Stepwise single-dose oral egg challenge: a multicenter prospective study

Clinical Implications•The stepwise single-dose oral food challenge, starting with a low dose and progressing to medium doses, is an effective and safe approach that enables children with egg allergies to avoid complete elimination and contributes to improving daily food allergy management. •The stepwise single-dose oral food challenge, starting with a low dose and progressing to medium doses, is an effective and safe approach that enables children with egg allergies to avoid complete elimination and contributes to improving daily food allergy management. Oral food challenges (OFCs) are important for the management and diagnosis of food allergies.1Muraro A. Werfel T. Hoffmann-Sommergruber K. Roberts G. Beyer K. Bindslev-Jensen C. et al.EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.Allergy. 2014; 69: 1008-1025Crossref PubMed Scopus (477) Google Scholar OFCs can enable children to avoid the complete elimination of the causative food2Yanagida N. Minoura T. Kitaoka S. Ebisawa M. A three-level stepwise oral food challenge for egg, milk, and wheat allergy.J Allergy Clin Immunol Pract. 2018; 6: 658-660.e10Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 3Yanagida N. Okada Y. Sato S. Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.Allergol Int. 2016; 65: 135-140Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and may accelerate oral tolerance.4Okada Y. Yanagida N. Sato S. Ebisawa M. Better management of wheat allergy using a very low-dose food challenge: a retrospective study.Allergol Int. 2016; 65: 82-87Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 5Okada Y. Yanagida N. Sato S. Ebisawa M. Better management of cow's milk allergy using a very low dose food challenge test: a retrospective study.Allergol Int. 2015; 64: 272-276Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Stepwise OFCs were recommended in the 2017 Japanese food allergy guidelines.6Ebisawa M. Ito K. Fujisawa T. Committee for Japanese Pediatric Guideline for Food Allergy, The Japanese Society of Pediatric Allergy and Clinical Immunology, The Japanese Society of AllergologyJapanese guidelines for food allergy 2017.Allergol Int. 2017; 66: 248-264Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar We previously reported the usefulness and safety of stepwise2Yanagida N. Minoura T. Kitaoka S. Ebisawa M. A three-level stepwise oral food challenge for egg, milk, and wheat allergy.J Allergy Clin Immunol Pract. 2018; 6: 658-660.e10Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 3Yanagida N. Okada Y. Sato S. Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.Allergol Int. 2016; 65: 135-140Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and single-dose OFCs.7Yanagida N. Minoura T. Kitaoka S. Allergic reactions to milk appear sooner than reactions to hen's eggs: a retrospective study.World Allergy Organ J. 2016; 9: 12Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Because these previous studies were retrospective single-center trials,2Yanagida N. Minoura T. Kitaoka S. Ebisawa M. A three-level stepwise oral food challenge for egg, milk, and wheat allergy.J Allergy Clin Immunol Pract. 2018; 6: 658-660.e10Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Yanagida N. Minoura T. Kitaoka S. Allergic reactions to milk appear sooner than reactions to hen's eggs: a retrospective study.World Allergy Organ J. 2016; 9: 12Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar they had an inherent bias that may have caused low positive rates of OFCs. To make up for this shortcoming, the present study with a multicenter design was conducted to confirm the safety and effectiveness of stepwise single-dose OFC. Stepwise single-dose OFC for heated egg was performed at 4 hospitals and 3 pediatric clinics from April 2016 to October 2017 in children who previously experienced an adverse reaction immediately after exposure. We first undertook single low-dose OFC for heated egg (protein dose: 250 mg; equivalent to 1/25 whole egg) (see Table E1 in this article's Online Repository at www.jaci-inpractice.org). Next, children who tolerated the single low-dose OFC proceeded to single medium-dose OFC for heated egg (769 mg; equivalent to 1/8 whole egg) within 12 months. The symptoms induced by the challenge and their severity are described in Table I and Table E2, available in this article's Online Repository at www.jaci-inpractice.org. After obtaining a negative result for the single low- or medium-dose OFC, children were allowed to consume egg protein up to the recommended doses.Table IData related to the severity of reactions induced during a positive challenge and the subsequent treatmentLow-dose egg reactivity (n = 52)Medium-dose egg reactivity (n = 16)Organ system affected Skin34 (65%)6 (75%) Respiratory8 (15%)5 (63%) Gastrointestinal34 (65%)8 (38%) Neurological0 (0%)0 (0%) Cardiovascular0 (0%)0 (0%)Severity Mild (grade 1)13 (25%)4 (25%) Moderate (grade 2)38 (73%)12 (75%) Severe (grade 3)1 (2%)0 (0%)Total severity score 114 (27%)3 (19%) 231 (60%)11 (69%) 35 (10%)1 (6%) 41 (2%)1 (6%) 51 (2%)0 (0%)Time of symptoms Initial symptoms (min)61 (25-102)48 (28-90) Maximum symptoms (min)80 (50-138)65 (49-100) Disappearing symptoms (min)120 (84-180)133 (86-153)Treatment Antihistamine (oral)34 (65%)13 (81%) Antihistamine (intravenous or intramuscular)6 (12%)1 (6%) Steroid (oral)15 (29%)6 (38%) Steroid (intravenous)1 (2%)0 (0%) Fluid infusion (intravenous)1 (2%)0 (0%) β2 stimulant inhalation5 (10%)4 (25%) Adrenaline inhalation1 (2%)0 (0%) Adrenaline (intramuscular)0 (0%)0 (0%) No treatment6 (12%)0 (0%)Data are presented as median (interquartile range) or n (%), as appropriate.Severity of symptoms was defined based on the severity of the organ symptom that was most affected (Table E2, available in this article's Online Repository at www.jaci-inpractice.org). Total severity score was defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other symptoms (Table E2). Open table in a new tab Data are presented as median (interquartile range) or n (%), as appropriate. Severity of symptoms was defined based on the severity of the organ symptom that was most affected (Table E2, available in this article's Online Repository at www.jaci-inpractice.org). Total severity score was defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other symptoms (Table E2). Written consent was obtained from all guardians. This study was approved by the ethics committee of the Sagamihara National Hospital (Approval number: 2016-2-18) (see Methods section in this article's Online Repository at www.jaci-inpractice.org). Of 297 children, 45 did not meet our eligibility criteria (Figure 1; Tables E3 and E4, available in this article's Online Repository at www.jaci-inpractice.org). Of the 252 children enrolled, 26 (10%) experienced egg-related anaphylaxis. The median age of the children was 1.7 years. The median levels of serum specific IgE (sIgE) to egg white and ovomucoid were 14.3 and 7.5 kUA/L, respectively. As shown in Figure 1, 200 children with egg allergies (79%) passed the single low-dose OFC. Thereafter, 164 children underwent a single medium-dose OFC at a median of 99 days after completing the single low-dose OFC. Of these children, 148 (90%) passed the single medium-dose OFC. Reactive and tolerant subjects differed significantly in age, egg white sIgE levels, and ovomucoid sIgE levels (Table E5 in this article's Online Repository at www.jaci-inpractice.org). Probability curves based on OFC results for the single low- and medium-dose OFCs are displayed in Figure E1, available in this article's Online Repository at www.jaci-inpractice.org. We predicted that approximately 50% of children would have a reaction to egg white (sIgE levels >100 kUA/L; Table E6 in this article's Online Repository at www.jaci-inpractice.org). Among the 52 single low-dose OFC-positive children, 1 (2%) had a severe reaction (barking cough that immediately improved with adrenaline inhalation). Moreover, 13 (25%) and 38 (73%) children had mild and moderate symptoms, respectively. No patient needed intramuscular adrenaline injection. Those with mild or moderate symptoms repeated low-dose OFC (Figure E2 in this article's Online Repository at www.jaci-inpractice.org). Among the 16 single medium-dose OFC-positive children, 4 (25%) and 12 (75%) had mild and moderate symptoms, respectively. No severe reactions occurred. The median times until the onset of the initial symptoms were 61 and 48 minutes in the single low- and medium-dose OFCs, respectively (Table I). This is the first multicenter prospective study to examine the effectiveness and safety of stepwise single-dose OFC. Most children passed low or medium doses safely. In terms of the safety of our OFC protocol, the 50% predictive decision point of the single low-dose OFC was an egg white sIgE level >100 kUA/L. Therefore, OFC can be acceptable even in children with high sIgE levels to egg white or ovomucoid. Moreover, the positive rate of the low-dose OFC in this study was similar to that reported in previous studies; in contrast, that of the medium-dose OFC was only 10%, which is much lower than the 36% reported in a previous study.2Yanagida N. Minoura T. Kitaoka S. Ebisawa M. A three-level stepwise oral food challenge for egg, milk, and wheat allergy.J Allergy Clin Immunol Pract. 2018; 6: 658-660.e10Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In this study, most children who passed the single low-dose OFC also passed the single medium-dose OFC after a short period. Therefore, it is reasonable to perform a single medium-dose OFC soon after confirming the negative results of a single low-dose OFC. Although the PRACTALL guidelines8Sampson H.A. Gerth van Wijk R. Bindslev-Jensen C. Sicherer S. Teuber S.S. Burks A.W. et al.Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report.J Allergy Clin Immunol. 2012; 130: 1260-1274Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar recommend a general challenge schedule comprising 3, 10, 30, 100, 300, 1000, and 3000 mg of food protein at intervals of at least 20 minutes, this interval may be too short.7Yanagida N. Minoura T. Kitaoka S. Allergic reactions to milk appear sooner than reactions to hen's eggs: a retrospective study.World Allergy Organ J. 2016; 9: 12Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Moreover, these intervals lead to overdosing of causative foods. Indeed, most children in the present study experienced symptoms >60 minutes after starting OFC. Accordingly, for an egg challenge, clinicians should carefully monitor children for >60 minutes after the last intake. In the Peanut Allergen Threshold Study, most children with peanut allergies could consume very low doses (1.5 mg) of the single-dose OFC.9Hourihane J.O. Allen K.J. Shreffler W.G. Dunngalvin G. Nordlee J.A. Zurzolo G.A. et al.Peanut Allergen Threshold Study (PATS): novel single-dose oral food challenge study to validate eliciting doses in children with peanut allergy.J Allergy Clin Immunol. 2017; 139: 1583-1590Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Our study also identified the doses of egg that the children could safely consume. This safely consumable dose will help improve the quality of food allergy management. Our study had several limitations. First, OFCs were not double blinded and placebo controlled. However, most children were aged 0 or 1 year, and most induced symptoms were objective; therefore, an assessment bias is likely limited. Second, 36 children who passed the single low-dose challenge did not undergo a medium-dose challenge. However, this would provide little if any effect (Figure E3 in this article's Online Repository at www.jaci-inpractice.org). Third, children suspected of an egg allergy who did not experience previous immediate reactions were not included. Therefore, studies should be conducted to confirm the safety and effectiveness of this approach for various food allergens and in children suspected of food allergies. In conclusion, this multicenter study confirmed that a stepwise single-dose OFC will help children with egg allergies avoid complete elimination of an egg and minimize the effect of complete elimination. We hope this will contribute to improving food allergy management. We would like to thank H. Saito for useful discussions and revising the manuscript. We are particularly grateful to all pediatricians, nutritionists, and nurses who participated in patient recruitment and data collection at all hospitals and clinics. We are particularly grateful to Mamoru Kimura at Kewpie Corporation and Takanori Hasegawa at NH Foods Ltd. for providing challenge foods. Editorial support, in the form of medical rewriting and creating high-resolution images based on the authors' detailed directions, collating author comments, copyediting, fact checking, and referencing, was provided by Editage, Cactus Communications. A stepwise oral food challenge (OFC) for egg with low-dose OFC and medium-dose OFC was administered to confirm tolerance acquisition safely at 4 hospitals and 3 clinics from April 2016 to October 2017. A stepwise OFC was administered according to European Academy of Allergology and Clinical Immunology guidelines.E1Muraro A. Werfel T. Hoffmann-Sommergruber K. Roberts G. Beyer K. Bindslev-Jensen C. et al.EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.Allergy. 2014; 69: 1008-1025Crossref PubMed Scopus (864) Google Scholar The symptoms and associated severity are described in Table E3. We included patients who first underwent a single low-dose OFC for heated egg (250 mg; equivalent to 1/25 whole egg) (Table E1). Patients who tolerated the single low-dose OFC underwent the single medium-dose OFC for heated egg (769 mg; equivalent to 1/8 of whole egg) within 6 months. The amount of protein was confirmed to be similar using enzyme-linked immunosorption (Table E2). We did not divide the challenge food and administered it all at the same time. We observed symptoms for 2 hours after patients consumed the challenge foods. The symptoms and associated severity are described in Table E3. After a negative result for the single low-dose OFC or single middle-dose OFC, patients were allowed to consume up to the recommended doses of egg protein as previously described.E2Yanagida N. Sato S. Asaumi T. Ogura K. Borres M.P. Ebisawa M. Safety and feasibility of heated egg yolk challenge for children with egg allergies.Pediatr Allergy Immunol. 2017; 28: 348-354Crossref PubMed Scopus (19) Google Scholar Serum levels of specific IgE (sIgE) against egg white, ovomucoid, milk, and wheat (Immuno CAPTM; Thermo Fisher Scientific/Phadia, Uppsala, Sweden) were measured within 6 months of OFC. If the sIgE for causative foods was >100 kUA/L, a dilution measurement was applied. Data were expressed as median values and interquartile ranges. The Mann-Whitney U test or Fisher's exact test was used, and a P value <.05 was considered statistically significant. We calculated the serum IgE concentration level in which approximately 5%, 10%, 50%, 90%, and 95% of the patients are predicted to have a reaction (5%, 10%, 50%, 90%, and 95% predictive decision points, respectively) using probability curves, as previously described.E3Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896Abstract Full Text Full Text PDF PubMed Scopus (1219) Google Scholar, E4Söderström L. Kober A. Ahlstedt S. de Groot H. Lange C.E. Paganelli R. et al.A further evaluation of the clinical use of specific IgE antibody testing in allergic diseases.Allergy. 2003; 58: 921-928Crossref PubMed Scopus (85) Google Scholar To create probability curves and determine the predictive decision points, we used regression analysis after logarithmic transformation of sIgE values.E4Söderström L. Kober A. Ahlstedt S. de Groot H. Lange C.E. Paganelli R. et al.A further evaluation of the clinical use of specific IgE antibody testing in allergic diseases.Allergy. 2003; 58: 921-928Crossref PubMed Scopus (85) Google ScholarLogit(Pr[Y=1|ln(kUA/L)]=α+βln(kUA/L) Values of predictive decision points were applied within ranges for the exact sIgE value. All analyses were performed using SPSS software (version 24.0 SPSS Inc., Chicago, Ill). This prospective study was approved by the ethical committee of Sagamihara National Hospital (Approval number: 2016-2-18). Written consent was obtained from all patients or guardians. All data were anonymized before the analysis. This study was registered with a clinical trial registry (UMIN000013026).Figure E2Proportion of patients who underwent repeated testing after a positive result on the low-dose oral food challenge (OFC). Patients who reacted to a single low-dose OFC were advised to avoid exposure completely and were rechallenged with a low-dose OFC yearly (at a median of 347 days after positive single low-dose OFC). This graph shows the result of rechallenges for low-dose OFC.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure E3Fitted probability curve demonstrating stepwise oral food challenge (OFC) outcomes with respect to IgE levels against A egg white and B ovomucoid. The probability curve was subdivided by the total cumulative dose of low-dose OFC and medium-dose OFC. Thirty-six patients did not receive medium-dose OFC. Patients who consumed medium doses at home (n = 6) were assumed to be tolerant to the medium dose. The remainder (n = 30) were assumed to be reactive to the medium dose. sIgE, Specific IgE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Stepwise oral food challenge with the amount of protein and amounts of detected egg protein in the challenge foodsChallenge foodEgg protein usedEgg protein measuredOrigin of materialLow-dose egg OFC (egg juice)250 mg265.8 mgEgg juice was made using 1 g of cooked egg powder and 39 mL of apple juice (total 40 mL). Cooked egg powder (Kewpie Corporation, Tokyo, Japan) was produced by boiling hen's egg at 95°C for 15 min, followed by pasteurization at 65°C for 20 min, and then spray-drying it.Medium-dose egg OFC (egg juice)769 mg730.5 mgEgg juice (NH Foods Ltd.) contains cooked egg powder (as above), hydrogenated maltose starch, citrate, fragrance, calcium phosphate, and sweetener (aspartame-l-phenylalanine compounds), and 25 mL of water.Scrambled egg (45.3 g)6591.5 mgBoiled whole egg (54.2 g)6749.2 mgRaw egg (52.1 g)6322.2 mgOFC, Oral food challenge.Challenge foods were prepared in the nutrition management room. The amounts of egg protein were measured using the FASTKIT version III enzyme-linked immunosorbent assay egg kit from NH Foods, Ltd. (Osaka, Japan) that detects whole egg protein. In the OFC, the challenge foods were administered all at once. Open table in a new tab Table E2Severity of symptoms during the oral food challenge1 (mild)2 (moderate)3 (severe)SkinLocalized urticaria, exanthema, wheal, pruritusGeneralized urticaria, exanthema, wheal, pruritus–Swollen eyelid or lipSwollen face–Gastrointestinal tractPruritus of the throat or oral cavityThroat pain–Mild abdominal painModerate abdominal painCrampsNausea, emesis, diarrheaRecurrent emesis, diarrheaContinuous emesis, loss of bowel controlRespiratory tractIntermittent cough, nasal congestion, sneezing, rhinorrheaRepetitive coughPersistent cough, hoarseness, "barky" cough–Chest tightness, wheezing detectable via auscultationAudible wheezing, dyspnea, cyanosis, saturation <92%, swallowing or speaking difficulties, throat tightness, respiratory arrestCardiovascular–Pale face, mild hypotension, tachycardia (increase >15 beats/min)Hypotension, dysrhythmia, severe bradycardia, cardiac arrestNeurologicalChange in activity level, tiredness"Light-headedness," feeling of "pending doom," somnolence, headacheConfusion, loss of consciousness, incontinenceThe severity score was based on the organ system that was most affected by the symptoms. Hypotension was defined as systolic blood pressure <70 mm Hg for children aged 1 mo to 1 <70 + mm Hg for children aged and mm Hg for children aged Mild was defined as systolic blood pressure mm Hg for children aged 1 mo to 1 + mm Hg for children aged and mm Hg for children aged detectable via with a was defined as mild wheezing was defined as wheezing detected a This severity score was defined in the anaphylaxis guidelines for N. Okada Y. Sato S. Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.Allergol Int. 2016; 65: 135-140Abstract Full Text Full Text PDF PubMed Scopus Google severity were defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other N. T. Sato S. Ebisawa M. intervals challenges the of adverse reactions in oral wheat 2015; Google Scholar Open table in a new tab Table of patients who did or did not undergo medium-dose oral food challenge who underwent medium-dose OFC (n = who did not undergo medium-dose OFC (n = of anaphylaxis to causative white sIgE sIgE IgE Oral food sIgE, specific are expressed as n or median with to interquartile ranges provided in Open table in a new tab Table of = of immediate reaction to of anaphylaxis to white sIgE sIgE IgE Specific are expressed as n or median with to interquartile ranges provided in In 1 ovomucoid sIgE data were Open table in a new tab Table of patients who reacted and tolerated low-dose or medium-dose oral food challenge (n = (n = (n = (n = of anaphylaxis to causative white sIgE sIgE IgE Specific are expressed as n or median with to interquartile ranges provided in patients (79%) passed single low-dose OFC. 164 patients underwent single medium-dose OFC at a median of 99 after completing single low-dose OFC. Of 148 patients (90%) passed single medium-dose OFC. Open table in a new tab Table of IgE for predicting positive oral food challenge predicted predicted predicted predicted predicted OFC (egg white OFC (egg white OFC OFC sIgE, specific values are presented in kUA/L. The exact ranges of egg white sIgE and ovomucoid sIgE were and kUA/L, respectively. we did not the values of these ranges. Open table in a new tab OFC, Oral food challenge. foods were prepared in the nutrition management room. The amounts of egg protein were measured using the FASTKIT version III enzyme-linked immunosorbent assay egg kit from NH Foods, Ltd. (Osaka, Japan) that detects whole egg protein. In the OFC, the challenge foods were administered all at once. The severity score was based on the organ system that was most affected by the symptoms. Hypotension was defined as systolic blood pressure <70 mm Hg for children aged 1 mo to 1 <70 + mm Hg for children aged and mm Hg for children aged Mild was defined as systolic blood pressure mm Hg for children aged 1 mo to 1 + mm Hg for children aged and mm Hg for children aged detectable via with a was defined as mild wheezing was defined as wheezing detected a This severity score was defined in the anaphylaxis guidelines for N. Okada Y. Sato S. Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.Allergol Int. 2016; 65: 135-140Abstract Full Text Full Text PDF PubMed Scopus Google Scholar Total severity were defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other N. T. Sato S. Ebisawa M. intervals challenges the of adverse reactions in oral wheat 2015; Google Scholar OFC, Oral food sIgE, specific Data are expressed as n or median with to interquartile ranges provided in sIgE, Specific Data are expressed as n or median with to interquartile ranges provided in In 1 ovomucoid sIgE data were sIgE, Specific Data are expressed as n or median with to interquartile ranges provided in patients (79%) passed single low-dose OFC. 164 patients underwent single medium-dose OFC at a median of 99 after completing single low-dose OFC. Of 148 patients (90%) passed single medium-dose OFC. sIgE, specific IgE values are presented in kUA/L. 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