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World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) Guidelines update – IV – A quality appraisal with the AGREE II instrument
Department of Pediatrics, NYU Grossman School of Medicine, Hassenfeld Childrens' Hospital, New York, NY, USADepartment of Pediatrics, Gastroenterology and Nutrition, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Lea and Arieh Pickel Chair for Pediatric Research, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
1 Members of the 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 Brozek, 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[1]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)
1 Members of the 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 Brozek, 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[1]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)
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 publication of the 2010 DRACMA guidelines, a number of other guidelines, expert opinions, and position papers for the management of CMA have been published. However, their quality has not been formally appraised. In 2016 a systematic review assessed the quality of guidelines on cow's milk allergy (CMA) published from 2010 through November 2015 using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.
Fifteen guidelines were included. Only the guidelines developed by recognized professional/scientific organizations such as the British Society for Allergy and Clinical Immunology (BSACI) and the European Academy of Allergy and Clinical Immunology (EAACI) were of the highest quality. In addition, the 2010 World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines,
the only Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines for CMA, were considered to be of high quality.
In 2018, the DRACMA panel committee re-assembled in order to update the DRACMA guidelines. The aim of this study was to systematically review the quality of the guidelines on CMA diagnosis and management in children and/or adults published from 2010 onwards, and to summarize specific recommendations.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
was followed during each stage of this review. The protocol was pre-defined and submitted to PROSPERO; however, it was not accepted for registration, as it was assessed as being outside of the scope of included protocols due to the lack of at least 1 outcome of direct patient or clinical relevance. The AGREE II User's Manual
was followed during the quality assessment of the included guidelines.
Search for guidelines
The MEDLINE (through PubMed), EMBASE, ISI Web of Science (Thomson Web of Knowledge), World Health Organization Global Index Medicus (GIM) (https://www.globalindexmedicus.net/), and Turning Research into Practice (TRIP) (https://www.tripdatabase.com/) databases were searched from January 2010 up until May 2020, and then the search was updated in April 2021. The rationale for choosing 2010 as the start date was that this is the issue date of the DRACMA guidelines. However, we recognized that an update of any guidelines/recommendations is generally required from 2 to 5 years after the issue date,
and therefore, some of the earlier guidelines could be outdated. MEDLINE and EMBASE were searched following a pre-specified search-strategy (see Supplemental Appendix 1). The websites of guideline repositories were also searched including: National Institute for Clinical Excellence (NICE, https://www.nice.org.uk/), The Guideline International Network (GIN, https://guidelines.ebmportal.com/), Scottish Intercollegiate Guidelines Network (SIGN) (https://www.sign.ac.uk), and Agency for Healthcare Research and Quality (AHRQ, https://www.ahrq.gov/).
References of all included guidelines and guideline publisher's websites were also searched for any supporting documents (ie, technical reports, methodological manuals).
The search was carried out independently by four reviewers (AS, AH, LD, and MR). No filters or restrictions other than English language were imposed.
Eligibility criteria
Inclusion criteria & exclusion criteria
Any clinical practice recommendations and/or guidelines focusing on the diagnosis and management of CMA in children and/or adults developed or endorsed by recognized scientific societies or organizations were included. In case of an updated version of a guideline, only the most recent document was considered for inclusion. Guidelines were included, regardless of CMA mechanism (ie, IgE-mediated, non-IgE-mediated, mixed); however, if feasible, they were assessed separately. Guidelines focusing on food allergy or a single disease (eg, food protein-induced enterocolitis syndrome [FPIES]) were not considered for inclusion in this review, unless there was a section focusing explicitly on CMA or cow's milk proteins.
Consensus-based and expert opinion clinical practice guidelines, if not endorsed by recognized scientific or professional organizations, were excluded based on their limited generalizability as well as our limited capability to evaluate the level of expertise, that these publications represent, and the audience addressed. Guidelines focused on a single specific management option (eg, immunotherapy) or prevention were excluded. Guidelines which were ongoing or unpublished were also excluded.
Data selection
As recommended, 4 reviewers (AS, AH, MR, and LD) screened the titles and abstracts of articles identified in the search to identify potentially eligible guidelines. The full texts of all potentially relevant articles were retrieved and critically assessed against the pre-defined inclusion criteria independently by each of the reviewers. Any discrepancies were first discussed by the 4 reviewers (AS, AH, MR, and HS).
Initially, members of the DRACMA panel not involved in the earlier process (AF, ANW, RS, JS, YV, CV, LD) provided their comments on the included and questionable documents and, if feasible, any unidentified papers, via an online survey using Google Forms. The list of excluded papers was also reviewed. Guidelines were included if at least 90% agreement was reached; in case of agreement ≤50%, a paper document was excluded. All of the comments were discussed. Then, all questionable documents (between 50% and 90% agreement) were put to a second vote by the members of DRACMA panel to determine eligibility for inclusion. Any discrepancies, as well as all other disagreements between the reviewers, were resolved through discussion until a consensus was reached.
Data extraction
Three reviewers (AS, MR, and LD) independently extracted data from all included guidelines. The reviewers extracted the following information: title, year of publication, organization (country), level of guideline development (ie, local, regional, national, or international), financial support, and conflicts of interest (number of people who obtained financial support and/or had conflicts of interest/number of all authors). Data extraction was performed using data-extraction forms developed by the reviewers. Any discrepancies were discussed until a consensus was reached.
Specific recommendations were summarized in a comparative table, focusing on possible gaps and common messages. A “List of specific recommendations to be assessed” had been pre-specified in the protocol. If feasible, recommendations were extracted separately for IgE-mediated, non-IgE-mediated, and mixed CMA, as well for each age group (ie, children, adults).
Assessment of guidelines using AGREE II
All appraisals were made using My AGREE PLUS interactive guideline appraisal platform (www.agreetrust.org) by 3 reviewers (AS, AH, and MR). Two authors had previous experience with the AGREE II instrument,
and one reviewer (AS) underwent the online AGREE II tutorial before the review (available at: http://www.agreetrust.org/).
The AGREE II is a 23-item tool organized within 6 domains: (1) scope and purpose; (2) stakeholder involvement; (3) rigor of development; (4) clarity of presentation; (5) applicability, and (6) editorial independence. The AGREE II instrument also contains 2 global rating items: (1) overall guideline assessment (that requires the appraiser to make an overall judgement of the practice guideline while considering how they rated the 23 key items) and (2) a question on whether the appraiser would recommend a guideline for use in practice (assessed on a 3-point scale [ie, yes, yes with modification, and no]). All of the AGREE II items and the overall guideline assessment item are assessed using a 7-point Likert agreement scale ranging from 1 (strongly disagree) to 7 (strongly agree). The reviewers discussed all scores that differed by 2 or more points among themselves, until a consensus was reached.
For each item and domain, the score was summed and calculated as a percentage of the maximum possible score for that item/domain using the formula provided by the AGREE II consortium:
[(score obtained – minimum possible score)/(maximum possible score – minimum possible score)] x 100. The possible standardized scores range from 0% (the minimum) to 100% (the maximum).
The AGREE II does not provide a minimum or maximum range for domain score quality to differentiate high- and low-quality guidelines and recommends that it should be done by the reviewer. In agreement with a previous quality appraisal with the AGREE II of the same clinical question carried out by members of the current review group,
a standardized domain score of above 60% for each domain has been chosen as the threshold.
Statistical analysis and data synthesis
Normality of quality scores was assessed using the Shapiro-Wilk test and based on visual assessment of histograms. Due to the lack of a normal distribution of scores, data are presented as the median followed by the quartiles (upper [Q3] and lower [Q1]) and IQR (interquartile range). Agreement between raters (inter-rater reliability) was analyzed using Fleiss' Kappa and intraclass correlation coefficient (ICC) estimates. The ICC calculation was based on a single rating, absolute agreement, two-way random effects model including a 95% confidence interval (CI). Analysis was conducted in R software, version 3.5.1 (http://cran.r-project.org). by an independent statistician. Although Kendall's W coefficient was pre-specified in the protocol to assess agreement between raters, after consultation with the statistician, it was changed to Fleiss' Kappa that is suitable for analysis of the agreement using ordinal or nominal parameters (either dichotomous or not).
We included 12 guidelines (for characteristics, see Table 1). Eight guidelines were developed by national organizations (India, Italy, France, Finland, 2 from Spain, and 2 from the United Kingdom), and 4 by international organizations and the International FPIES Association [I-FPIES] advocacy group; Gastroenterology Committee of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition [ESPGHAN]; General Practice Infant Feeding Network [GPIFN] and the Milk Allergy in Primary [MAP] Care team; and the World Allergy Organization [WAO] Special Committee on Food Allergy).
Table 1Characteristics of the included guidelines.
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).
Spanish Society of Pediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP)The Spanish Association of Pediatric Primary Care (AEPAP)The Spanish Society of Extra-hospital Paediatrics and Primary Health Care (SEPEAP)The Spanish Society of Pediatric Clinical Immunology, Allergy, and Asthma (SEICAP)
Population
Children
Financial support
Funding not reported.
Conflict of interest
7/11 authors declared to have financial conflict of interest.
The World Allergy Organization (WAO) Special Committee on Food Allergy identified targeted (and tapped for their expertise), both on the DRACMA panel or as nonsitting reviewers, were allergists, pediatricians (allergists and generalists), gastroenterologists, dermatologists, epidemiologists, methodologists, dieticians, food chemists, and representatives of allergic patient organizations
Population
All ages, especially young ones
Financial support
The WAO Special Committee on Food Allergy is supported through unrestricted educational grants from various charities and companies that are representative of the food industry: Danone, Heinz, Ordesa, Nestle Nutrition, Dicofarm, and Invest for Children.The content of the Guidelines was developed independently, and the GRADE evaluation of the Guidelines was independently conducted at McMaster University in Hamilton, Ontario, Canada, under Holger Schunemann assisted by Jan Brozek, Enrico Compalati and Luigi Terracciano.
Members of General Practice Infant Feeding Network (GPIFN) and other infant feeding healthcare leads and the Milk Allergy in Primary (MAP) Care team. Dr Lovis joining them to work alongside representatives from the Cows' Milk Allergy Support group. The current iteration of the MAP guideline has received patient input from members of a large, online CMA community, Cow's Milk Protein Allergy Support, members of the General Practice Infant Feeding Network and other infant feeding healthcare leads, none of whom has any industry ties (UK).
Population
Children, especially infants
Financial support
No funding was received for any aspect of this work.
Conflict of interest
iMAP was developed without any funding or support from industry but 9/12 authors made declarations of interest.
The pediatric gastroenterology sub-specialty chapter of Indian Academy of Pediatrics (Indian Society of Pediatric Gastroenterology, Hepatology & Nutrition ISPGHAN).A group of experts.
Population
Children
Financial support
There was no funding.
Conflict of interest
The authors have no conflict of interest to declare.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
The Adverse Reactions to Food Committee. American Academy of Allergy, Asthma and Immunology, AAAAI, International FPIES Association advocacy group, I-FPIES
Population
Children
Financial support
This project has been developed in collaboration with The International FPIES (I-FPIES) Association.
Conflict of interest
25/41 authors declared to have potential financial conflict of interest outside of the scope of the guidelines.
12. Finnish guidelines (the Finnish Allergy Programme) (Finland, 2012)
The Finnish Allergy Programme 2008–2018.Local Allergy Working Group has been created in different part of Finland (Finland).
Population
Children
Financial support
This work was supported by the European Research Council Advanced Grant 232826 to I.H., the European Commissions 7th Framework Programme under grant agreement 261357, Ministry of Social Welfare and Health, Academy of Finland, Helsinki University Hospital, and the Juselius Foundation.
Conflict of interest
Conflict of interest not reported.
AAAAI, American Academy of Allergy, Asthma and Immunology; AEPAP, Spanish Association of Paediatric Primary Care; BSACI, British Society for Allergy and Clinical Immunology; CNSFP, Committee of Nutrition of the French Society of Paediatrics; ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; EWGPAG, the Emilia-Romagna Working Group for Paediatric Allergy and that for Paediatric Gastroenterology; GPIFN, General Practice Infant Feeding Network; I-FPIES, International Food Protein-Induced Enterocolitis Syndrome (FPIES) Association; ISPGHAN, Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition; MAP, Milk Allergy in Primary; NICE, National Institute for Health and Care Excellence; SEICAP, Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology; SEGHPN, Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition; SEICAP, Spanish Society of Paediatric Clinical Immunology Allergy, and Asthma SEPEAP, Spanish Society of Extra-hospital Paediatrics and Primary Health Care; WAO, World Allergy Organization
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
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).
provided recommendation only for IgE-mediated CMA (and non-IgE-mediated CMA recommendations were in a review). One set of guidelines reported recommendations on the diagnosis and management of infants only with FPIES.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Quality of included guidelines (the AGREE II quality scores)
Table 2 provides the individual domain scores as well as the overall scores for CMA guidelines assessed using the AGREE II instrument. The scores for each domain varied. Of all the domains, the clarity of presentation domain had the highest median score (92%; Q1-Q3: 81–100%), whereas rigor of development was assessed with the lowest median score (30%; Q1-Q3: 15–67%).
Table 2Domain scores and overall assessment of CMA guidelines using the AGREE II instrument.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
All individual items for each domain and overall score were assessed using 1–7 point Likert scale. AGREE II domain and overall scores were calculated by summing up the individual scores for all items of each domain/all ratings of the overall quality and calculating as a percentage of the maximum possible score for that domain (where 0% was the minimum, and 100% was the maximum), using the formula provided by the AGREE II consortium
: [(score obtained – minimum possible score)/(maximum possible score – minimum possible score)] x 100.
AAAAI, American Academy of Allergy, Asthma and Immunology; AEPAP, Spanish Association of Paediatric Primary Care; BSACI, British Society for Allergy and Clinical Immunology; CNSFP, Committee of Nutrition of the French Society of Paediatrics; ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; EWGPAG, the Emilia-Romagna Working Group for Paediatric Allergy and that for Paediatric Gastroenterology; GPIFN, General Practice Infant Feeding Network; MAP, Milk Allergy in Primary; I-FPIES, International Food Protein-Induced Enterocolitis Syndrome (FPIES) Association; ISPGHAN, Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition; NICE, National Institute for Health and Care Excellence; SEGHPN, Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition; SEICAP, Spanish Society of Paediatric Clinical Immunology Allergy, and Asthma SEPEAP, Spanish Society of Extra-hospital Paediatrics and Primary Health Care; WAO, World Allergy Organization
Inter-rater agreement measured with Fleiss' Kappa varied from 0.552 to 0.730 with the median value across all guidelines of 0.813 (Q1-Q3: 0.7325 to 0.873). ICC absolute agreements varied from 0.574 (95% CI, 0.338 to 0.770) to 0.993 (95% CI, 0.986 to 0.997). For one set of guidelines (National Institute for Health and Care Excellence [NICE]),
there was no variation in responses measured with Fleiss’ Kappa and ICC (100% agreement).
Scope and purpose (domain 1)
The median score for the scope and purpose domain was 82% (Q1-Q3: 70–99%) across all guidelines. Three guidelines (British Society for Allergy and Clinical Immunology [BSACI], Spanish on non-IgE-mediated CMA and WAO)
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
did not achieve a median score of 60% for this domain. The main reason for such low scores was a lack of assessment of the views and preferences of the target population (patient, public, etc.).
Rigor of development (domain 3)
For this domain, the median score was 30% (Q1-Q3: 15–67%). The highest median score (100%) was achieved only by 1 set of guidelines (NICE).
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).
did not exceed 44%. The main reasons for low scores for this domain were unclear description of strengths and limitations of the body of evidence and a lack of reporting of the procedures for updating the guidelines.
Clarity of presentation (domain 4)
The median score for this domain was 92% (Q1-Q3: 81–100%). Five guidelines (AAAAI and I-FPIES, BSACI, NICE, Spanish on non-IgE-mediated CMA and WAO)
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
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).
did not exceed 60% (Q1-Q3: 14–58%). The main limitation was a lack of or not clearly described facilitators and barriers for application of these guidelines.
Editorial independence (domain 6)
For this domain, the median score was 75% (Q1-Q3: 69–100%). Five guidelines (AAAAI and I-FPIES, BSACI, GPIFN and MAP, Indian Society of Pediatric Gastroenterology [ISPGHAN], and NICE)
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
had a median score below 60%. The low score was mainly due to the lack of reporting of the competing interests of the guideline development group members.
Overall quality score
The median overall score was 70% (Q1-Q3: 58–89%). The maximum possible overall score was 100% and it was achieved by four guidelines (AAAAI and I-FPIES, BSACI, NICE, WAO).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Recommendation for a collection of clinical history of typical signs and symptoms for both acute and chronic FPIES, and to consider a broad differential for a patient with acute vomiting in a diagnosis of FPIES.
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).
Recommendation for a specifically allergy-focused clinical history and physical examination, including: nutritional status and growth (weight, length/height, and calculation of BMI), any signs of a clinical reaction, or comorbid conditions such as atopic eczema, asthma, and/or allergic rhinitis, or suggesting an alternative diagnosis.
Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with OFC. If IgE-mediated CMA, supervised challenge in minority of cases.Not recommended in:
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exclusively breastfed infants with bloody stools (proctocolitis),
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with suspected reaction to CMA and mild symptoms,
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with mild AD and negative history for CM reactions.
Children with any severe symptoms should be referred to a specialized center.
Suspected IgE-mediated CMA: In settings in which an OFC is not a requirement, in patients with an average pretest probability of IgE-mediated CMA, suggestion for use of OFC with CM as the only test without measuring milk sIgE levels as a triage or add-on test.
Recommendation for use of elimination diet with no milk or egg and, in case of resolution of symptoms, referral to a specialist who will supervise an OFC.
Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with standardized OFC (not if clear immediate type reaction or anaphylaxis).
Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with OFC (in IgE-mediated CMA; if diagnostic uncertainty [conflict between the history and diagnostic tests], in non-IgE-mediated CMA, a gold standard).
Recommendation for controlled oral provocation: (1) if negative SPT and/or sIgE, (2) in patients with chronic symptoms such as AD and urticaria, and positive allergy test,
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Diagnosis primarily based on a clinical history of typical characteristics signs and symptoms with improvement after withdrawal of the suspected trigger food.Recommendation for exclusion of other potential causes and use of OFC only if the unclear history and a favorable risk/benefit ratio.In patients with suspected chronic FPIES, who become asymptomatic and maintain normal growth when the trigger food is eliminated from the diet, subsequent reintroduction of the trigger food induces acute FPIES symptoms within 1–4 h.
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).
Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with OFC (depends if severe cases, suspected FPIES, or possible IgE-mechanism).If severe cases or suspected FPIES, or no improvement on elimination diet, referral to specialist.If CMA is still suspected despite of lack of response to diet, a suggestion for the exclusion of other foods (ie, soy protein and egg), and in case of formula-fed infants to switch to another EHF or hydrolyzed rice formula.
Mild to moderate IgE-mediated CMA: Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with OFC (mostly in non-IgE-mediated CMA).Mild to moderate non-IgE-mediated CMA: Re-introduction of CM at home. CMA is confirmed only if symptom improves after return to elimination diet after home re-introduction.Severe non-IgE-mediated or mild to moderate IgE-mediated CMA: Referral to local pediatric allergy service (also if no improvement despite elimination diet and CMA still suspected) and dietitian.Severe IgE-mediated CMA (anaphylaxis): Emergency treatment and admission.
Recommendation for use of CMP elimination diet and, in case of resolution of symptoms, confirmation with OFC (home reintroduction). CMA confirmed only if symptom improves after return to elimination diet after OFC. If CMA still suspected despite a lack of response to diet, referral to specialist for advice to eliminate other foods (ie, soy protein or egg), in formula-fed infants switching EHF to AAF.Recommendation for use of OFC to confirm diagnosis of IgE-mediated CMA if inconsistency between the history and diagnostic tests. Referral to a specialist allergy clinic and/or pediatric dietitian with the urgency depending on clinical judgement (indications in guidelines).
2–4 week period (4 weeks for gastrointestinal symptoms), 10 days if enterocolitis syndrome, 1–3 weeks for enteropathy, 6 weeks for eosinophilic esophagogastroenteropathy.
1–2 weeks if early and late reactions (ie, vomiting, atopic eczema), 2–4 week if gastrointestinal symptoms (ie, diarrhea, constipation). If the history suggests an immediate reaction, only 3 to 6 days. If delayed reactions are suspected (eg, allergic proctocolitis), then up to 14 days.
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).
2–4 weeks depending on symptoms and severity: 1–5 days in acute forms (acute FPIES, vomiting), 1–2 weeks for eczema/gastrointestinal bleeding, 2–4 weeks in cases of constipation, diarrhea, growth faltering.
From 3 to 5 days (IgE-mediated CMA) to 2–4 weeks (other than IgE-mediated, max 4 weeks). 1–2 week for most, 2–4 week for chronic symptoms. [Differences in the paper: The maternal elimination diet is maintained for 3 to 6 days in those with IgE-mediated allergy, while in non-IgE mediated it is two weeks in those without atopy, and 4 weeks in those with atopic dermatitis or allergic]
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Under medical supervision, in a setting with emergency facilities, especially in case of positive SPT or sIgE to CM and infants at risk of an immediate reaction.
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Open or blinded challenge.
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Recommendation against OFC in children with immediate reactions or late gastrointestinal reactions with anemia, poor growth, or hypoalbuminemia if causative role of CM is clear.
Under the supervision of a specialist. Except delayed allergic reaction (chronic diarrhea, colitis, allergic proctocolitis, gastroesophageal reflux) without sIgE, OFC in hospital settings.
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Double-blind placebo-controlled food challenge method of choice in research and delayed reaction settings, and with uncertain outcome. In other cases, open OFC.
Challenge food is baked or fresh milk, reactions to baked milk are less likely to be severe, and tolerance to baked milk is developed earlier than to fresh milk (home baked CM reintroduction).
Double-blind placebo-controlled food challenge is the gold standard (reserved for research), however, open provocation or simple-blinding test acceptable in daily practice.
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Recommendation against if a positive SPT/sIgE for milk with a recent clinical episode (within the last 3 months).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
In medically supervised setting with access to rapid fluid resuscitation and prolonged observation.
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Recommendation against the home OFCs to a food suspected of triggering FPIES given the potential for severe reactions.
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It is generally recommended not to exceed a total of 3 g of protein or 10 g of total food (100 mL of liquid) for an initial feeding (which aims to OFC if there approximate a serving size) and observe the patient for 4 to 6 h.
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).
Home reintroduction, only if there is confirmed lack of IgE sensitization.
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Under supervision of the pediatrician in patients with proctocolitis, GOR, colic, constipation and other mild gastrointestinal symptoms.
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In hospital, in cases of the immediate reactions, severe atopic dermatitis, FPIES, moderate to severe enteropathy, in whom an IgE-mediated mechanism is suspected.
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The period of observation after reintroduction of CMP should be of at least 2 weeks and of up to 4 weeks, especially in cases with constipation or enteropathy.
Non-IgE-mediated CMA: home reintroduction with CM (return to regular maternal or infant's diet, or standard CM formula)
-
IgE-mediated CMA: the administration of increasing quantities of baked or fresh CM under medical supervision, starting with direct mucosal exposure (allergen contact with the lips) and then titrated oral ingestion as tolerated. The rate of dose escalation, the time interval between doses, and observation period after the challenge depends on the individual child's presentation.
In setting where OFC is not a requirement and high pretest probability of IgE-mediated CMA, and SPT with a cut-off value of ≥3 mm – no OFC; or low patient pretest probability of CMA if SPT below cut-off value – no OFC.
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In setting where OFC is not a requirement and high pretest probability of IgE-mediated CMA, sIgE with a threshold of 0.7 IU/L – if positive, no OFC. If low pretest probability of IgE-mediated CMA, sIgE with a cut-off value of ≥0.35 IU/L – if negative, no OFC.
Recommendation for sIgE and elimination diet in infants with presence of anaphylaxis or clear immediate type reaction (if negative result, the OFC).
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The presence of CMP-sIgE and/or a positive SPT to CM indicates IgE-mediated CMA; however, results must be interpreted in the context of medical history and OFC.
The clinical diagnosis of IgE-mediated CMA based on combination of typically presented symptoms soon after ingestion of CM and evidence of sensitization (sIgE and/or SPT tests). SPT, if IgE-mediated CMA suspected. If below 3 mm, to repeat or consider sIgE. If SPT weal diameter 2–4 mm, to consider OFC. A SPT weal size ≥5 mm (≥2 mm in younger infants) is strongly predictive of CMA.
SPT and/or sIgE recommended. If negative, to reconsider diagnosis, and controlled OFC. If positive SPT and/or sIgE, but not recent episode, an OFC. For sIgE, a positivity cut-off value is 0.35 kUA/L. For SPT, positivity cut off is at least 3 mm SPT size wheal.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Recommendation against routinely performed testing for food sIgE to identify food triggers of FPIES (non-IgE-mediated process). sIgE may be considered in patients with CM-FPIES only with certain comorbid conditions as IgE-mediated allergies, AD or respiratory allergic disorders.
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).
Recommendation for use of sIgE or SPT in patients with severe AD and/or FPIES before OFC (if positive result, the OFC following the protocol of IgE-mediated reaction).Recommendation against use of SPT or sIgE, if any doubt about an IgE mechanism.
sIgE and SPT not useful in diagnosis of non-IgE-mediated CMA.
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SPT can be considered in IgE-mediated CMA: a positive test do not confirm allergy, a negative SPT rules out IgE-mediated CMA.
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Acute/life threatening symptoms (ie, stridor, wheeze, angioedema and anaphylaxis): if CMP-sIgE positive and resolution of symptom with an elimination diet, the OFC may be delayed by a year.
Atopy patch testing, determination of total IgE, the ratio of sIgE to total IgE, determination of IgG antibodies or IgG subclass antibodies against CMP, applied kinesiology (muscle strength testing) and hair analysis (assessing mineral content), facial thermography, gastric juice analysis, provocation neutralization, cytotoxicity assay, electrodermal testing, intradermal testing (a risk of systemic allergic reaction in highly sensitized individuals).Basophil/histamine release/activation, lymphocyte stimulation, mediator release assay, endoscoping allergen provocation recommended in research, but not in clinical practice.
Hair analysis, kinesiology, iridology, electrodermal testing (Vega), lymphocyte stimulation tests and food-specific IgG and IgG4, histamine, tryptase, and chymase assays.Recommendation against routine use of molecular-component resolved diagnostics
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).
Routine radiographic testing if CM-FPIES suspected, and routine performance of laboratory tests, and routine endoscopy, unless the diagnosis is uncertain, or patient do not respond to elimination diet with endoscopy based on judgement of gastroenterologist.Recommendation against atopy patch testing.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Assessment of chemistry or blood count in the acute setting in differential diagnosis of FPIES.
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A work-up to rule out other gastrointestinal diseases (eg, enteropathy, eosinophilic esophagitis, very early onset inflammatory bowel disease, primary immunodeficiency syndromes) resulting in symptoms that overlap with FPIES.
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).
Breast-fed infants: a diagnostic maternal diet without CM not recommended for mild symptoms. Infants with bloody stools (proctocolitis): recommendation against the maternal diet without egg and CM.
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Elimination of CMP, eggs, and other foods recommended in infants with moderate-severe symptoms only with history of unequivocal reaction.
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Confirmed non-IgE CMA (moderate-severe symptoms): the maternal CM elimination diet with supplemental intake of calcium. If the insufficient volume of breast milk, EHF or SF formula (if > 6 months). If no symptoms after the reintroduction of CM in mother's diet, the excluded foods introduced one by one in the diet.
Recommendation for continuation of breastfeeding with the maternal CMP-free diet.
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Supplementation: calcium supplements (ie, 1000 mg/day spread across the day).
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Referral to dietitian.
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If there is no improvement: child should be further evaluated.
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CMA confirmed: continuation of breastfeeding while maintaining a CMP-free diet (referral to dietitian and supplementation as above)
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Symptoms recur on breast milk despite a strict maternal CMP-free diet: further elimination of other highly allergenic foods or weaning from breast milk to a hypoallergenic formula.
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The first feeding with CM–based formula in a breast-fed infant causes symptoms: return to exclusive breast-feeding without any elimination in the maternal diet.
Continuation of breastfeeding with maternal CMP elimination diet only if infant is symptomatic. Assessment of mother's need for calcium and vitamin D supplementation.
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All breastfed infants over 6 months vitamin D supplementation in the form of vitamin drops.
Exclusively breastfed infants: recommendation for continuation of breastfeeding with maternal milk and dairy product exclusion diet elimination diet.
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Only when breastfeeding not possible: SF, EHF based on CMP, partially hydrolyzed formulae based on rice, or AAF started or added.
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Recommendation against maternal elimination diet in infants with atopic dermatitis.
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Supplementation: Ca (1000 mg per day).
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Infants with mixed feeding: If breastfed without problems and develops symptoms with the introduction of adapted CM formulas, breastfeeding continued without the need for the maternal exclusion diet.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Recommendation for dietary elimination of the trigger food(s) in the primary management of FPIES.Recommendation against routine maternal dietary elimination of offending triggers while breast-feeding if the infant is thriving and remains asymptomatic.
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).
Exclusively breastfed children: continuation of breastfeeding with CMP-free maternal diet.
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Persistence of symptoms despite adequate adherence to the CMP-free diet: to consider the exclusion of other potential food trigger (ie, soy and/or egg).
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In mixed-fed infants: if the onset of symptoms coincides with the introduction of formula feeds, return to exclusive breastfeeding (maternal elimination diet mostly not necessary).
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Supplementation with calcium (1 g/day) and vitamin D (600 IU/day).
Exclusively breastfeeding mother: if symptomatic on breastfeeding only, trial exclusion of all CMP from her own diet.
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Mixed-fed infant: revert to exclusive breastfeeding. If infants asymptomatic on exclusive breastfeeding, recommendation against maternal elimination diet.
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Infants with severe AD or more severe gut symptoms: consider seeking specialist advice to also exclude soy protein/egg.
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No clear improvement, but CMA still suspected: referral to local pediatric allergy service and to consider exclusion of other maternal foods (ie, soy, egg, only with specialist advice).
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Supplementation: calcium and vitamin D following local guidelines.
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Referral to dietitian.
Treatment of non-IgE CMA (mild to moderate): strict adherence to CM-free diet for the mother/infant until the child is 9–12 month and for at least 6 months with support of dietitian.
Exclusively breastfed infants: recommendation for continuation of breastfeeding with maternal elimination diet without CMP.
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Mixed-fed infant: revert to exclusive breastfeeding.
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Infants asymptomatic on exclusive breastfeeding: recommendation against maternal elimination diet.
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Infants with severe non-IgE-mediated allergy and/or AD: consider seeking specialist advice to also exclude soy protein and egg.
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Supplementation: calcium and vitamin D according to local protocols.
Treatment of non-IgE CMA (mild to moderate), strict adherence to CM-free diet for the mother/infant until the child is 9–12 month and for at least 6 months.
Children <12 months and in older children with severe gastrointestinal symptoms: EHF or AAF.
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Children >12 months with anaphylaxis: CM substitutes not always required.
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Severe symptoms: EHF or AAF in formula-fed children; if poor growth, anemia, or hypoalbuminemia, AAF for days to 6 week (to switch to EHF).
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Mild-moderate symptoms: SF (if older than 6 months of age and no gastrointestinal symptoms) or EHF or AAF. EHF and SF started only under medical supervision. AAF for 2 weeks and then switched to SF or EHF.
IgE-mediated CMA at low risk of anaphylactic reactions (no prior history of anaphylaxis or currently on EHF): EHFs suggested over AAF, and rather than SF, and extensively hydrolyzed rice formula.
Formula-fed infants: EHF with proven efficacy usually a first-line choice. Choice of formula depends mostly on the patient age and the other food allergies.
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Confirmed CMA: the continuation of elimination diet for at least 6 months or until 9 to 12 months of age.
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Infants/children with severe immediate IgE-mediated CMA: elimination diet for 12 or even 18 months before re-challenge after repeated testing for sIgE. The choice of depends on residual allergenic potential, formula composition, costs, availability, infant's acceptance, and clinical data of the formula efficacy.
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Infants with enteropathy, diarrhea, and lactose intolerance: a lactose-free EHF as first-line.
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Non–breast-fed infants: avoidance of CM–based formula and supplementary foods containing CMP or other unmodified animal milk proteins (eg, goat's milk, sheep's milk)
The choice of CM substitute depends on the age of the child, the severity of the allergy, and the nutritional composition of the substitute (a risk of faltering growth and specific nutritional deficiencies).
Mixed or formula-fed infant: a substitution formula with demonstrated efficacy in CMA.
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Symptoms after the intake of EHF: switched to a different EHF or to AAF.
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Coexisting secondary lactose intolerance, particularly in infants suffering important digestive alterations with enteropathy and diarrhea: evaluation of lactose-free diet.
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Patients extremely sensitive to CMP with positive skin tests with casein hydrolysates: controlled exposure testing with the hydrolysate to check tolerance before introduction; not necessary with products from other sources (rice, soy) or elemental AAF.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
A formula with proven safety and suitability in children with CMA should be favored. The efficacy of formulas available in most industrialized countries not always proven by a clinical trial.In a review: In non-breastfed infants: EHFs as the first option.
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).
Formula-fed infants with mild to moderate non-IgE-mediated CMA: casein- or whey-EHF as the first-line choice.In a review: EHFs with medium chain triglycerides should be considered in infants with growth faltering, including formulas containing lactose if lactose intolerance is not suspected.
Mild to Moderate IgE-mediated CMA: If mother unable to revert to fully breastfeeding, EHF as first choice. If diagnosis confirmed (by IgE testing or a supervised challenged in a minority of cases): follow-up with serial IgE testing and later planned challenge to test for acquired tolerance. Dietetic referral required.
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Mild to moderate non-IgE-mediated CMA: if mother unable to revert to fully breastfeeding, EHF.
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Severe non-IgE-mediated CMA: if mother unable to revert to fully breastfeeding, AAF. Infant asymptomatic on breastfeeding alone: do not exclude CM from maternal diet. Urgent referral to local pediatric allergy service and dietetic referral.
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Exclusively breastfed infants with confirmed mild to moderate CMA and need of top-up/supplemental formula: EHF.
Infants with suspected non-IgE mediated or IgE-mediated CMA who are formula-fed or mixed-fed, and the mother is unable to return to exclusive breastfeeding: EHF, usually used as first-line (whey or casein-based).
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Partially hydrolyzed formulas: not recommended.
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Lactose-free formulas not recommended in suspected or confirmed CMA.
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The choice of CM substitute should take into account the child's age, growth, severity of symptoms, and nutritional composition. A referral to pediatric dietitian for consideration.
Formula-fed infants with mild to moderate IgE or non-IgE-mediated CMA: EHF the first choice (and elimination of all sources of CMP).Infants <6 months of age with mild to moderate reaction: EHF with proven efficacy recommended.Older children: elimination of all forms of milk and milk products.
Modified extensively hydrolyzed formula for CMA (supplemented with pro-, pre- and/or postbiotics)
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Children with IgE-mediated CMA at high risk of anaphylactic reactions (prior history of anaphylaxis and currently not using EHF): suggested AAF rather than EHF.
Infants with extremely severe or life-threatening symptoms or reacting to EHF: AAF may be considered as the first choice.No improvement within 2 weeks on elimination diet (EHF) or infants with significant gastrointestinal symptoms with no improvement using EHF or SF: trial of AAF before CMA is ruled out.Suspected multiple food allergies in highly atopic children or in cases of eosinophilic disorders of the digestive tract: AAF before OFC.Infants with severe anaphylactic reactions or with severe enteropathy indicated by hypoproteinemia and faltering growth: AAF may be considered a first-line treatment despite limited evidence.No improvement on AAF: CMA may be ruled out.
AAF for infants with: (1) multiple food allergies, (2) severe CMA, (3) allergic symptoms or severe atopic eczema when exclusively breastfed, (4) severe forms of non-IgE-mediated CMA such as eosinophilic esophagitis, enteropathies, and FPIES, (5) faltering growth and (6) reacting to or refusing to take EHF at nutritional risk.Infants (who meet the criteria for an amino acid milk) require additional energy, Ca, and iron or a flavored product: amino acid follow-on formulas.
AAFs used in cases of serious anaphylactic manifestations and maintained until exposure testing to EHF.AAF considered when EHFs are rejected due to palatability problems.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
Mild to moderate non-IgE-mediated CMA:No clear improvement after formula fed or ‘Mixed Feeding’: strict CMP-free diet, but CMA still suspected: consideration of AAF and referral to local pediatric allergy service.If top-up/supplement formula feeds needed and EHF is not clinically tolerated: AAF.If formula-fed or mixed-fed with severe symptoms and mother unable to revert to fully breastfeeding, trial of AAF and refer onwards to specialist care.
AAFs should be reserved for children: (1) with severe symptoms of IgE- or non-IgE-mediated allergy or a history of anaphylaxis, (2) who cannot tolerate or have ongoing symptoms with EHFs, (3) whose symptoms do not respond to maternal avoidance of CM, or have symptoms while exclusively breastfeeding.
Children with soy protein allergy, or allergy to other components of the EHF that has been used during milk restriction, or infants with multiple food allergies (such as egg, wheat, soy, nuts, sea fish): AAF.The diagnosis is reasonably certain with no improvement within 2 weeks of EHF,: AAF before CMA is ruled out.Infants who are sick or have severe or life-threatening symptoms: AAF as the first choice rather than EHF.IgE-mediated CMA: No response to EHFs: AAF. Severe allergy that requires hospitalization: AAF.
Plant-based formula (ie, soya-based, rice-based) for CMARice formula
Hydrolyzed rice formula (partially or extensively hydrolyzed formula) may be considered in infants refusing or not tolerating an EHF based on CMP, or in vegan families.
Partial rice hydrolysate (long-term nutritional studies are lacking) is an option.Hydrolyzed rice protein formula has evidence of safety and nutritional suitability.
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Infants over 6 months of age: may be used.The recommendation against use of SF in infants under 6 months of age (not adequate from the nutritional perspective), and in situations of enteropathy sensitive to CMP or in non-IgE-mediated allergies.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Not reported as recommendation. In infants with CM-induced FPIES, introduction of SF under a physician's supervision and vice versa.SF as an alternative, especially in infants older than 6 months; a risk of potential co-reactivity between patients with soy-induced FPIES and those with CM-induced FPIES.
Not recommended as first-line treatment in infant <6 months (an increased risk of cross-reaction and unclear effect of phytoestrogen on hormonal balance).
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).
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Not nutritionally adequate. Goat's milk commonly provokes clinical reactions in more than 90% of children with CMA, donkey's milk in about 15% and has a high cost.
Not reported as a recommendation.The option of another milk should be weighed individually against allergy, clinical, and nutritional considerations.Goat's, ewe's and buffalo's milks: not recommended (risk of severe reactions).Camel's milk: a substitute for children after 2 years.Equine milks: substitutes, in particular for children with delayed-onset CMA.
The use of unmodified milk from other mammals (eg, sheep, goat, etc.): not advisable (risk of cross-reactivity with the CMP).Equine milk (mare, donkey): an alternative (the fat contents must be balanced to meet the nutritional requirements of children).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Not reported as recommendation.Goat and sheep milk: not recommended in patients with CM-FPIES (based on high homology of the protein sequences in these animal milks).Milks from donkeys, camels, or both: might be tolerated in patients with CM-FPIES (usually well tolerated in those with IgE-mediated CMA).
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).
Other mammalian milk proteins (including unmodified cow, sheep, buffalo, horse, or goat's milk): not recommended (not adequately nutritious to provide the sole food source for infants, and risk of possible allergenic cross-reactivity with CM or formulas based on other mammalian milk proteins).
Industrial juices made of soy, rice, almond, coconut, or chestnut, improperly called ‘‘milks’: not recommended (unsuitable to meet infant nutritional needs).
not a main drink under 1 year of age (can be used for cooking); a nutritionally complete formula preferably to 2 years of age,
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use under the guidance of a dietitian in children (risk of deficiency of energy, protein, Ca, riboflavin, vitamin A and D, and essential fatty acids), with regular monitoring of weight and growth, and in older children and adults (to ensure adequate Ca intake),
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not in families with financial constraints,
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need to ensure that specific ingredients are not allergenic,
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rice milk: not recommended <4.5 years (natural inorganic arsenic content)
Not reported as recommendation. Vegetable drinks: not nutritionally suited to the exclusive or partial feeding of infants; as complementary food in an otherwise well-balanced diet.
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).
Alternative 'milk' beverages (ie, almond, oat, coconut, or rice milks): not suitable for use as an infant's main drink under one year of age (poor nutritional value compared with cow's milk).Rice milk: not advised before the age of 4.5 years (natural inorganic arsenic content).Lactose-free formulas: not recommended in suspected or confirmed CMA (contain intact CMP).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
A child fed with CM formula with mild-moderate symptoms: if the oral food challenge is positive, the child elimination diet and re-challenged after 6 months (a shorter period for GORD) and in any case, after 9–12 months of age.
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A child fed with CM formula with severe symptoms: the OFC for tolerance acquisition performed not before 6–12 months after the last reaction. Child elimination of CM until 12 months of age, but in those with enterocolitis syndrome, until 2–3 years of age.
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A breasted child with moderate-severe symptoms: food challenge after 6–12 months of avoidance. If lack of symptoms after the reintroduction of CM in mother's diet, the introduction of excluded foods one by one in the diet.
Not reported as recommendation. Re-evaluation of all dietary interventions and avoidance strategies with patients and their families on a yearly basis, ideally through an OFC carried out under medical. Convincing symptoms after accidental ingestion equivalent to positive OFC and reschedule of the follow-up procedure accordingly.
Not discussed in CMA section but with regard to food allergies in general.
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A follow up of a child with food allergy by the basic health service. In case of a serious allergy for an important food (milk, grain), a follow up at the specialist-level health service.
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In milk allergy, a trial with small amount milk made at home at the age of 18 months.
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If CMA first appeared in the form of a serious allergy symptom, then milk provocation at specialist-level health care. Return of eliminated foods into the diet tried at 6-month intervals during the first 3 years and then at 12-month intervals.
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Child 5-year visit (if not earlier): the examination of diet to ascertain whether based on an elimination–provocation trial and assess a need for consultation with a specialist.
Reassessment of individuals at 6–12 monthly intervals from 12 months of age to assess for suitability of reintroduction.
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The challenge food in CMA: either baked or fresh milk. Baked milk for initial use (less allergenic, reactions less likely severe).
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Home reintroduction using a ladder approach in children who have had only mild symptoms (only cutaneous symptoms) on noteworthy exposure (eg, a mouthful of fresh milk) and no reaction to milk in the past 6 months and in IgE-mediated disease, a significant reduction in sIgE/SPT weal diameter.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Evaluation of patients with FPIES at regular intervals according to the patient's age and food allergen to determine whether she or he is still allergic. Recognition the age of development of tolerance varies by type of food trigger and country of origin. Development of tolerance in patients with CM-FPIES at an earlier age than tolerance in cereal grain- or other solid food induced FPIES.
A challenge under medical supervision to test the tolerance of baked milk in children from 1 year of age. The appropriateness and timing of its introduction assessed individually.Not reported as recommendation. Infants with proven CMA: a CM-free diet until 9–12 months of age and for at least 6 months before attempting to reintroduce it.
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).
Periods of treatment with a CMP-free diet: from 3 to 6 months in mild forms, to up to 12 months in the most severe cases. Unfavorable response to reintroduction of CMP: periodical re-evaluation of tolerance every 6 to 12 months.Mild cases: testing for tolerance at home under medical supervision.Child with a personal history of atopy, immediate reactions (onset within 2 h from ingestion), FPIES and all severe forms of allergy: a sIgE test and/or a SPT before reintroducing CMP. Based on the results of specific IgE or SPT: tolerance tested in a hospital setting.
Confirmed CMA: CM-free diet until 9–12 months of age and for at least 6 months – with a support of a dietitian. Then a planned reintroduction or supervised challenge using a ladder approach to determine tolerance acquisition.No current AD and no history at any time of immediate onset symptoms: no need to test IgE or SPT: reintroduction at home, using a milk ladder.Current AD: check serum sIgE or SPT. If negative: and still no history at any age of immediate onset symptoms - reintroduction at home using a milk ladder. If positive, refer to local pediatric allergy service.History of immediate onset symptoms at any time: sIgE or SPT. If negative, referral to local allergy service for re- challenge. If positive or test not available, refer to local pediatric allergy service.
Re-testing: arranged every 12–18 months depending on local pathways and protocols.Strict adherence to a CM-free diet for the mother/infant until the child is 9–12 months old and for at least 6 months. If symptoms do not improve over this time: (1) and CMA no longer suspected, the mother/infant resume normal feeding - referral to a pediatrician if symptom persist; (2) and CMA still suspected, referral to an allergology specialist and seeking specialist advice to avoid soy protein and egg.Child with non-IgE-mediated allergy: following a CM-free diet, a planned home reintroduction of cow's milk into the mother's or infant's diet. Tolerance to CMP e assessed using a 'milk ladder' and monitoring the symptoms (baked milk products reintroduced first (heating reduces allergenicity)).Signs of current atopic eczema or any history at any time of immediate-onset symptoms: home reintroduction contradicted and referral to an allergy specialist for allergy testing.Established tolerance: greater exposure of less processed milk gradually encouraged, ending in the reintroduction of fresh CM. Oral antihistamines available at home, in case of symptoms on reintroduction.Symptoms return on reintroduction of CM: a CM-free diet continued, and re-evaluation after a 6 to 12 months.Confirmed IgE-mediated CMA: follow-up arranged by the specialist allergy service (may include serial allergy testing and subsequent OFC).
OFC required before reintroduction of the allergen after therapeutic elimination period to confirm development of tolerance. Infant with IgE-mediated CMA: the elimination diet continued for at least one year and re-evaluation every 6 months subsequently.
Home-made meals a dietary option after 4 months of age.
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Breastfed infants: weaned as recommended for healthy children, but with avoidance of CM until 9–12 months of age and for at least 6 months from the beginning of the diet.
Not discussed in CMA section but with regard to food allergies in general.
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Introduction of additional foods in all children on a child-by-child basis beginning at the age of 4–6 months while breastfeeding is continued. Recommendation for introduction of wheat and oats before 6 months.
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At about 1 year of age, to consider the start of eating the same food as the rest of the family. Regular and varied meals, and eating meals together additionally beneficial. School children's snacks require attention; healthy alternatives favored over soft drinks, candy, and doughnuts.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Possible increased risk of having FPIES to other foods (most commonly rice or oats) in infants with CM-induced FPIES.
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Recommendation against delay in introducing complementary foods past 6 months of life. A practical ordering for introducing solids at home start with fruits and vegetables, followed by other foods, such as red meats and cereals. In case of tolerance to a variety of early food proteins, more liberal subsequent introduction.
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In an infant with severe CM-induced FPIES, consideration of supervised introduction of solids. Possibility of excluding the risk of severe reactions to small amounts in case of supervised OFCs to a mixture of several solids, followed by gradual build up to regular age-appropriate serving size at home.
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Recommendation for a provision of guidance to parents during the introduction of complementary foods and consultation with a dietitian.
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It is commonly recommended to introduce a new food as a single ingredient and, in the case of high-risk foods, to wait at least 4 days before introducing another food to observe for the development of a reaction. Even single-food elimination can be associated with significant nutritional deficiency.
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Recommendation for foods that enhance developmental skills in infants (of various tastes and textures) to prevent aversive feeding behaviors and delay in the development of food acceptance and feeding skills.
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Recommendation against routine avoidance of products with precautionary allergen labelling in patients with FPIES.
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).
Complementary feeding in children with CMA: adherence to the guidelines applied to any other child under similar circumstances, save for the exclusion of CMP from the diet.
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No need to elimination of beef and similar meats, always well cooked.
Recommendations on how to advise caregivers on sources of information and support, and how to check and interpret food labels and recognize food allergens in ingredients lists of food products (includes lists of alternative terms for specific food allergen, and advice on precautionary allergen labeling, such as 'may contain' or 'not suitable for' statements) included in the guidelines.
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A consideration for avoidance of the loose foods (for example bought from markets or open bakeries) and foods imported from outside the EU, due to risk of lacking food ingredient labeling.
Introduction of supplementary foods one at a time in small quantities, preferably during the breastfeeding but not before the infant is at least 17 weeks of age to prevent other allergies.
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No evidence to suggest any protective effect of delaying introduction of solid foods, or even potentially allergenic foods, beyond age 4–6 months.
OIT in IgE-mediated CMA: a promising treatment to achieve desensitization in most cases, inducing immune modulating changes, and promoting tolerance.
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Always used in a center with experience in the management of OIT and with the capacity to deal with the possible adverse reactions.
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Long-term controlled trials are needed before general use of OIT in patients with CMA.
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The risk/benefit ratio of OIT in early infancy must be considered (an experience of spontaneous resolution of their IgE-mediated CMA vs. a need of regular exposure to the allergen in order to maintain tolerance).
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Before starting treatment based on OIT for milk and with the purpose of determining the clinical reactivity threshold, a consideration of careful controlled exposure test.
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A need for further exploration of immunotherapy with food allergens, although especially in subcutaneous and oral immunotherapy association with significant adverse effects.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
Dietary elimination of the trigger food or foods for the primary management of FPIES and education of caregivers and other care providers regarding avoidance strategies.
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).
Acute FPIES treated as a medical emergency with possibility to provide aggressive fluid resuscitation. Individual management of acute FPIES according to severity and review treatment strategies with the caregivers of each patient. Consideration of ondansetron as an adjunctive management of emesis.
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Dietary elimination of the trigger food or foods for the primary management of FPIES and education of caregivers and other care providers regarding avoidance strategies. Infants with suspected CM-induced FPIES generally advised to avoid all forms of these foods, including baked and processed foods, unless already included in the diet. Introduction of baked CM and egg under physician supervision.
Immediate ambulance transfer to Accident and Emergency, if systemic symptoms or suspected anaphylaxis with or without angioedema.
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Referral to a specialist allergy clinic for allergy testing to confirm the diagnosis and guide management, the urgency depending on clinical judgement, if a history of one or more severe systemic reactions. Whilst awaiting specialist assessment, consider referral to a pediatric dietitian.
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Written advice given to parents/carers on prompt recognition and management of acute symptoms following accidental or new exposures.
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Oral antihistamines available at home, in case of a return of symptoms on reintroduction or any accidental exposure.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Not reported as recommendation. A balanced calorie-protein ratio, amino-acid composition and an adequate Ca source required. The major risk of imbalanced diets are rickets (described vitamin D deficiency rickets) and poor growth.
Children with CMA beyond the first 12 months of age need individualized nutritional advice. Dietetic assessment is required to: (1) assess the intake of nutrients, especially proteins, Ca, vitamin D, and vitamin A, and (2) check a need for therapeutic formula or supplements to support normal growth for age.
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Supervision of the diet by a specialist dietician/pediatrician trained in pediatric nutrition strongly recommended.
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Chronic iron-deficiency anemia may be the sole manifestation of CMA in infants and children.
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Failure to thrive is nonspecific but can have severe consequences for a growing child.
A risk of lesser intake of nutrients than recommended may affect growth and development.
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In older children: individualized dietetic controls are sometimes needed to ensure an adequate intake of proteins, calcium and vitamins A and D, with periodic monitoring to make sure that growth is normal for the age of the patient.
An assessment of Ca and vitamin D intakes and counseling to reach RDA for these nutrients in all children with CMA. Counseling should include the importance and sources of Ca intake, and the expected objectives and timeline.
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The assessment of bone metabolism (BMD and metabolic bone profile) advised only if suspected bone fragility (fracture(s); rickets; CMA associated with another chronic disease or multiple food allergies; the association of low Ca intake, low vitamin D intake, low energy intake, period of rapid growth, and persisting CMA such as during eosinophilic esophagitis).
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).
Growth (weight, length/height, and head circumference) assessed at regular intervals based on national standards. Main nutrients of concern: calcium, protein, fat, vitamin D
A risk of inadequate nutritional intake, malabsorption, and faltering growth in children if food allergens that contribute essential nutrients are eliminated (ie, iron).
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Consideration of referral to a pediatric dietitian if IgE-mediated, and if non-IgE-mediated CMA suspected. Referral to a pediatric dietitian in case of confirmed mild-to-moderate non-IgE-mediated allergy,
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
Not reported as a recommendation. Some studies suggested a positive effect of probiotic interventions on atopic dermatitis, but meta-analyses did not confirm it. More RCTs need to be conducted to elucidate whether probiotics are useful for the treatment of AD.
Not discussed in CMA section but with regard to food allergies in general. Lactobacillus rhamnosus GG inhibits and ameliorates atopic eczema to some extent. There is no consistent evidence for the usefulness of probiotic bacteria in airways allergies.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
Not reported as recommendation. The use of PUFAs to treat CMA could be attempted in well-defined cases, but there is a need for more and comprehensive (pre-clinical) data for widespread recommendation.
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary-workgroup report of the adverse reactions to foods committee, American Academy of allergy, Asthma & Immunology.
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).
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