A three-level stepwise oral food challenge for egg, milk, and wheat allergy

Clinical Implication•The 3-level stepwise oral food challenge, starting with a low dose and progressing to medium and full doses, is an effective approach to enable children with allergies to determine the maximal quantity of the allergen that they can safely consume. •The 3-level stepwise oral food challenge, starting with a low dose and progressing to medium and full doses, is an effective approach to enable children with allergies to determine the maximal quantity of the allergen that they can safely consume. Oral food challenges (OFCs) are necessary for food allergy management.1Burks A.W. Tang M. Sicherer S. Muraro A. Eigenmann P.A. Ebisawa M. et al.ICON: food allergy.J Allergy Clin Immunol. 2012; 129: 906-920Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 2Muraro 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 (284) Google Scholar, 3Sampson 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 The threshold dose varies among patients.4Turner P.J. Wainstein B.K. Crossing the threshold: can outcome data from food challenges be used to predict risk of anaphylaxis in the community?.Allergy. 2016; 72: 9-12Crossref Scopus (19) Google Scholar Administration of a higher dose OFC after a low-dose OFC5Yanagida 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 (47) Google Scholar can avoid complete elimination.5Yanagida 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 (47) Google Scholar, 6Yanagida N. Minoura T. Kitaoka S. Butter tolerance in children allergic to cow's milk.Allergy Asthma Immunol Res. 2015; 7: 186-189Crossref PubMed Scopus (13) Google Scholar Our study aimed to clarify the safety and effectiveness of a stepwise OFC. A 3-level stepwise OFC with a low-dose OFC was administered to diagnose food allergy or confirm tolerance acquisition safely at Sendai Medical Center. We included patients who first underwent a low-dose OFC for egg, milk, or wheat (STEP 1: 213 mg, 850 mg, and 374 mg, respectively) (Tables E1 and E2, available in this article's Online Repository at www.jaci-inpractice.org). Patients who tolerated the low-dose OFC received the medium-dose OFC for egg, milk, or wheat (STEP 2: 1550 mg, 3400 mg, and 2600 mg, respectively) within 12 months. If patients showed no reaction at STEP 2, a full-dose OFC for egg, milk, or wheat (STEP 3: 6200 mg, 6800 mg, and 5200 mg, respectively) was administered within 12 months. The symptoms and associated severity are described in Table E3, available in this article's Online Repository at www.jaci-inpractice.org. After a negative result for each OFC, patients were allowed to consume up to the recommended doses of protein from each suspected causative food. For suspected high-risk cases, a very-low-dose OFC for egg, milk, or wheat (STEP 0: 1.8 mg, 99 mg, and 146 mg, respectively) was implemented before STEP 1 (see detailed methods in this article's Online Repository at www.jaci-inpractice.org). Of 909 patients, 149 did not meet our eligibility criteria (Figure 1). Of the 760 patients enrolled from 2010 to 2012, 432 had a suspected egg allergy, 210 a suspected milk allergy, and 118 a suspected wheat allergy. As shown in Table E4 (available in this article's Online Repository at www.jaci-inpractice.org), 516 patients (68%) reported a prior immediate reaction to a causative food, and 238 patients (31%) experienced food-related anaphylaxis. The median age of patients enrolled was 4 years. As shown in Figure 1, 379 suspected egg-allergy patients (88%), 119 suspected milk-allergy patients (57%), and 71 suspected wheat-allergy patients (60%) passed STEP 1. STEP 2 was implemented approximately 195 days after completing STEP 1. Of these, 275 suspected egg-allergy patients (64%), 71 suspected milk-allergy patients (34%), and 43 suspected wheat-allergy patients (36%) passed STEP 2. STEP 3 was implemented approximately 190 days after completing STEP 2. Per our results, 126 suspected egg-allergy patients (29%), 42 suspected milk-allergy patients (20%), and 36 suspected wheat-allergy patients (31%) passed STEP 3. Patients in the 4 groups, divided by their threshold doses, differed significantly in serum specific IgE (sIgE) levels against causative foods (Fig E1, available in this article's Online Repository at www.jaci-inpractice.org). Probability curves based on OFC results for each step showed intergroup variability (Figure 2). Probability curves subdivided by age (≤4 years or >4 years) were different in wheat allergic patients (Figs E2 and E3, available in this article's Online Repository at www.jaci-inpractice.org) as previously reported.7Komata T. Soderstrom L. Borres M.P. Tachimoto H. Ebisawa M. Usefulness of wheat and soybean specific IgE antibody titers for the diagnosis of food allergy.Allergol Int. 2009; 58: 599-603Abstract Full Text PDF PubMed Scopus (37) Google Scholar Analyses of the best and worst cases, including data for excluded patients, revealed little change in the outcome (Figs E4 and E5, available in this article's Online Repository at www.jaci-inpractice.org). The positive rate of rechallenge after approximately 182 days since the initial positive OFC was 44% (97/222) (Table E5, available in this article's Online Repository at www.jaci-inpractice.org). Among high-risk patients with a previously documented reaction, 159 (n = 60 [egg]; n = 71 [milk]; n = 28 [wheat]) underwent STEP 0 OFC before STEP 1. Of these patients, 16 exhibited reactions (n = 5 [egg]; n = 6 [milk]; n = 5 [wheat]), and no patients passed STEP 1 with the decreased total amount. The 90% positive predictive value (PPV) of STEP 1 for any of the foods was >100 kUA/L (Table E6, available in this article's Online Repository at www.jaci-inpractice.org). Among the 556 patients who showed a positive reaction at any step, 14 showed a severe reaction (3%). Intramuscular adrenaline was needed in 1 patient (0.2%), and the most severe reactions occurred in STEP 1 for milk (Tables E7 and E8, available in this article's Online Repository at www.jaci-inpractice.org). This study examined the effectiveness and safety of a 3-level stepwise OFC. Although most patients did not tolerate the full allergen dose, most could tolerate the low or medium doses, thereby safely avoiding complete elimination of the causative food. Taking a low dose may enable patients to tolerate the higher dose more quickly. Severe symptoms were rare, and only one case of adrenaline required anaphylaxis occurred, further supporting the safe approach of this stepwise protocol. The 90% PPV of STEP 1 for any of the foods was >100 kUA/L. Therefore, STEP 1 OFC need not be avoided because of a high sIgE level against causative foods. More than half of the patients passed the rechallenge OFC after approximately 6 months. This may be because most participants were young and most participants underwent an egg OFC. The positive rates of rechallenge of the egg OFC have been reportedly low.8Yanagida 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 The PRACTALL guidelines3Sampson 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 consisting of 3, 10, 30, 100, 300, 1000, and 3000 mg of food protein at intervals of at least 20 minutes. This method provides information on patients' reactions to the cumulative dose of food protein but does not examine the highest safe dose, as most symptoms develop after 20 minutes.9Yanagida 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: 12Crossref PubMed Scopus (12) Google Scholar The 3-level stepwise OFC can determine whether patients with allergies to egg, milk, or wheat can safely consume these foods at low or medium doses. Our study had several limitations. First, OFCs were not double-blinded or placebo-controlled. However, most symptoms induced were objective, limiting assessment bias. Second, almost 25% of patients reacted to STEP 1, and 10% reacted to STEP 0. For safety reasons, we may recommend a 4-level stepwise OFC with all patients starting at STEP 0. Third, we should consider the inherent differences in antigenicity of heated foods. Lastly, most patients were young children who will likely outgrow these food allergies. Findings may be different in older children or children with peanut, tree nut, sesame, fish, and/or shellfish allergies. Therefore, multicenter, prospective studies should be conducted in the future to confirm the safety and effectiveness of this approach for various food allergens and for older children. In conclusion, the 3-level stepwise OFC proposed here will help to avoid complete elimination of suspected food allergens, and contribute to improved food allergy management. N.Y. conceived of this study, wrote this manuscript, analyzed the data, and generated figure. T.M. revised this manuscript and figures critically. N.Y., T.M. and S.K. collected data. S.K. helped to underwent this study. M.E. advised study design and helped to conceive of this study. All authors read and approved the final manuscript. The authors thank the pediatricians and nurses who participated in the recruitment of study subjects and data collection at Sendai Medical Center. A 3-level stepwise oral food challenge (OFC) with a low-dose OFC was administered to diagnose food allergy or confirm tolerance acquisition safely, according to European Academy of Allergology and Clinical Immunology GuidelinesE1Muraro 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 at Sendai Medical Center from 2010 to 2012. We included patients who first underwent a low-dose OFC for egg, milk, or wheat (STEP 1: 213 mg, 850 mg, and 374 mg, respectively) (Tables E1 and E2). Patients who tolerated the low-dose OFC received the medium-dose OFC for egg, milk, or wheat (STEP 2: 1550 mg, 3400 mg, and 2600 mg, respectively) within 12 months. If patients showed no reaction at STEP 2, a full-dose OFC for egg, milk, or wheat (STEP 3: 6200 mg, 6800 mg, and 5200 mg, respectively) was administered within 12 months. For suspected high-risk cases, a very-low-dose OFC for egg, milk, or wheat (STEP 0: 1.8 mg, 99 mg, and 146 mg, respectively) was implemented before STEP 1. The symptoms and the associated severity are described in Table E3. We excluded patients with missing clinical information or laboratory data, those who did not complete the subsequent OFC after a negative result for STEP 1 or STEP 2, and those who started oral immunotherapy. Patients' levels of serum 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, dilution measurement was applied. The Mann-Whitney U test or Fisher exact test was performed, and a P value <.05 was considered statistically significant. We calculated predictive decision points (positive predictive value [PPV]) and probability curves, as previously described.E2Sampson 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, E3Soderstrom 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 PPV, we used regression analysis after logarithmic transformation of sIgE values.E3Soderstrom 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 Logit (Pr[Y = 1 | ln(kUA/L)]) = α + β ln(kUA/L) PPVs were applied within ranges that have the exact number of patients. All analyses were performed using SPSS software (version 24.0 SPSS, Chicago, Ill). This retrospective study was approved by the ethical committee of Sendai Medical Center. Written consent was obtained from all patients or guardians. All data were anonymized before the analysis.Figure E2Fitted probability curves demonstrating stepwise oral food challenge (OFC) outcomes among patients aged 4 years or younger with respect to immunoglobulin E levels against (A) egg white, (B) ovomucoid, (C) milk, and (D) wheat. sIgE, Specific IgE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure E3Fitted probability curves demonstrating stepwise oral food challenge (OFC) outcomes among patients older than 4 years with respect to immunoglobulin E levels against (A) egg white, (B) ovomucoid, (C) milk, and (D) wheat. sIgE, Specific IgE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure E4Fitted probability curves demonstrating stepwise oral food challenge (OFC) outcomes for the best case with respect to immunoglobulin E levels against (A) egg white, (B) ovomucoid, (C) milk, and (D) wheat. This analysis included patients who received oral immunotherapy or patients who did not undergo STEP 2 or STEP 3 oral food challenges. Patients who did not undergo STEP 2 or STEP 3 were regarded as those who tolerated STEP 3. sIgE, Specific IgE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure E5Fitted probability curves demonstrating stepwise oral food challenge (OFC) outcomes for the worst case with respect to immunoglobulin E levels against (A) egg white, (B) ovomucoid, (C) milk, and (D) wheat. This analysis included patients who received oral immunotherapy or patients who did not undergo STEP 2 or STEP 3 oral food challenges. Patients who did not undergo STEP 2 or STEP 3 were regarded as those who reacted to STEP 2 or STEP 3. sIgE, Specific IgE.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Stepwise oral food challenge with the amount of protein∗Amount of protein is provided in parentheses. ingested for each challenge foodSTEPEggCow's milkWheat0 (very low dose)1/4 boiled egg yolk (egg white 0.5 mg)Sweet potato cake containing 10 g of butter (milk 99 mg)One piece of wheat gluten cake (wheat 146 mg)1 (low dose)Pumpkin cake containing one heated egg yolk (egg white 148 mg)Pumpkin cake containing 25 mL of heated milk (milk 850 mg)2 pieces of a cookie (wheat 374 mg)2 (medium dose)Pumpkin cake containing 1/4 heated whole egg (egg white 1076 mg)96 g of yogurt (milk 3400 mg)100 g of udon noodles (wheat 2600 mg)3 (full dose)One scrambled egg (egg white 4303 mg)200 mL of cow's milk (milk 6800 mg)1 slice of white bread (wheat 5200 mg)Challenge foods were prepared in the nutrition management room. STEP 1 was implemented in the hospital or in the outpatient clinic setting. STEP 2 and STEP 3 were implemented after hospital admission. A STEP 0 oral food challenge (OFC) (egg: whole egg protein 1.8 mg, egg yolk 0.6 mg, egg white 0.5 mg; cow's milk: milk protein 102 mg; wheat: wheat protein 146 mg) was implemented when a patient had a history of immediate reaction to a low dose of the causative food. In the OFC, 2 portions of the challenge food were administered, starting with 1/4 of the total load, followed by the remainder at 1 hour after starting the OFC. One slice of Japanese white bread contains much more wheat protein than a slice of white bread in the United States. These protein data were almost the same as those reported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2015) (http://www.mext.go.jp/).∗ Amount of protein is provided in parentheses. Open table in a new tab Table E2Amounts of egg and milk protein in the challenge foodsChallenge foodEgg proteinMilk protein1/4 of a boiled egg yolk (3.5 g)(Egg STEP 0)1.8 mgPumpkin cake containing one egg yolk (70 g)(Egg STEP 1)213.2 mgPumpkin cake containing 1/4 of a whole egg (24.2 g)(Egg STEP 2)1657.1 mgScrambled egg (45.3 g)(Egg STEP 3)6591.5 mgBoiled whole egg (54.2 g)6749.2 mgRaw egg (52.1 g)6322.2 mgPumpkin cake containing 25 mL of heated milk (63.3 g)(Milk STEP 1)710.1 mgRaw milk (200 mL)(Milk STEP 3)6710.0 mgThe amounts of egg protein and milk protein were measured using the FASTKIT version III enzyme-linked immunosorbent assay egg kit and milk kit from NH Foods (Osaka, Japan) that detects whole egg protein and milk protein. Open table in a new tab Table E3Severity 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 or throat tightness, severe in of loss of severity was based on the that was most by the was as for children aged 1 to 1 + for children aged and for children aged years. was as for children aged 1 to 1 + for children aged and for children aged years. detectable with a was as wheezing was as wheezing a This severity was in the anaphylaxis for Okada Sato Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral 2016; Open table in a new tab Table of (n = (n = (n = of immediate reaction to causative of anaphylaxis to causative white sIgE sIgE sIgE sIgE IgE Specific are as n or median with 25% to ranges provided in parentheses. Open table in a new tab Table results of oral food 556 subjects who showed a reaction to the oral food challenge, were after a median of 182 Of these patients, 44% (97/222) experienced a positive reaction to the Open table in a new tab Table of IgE for predicting positive STEP 1 (egg white STEP 2 (egg white STEP 3 (egg white STEP 1 STEP 2 STEP 3 STEP 1 (milk STEP 2 (milk STEP 3 (milk STEP 1 (wheat STEP 2 (wheat STEP 3 (wheat OFC, oral food sIgE, serum specific are in exact ranges of egg white milk and wheat specific IgE are and we did not the of these Open table in a new tab Table to the severity of reactions induced during a positive challenge and the subsequent (n = (n = (n = are as n Severe or (31%) are as n Open table in a new tab Table to severe reactions induced during a positive challenge among different are as severe positive adrenaline was needed in 1 patient in the milk STEP are as severe positive Open table in a new tab foods were prepared in the nutrition management room. STEP 1 was implemented in the hospital or in the outpatient clinic setting. STEP 2 and STEP 3 were implemented after hospital admission. A STEP 0 oral food challenge (OFC) (egg: whole egg protein 1.8 mg, egg yolk 0.6 mg, egg white 0.5 mg; cow's milk: milk protein 102 mg; wheat: wheat protein 146 mg) was implemented when a patient had a history of immediate reaction to a low dose of the causative food. In the OFC, 2 portions of the challenge food were administered, starting with 1/4 of the total load, followed by the remainder at 1 hour after starting the OFC. One slice of Japanese white bread contains much more wheat protein than a slice of white bread in the United States. These protein data were almost the same as those reported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2015) The amounts of egg protein and milk protein were measured using the FASTKIT version III enzyme-linked immunosorbent assay egg kit and milk kit from NH Foods (Osaka, Japan) that detects whole egg protein and milk protein. The severity was based on the that was most by the was as for children aged 1 to 1 + for children aged and for children aged years. was as for children aged 1 to 1 + for children aged and for children aged years. detectable with a was as wheezing was as wheezing a This severity was in the anaphylaxis for Okada Sato Ebisawa M. New approach for food allergy management using low-dose oral food challenges and low-dose oral 2016; sIgE, Specific are as n or median with 25% to ranges provided in parentheses. Among 556 subjects who showed a reaction to the oral food challenge, were after a median of 182 Of these patients, 44% (97/222) experienced a positive reaction to the OFC, oral food sIgE, serum specific IgE are in kUA/L. The exact ranges of egg white milk and wheat specific IgE are and we did not the of these Intramuscular adrenaline was needed in 1 patient in the milk STEP 1.