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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.

Background: The basis for qualification for venom immunotherapy (VIT) is the fulfilment of both the clinical and immunological criteria. Diagnostic tests that confirm the immunological criterion of an IgE-mediated sensitization include skin prick tests (SPT), intradermal tests (IDT), and serum specific IgE (sIgE) for the culprit venom. Objective: This study aimed to assess the usefulness of SPT as the immunological marker in the diagnosis of insect venom sensitization in children with history of systemic reaction (SR) to insect sting evaluated by means of I-IV-grades Mueller's scale. There are no such studies in children. Methods: This cross-sectional study sample consisted of 416 children aged 3–18 years (mean age 10.6 ± 3.8), 76% males, all with the history of a systemic reaction (SR) after a Hymenoptera sting (48% of grade III/IV according to Mueller scale), diagnosed between 1999 and 2019 in the tertiary referral centre. The standard diagnostic tests were used. Specificity, sensitivity, and positive and negative predictive values were computed to assess the diagnostic properties of the clinical tests to distinguish between mild and severe SR. To assess the relative value of an individual test in predicting the qualification to VIT we incorporated the Shapley value (SV). Results: Positive SPT results were found in up to no more than 3% of children; among them less than 1% had only positive SPT and were negative for sIgE and IDT. Approximately 85% of the children had detectable venom sIgE, followed by positive IDT (75%). Almost 70% of children had positive both sIgE and IDT results. In children with grade III/IV reaction, about 80% of children had positive results of both of these tests. sIgE and IDT had sensitivity >0.80, whereas SPT had high specificity (>0.97) in differentiating between mild and severe SR. Relative value of diagnostic tests in predicting qualification to VIT varied between venoms. Bee venom IDT had higher SV (0.052) than sIgE (0.041). In contrast, wasp venom sIgE had higher SV (0.075) than IDT (0.035). Conclusion: SPTs are not an useful immunological marker of venom sensitization in children, and eliminating SPT does not result in a loss of diagnostic accuracy. Limiting diagnostics to venom sIgE and IDT would shorten the procedure and reduce costs. Future studies are needed to determine if venom sIgE as the first line diagnostic test, with IDT added only if the venom sIgE is undetectable, is an optimal diagnostic process.

Background: Since the publication of The World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines in 2010, a number of other guidelines, expert opinions, and position papers relating to the management of cow's milk allergy (CMA) have been published. We aimed to systematically review the quality of the guidelines on CMA diagnosis and management in children and/or adults published between 2010 and 2020. Methods: The MEDLINE, EMBASE, ISI Web of Science, World Health Organization Global Index Medicus, and Turning Research into Practice databases as well as website guideline repositories were searched from January 2010 until May 2020. Any clinical practice recommendations and/or guidelines focusing on the diagnosis and management of CMA in children and/or adults developed or endorsed by professional scientific societies or organizations were included. The guidelines were evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, a 23-item tool organized within 6 domains and 2 global rating items. Results: We included 12 guidelines; 8 were developed by national and 4 by international organizations. The quality scores for each domain varied: of all domains, the clarity of presentation domain had the highest median score (92%; Q1-Q3 81–100%), whereas rigor of development had the lowest median score (30%; Q1-Q3 15–67%). The median scores (Q1-Q3) for individual domains were as follows: scope and purpose 82% (70–99%), stakeholder involvement 63% (21–79%), rigor of development 30% (15–67%), clarity of presentation 92% (81–100%), applicability 68% (57–75%), and editorial independence 75% (69–100%). The median overall score was 70% (58–89%). Only 1 guideline (from the National Institute for Health and Care Excellence [NICE]) achieved top ratings (100%) in five domains and the overall score. Three guidelines (from the NICE, the British Society for Allergy & Clinical Immunology [BSACI] and WAO) achieved the highest ratings (100%) in at least 3 domains and the overall score. Conclusion: The majority of identified guidelines were of good or very good quality. However, the weakest point was the rigor of development domain, mostly due to unclear description of strengths and limitations of the body of evidence and the procedure for updating the guidelines.

Since the World Allergy Organization (WAO) Diagnosis and Rationale against Cow's Milk Allergy (DRACMA) Guidelines were published 10 years ago, new evidence has accumulated about the diagnosis, therapy, and specific immunotherapy for cow's milk allergy (CMA). For this reason, WAO has felt the need to update the guidelines.We introduce here this update. The new DRACMA guidelines aim to comprehensively address the guidance on diagnosis and therapy of both IgE non-IgE-mediated forms of cow's milk allergy in children and adults. They will be divided into 18 chapters, each of which will be dedicated to an aspect. The focus will be on the meta-analyzes and recommendations that will be expressed for the 3 most relevant clinical aspects: (a) the diagnostic identification of the condition; (b) the choice of the replacement formula in case of CMA in infancy when the mother is not able to breastfeed, and (c) the use of specific immunotherapy for cow's milk protein allergy.

The diagnosis of cow's milk allergy (CMA) in infants and young children remains a challenge because many of the presenting symptoms are similar to those experienced in other diagnoses. Both over- and under-diagnosis occur frequently. Misdiagnosis carries allergic and nutritional risks, including acute reactions, growth faltering, micronutrient deficiencies and a diminished quality of life for infants and caregivers. An inappropriate diagnosis may also add a financial burden on families and on the healthcare system.Elimination and reintroduction of cow's milk (CM) and its derivatives is essential for diagnosing CMA as well as inducing tolerance to CM. In non-IgE mediated CMA, the diagnostic elimination diet typically requires 2–4 weeks before reintroduction, while for IgE mediated allergy the time window may be shorter (1–2 weeks). An oral food challenge (OFC) under medical supervision remains the most reliable diagnostic method for IgE mediated and more severe types of non-IgE mediated CMA such as food protein induced enterocolitis syndrome (FPIES). Conversely, for other forms of non-IgE mediated CMA, reintroduction can be performed at home. The OFC cannot be replaced by the milk ladder after a diagnostic elimination diet. The duration of the therapeutic elimination diet, once a diagnosis was confirmed, can only be established through testing changes in sensitization status, OFCs or home reintroduction, which are directed by local protocols and services' availability. Prior non-evidence-based recommendations suggest that the first therapeutic elimination diet should last for at least 6 months or up to the age of 9–12 months, whichever is reached first. After a therapeutic elimination diet, a milk-ladder approach can be used for non-IgE mediated allergies to determine tolerance. Whilst some centers use the milk ladder also for IgE mediated allergies, there are concerns about the risk of having immediate-type reactions at home. Milk ladders have been adapted to local dietary habits, and typically start with small amounts of baked milk which then step up in the ladder to less heated and fermented foods, increasing the allergenicity.This publication aims to narratively review the risks associated with under- and over-diagnosis of CMA, therefore stressing the necessity of an appropriate diagnosis and management.

Background: While several scoring systems for the severity of anaphylactic reactions have been developed, there is a lack of consensus on definition and categorisation of severity of food allergy disease as a whole. Aim: To develop an international consensus on the severity of food allergy (DEfinition of Food Allergy Severity, DEFASE) scoring system, to be used globally. Methods: Phase 1: We conducted a mixed-method systematic review (SR) of 11 databases for published and unpublished literature on severity of food allergy management and set up a panel of international experts. Phase 2: Based on our findings in Phase 1, we drafted statements for a two-round modified electronic Delphi (e-Delphi) survey. A purposefully selected multidisciplinary international expert panel on food allergy (n = 60) was identified and sent a structured questionnaire, including a set of statements on different domains of food allergy severity related to symptoms, health-related quality of life, and economic impact. Participants were asked to score their agreement on each statement on a 5-point Likert scale ranging from “strongly agree” to “strongly disagree”. Median scores and percentage agreements were calculated. Consensus was defined a priori as being achieved if 70% or more of panel members rated a statement as “strongly agree” to “agree” after the second round. Based on feedback, 2 additional online voting rounds were conducted. Results: We received responses from 92% of Delphi panel members in round 1 and 85% in round 2. Consensus was achieved on the overall score and in all of the 5 specific key domains as essential components of the DEFASE score. Conclusions: The DEFASE score is the first comprehensive grading of food allergy severity that considers not only the severity of a single reaction, but the whole disease spectrum. An international consensus has been achieved regarding a scoring system for food allergy disease. It offers an evaluation grid, which may help to rate the severity of food allergy. Phase 3 will involve validating the scoring system in research settings, and implementing it in clinical practice.

Background: The immunopathogenesis of cow's milk protein allergy (CMPA) is based on different mechanisms related to immune recognition of protein epitopes, which are affected by industrial processing. Purpose: The purpose of this WAO DRACMA paper is to: (i) give a comprehensive overview of milk protein allergens, (ii) to review their immunogenicity and allergenicity in the context of industrial processing, and (iii) to review the milk-related immune mechanisms triggering IgE-mediated immediate type hypersensitivity reactions, mixed reactions and non-IgE mediated hypersensitivities. Results: The main cow’s milk allergens – α-lactalbumin, β-lactoglobulin, serum albumin, caseins, bovine serum albumins, and others – may determine allergic reactions through a range of mechanisms. All marketed milk and milk products have undergone industrial processing that involves heating, filtration, and defatting. Milk processing results in structural changes of immunomodulatory proteins, leads to a loss of lipophilic compounds in the matrix, and hence to a higher allergenicity of industrially processed milk products. Thereby, the tolerogenic capacity of raw farm milk, associated with the whey proteins α-lactalbumin and β-lactoglobulin and their lipophilic ligands, is lost. Conclusion: The spectrum of immunopathogenic mechanisms underlying cow's milk allergy (CMA) is wide. Unprocessed, fresh cow's milk, like human breast milk, contains various tolerogenic factors that are impaired by industrial processing. Further studies focusing on the immunological consequences of milk processing are warranted to understand on a molecular basis to what extent processing procedures make single milk compounds into allergens.

Food allergy affects approximately 2–4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.