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

  • Alessandro Fiocchi
    Correspondence
    Corresponding author. Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4, Rome 00165, Italy
    Affiliations
    Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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  • Antonio Bognanni
    Affiliations
    Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada
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  • Jan Brożek
    Affiliations
    Department of Medicine, Division of Clinical Immunology and Allergy, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada
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  • Motohiro Ebisawa
    Affiliations
    Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan
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  • Holger Schünemann
    Affiliations
    Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada

    Cochrane Canada and McMaster GRADE Centre, Hamilton, Ontario, Canada
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  • On behalf of
    Author Footnotes
    Members of the WAO DRACMA guideline group: Ignacio J. Ansotegui, MD, PhD (Department of Allergy & Immunology, Hospital Quironsalud Bizkaia, Erandio, Bilbao, Spain); Stefania Arasi, MD, PhD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Amal H. Assa'ad, MD (Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA); Sami L. Bahna, MD, DrPH (Allergy/Immunology Section, Louisiana State University Health Sciences Center, Shreveport, LA, USA); Roberto Berni Canani, MD, PhD (Department of Translational Medical Science, University of Naples Federico II, Naples, Italy); Antonio Bognanni, MD (Department of Health Research Methods, Evidence and Impact - HEI, McMaster University, Hamilton, ON, Canada); Martin Bozzola, MD (Department of Pediatrics, Pediatric Allergy/Immunology Section, British Hospital, Buenos Aires, Argentina); Jan Brożek, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Derek K. Chu, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy; Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Lamia Dahdah, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Christophe Dupont, MD, PhD (Paris Descartes University, Pediatric Gastroenterology, Necker Hospital, Paris, Clinique Marcel Sembat, Boulogne-Billancourt, France); Motohiro Ebisawa, MD, PhD (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan); Alessandro Fiocchi, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Ramon Targino Firmino MD (Faculty of Medical Sciences of Campina Grande, UNIFACISA University Centre, Campina Grande, Paraiba, Brazil); Elena Galli, MD, PhD (Pediatric Allergy Unit, Research Center, San Pietro-Fatebenefratelli Hospital, Rome, Italy); Rose Kamenwa, MD (Department of Pediatrics and Child Health, Aga Khan University Hospital, Nairobi, Kenya); Gideon Lack, MBBCh (Department of Women and Children's Health/Peter Gorer Department of Immunobiology, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, UK; Evelina London Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK), Haiqi Li, MD (Pediatric Division Department of Primary Child Care, Children's Hospital, Chongqing Medical University, Chongqing, China); Alberto Martelli, MD (Italian Society of Pediatric Allergy and Immunology, Milano, Italy); Anna H. Nowak-Wegrzyn, MD, PhD (Department of Pediatrics, New York University Langone Health, New York, NY, USA; Department of Pediatrics, Gastroenterology and Nutrition, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland); Nikolaos G. Papadopoulos, MD, PhD (Allergy Unit, 2nd Pediatric Clinic, University of Athens, Athens, Greece; Division of Infection, Immunity & Respiratory Medicine, University of Manchester, UK); Ruby Pawankar, MD, PhD (Department of Pediatrics, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan); Maria Said, RN (Allergy & Anaphylaxis Australia (A&AA), Castle Hills, New South Wales, Australia); Mario Sánchez-Borges MD (Department of Allergy and Clinical Immunology, Centro Médico-Docente La Trinidad Caracas, Venezuela); Holger J. Schünemann, MD, MSc, PhD (Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada, and Cochrane Canada and McMaster GRADE Centre, Hamilton, ON, Canada); Raanan Shamir, MD, PhD (Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach-Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel); Jonathan M. Spergel, MD, PhD (Division of Allergy and Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA), Hania Szajewska, MD (The Medical University of Warsaw - Department of Paediatrics, Warsaw, Poland); Luigi Terracciano, MD (Italian NHS and Italian Society of Social and Preventive Pediatrics, Milano, Italy); Yvan Vandenplas, MD, PhD (Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium); Carina Venter, PhD, RD (Section of Allergy & Immunology, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, CO, USA); Amena Warner, RN, SN (PG Dip) (Allergy UK, Planwell House, Sidcup, Kent, UK); Susan Waserman, MD, MSc (Division of Clinical Immunology and Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada); Gary W. K. Wong, MD (Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China)
    the WAO DRACMA guideline group
    Footnotes
    Members of the WAO DRACMA guideline group: Ignacio J. Ansotegui, MD, PhD (Department of Allergy & Immunology, Hospital Quironsalud Bizkaia, Erandio, Bilbao, Spain); Stefania Arasi, MD, PhD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Amal H. Assa'ad, MD (Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA); Sami L. Bahna, MD, DrPH (Allergy/Immunology Section, Louisiana State University Health Sciences Center, Shreveport, LA, USA); Roberto Berni Canani, MD, PhD (Department of Translational Medical Science, University of Naples Federico II, Naples, Italy); Antonio Bognanni, MD (Department of Health Research Methods, Evidence and Impact - HEI, McMaster University, Hamilton, ON, Canada); Martin Bozzola, MD (Department of Pediatrics, Pediatric Allergy/Immunology Section, British Hospital, Buenos Aires, Argentina); Jan Brożek, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Derek K. Chu, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy; Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Lamia Dahdah, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Christophe Dupont, MD, PhD (Paris Descartes University, Pediatric Gastroenterology, Necker Hospital, Paris, Clinique Marcel Sembat, Boulogne-Billancourt, France); Motohiro Ebisawa, MD, PhD (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan); Alessandro Fiocchi, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Ramon Targino Firmino MD (Faculty of Medical Sciences of Campina Grande, UNIFACISA University Centre, Campina Grande, Paraiba, Brazil); Elena Galli, MD, PhD (Pediatric Allergy Unit, Research Center, San Pietro-Fatebenefratelli Hospital, Rome, Italy); Rose Kamenwa, MD (Department of Pediatrics and Child Health, Aga Khan University Hospital, Nairobi, Kenya); Gideon Lack, MBBCh (Department of Women and Children's Health/Peter Gorer Department of Immunobiology, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, UK; Evelina London Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK), Haiqi Li, MD (Pediatric Division Department of Primary Child Care, Children's Hospital, Chongqing Medical University, Chongqing, China); Alberto Martelli, MD (Italian Society of Pediatric Allergy and Immunology, Milano, Italy); Anna H. Nowak-Wegrzyn, MD, PhD (Department of Pediatrics, New York University Langone Health, New York, NY, USA; Department of Pediatrics, Gastroenterology and Nutrition, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland); Nikolaos G. Papadopoulos, MD, PhD (Allergy Unit, 2nd Pediatric Clinic, University of Athens, Athens, Greece; Division of Infection, Immunity & Respiratory Medicine, University of Manchester, UK); Ruby Pawankar, MD, PhD (Department of Pediatrics, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan); Maria Said, RN (Allergy & Anaphylaxis Australia (A&AA), Castle Hills, New South Wales, Australia); Mario Sánchez-Borges MD (Department of Allergy and Clinical Immunology, Centro Médico-Docente La Trinidad Caracas, Venezuela); Holger J. Schünemann, MD, MSc, PhD (Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada, and Cochrane Canada and McMaster GRADE Centre, Hamilton, ON, Canada); Raanan Shamir, MD, PhD (Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach-Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel); Jonathan M. Spergel, MD, PhD (Division of Allergy and Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA), Hania Szajewska, MD (The Medical University of Warsaw - Department of Paediatrics, Warsaw, Poland); Luigi Terracciano, MD (Italian NHS and Italian Society of Social and Preventive Pediatrics, Milano, Italy); Yvan Vandenplas, MD, PhD (Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium); Carina Venter, PhD, RD (Section of Allergy & Immunology, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, CO, USA); Amena Warner, RN, SN (PG Dip) (Allergy UK, Planwell House, Sidcup, Kent, UK); Susan Waserman, MD, MSc (Division of Clinical Immunology and Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada); Gary W. K. Wong, MD (Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China)
    Authors List
  • Author Footnotes
    Members of the WAO DRACMA guideline group: Ignacio J. Ansotegui, MD, PhD (Department of Allergy & Immunology, Hospital Quironsalud Bizkaia, Erandio, Bilbao, Spain); Stefania Arasi, MD, PhD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Amal H. Assa'ad, MD (Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA); Sami L. Bahna, MD, DrPH (Allergy/Immunology Section, Louisiana State University Health Sciences Center, Shreveport, LA, USA); Roberto Berni Canani, MD, PhD (Department of Translational Medical Science, University of Naples Federico II, Naples, Italy); Antonio Bognanni, MD (Department of Health Research Methods, Evidence and Impact - HEI, McMaster University, Hamilton, ON, Canada); Martin Bozzola, MD (Department of Pediatrics, Pediatric Allergy/Immunology Section, British Hospital, Buenos Aires, Argentina); Jan Brożek, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Derek K. Chu, MD, PhD (Department of Medicine, Division of Clinical Immunology and Allergy; Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Canada); Lamia Dahdah, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Christophe Dupont, MD, PhD (Paris Descartes University, Pediatric Gastroenterology, Necker Hospital, Paris, Clinique Marcel Sembat, Boulogne-Billancourt, France); Motohiro Ebisawa, MD, PhD (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan); Alessandro Fiocchi, MD (Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy); Ramon Targino Firmino MD (Faculty of Medical Sciences of Campina Grande, UNIFACISA University Centre, Campina Grande, Paraiba, Brazil); Elena Galli, MD, PhD (Pediatric Allergy Unit, Research Center, San Pietro-Fatebenefratelli Hospital, Rome, Italy); Rose Kamenwa, MD (Department of Pediatrics and Child Health, Aga Khan University Hospital, Nairobi, Kenya); Gideon Lack, MBBCh (Department of Women and Children's Health/Peter Gorer Department of Immunobiology, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, UK; Evelina London Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK), Haiqi Li, MD (Pediatric Division Department of Primary Child Care, Children's Hospital, Chongqing Medical University, Chongqing, China); Alberto Martelli, MD (Italian Society of Pediatric Allergy and Immunology, Milano, Italy); Anna H. Nowak-Wegrzyn, MD, PhD (Department of Pediatrics, New York University Langone Health, New York, NY, USA; Department of Pediatrics, Gastroenterology and Nutrition, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland); Nikolaos G. Papadopoulos, MD, PhD (Allergy Unit, 2nd Pediatric Clinic, University of Athens, Athens, Greece; Division of Infection, Immunity & Respiratory Medicine, University of Manchester, UK); Ruby Pawankar, MD, PhD (Department of Pediatrics, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan); Maria Said, RN (Allergy & Anaphylaxis Australia (A&AA), Castle Hills, New South Wales, Australia); Mario Sánchez-Borges MD (Department of Allergy and Clinical Immunology, Centro Médico-Docente La Trinidad Caracas, Venezuela); Holger J. Schünemann, MD, MSc, PhD (Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada, and Cochrane Canada and McMaster GRADE Centre, Hamilton, ON, Canada); Raanan Shamir, MD, PhD (Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach-Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel); Jonathan M. Spergel, MD, PhD (Division of Allergy and Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA), Hania Szajewska, MD (The Medical University of Warsaw - Department of Paediatrics, Warsaw, Poland); Luigi Terracciano, MD (Italian NHS and Italian Society of Social and Preventive Pediatrics, Milano, Italy); Yvan Vandenplas, MD, PhD (Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium); Carina Venter, PhD, RD (Section of Allergy & Immunology, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, CO, USA); Amena Warner, RN, SN (PG Dip) (Allergy UK, Planwell House, Sidcup, Kent, UK); Susan Waserman, MD, MSc (Division of Clinical Immunology and Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada); Gary W. K. Wong, MD (Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China)
Open AccessPublished:January 31, 2022DOI:https://doi.org/10.1016/j.waojou.2021.100609

      Abstract

      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.

      Keywords

      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.
      • Fiocchi A.
      • Brozek J.
      • Schünemann H.
      • et al.
      World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines.
      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.
      • Dahdah L.
      • Arasi S.
      • Valluzzi R.L.
      • Fierro V.
      • Fiocchi A.
      How guideline can shape clinical practice globally: the diagnosis and rationale for action against cow's milk allergy experience.
      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.
      • Brożek J.L.
      • Terracciano L.
      • Hsu J.
      • et al.
      Oral immunotherapy for IgE-mediated cow's milk allergy: a systematic review and meta-analysis.
      Image 1
      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.
      • Pettersson M.E.
      Prediction of the severity of allergic reactions to foods.
      Also, there is no direct correlation between the eliciting threshold experienced by children during an OFC and the reaction's severity upon accidental exposure.
      • Eigenmann P.A.
      • Ebisawa M.
      • Greenhawt M.
      • et al.
      Addressing risk management difficulties in children with food allergies.
      Tools such as the Basophil Activation Test (BAT) have been developed to minimize the risk of severe reactions to the OFC,
      • Santos A.F.
      • Du Toit G.
      • O'Rourke C.
      • et al.
      Biomarkers of severity and threshold of allergic reactions during oral peanut challenges.
      ,
      • Kawahara T.
      Risk prediction of severe reaction to oral challenge test of cow's milk.
      being also proposed as replacement tests of the OFC.
      • Santos A.F.
      • Brough H.A.
      Making the most of in vitro tests to diagnose food allergy.
      In addition, serious reactions to the OFC have been described, up to a case of fatal reaction.
      Statement by the American College of Allergy, Asthma & Immunology, American Academy of Allergy, Asthma & Immunology, and the Canadian Society of Allergy and Clinical Immunology
      Allergists respond to death of 3 year-old boy during oral food challenge.
      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.
      • Fiocchi A.
      • Nowak-Węgrzyn A.
      The fascinating world of molecular diagnosis in the management of food allergy: nondum matura est.
      ,
      • Foong R.X.
      • Dantzer J.A.
      • Wood R.A.
      • Santos A.F.
      Improving diagnostic accuracy in food allergy.
      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
      • Kim J.S.
      Dietary baked milk accelerates the resolution of cow's milk allergy in children.
      Image 2
      In synthesis, reconciling the diagnostic procedures for the different forms of CMA will be a challenge for the new DRACMA guidelines.
      • Dahdah L.
      • Fierro V.
      • Mennini M.
      • Arasi S.
      • Fiocchi A.
      What's next for DRACMA?.
      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.
      • Munblit D.
      • Perkin M.R.
      • Palmer D.J.
      • Allen K.J.
      • Boyle R.J.
      Assessment of evidence about common infant symptoms and cow's milk allergy.
      In the past 10 years, the involvement of formulas in the management of CMA has been profoundly expanded, with extensively hydrolyzed formulas (eHFs),
      • Stróżyk A.
      • Horvath A.
      • Meyer R.
      • Szajewska H.
      Efficacy and safety of hydrolyzed formulas for cow's milk allergy management: a systematic review of randomized controlled trials.
      rice hydrolyzed formula (HRF),
      • Vandenplas Y.
      • De Greef E.
      • Hauser B.
      Paradice Study Group
      Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow's milk protein allergy.
      amino acid formulae (AAF),
      • Fierro V.
      • Valluzzi R.L.
      • Banzato C.
      • et al.
      A well-tolerated new amino acid-based formula for cow's milk allergy.
      camel and dromedary milk,
      • Maryniak N.Z.
      • Hansen E.B.
      • Ballegaard A.R.
      • Sancho A.I.
      • Bøgh K.L.
      Comparison of the Allergenicity and Immunogenicity of Camel and Cow's Milk-A Study in Brown Norway Rats.
      and donkey milk
      • Sarti L.
      • Martini M.
      • Brajon G.
      • et al.
      Donkey's Milk in the Management of Children with Cow's Milk protein allergy: nutritional and hygienic aspects.
      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.
      • Berni Canani R.
      • Di Costanzo M.
      • Bedogni G.
      • et al.
      Extensively hydrolyzed casein formula containing Lactobacillus rhamnosus GG reduces the occurrence of other allergic manifestations in children with cow's milk allergy: 3-year randomized controlled trial.
      ,
      • Scalabrin D.
      • Harris C.
      • Johnston W.H.
      • Berseth C.L.
      Long-term safety assessment in children who received hydrolyzed protein formulas with Lactobacillus rhamnosus GG: a 5-year follow-up.
      Another issue that will be investigated is the employment of new synbiotic-supplemented amino acid-based formulas.
      • Candy D.C.A.
      • Van Ampting M.T.J.
      • Oude Nijhuis M.M.
      • et al.
      A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants.
      ,
      • Fox A.T.
      • Wopereis H.
      • Van Ampting M.T.J.
      • et al.
      ASSIGN study group
      A specific synbiotic-containing amino acid-based formula in dietary management of cow's milk allergy: a randomized controlled trial.
      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
      • Pajno G.B.
      • Caminiti L.
      • Ruggeri P.
      • et al.
      Oral immunotherapy for cow's milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study.
      or slow up-dosing regimens,
      • Kaneko H.
      • Teramoto T.
      • Kondo M.
      • et al.
      Efficacy of the slow dose-up method for specific oral tolerance induction in children with cow's milk allergy: comparison with reported protocols.
      the rapid oral desensitization combined with omalizumab,
      • Nadeau K.C.
      • Schneider L.C.
      • Hoyte L.
      • Borras I.
      • Umetsu D.T.
      Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy.
      different maintenance feeding regimens,
      • Pajno G.B.
      • Caminiti L.
      • Salzano G.
      • et al.
      Comparison between two maintenance feeding regimens after successful cow's milk oral desensitization.
      and baked milk oral immunotherapy
      • Goldberg M.R.
      • Nachshon L.
      • Appel M.Y.
      • et al.
      Efficacy of baked milk oral immunotherapy in baked milk-reactive allergic patients.
      • Kim J.S.
      • Nowak-Węgrzyn A.
      • Sicherer S.H.
      • Noone S.
      • Moshier E.L.
      • Sampson H.A.
      Dietary baked milk accelerates the resolution of cow's milk allergy in children.
      • Dang T.D.
      • Peters R.L.
      • Allen K.J.
      Debates in allergy medicine: baked egg and milk do not accelerate tolerance to egg and milk.
      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.
      • Yeung J.P.
      • Kloda L.A.
      • McDevitt J.
      • Ben-Shoshan M.
      • Alizadehfar R.
      Oral immunotherapy for milk allergy.
      ,
      • Nurmatov U.
      • Dhami S.
      • Arasi S.
      • et al.
      Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis.
      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.
      Table 1Main consensus, position papers, and guidelines produced worldwide between 2010 and 2020
      Country/regionIssuing scientific societyGuideline identificationDRACMA based?Main characteristicsRef.
      EuropeESPGHANESPGHAN CMPA guidelinesNoFocus on non-IgE CMA
      • Koletzko S.
      • Niggemann B.
      • Arato A.
      • et al.
      European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Diagnostic approach and management of cow's-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines.
      EuropeEuropean Academy of Allergy and Clinical Immunology (EAACI)EAACI food allergy guidelinesNoNot limited to CMA
      • Muraro A.
      • Werfel T.
      • Hoffmann-Sommergruber K.
      • et al.
      EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy.
      FranceSociété Française de PédiatrieDietetic treatment of cow's milk protein allergy.NoLimited to treatment
      • Dupont C.
      • Chouraqui J.P.
      • de Boissieu D.
      • et al.
      Comité de nutrition de la Société française de pédiatrie. Prise en charge diététique de l'allergie aux protéines du lait de vache [Dietetic treatment of cow's milk protein allergy].
      ItalyEmilian Working Group on Pediatric Allergy and GastroenterologyA practical guideNoFocus on diagnosis and management in primary care
      • Caffarelli C.
      • Baldi F.
      • Bendandi B.
      • Calzone L.
      • Marani M.
      • Pasquinelli P.
      Emilian Working Group on Pediatric Allergy and Gastroenterology. Cow's milk protein allergy in children: a practical guide.
      ItalyItalian Society of Pediatric AllergyDRACMAYesItalian translation
      • Fiocchi A.
      • Brozek J.
      • Schunemann H.J.
      • et al.
      Organizzazione mondiale dell’allergia: le line-guida DRACMA (diagnosi e terapia della allergia alle proteine del latte vaccino).
      United KingdomNational Institute for Health and Care Excellence (NICE)MAP (Milk Allergy in Primary Care)NoFocus on non IgE-CMA in primary care
      • Venter C.
      • Brown T.
      • Shah N.
      • Walsh J.
      • Fox A.T.
      Diagnosis and management of non-IgE-mediated cow's milk allergy in infancy – a UK primary care practical guide.
      United KingdomNICE-derivedi-MAP (international MAP)PartlyFocus on non IgE CMA in primary care
      • Venter C.
      • Brown T.
      • Meyer R.
      • et al.
      Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline.
      United KingdomBritish Society for Allergy and Clinical Immunology (BSACI)BSACI cow's milk allergy guidelineNoComprehensive
      • Luyt D.
      • Ball H.
      • Makwana N.
      • et al.
      British Society for Allergy and Clinical Immunology (BSACI) guideline for the diagnosis and management of cow's milk allergy.
      United KingdomNICE-derivedUpdated i-MAP (international MAP)PartlyFocus on CMA in primary care
      • Fox A.
      • Brown T.
      • Walsh J.
      • et al.
      An update to the Milk Allergy in Primary Care guideline.
      FinlandFinnish Allergy Programme

      2008–2018
      Practical recommendations of the Finnish Allergy Programme 2008–2018 for prevention, diagnosis, and treatmentNoCMA as part of food allergy management in children
      • Pelkonen A.S.
      • Kuitunen M.
      • Dunder T.
      • Reijonen T.
      • Valovirta E.
      • Mäkelä M.J.
      Allergy in children: practical recommendations of the Finnish Allergy Programme 2008-2018 for prevention, diagnosis, and treatment.
      SpainSpanish Society of Pediatric Clinical Immunology and Allergology (SEICAP)Spanish CM guidelinePartlyComprehensive
      • Martorell-Aragonés A.
      • Echeverría-Zudaire L.
      • Alonso-Lebrero E.
      • et al.
      Food allergy committee of SEICAP (Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology). Position document: IgE-mediated cow's milk allergy.
      SpainSpanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP), Spanish Association of Paediatric Primary Care (AEPAP), Spanish Society of Extra-hospital Paediatrics and Primary Health Care (SEPEAP), and the Spanish Society of Paediatric ClinicaL Immunology, Allergy, and Asthma (SEICAP)Spanish CM guideline for non IgE-mediated CMANoFocus on non IgE CMA
      • Espin Jaime B.
      • Diaz Martin J.J.
      • Blesa Baviera L.C.
      • et al.
      Non-IgE-mediated cow's milk allergy: consensus document of the Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP), the Spanish Association of Paediatric Primary Care (AEPAP), the Spanish Society of Extra-hospital Paediatrics and Primary Health Care (SEPEAP), and the Spanish Society of Paediatric ClinicaL Immunology, Allergy, and Asthma (SEICAP).
      TurkeyTurkish Society of PediatricsTurkish ConsensusPartlyFocus on primary care
      • Kansu A.
      • Yüce A.
      • Dalgıç B.
      • Şekerel B.E.
      • Çullu-Çokuğraş F.
      • Çokuğraş H.
      Consensus statement on diagnosis, treatment and follow-up of cow's milk protein allergy among infants and children in Turkey.
      Middle EastIndependent groupMiddle East consensusYesFocus on primary care
      • Vandenplas Y.
      • Abuabat A.
      • Al-Hammadi S.
      • et al.
      Middle East consensus statement on the prevention, diagnosis, and management of cow's milk protein allergy.
      IndiaIndian Society of Pediatric Gastroenterology, Hepatology and NutritionIndian ConsensusNoFocus on primary care
      • Matthai J.
      • Sathiasekharan M.
      • Poddar U.
      • et al.
      Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition; Pediatric Gastroenterology Chapter of Indian Academy of Pediatrics. Guidelines on Diagnosis and Management of Cow's Milk Protein Allergy.
      ChinaWorld Allergy Organization (WAO)DRACMAYesMandarin translation
      • Fiocchi A.
      • Brozek J.
      • Schunemann H.J.
      • et al.
      World Allergy Organization
      The outline of World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guidelines.
      ChinaIndependent groupIntensive DRACMA readingYesImplementation in China
      • Li H.Q.
      Intensive reading of World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline.
      JapanJapanese Society of Pediatric Allergy and Clinical Immunology (JSPACI); Japanese Society of Allergology (JSA)Japanese guidelinesPartlyNot limited to CMA
      • Ebisawa M.
      • Ito K.
      • Fujisawa T.
      Committee for Japanese Pediatric Guideline for Food Allergy, The Japanese Society of Pediatric Allergy and Clinical Immunology; Japanese Society of Allergology
      Japanese guidelines for food allergy 2020.
      MexicoIndependent groupGL-APLVPartlyComprehensive
      • Montijo-Barrios E.
      • López-Ugalde M.V.
      • Ramírez-Mayans J.
      • et al.
      Guía latinoamericana para el diagnóstico y tratamiento de alergia a las proteínas de la leche de vaca (GL-APLV).
      South AmericaWorld Allergy Organization (WAO)DRACMAYesSpanish translation

      Fiocchi A, Brozek J, Schunemann HJ, et al. Pautas de la Organización Mundial sobre Alergia para el Diagnóstico y Fundamento de la Acción Contra la Alergia a la Leche de Vaca. http://www.scp.com.co/ArchivosSCP/PDF/DRACMA.pdf, accessed May 5th, 2021.

      Among the publications above, the one most implemented is the UK NICE – derived guideline, the iMAP guideline. It includes an algorithm for the diagnostic and therapeutic approaches, based on the heterogeneous clinical manifestations of CMA (both non-IgE and IgE).
      • Venter C.
      • Brown T.
      • Meyer R.
      • et al.
      Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline.
      Interestingly, the diagnostic process for CMA accounts for a diagnosis not confirmed through OFC, given that a series of conditions are met (improvement on a strict cow's milk protein-free elimination diet for at least 2 weeks; clinical relapse on subsequent cow's milk open challenge), possibly leading to an overestimation of non-IgE-CMA. After their implementation in Northern Ireland, the use of hypoallergenic formulas largely increased, exceeding the expected epidemiological figures
      • Wauters L.
      • Brown T.
      • Venter C.
      • et al.
      Cow’s Milk Allergy Prescribing is influenced by Regional and National Guidance.
      ,
      • Fiocchi A.
      • Fierro V.
      • La Marra F.
      Interpreting the results of guideline implementation: a long and winding road.
      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.
      • Ruszczyński M.
      • Horvath A.
      • Dziechciarz P.
      • Szajewska H.
      Cow's milk allergy guidelines: a quality appraisal with the AGREE II instrument.
      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.
      • Schünemann H.J.
      • Lerda D.
      • Dimitrova N.
      • et al.
      European Commission Initiative on Breast Cancer Contributor Group
      Methods for development of the European Commission initiative on breast Cancer guidelines: recommendations in the era of guideline transparency.
      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-to-decision (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.
      Table 2Plan of the DRACMA publications
      TopicMethod of preparation
      General
      1.Overview and definitionsThis paper
      2.CMA epidemiology and natural historyNarrative review
      3.CM allergens and immunologic mechanismsNarrative review
      4.Clinical presentations: IgE-mediatedNarrative review
      5.Clinical presentations: non IgE-mediatedNarrative review
      6.Comparison among different guidelinesSystematic review
      7.DRACMA methodologySynthesis of methods
      CMA diagnosis
      8.Diagnosis of CMASystematic review
      9.Recommendations on CMA diagnosisGuideline
      Treatment options
      10.Breastfeeding a baby with CMANarrative review
      11.Substitutive formulaeSystematic review
      12.Recommendations on substitutive treatmentGuideline
      13.Oral Immunotherapy for CMASystematic review
      14.Recommendations on CMA OITGuideline
      15.Other milks (goat's, ewe's, mare's, donkey's, camel's, and substitutes from non-animal sources)Narrative review
      16.Nutritional considerations in CMA infantsNarrative review
      Conclusions
      17.Which is the 1st choice formula case by case?Synthesis of recommendations
      18.Unmet needs. Recommendations for research. Recommendation for the implementation of the DRACMA guidelines. Periodical update of DRACMA.Synthesis of recommendations

      Glossary of CMA

      In developing the metanalyses and the guidelines, we adhered to the following definitions:
      • -
        Cow's milk hypersensitivity indicates non-allergic 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
        • Johansson S.G.
        • Bieber T.
        • Dahl R.
        Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, 2003.
      • -
        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.
        • Anvari S.
        • Miller J.
        • Yeh C.Y.
        • Davis C.M.
        IgE-mediated food allergy.
      • -
        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.
        • Cardona V.
        • Ansotegui I.J.
        • Ebisawa M.
        • et al.
        World allergy organization anaphylaxis guidance 2020.
      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.

      Consent to publish

      All authors agree to the publication of this manuscript in World Allergy Organization Journal.

      Ethics statement

      This manuscript is an editorial. It did not involve human subjects.

      Author contributions

      AF initiated the concept and contributed made the first draft. AB, JB, ME, and HS participated in the development of the document. All authors reviewed and approved the final manuscript.

      Funding

      This document was supported by the World Allergy Organization .

      Declaration of competing interest

      S Arasi, S Bahna, Bognanni, J Brożek, D Chu, L Dahdah, E Galli, R Kamenwa, H Li, A Martelli, R Pawankar, H Schünemann, 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. 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. S Waserman – Novartis-basic science work on peanut allergy, Aimmune-peanut OIT trial, Medical Advisor to Food Allergy Canada, and Pfizer, Bausch, Kaleo-consultant for epinephrine autoinjectors. GWK Wong – Nestle, Danone.

      Acknowledgement

      Mario Sánchez Borges, MD, of Caracas, Venezuela, and a Past President of the World Allergy Organization (2016–2017), was a major contributor to the development of the guidelines until his death in early 2021. His contributions to the field are immense. He will be greatly missed both professionally and personally.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

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