Komata T, Söderström L, Borres MP, Tachimoto H, Ebisawa M.
The predictive relationship of food-specific serum IgE concentrations to challenge outcomes for egg and milk varies by patient age.
J Allergy Clin Immunol. 2007 May;119(5):1272-4. doi: 10.1016/j.jaci.2007.01.038. Epub 2007 Mar 2.
Abstract/Text
Sampson HA.
Utility of food-specific IgE concentrations in predicting symptomatic food allergy.
J Allergy Clin Immunol. 2001 May;107(5):891-6. doi: 10.1067/mai.2001.114708.
Abstract/Text
BACKGROUND: The double-blind, placebo-controlled food challenge is considered the gold standard for diagnosing food allergy. However, in a retrospective analysis of children and adolescents with atopic dermatitis and food allergy, discrete food-specific IgE concentrations were established that could predict clinical reactivity to egg, milk, peanut, and fish with greater than 95% certainty.
OBJECTIVE: The purpose of this investigation was to determine the utility of these 95% predictive decision points in a prospective evaluation of food allergy.
METHODS: Sera from 100 consecutive children and adolescents referred for evaluation of food allergy were analyzed for specific IgE antibodies to egg, milk, peanut, soy, wheat, and fish by using the Pharmacia CAP System FEIA. Food-specific IgE values were compared with history and the results of skin prick tests and food challenges to determine the efficacy of previously established 95% predictive decision points in identifying patients with increased probability of reacting during a specific food challenge.
RESULTS: One hundred children (62% male; median age, 3.8 years; range, 0.4-14.3 years) were evaluated for food allergy. The diagnosis of food allergy was established by means of history or oral food challenge. On the basis of the previously established 95% predictive decision points for egg, milk, peanut, and fish allergy, greater than 95% of food allergies diagnosed in this prospective study were correctly identified by quantifying serum food-specific IgE concentrations.
CONCLUSION: In a prospective study of children and adolescents referred for evaluation of food allergy, previously established 95% predictive decision points of food-specific IgE antibody concentrations for 4 major food allergens were effective in predicting clinical reactivity. Quantification of food-specific IgE is a useful test for diagnosing symptomatic allergy to egg, milk, peanut, and fish in the pediatric population and could eliminate the need to perform double-blind, placebo-controlled food challenges in a significant number of children.
Ando H, Movérare R, Kondo Y, Tsuge I, Tanaka A, Borres MP, Urisu A.
Utility of ovomucoid-specific IgE concentrations in predicting symptomatic egg allergy.
J Allergy Clin Immunol. 2008 Sep;122(3):583-8. doi: 10.1016/j.jaci.2008.06.016. Epub 2008 Aug 9.
Abstract/Text
BACKGROUND: Children with allergy to raw egg white might tolerate low amounts of heated egg. Ovomucoid-specific IgE antibodies have been suggested to be predictors of whether children could tolerate heat-treated egg.
OBJECTIVE: The aim was to evaluate the clinical usefulness and added diagnostic value of measurements of IgE antibodies to egg white, ovalbumin, and ovomucoid in children with egg allergy.
METHODS: One hundred eight patients (median age, 34.5 months) with suspected egg allergy underwent double-blind, placebo-controlled food challenges with raw and heated egg. The outcomes of the challenges were related to the serum concentration of specific IgE antibodies and total IgE by using ImmunoCAP.
RESULTS: Reactions to heated egg white were observed in 38 patients (considered allergic to raw and heated egg), 29 patients reacted to only raw egg white, and 41 patients were tolerant. Correlation was observed between the serologic parameters studied. Receiver operating characteristic analysis showed that egg white ImmunoCAP was useful in the diagnosis of allergy to raw egg white. The positive decision point, based on 95% clinical specificity, was 7.4 kU(A)/L, and the negative decision point, based on 95% clinical sensitivity, was 0.6 kU(A)/L. For reaction to heated egg white, ovomucoid ImmunoCAP was superior. The positive decision point was 10.8 kU(A)/L, and the negative decision point was 1.2 kU(A)/L.
CONCLUSIONS: Quantitative measurements of specific IgE antibodies to both egg white and ovomucoid and the evaluation against the suggested positive and negative decision points for specific IgE will be useful in the diagnosis of egg allergy.
Ito K, Futamura M, Borres MP, Takaoka Y, Dahlstrom J, Sakamoto T, Tanaka A, Kohno K, Matsuo H, Morita E.
IgE antibodies to omega-5 gliadin associate with immediate symptoms on oral wheat challenge in Japanese children.
Allergy. 2008 Nov;63(11):1536-42. doi: 10.1111/j.1398-9995.2008.01753.x.
Abstract/Text
BACKGROUND: Gliadins have been implicated in immunoglobulin E (IgE)-mediated allergy to ingested wheat and omega-5-gliadin is known to represent a major allergen in wheat-dependent exercise-induced anaphylaxis. Less known is whether omega-5-gliadin is a clinically relevant allergen in children with immediate allergy to ingested wheat. This study investigates whether specific IgE antibodies to omega-5-gliadin (sIgE-omega-5-gliadin-ab) could be used as a marker for oral wheat challenge outcome in wheat-sensitized children. A secondary objective was to study whether the level of sIgE-omega-5-gliadin was related to symptom severity in children with a positive challenge test.
METHODS: Serum samples from 88 children sensitized to wheat, of whom 35 underwent wheat challenge, were collected consecutively. sIgE-omega-5-gliadin-ab was related to a physician's diagnosis of wheat allergy and challenge symptoms.
RESULTS: The mean concentration of sIgE-omega-5-gliadin-ab was 7.25 kU(A)/l in patients with wheat allergy and 1.08 kU(A)/l in patients with no wheat allergy (P < 0.01). sIgE-omega-5-gliadin-ab was only detected in 12 of the non-wheat allergic children and 11 of them had a specific IgE to wheat below 1.30 kU(A)/l. Children reacting with severe symptoms upon challenge (n = 8) had increased levels of sIgE-omega-5-gliadin-ab compared to children with moderate, mild or no symptoms (P < 0.001).
CONCLUSIONS: The presence of sIgE-omega-5-gliadin-ab is related to the reaction level to wheat challenge outcome in wheat-sensitized children. The sIgE-omega-5-gliadin-ab was found to be associated with a strong convincing history of wheat allergy also in those cases when oral food challenge was avoided. The sIgE-omega-5-gliadin-ab level may serve as a marker for clinical reactivity in wheat-sensitized individuals.
Ebisawa M, Shibata R, Sato S, Borres MP, Ito K.
Clinical utility of IgE antibodies to ω-5 gliadin in the diagnosis of wheat allergy: a pediatric multicenter challenge study.
Int Arch Allergy Immunol. 2012;158(1):71-6. doi: 10.1159/000330661. Epub 2011 Dec 29.
Abstract/Text
BACKGROUND: There are contradictory results regarding the clinical usefulness of the determination of IgE antibodies to ω-5 gliadin in children with a suspicion of wheat allergy (WA).
METHODS: The study comprised 311 children and young adults with suspected wheat intolerance treated at three separate pediatric clinics and, with the exception of 25, were found to be positive in specific IgE antibody determinations to wheat. Their ages ranged from 6 months to 20.4 years (median age, 2.3 years). Possible relationships between IgE antibodies to ω-5 gliadin and a physician's diagnosis of WA and challenge symptoms were studied.
RESULTS: The mean concentration of IgE antibodies to ω-5 gliadin was 1.2 kU(A)/l in WA patients and <0.35 kU(A)/l in patients without WA (p < 0.0001). Seventy-two percent of the WA patients had positive ω-5 gliadin levels and 75% of the patients without WA had negative levels. Logistic regression showed a significant relationship between the probability of WA and the concentration of IgE antibodies to ω-5-gliadin with a 2.6-fold (95% CI: 2.0-3.3) increased risk. Age was an important factor to consider as the risk of WA increased 5.4-fold (95% CI: 1.4-21) for children ≤1 year of age and 2.5-fold (95% CI: 2.0-3.2) for children >1 year of age with increasing levels of IgE.
CONCLUSION: Detection of IgE to ω-5 gliadin seems to be associated with responsiveness to the challenge test and is particularly useful in infants with a suspicion of WA.
Copyright © 2011 S. Karger AG, Basel.
Maeda M, Kuwabara Y, Tanaka Y, Nishikido T, Hiraguchi Y, Yamamoto-Hanada K, Okafuji I, Yamada Y, Futamura M, Ebisawa M.
Is oral food challenge test useful for avoiding complete elimination of cow's milk in Japanese patients with or suspected of having IgE-dependent cow's milk allergy?
Allergol Int. 2022 Apr;71(2):214-220. doi: 10.1016/j.alit.2021.09.001. Epub 2021 Sep 27.
Abstract/Text
BACKGROUND: Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known.
METHODS: After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events.
RESULTS: Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%).
CONCLUSIONS: This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.
Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
Murai H, Irahara M, Sugimoto M, Takaoka Y, Takahashi K, Wada T, Yamamoto-Hanada K, Okafuji I, Yamada Y, Futamura M, Ebisawa M.
Is oral food challenge useful to avoid complete elimination in Japanese patients diagnosed with or suspected of having IgE-dependent hen's egg allergy? A systematic review.
Allergol Int. 2022 Apr;71(2):221-229. doi: 10.1016/j.alit.2021.09.005. Epub 2021 Oct 16.
Abstract/Text
BACKGROUND: IgE-mediated egg allergy is a common food allergy worldwide. Patients with egg allergy are known to easily achieve tolerance compared to other allergens such as nuts. Oral food challenge (OFC) is often performed on patients diagnosed with or suspected of having IgE-mediated food allergy, but whether hen's egg OFC is useful in IgE-dependent egg allergy patients to avoid complete elimination remains unknown.
METHODS: We identified articles in which OFCs were performed in Japanese patients diagnosed with or suspected of having IgE-mediated egg allergy. We evaluated whether the OFCs were useful to avoid the complete elimination of eggs by assessing the following: (1) the number of patients who could avoid complete elimination; (2) the number of patients who experienced serious adverse events (SAEs); or (3) adverse events (AEs); (4) improvement in quality of life (QOL); and (5) immunological changes.
RESULTS: Fifty-nine articles were selected in the study; all the references were case series or case studies in which OFC was compared to pre-challenge conditions. The overall negative ratio against egg OFC was 62.7%, but an additional 71.9% of OFC-positive patients could take eggs when expanded to partial elimination. Of the 4182 cases, 1146 showed AEs in the OFC, and two cases reached an SAE. Two reports showed an improvement in QOL and immunological changes, although the evidence was weak.
CONCLUSIONS: OFCs against eggs may be useful to avoid complete elimination, but medical professionals should proceed with the test safely and carefully.
Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
海老澤元宏、伊藤浩明、藤澤隆夫 監修、日本小児アレルギー学会食物アレルギー委員会：食物アレルギー診療ガイドライン2021、p196.
相原雄幸：食物依存性運動誘発アナフィラキシー、アレルギー 56(5), 451-456, 2007.
Matsuo H, Kohno K, Niihara H, Morita E.
Specific IgE determination to epitope peptides of omega-5 gliadin and high molecular weight glutenin subunit is a useful tool for diagnosis of wheat-dependent exercise-induced anaphylaxis.
J Immunol. 2005 Dec 15;175(12):8116-22. doi: 10.4049/jimmunol.175.12.8116.
Abstract/Text
Wheat omega-5 gliadin and a high m.w. glutenin subunit (HMW-glutenin) have been reported as major allergens in wheat-dependent exercise-induced anaphylaxis. A simultaneous detection of specific IgE to epitope sequences of both proteins is considered to be a reliable method for diagnosis of wheat-dependent exercise-induced anaphylaxis. However, the IgE-binding epitope of HMW-glutenin remains unknown. The aim of this study was to determine the IgE-binding epitopes of HMW-glutenin to establish a useful system of identifying patients with wheat-dependent exercise-induced anaphylaxis. For determination of IgE-binding epitopes of HMW-glutenin overlapping peptides were synthesized and reactivities of IgE Abs in the sera of patients to those peptides were analyzed. Three IgE-binding epitopes, QQPGQ, QQPGQGQQ, and QQSGQGQ, were identified within primary sequence of HMW-glutenin. Epitope peptides, which include IgE-binding sequences of omega-5 gliadin and a HMW-glutenin, were synthesized and peptide-specific IgE Abs were measured by CAP-System fluorescent enzyme immunoassay. Twenty-nine of 30 patients with wheat-dependent exercise-induced anaphylaxis had specific IgE Abs to these epitope peptides. None of the 25 sera from healthy subjects reacted to both epitope peptides. Twenty-five patients with atopic dermatitis who had specific IgE to wheat and/or gluten had very low or nonexistent levels of epitope peptide-specific IgE Abs. These results indicated that measurement of IgE levels specific to epitope peptides of omega-5 gliadin and HMW-glutenin is useful as an in vitro diagnostic method for the assessment of patients with wheat-dependent exercise-induced anaphylaxis.
Kramer MS, Kakuma R.
Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child.
Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD000133. doi: 10.1002/14651858.CD000133.pub3. Epub 2012 Sep 12.
Abstract/Text
BACKGROUND: Some breastfed infants with atopic eczema benefit from elimination of cow milk, egg, or other antigens from their mother's diet. Maternal dietary antigens are also known to cross the placenta.
OBJECTIVES: To assess the effects of prescribing an antigen avoidance diet during pregnancy or lactation, or both, on maternal and infant nutrition and on the prevention or treatment of atopic disease in the child.
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 July 2012).
SELECTION CRITERIA: All randomized or quasi-randomized comparisons of maternal dietary antigen avoidance prescribed to pregnant or lactating women. We excluded trials of multimodal interventions that included manipulation of the infant's diet other than breast milk or of non-dietary aspects of the infant's environment.
DATA COLLECTION AND ANALYSIS: We extracted data from published reports, supplemented by additional information received from the trialists we contacted.
MAIN RESULTS: The evidence from five trials, involving 952 participants, does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 18 months of life. Data on allergic rhinitis or conjunctivitis, or both, and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a non-significantly higher risk of preterm birth, and a non-significant reduction in mean birthweight.The evidence from two trials, involving 523 participants, did not observe a significant protective effect of maternal antigen avoidance during lactation on the incidence of atopic eczema during the first 18 months or on positive skin-prick tests to cow milk, egg, or peanut antigen at one, two, or seven years.One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a non-significant reduction in eczema severity.
AUTHORS' CONCLUSIONS: Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal or fetal nutrition, or both. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed.Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed.
海老澤元宏、伊藤浩明、藤澤隆夫 監修、日本小児アレルギー学会食物アレルギー委員会：食物アレルギー診療ガイドライン2021. p65、協和企画、2021.
Fleischer DM, Chan ES, Venter C, Spergel JM, Abrams EM, Stukus D, Groetch M, Shaker M, Greenhawt M.
A Consensus Approach to the Primary Prevention of Food Allergy Through Nutrition: Guidance from the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and the Canadian Society for Allergy and Clinical Immunology.
J Allergy Clin Immunol Pract. 2021 Jan;9(1):22-43.e4. doi: 10.1016/j.jaip.2020.11.002. Epub 2020 Nov 26.
Abstract/Text
Recently published data from high-impact randomized controlled trials indicate the strong potential of strategies to prevent the development of food allergy in high-risk individuals, but guidance in the United States at present is limited to a policy for only the prevention of peanut allergy, despite other data being available and several other countries advocating early egg and peanut introduction. Eczema is considered the highest risk factor for developing IgE-mediated food allergy, but children without risk factors still develop food allergy. To prevent peanut and/or egg allergy, both peanut and egg should be introduced around 6 months of life, but not before 4 months. Screening before introduction is not required, but may be preferred by some families. Other allergens should be introduced around this time as well. Upon introducing complementary foods, infants should be fed a diverse diet, because this may help foster prevention of food allergy. There is no protective benefit from the use of hydrolyzed formula in the first year of life against food allergy or food sensitization. Maternal exclusion of common allergens during pregnancy and/or lactation as a means to prevent food allergy is not recommended. Although exclusive breast-feeding is universally recommended for all mothers, there is no specific association between exclusive breast-feeding and the primary prevention of any specific food allergy.
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Halken S, Muraro A, de Silva D, Khaleva E, Angier E, Arasi S, Arshad H, Bahnson HT, Beyer K, Boyle R, du Toit G, Ebisawa M, Eigenmann P, Grimshaw K, Hoest A, Jones C, Lack G, Nadeau K, O'Mahony L, Szajewska H, Venter C, Verhasselt V, Wong GWK, Roberts G; European Academy of Allergy and Clinical Immunology Food Allergy and Anaphylaxis Guidelines Group.
EAACI guideline: Preventing the development of food allergy in infants and young children (2020 update).
Pediatr Allergy Immunol. 2021 Jul;32(5):843-858. doi: 10.1111/pai.13496. Epub 2021 Mar 29.
Abstract/Text
BACKGROUND: This guideline from the European Academy of Allergy and Clinical Immunology (EAACI) recommends approaches to prevent the development of immediate-onset / IgE-mediated food allergy in infants and young children. It is an update of a 2014 EAACI guideline.
METHODS: The guideline was developed using the AGREE II framework and the GRADE approach. An international Task Force with representatives from 11 countries and different disciplinary and clinical backgrounds systematically reviewed research and considered expert opinion. Recommendations were created by weighing up benefits and harms, considering the certainty of evidence and examining values, preferences and resource implications. The guideline was peer-reviewed by external experts, and feedback was incorporated from public consultation.
RESULTS: All of the recommendations about preventing food allergy relate to infants (up to 1 year) and young children (up to 5 years), regardless of risk of allergy. There was insufficient evidence about preventing food allergy in other age groups. The EAACI Task Force suggests avoiding the use of regular cow's milk formula as supplementary feed for breastfed infants in the first week of life. The EAACI Task Force suggests introducing well-cooked, but not raw egg or uncooked pasteurized, egg into the infant diet as part of complementary feeding. In populations where there is a high prevalence of peanut allergy, the EAACI Task Force suggests introducing peanuts in an age-appropriate form as part of complementary feeding. According to the studies, it appears that the most effective age to introduce egg and peanut is from four to 6 months of life. The EAACI Task Force suggests against the following for preventing food allergy: (i) avoiding dietary food allergens during pregnancy or breastfeeding; and (ii) using soy protein formula in the first 6 months of life as a means of preventing food allergy. There is no recommendation for or against the following: use of vitamin supplements, fish oil, prebiotics, probiotics or synbiotics in pregnancy, when breastfeeding or in infancy; altering the duration of exclusive breastfeeding; and hydrolysed infant formulas, regular cow's milk-based infant formula after a week of age or use of emollients.
CONCLUSIONS: Key changes from the 2014 guideline include suggesting (i) the introduction of peanut and well-cooked egg as part of complementary feeding (moderate certainty of evidence) and (ii) avoiding supplementation with regular cow's milk formula in the first week of life (low certainty of evidence). There remains uncertainty in how to prevent food allergy, and further well-powered, multinational research using robust diagnostic criteria is needed.
© 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Boyle RJ, Ierodiakonou D, Khan T, Chivinge J, Robinson Z, Geoghegan N, Jarrold K, Afxentiou T, Reeves T, Cunha S, Trivella M, Garcia-Larsen V, Leonardi-Bee J.
Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis.
BMJ. 2016 Mar 8;352:i974. doi: 10.1136/bmj.i974. Epub 2016 Mar 8.
Abstract/Text
OBJECTIVE: To determine whether feeding infants with hydrolysed formula reduces their risk of allergic or autoimmune disease.
DESIGN: Systematic review and meta-analysis, as part of a series of systematic reviews commissioned by the UK Food Standards Agency to inform guidelines on infant feeding. Two authors selected studies by consensus, independently extracted data, and assessed the quality of included studies using the Cochrane risk of bias tool.
DATA SOURCES: Medline, Embase, Web of Science, CENTRAL, and LILACS searched between January 1946 and April 2015.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective intervention trials of hydrolysed cows' milk formula compared with another hydrolysed formula, human breast milk, or a standard cows' milk formula, which reported on allergic or autoimmune disease or allergic sensitisation.
RESULTS: 37 eligible intervention trials of hydrolysed formula were identified, including over 19,000 participants. There was evidence of conflict of interest and high or unclear risk of bias in most studies of allergic outcomes and evidence of publication bias for studies of eczema and wheeze. Overall there was no consistent evidence that partially or extensively hydrolysed formulas reduce risk of allergic or autoimmune outcomes in infants at high pre-existing risk of these outcomes. Odds ratios for eczema at age 0-4, compared with standard cows' milk formula, were 0.84 (95% confidence interval 0.67 to 1.07; I(2)=30%) for partially hydrolysed formula; 0.55 (0.28 to 1.09; I(2)=74%) for extensively hydrolysed casein based formula; and 1.12 (0.88 to 1.42; I(2)=0%) for extensively hydrolysed whey based formula. There was no evidence to support the health claim approved by the US Food and Drug Administration that a partially hydrolysed formula could reduce the risk of eczema nor the conclusion of the Cochrane review that hydrolysed formula could allergy to cows' milk.
CONCLUSION: These findings do not support current guidelines that recommend the use of hydrolysed formula to prevent allergic disease in high risk infants.
REVIEW REGISTRATION: PROSPERO CRD42013004252.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Sakihara T, Otsuji K, Arakaki Y, Hamada K, Sugiura S, Ito K.
Randomized trial of early infant formula introduction to prevent cow's milk allergy.
J Allergy Clin Immunol. 2021 Jan;147(1):224-232.e8. doi: 10.1016/j.jaci.2020.08.021. Epub 2020 Sep 2.
Abstract/Text
BACKGROUND: Previous research has produced conflicting evidence on the preventive effects of early introduction of cow's milk protein on cow's milk allergy (CMA).
OBJECTIVE: Through a randomized controlled trial, we sought to determine whether the early introduction of cow's milk formula (CMF) could serve as an effective strategy in the primary prevention of CMA in a general population.
METHODS: We recruited newborns from 4 hospitals in Okinawa, Japan. Participants were randomly allocated to ingest at least10 mL of CMF daily (ingestion group) or avoid CMF (avoidance group) between 1 and 2 months of age. In the avoidance group breast-feeding was supplemented with soy formula as needed. Oral food challenge was performed at 6 months of age to assess CMA development. Continuous breast-feeding was recommended for both groups until 6 months of age.
RESULTS: We identified 504 infants for randomization into the 2 groups. In all, the parents of 12 participants declined to receive the intervention, and the study sample comprised 491 participants (242 in the ingestion group and 249 in the avoidance group) for a modified intention-to-treat analysis. There were 2 CMA cases (0.8%) among the 242 members of the ingestion group and 17 CMA cases (6.8%) among the 249 participants in the avoidance group (risk ratio = 0.12; 95% CI = 0.01-0.50; P < .001). The risk difference was 6.0% (95% CI = 2.7-9.3). Approximately 70% of the participants in both groups were still being breast-fed at 6 months of age.
CONCLUSIONS: Daily ingestion of CMF between 1 and 2 months of age prevents CMA development. This strategy does not compete with breast-feeding.
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Urashima M, Mezawa H, Okuyama M, Urashima T, Hirano D, Gocho N, Tachimoto H.
Primary Prevention of Cow's Milk Sensitization and Food Allergy by Avoiding Supplementation With Cow's Milk Formula at Birth: A Randomized Clinical Trial.
JAMA Pediatr. 2019 Dec 1;173(12):1137-1145. doi: 10.1001/jamapediatrics.2019.3544.
Abstract/Text
IMPORTANCE: Cow's milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice.
OBJECTIVE: To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow's milk protein and/or clinical food allergy, including cow's milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels.
DESIGN, SETTING, AND PARTICIPANTS: The Atopy Induced by Breastfeeding or Cow's Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018.
INTERVENTIONS: Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid-based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (BF plus CMF group).
MAIN OUTCOMES AND MEASURES: The primary outcome was sensitization to cow's milk (IgE level, ≥0.35 allergen units [UA]/mL) at the infant's second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 UA/mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age.
RESULTS: Of the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50; P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types.
CONCLUSIONS AND RELEVANCE: The evidence suggests that sensitization to cow's milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life.
TRIAL REGISTRATION: http://umin.ac.jp Identifier: UMIN000011577.
Zutavern A, Brockow I, Schaaf B, von Berg A, Diez U, Borte M, Kraemer U, Herbarth O, Behrendt H, Wichmann HE, Heinrich J; LISA Study Group.
Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA.
Pediatrics. 2008 Jan;121(1):e44-52. doi: 10.1542/peds.2006-3553.
Abstract/Text
OBJECTIVE: Current prophylactic feeding guidelines recommend a delayed introduction of solids for the prevention of atopic diseases. This study investigates whether a delayed introduction of solids (past 4 or 6 months) is protective against the development of eczema, asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years.
METHODS: Data from 2073 children in the ongoing LISA birth cohort study were analyzed at 6 years of age. Multivariate logistic regression analyses were performed for all children and for children without skin or allergic symptoms within the first 6 months of life to take into account reverse causality.
RESULTS: A delayed introduction of solids (past 4 or 6 months) was not associated with decreased odds for asthma, allergic rhinitis, or sensitization against food or inhalant allergens at 6 years of age. On the contrary, food sensitization was more frequent in children who were introduced to solids later. The relationship between the timing of solid food introduction and eczema was not clear. There was no protective effect of a late introduction of solids or a less diverse diet within the first 4 months of life. However, in children without early skin or allergic symptoms were considered, eczema was significantly more frequent in children who received a more diverse diet within the first 4 months.
CONCLUSIONS: This study found no evidence supporting a delayed introduction of solids beyond 4 or 6 months for the prevention of asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years. For eczema, the results were conflicting, and a protective effect of a delayed introduction of solids cannot be excluded. Positive associations between late introduction of solids and food sensitization have to be interpreted with caution. A true protective effect of a delayed introduction of solids on food sensitization seems unlikely.
Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, Fox AT, Turcanu V, Amir T, Zadik-Mnuhin G, Cohen A, Livne I, Lack G.
Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
J Allergy Clin Immunol. 2008 Nov;122(5):984-91. doi: 10.1016/j.jaci.2008.08.039.
Abstract/Text
BACKGROUND: Despite guidelines recommending avoidance of peanuts during infancy in the United Kingdom (UK), Australia, and, until recently, North America, peanut allergy (PA) continues to increase in these countries.
OBJECTIVE: We sought to determine the prevalence of PA among Israeli and UK Jewish children and evaluate the relationship of PA to infant and maternal peanut consumption.
METHODS: A clinically validated questionnaire determined the prevalence of PA among Jewish schoolchildren (5171 in the UK and 5615 in Israel). A second validated questionnaire assessed peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel).
RESULTS: The prevalence of PA in the UK was 1.85%, and the prevalence in Israel was 0.17% (P < .001). Despite accounting for atopy, the adjusted risk ratio for PA between countries was 9.8 (95% CI, 3.1-30.5) in primary school children. Peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the UK. The median monthly consumption of peanut in Israeli infants aged 8 to 14 months is 7.1 g of peanut protein, and it is 0 g in the UK (P < .001). The median number of times peanut is eaten per month was 8 in Israel and 0 in the UK (P < .0001).
CONCLUSIONS: We demonstrate that Jewish children in the UK have a prevalence of PA that is 10-fold higher than that of Jewish children in Israel. This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity. Israeli infants consume peanut in high quantities in the first year of life, whereas UK infants avoid peanuts. These findings raise the question of whether early introduction of peanut during infancy, rather than avoidance, will prevent the development of PA.
Fleischer DM, Sicherer S, Greenhawt M, Campbell D, Chan E, Muraro A, Halken S, Katz Y, Ebisawa M, Eichenfield L, Sampson H, Lack G, Du Toit G, Roberts G, Bahnson H, Feeney M, Hourihane J, Spergel J, Young M, As'aad A, Allen K, Prescott S, Kapur S, Saito H, Agache I, Akdis CA, Arshad H, Beyer K, Dubois A, Eigenmann P, Fernandez-Rivas M, Grimshaw K, Hoffman-Sommergruber K, Host A, Lau S, O'Mahony L, Mills C, Papadopoulos N, Venter C, Agmon-Levin N, Kessel A, Antaya R, Drolet B, Rosenwasser L; American Academy of Allergy, Asthma & Immunology; American Academy of Pediatrics, American College of Allergy; Asthma & Immunology, Australasian Society of Clinical Immunology and Allergy; Canadian Society of Allergy and Clinical Immunology; European Academy of Allergy and Clinical Immunology; Israel Association of Allergy and Clinical Immunology; Japanese Society for Allergology; Society for Pediatric Dermatology; World Allergy Organization.
Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants.
J Allergy Clin Immunol. 2015 Aug;136(2):258-61. doi: 10.1016/j.jaci.2015.06.001. Epub 2015 Jun 20.
Abstract/Text
The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology, American Academy of Pediatrics, American College of Allergy, Asthma & Immunology, Australasian Society of Clinical Immunology and Allergy, Canadian Society of Allergy and Clinical Immunology, European Academy of Allergy and Clinical Immunology, Israel Association of Allergy and Clinical Immunology, Japanese Society for Allergology, Society for Pediatric Dermatology, and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases-sponsored Working Group and the European Academy of Allergy and Clinical Immunology.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, Saito M, Kishino A, Takimoto T, Inoue E, Tang J, Kido H, Wong GW, Matsumoto K, Saito H, Ohya Y; PETIT Study Team.
Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial.
Lancet. 2017 Jan 21;389(10066):276-286. doi: 10.1016/S0140-6736(16)31418-0. Epub 2016 Dec 9.
Abstract/Text
BACKGROUND: Evidence is accumulating that early consumption is more beneficial than is delayed introduction as a strategy for primary prevention of food allergy. However, allergic reactions caused by early introduction of such solid foods have been a problematic issue. We investigated whether or not early stepwise introduction of eggs to infants with eczema combined with optimal eczema treatment would prevent egg allergy at 1 year of age.
METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled infants 4-5 months of age with eczema from two centres in Japan. Exclusion criteria were being born before 37 weeks of gestational age, experience of ingestion of hen's eggs or egg products, history of immediate allergic reaction to hen's eggs, history of non-immediate allergic reaction to a particular type of food, and complications of any severe disease. Infants were randomly assigned (block size of four; stratified by institution and sex) to early introduction of egg or placebo (1:1). Participants in the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age. We aggressively treated participants' eczema at entry and maintained control without exacerbations throughout the intervention period. Participants and physicians were masked to assignment, and allocation was concealed. The primary outcome was the proportion of participants with hen's egg allergy confirmed by open oral food challenges at 12 months of age, assessed blindly by standardised methods, in all randomly allocated participants who received the intervention. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000008673.
FINDINGS: Between Sept 18, 2012, and Feb 13, 2015, we randomly allocated 147 participants (73 [50%] to the egg group and 74 [50%] to the placebo group). This trial was terminated on the basis of the results of the scheduled interim analysis of 100 participants, which showed a significant difference between the two groups (four [9%] of 47 participants had an egg allergy in the egg group vs 18 [38%] of 47 in the placebo group; risk ratio 0·222 [95% CI 0·081-0·607]; p=0·0012). In the primary analysis population, five (8%) of 60 participants had an egg allergy in the egg group compared with 23 (38%) of 61 in the placebo group (risk ratio 0·221 [0·090-0·543]; p=0·0001). The only difference in adverse events between groups was admissions to hospital (six [10%] of 60 in the egg group vs none in the placebo group; p=0·022). 19 acute events occurred in nine (15%) participants in the egg group versus 14 events in 11 (18%) participants in the placebo group after intake of the trial powder.
INTERPRETATION: Introduction of heated egg in a stepwise manner along with aggressive eczema treatment is a safe and efficacious way to prevent hen's egg allergy in high-risk infants. In this study, we developed a practical approach to overcome the second wave of the allergic epidemic caused by food allergy.
FUNDING: Ministry of Health, Labour and Welfare, and National Centre for Child Health and Development, Japan.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Ierodiakonou D, Garcia-Larsen V, Logan A, Groome A, Cunha S, Chivinge J, Robinson Z, Geoghegan N, Jarrold K, Reeves T, Tagiyeva-Milne N, Nurmatov U, Trivella M, Leonardi-Bee J, Boyle RJ.
Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis.
JAMA. 2016 Sep 20;316(11):1181-1192. doi: 10.1001/jama.2016.12623.
Abstract/Text
IMPORTANCE: Timing of introduction of allergenic foods to the infant diet may influence the risk of allergic or autoimmune disease, but the evidence for this has not been comprehensively synthesized.
OBJECTIVE: To systematically review and meta-analyze evidence that timing of allergenic food introduction during infancy influences risk of allergic or autoimmune disease.
DATA SOURCES: MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS databases were searched between January 1946 and March 2016.
STUDY SELECTION: Intervention trials and observational studies that evaluated timing of allergenic food introduction during the first year of life and reported allergic or autoimmune disease or allergic sensitization were included.
DATA EXTRACTION AND SYNTHESIS: Data were extracted in duplicate and synthesized for meta-analysis using generic inverse variance or Mantel-Haenszel methods with a random-effects model. GRADE was used to assess the certainty of evidence.
MAIN OUTCOMES AND MEASURES: Wheeze, eczema, allergic rhinitis, food allergy, allergic sensitization, type 1 diabetes mellitus, celiac disease, inflammatory bowel disease, autoimmune thyroid disease, and juvenile rheumatoid arthritis.
RESULTS: Of 16 289 original titles screened, data were extracted from 204 titles reporting 146 studies. There was moderate-certainty evidence from 5 trials (1915 participants) that early egg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR], 0.56; 95% CI, 0.36-0.87; I2 = 36%; P = .009). Absolute risk reduction for a population with 5.4% incidence of egg allergy was 24 cases (95% CI, 7-35 cases) per 1000 population. There was moderate-certainty evidence from 2 trials (1550 participants) that early peanut introduction at 4 to 11 months was associated with reduced peanut allergy (RR, 0.29; 95% CI, 0.11-0.74; I2 = 66%; P = .009). Absolute risk reduction for a population with 2.5% incidence of peanut allergy was 18 cases (95% CI, 6-22 cases) per 1000 population. Certainty of evidence was downgraded because of imprecision of effect estimates and indirectness of the populations and interventions studied. Timing of egg or peanut introduction was not associated with risk of allergy to other foods. There was low- to very low-certainty evidence that early fish introduction was associated with reduced allergic sensitization and rhinitis. There was high-certainty evidence that timing of gluten introduction was not associated with celiac disease risk, and timing of allergenic food introduction was not associated with other outcomes.
CONCLUSIONS AND RELEVANCE: In this systematic review, early egg or peanut introduction to the infant diet was associated with lower risk of developing egg or peanut allergy. These findings must be considered in the context of limitations in the primary studies.
Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, Brough H, Marrs T, Radulovic S, Craven J, Flohr C, Lack G; EAT Study Team.
Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.
N Engl J Med. 2016 May 5;374(18):1733-43. doi: 10.1056/NEJMoa1514210. Epub 2016 Mar 4.
Abstract/Text
BACKGROUND: The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy.
METHODS: We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age.
RESULTS: In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe.
CONCLUSIONS: The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).
