- Email: [email protected]
Differences in egg and milk food challenge outcomes based on tolerance to the baked form
Accepted Manuscript
Differences in egg and milk food challenge outcomes based on tolerance to the baked form Peter Capucilli MD , Antonella Cianferoni MDPhD , Joel Fiedler MD , Laura Gober MD , Nicholas Pawlowski MD , Gita Ram MD , Rushani Saltzman MD , Jonathan M. Spergel MDPhD , Jennifer Heimall MD PII: DOI: Reference:
S1081-1206(18)30581-7 10.1016/j.anai.2018.07.018 ANAI 2631
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
27 January 2018 12 July 2018 14 July 2018
Please cite this article as: Peter Capucilli MD , Antonella Cianferoni MDPhD , Joel Fiedler MD , Laura Gober MD , Nicholas Pawlowski MD , Gita Ram MD , Rushani Saltzman MD , Jonathan M. Spergel MDPhD , Jennifer Heimall MD , Differences in egg and milk food challenge outcomes based on tolerance to the baked form, Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.07.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Differences in egg and milk food challenge outcomes based on tolerance to the baked form
Authors: Peter Capucilli, MD*,†, Antonella Cianferoni, MD, PhD*,†, Joel Fiedler, MD*,†, Laura
Jonathan M. Spergel, MD, PhD*,†, and Jennifer Heimall, MD*,†
Author Affiliations:
Division of Allergy and Immunology, Children’s Hospital of Philadelphia, 3401 Civic Center
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*
Blvd, Philadelphia, PA 19104
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
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†
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Gober, MD*,†, Nicholas Pawlowski, MD*,†, Gita Ram, MD*,†, Rushani Saltzman, MD*,†,
Author Comments: Express permission for additional authorship was obtained by email on
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January 16, 2018, with approval by Dr. Gailen D. Marshall, Editor-in-Chief. All authors including, Peter Capucilli, Antonella Cianferoni, Joel Fiedler, Laura Gober, Nicholas Pawlowski,
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Gita Ram, Rushani Saltzman, Jonathan M. Spergel, and Jennifer Heimall, MD met full
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authorship criteria including the following: (1) made substantial contributions to conception and design, acquisition of data, and/or analysis and interpretation of the data; (2) drafted the article or
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reviewed it critically for important intellectual content; (3) gave final approval of the version to be published; (4) agree to be accountable for all aspects of the work related to its accuracy or integrity.
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Corresponding Author: Peter Capucilli, MD, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, Tel: 215-590-2549, Fax:215-590-4529, Email: [email protected]
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Conflicts of Interest: The following authors have no conflicts of interest to report: Peter
Capucilli, Antonella Cianferoni, Joel Fiedler, Laura Gober, Nicholas Pawlowski, Gita Ram, Rushani Saltzman, Jennifer Heimall. Jonathan M. Spergel reports no conflicts of interest related to this article. He reports unrelated funding from DBV Technology, Aimmune Therapeutics,
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Dannone, NIH, Food Allergy Research Education, Medscape and Uptodate.
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Funding Source: The Children’s Hospital of Philadelphia Food Allergy Fund
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Clinical Trial Registration: Not applicable
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Keywords: Baked egg; baked milk; food challenge; food allergy; eliciting dose
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Abbreviations/Acronyms: ARC, allergic rhinoconjunctivitis; BE, baked egg; BM, baked milk; CM, cow’s milk; FA, food allergy; NI, never ingested; OFC, oral food challenge; SPT, skin prick
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test
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INTRODUCTION Cow's milk (CM) and egg allergy remain the leading causes of food allergy in children, with estimated prevalence of roughly 2% for both foods1-3. There exists a significant economic burden associated with food allergy, both for healthcare systems and for families affected, including
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costs of routine office visits and oral food challenges (OFC)4. Likewise, the considerable impact on patient and family quality of life contributes to challenges in food allergy management5. The prognosis of childhood CM or egg allergy is generally favorable with roughly 80% of children eventually developing tolerance6. Nevertheless, allergic sensitivity and risk for allergic reaction
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may persist through childhood, with some patients only developing tolerance in adolescence or later7,8.
It is well described that some children with native CM or egg allergy are able to tolerate
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these foods in the baked form9. Reports have further suggested that inclusion of baked milk (BM) or baked egg (BE) in the diet may even accelerate native tolerance,9-11 though a recent
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meta-analysis by Lambert et al. found little evidence to support this hypothesis12. While reports suggest that up to 70-80% of children fall into the baked tolerant category13-17, determining
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which children will prove to be intolerant remains difficult without performing a direct oral
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challenge. Several studies have attempted to establish predictive cut off values for baked tolerance using skin prick testing (SPT) and specific IgE levels14,16, but results have shown
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variability and clear risk for severe reactions even at low cut off values, and thus OFC remains a necessary obstacle to baked introduction9,12. Still, with the potential to positively impact children’s allergenicity, further studies to understand differences in tolerance and reactivity to native egg and CM based on baked tolerance are needed.
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In the clinical setting, children with egg or CM allergy often present with history of tolerance, intolerance or avoidance to the baked form, with others who have had no direct exposure, deferring introduction following positive allergy testing. To assess potential differences in native egg and CM reactivity based on children’s presenting history of baked
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tolerance and exposure, we retrospectively reviewed OFC outcomes to egg and CM in the native form. Specifically, we sought to determine if in children presenting to allergy clinics for egg or CM food challenges, does the historical feature of tolerating BE/BM versus avoiding BE/BM (with largely unknown tolerance) versus never eating any egg/CM predict the rate of passing the
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challenge, or impact other challenge outcomes. We hypothesized that children who had
incorporated BE or BM into their diet would demonstrate more favorable OFC outcomes and
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increased native tolerance compared to those with baked avoidance or no previous exposure.
METHODS
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We conducted a retrospective chart review of all patients who underwent native egg and CM OFCs at the Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, between January
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2012 and December 2015. We elicited patient clinical data including previous histories of
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asthma, atopic dermatitis, allergic rhinoconjunctivitis, and history of other food allergies as well as skin prick test (SPT) and CM or egg-specific IgE antibody levels. Food challenge outcomes,
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reaction type, eliciting dose and treatments were also obtained. In addition, we elicited patients’ previous history of known ingestion or exposure to CM or egg in the baked form prior to challenge date. As depicted in Figure 1, subjects were then defined into three subgroups for primary analysis: (a) those with history of allergic reaction to native egg or CM, with subsequent tolerance (Tol) of the respective food in the baked form (BE/BM Tol), (b) those with prior
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reaction to native egg or CM, who maintained strict avoidance (Avoid) of the baked form (BE/BM Avoid), and (c) those who never ingested (NI) egg or CM in the native or baked form, maintaining strict avoidance following positive food allergy testing (Egg/Milk NI). All children had positive SPT and/or specific IgE antibody level prior to food challenge to confirm allergic
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sensitization to the given food. We then compared differences in OFC outcomes, eliciting doses, and epinephrine use based on these subgroup differentiations. Additionally, we evaluated
differences in reaction classification for positive (failed) challenges. Finally, we sought to
determine if differences in subgroup OFC outcomes were reflected in SPT or IgE levels prior to
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challenge date. The study was reviewed and approved by the CHOP Institutional Review Board, IRB number 07-005420.
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Food Challenge Protocol
We performed open OFCs based on previously described challenge protocols18,19. Challenge
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doses administered were 125mg, 250mg, 500mg,1g, 2g, 4g, 8g, and ad lib. In certain clinical scenarios, a lower starting dose (40-60mg) was used with concern for high risk of reaction.
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Challenges were administered using egg or CM powdered protein (Barry Farm Enterprises,
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Wapakoneta, OH, USA) that was masked in foods such as applesauce, pudding or juice20,21. Doses were administered in 20-minute observation intervals until the patient reached the final
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dose or experienced an objective reaction. Following completion of the challenge, patients were monitored for 2.5 hours prior to discharge. Challenges were stopped for respiratory, gastrointestinal, cardiovascular, and neurologic symptoms as well as non-contact cutaneous reactions or multi-system reactions. The protocol was standardized among providers with the
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usual anaphylaxis rescue medications available during all challenges. All children withheld antihistamines for at least 3 days prior to OFC.
Classification of Reactions
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Reactions were categorized based on previously established classifications19 as either isolated cutaneous, respiratory, gastrointestinal, or multi-organ system anaphylaxis. Cutaneous reactions included hives, atopic dermatitis flare, flushing, or angioedema, but did not include mild contact reaction around the mouth. Respiratory symptoms included rhinitis, sneezing, throat closing,
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voice change as well as lower respiratory symptoms consisting of cough, wheeze, shortness of breath, increased work of breathing, tachypnea. Gastrointestinal reactions included abdominal pain or discomfort, emesis, and diarrhea. Anaphylaxis was characterized by symptoms involving
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following any allergic reaction.
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multiple organ systems as per established guidelines22. Patients were monitored for 2.5 hours
Skin Prick and Serum IgE Testing
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Skin testing was performed by the prick method using bifurcated needles and commercial
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extracts (Bayer Laboratories, Spokane, WA; Greer Laboratories, Lenoir, NC, USA). All skin tests were performed within 1 year of challenge date. Maximum wheal and flare diameter were
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measured at 15 minutes with a wheal of 3mm greater than the negative control, accompanied by a flare, considered positive. A positive control of 10mg/mL of histamine dihydrochloride was also placed. Serum samples included whole egg or CM-specific IgE antibody concentrations by the Pharmacia CAP system FEIA (Pharmacia and Upjohn Diagnostics, Uppsala, Sweden). IgE levels were drawn at variable intervals prior to OFC date (Median: 6 months, Range: 0.25-81
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months), with the most recent level used for analysis. A value of 0.35 kU/L was considered the lower limit of detection, as previously detailed18.
Statistical Analysis
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Median and range values were calculated for patient age at time of challenge, SPT, specific IgE level and eliciting dose for positive reactions. Prevalence rates for baseline characteristics,
epinephrine use and overall challenge outcomes were also determined. The Mann-Whitney U test (to compare two subgroups) and the Kruskal Wallis test (to compare three groups) were used
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to compare differences in age, SPT wheal diameter, specific IgE level, and eliciting dose
between subgroups, assuming these variables were not normally distributed. The chi-square analysis of independent variables was used to compare differences in subgroup history of
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asthma, atopic dermatitis, allergic rhinitis, presence of other food allergy, and gender. Dichotomous variables were analyzed using the Fisher’s exact test, including rates for challenge
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outcome and use of epinephrine. We created a Kaplan-Meier survival curve to further assess differences in OFC pass rate by increasing eliciting dose and calculated differences between
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cohorts using a Log-rank (Mantel-Cox) test for trend. A p value <0.05 was considered
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statistically significant. A multivariable logistic regression analysis for all primary outcomes (pass rate, eliciting dose, epinephrine use) considering age as a variable was performed using
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Stata v15 (StataCorp LP, College Station, Tex). All other statistical analysis performed with GraphPad Version 7 (Prism Software, San Diego, CA).
RESULTS Subjects and Demographics
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A total of 580 charts were reviewed with 11 challenges (4 egg and 7 CM) excluded due to insufficient intake or illness at time of challenge, leaving 569 challenges that were included in our final analysis. The total number and percentage of subjects in each cohort is depicted in Figure 1. For the Egg NI and Milk NI cohorts, the documented indication for allergy testing prior
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to ingestion is also shown. Reported reasoning for food allergy testing included five primary indications with roughly half of patients (52%) tested in the setting of atopic dermatitis thought to be secondary to food allergy. Another 1/3rd were tested following diagnosis of IgE-mediated allergy to another food or with history of sibling with food allergy.
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Patients ranged from 11 months - 17 years of age with a median overall age of 5 years. Differences in patient demographics were compared by three-way analysis of egg or CM subgroups. For egg, a significant difference was found for overall patient age between the three
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subgroups (P=0.02). Subjects who never ingested egg (Egg NI) showed higher rates of atopic dermatitis (P=0.01), history of other food allergy (P=0.002) and had higher overall SPT values
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(P=0.004) and specific-IgE levels (P=0.049) comparatively. A difference in overall patient age between CM cohorts was also appreciated (P=0.0023), with the rate of atopic dermatitis also
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notably highest in the Milk NI subgroup (P=0.004). Specific IgE levels to CM were highest in
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BM tolerant subjects (P=0.03). Analysis of other subject demographics found no differences between egg and CM subgroups for gender, history of asthma, or history of allergic
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rhinoconjunctivitis (Table 1).
Oral Food Challenge Outcomes Of the 569 challenges analyzed, there were 342 egg challenges, 115 (34%) of which elicited a positive reaction. Of the 227 challenges to CM, 70 (31%) were positive. For egg challenges, a
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higher proportion of the BE Tol group (n=158) passed OFC compared to the BE Avoid group(n=42)(75% vs. 58%; P=0.01), and compared to the Egg NI group (n=27)(75% vs. 45%; P<0.0001). No significant difference was found in pass rate between BE Avoid and Egg NI subgroups (P=0.16). For CM, no differences were found for OFC pass rate between subgroups
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(Fig.2A).
For positive reactions, BE Tol subjects (n=53) reacted at higher eliciting doses (Median 3.0g, range 0.125-15.75g) compared to BE Avoid subjects (n= 30) (Median 0.69g, range 0.1310.0g; P=0.03) and Egg NI subjects (n=32) (Median 0.88g, range 0.13-13.88g; P=0.01). Eliciting
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doses were no different between BE Avoid and Egg NI subgroups (P=0.85). Further, no
differences in eliciting dose by subgroup analysis were appreciated in challenges to CM (Fig. 2B). Log-rank survival analysis for percent of negative (passed) OFCs compared to increasing
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eliciting dose (g) was also significantly different between subgroups for egg challenges (P<0.0001), with no differences appreciated for CM (P=0.98) (Fig. 3 A/B).
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Finally, a total of 57 reactions to egg and 34 reactions to CM required epinephrine. This accounted for 50% of all positive reactions to egg and 49% of all positive reactions to CM and
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17% and 15% of total challenges to egg and CM, respectively. Compared to BE Tol
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subjects(n=22), BE Avoid subjects (n=16) required epinephrine more frequently for positive reactions (10% vs. 22%; P=0.02). Egg NI subjects (n=19) similarly required a higher rate of
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epinephrine administration (32%) compared to BE Tol subjects(P=0.0001), but not compared to BE Avoid subjects (P=0.24). As with pass rate and eliciting dose outcomes, no significant differences in epinephrine use were appreciated for CM challenges between subgroups (Fig. 2C). In a multivariable logistic regression analysis model for all primary outcomes (pass rate, eliciting
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dose, epinephrine use), age was not found to be a significant contributing factor for differences between egg or milk cohorts.
Differences in Reaction Classification
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Symptoms were categorized for egg and CM reactions for positive (failed) challenges by
subgroup differentiation in Table 2. For all groups, the majority of reactions involved symptoms from multiple organ systems (anaphylaxis), with isolated respiratory reactions being most rare, as similarly reported in previous studies19,23. Within the baked egg subgroups, isolated cutaneous
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reactions were seen with higher frequency in the BE Tol cohort compared to other groups, a difference that was not appreciated between the CM cohorts. No other significant differences in
Differences in SPT and IgE Values
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reaction classification were determined.
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In the evaluation of passed OFCs, we found a significant difference in specific-IgE levels between BM Tol subjects (Median 1.7 kU/L, Range 0-22 kU/L), BM Avoid subjects (Median 0.4
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kU/L, Range 0.05-68.5 kU/L), and those in the Milk NI subgroup (0.4 kU/L, Range 0.2-
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0.6)(P=0.0009). No other statistically significant differences were appreciated in the comparison of tolerated and failed OFCs between egg and CM subgroups for both SPT and specific IgE
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levels (Table 3). DISCUSSION
In this study, we evaluated OFC outcomes to assess for differences in native egg and CM tolerance based on subjects’ previous known history of tolerance, avoidance and exposure to these foods in the baked form. We found that egg allergic children tolerating BE were more
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likely to pass native egg challenges compared to egg allergic children actively avoiding BE and compared to those with no previous exposure to egg, maintaining avoidance secondary to positive allergy testing. Additionally, BE tolerant subjects were able to consume higher doses of native egg before eliciting a positive reaction compared to those avoiding BE and compared to
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those with no prior egg ingestion. Finally, subjects tolerant to BE required less epinephrine
during positive challenges compared to both the baked avoidant and no exposure cohorts. We found no differences in primary challenge outcomes comparing those avoiding BE and those with no egg exposure. Interestingly, we also did not appreciate any differences in CM challenge
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outcomes based on differences in BM tolerance or avoidance history. Together these results suggest that patients tolerant of BE are less sensitive to native egg compared to other subgroups. These data are consistent with previous reports suggesting children who tolerate BE show
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increased tolerance to native egg,9,11-12,24 but are inconsistent with other reports6,9-10 suggesting the same influence for BM in children with CM allergy.
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The exact mechanism by which BE or BM ingestion might influence native food allergy is not fully known. Children’s tolerance of their allergen in the baked form has been attributed to
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altered protein epitopes in heated or matrixed goods, with less allergenic IgE recognition25,26.
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Related to this, studies have demonstrated immunologic patters of tolerance in those ingesting BE or BM consistent with development of natural tolerance or tolerance via subcutaneous
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immunotherapy10,11. In contrast, a recent randomized control trial of BE introduction in children with egg allergy found no impact of BE ingestion on native egg tolerance with both the control and intervention group demonstrating a more egg-tolerant immune profile over time27. In our study, we demonstrated a unique discrepancy in the apparent impact of BE compared to BM on native tolerance, which might be attributed to several potential factors. We considered the
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possibility that patients ingesting BE had more frequent ingestion and subsequent effective desensitization. Peters et al. found that children were 3 times more likely to outgrow their egg allergy by 1 year of age with frequent ingestion of BE, compared to infrequent ingestion or avoidance24. Second, given our patient population is made up of a large referral base, it is
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possible that our CM allergy patients were those that selectively had more persistent and
unremitted allergy and thus showed no significant response to BM exposure. Finally, we
considered theoretical differences in epitope bioavailability in BE products compared to BM products. While this might have contributed to outcomes seen in our patient population, future
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studies would be necessary to explore these hypotheses.
Regarding our primary outcomes, the tolerance patterns observed between our egg cohorts may reflect intrinsic differences in baseline allergy severity between each group. That is,
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children with BE tolerance were those children more likely to outgrow their native egg allergy. This hypothesis would be consistent with result from the aforementioned meta-analysis12. We
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might next assess the severity of children’s diagnostic (initial) reaction to egg or CM and prospectively follow baked tolerance and native eliciting dose using our defined cohorts over
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time to better assess the degree to which BE directly contributed to desensitization.
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We unexpectedly found specific IgE levels to be highest in BM tolerant subjects who then passed food challenge. Differences in SPT and specific IgE levels based on baked tolerance
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and exposure history were otherwise not appreciated. While the exact etiology of these findings is not immediately apparent, they also do not appear to be consistent in clinical outcomes and should likely be reevaluated in future studies. We also found no difference in the rate of multi-systemic anaphylaxis between subgroups, though differences in epinephrine use between egg subgroups was notable. At time
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of OFC, the same rescue medications were prepared individually for each patient, with all medications equally and immediately accessible to providers upon request. While epinephrine would be indicated for any multi-system reaction, consistent with anaphylaxis, we considered that the severity of reactions in the closely observed food challenge setting may be assessed with
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subjective variability by providers, despite meeting strict clinical criteria for anaphylaxis, and thus may have impacted the decision to administer epinephrine. In the design of a prospective study using identical cohorts, one could ensure well-structured indications for epinephrine administration during OFC, in order to decrease bias in clinical interpretation of reaction
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severity.
Our study is unique in the comparison of OFC outcomes in subjects with reaction-defined allergy and those never exposed to the food in either native or baked form. In our population, the
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majority of children in the Milk NI or Egg NI cohorts were those with positive skin prick or specific IgE testing done in the setting of atopic dermatitis. Previous studies have suggested that
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children with atopic dermatitis are more likely to develop other atopic disease, including food allergy28,29. This is particularly interesting given that the rate of atopic dermatitis was found to be
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highest in both the Egg and Milk NI cohorts, the subgroups also found to have the poorest OFC
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outcomes. In this case, allergen testing prior to ingestion may have selected for children with the most severe food allergy. However, we also acknowledge work by Fleischer and colleagues,
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which found a high false-positive rate for food allergy testing in children with atopic dermatitis30. Thus, we suggest the possibility that avoidance of egg and possibly CM secondary to allergen testing might have increased patient’s risk for iatrogenic development of food allergy of profound severity. Future studies are needed to assess food avoidance patterns and subsequent food allergy development by prospective and longitudinal methods.
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We considered limitations in our data outcomes and interpretation, notably in our design of the study as a retrospective chart review. Further, our data comprise outcomes from a single tertiary care center with a large referral base and may be prone to selection bias. We attempted to minimize bias in defining our subgroup populations through systematic chart review for all
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patients. All progress notes from the day of OFC were reviewed with previous outpatient visit notes reviewed to elicit a complete clinical history. For those with documented tolerance to BE or BM, we assumed tolerance at time of OFC. We notably did not investigate, however,
differences in dose and frequency of baked food ingestion in these subjects, which might have
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impacted our results and would be worthwhile to control for in future studies. Subjects were defined as baked avoidant with documentation of strict avoidance to the respective allergen following initial reaction. This included subjects with native egg or CM reaction who never
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attempted introduction of BE or BM, as well as those who had directly reacted to the food in the baked form, though the latter group was found to be considerably smaller. In this cohort, as well
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as the Egg/Milk NI cohorts, we acknowledge inclusion of subjects who may have developed tolerance to egg or CM in the baked form prior to OFC date, thus potentially biasing our data
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through misclassification.With a larger and more powerful study, specific analysis of patients
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reactive to both native and baked egg or CM may further expand upon our findings, as this cohort was too small for independent analysis in our population.
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Our study is strengthened, however, by the practicality of our subgroup differentiation. In clinical practice, children with egg or CM allergy may present with history of exposure and tolerance to egg or CM in the baked form, reaction, avoidance or no previous exposure. In each case, our data can be considered in the decision to pursue OFC and might provide insight regarding severity associated with positive challenge reactions.
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In summary, our study found that children who tolerate BE are less sensitive to native egg. They are more likely to pass egg challenges, tolerate higher overall doses of egg and experience less severe reactions compared to those avoiding BE and compared to those never exposed. These differences were not seen in CM challenge outcomes. Additionally, food allergic
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children with atopic dermatitis and no prior exposure to egg or CM may be at higher risk for adverse reactions during native OFCs. While the impact of BE or BM on children’s ability to outgrow their native allergy remains uncertain, our data suggest that incorporating BE into the diet may afford a higher tolerance to the native form. We suggest that differences in historical
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tolerance and exposure to baked foods serve a valuable and supportive role in patient risk assessment, particularly in the clinician’s decision to pursue OFC to egg and CM and in
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anticipation of challenge outcomes.
Acknowledgements
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We would like to acknowledge the efforts of our nurses, physicians and participants involved in
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trial of a baked egg intervention in young children allergic to raw egg but not baked egg. World
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Allergy Org J. 2017; 10 (1):22. DOI 10.1186/s40413-017-0152-5.
28. Martin PE, Eckert JK, Koplin JJ, et al. HealthNuts Study Investigators. Which infants with
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eczema are at risk of food allergy? Results from a population-based cohort. Clin Exp Allergy.
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2015; 45(1):255-264.
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29. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgEmediated food allergy among children with atopic dermatitis. Pediatrics. 1998;101(3):E8
30. Fleischer DM, Bock SA, Spears GC, et al. Oral food challenges in children with a diagnosis of food allergy. J Pediatr. 2011; 158(4):578–583.e1
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FIGURE LEGENDS
Figure 1: Definition of Study Subgroups: (a) Subjects reactive to native egg/CM, with
tolerance of BE/BM, (b) Subjects reactive to native egg/CM, strictly avoiding BE/BM, (c)
Subjects with no previous ingestion of both native and baked egg/CM. Abbreviations: BE, baked
Total n (%) Egg | CM Challenges
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(b) BE | BM Avoidant
Testing Indication: Atopic Dermatitis:
(c) Never Ingested
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(a) BE | BM Tolerant
Reacts to
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Tolerate s
Excluded: n (%) Illness or
Never Ingested (+) test
Previous reaction to native
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egg; BM, baked milk; CM, cow’s milk; FA, food allergy; Hx, history.
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Figure 2: Egg and CM Food Challenge Outcomes: Differences in OFC Pass Rate (A), Eliciting Dose (B), and Epinephrine Rate (C) for BE/BM Tol vs. BE/BM Avoid vs. Egg/Milk NI subgroups. Box and whisker plots in (B) showing differences in median eliciting dose with minimum and maximum observation and 25th-75th interquartile ranges represented. Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; CM, cow’s milk; NI, never ingested; ns, non-significant; OFC, oral food challenge; Tol, tolerant.
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Figure 3. Kaplan-Meier Survival Analysis for Egg (A) and CM (B) Food Challenges: Food challenge pass rate by increasing eliciting dose for egg (A) and CM (B) subgroups. Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; CM, cow’s milk; OFC, oral food challenge; Tol, tolerant.
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B
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TABLES
Table 1. Demographics BE Avoid N=72
Egg NI N=59
BM Tol N=104
Age (years) Median (Range)
5 (1-17)
5 (1-16)
4 (1-10)*
7 (1-17)
4 (0.9-15)
4.5 (1-16)†
Gender Female N (%) Male N (%)
65 (31) 146 (69)
20 (28) 52 (72)
15 (25) 44 (75)
30 (29) 74 (71)
42 (39) 67 (61)
32 (39) 50 (61)
Atopic History: Asthma N (%) AD N (%) ARC N (%) Other FA N (%)
122 (58) 105 (50) 118 (56) 136 (64)
35 (49) 29 (40) 32 (44) 37 (51)
34 (58) 39 (66)* 31 (53) 48 (81)*
47 (45) 40 (38) 46 (44) 63 (61)
52 (48) 49 (45) 51 (47) 72 (66)
7 (50) 12 (86)† 7 (50) 11 (79)
4 (0-20)
4 (0-10)
5 (0-12)*
5 (0-20)
5 (0-20)
4.5 (0-25)
1.93 (<0.35-88.8)
1.15 (<0.35-28.0)
3.4 (<0.35-100)*
2.25 (<0.35-96.1)
0.68 (<0.35-100)
0.55 (<0.35-100)†
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Specific IgE Median (Range) (kU/L)
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SPT Median (Range) (mm)
BM Avoid N=109
Milk NI N=14
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BE Tol N=211
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Abbreviations: AD, atopic dermatitis; ARC, allergic rhinoconjunctivitis; Avoid, avoidant; BE, baked egg; BM, baked milk; FA, food allergy; NI, never ingested; SPT, skin prick test; Tol, tolerant. * P < 0.05 for mean difference in demographic outcome between egg subgroups. † P< 0.05 for mean difference demographic outcomes between milk subgroups.
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Table 2. Reaction Classification for Positive Food Challenges
BE Tol BE Avoid Egg NI BM Tol BM Avoid Milk NI
53 (25) 30 (42) 32 (54) 31 (30) 35 (32) 4 (29)
Cutaneous†
Respiratory
13 (24) 0 (0) 2 (6) 4 (13) 6 (17) 0 (0)
3 (6) 2 (7) 1 (3) 1 (3) 1 (3) 0 (0)
No. (%) patients Gastrointestinal 3 (6) 3 (10) 3 (9) 3 (10) 4 (11) 0 (0)
Anaphylaxis 34 (64) 25 (83) 26 (82) 23 (74) 24 (69) 4 (100)
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No. (%) Fail
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Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; NI, never ingested; Tol, tolerant. †P = 0.03 comparing number of isolated cutaneous reactions between egg subgroups. No other statistically significant differences were found between subgroups for reaction type (P <0.05).
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Table 3. Subgroup comparison of SPT and IgE levels by challenge outcome
BM Tolerated BM Avoid Milk NI
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IgE (Failed Challenges) BE Tol BE Avoid Egg NI
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0.27
5 (0-20) 3 (0-10) 6 (1-12)
0.27
6 (0-20) 6 (0-20) 7 (5-25)
0.71
Median (Range) (kU/L) 1.4 (<0.35-60.2) 0.60 (<0.35-11.8) 1.3 (<0.35 -13.6)
P value 0.13
1.7 (<0.35-22) 0.4 (<0.35-68.5) 0.4 (<0.35-0.6)
0.0009†
3.2 (<0.35-88.8) 2.6 (0.79-28) 5.4 (<0.35-100)
0.63
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BM Tol BM Avoid Milk NI
4 (0-13) 4 (0-10) 4 (0-6)
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IgE (Passed Challenges) BE Tol BE Avoid Egg NI
0.33
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SPT (Failed Challenges) BE Tol BE Avoid Egg NI
P value
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BM Tol BM Avoid Milk NI
Median (Range) (mm) 3 (0-15) 3 (0-10) 4.5 (0-9)
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SPT (Passed Challenges) BE Tol BE Avoid Egg NI
2.9 (<0.35-96.1) BM Tol 2.8 (<0.35-100) 0.16 BM Avoid 55.6 (11.2-100) Milk NI Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; NI, never ingested; SPT, skin prick test; Tol, tolerant. † Significant difference in specific-IgE levels for passed milk challenges between milk subgroups. No other differences were found between subgroups for SPT and specific IgE levels (P <0.05).
Differences in egg and milk food challenge outcomes based on tolerance to the baked form Peter Capucilli MD , Antonella Cianferoni MDPhD , Joel Fiedler MD , Laura Gober MD , Nicholas Pawlowski MD , Gita Ram MD , Rushani Saltzman MD , Jonathan M. Spergel MDPhD , Jennifer Heimall MD PII: DOI: Reference:
S1081-1206(18)30581-7 10.1016/j.anai.2018.07.018 ANAI 2631
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
27 January 2018 12 July 2018 14 July 2018
Please cite this article as: Peter Capucilli MD , Antonella Cianferoni MDPhD , Joel Fiedler MD , Laura Gober MD , Nicholas Pawlowski MD , Gita Ram MD , Rushani Saltzman MD , Jonathan M. Spergel MDPhD , Jennifer Heimall MD , Differences in egg and milk food challenge outcomes based on tolerance to the baked form, Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.07.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Differences in egg and milk food challenge outcomes based on tolerance to the baked form
Authors: Peter Capucilli, MD*,†, Antonella Cianferoni, MD, PhD*,†, Joel Fiedler, MD*,†, Laura
Jonathan M. Spergel, MD, PhD*,†, and Jennifer Heimall, MD*,†
Author Affiliations:
Division of Allergy and Immunology, Children’s Hospital of Philadelphia, 3401 Civic Center
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Blvd, Philadelphia, PA 19104
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
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†
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Gober, MD*,†, Nicholas Pawlowski, MD*,†, Gita Ram, MD*,†, Rushani Saltzman, MD*,†,
Author Comments: Express permission for additional authorship was obtained by email on
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January 16, 2018, with approval by Dr. Gailen D. Marshall, Editor-in-Chief. All authors including, Peter Capucilli, Antonella Cianferoni, Joel Fiedler, Laura Gober, Nicholas Pawlowski,
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Gita Ram, Rushani Saltzman, Jonathan M. Spergel, and Jennifer Heimall, MD met full
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authorship criteria including the following: (1) made substantial contributions to conception and design, acquisition of data, and/or analysis and interpretation of the data; (2) drafted the article or
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reviewed it critically for important intellectual content; (3) gave final approval of the version to be published; (4) agree to be accountable for all aspects of the work related to its accuracy or integrity.
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Corresponding Author: Peter Capucilli, MD, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA, 19104, Tel: 215-590-2549, Fax:215-590-4529, Email: [email protected]
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Conflicts of Interest: The following authors have no conflicts of interest to report: Peter
Capucilli, Antonella Cianferoni, Joel Fiedler, Laura Gober, Nicholas Pawlowski, Gita Ram, Rushani Saltzman, Jennifer Heimall. Jonathan M. Spergel reports no conflicts of interest related to this article. He reports unrelated funding from DBV Technology, Aimmune Therapeutics,
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Dannone, NIH, Food Allergy Research Education, Medscape and Uptodate.
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Funding Source: The Children’s Hospital of Philadelphia Food Allergy Fund
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Clinical Trial Registration: Not applicable
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Keywords: Baked egg; baked milk; food challenge; food allergy; eliciting dose
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Abbreviations/Acronyms: ARC, allergic rhinoconjunctivitis; BE, baked egg; BM, baked milk; CM, cow’s milk; FA, food allergy; NI, never ingested; OFC, oral food challenge; SPT, skin prick
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test
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INTRODUCTION Cow's milk (CM) and egg allergy remain the leading causes of food allergy in children, with estimated prevalence of roughly 2% for both foods1-3. There exists a significant economic burden associated with food allergy, both for healthcare systems and for families affected, including
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costs of routine office visits and oral food challenges (OFC)4. Likewise, the considerable impact on patient and family quality of life contributes to challenges in food allergy management5. The prognosis of childhood CM or egg allergy is generally favorable with roughly 80% of children eventually developing tolerance6. Nevertheless, allergic sensitivity and risk for allergic reaction
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may persist through childhood, with some patients only developing tolerance in adolescence or later7,8.
It is well described that some children with native CM or egg allergy are able to tolerate
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these foods in the baked form9. Reports have further suggested that inclusion of baked milk (BM) or baked egg (BE) in the diet may even accelerate native tolerance,9-11 though a recent
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meta-analysis by Lambert et al. found little evidence to support this hypothesis12. While reports suggest that up to 70-80% of children fall into the baked tolerant category13-17, determining
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which children will prove to be intolerant remains difficult without performing a direct oral
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challenge. Several studies have attempted to establish predictive cut off values for baked tolerance using skin prick testing (SPT) and specific IgE levels14,16, but results have shown
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variability and clear risk for severe reactions even at low cut off values, and thus OFC remains a necessary obstacle to baked introduction9,12. Still, with the potential to positively impact children’s allergenicity, further studies to understand differences in tolerance and reactivity to native egg and CM based on baked tolerance are needed.
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In the clinical setting, children with egg or CM allergy often present with history of tolerance, intolerance or avoidance to the baked form, with others who have had no direct exposure, deferring introduction following positive allergy testing. To assess potential differences in native egg and CM reactivity based on children’s presenting history of baked
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tolerance and exposure, we retrospectively reviewed OFC outcomes to egg and CM in the native form. Specifically, we sought to determine if in children presenting to allergy clinics for egg or CM food challenges, does the historical feature of tolerating BE/BM versus avoiding BE/BM (with largely unknown tolerance) versus never eating any egg/CM predict the rate of passing the
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challenge, or impact other challenge outcomes. We hypothesized that children who had
incorporated BE or BM into their diet would demonstrate more favorable OFC outcomes and
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increased native tolerance compared to those with baked avoidance or no previous exposure.
METHODS
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We conducted a retrospective chart review of all patients who underwent native egg and CM OFCs at the Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, between January
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2012 and December 2015. We elicited patient clinical data including previous histories of
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asthma, atopic dermatitis, allergic rhinoconjunctivitis, and history of other food allergies as well as skin prick test (SPT) and CM or egg-specific IgE antibody levels. Food challenge outcomes,
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reaction type, eliciting dose and treatments were also obtained. In addition, we elicited patients’ previous history of known ingestion or exposure to CM or egg in the baked form prior to challenge date. As depicted in Figure 1, subjects were then defined into three subgroups for primary analysis: (a) those with history of allergic reaction to native egg or CM, with subsequent tolerance (Tol) of the respective food in the baked form (BE/BM Tol), (b) those with prior
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reaction to native egg or CM, who maintained strict avoidance (Avoid) of the baked form (BE/BM Avoid), and (c) those who never ingested (NI) egg or CM in the native or baked form, maintaining strict avoidance following positive food allergy testing (Egg/Milk NI). All children had positive SPT and/or specific IgE antibody level prior to food challenge to confirm allergic
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sensitization to the given food. We then compared differences in OFC outcomes, eliciting doses, and epinephrine use based on these subgroup differentiations. Additionally, we evaluated
differences in reaction classification for positive (failed) challenges. Finally, we sought to
determine if differences in subgroup OFC outcomes were reflected in SPT or IgE levels prior to
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challenge date. The study was reviewed and approved by the CHOP Institutional Review Board, IRB number 07-005420.
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Food Challenge Protocol
We performed open OFCs based on previously described challenge protocols18,19. Challenge
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doses administered were 125mg, 250mg, 500mg,1g, 2g, 4g, 8g, and ad lib. In certain clinical scenarios, a lower starting dose (40-60mg) was used with concern for high risk of reaction.
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Challenges were administered using egg or CM powdered protein (Barry Farm Enterprises,
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Wapakoneta, OH, USA) that was masked in foods such as applesauce, pudding or juice20,21. Doses were administered in 20-minute observation intervals until the patient reached the final
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dose or experienced an objective reaction. Following completion of the challenge, patients were monitored for 2.5 hours prior to discharge. Challenges were stopped for respiratory, gastrointestinal, cardiovascular, and neurologic symptoms as well as non-contact cutaneous reactions or multi-system reactions. The protocol was standardized among providers with the
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usual anaphylaxis rescue medications available during all challenges. All children withheld antihistamines for at least 3 days prior to OFC.
Classification of Reactions
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Reactions were categorized based on previously established classifications19 as either isolated cutaneous, respiratory, gastrointestinal, or multi-organ system anaphylaxis. Cutaneous reactions included hives, atopic dermatitis flare, flushing, or angioedema, but did not include mild contact reaction around the mouth. Respiratory symptoms included rhinitis, sneezing, throat closing,
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voice change as well as lower respiratory symptoms consisting of cough, wheeze, shortness of breath, increased work of breathing, tachypnea. Gastrointestinal reactions included abdominal pain or discomfort, emesis, and diarrhea. Anaphylaxis was characterized by symptoms involving
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following any allergic reaction.
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multiple organ systems as per established guidelines22. Patients were monitored for 2.5 hours
Skin Prick and Serum IgE Testing
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Skin testing was performed by the prick method using bifurcated needles and commercial
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extracts (Bayer Laboratories, Spokane, WA; Greer Laboratories, Lenoir, NC, USA). All skin tests were performed within 1 year of challenge date. Maximum wheal and flare diameter were
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measured at 15 minutes with a wheal of 3mm greater than the negative control, accompanied by a flare, considered positive. A positive control of 10mg/mL of histamine dihydrochloride was also placed. Serum samples included whole egg or CM-specific IgE antibody concentrations by the Pharmacia CAP system FEIA (Pharmacia and Upjohn Diagnostics, Uppsala, Sweden). IgE levels were drawn at variable intervals prior to OFC date (Median: 6 months, Range: 0.25-81
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months), with the most recent level used for analysis. A value of 0.35 kU/L was considered the lower limit of detection, as previously detailed18.
Statistical Analysis
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Median and range values were calculated for patient age at time of challenge, SPT, specific IgE level and eliciting dose for positive reactions. Prevalence rates for baseline characteristics,
epinephrine use and overall challenge outcomes were also determined. The Mann-Whitney U test (to compare two subgroups) and the Kruskal Wallis test (to compare three groups) were used
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to compare differences in age, SPT wheal diameter, specific IgE level, and eliciting dose
between subgroups, assuming these variables were not normally distributed. The chi-square analysis of independent variables was used to compare differences in subgroup history of
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asthma, atopic dermatitis, allergic rhinitis, presence of other food allergy, and gender. Dichotomous variables were analyzed using the Fisher’s exact test, including rates for challenge
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outcome and use of epinephrine. We created a Kaplan-Meier survival curve to further assess differences in OFC pass rate by increasing eliciting dose and calculated differences between
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cohorts using a Log-rank (Mantel-Cox) test for trend. A p value <0.05 was considered
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statistically significant. A multivariable logistic regression analysis for all primary outcomes (pass rate, eliciting dose, epinephrine use) considering age as a variable was performed using
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Stata v15 (StataCorp LP, College Station, Tex). All other statistical analysis performed with GraphPad Version 7 (Prism Software, San Diego, CA).
RESULTS Subjects and Demographics
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A total of 580 charts were reviewed with 11 challenges (4 egg and 7 CM) excluded due to insufficient intake or illness at time of challenge, leaving 569 challenges that were included in our final analysis. The total number and percentage of subjects in each cohort is depicted in Figure 1. For the Egg NI and Milk NI cohorts, the documented indication for allergy testing prior
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to ingestion is also shown. Reported reasoning for food allergy testing included five primary indications with roughly half of patients (52%) tested in the setting of atopic dermatitis thought to be secondary to food allergy. Another 1/3rd were tested following diagnosis of IgE-mediated allergy to another food or with history of sibling with food allergy.
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Patients ranged from 11 months - 17 years of age with a median overall age of 5 years. Differences in patient demographics were compared by three-way analysis of egg or CM subgroups. For egg, a significant difference was found for overall patient age between the three
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subgroups (P=0.02). Subjects who never ingested egg (Egg NI) showed higher rates of atopic dermatitis (P=0.01), history of other food allergy (P=0.002) and had higher overall SPT values
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(P=0.004) and specific-IgE levels (P=0.049) comparatively. A difference in overall patient age between CM cohorts was also appreciated (P=0.0023), with the rate of atopic dermatitis also
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notably highest in the Milk NI subgroup (P=0.004). Specific IgE levels to CM were highest in
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BM tolerant subjects (P=0.03). Analysis of other subject demographics found no differences between egg and CM subgroups for gender, history of asthma, or history of allergic
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rhinoconjunctivitis (Table 1).
Oral Food Challenge Outcomes Of the 569 challenges analyzed, there were 342 egg challenges, 115 (34%) of which elicited a positive reaction. Of the 227 challenges to CM, 70 (31%) were positive. For egg challenges, a
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higher proportion of the BE Tol group (n=158) passed OFC compared to the BE Avoid group(n=42)(75% vs. 58%; P=0.01), and compared to the Egg NI group (n=27)(75% vs. 45%; P<0.0001). No significant difference was found in pass rate between BE Avoid and Egg NI subgroups (P=0.16). For CM, no differences were found for OFC pass rate between subgroups
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(Fig.2A).
For positive reactions, BE Tol subjects (n=53) reacted at higher eliciting doses (Median 3.0g, range 0.125-15.75g) compared to BE Avoid subjects (n= 30) (Median 0.69g, range 0.1310.0g; P=0.03) and Egg NI subjects (n=32) (Median 0.88g, range 0.13-13.88g; P=0.01). Eliciting
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doses were no different between BE Avoid and Egg NI subgroups (P=0.85). Further, no
differences in eliciting dose by subgroup analysis were appreciated in challenges to CM (Fig. 2B). Log-rank survival analysis for percent of negative (passed) OFCs compared to increasing
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eliciting dose (g) was also significantly different between subgroups for egg challenges (P<0.0001), with no differences appreciated for CM (P=0.98) (Fig. 3 A/B).
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Finally, a total of 57 reactions to egg and 34 reactions to CM required epinephrine. This accounted for 50% of all positive reactions to egg and 49% of all positive reactions to CM and
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17% and 15% of total challenges to egg and CM, respectively. Compared to BE Tol
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subjects(n=22), BE Avoid subjects (n=16) required epinephrine more frequently for positive reactions (10% vs. 22%; P=0.02). Egg NI subjects (n=19) similarly required a higher rate of
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epinephrine administration (32%) compared to BE Tol subjects(P=0.0001), but not compared to BE Avoid subjects (P=0.24). As with pass rate and eliciting dose outcomes, no significant differences in epinephrine use were appreciated for CM challenges between subgroups (Fig. 2C). In a multivariable logistic regression analysis model for all primary outcomes (pass rate, eliciting
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dose, epinephrine use), age was not found to be a significant contributing factor for differences between egg or milk cohorts.
Differences in Reaction Classification
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Symptoms were categorized for egg and CM reactions for positive (failed) challenges by
subgroup differentiation in Table 2. For all groups, the majority of reactions involved symptoms from multiple organ systems (anaphylaxis), with isolated respiratory reactions being most rare, as similarly reported in previous studies19,23. Within the baked egg subgroups, isolated cutaneous
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reactions were seen with higher frequency in the BE Tol cohort compared to other groups, a difference that was not appreciated between the CM cohorts. No other significant differences in
Differences in SPT and IgE Values
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reaction classification were determined.
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In the evaluation of passed OFCs, we found a significant difference in specific-IgE levels between BM Tol subjects (Median 1.7 kU/L, Range 0-22 kU/L), BM Avoid subjects (Median 0.4
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kU/L, Range 0.05-68.5 kU/L), and those in the Milk NI subgroup (0.4 kU/L, Range 0.2-
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0.6)(P=0.0009). No other statistically significant differences were appreciated in the comparison of tolerated and failed OFCs between egg and CM subgroups for both SPT and specific IgE
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levels (Table 3). DISCUSSION
In this study, we evaluated OFC outcomes to assess for differences in native egg and CM tolerance based on subjects’ previous known history of tolerance, avoidance and exposure to these foods in the baked form. We found that egg allergic children tolerating BE were more
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likely to pass native egg challenges compared to egg allergic children actively avoiding BE and compared to those with no previous exposure to egg, maintaining avoidance secondary to positive allergy testing. Additionally, BE tolerant subjects were able to consume higher doses of native egg before eliciting a positive reaction compared to those avoiding BE and compared to
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those with no prior egg ingestion. Finally, subjects tolerant to BE required less epinephrine
during positive challenges compared to both the baked avoidant and no exposure cohorts. We found no differences in primary challenge outcomes comparing those avoiding BE and those with no egg exposure. Interestingly, we also did not appreciate any differences in CM challenge
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outcomes based on differences in BM tolerance or avoidance history. Together these results suggest that patients tolerant of BE are less sensitive to native egg compared to other subgroups. These data are consistent with previous reports suggesting children who tolerate BE show
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increased tolerance to native egg,9,11-12,24 but are inconsistent with other reports6,9-10 suggesting the same influence for BM in children with CM allergy.
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The exact mechanism by which BE or BM ingestion might influence native food allergy is not fully known. Children’s tolerance of their allergen in the baked form has been attributed to
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altered protein epitopes in heated or matrixed goods, with less allergenic IgE recognition25,26.
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Related to this, studies have demonstrated immunologic patters of tolerance in those ingesting BE or BM consistent with development of natural tolerance or tolerance via subcutaneous
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immunotherapy10,11. In contrast, a recent randomized control trial of BE introduction in children with egg allergy found no impact of BE ingestion on native egg tolerance with both the control and intervention group demonstrating a more egg-tolerant immune profile over time27. In our study, we demonstrated a unique discrepancy in the apparent impact of BE compared to BM on native tolerance, which might be attributed to several potential factors. We considered the
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possibility that patients ingesting BE had more frequent ingestion and subsequent effective desensitization. Peters et al. found that children were 3 times more likely to outgrow their egg allergy by 1 year of age with frequent ingestion of BE, compared to infrequent ingestion or avoidance24. Second, given our patient population is made up of a large referral base, it is
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possible that our CM allergy patients were those that selectively had more persistent and
unremitted allergy and thus showed no significant response to BM exposure. Finally, we
considered theoretical differences in epitope bioavailability in BE products compared to BM products. While this might have contributed to outcomes seen in our patient population, future
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studies would be necessary to explore these hypotheses.
Regarding our primary outcomes, the tolerance patterns observed between our egg cohorts may reflect intrinsic differences in baseline allergy severity between each group. That is,
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children with BE tolerance were those children more likely to outgrow their native egg allergy. This hypothesis would be consistent with result from the aforementioned meta-analysis12. We
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might next assess the severity of children’s diagnostic (initial) reaction to egg or CM and prospectively follow baked tolerance and native eliciting dose using our defined cohorts over
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time to better assess the degree to which BE directly contributed to desensitization.
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We unexpectedly found specific IgE levels to be highest in BM tolerant subjects who then passed food challenge. Differences in SPT and specific IgE levels based on baked tolerance
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and exposure history were otherwise not appreciated. While the exact etiology of these findings is not immediately apparent, they also do not appear to be consistent in clinical outcomes and should likely be reevaluated in future studies. We also found no difference in the rate of multi-systemic anaphylaxis between subgroups, though differences in epinephrine use between egg subgroups was notable. At time
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of OFC, the same rescue medications were prepared individually for each patient, with all medications equally and immediately accessible to providers upon request. While epinephrine would be indicated for any multi-system reaction, consistent with anaphylaxis, we considered that the severity of reactions in the closely observed food challenge setting may be assessed with
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subjective variability by providers, despite meeting strict clinical criteria for anaphylaxis, and thus may have impacted the decision to administer epinephrine. In the design of a prospective study using identical cohorts, one could ensure well-structured indications for epinephrine administration during OFC, in order to decrease bias in clinical interpretation of reaction
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severity.
Our study is unique in the comparison of OFC outcomes in subjects with reaction-defined allergy and those never exposed to the food in either native or baked form. In our population, the
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majority of children in the Milk NI or Egg NI cohorts were those with positive skin prick or specific IgE testing done in the setting of atopic dermatitis. Previous studies have suggested that
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children with atopic dermatitis are more likely to develop other atopic disease, including food allergy28,29. This is particularly interesting given that the rate of atopic dermatitis was found to be
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highest in both the Egg and Milk NI cohorts, the subgroups also found to have the poorest OFC
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outcomes. In this case, allergen testing prior to ingestion may have selected for children with the most severe food allergy. However, we also acknowledge work by Fleischer and colleagues,
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which found a high false-positive rate for food allergy testing in children with atopic dermatitis30. Thus, we suggest the possibility that avoidance of egg and possibly CM secondary to allergen testing might have increased patient’s risk for iatrogenic development of food allergy of profound severity. Future studies are needed to assess food avoidance patterns and subsequent food allergy development by prospective and longitudinal methods.
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We considered limitations in our data outcomes and interpretation, notably in our design of the study as a retrospective chart review. Further, our data comprise outcomes from a single tertiary care center with a large referral base and may be prone to selection bias. We attempted to minimize bias in defining our subgroup populations through systematic chart review for all
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patients. All progress notes from the day of OFC were reviewed with previous outpatient visit notes reviewed to elicit a complete clinical history. For those with documented tolerance to BE or BM, we assumed tolerance at time of OFC. We notably did not investigate, however,
differences in dose and frequency of baked food ingestion in these subjects, which might have
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impacted our results and would be worthwhile to control for in future studies. Subjects were defined as baked avoidant with documentation of strict avoidance to the respective allergen following initial reaction. This included subjects with native egg or CM reaction who never
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attempted introduction of BE or BM, as well as those who had directly reacted to the food in the baked form, though the latter group was found to be considerably smaller. In this cohort, as well
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as the Egg/Milk NI cohorts, we acknowledge inclusion of subjects who may have developed tolerance to egg or CM in the baked form prior to OFC date, thus potentially biasing our data
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through misclassification.With a larger and more powerful study, specific analysis of patients
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reactive to both native and baked egg or CM may further expand upon our findings, as this cohort was too small for independent analysis in our population.
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Our study is strengthened, however, by the practicality of our subgroup differentiation. In clinical practice, children with egg or CM allergy may present with history of exposure and tolerance to egg or CM in the baked form, reaction, avoidance or no previous exposure. In each case, our data can be considered in the decision to pursue OFC and might provide insight regarding severity associated with positive challenge reactions.
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In summary, our study found that children who tolerate BE are less sensitive to native egg. They are more likely to pass egg challenges, tolerate higher overall doses of egg and experience less severe reactions compared to those avoiding BE and compared to those never exposed. These differences were not seen in CM challenge outcomes. Additionally, food allergic
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children with atopic dermatitis and no prior exposure to egg or CM may be at higher risk for adverse reactions during native OFCs. While the impact of BE or BM on children’s ability to outgrow their native allergy remains uncertain, our data suggest that incorporating BE into the diet may afford a higher tolerance to the native form. We suggest that differences in historical
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tolerance and exposure to baked foods serve a valuable and supportive role in patient risk assessment, particularly in the clinician’s decision to pursue OFC to egg and CM and in
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anticipation of challenge outcomes.
Acknowledgements
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We would like to acknowledge the efforts of our nurses, physicians and participants involved in
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FIGURE LEGENDS
Figure 1: Definition of Study Subgroups: (a) Subjects reactive to native egg/CM, with
tolerance of BE/BM, (b) Subjects reactive to native egg/CM, strictly avoiding BE/BM, (c)
Subjects with no previous ingestion of both native and baked egg/CM. Abbreviations: BE, baked
Total n (%) Egg | CM Challenges
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(b) BE | BM Avoidant
Testing Indication: Atopic Dermatitis:
(c) Never Ingested
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(a) BE | BM Tolerant
Reacts to
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Tolerate s
Excluded: n (%) Illness or
Never Ingested (+) test
Previous reaction to native
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egg; BM, baked milk; CM, cow’s milk; FA, food allergy; Hx, history.
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Figure 2: Egg and CM Food Challenge Outcomes: Differences in OFC Pass Rate (A), Eliciting Dose (B), and Epinephrine Rate (C) for BE/BM Tol vs. BE/BM Avoid vs. Egg/Milk NI subgroups. Box and whisker plots in (B) showing differences in median eliciting dose with minimum and maximum observation and 25th-75th interquartile ranges represented. Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; CM, cow’s milk; NI, never ingested; ns, non-significant; OFC, oral food challenge; Tol, tolerant.
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Figure 3. Kaplan-Meier Survival Analysis for Egg (A) and CM (B) Food Challenges: Food challenge pass rate by increasing eliciting dose for egg (A) and CM (B) subgroups. Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; CM, cow’s milk; OFC, oral food challenge; Tol, tolerant.
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A
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B
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TABLES
Table 1. Demographics BE Avoid N=72
Egg NI N=59
BM Tol N=104
Age (years) Median (Range)
5 (1-17)
5 (1-16)
4 (1-10)*
7 (1-17)
4 (0.9-15)
4.5 (1-16)†
Gender Female N (%) Male N (%)
65 (31) 146 (69)
20 (28) 52 (72)
15 (25) 44 (75)
30 (29) 74 (71)
42 (39) 67 (61)
32 (39) 50 (61)
Atopic History: Asthma N (%) AD N (%) ARC N (%) Other FA N (%)
122 (58) 105 (50) 118 (56) 136 (64)
35 (49) 29 (40) 32 (44) 37 (51)
34 (58) 39 (66)* 31 (53) 48 (81)*
47 (45) 40 (38) 46 (44) 63 (61)
52 (48) 49 (45) 51 (47) 72 (66)
7 (50) 12 (86)† 7 (50) 11 (79)
4 (0-20)
4 (0-10)
5 (0-12)*
5 (0-20)
5 (0-20)
4.5 (0-25)
1.93 (<0.35-88.8)
1.15 (<0.35-28.0)
3.4 (<0.35-100)*
2.25 (<0.35-96.1)
0.68 (<0.35-100)
0.55 (<0.35-100)†
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Specific IgE Median (Range) (kU/L)
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SPT Median (Range) (mm)
BM Avoid N=109
Milk NI N=14
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BE Tol N=211
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Abbreviations: AD, atopic dermatitis; ARC, allergic rhinoconjunctivitis; Avoid, avoidant; BE, baked egg; BM, baked milk; FA, food allergy; NI, never ingested; SPT, skin prick test; Tol, tolerant. * P < 0.05 for mean difference in demographic outcome between egg subgroups. † P< 0.05 for mean difference demographic outcomes between milk subgroups.
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Table 2. Reaction Classification for Positive Food Challenges
BE Tol BE Avoid Egg NI BM Tol BM Avoid Milk NI
53 (25) 30 (42) 32 (54) 31 (30) 35 (32) 4 (29)
Cutaneous†
Respiratory
13 (24) 0 (0) 2 (6) 4 (13) 6 (17) 0 (0)
3 (6) 2 (7) 1 (3) 1 (3) 1 (3) 0 (0)
No. (%) patients Gastrointestinal 3 (6) 3 (10) 3 (9) 3 (10) 4 (11) 0 (0)
Anaphylaxis 34 (64) 25 (83) 26 (82) 23 (74) 24 (69) 4 (100)
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No. (%) Fail
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Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; NI, never ingested; Tol, tolerant. †P = 0.03 comparing number of isolated cutaneous reactions between egg subgroups. No other statistically significant differences were found between subgroups for reaction type (P <0.05).
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Table 3. Subgroup comparison of SPT and IgE levels by challenge outcome
BM Tolerated BM Avoid Milk NI
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IgE (Failed Challenges) BE Tol BE Avoid Egg NI
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0.27
5 (0-20) 3 (0-10) 6 (1-12)
0.27
6 (0-20) 6 (0-20) 7 (5-25)
0.71
Median (Range) (kU/L) 1.4 (<0.35-60.2) 0.60 (<0.35-11.8) 1.3 (<0.35 -13.6)
P value 0.13
1.7 (<0.35-22) 0.4 (<0.35-68.5) 0.4 (<0.35-0.6)
0.0009†
3.2 (<0.35-88.8) 2.6 (0.79-28) 5.4 (<0.35-100)
0.63
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BM Tol BM Avoid Milk NI
4 (0-13) 4 (0-10) 4 (0-6)
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IgE (Passed Challenges) BE Tol BE Avoid Egg NI
0.33
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SPT (Failed Challenges) BE Tol BE Avoid Egg NI
P value
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BM Tol BM Avoid Milk NI
Median (Range) (mm) 3 (0-15) 3 (0-10) 4.5 (0-9)
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SPT (Passed Challenges) BE Tol BE Avoid Egg NI
2.9 (<0.35-96.1) BM Tol 2.8 (<0.35-100) 0.16 BM Avoid 55.6 (11.2-100) Milk NI Abbreviations: Avoid, avoidant; BE, baked egg; BM, baked milk; NI, never ingested; SPT, skin prick test; Tol, tolerant. † Significant difference in specific-IgE levels for passed milk challenges between milk subgroups. No other differences were found between subgroups for SPT and specific IgE levels (P <0.05).