10.1016/j.jaci.2013.12.1041

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Horimukai K, Hayashi K, Tsumura Y, Nomura I, Narita M, Ohya Y, et al. Total serum IgE level influences oral food challenge tests for IgE-mediated food allergies. Allergy. (2015) 70(3):334–7. doi: 10.1111/all.12562

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. (2001) 107(5):891–6. doi: 10.1067/mai.2001.114708

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Komata T, Söderström L, Borres MP, Tachimoto H, Ebisawa M. The predictive relationship of food-specific serum IgE concentrations to challenge outcomes for egg and milk varies by patient age. J Allergy Clin Immunol. (2007) 119(5):1272–4. doi: 10.1016/j.jaci.2007.01.038

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Beigelman A, Strunk RC, Garbutt JM, Schechtman KB, Jaenicke MW, Stein JS, et al. Clinical and laboratory factors associated with negative oral food challenges. Allergy Asthma Proc. (2012) 33(6):467–73. doi: 10.2500/aap.2012.33.3607

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Nowak-Wegrzyn A, Assa’ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS,, et al. Work group report: oral food challenge testing. J Allergy Clin Immunol. (2009) 123(6 Suppl):S365–83. doi: 10.1016/j.jaci.2009.03.042

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Haneda Y, Kando N, Yasui M, Kobayashi T, Maeda T, Hino A, et al. Ovomucoids IgE is a better marker than egg white-specific IgE to diagnose boiled egg allergy. J Allergy Clin Immunol. (2012) 129:1681–2. doi: 10.1016/j.jaci.2012.03.041

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Mehl A, Verstege A, Staden U, Kulig M, Nocon M, Beyer K, et al. Utility of the ratio of food-specific IgE/total IgE in predicting symptomatic food allergy in children. Allergy. (2005) 60(8):1034–9. doi: 10.1111/j.1398-9995.2005.00806.x

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Christensen LH, Holm J, Lund G, Riise E, Lund K. Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge. J Allergy Clin Immunol. (2008) 122(2):298–304. doi: 10.1016/j.jaci.2008.05.026

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Vultaggio A, Matucci A, Virgili G, Rossi O, Filì L, Parronchi P, et al. Influence of total serum IgE levels on the in vitro detection of beta-lactams-specific IgE antibodies. Clin Exp Allergy. (2009) 39(6):838–44. doi: 10.1111/j.1365-2222.2009.03219.x

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Sturm GJ, Heinemann A, Schuster C, Wiednig M, Groselj-Strele A, Sturm EM, et al. Influence of total IgE levels on the severity of sting reactions in hymenoptera venom allergy. Allergy. (2007) 62(8):884–9. doi: 10.1111/j.1398-9995.2007.01413.x

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Muraro A, Fernandez-Rivas M, Beyer K, Cardona V, Clark A, Eller E, et al. The urgent need for a harmonized severity scoring system for acute allergic reactions. Allergy. (2018) 73(9):1792–800. doi: 10.1111/all.13408

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M, Fineman S, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. (2020) 13(10):100472. doi: 10.1016/j.waojou.2020.100472

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Stiefel G, Roberts G. How to use serum-specific IgE measurements in diagnosing and monitoring food allergy. Arch Dis Child Educ Pract Ed. (2012) 97(1):29–36; quiz 34. doi: 10.1136/archdischild-2011-300569

PubMed Abstract | CrossRef Full Text | Google Scholar

18. de Boissieu D, Matarazzo P, Rocchiccioli F, Dupont C. Multiple food allergy: a possible diagnosis in breastfed infants. Acta Paediatr. (1997) 86(10):1042–6. doi: 10.1111/j.1651-2227.1997.tb14803.x

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Järvinen KM, Suomalainen H. Development of cow’s milk allergy in breast-fed infants. Clin Exp Allergy. (2001) 31(7):978–87. doi: 10.1046/j.1365-2222.2001.01151.x

CrossRef Full Text | Google Scholar

20. Boyano Martínez T, García-Ara C, Díaz-Pena JM, Muñoz FM, García Sánchez G, Esteban MM. Validity of specific IgE antibodies in children with egg allergy. Clin Exp Allergy. (2001) 31(9):1464–9. doi: 10.1046/j.1365-2222.2001.01175.x

CrossRef Full Text | Google Scholar

21. Martorell A, Plaza AM, Boné J, Nevot S, García Ara MC, Echeverria L, et al. Cow’s milk protein allergy. A multi-centre study: clinical and epidemiological aspects. Allergol Immunopathol (Madr). (2006) 34(2):46–53. doi: 10.1157/13086746

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Martorell A, Alonso E, Boné J, Echeverría L, López MC, Martín F, et al. Position document: IgE-mediated allergy to egg protein. Allergol Immunopathol (Madr). (2013) 41(5):320–36. doi: 10.1016/j.aller.2013.03.005

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Høst A. Cow’s milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol. (1994) 5(5 Suppl):1–36.

Google Scholar

24. Boyano-Martínez T, García-Ara C, Díaz-Pena JM, Martín-Esteban M. Prediction of tolerance on the basis of quantification of egg white-specific IgE antibodies in children with egg allergy. J Allergy Clin Immunol. (2002) 110(2):304–9. doi: 10.1067/mai.2002.126081

CrossRef Full Text | Google Scholar

25. Clark A, Islam S, King Y, Deighton J, Szun S, Anagnostou K, et al. A longitudinal study of resolution of allergy to well-cooked and uncooked egg. Clin.Exp.Allergy. (2011) 41(5):706–12. doi: 10.1111/j.1365-2222.2011.03697.x

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. (2014) 69(8):1008–25. doi: 10.1111/all.12429

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Al-Mughales JA. Diagnostic utility of total IgE in foods, inhalant, and multiple allergies in Saudi Arabia. J Immunol Res. (2016) 2016:1058632. doi: 10.1155/2016/1058632

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Esty B, Maciag MC, Bartnikas LM, Petty CR, MacGinnitie AJ, Sheehan WJ, et al. Predicting outcomes of baked egg and baked milk oral food challenges by using a ratio of food-specific IgE to total IgE. J Allergy Clin Immunol Pract. (2021) 9(4):1750–2. doi: 10.1016/j.jaip.2020.11.004

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Matricardi PM, Bockelbrink A, Grüber C, Keil T, Hamelmann E, Wahn U, et al. Longitudinal trends of total and allergen-specific IgE throughout childhood. Allergy. (2009) 64(7):1093–8. doi: 10.1111/j.1398-9995.2009.02055.x

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Calvani M, Arasi S, Bianchi A, Caimmi D, Cuomo B, Dondi A, et al. Is it possible to make a diagnosis of raw, heated, and baked egg allergy in children using cutoffs? A systematic review. Pediatr Allergy Immunol. (2015) 26(6):509–21. doi: 10.1111/pai.12432

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Dang TD, Peters RL, Koplin JJ, Dharmage SC, Gurrin LC, Ponsonby AL, et al. Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts. Allergy. (2019) 74(2):318–26. doi: 10.1111/all.13572

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict the development of tolerance in cow’s milk and hen’s egg allergy. J Allergy Clin Immunol. (2004) 114(2):387–91. doi: 10.1016/j.jaci.2004.04.032

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Crespo JF, Pascual C, Ferrer A, Burks AW, Diaz Pena JM, Martin Esteban M. Egg white-specific IgE level as a tolerance marker in the follow up of egg allergy. Allergy Proc. (1994) 15(2):73–6. doi: 10.2500/108854194778703099

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Martorell A, García Ara MC, Plaza AM, Boné J, Nevot S, Echeverria L, et al. The predictive value of specific immunoglobulin E levels in serum for the outcome of the development of tolerance in cow’s milk allergy. Allergol Immunopathol (Madr). (2008) 36(6):325–30. doi: 10.1016/s0301-0546(08)75864-6

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Ando H, Movérare R, Kondo Y, Tsuge I, Tanaka A, Borres MP, et al. Utility of ovomucoid-specific IgE concentrations in predicting symptomatic egg allergy. J Allergy Clin Immunol. (2008) 122(3):583–8. doi: 10.1016/j.jaci.2008.06.016

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Benhamou AH, Zamora SA, Eigenmann PA. Correlation between specific immunoglobulin E levels and the severity of reactions in egg allergic patients. Pediatr Allergy Immunol. (2008) 19(2):173–9. doi: 10.1111/j.1399-3038.2007.00602.x

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. (2004) 114(1):144–9. doi: 10.1016/j.jaci.2004.04.009

PubMed Abstract | CrossRef Full Text | Google Scholar