World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update – I – Plan and definitions

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.


INTRODUCTION
IgE-mediated cow's milk protein allergy (IgE-CMA) has been a primary topic of interest for WAO since 2010, the year in which the first Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-based guidelines on the management of this condition were published. 1 Of notice, the World Allergy Organization (WAO) Diagnosis and Rationale against Cow's Milk Allergy (DRACMA) Guidelines had a noticeable impact on clinical practice regarding IgE-CMA, raising awareness on several aspects. 2 First, the DRACMA guidelines presented a more nuanced and comprehensive diagnostic process, which, despite being generally based on oral food challenges (OFCs), could be supplemented, and in some cases replaced by an appropriate use of other tests such as skin prick test (SPT) and specific IgE determination (sIgE). The decision of which approach should be employed required an high-degree of personal contextualization, both depending on the specific circumstances and the values and preferences of the clinicians/patients. Second, the guidelines pointed out the necessity by infants aged <2 years of a substitutive formula whenever their mother could not breastfeed, with the best choice being frequently cow's milk extensively Hydrolyzed Formula (eHF). Where available, Hydrolyzed Rice Formula (HRF) was considered equivalent, while Amino Acid Formulae (AAF) was to be reserved for the most severe cases. Soy formulae were generally deemed not to be a first choice, while milk from other mammals (eg, donkey, camel, mare, sheep, and ewe) was not to be used given the mismatch with the infants' nutritional needs. Also in this case, the choice should rely on the context, and the values and preferences of the clinicians/patients. Third, Oral Immunotherapy (OIT) with milk was considered as an experimental procedure, not suitable for routine clinical practice. 3 Ten years later, despite the DRACMA methods still being valid, 4 the scenario has dramatically evolved, prompting an update in guidance. Differently from other food allergies, reported by many as increasingly prevalent, CMA appears to have not undergone this trajectory. 5,6 Even so, milk allergy remains a priority concern for allergists and pediatrician worldwide, with dairy anaphylaxis being now more common than peanut anaphylaxis, and the most frequently associated to lethal allergic reactions, as shown in a recent review on school-aged children with CMA. 7 We introduce herein the updated DRACMA guidelines. We aim to illustrate the progress in diagnosis, therapy, and immunotherapy of IgE-CMA that could tailor the management of CMA. We will shortly indicate the guidelines published after DRACMA, over the decade 2010/2020. Finally, we will present the structure of the reviewed guidelines that took place between 2016 and 2021 and whose publication begins with this issue of the World Allergy Organization Journal. The new DRACMA guidelines aim to comprehensively address the guidance on diagnosis and therapy of both IgE non-IgE-mediated forms of CMA.

2010-2020: OPEN QUESTIONS IN DIAGNOSIS, THERAPY, AND IMMUNOTHERAPY OF CMA
The diagnosis was preached by the DRACMA guidelines on the use of the OFC as a "gold standard" for IgE-CMA. This somewhat bombastic definition emphasize the need of a scientifically correct diagnosis, in order to prevent CMA overdiagnosis. The OFC certainly retains its validity, but over the years, its limitations have become increasingly evident. For example, OFC results are not predictive of the severity of subsequent reactions. 8 Also, there is no direct correlation between the eliciting threshold experienced by children during an OFC and the reaction's severity upon accidental exposure. 9 Tools such as the Basophil Activation Test (BAT) have been developed to minimize the risk of severe reactions to the OFC, 10,11 being also proposed as replacement tests of the OFC. 12 In addition, serious reactions to the OFC have been described, up to a case of fatal reaction. 13 These considerations will affect the direction of recommendations formulated by the guideline panel for the diagnosis of IgE mediated allergy. Other challenges inherent the diagnosis of IgE-CMA are the reassessment of the role of total and specific IgE assay, the interpretation of skin tests, and the possible role of molecular testing in diagnostic evaluation. 14,15 Finally, as about 70% of IgE-CMA patients are found to tolerate baked milk, the latter might be considered for a role in the CMA diagnostic pathway, prior to fresh milk testing 16 The elimination diet for milk, which prepares the OFC in IgE-mediated food allergy, completely replaces it in most guidelines for the diagnosis of non IgE-mediated CMA (non-IgE-CMA). 17 We will see later how this might have profound influence over the epidemiologic estimates of the disease, which will be among the priority topics to be addressed in the new DRACMA guidelines. Specifically, we will try to address in an evidence-based manner the following questions: Should an elimination diet be followed by OFC in the individuals suspected of non-IgEmediated CMA? Is there any use of atopy patch test to milk in these children? Is there any role for endoscopy AE biopsy in children with suspected milk-induced Eosinophilic Esophagitis (EoE) or non-esophageal Eosinophilic Gastrointestinal Disorders (EGIDs), including eosinophilic gastroenteritis and colitis? Are the diagnostic challenge procedures, recommended by specific guidelines for Food-Protein-Induced Enterocolitis Syndrome (FPIES), 18 adequately informed by evidence?
In synthesis, reconciling the diagnostic procedures for the different forms of CMA will be a challenge for the new DRACMA guidelines. 19 A peculiar issue to consider, in the treatment of CMA, given the pivotal importance of maternal milk for children up to 24/36 months of age, is to confirm the evidence underlying the suggestion of cow's milk (CM) elimination diet for mothers breastfeeding allergic infants. 20 In the past 10 years, the involvement of formulas in the management of CMA has been profoundly expanded, with extensively hydrolyzed formulas (eHFs), 21 rice hydrolyzed formula (HRF), 22 amino acid formulae (AAF), 23 camel and dromedary milk, 24 and donkey milk 25 receiving increasing attention from the health community and being implemented in medical practice. To properly represent the change of the topic, we will update the systematic review investigating the effect of formulas in the management of CMA.
Another important aspect to account for is the reported effect of associating probiotics with formulas, either administered separately or mixed in the same formulation, on the duration of IgE-CMA. 26,27 Another issue that will be investigated is the employment of new synbiotic-supplemented amino acid-based formulas. 28,29 Over the course of the last decade, several advances have been done in developing novel protocols of CM oral immunotherapy, with the most notable examples being the weekly 30 or slow updosing regimens, 31 the rapid oral desensitization combined with omalizumab, 32 different maintenance feeding regimens, 33 and baked milk oral immunotherapy [34][35][36] Previous systematic reviews investigating this aspect of IgE-CMA management were published in 2012 and 2017 including, but not limited to, OIT for IgE-CMA. 37,38 The systematic review and guideline publication focusing on this topic will be the first among the 2021 DRACMA-related publications.

CMA GUIDELINES PUBLISHED AFTER DRACMA
Since the first edition of DRACMA, other guidelines, consensuses, and position papers have been issued on CMA at the regional or national level. Some of them were national guidance items, implementing locally the DRACMA guidelines, others were de novo publications, developed using different methodologies. We report in Table 1 a list of the main CMA guidelines published over the course of the past 10 years.
Among the publications above, the one most implemented is the UK NICEderived guideline,  The quality of guidelines on CMA, published between 2010 and 2015, was assessed through the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. 60 The appraisal highlighted the lack of a defined quality standard, as only 3 presented satisfactory scores across the key domains. In light of this, in the present update of the DRACMA guidelines we strive to adhere to the highest methodological standards in the evaluation of evidence and its translation into recommendations.

METHODS APPLIED IN THE 2021 DRACMA GUIDELINES
We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach {PMID: 21195583} and the European Commission methods for developing practice guidelines. 61 WAO established a multidisciplinary guideline panel (DRACMA Scientific Committee) composed of content experts and representatives of key stakeholders, including patient representatives, nutritionists, and general practitioners. All panel members declared their actual, potential, and/or perceived competing interests. Those were reviewed by an anonymous WAO committee that decided which panel members should abstain from voting on selected recommendations related to immunotherapy, formulas, and diagnosis of CMA.
A group of methodology experts from the McMaster GRADE Centre performed systematic reviews of the evidence and led the process of developing recommendations.
The DRACMA guideline panel generated a set of 61 questions and determined their priority to be answered with recommendations (Supplementary material). The methodology group performed necessary systematic reviews and prepared GRADE summary of findings tables. The voting panel members followed the evidence-todecision (EtD) framework to develop recommendations either by in-person or online discussion following the modified Delphi approach. We published all decisions and the rationale for the recommendations as appendices to the guidelines.

GENERAL STRUCTURE OF THE 2021 DRACMA GUIDELINES
The original guideline comprised 19 chapters merged into a single publication. This time we decided to publish the chapters separately in a dedicated series in the World Allergy Organization Journal to facilitate the dissemination and the implementation of the guideline. For this reason the chapters have been separated, and every topic will be published in a single article. Table 2 shows the publication plan. Due to peer review process, the articles will not necessarily be published in the order indicated. We will start with the guidelines on OIT, those for which a greater harvest of new data has been produced. The guideline is submitted together with the metanalysis supporting it. Other articles will be published regularly, so that the project will configure a Summa of the relevant information about CMA.

GLOSSARY OF CMA
In developing the metanalyses and the guidelines, we adhered to the following definitions: -Cow's milk hypersensitivity indicates nonallergic hypersensitivity (traditionally termed "cow's milk intolerance") and allergic milk hypersensitivity -Cow's milk allergy (CMA) indicates "a hypersensitivity reaction initiated by specific immunological mechanisms" 62 -IgE-mediated CMA (IgE-CMA) indicates a hypersensitivity reaction to cow's milk proteins initiated by specific Immunoglobulin E binding to Fcε receptors on effector cells as mast cells and basophils. This causes release of histamine and other preformed mediators, and rapid symptom onset. 63 -Non IgE-mediated CMA (non-IgE-CMA) indicates a hypersensitivity reaction to cow's milk proteins initiated by non-IgE mediated (mainly cell-mediated) mechanisms. Non-IgE-mediated milk reactions are typically delayed in onset -Anaphylaxis is defined according to the amended WAO criteria for the diagnosis of anaphylaxis. 64 Many other definitions of clinical presentations and pathologic mechanisms have been adopted during the development of the guidelines. When necessary, they will be specified in the respective papers.

WHAT IS NEXT
One of the determinants of the profound heterogeneity in the management of CMA consists in the wide spectrum of professional figures (paediatrician, allergists, gastroenterologists, and so forth) dealing with it. Another is the contradictory guidance provided by a large number of guidelines and position papers. As a consequence, the 2021 updated DRACMA guidelines aim to comprehensively address the diagnostic and therapeutic fields of CMA, harmonizing the collaboration between the various specialist figures.
By their very nature, guidelines make clarity. Clarity is bound to reduce both underdiagnosis and especially overdiagnosis of CMA. We hope we have done the allergy community a good service, and we apologize right now if something went wrong.

MARIO SÁNCHEZ-BORGES
Before proceeding with the publication of the guidelines, we want to celebrate the remarkable life and academic accomplishments of one of our fellow authors. Mario Sánchez-Borges, MD, was a true leader for the entire international allergy community, without whose guidance and contribution, the realization of these guidelines would not have been possible. As a previous WAO president (2016-2017) and Councilor, Mario has been an impulse and prime mover of DRACMA. He participated in the drafting of all the parts that will report him as author. His kindness and generosity will stay unperished, living through the numerous and joyful memories he left in so many of us.