Threshold levels in food challenge and specific IgE in patients with egg allergy: Is there a relationship?

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1 Threshold levels in food challenge and specific IgE in patients with egg allergy: Is there a relationship? Morten Osterballe, MD, and Carsten Bindslev-Jensen, MD, PhD, DSc Odense, Denmark Background: Previously published articles described a relationship between food-specific IgE and the outcome of food challenge in children with egg allergy. These investigations defined different levels of predictive values in different study populations and thus pointed toward the possibility of a certain level of specific IgE to egg white predicting a positive outcome in food challenge. Objective: The purpose of this study was to determine the utility of specific IgE in estimating threshold level to predict a positive outcome in food challenge. Methods: Fifty-six children were evaluated for egg allergy by titrated oral challenges. Sera were analyzed for specific IgE to egg white in 56 patients by using the Magic Lite test and 32 of 56 patients also by the CAP test. Values of specific IgE to egg white were compared to the outcome of challenges and the threshold level. Results: The diagnostic level of specific IgE predicting clinical reactivity in this population with greater than 95% certainty was identified as 10.8 standardized units/ml (Magic Lite) and 1.5 kilounits of allergen-specific IgE/L (CAP), respectively. We found no significant relationship between the specific IgE concentration (egg white) and the challenge threshold level. Conclusion: Although the specific IgE concentration correlated to a positive outcome in food challenge, there was no significant relationship between the quantification of specific IgE and the challenge threshold level. Therefore the standardized food challenge still remains the gold standard in the diagnosis of food allergy. (J Allergy Clin Immunol 2003;112: ) From the Allergy Center, Department of Dermatology, Odense University Hospital Received for publication February 5, 2003; revised April 5, 2003; accepted for publication April 16, Reprint requests: Morten Osterballe, MD, Allergy Center, Department of Dermatology, Odense University Hospital, Sdr. Boulevard 29, DK 5000 Odense C, Denmark Mosby, Inc. All rights reserved /2003 $ doi: /mai Abbreviations used KU A /L: Kilounits of allergen-specific IgE per liter LOAEL: Lowest observed adverse effect level ML: Magic Lite NOAEL: No observed adverse effect level SU/mL: Standardized units per milliliter Key words: Food hypersensitivity, specific IgE, egg, threshold The gold standard in the diagnosis of food allergy is the standardized oral challenge test. 1 However, the oral challenge test is time-consuming and places the patient at risk for a severe allergic reaction. It is therefore obvious that a substitute for the oral challenge test would be useful in daily practice. Previous studies have suggested that the oral challenge test might be superfluous in a significant number of patients after quantification of food-specific IgE. Two articles published by Sampson et al 2,3 demonstrated that a cutoff level at 6 kilounits of allergen-specific IgE per liter (KU A /L) (CAP; Pharmacia, Uppsala, Sweden) to egg white predicts a clinical allergic reaction with more than 95% certainty in patients with egg allergy. Boyano et al 4 found the oral challenge test unnecessary in infants younger than 2 years of age, provided they had a positive case history of an immediate allergic reaction to egg and a specific IgE concentration to egg white (CAP) exceeding 0.35 KU A /L. Roehr et al 5 reported that a specific IgE concentration of 17.5 KU A /L or greater (CAP, egg white) would render the oral challenge test unnecessary. However, none of these reports described a correlation to the threshold level in food challenge. The threshold level for an allergenic food has attracted much awareness in recent years. At a conference held in the United States in 1999, scientists focused on the lowest eliciting dose of an allergenic food. 6 The results demonstrated that a zero level (at which even the most sensitive patients would not react) was very problematic, especially in labeling of foods to avoid allergic reactions in very sensitive patients. Information about the individual threshold level is of great concern, because there are several case reports about severe allergic reactions to micrograms of food. 7,8 Labeling of foods is therefore a central measure to avoiding allergic reactions in the most sensitive patients. A recent study, based on data available from the literature, demonstrated the possibility of estimating threshold level for foods eliciting allergic reactions in susceptible patients. These data showed that the threshold dose giving a reaction in 1 in 1 million patients with egg allergy was mg and in 1 in 100 patients it was 3.4 mg. 9 However, little focus has been drawn to examine the relationship between food-specific IgE and threshold level in oral challenges. Sicherer et al 10 did not find a strong correlation between dose response in the oral challenge test and food-specific IgE (CAP). However, the starting dose was high, and the percentage of patients reacting at the first challenge dose was 49%. Examination then was based on the lowest observed adverse effect level (LOAEL) and not the threshold level in the majority of patients.

2 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 1 Osterballe and Bindslev-Jensen 197 The objective of this investigation was to determine the utility of quantification of specific IgE (CAP and Magic Lite [ML; ALK-ABELLÓ, Hørsholm, Denmark]) to egg white in predicting clinical allergy and the threshold level in patients with a positive case history to egg. METHODS Study population Fifty-six children with atopic eczema dermatitis syndrome had been referred to the Allergy Center, Odense University Hospital, with suspected egg allergy. Serum samples were obtained from all 56 patients (female/male 25:31; median age, 2.2 years; range, 0.5 to 4.9 years) for quantification of specific IgE to egg white by using the ML technique, and 32 of 56 (female/male 15:17; median age, 2.3 years; range, 0.5 to 4.9 years) were analyzed by the CAP system as well. The subgroup analyzed by the CAP system was randomly selected. The children were divided into 2 groups of younger than 2 years of age (female/male 10:18; median age, 1.1 years) and older than 2 years of age (female/male 15:13; median age, 3.3 years). A detailed case history was obtained in all patients combined with physical examination, skin prick test, and a standardized oral challenge test with egg. Laboratory studies Serum samples were analyzed for specific IgE to egg white by the ML and the CAP systems according to the manufacturer s instructions ( 11 The ML system is an immunocheminometric assay for specific IgE by using paramagnetic particles coupled with standardized allergens as the solid phase, whereas the CAP system is an immunoassay based on a cellulose polymer encased in a capsule. Skin prick test The patients were tested with a 1-mm lancet (ALK-ABELLÓ) at the volar surface of the forearm with fresh pasteurized whole egg, histamine standard (10 mg/ml) and diluent as negative control. The prick-prick technique was used. 12 The skin prick test was done in duplicate according to the EAACI guidelines, and wheals were read after 15 minutes. 13 The mean value of duplicate tests was used. The wheal reactions were outlined with a marker and transferred to paper with transparent tape. The wheal size was measured by using the formula (D + d)/2, where D is the maximum diameter and d is its perpendicular diameter. 13 A net wheal diameter exceeding 3 mm was regarded as positive. Oral food challenge An open standardized food challenge was performed in all the patients. The dose steps were 0.011, 0.044, 0.25, 0.5, 1, 2.5, 5, and 40 g of pasteurized whole egg, in total g (approximately 1 egg). The dose interval was 15 minutes. The criterion for a positive outcome of challenge (egg allergy) was an immediate (maximum 2 hours after the last dose) objective reaction. The threshold dose was defined as the lowest amount of egg eliciting objective symptoms in the patient. 6 The no observed adverse effect level (NOAEL) was defined as the highest dose in the food challenge not eliciting an adverse reaction, and the LOAEL was the lowest provoking dose for each individual patient. 6 Statistics The sensitivity is the fraction of positive cases that are correctly classified by the diagnostic test, and the specificity is the fraction of negative cases that are correctly classified. 14 The positive and negative predictive values are the likelihood that a positive or negative test result reflects the presence or absence of egg allergy. The performance characteristics were calculated for a cutoff point of 1.43 standardized units per milliliter (SU/mL) and 0.35 KU A /L (the limit of measurable IgE in the ML and CAP systems, respectively) and of the 95% decision points. The Mann-Whitney nonparametric test was used to compare the medians of the specific IgE concentration between patients with and without egg allergy and the medians of the threshold dose and the NOAEL in the different age groups. The Spearman correlation coefficient was used to compare the relationship between the threshold dose, the NOAEL, the age, and the specific IgE concentration. The receiver operating characteristic (ROC) analysis was used to quantify the accuracy of the diagnostic tests (ML and CAP) to discriminate between a positive or negative outcome in the food challenge. The analysis uses the ROC curve, a graph of the sensitivity versus 1 specificity of the diagnostic test. The greater the area is under the ROC curve, the better is the performance of the diagnostic test. The optimal cutoff point is examined from the ROC curve with equal weight of sensitivity and specificity. Logistic regression was used to generate probability curves that depict the likelihood of patients with a particular IgE concentration to egg white (CAP, ML) generating a positive outcome in food challenge. The calculations were made with the STATA (Stata Corporation, College Station, Texas) PC statistical software. Values were considered significant at the P less than.05 level. RESULTS Fifty-six children with suspected egg allergy were enrolled in the study. The diagnosis of egg allergy and the threshold dose for eliciting symptoms were established by 56 challenges with fresh whole egg. Symptoms elicited during challenge consisted of immediate urticaria in the majority of patients (95%), and rhinoconjunctivitis occurred in a minority (5%). The prevalence of positive challenges was 64% (36 positive challenges of 56) in the group analyzed by ML and 63% in the group analyzed by CAP (20 positive challenges of 32). Table I depicts the performance characteristics of the threshold dose and the NOAEL. There was an outlier in the ML group with a threshold dose at 49 g. The threshold dose and the NOAEL were not significantly different between the age groups. The mean threshold dose was 3.7 g whole egg (range, to 49 g) in the group analyzed by ML and 2.2 g (range, to g) in the group analyzed by the CAP system. The NOAEL was established in 94% (ML) and in 100% (CAP) of the positive oral challenges. The NOAEL was estimated to be 1.7 g in the ML group and 1.4 g in the CAP group. The LOAEL was recorded in 2 cases (0.011 g) in the group younger than 2 years of age. There was no significant relationship between the threshold level and the age of the patients. The patients with a positive outcome of challenge all had positive results in the skin prick test (mean, 5.7 ± 2.4 mm). The patients with a positive outcome of the oral challenge test (egg allergy) had a significantly (P <.01) higher IgE concentration to egg white than the patients with a negative outcome: 4.6 vs 0.6 KU A /L (CAP), 35 vs 3.6 SU/mL (ML). Table II lists the performance characteristics of the ROC curves. The optimal cutoff points were 0.8 KU A /L (CAP) and 7.5 SU/mL (ML). The optimal cutoff points

3 198 Osterballe and Bindslev-Jensen J ALLERGY CLIN IMMUNOL JULY 2003 FIG 1. ROC curves, relationship between CAP and Magic Lite. TABLE I. Performance characteristics of the NOAEL (in grams of whole egg) in different age groups Age (y) Threshold (g) NOAEL (g) >2 6.1 (3.4)* 2.2 (2.6)* 0.5 to to (2.5)* 1.7 (1.5)* All differences not significant (P >.05) *The calculations after exclusion of the outlier at 49 g. The group analyzed by the CAP test. The group analyzed by the ML test. allergy. With these cutoff points, the need for the oral challenge test could be reduced with 60% (CAP) and 72% (ML) in this study population. The positive predictive values for the patients younger than 2 years were estimated as 15.2 SU/mL (ML) and 1.5 KU A /L (CAP) and for the patients older than 2 years of age as 10.8 SU/mL (ML) and 1.3 KU A /L (CAP). Fig 3 illustrates the correlation between the threshold dose and the specific IgE concentration by using the CAP and ML systems. The relationship between the IgE concentration (egg white) and the threshold level was not significant with the ML or CAP system. in the age groups were estimated to be 0.8 KU A /L (CAP) and 3.3 SU/ml (ML) in the patients younger than 2 years of age and 0.8 KU A /L (CAP) and 8.8 SU/mL (ML) in the patients older than 2 years of age. We found no significant difference in the areas under the ROC curves, meaning no difference between the CAP and the ML tests in the ability to identify patients correctly (Fig 1). Table III lists the performance characteristics of the CAP and the ML tests at a cutoff level of a positive IgE response (0.35 KU A /L and 1.43 SU/mL, respectively) and the cutoff values predicting clinical reactivity with greater than 95% certainty. The probabilities of a positive reaction to egg at a given IgE level (ML and CAP) are illustrated in Fig 2. The positive predictive value by any positive IgE response was 71% in the ML test and 75% in the CAP test. The sensitivity was found to be 97% (ML) and 90% (CAP), and the specificity was 30% (ML) and 50% (CAP). A specific IgE concentration to egg white exceeding 10.8 SU/mL (ML) or 1.5 KU A /L (CAP) correlated to a greater than 95% likelihood of the patient having egg DISCUSSION Previous studies have suggested that at a certain level of specific serum IgE to egg white, it was possible to eliminate the need to perform the oral challenge test in a significant number of patients. 2-5 In this study the specific IgE concentration to egg white predicting a positive outcome of challenge with greater than 95% certainty was estimated to be 1.5 KU A /L (CAP) and 10.8 SU/mL (ML). These decision points reduced the need for the oral challenge test with 60% (CAP) and 72% (ML). Our cutoff points were different from the values found in previous studies, in which Sampson et al 2,3 estimated that a level of egg-specific IgE of 6 KU A /L (CAP), Boyano et al 4 estimated a level of 0.35 KU A /L (CAP), and Roehr et al 5 estimated a level of 17.5 KU A /L (CAP) would predict clinical reactivity with greater than 95% certainty. This discordance could be due to the different study populations. Sampson et al examined a study population with a median age of 5.2 years, whereas the median age in the patients of Boyano et al and Roehr et al were 16 months

4 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 1 Osterballe and Bindslev-Jensen 199 A B FIG 2. A, Probability curve, Magic Lite; B, probability curve, CAP. TABLE II. Performance characteristics of the optimal cutoff values established by the ROC analysis Age (y) Test Cut-point Sensitivity Specificity Positive predictive value Negative predictive value 2 CAP ML >2 CAP >2 ML to 4.9 CAP to 4.9 ML

5 200 Osterballe and Bindslev-Jensen J ALLERGY CLIN IMMUNOL JULY 2003 A B FIG 3. A, Relation between Magic Lite and challenge threshold level; B, relation between CAP and challenge threshold level. TABLE III. Performance characteristics of CAP and ML systems at different cutoff levels and age Age (y) Test Cut-point Sensitivity Specificity Positive predictive value Negative predictive value 2 CAP ML >2 CAP >2 ML CAP ML >2 CAP >2 ML to 4.9 CAP to 4.9 ML to 4.9 CAP to 4.9 ML

6 J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 1 Osterballe and Bindslev-Jensen 201 and 13 months, respectively, compared to 2.2 years in this study. However, this could not be the explanation of the different cutoff points because the median age was 1.2 years in this study in the group younger than 2 years of age, which was comparable to the results in the studies by Boyano et al and Roehr et al. The study population in the study by Sampson et al with a median age of 5.2 years was not directly comparable to the patients older than 2 years in this study (mean age, 3.3 years). A different explanation for the predictive values greater than 95% could be different techniques and different reagents to perform the CAP test. However, if according to the manufacturer s instructions uniform reagents and uniform techniques are used worldwide, this would ensure comparability between the studies. Sampson et al 2,3 reported a median IgE concentration to egg white of 9.8 KU A /L (CAP), whereas Boyano et al 4 reported 2.01 KU A /L (CAP) compared to 4.6 KU A /L (CAP) in this study. Sampson et al reduced the need for the oral challenge test with 40% and Boyano et al with nearly 100%, and in this study the need for the oral challenge test could be reduced by 72% (ML) and 60% (CAP). On the basis of published data the variability in the specific IgE level predicting clinical egg allergy thus varied from 0.35 KU A /L or greater (Boyano et al 4 ), 1.5 KU A /L or greater (this study), and 6 KU A /L or greater (Sampson et al 2,3 ) to 17.5 KU A /L or greater (Roehr et al 5 ); therefore data obtained in one population cannot readily be transferred to other clinics. It would be clinically important if laboratory parameters could predict a threshold level and severity of reactions in patients with food allergy. It might be assumed that increasing concentrations of food-specific IgE would correlate to the threshold level and thereby clinical sensitivity in the single patient. In this study we were unable to demonstrate a significant relationship between the specific IgE concentration (ML and CAP) and the challenge threshold level. This is in agreement with Sicherer et al, 10 even though these data were based on the LOAEL in the majority of patients. Furthermore, for a given challenge threshold dose the specific IgE concentration might vary up to a factor of 40 (Fig 3), hampering the usefulness in daily practice. In conclusion, although quantification of the specific IgE concentration to egg white correlates to a positive outcome of food challenge in a given population, no agreement has been found between different study populations, and no correlation to the challenge threshold level has been estimated. The standardized food challenge therefore remains the gold standard in the diagnosis of food allergy. REFERENCES 1. Bruijnzeel-Koomen C, Ortolani C, Aas K, Bindslev-Jensen C, Bjorksten B, Moneret-Vautrin D, et al. Adverse reactions to food: European Academy of Allergology and Clinical Immunology Subcommittee. Allergy 1995;50: Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107: Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100: Boyano MT, Garcia-Ara C, Diaz-Pena JM, Munoz FM, Garcia SG, Esteban MM. Validity of specific IgE antibodies in children with egg allergy. Clin Exp Allergy 2001;31: Roehr CC, Reibel S, Ziegert M, Sommerfeld C, Wahn U, Niggemann B. Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 2001;107: Taylor SL, Hefle SL, Bindslev-Jensen C, Bock SA, Burks AW Jr, Christie L, et al. Factors affecting the determination of threshold doses for allergenic foods: how much is too much? J Allergy Clin Immunol 2002;109: Wuthrich B, Ballmer-Weber BK. Food-induced. Allergy 2001;56: Wuthrich B. Lethal or life-threatening allergic reactions to food. J Investig Allergol Clin Immunol 2000;10: Bindslev-Jensen C, Briggs D, Osterballe M. Can we determine a threshold level for allergenic foods by statistical analysis of published data in the literature? Allergy 2002;57: Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 2000;105: Woodhead JS, Weeks I. Magic Lite design and development. J Biolumin Chemilumin 1989;4: Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989;83: The European Academy of Allergology and Clinical Immunology. Position paper: allergen standardization and skin tests. Allergy 1993;48(suppl): Bland JM. An introduction to medical statistics, 3rd ed. New York: Oxford University Press; 2000.

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