Severe reactions may develop during cow's milk (CM) oral immunotherapy (OIT). We investigated the safety and efficacy of low-dose OIT with heated milk (HM) or unheated milk (UM) in children with anaphylaxis.Children with symptom onset after ingestion of 3-mL HM on a double-blind, placebo-controlled food challenge were randomly assigned to the HM (n = 17) or UM (n = 16) group. HM group ingested milk powder heated at 125°C for 30 seconds, whereas the UM group used UM. Patients were hospitalized for 5 days; the HM or UM was gradually increased to 3 mL/day; 3-mL/day ingestion was continued at home. One year later, the patients underwent 2-day consecutive 3- and 25-mL HM-oral food challenges (OFCs) after 2-week avoidance.At baseline, milk- and casein-specific immunoglobulin E (IgE) levels were 56.0 and 51.4 kUA/L in the HM group, and 55.2 and 65.6 kUA/L in the UM group, respectively. One year later, 35% and 18% in the HM group and 50% and 31% in UM group passed the 3 and 25 mL OFCs, respectively. Rates of moderate or severe symptoms and respiratory symptoms per home dose were significantly lower in the HM than in the UM group (0.7% and 1.2% vs 1.4% and 2.6%, respectively, P < .001). β-lactoglobulin-specific IgG4 levels significantly increased from baseline only in the UM group, whereas casein-specific IgG4 levels significantly increased from baseline in both groups.HM-OIT induced immunological changes more safely than the UM-OIT. The possibility of lower treatment efficacy with HM-OIT needs to be evaluated in larger studies.
Background: Reports on oral immunotherapy (OIT) for anaphylactic food allergy are lacking. We investigated the efficacy and safety of peanut OIT for anaphylactic patients. Methods: We enrolled 22 peanut anaphylactic patients who underwent OIT between 2011 and 2013, all of whom demonstrated anaphylaxis during a baseline double-blind, placebo-controlled food challenge. After starting in-hospital OIT, participants gradually increased ingestion to 795 mg of peanut protein per day at home and then took a maintenance dose (795 mg) daily. After 3 asymptomatic months, participants underwent an oral food challenge (OFC) of 795 mg after 2 weeks of peanut avoidance to confirm sustained unresponsiveness. The historical control group consisted of 11 patients with anaphylaxis by OFC and underwent the second OFC after 2 years. Results: All patients (22/22) achieved desensitization by 8 months after starting OIT and completed the protocol within 2 years. Two years later, 15/22 patients (68.1%) in the OIT group achieved sustained unresponsiveness, whereas only 2 (18.1%) in the control group passed the second OFC. After 2 years, the median peanut-specific IgE had significantly decreased (from 38.5 to 12.4 kUA/L) in the OIT group, but not in the control group. Median peanut- and Ara h 2-specific IgG4 in the OIT group had significantly increased from baseline after 1 month. The adverse reaction rate per ingestion was 43% in hospital and 5% at home. Three patients received adrenaline at the hospital and 2 at home. Conclusions: These data suggest that for patients with peanut anaphylaxis, OIT can increase the threshold and support achieving sustained unresponsiveness with relative safety.
Background: The minimal dose for oral immunotherapy (OIT) tolerance is unknown. We investigated the efficacy and safety of low-dose OIT with 1/32 of the volume of a whole egg. Methods: Thirty-three children (aged ≥5 years) with egg allergies confirmed by oral food challenge against 1/32 of a heated whole egg (194 mg of egg protein) were enrolled. The OIT group ingested a scrambled egg once a day. The volume was gradually increased up to a maximum of 1/32 of a heated whole egg. Egg consumption was completely absent in the control group. Results: There were no significant differences in background between the OIT and control groups. Respectively, 71% (15/21) and 0% (0/12) of the patients in the OIT and control groups exhibited sustained unresponsiveness to 1/32 of a whole egg 2 weeks after stopping OIT after 12 months (p < 0.001); 33% (7/21) and 0% (0/12; p = 0.032), respectively, showed sustained unresponsiveness to 1/2 of a whole egg. Egg white- or ovomucoid-specific IgE levels in the OIT group were significantly lower than at baseline after 12 months. Egg white- or ovomucoid-specific IgG as well as IgG4 levels in the OIT group were significantly higher than baseline levels after 1, 3, 6, and 12 months. Adverse allergic reactions were rare, and most symptoms were mild. Conclusions: Low-dose OIT induced sustained unresponsiveness to 1/32 and 1/2 of a whole egg, with no severe symptoms. To improve food allergies, continuous intake of small amounts of these foods may be as effective as the consumption of larger quantities.
Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described.A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes.The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months.Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT.UMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.
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 y, <70 + (2 × age) mm Hg for children aged 1-10 y), and <90 mm Hg for children aged >11 y. Mild hypotension was defined as systolic blood pressure <80 mm Hg for children aged 1 mo to 1 y, <80 + (2 × age) mm Hg for children aged 1-10 y, and <100 mm Hg for children aged >11 y. Wheezing detectable via auscultation with a stethoscope was defined as mild wheezing. Audible wheezing was defined as wheezing detected without a stethoscope. This severity score was defined in the anaphylaxis guidelines for Japan.E5Yanagida 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 ScholarTotal severity scores were defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other symptoms.E6Yanagida N. Imai T. Sato S. Ebisawa M. Do longer intervals between challenges reduce the risk of adverse reactions in oral wheat challenges?.PLoS One. 2015; 10: e0143717PubMed Google Scholar Open table in a new tab Table E3Background difference of patients who did or did not undergo medium-dose oral food challenge (OFC)Patients who underwent medium-dose OFC (n = 164)Patients who did not undergo medium-dose OFC (n = 36)P valueSex (male)101 (62%)18 (50%).260Age (y), median1.5 (1.1-3.4)2.2 (1.3-5.6).031History of anaphylaxis to causative food18 (11%)2 (6%).539Atopic dermatitis, current70 (43%)12 (33%).352Bronchial asthma, current12 (7%)3 (8%).736Allergic rhinitis, current5 (3%)2 (6%).612Egg white sIgE (kUA/L)9.6 (3.6-27.5)13.6 (5.7-32.1).183Ovomucoid sIgE (kUA/L)4.9 (0.8-19.3)7.0 (3.5-22.5).117Total IgE (IU/mL)120 (40-428)225 (82-679).080OFC, Oral food challenges; sIgE, specific IgE.Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. Open table in a new tab Table E4Background of patients(n = 252)Sex (male)152 (60%)Age (y), median1.7 (1.2-4.6)History of immediate reaction to egg252 (100%)History of anaphylaxis to egg26 (10%)Atopic dermatitis, current109 (43%)Bronchial asthma, current23 (9%)Allergic rhinitis, current12 (5%)Egg white sIgE (kUA/L)14.3 (4.8-33.8)Ovomucoid sIgE (kUA/L)7.5 (1.6-24.5)Total IgE (IU/mL)172 (53-611)sIgE, Specific IgE.Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. In 1 patient, ovomucoid sIgE data were missing. Open table in a new tab Table E5Background differences of patients who reacted and tolerated low-dose or medium-dose oral food challenge (OFC)Low-dose OFCP valueMedium-dose OFCP valueReactive (n = 52)Tolerant (n = 200)Reactive (n = 16)Tolerant (n = 148)Sex (male)33 (64%)119 (60%).63612 (75%)89 (60%).290Age (y), median4.2 (1.9-6.4)1.5 (1.2-5.4)<.0012.9 (1.3-7.9)1.4 (1.0-2.9).023History of anaphylaxis to causative food6 (12%)20 (10%).7982 (13%)16 (11%).835Atopic dermatitis, current27 (52%)82 (41%).1626 (38%)64 (43%).793Bronchial asthma, current8 (15%)15 (8%).1020 (0%)12 (8%).609Allergic rhinitis, current5 (10%)7 (4%).0762 (13%)3 (2%).075Egg white sIgE (kUA/L)33.0 (14.2-89.8)10.8 (4.0-28.2)<.00114.6 (3.8-23.9)9.1 (3.5-29.0).885Ovomucoid sIgE (kUA/L)22.6 (10.5-73.0)5.6 (1.1-19.3)<.0017.6 (2.0-19.9)4.7 (0.7-19.3).300Total IgE (IU/mL)608 (93-1355)137 (47-445)<.001141 (52-1120)120 (37-414).291sIgE, Specific IgE.Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. Two hundred egg-allergic patients (79%) passed single low-dose OFC. Consequently, 164 patients underwent single medium-dose OFC at a median of 99 d after completing single low-dose OFC. Of these, 148 egg-allergic patients (90%) passed single medium-dose OFC. Open table in a new tab Table E6Clinical efficacy of antigen-specific IgE for predicting positive oral food challenge (OFC)Group5% predicted probability10% predicted probability50% predicted probability90% predicted probability95% predicted probabilityLow-dose OFC (egg white sIgE)0.52.8375.7n.e.n.e.Medium-dose OFC (egg white sIgE)0.20.969.3n.e.n.e.Low-dose OFC (ovomucoid sIgE)0.41.8147.9n.e.n.e.Medium-dose OFC (ovomucoid sIgE)0.10.537.0n.e.n.e.n.e., Not estimated; sIgE, specific IgE.IgE values are presented in kUA/L. The exact ranges of egg white sIgE and ovomucoid sIgE were 0.1-731 and 0.1-342 kUA/L, respectively. Thus, we did not calculate the values outside of these ranges. Open table in a new tab OFC, 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. 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 y, <70 + (2 × age) mm Hg for children aged 1-10 y), and <90 mm Hg for children aged >11 y. Mild hypotension was defined as systolic blood pressure <80 mm Hg for children aged 1 mo to 1 y, <80 + (2 × age) mm Hg for children aged 1-10 y, and <100 mm Hg for children aged >11 y. Wheezing detectable via auscultation with a stethoscope was defined as mild wheezing. Audible wheezing was defined as wheezing detected without a stethoscope. This severity score was defined in the anaphylaxis guidelines for Japan.E5Yanagida 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 Total severity scores were defined as the grade of cardiovascular symptoms + the grade of respiratory symptoms + the maximum grade of other symptoms.E6Yanagida N. Imai T. Sato S. Ebisawa M. Do longer intervals between challenges reduce the risk of adverse reactions in oral wheat challenges?.PLoS One. 2015; 10: e0143717PubMed Google Scholar OFC, Oral food challenges; sIgE, specific IgE. Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. sIgE, Specific IgE. Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. In 1 patient, ovomucoid sIgE data were missing. sIgE, Specific IgE. Data are expressed as n (%) or median values, with 25% to 75% interquartile ranges provided in parentheses. Two hundred egg-allergic patients (79%) passed single low-dose OFC. Consequently, 164 patients underwent single medium-dose OFC at a median of 99 d after completing single low-dose OFC. Of these, 148 egg-allergic patients (90%) passed single medium-dose OFC. n.e., Not estimated; sIgE, specific IgE. IgE values are presented in kUA/L. The exact ranges of egg white sIgE and ovomucoid sIgE were 0.1-731 and 0.1-342 kUA/L, respectively. Thus, we did not calculate the values outside of these ranges. Managing Cross-Reactivity in Those with Peanut AllergyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 2PreviewPeanut is an allergenic legume that can cross-react with other plant-based foods, notably other legumes and tree nuts. Peanut-allergic individuals can be both cosensitized and coallergic to such items, requiring foresight when eliciting a clinical history of a reaction, in the diagnostic evaluation of such allergies, and in the counseling of patients as to food avoidances after a diagnosis is made. Legume allergens belong to the Fabaceae family and encompass the cupin, prolamin, PR-10, and lipid transfer protein families, which mediate cross-sensitization including that between peanut and tree nut. Full-Text PDF Current and Future Treatment of Peanut AllergyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 2PreviewBased on productive translational research programs conducted over the last 20 years, the clinical landscape of peanut allergy is now rapidly changing. In this review, we review data from recent trials of investigational peanut oral and epicutaneous immunotherapies, explore the pipeline of novel therapies in early development, and identify future research needs and priorities. Full-Text PDF Management of Peanut AllergyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 2PreviewPeanut allergy is a growing public health concern in westernized countries. Peanut allergy is characterized as an often severe and lifelong allergy, which can have detrimental effects on quality of life and trigger anxiety. Although multiple therapeutic options are emerging, the focus of current management strategies is strict peanut avoidance and carriage of self-injectable epinephrine. The greatest risk of reacting to peanut comes from direct ingestion, whereas casual skin contact or airborne exposure is highly unlikely to provoke significant symptoms. Full-Text PDF Preventing Peanut Allergy: Where Are We Now?The Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 2PreviewPeanut allergy affects 1% to 3% of the Western world, usually begins in early childhood, is rarely outgrown, and has no currently approved treatment. The identification and application of prevention strategies is therefore essential. In 2015, the Learning Early About Peanuts study findings found that early consumption of peanut protein was effective in preventing peanut allergy in high-risk children as compared with peanut avoidance. These findings resulted in changes to allergy prevention guidelines and policy across the world. Full-Text PDF Diagnosing Peanut Allergy with Fewer Oral Food ChallengesThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 2PreviewDiagnosis of peanut allergy presents a significant clinical challenge. Accurate diagnosis is critical for patient management and prevention of allergic reactions, whereas overdiagnosis or failure to diagnose tolerance in a previously allergic patient can lead to unnecessary dietary restrictions and impaired quality of life. Oral food challenges, the criterion standard for diagnosis, pose a risk of potentially severe allergic reactions, and are time- and resource- intensive. In this article, we review other currently available tests for peanut allergy and present the strengths and weaknesses of each to assist the clinician in determining which test might be appropriate for their patients, as well as highlighting emerging tests currently in development. Full-Text PDF CorrectionThe Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 5PreviewWith regard to the article in the February 2019 issue entitled "Stepwise single-dose oral egg challenge: a multicenter prospective study" (J Allergy Clin Immunol Pract 2019;7(2):716-718), Figure 1 was incorrect. The medium-dose OFC n value should be 164 instead of 115. Please see the following for an updated figure. The authors regret the error. Full-Text PDF
There are limited reports on the natural history of hen's egg (HE) allergy (HEA) in children <6 years. We aimed to investigate the natural history of HEA in children aged 6-12 years and the factors affecting its tolerance acquisition.Using the database in our hospital, a total of 137 patients diagnosed with a definitive immediate-type reaction to HE when they turned 6 years were enrolled, and the natural course of HEA was prospectively examined until patients turned 12 years. Tolerance was defined as being able to pass an oral food challenge to consume a half or whole heated HE or consume heated HE freely without symptoms. Thirty patients (21.9%) who were enrolled for oral immunotherapy and 21 (15.3%) who discontinued follow-up were considered dropouts. Kaplan-Meier estimation was used to evaluate the rate of tolerance.Fifty-five of the 137 patients (40.1%) had a previous HE anaphylaxis history; 61 (44.5%) patients had acquired tolerance to HE by age 12 years; and 25 (18.2%) continued total or partial HE elimination. The estimated acquired tolerance rates by ages 7, 9, and 12 years were 14.6%, 40.8%, and 60.5%, respectively. A previous history of HE anaphylaxis before 6 years of age, reacting to small amounts of heated HE by 6 years of age, and higher ovomucoid-specific immunoglobulin E values at the same age were associated with persistent HEA.This study provides important insights into the natural course of HEA beyond early childhood, with the acquisition of HE tolerance continuing throughout the duration of the study.
This study aimed to investigate the efficacy and safety of low-dose-induction oral immunotherapy (OIT) with 3 ml of milk, which is a lower target volume than is conventionally used.Children aged ≥5 years with milk allergies [confirmed by oral food challenge (OFC) against 3 ml of milk] were enrolled. The OIT group was admitted to the hospital for 5 days for build-up. Subsequently, at home, the volume was gradually increased by up to a maximum of 3 ml every 5 days. While the OIT group ingested a small amount of milk every day, the control group completely eliminated their milk intake. Both groups underwent OFCs approximately 1 year later in order to assess their responsiveness to 3 ml and 25 ml of cow's milk.The OIT and control groups had no background differences; the proportion of patients unresponsive to 3 ml of milk after 1 year was 58.3% (7/12) and 13.8% (4/25), respectively (p = 0.018), while the proportion unresponsive to 25 ml of milk was 33.3% (4/12) and 0.0% (0/25), respectively (p = 0.007). Furthermore, a significant decrease in the casein-specific immunoglobulin E levels was seen after 12 months when compared to baseline in the OIT group (p = 0.033). Adverse allergic reactions were rare and most symptoms were mild.This study of a high-risk population reacting to very low amounts of milk showed that low-dose-induction OIT appeared effective for acquiring unresponsiveness to 3 ml and 25 ml of milk, with severe symptoms being rare, indicating that for improvement of food allergies, continuous intake of small amounts may be as effective as intake of larger amounts.
AimsCatheter ablation for persistent atrial fibrillation (AF) is currently performed with different procedural endpoints. When AF did not terminate during ablation procedure, electrical cardioversion was performed at different defibrillation threshold (DFT) according to AF characteristics and atrial electrophysiologic substrates. We sought to evaluate the impact of atrial DFT after catheter ablation for persistent AF on clinical outcome.
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