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Background: Cow's milk allergy (CMA) is the most complex and common food allergy in infants. Elimination of cow's milk from the diet and replacement with a specialized formula for infants with cow's milk allergy who cannot be breastfed is an established approach to minimize the risk of severe allergic reactions while avoiding nutritional deficiencies. Given the availability of multiple options, such as extensively hydrolyzed cow's milk-based formula (eHF-CM), aminoacid formula (AAF), hydrolyzed rice formula (HRF), and soy formula (SF), there is some uncertainty regarding which formula might represent the most suitable choice with respect to health outcomes. The addition of probiotics to a specialized formula has also been proposed as a potential approach to possibly increase the benefit. We systematically reviewed specialized formulas for infants with CMA to inform the updated World Allergy Organization (WAO) DRACMA guidelines., Objective: To systematically review and synthesize the available evidence about the use of specialized formulas for the management of individuals with CMA., Methods: We searched from inception PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations, for randomized and non-randomized trials of any language investigating specialized formulas with or without probiotics. We included all studies irrespective of the language of the original publication. The last search was conducted in January 2024. We synthesized the identified evidence quantitatively or narratively as appropriate and summarized it in the evidence profiles. We conducted this review following the PRISMA, Cochrane methods, and the GRADE approach., Results: We identified 3558 records including 14 randomized trials and 7 observational studies. Very low certainty evidence suggested that in infants with IgE-mediated CMA, eHF-CM, compared with AAF, might have higher probability of outgrowing CMA (risk ratio (RR) 2.32; risk difference (RD) 25 more per 100), while showing potentially lower probability of severe vomiting (RR 0.12, 95% CI 0.02 to 0.88; RD 23 fewer per 100, 95% CI 3 to 26) and developing food protein-induced enterocolitis syndrome (FPIES) (RR 0.15, 95% CI 0.03 to 0.82; RD 34 fewer per 100, 95% CI 7 to 39). We also found, however, that eHF-CM might be inferior to AAF in supporting a physiological growth, with respect to both weight (-5.5% from baseline, 95%CI -9.5% to -1.5%) and length (-0.7 z-score change, 95%CI -1.15 to -0.25) (very low certainty). We found similar effects for eHF-CM, compared with AAF, also in non-IgE CMA. When compared with SF, eHF-CM might favor weight gain for IgE CMA infants (0.23 z-score change, 95%CI 0.01 to 0.45), and tolerance acquisition (RR 1.86, 95%CI 1.03 to 3.37; RD 27%, 95%CI 1%-74%) for non-IgE CMA (both at very low certainty of the evidence (CoE)). The comparison of eHF-CM vs. HRF, and HRF vs. SF, showed no difference in effect (very low certainty). For IgE CMA patients, low certainty evidence suggested that adding probiotics ( L. rhamnosus GG, L. casei CRL431 and B. lactis Bb-12) might increase the probability of developing CMA tolerance (RR 2.47, 95%CI 1.03 to 5.93; RD 27%, 95%CI 1%-91%), and reduce the risk of severe wheezing (RR 0.12, 95%CI 0.02 to 0.95; RD -23%, 95%CI -8% to -0.4%). However, in non-IgE CMA infants, the addition of probiotics ( L. rhamnosus GG) showed no significant effect, as supported by low to very low CoE., Conclusions: Currently available studies comparing eHF-CM, AAF, HRF, and SF provide very low certainty evidence about their effects in infants with IgE-mediated and non-IgE-mediated CMA. Our review revealed several limitations in the current body of evidence, primarily arising from concerns related to the quality of studies, the limited size of the participant populations and most importantly the lack of diversity and standardization in the compared interventions. It is therefore imperative for future studies to be methodologically rigorous and investigate a broader spectrum of available interventions. We encourage clinicians and researchers to review current World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines for suggestions on how to use milk replacement formulas in clinical practice and what additional research would be the most beneficial., Competing Interests: HJS and JLB, on behalf of McMaster University, received a research grant from the World Allergy Organization to conduct this review that was deposited into the university research account. RS participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott, Else, and Nestlé. HS serves as a board member of the International Scientific Association for Probiotics and Prebiotics (ISAPP), an unpaid and voluntary role. They have participated as a clinical investigator, advisory board member, consultant, and speaker for several companies, including Arla, BioGaia, Biocodex, Danone, Dicofarm, Nestlé, NNI, Nutricia, Mead Johnson, and Novalac. YV has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott Nutrition, Alba Health, Arla, Ausnutria, Biogaia, By Heart, CHR Hansen, Danone, ELSE Nutrition, Friesland Campina, Nestle Health Science, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, Pileje, Sanulac, United Pharmaceuticals (Novalac), Yakult, Wyeth. SW is the president of the Canadian Allergy Asthma and Immunology Foundation, and participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Pfizer, Kaleo, Bausch Health, GSK, AZ, Sanofi, CSL Behring, Leo, AbbVie, Takeda, Medexus Pharma, MiravoHealth, BioCryst, ALK, Novartis. They also covered the positions of: BOD Asthma Canada, CHAEN. MS works for Allergy & Anaphylaxis Australis, which receives unrestricted educational grants from infant formula companies. AW works for Allergy UK works with corporate partners including those providing foods for special medical purposes, such as Nutricia/Danone, Abbott, Reckitt Benckiser/Mead Johnson. They have been a speakers for 2 Nutricia symposia, with honoraria being paid to the charity. All other authors declare that they have no relevant conflicts of interest to disclose., (© 2024 The Author(s).)

Antigen-specific IgG2 and IgG3 are rarely measured in food allergy clinical trials despite known function in preventing mast cell and basophil activation. Our objective was to determine whether measuring peanut-specific IgG2 and IgG3 levels would correlate with peanut allergy status. Peanut-specific IgG subclasses were measured via ELISA assays in Learning Early About Peanut allergy (LEAP) trial participants at 5 years of age and were correlated with peanut allergy vs peanut sensitization vs non-peanut allergic and peanut consumption vs peanut avoidance. Peanut-specific IgG1, IgG2, IgG3, and IgG4 levels were significantly different between participants with peanut allergy vs peanut sensitization vs non-peanut allergic, and a multivariate logistic regression model and stepwise selection found that IgG1 most closely associated with peanut allergy status. Similarly, all subclasses differentiated those consuming vs those avoiding peanut, but subsequent modeling found that IgG4 most closely associated with consumption status. Amongst the peanut-specific IgG subclasses, IgG1 was the best biomarker for peanut allergy, while IgG4 was the best biomarker for peanut antigen exposure in this highly atopic cohort. Our study did not find added value from evaluating peanut-specific IgG 2 and 3 as biomarkers of peanut allergy, although they did correlate with peanut allergy. Subsequent studies should assess the value of adding IgG subclasses to multivariate models predicting peanut allergy status., Competing Interests: Carolyn H. Baloh, MD: no conflicts of interest to report. Noha Lim, PhD: no conflicts of interest to report. Michelle F. Huffaker, MD: no conflicts of interest to report. Pooja Patel, MD: no conflicts of interest to report. Jody Tversky, MD: reports research funding from Regeneron and AstraZenica. George du Toit, MB BCh: reports grants from National Institute of Allergy and Infectious Diseases (NIAID, NIH), Food Allergy & Research Education (FARE), MRC & Asthma UK Centre, UK Dept of Health through NIHR, Action Medical Research and National Peanut Board. Scientific Advisory Board member Aimmune. Investigator on pharma-sponsored allergy studies (Aimmune, and DBV Technologies). Scientific advisor to Aimmune, DBV and Novartis. Gideon Lack, MB BCh: reports grants from National Institute of Allergy and Infectious Diseases (NIAID, NIH), other from Food Allergy & Research Education (FARE), other from MRC & Asthma UK Centre, other from UK Dept of Health through NIHR, other from National Peanut Board (NPB), other from The Davis Foundation, during the conduct of the study; shareholder in DBV Technologies, and Mighty Mission Me, personal fees from Novartis, personal fees from Sanofi-Genyzme, personal fees from Regeneron, personal fees from ALK-Abello, personal fees from Lurie Children's Hospital, outside the submitted work. Tanya M. Laidlaw, MD: reports grants from National Institute of Allergy and Infectious Diseases (NIAID, NIH), and has served on scientific advisory boards for GlaxoSmithKline, Sanofi-Genzyme, Novartis, Eli Lilly, and Regeneron. Donald W. MacGlashan Jr, MD, PhD: No conflicts of interest to report., (© 2024 The Authors.)

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit., Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA., Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders., Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as "conditional" following the GRADE approach due to the very low certainty about the health effects based on the available evidence., Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers' values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable., Competing Interests: The conduction of these guidelines was funded by WAO and the McMaster University GRADE Centre. Direct funding by for-profit companies was not accepted. The guideline panel members received travel reimbursement for attendance at in-person meetings but received no other payments. The funding was also used as salary support for the information scientist running the original searches, and for research assistants and students conducting the systematic reviews. Some members of the method team who contributed to the systematic review conduction participated without remuneration to fulfill requirements of an academic degree or program. COIs of all participants were managed according to WAO policies based on guidance by the National Academy of Medicine2 and GIN3. Before commencing the project, all the participants were asked to disclose any financial and nonfinancial interests relevant to the guidelines by completing the World Health Organization (WHO) declaration of interest forms. An independent and anonymous WAO committee revised the disclosed interests looking for COIs. The revision committee reviewed the forms and deliberated on including panel members aiming to achieve a diversity of expertise and perspectives, while minimizing the inclusion of panel members with the same or similar conflicts. Specifically, the committee placed a high value on addressing conflicts from direct financial interests from for-profit companies related to the guidelines' field. Throughout the guidelines’ development, the members of the panel and method team were asked to update the interest disclosure forms, which were again revised by the WAO committee. At the time of appointment, most of the guideline panel, including one of the guideline panel co-chair (HJS), had no conflicts of interest. The other co-chair (AF) was aware of economic support by for-profit entities provided to WAO in the form of educational grants; therefore, he abstained from voting on all recommendations in the DRACMA guidelines. The method team members deemed to have a real, potential, or perceived conflict of interest related to the topic of a systematic review were excluded from partaking in that review. Likewise, guideline panel members with manageable real, potential, or perceived conflict of interest abstained from voting on recommendations related to that interest, while being still able to provide intellectual input and clinical expertise. The Evidence-to-Decision (EtD) tables for each recommendation list individuals who were excused from voting. One proposed panel member was found with disqualifying competing interests and was excluded from the DRACMA project entirely.S Arasi, S Bahna, A Bognanni, J Brozek, D Chu, L Dahdah, P Dziechciarz, E Galli, R Kamenwa, H Li, A Martelli, R Pawankar, H Schunemann, R Targino, L Terracciano, and A Warner have no conflicts to disclose. Relationships reported related to the submitted work: IJ Anstotegui – Abbott, Amgen, Astra Zeneca, Bayer, Bial, Faes Farma, Hikma, Menarini, Merck, Mundipharma, Roxall, Sanofi, Stallergenes, UCB. A Assa'ad – Aimmune Therapeutics, DBV Technologies, Astella, ABBVIE, Novartis, Sanofi, FARE, NIH and an intellectual property patent licensed to Hoth. R Berni Canani – Ch.Hansen, Danone, DVB, Humana, iHealth, Kraft Heinz, Mead Johnson, Nestlè, Novalac, Nutricia, Sanofi. M Bozzola – Danone. C Dupont – Nestle Health Science, Nestle France, Nutricia, Novalac, Sodilac, Abbott, Danone, and stock ownership at DBV Technologies. M Ebisawa – DBV Technologies, Mylan, ARS Pharmaceuticals, Novartis. A Fiocchi – Abbott, Danone. G Lack – FARE, National Peanut Board (NPB), The Davis Foundation, Action Medical Research, UK Food Standards Agency, Medical Research Council, DBV Technologies, Mission Mighty Me, Novartis, Sanofi-Genyzme, Regeneron, ALK-Abello, Lurie Children's Hospital. A Nowak-Wegrzyn – Nestle, Nutricia, Novartis, Gerber, Aimmune. N Papadopoulos – Novartis, Nutricia, HAL Allergy, Menarini/Faes Farma, Sanofi, Mylan/Meda, Biomay, AstraZeneca, GSK, MSD, ASIT Biotech, Boehringer Ingelheim, Gerolymatos International SA, Capricare. M Said – Nestle, Nutricia, Abbott, Bayer for Anaphylaxis Australia. R Shamir - Abbott, Else, Nestle. J Spergel – DBV Technologies, Regeneron, Sanofi, and Aimmune. H Szajewska – Ausnutria, Cargill, Danone, Else Nutrition, Hipp, Nestle, and Nestle Nutrition Institute. Y Vandenplas – Abbott Nutrition, Biogaia, Biocodex, By Heart, CHR Hansen, Danone, ELSE Nutrition, Friesland Campina, Hero, Hypocrata, Nestle Health Science, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, Orafti, Phacobel, Phathom Pharmaceuticals, Sari Husada, United Pharmaceuticals (Novalac), Wyeth, Yakult. C Venter – Reckitt Benckiser, Nestle Nutrition Institute, Danone, Abbott Nutrition, Else Nutrition, and Before Brands, DBV Technologies. A Warner - Nutricia/Danone, Abbott, Reckitt Benckiser/Mead Johnson, Nutricia/Danone for Allergy UK. S Waserman – Novartis-basic science work on peanut allergy, Aimmune-peanut OIT trial, Medical Advisor to Food Allergy Canada, and Pfizer, Bausch, Kaleoconsultant for epinephrine autoinjectors. GWK Wong – Nestle, Danone., (© 2024 The Author(s).)

Background: Many children are consuming some egg when they are diagnosed with egg allergy. We hypothesized that egg consumption could modify the diagnostic performance of allergy tests., Objective: To stratify diagnostic performance of tests according to egg consumption status., Methods: The BAT2 study (NCT03309488) participants underwent oral food challenge (OFC), food-frequency questionnaires, skin prick test (SPT), specific immunoglobulin E (sIgE) and specific immunoglobulin G4 (sIgG4) and basophil activation test (BAT)., Results: At study entry, 45% of participants reported partial egg consumption ("consumers") and 55% were avoiding egg strictly ("avoiders"). Avoiders had larger SPT (P < .001), higher BAT to egg (P < .001), sIgE to egg white (EW; P = .001) and to ovalbumin (OVA; P = .001), but not to ovomucoid (P = .231). Consumers had higher levels of sIgG4 to all egg allergens (P < .001) than avoiders. In consumers, the test with the best diagnostic performance was BAT (area under the curve [AUC] = .912) followed by SPT to raw egg (AUC = 0.805), EW-sIgE (AUC = 0.738), and OVA-sIgE (AUC = 0.732). In avoiders, the best tests were BAT (AUC = 0.834) and EW-sIgE (AUC = 0.833) followed by OVA-sIgE (AUC = 0.793) and SPT to EW (AUC=0.789). Using 100% sensitivity and 100% specificity cut-offs, the proportion of patients requiring OFC were 33% for BAT, 53% for SPT to raw egg, 61% for OVA-sIgE, and 73% for EW-sIgE for consumers; and 73% for BAT, 79% for EW-sIgE, and 93% for SPT to EW for avoiders., Conclusions: The diagnostic performance of tests is influenced by the immunomodulatory effect of egg consumption. BAT is the most reliable test and reduced the need for OFC, particularly in partial egg consumers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Allergen immunotherapy is highly effective for seasonal pollinosis. Three years of treatment results in long-term efficacy. This disease modification is accompanied by downregulation of allergen-specific Th2 responses and the induction of persistent specific IgG- and IgA-associated IgE-blocking activity. In children with seasonal rhinitis, both subcutaneous and sublingual pollen immunotherapy have been shown to reduce the development of asthma symptoms and asthma medication requirements. House dust mite tablet allergen immunotherapy has been shown to be effective for perennial mite-driven rhinitis in adults and children and may suppress asthma exacerbations, whereas its long-term efficacy has yet to be explored. The success of primary prevention of peanut allergy in childhood by introduction of peanut into the diet during infancy provides a strong rationale to explore whether primary prevention of inhalant allergies and asthma may also be possible. House dust mite allergy is a major risk factor for developing asthma. Preliminary data in at-risk children suggest that sublingual house dust mite immunotherapy initiated during infancy could reduce the onset of multiple allergen sensitizations and prevent the development of asthma at age 6 years. This possibility should now be explored in an adequately powered, prospectively randomized controlled trial., (Copyright © 2023. Published by Elsevier Inc.)

Background: A precise diagnosis of peanut allergy is extremely important. We identified 4 Ara h 2 peptides that improved Ara h 2-specific IgE (sIgE) diagnostic accuracy., Objective: To assess the diagnostic utility of sIgE to the mixture of these peptides and their role in mast cell response to peanut allergens., Methods: sIgE to the peptide mix was determined using ImmunoCAP. Its diagnostic utility was compared with Ara h 2-sIgE and sIgE to the individual peptides. The functional relevance of the peptides was tested on the mast cell activation test using laboratory of allergic diseases 2 cell line and flow cytometry., Results: A total of 52 peanut-allergic (PA), 36 peanut-sensitized but tolerant, and 9 nonsensitized nonallergic children were studied. Peptide mix-sIgE improved the diagnostic performance of Ara h 2-sIgE compared with Ara h 2-sIgE alone (area under the receiver operating characteristic curve .92 vs .89, respectively; P = .056). The sensitivity and specificity of Ara h 2-sIgE combined with the peptide mix were 85% and 96%, respectively. sIgE to individual peptides had the highest specificity (91%-96%) but the lowest sensitivity (10%-52%) compared with Ara h 2-sIgE (69% specificity and 87% sensitivity) or with peptide mix-sIgE (82% specificity and 63% sensitivity). Peptide 3 directly induced mast cell activation, and the peptide mix inhibited Ara h 2-induced activation of mast cells sensitized with plasma from Ara h 2-positive PA patients., Conclusions: sIgE to the peptide mix improved the diagnostic performance of Ara h 2-sIgE similarly to sIgE to individual peptides. The peptides interfered with Ara h 2-induced mast cell activation, confirming its relevance in peanut allergy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result., Objective: To investigate how well the algorithm determined allergy status in LEAP; to develop a new prediction model to determine peanut allergy status when OFC results are not available in LEAP Trio, a follow-up study of LEAP participants and their families; and to compare the new prediction model with the algorithm., Methods: The algorithm was developed for the LEAP protocol before the analysis of the primary outcome. Subsequently, a prediction model was developed using logistic regression., Results: Using the protocol-specified algorithm, 73% (453/617) of allergy determinations matched the OFC, 0.6% (4/617) were mismatched, and 26% (160/617) participants were nonevaluable. The prediction model included SPT, peanut-specific IgE, Ara h 1, Ara h 2, and Ara h 3. The model inaccurately predicted 1 of 266 participants as allergic who were not allergic by OFC and 8 of 57 participants as not allergic who were allergic by OFC. The overall error rate was 9 of 323 (2.8%) with an area under the curve of 0.99. The prediction model additionally performed well in an external validation cohort., Conclusion: The prediction model performed with high sensitivity and accuracy, eliminated the problem of nonevaluable outcomes, and can be used to estimate peanut allergy status in the LEAP Trio study when OFC is not available., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ara h 2-specific IgE (Arah2-sIgE) is an excellent serologic marker for peanut allergy. However, not all subjects with detectable Arah2-sIgE react clinically., Objective: To assess the importance of functional characteristics of Arah2-sIgE for Ara h 2-induced mast cell activation., Methods: We studied a cohort of children assessed for peanut allergy. We determined Arah2-sIgE levels, Ara h 2/total IgE ratios and IgE avidity for Ara h 2 using ImmunoCAP (Thermo Fisher) and mast cell activation to Ara h 2 using flow cytometry., Results: Samples from 61 of 100 children (46 peanut-allergic [PA] and 15 peanut-sensitized tolerant) who had Arah2-sIgE levels 0.10 kU/L or greater were studied. Arah2-sIgE and Ara h 6-specific IgE levels, Ara h 2/total IgE ratios, and the diversity of IgE for Ara h 2 epitopes were higher in PA compared with peanut-sensitized tolerant samples. The levels of IgE to peanut, Ara h 1, and Ara h 3 were not significantly different between groups. Results from the mast cell activation test to Ara h 2 strongly correlated with Arah2-sIgE levels (r = 0.722; P < .001) and Ara h 2/total IgE ratios (r = 0.697; P < .001) and moderately with Arah2-sIgE diversity (r = 0.540; P < .001). On a linear regression model, Arah2-sIgE levels (standardized β-coefficient = 0.396; P = .008) and Ara h 2/total IgE ratios (standardized β-coefficient = 0.0.669; P = .002) were the main determinants of mast cell response to Ara h 2., Conclusions: Most children sensitized to Ara h 2 are PA. Ara h 2-specific IgE titers and specific activity are the major determinants of mast cell response to Ara h 2., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of cow's milk allergy (CMA) is approximately 2-4.5% in infants and less than 0.5% in adults. Most children outgrow cow's milk allergy in early childhood, particularly that to the baked milk products. Immunotherapy with unheated cow's milk has been used as a treatment option for those who have not yet outgrown CMA, but the benefits must be balanced with the adverse effects., Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of oral and epicutaneous immunotherapy for the treatment of IgE-mediated CMA., Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment., Results: After a careful review of the summarized evidence and thorough discussions the WAO guideline panel suggests: a) using oral immunotherapy with unheated cow's milk in those individuals with confirmed IgE-mediated CMA who value the ability to consume controlled quantities of milk more than avoiding the large adverse effects of therapy, b) not using oral immunotherapy with unheated cow's milk in those who value avoiding large adverse effects of therapy more than the ability to consume controlled quantities of milk, c) using omalizumab in those starting oral immunotherapy with unheated cow's milk, d) not using oral immunotherapy with baked cow's milk in those who do not tolerate both unheated and baked milk, and e) not using epicutaneous immunotherapy outside of a research setting. The recommendations are labeled "conditional" due to the low certainty about the health effects based on the available evidence., Conclusions: Clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable effects of oral immunotherapy for IgE-mediated CMA and integrate them with the patients' values and preferences before deciding on a treatment option. More robust research is needed to determine with greater certainty which interventions are likely to be the most beneficial with the least harms, and to develop safer, low-cost, and equitable treatments., (© 2022 The Authors.)

Background: IgE to peanut often occurs in the absence of peanut allergy. Detection of allergen component specific IgE (sIgE) has improved diagnosis and birthed molecular allergen component arrays, in which sensitization to multiple allergen components can be measured simultaneously., Objective: To improve the diagnostic utility of serology for peanut allergy, by mapping interactions of sIgE to multiple components and IgE functional characteristics., Methods: A cohort of 100 children was studied, with a 60-children cohort employed for external validation. Levels of total IgE, sIgE to peanut, and peanut components were measured using singleplex ImmunoCAP and multiplex immuno solid-phase allergen chip (ISAC). Peanut IgE specific activity, avidity, and diversity were determined. Diagnostic modeling was performed using a Bayesian hierarchical model., Results: Sensitization to the 112 allergens on ISAC (model 1) demonstrated the highest accuracy to diagnose peanut allergy (area under the curve [AUC] = 0.92). Sensitization to peanut components on ISAC (model 2) reported an AUC of 0.86 and on singleplex (model 3) an AUC of 0.92, which was greater than that of Ara h 2 sIgE alone (AUC = 0.90). Functional characteristics of peanut sIgE (model 4) reported an AUC of 0.89, which was greater than that of peanut sIgE (AUC = 0.75). Model 3 offered the highest predictive value and the second highest overall diagnostic accuracy., Conclusions: sIgE to a combination of allergen components (Ara h 1, 2, 3, and 6) is highly predictive of peanut allergy and superior to individual markers. Combining the functional characteristics of IgE was superior to peanut sIgE levels alone. These models can be applied in real time during clinical consultations using online calculators., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nut allergic patients are often IgE sensitized to other nuts/seeds and need multiple oral food challenges (OFCs) before the safe nuts can be introduced in the diet. However, OFCs are time-consuming and risky procedures., Objective: To assess the utility of the basophil activation test (BAT) to predict the allergic status and reduce the need for an OFC in children with 1 or more nut or seed allergies., Methods: Participants in the Pronuts study recruited at the Geneva and the London centers were tested on the BAT to hazelnut, cashew nut, sesame, almond, and peanut, Ara h 1, Ara h 2, Ara h 6, using FlowCAST, a commercially available BAT kit, and flow cytometry., Results: The BAT to hazelnut, cashew nut, sesame, almond, and peanut discriminated between allergic and nonallergic children, to the respective nut or seed. The optimal allergen concentration and their optimal, positive, and negative cutoffs were identified for the BAT and the other tests, for each nut and seed. Using the BAT as a second step in the diagnostic process, after equivocal skin prick test and IgE to extracts and components, reduced the number of total OFCs by 5% to 15% and positive OFCs by 33% to 75% (except for hazelnut) with 0% false-negatives and a diagnostic accuracy of 96% to 100%., Conclusion: The BAT proved to be a useful diagnostic tool, used in a stepwise approach, to predict the allergic status and reduce the number of OFCs in the Pronuts study participants with at least 1 nut allergy willing to consume selected nuts., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Peanut 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. There are country-specific variations to guidelines, but, within these variations, feeding peanut to children in infancy is a common theme. There are numerous logistical challenges surrounding the implementation of contemporary guidelines at a population level. In the United States, guidelines advise according to risk level with prescreening recommended for high-risk children (mod/severe eczema, egg allergy). Even though high-risk children represent the minority of the childhood population, there are still significant challenges associated with identifying and screening such infants. The need for conducting allergy testing before first giving peanut protein to high-risk infants is debated; although adopting this approach promotes safety, it is financially and logistically challenging. Clinical trials that explore the real-life application of these guidelines are needed as is an assessment of guidelines (Australia, for example) that do not adopt the approach of screening., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The 2010 Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guidelines are the only Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines for cow's milk allergy (CMA). They indicate oral food challenge (OFC) as the reference test for diagnosis, and suggest the choice of specific alternative formula in different clinical conditions. Their recommendations are flexible, both in diagnosis and in treatment., Objectives & Methods: Using the Scopus citation records, we evaluated the influence of the DRACMA guidelines on milk allergy literature. We also reviewed their impact on successive food allergy and CMA guidelines at national and international level. We describe some economic consequences of their application., Results: DRACMA are the most cited CMA guidelines, and the second cited guidelines on food allergy. Many subsequent guidelines took stock of DRACMA's metanalyses adapting recommendations to the local context. Some of these chose not to consider OFC as an absolute requirement for the diagnosis of CMA. Studies on their implementation show that in this case, the treatment costs may increase and there is a risk of overdiagnosis. Interestingly, we observed a reduction in the cost of alternative formulas following the publication of the DRACMA guidelines., Conclusions: DRACMA reconciled international differences in the diagnosis and management of CMA. They promoted a cultural debate, improved clinician's knowledge of CMA, improved the quality of diagnosis and care, reduced inappropriate practices, fostered the efficient use of resources, empowered patients, and influenced some public policies. The accruing evidence on diagnosis and treatment of CMA necessitates their update in the near future., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Clinical studies to prevent the development of food allergy have recently helped reshape public policy recommendations on the early introduction of allergenic foods. These trials are also prompting new research, and it is therefore important to address the unique design and analysis challenges of prevention trials. We highlight statistical concepts and give recommendations that clinical researchers may wish to adopt when designing future study protocols and analysis plans for prevention studies. Topics include selecting a study sample, addressing internal and external validity, improving statistical power, choosing alpha and beta, analysis innovations to address dilution effects, and analysis methods to deal with poor compliance, dropout, and missing data., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Peanut and tree nut allergies have become a public health problem over the last 2 decades. The diagnostic procedure relies on a suggestive history, as well as on evidence of sensitization (skin prick testing and/or specific IgE blood testing), followed in selected cases by a food challenge. Standard IgE tests may be positive to more than 1 nut, due to cross-reactivity (allergens common to several nuts) or cosensitivity (frequently associated positive test results without cross-reactivity). Thus, many patients with a peanut or a tree nut allergy avoid all nuts, relying on positive test results without clinical evidence of reactivity. In addition, coexisting pollen sensitivity may add to diagnostic uncertainty due to potential cross-reactivity between pollens and nuts. In this article, we discuss challenges in diagnosis and clinical management of peanut and tree nut allergy related to cross-reactivity and cosensitization, as well as the avoidance of nuts tested positive to reduce the risk of reactions by cross-contamination. Studies to provide more accurate characterization of genuine clinically relevant cross-reactivity or cosensitivity to multiple nuts are needed., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Food allergies are commonly seen by the practitioner, and managing these patients is often challenging. Recent epidemiologic studies report that as many as 1 in 13 children in the United States may have a food allergy, which makes this an important disease process to appropriately diagnose and manage for primary care physicians and specialists alike. Having a understanding of the basic immunologic processes that underlie varying presentations of food-induced allergic diseases will guide the clinician in the initial workup. This review will cover the basic approach to understanding the immune response of an individual with food allergy after ingestion and will guide the clinician in applying appropriate testing modalities when needed by conducting food challenges if indicated and by educating the patient and his or her guardian to minimize the risk of accidental ingestion., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.

Background: : Probiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness., Objective: : A World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy., Methods: : A qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications., Results: : Despite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications., Conclusions: : Probiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful.

Background: Food frequency questionnaires (FFQs) are essential tools to investigate the relationship between peanut consumption and the development of peanut allergy. The aim was to validate a 50-item FFQ for use in peanut protein sensitization studies., Methods: There were 38 mother-child pairs visiting a pediatric clinic of a London hospital included. Mothers recorded their own and their child's diet, using a 7 day food diary (7DFDR), completed prospectively over week. Six months later, they tried to recall the consumption of food items for the index week on a FFQ., Results: Of these, 33 out of 38 mothers completed both the 7DFDR and the recall FFQ. Although there was considerable variation at the individual level between the 2 tools, there was extremely close agreement between the mean 7DFDR response and the FFQ when considering groups of fives with similar FFQ levels. Agreement was apparent on both peanut and other control foods consumption patterns., Conclusion: The FFQ will reliably divide the population into groups with markedly different peanut consumption levels. It accurately reflects true adults and children peanut consumption, especially at low levels of peanut consumption, as it was validated against the gold standard, the 7DFDR. It also provides a good measure of other foods consumption.