Stró_zyk et al.

World Allergy Organization Journal (2022) 15:100613

[Link]

Open Access
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
 ski, MDa, Andrea Horvath, MDa, Lamia Dahdah, MDb,
Agata Stró_zyka, Marek Ruszczyn
Alessandro Fiocchi, MD , Anna Nowak-Węgrzyn, MD, PhDc,h, Raanan Shamir, MD, PhDd,
b

Jonathan Spergel, MD, PhDe, Yvan Vandenplas, MD, PhDf, Carina Venter, PhD, RDg and
Hania Szajewska, MDa*, on behalf of the WAO DRACMA guideline group1

a
Department of Paediatrics, The Medical University of Warsaw, Warsaw, MD, PhD (Pediatric Allergy Unit, Research Center, San Pietro[1]
Poland Fatebenefratelli Hospital, Rome, Italy); Rose Kamenwa, MD (Department of
b
Allergy Unit, Pediatric University Department, Bambino Gesù Children’s Pediatrics and Child Health, Aga Khan University Hospital, Nairobi, Kenya);
Hospital, Rome, Italy Gideon Lack, MBBCh (Department of Women and Children’s Health/Peter
c
Department of Pediatrics, NYU Grossman School of Medicine, Hassenfeld Gorer Department of Immunobiology, School of Life Course Sciences,
Childrens’ Hospital, New York, NY, USA Faculty of Life Sciences & Medicine, King’s College London, UK; Evelina
d
Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider London Children’s Hospital, Guy’s and St Thomas’ Hospital NHS Foundation
Children’s Medical Center, Lea and Arieh Pickel Chair for Pediatric Research, Trust, London, UK), Haiqi Li, MD (Pediatric Division Department of Primary
Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel Child Care, Children’s Hospital, Chongqing Medical University, Chongqing,
e
Division of Allergy-Immunology, Children’s Hospital of Philadelphia, China); Alberto Martelli, MD (Italian Society of Pediatric Allergy and
Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, Immunology, Milano, Italy); Anna H. Nowak-Wegrzyn, MD, PhD (Department
USA of Pediatrics, New York University Langone Health, New York, NY, USA;
f
KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium Department of Pediatrics, Gastroenterology and Nutrition, Collegium
g
Section of Allergy and Immunology, University of Colorado and Children’s Medicum, University of Warmia and Mazury, Olsztyn, Poland); Nikolaos G.
Hospital Colorado, Aurora, CO, USA Papadopoulos, MD, PhD (Allergy Unit, 2nd Pediatric Clinic, University of
h
Department of Pediatrics, Gastroenterology and Nutrition, Collegium Athens, Athens, Greece; Division of Infection, Immunity & Respiratory
Medicum, University of Warmia and Mazury, Olsztyn, Poland Medicine, University of Manchester, UK); Ruby Pawankar, MD, PhD
*Corresponding author. Department of Paediatrics, The Medical University (Department of Pediatrics, Nippon Medical School, Bunkyo-Ku, Tokyo,
_
of Warsaw, Zwirki i Wigury 63A, 02-091 Warsaw, Poland. E-mail: Japan); Maria Said, RN (Allergy & Anaphylaxis Australia (A&AA), Castle Hills,
hszajewska@[Link] New South Wales, Australia); Mario Sánchez-Borges MD (Department of
1
Members of the DRACMA guideline group: Ignacio J. Ansotegui, MD, Allergy and Clinical Immunology, Centro Médico-Docente La Trinidad
PhD (Department of Allergy & Immunology, Hospital Quironsalud Bizkaia, Caracas, Venezuela); Holger J. Schünemann, MD, MSc, PhD (Department of
Erandio, Bilbao, Spain); Stefania Arasi, MD, PhD (Translational Research in Health Research Methods, Evidence and Impact (HEI), McMaster University,
Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children’s Hamilton, ON, Canada, and Cochrane Canada and McMaster GRADE
Hospital, IRCCS, Rome, Italy); Amal H. Assa’ad, MD (Division of Allergy and Centre, Hamilton, ON, Canada); Raanan Shamir, MD, PhD (Institute of
Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, Gastroenterology, Nutrition and Liver Disease, Schneider Children’s Medical
USA); Sami L. Bahna, MD, DrPH (Allergy/Immunology Section, Louisiana Center, Petach-Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University,
State University Health Sciences Center, Shreveport, LA, USA); Roberto Berni Tel-Aviv, Israel); Jonathan M. Spergel, MD, PhD (Division of Allergy and
Canani, MD, PhD (Department of Translational Medical Science, University Immunology, Department of Pediatrics, The Children’s Hospital of
of Naples Federico II, Naples, Italy); Antonio Bognanni, MD (Department of Philadelphia, Perelman School of Medicine at University of Pennsylvania,
Health Research Methods, Evidence and Impact - HEI, McMaster University, Philadelphia, PA, USA), Hania Szajewska, MD (The Medical University of
Hamilton, ON, Canada); Martin Bozzola, MD (Department of Pediatrics, Warsaw - Department of Paediatrics, Warsaw, Poland); Luigi Terracciano,
Pediatric Allergy/Immunology Section, British Hospital, Buenos Aires, MD (Italian NHS and Italian Society of Social and Preventive Pediatrics,
Argentina); Jan Brozek, MD, PhD (Department of Medicine, Division of _ Milano, Italy); Yvan Vandenplas, MD, PhD (Department of Pediatrics, UZ
Clinical Immunology and Allergy, Department of Clinical Epidemiology & Brussel, Vrije Universiteit Brussel, Brussels, Belgium); Carina Venter, PhD, RD
Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, (Section of Allergy & Immunology, University of Colorado Denver School of
Canada); Derek K. Chu, MD, PhD (Department of Medicine, Division of Medicine, Children’s Hospital Colorado, Aurora, CO, USA); Amena Warner,
Clinical Immunology and Allergy; Department of Clinical Epidemiology & RN, SN (PG Dip) (Allergy UK, Planwell House, Sidcup, Kent, UK); Susan
Biostatistics, McMaster University Health Sciences Centre, Hamilton, ON, Waserman, MD, MSc (Division of Clinical Immunology and Allergy,
Canada); Lamia Dahdah, MD (Translational Research in Pediatric Specialities Department of Medicine, McMaster University, Hamilton, ON, Canada);
Area, Division of Allergy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Gary W. K. Wong, MD (Department of Paediatrics, Faculty of Medicine, The
Italy); Christophe Dupont, MD, PhD (Paris Descartes University, Pediatric Chinese University of Hong Kong, Hong Kong, China)
Gastroenterology, Necker Hospital, Paris, Clinique Marcel Sembat, [Link]
Boulogne-Billancourt, France); Motohiro Ebisawa, MD, PhD (Clinical Received 3 August 2021; Received in revised from 20 October 2021;
Research Center for Allergy and Rheumatology, National Hospital Accepted 5 November 2021
Organization Sagamihara National Hospital, Kanagawa, Japan); Alessandro Online publication date 2 March 2022
Fiocchi, MD (Translational Research in Pediatric Specialities Area, Division of
1939-4551/© 2021 The Authors. Published by Elsevier Inc. on behalf of
Allergy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy); Ramon
World Allergy Organization. This is an open access article under the CC BY
Targino Firmino MD (Faculty of Medical Sciences of Campina Grande,
license ([Link]
UNIFACISA University Centre, Campina Grande, Paraiba, Brazil); Elena Galli,
2 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

ABSTRACT
Background: Since the publication of The World Allergy Organization (WAO) Diagnosis and
Rationale for Action against Cow’s Milk Allergy (DRACMA) Guidelines in 2010, a number of other
guidelines, expert opinions, and position papers relating to the management of cow’s milk allergy
(CMA) have been published. We aimed to systematically review the quality of the guidelines on
CMA diagnosis and management in children and/or adults published between 2010 and 2020.
Methods: The MEDLINE, EMBASE, ISI Web of Science, World Health Organization Global Index
Medicus, and Turning Research into Practice databases as well as website guideline repositories
were searched from January 2010 until May 2020. Any clinical practice recommendations and/or
guidelines focusing on the diagnosis and management of CMA in children and/or adults devel-
oped or endorsed by professional scientific societies or organizations were included. The guide-
lines 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 or-
ganizations. 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 do-
mains 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.
Keywords: Children, Cow’s milk allergy, Guidelines, AGREE II

INTRODUCTION the European Academy of Allergy and Clinical

Immunology (EAACI) were of the highest quality.
Since the publication of the 2010 DRACMA In addition, the 2010 World Allergy Organization
guidelines, a number of other guidelines, expert (WAO) Diagnosis and Rationale for Action against
opinions, and position papers for the management Cow’s Milk Allergy (DRACMA) Guidelines,2 the
of CMA have been published. However, their only Grading of Recommendations Assessment,
quality has not been formally appraised. In 2016 a Development and Evaluation (GRADE) guidelines
systematic review assessed the quality of guidelines for CMA, were considered to be of high quality.
on cow’s milk allergy (CMA) published from 2010
through November 2015 using the Appraisal of
Guidelines for Research and Evaluation (AGREE II) In 2018, the DRACMA panel committee re-
tool.1 Fifteen guidelines were included. Only the assembled in order to update the DRACMA
guidelines developed by recognized professional/ guidelines. The aim of this study was to systemat-
scientific organizations such as the British Society ically review the quality of the guidelines on CMA
for Allergy and Clinical Immunology (BSACI) and diagnosis and management in children and/or
Volume 15, No. 2, February 2022 3

adults published from 2010 onwards, and to earlier guidelines could be outdated. MEDLINE and
summarize specific recommendations. EMBASE were searched following a pre-specified
search-strategy (see Supplemental Appendix 1).
METHODS The websites of guideline repositories were also
searched including: National Institute for Clinical
The Preferred Reporting Items for Systematic Excellence (NICE, [Link] The
Reviews and Meta-Analyses (PRISMA) statement3 Guideline International Network (GIN, https://
was followed during each stage of this review. [Link]/), Scottish Intercollegiate
The protocol was pre-defined and submitted to Guidelines Network (SIGN) ([Link]
PROSPERO; however, it was not accepted for uk), and Agency for Healthcare Research and
registration, as it was assessed as being outside of Quality (AHRQ, [Link]
the scope of included protocols due to the lack of
at least 1 outcome of direct patient or clinical References of all included guidelines and
relevance. The AGREE II User’s Manual4 was guideline publisher’s websites were also searched
followed during the quality assessment of the for any supporting documents (ie, technical re-
included guidelines. ports, methodological manuals).
The search was carried out independently by
Search for guidelines
four reviewers (AS, AH, LD, and MR). No filters or
The MEDLINE (through PubMed), EMBASE, ISI restrictions other than English language were
Web of Science (Thomson Web of Knowledge), imposed.
World Health Organization Global Index Medicus
(GIM) ([Link] and Eligibility criteria
Turning Research into Practice (TRIP) ([Link]
[Link]/) databases were searched from Inclusion criteria & exclusion criteria
January 2010 up until May 2020, and then the search Any clinical practice recommendations and/or
was updated in April 2021. The rationale for guidelines focusing on the diagnosis and man-
choosing 2010 as the start date was that this is the agement of CMA in children and/or adults devel-
issue date of the DRACMA guidelines. However, we oped or endorsed by recognized scientific
recognized that an update of any guidelines/rec- societies or organizations were included. In case of
ommendations is generally required from 2 to 5 an updated version of a guideline, only the most
years after the issue date,5 and therefore, some of the recent document was considered for inclusion.
4 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Guidelines were included, regardless of CMA Data extraction

mechanism (ie, IgE-mediated, non-IgE-mediated,
Three reviewers (AS, MR, and LD) independently
mixed); however, if feasible, they were assessed
extracted data from all included guidelines. The
separately. Guidelines focusing on food allergy or a
reviewers extracted the following information: title,
single disease (eg, food protein-induced entero-
year of publication, organization (country), level of
colitis syndrome [FPIES]) were not considered for
guideline development (ie, local, regional, na-
inclusion in this review, unless there was a section
tional, or international), financial support, and
focusing explicitly on CMA or cow’s milk proteins.
conflicts of interest (number of people who ob-
tained financial support and/or had conflicts of
Consensus-based and expert opinion clinical
interest/number of all authors). Data extraction was
practice guidelines, if not endorsed by recognized
performed using data-extraction forms developed
scientific or professional organizations, were
by the reviewers. Any discrepancies were dis-
excluded based on their limited generalizability as
cussed until a consensus was reached.
well as our limited capability to evaluate the level
of expertise, that these publications represent, and Specific recommendations were summarized in
the audience addressed. Guidelines focused on a a comparative table, focusing on possible gaps
single specific management option (eg, immuno- and common messages. A “List of specific recom-
therapy) or prevention were excluded. Guidelines mendations to be assessed” had been pre-
which were ongoing or unpublished were also specified in the protocol. If feasible, recommen-
excluded. dations were extracted separately for IgE-
mediated, non-IgE-mediated, and mixed CMA, as
Data selection well for each age group (ie, children, adults).
As recommended, 4 reviewers (AS, AH, MR, and
LD) screened the titles and abstracts of articles Assessment of guidelines using AGREE II
identified in the search to identify potentially All appraisals were made using My AGREE PLUS
eligible guidelines. The full texts of all potentially interactive guideline appraisal platform (www.
relevant articles were retrieved and critically [Link]) by 3 reviewers (AS, AH, and MR).
assessed against the pre-defined inclusion criteria Two authors had previous experience with the
independently by each of the reviewers. Any dis- AGREE II instrument,6 and one reviewer (AS)
crepancies were first discussed by the 4 reviewers underwent the online AGREE II tutorial before the
(AS, AH, MR, and HS). review (available at: [Link]

Initially, members of the DRACMA panel not The AGREE II is a 23-item tool organized within
involved in the earlier process (AF, ANW, RS, JS, 6 domains: (1) scope and purpose; (2) stakeholder
YV, CV, LD) provided their comments on the involvement; (3) rigor of development; (4) clarity of
included and questionable documents and, if presentation; (5) applicability, and (6) editorial in-
feasible, any unidentified papers, via an online dependence. The AGREE II instrument also con-
survey using Google Forms. The list of excluded tains 2 global rating items: (1) overall guideline
papers was also reviewed. Guidelines were assessment (that requires the appraiser to make an
included if at least 90% agreement was reached; in overall judgement of the practice guideline while
case of agreement 50%, a paper document was considering how they rated the 23 key items) and
excluded. All of the comments were discussed. (2) a question on whether the appraiser would
Then, all questionable documents (between 50% recommend a guideline for use in practice
and 90% agreement) were put to a second vote by (assessed on a 3-point scale [ie, yes, yes with
the members of DRACMA panel to determine modification, and no]). All of the AGREE II items
eligibility for inclusion. Any discrepancies, as well and the overall guideline assessment item are
as all other disagreements between the reviewers, assessed using a 7-point Likert agreement scale
were resolved through discussion until a ranging from 1 (strongly disagree) to 7 (strongly
consensus was reached. agree). The reviewers discussed all scores that
Volume 15, No. 2, February 2022 5

Records iden fied through database

Identification

searching: Addi onal records iden fied

(n = 1548) through other sources
PubMed (n = 770) (n = 51)
EMBASE (n = 778)

Records screened Records excluded

Screening

(n = 1599) (n = 1379)

Full-text ar cles assessed for eligibility (n = 220)

•Preliminary selec on: included: 15, ques onable: 11 (12
records), excluded: 187 records
• A er first DRACMA panel vo ng: included: 10, ques onable: 5
(6 records), excluded: 198 records
Eligibility

•A er second DRACMA panel vo ng: included: 12, excluded: Full-text ar cles excluded,
201 (202 records) with reasons
•One guideline excluded during data extrac on, and one (n = 208 records)
guidelines recently published included before AGREE II
assessment
•April 2014 (update): six assessed for eligibility, and all excluded.
Included

Guidelines included in qualita ve synthesis

(n = 12)

Fig. 1 Study selection (PRISMA Flow chart)

differed by 2 or more points among themselves, possible score)] x 100. The possible standardized
until a consensus was reached. scores range from 0% (the minimum) to 100%
(the maximum).
For each item and domain, the score was sum-
med and calculated as a percentage of the The AGREE II does not provide a minimum or
maximum possible score for that item/domain us- maximum range for domain score quality to
ing the formula provided by the AGREE II con- differentiate high- and low-quality guidelines and
sortium:4 [(score obtained – minimum possible recommends that it should be done by the
score)/(maximum possible score – minimum reviewer. In agreement with a previous quality
6 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]
1. EWGPAG (Italy, 2010)8
Organization The Emilia-Romagna Working Group for Paediatric
Allergy and for Paediatric Gastroenterology
(EWGPAG)
Population Children, mainly refers to the first year of age
Financial support Funding not reported.
Conflict of interest No competing interests have been declared.
9
2. CNSFP (France, 2018)
Organization Committee on Nutrition of the French Society of
Paediatrics (CNFSP)
Population Children
Financial support Funding not reported.
Conflict of interest 6/12 authors declared to have financial conflict of
interest
3. Spanish on non-IgE-mediated CMA (Spain, 2019)15
Organization 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.
4. WAO (international, 2010)2
Organization 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
(continued)
Volume 15, No. 2, February 2022 7

McMaster University in Hamilton, Ontario, Canada,

under Holger Schunemann assisted by Jan Brozek,
Enrico Compalati and Luigi Terracciano.
Conflict of interest Individual conflict of interest not reported.
5. GPIFN and MAP (international, 2019)10
Organization 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.
6. ESPGHAN (Europe, 2012)11
Organization European Society for Paediatric Gastroenterology,
Hepatology, and Nutrition (ESPGHAN)
Gastroenterology (GI) Committee
Population Infants and children
Financial support Funding not reported.
Conflict of interest 11/12 authors declared to have financial conflict of
interest.
7. BSACI (United Kingdom, 2014)17
Organization Standards of Care Committee (SOCC) of the
British Society for Allergy and Clinical Immunology
(BSACI)
Population Children and adults
Financial support Funding not reported.
Conflict of interest 6/7 authors declared to have financial conflict of
interest.
(continued)
8 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

8. Spanish on IgE-mediated CMA (SEICAP) (Spain, 2015)16

Organization Food allergy committee of SEICAP (Spanish
Society of Pediatric Allergy, Asthma and Clinical
Immunology)
Population Children and adults
Financial support Funding not reported.
Conflict of interest The authors have no conflict of interest to declare.
9. ISPGHAN (Indie, 2020)12
Organization 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.
10. NICE (United Kingdom, 2019)18
Organization National Institute for Health and Care Excellence
(NICE)
Population Children. Focused on aged 5 years and younger.
These guidelines do not cover the management of
cow’s milk allergy in older children and adults.
Financial support Nothing to declare.
Conflict of interest Nothing to declare.
13
11. AAAAI and I-FPIES (international, 2017)
Organization 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)14
Organization The Finnish Allergy Programme 2008–2018.
Local Allergy Working Group has been created in
different part of Finland (Finland).
Population Children
(continued)
Volume 15, No. 2, February 2022 9

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.
Table 1. (Continued) Characteristics of the included guidelines. 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

appraisal with the AGREE II of the same clinical Characteristics of included guidelines
question carried out by members of the current
We included 12 guidelines (for characteristics, see
review group,1 a standardized domain score of
Table 1). Eight guidelines were developed by
above 60% for each domain has been chosen as
national organizations (India, Italy, France, Finland,
the threshold.
2 from Spain, and 2 from the United Kingdom), and
4 by international organizations and the
Statistical analysis and data synthesis International FPIES Association [I-FPIES] advocacy
Normality of quality scores was assessed using group; Gastroenterology Committee of the
the Shapiro-Wilk test and based on visual assess- European Society for Paediatric Gastroenterology,
ment of histograms. Due to the lack of a normal Hepatology, and Nutrition [ESPGHAN]; General
distribution of scores, data are presented as the Practice Infant Feeding Network [GPIFN] and the
median followed by the quartiles (upper [Q3] and Milk Allergy in Primary [MAP] Care team; and the
lower [Q1]) and IQR (interquartile range). Agree- World Allergy Organization [WAO] Special
ment between raters (inter-rater reliability) was Committee on Food Allergy).
analyzed using Fleiss’ Kappa and intraclass corre-
Eight guidelines were focused only on chil-
lation coefficient (ICC) estimates. The ICC calcula-
dren.8–15 Two guidelines were not only on the
tion was based on a single rating, absolute
management of CMA in children, but also in
agreement, two-way random effects model
adults.16,17 One set of guidelines, although
including a 95% confidence interval (CI). Analysis
developed with regard to all ages, was focused
was conducted in R software, version 3.5.1 (http://
especially on young ones;2 the second was
[Link]). by an independent statistician.
directed mostly at children aged 5 years and
Although Kendall’s W coefficient was pre-specified
younger,18 however, older children and adults
in the protocol to assess agreement between
were also discussed.
raters, after consultation with the statistician, it was
changed to Fleiss’ Kappa that is suitable for anal- Three guidelines were focused on the diagnosis
ysis of the agreement using ordinal or nominal and management of infants with any CMA.8,9,14
parameters (either dichotomous or not).7 Among 2 Spanish guidelines, one15 included
recommendations for management of infants
only with non-IgE-mediated CMA, and one16 for
RESULTS
infants only with IgE-mediated CMA. Five guide-
For the guideline selection process, see Fig. 1. lines provided recommendations with regard to
Excluded guidelines with reasons for exclusion IgE-mediated and non-IgE-mediated CMA sepa-
are summarized in Supplementary Table 1. rately.10–12,17,18 One set of guidelines2 provided
 10
[Link]
Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
AGREE II domain scores

Endorsed society of guidelines (country, 1 2 3 4 5 6 Overall

year) scope score
stakeholder rigor of clarity of editorial
and applicability
involvement development presentation independence
purpose
NICE (United Kingdom, 2019)18 98% 100% 100% 100% 100% 100% 100%
BSACI (United Kingdom, 2014)17 100% 74% 91% 100% 82% 100% 100%
WAO (international, 2010)2 100% 100% 97% 100% 89% 58% 100%
AAAAI and I-FPIES (international, 2017)13 89% 56% 90% 100% 67% 100% 100%
8
EWGPAG (Italy, 2010) 89% 83% 32% 94% 68% 75% 78%
Spanish on non-IgE-mediated CMA 100% 70% 44% 100% 47% 75% 72%
(SEGHPN, AEPAP, SEPEAP, and SEICAP)
(Spain, 2019)15
GPIFN and MAP (international, 2019)10 70% 85% 28% 81% 69% 100% 50%
12
ISPGHAN (Indie, 2020) 72% 24% 14% 89% 58% 100% 67%
Spanish on IgE-mediated CMA (SEICAP) 74% 9% 15% 83% 81% 72% 61%
(Spain, 2015)16
ESPGHAN (Europe, 2012)11 69% 22% 20% 81% 63% 75% 61%
CNSFP (France, 2018)9 59% 17% 13% 81% 53% 56% 44%
Finnish guidelines (the Finnish Allergy 22% 15% 4% 50% 14% 53% 17%
Programme) (Finland, 2012)14

Median 82% 63% 30% 92% 68% 75% 70%

q1 70% 21% 15% 81% 57% 69% 58%
Volume 15, No. 2, February 2022 11

recommendation only for IgE-mediated CMA (and

score for that domain (where 0% was the minimum, and 100% was the maximum), using the formula provided by the AGREE II consortium4: [(score obtained – minimum possible score)/(maximum possible score –
Table 2. Domain scores and overall assessment of CMA guidelines using the AGREE II instrument. 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

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

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
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

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;
non-IgE-mediated CMA recommendations were in
89%
31%

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 a review). One set of guidelines reported recom-
mendations on the diagnosis and management of
infants only with FPIES.13 Half of the included
guidelines9,10,12,13,16,18 were published in the
100%
32%

last 5 years.

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
75%
18%

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%

100%), whereas rigor of development was

19%

assessed with the lowest median score (30%; Q1-

Q3: 15–67%).
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:
67%
52%

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 (Na-
tional Institute for Health and Care Excellence
[NICE]),18 there was no variation in responses
79%
58%

measured with Fleiss’ Kappa and ICC (100%

agreement).

Scope and purpose (domain 1)

99%
29%

The median score for the scope and purpose

domain was 82% (Q1-Q3: 70–99%) across all
guidelines. Three guidelines (British Society for Al-
lergy and Clinical Immunology [BSACI], Spanish on
non-IgE-mediated CMA and WAO)2,15,17 achieved
the highest median score (100%), and one set of
guidelines (NICE)18 achieved a median score
equal to 98%. Two guidelines with the lowest
ratings achieved median scores for this domain
below 60%.9,14 Low scores were mainly due to a
lack of proper reporting, including a non-specified
WAO, World Allergy Organization

overall objective and a poor description of a

target population.

Stakeholder involvement (domain 2)

For the stakeholder involvement domain, the
median score was 63% (Q1-Q3: 21–79%). Two
guidelines (NICE, WAO)2,18 achieved the maximum
IQR
q3

median score (100%). Six guidelines9,11–14,16 did

12 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Diagnosis of CMA
EWPGAG 20108 Any CMA
WAO 20102 Only for IgE-mediated CMA (non-IgE-mediated in a
review)
Finnish guidelines 201214 Any CMA
11
ESPGHAN 2012 Separately for IgE-mediated and non-IgE-mediated
CMA
BSACI 201417 Separately for IgE-mediated and non-IgE-mediated
CMA
SEICAP 201516 Only for IgE-mediated CMA
13
AAAAI and I-FPIES 2017 Only for CM-FPIES
CNSFP 20189 Not reported
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Only for non-IgE-mediated CMA
GPIFN and MAP 201910 Separately for IgE-mediated (only diagnosis) and
non-IgE-mediated CMA
NICE 201918 Separately for IgE-mediated and non-IgE-mediated
CMA
ISPGHAN 202012 Separately for IgE-mediated and non-IgE-mediated
CMA
Clinical history and physical examination to
establish suspicion of CMA
EWPGAG 20108 Recommendation for a collection of detailed history
of symptoms to establish suspicion of CMA.
WAO 20102 Not as official recommendation.
ESPGHAN 201211 Recommendation for a collection of detailed history
of symptoms and physical examination.
BSACI 201417 Recommendation for a collection of detailed history
of symptoms (including severity evaluation).
SEICAP 201516 Recommendation for a collection of detailed history
of symptoms and physical examination.
AAAAI and I-FPIES 201713 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Recommendation for a collection of detailed history
of symptoms, physical examination, growth
assessment, and feeding history.
GPIFN and MAP 201910 Recommendation for a specifically allergy-focused
clinical history and physical examination.
(continued)
Volume 15, No. 2, February 2022 13

Clinical history and physical examination to

establish suspicion of CMA
NICE 201918 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.
ISPGHAN 202012 Recommendation for a collection of detailed history
of symptoms and physical examination.
Other guidelines9,14 Not reported.
Elimination-reintroduction
EWPGAG 20108 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:
- exclusively breastfed infants with bloody stools
(proctocolitis),
- with suspected reaction to CMA and mild
symptoms,
- with mild AD and negative history for CM
reactions.
Children with any severe symptoms should be
referred to a specialized center.
WAO 20102 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.
Finnish guidelines 201214 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.
ESPGHAN 201211 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).
BSACI 201417 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).
SEICAP 201516 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,
(continued)
14 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Elimination-reintroduction
AAAAI and I-FPIES 201713 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 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.
GPIFN and MAP 201910 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.
NICE 201918 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).
(continued)
Volume 15, No. 2, February 2022 15

Elimination-reintroduction
ISPGHAN 202012 Recommendation for use of CMP elimination diet
and, in case of resolution of symptoms, OFC.
CNSFP 20189 Not reported.
Duration of diagnostic elimination diet
EWPGAG 20108 2–4 week period (4 weeks for gastrointestinal
symptoms), 10 days if enterocolitis syndrome, 1–3
weeks for enteropathy, 6 weeks for eosinophilic
esophagogastroenteropathy.
WAO 20102 Not as official recommendation.
Finnish guidelines 201214 1–2 weeks if skin symptoms, 2–4 weeks if
gastrointestinal symptoms.
ESPGHAN 201211 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.
BSACI 201417 At least 6 weeks in infants with eczema.
SEICAP 201516 No longer than 2–3 weeks.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 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.
GPIFN and MAP 201910 2–4 weeks.
NICE 201918 2–4 weeks.
12
ISPGHAN 2020 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]
Other guidelines9,13 Not reported.
Settings of OFC
EWPGAG 20108 - 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.
- Open or blinded challenge.
- 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.
(continued)
16 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Settings of OFC
WAO 20102 - Under the supervision of a specialist. Except
delayed allergic reaction (chronic diarrhea, colitis,
allergic proctocolitis, gastroesophageal reflux)
without sIgE, OFC in hospital settings.
- Double-blind placebo-controlled food challenge
method of choice in research and delayed
reaction settings, and with uncertain outcome. In
other cases, open OFC.
Finnish guidelines 201214 Under specialist supervision.
ESPGHAN 201211 Standardized OFC under medical supervision
(inpatient or outpatient settings).
BSACI 201417 - In hospital (attached protocol).
- 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).
SEICAP 201516 - Under medical supervision.
- Double-blind placebo-controlled food challenge
is the gold standard (reserved for research),
however, open provocation or simple-blinding
test acceptable in daily practice.
- Recommendation against if a positive SPT/sIgE
for milk with a recent clinical episode (within the
last 3 months).
AAAAI and I-FPIES 201713 - In medically supervised setting with access to
rapid fluid resuscitation and prolonged
observation.
- Recommendation against the home OFCs to a
food suspected of triggering FPIES given the
potential for severe reactions.
- 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 - Home reintroduction, only if there is confirmed
lack of IgE sensitization.
- Under supervision of the pediatrician in patients
with proctocolitis, GOR, colic, constipation and
other mild gastrointestinal symptoms.
- In hospital, in cases of the immediate reactions,
severe atopic dermatitis, FPIES, moderate to
severe enteropathy, in whom an IgE-mediated
mechanism is suspected.
- 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.
GPIFN and MAP 201910 - Mild to moderate IgE mediated CMA: some may
need OFC in hospital setting
(continued)
Volume 15, No. 2, February 2022 17

Settings of OFC
- Mild to moderate non-IgE mediated CMA: home
reintroduction with CMP (return to regular
maternal or infant’s diet or standard CM formula)
NICE 201918 - 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.
ISPGHAN 202012 - Under medical supervision.
- Double-blind placebo-controlled food challenge
is the gold standard; however, mostly open
challenge is performed.
- Not recommended if patient with severe
anaphylaxis.
CNSFP 20189 Not reported.
Cow’s milk specific IgE (sIgE) and skin prick tests
(SPT)
EWPGAG 20108 Infant with immediate and late reactions: Referral to
a specialized clinic for SPT and/or sIgE.
WAO 20102 - 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.
- 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.
ESPGHAN 201211 - Recommendation for sIgE and elimination diet in
infants with presence of anaphylaxis or clear
immediate type reaction (if negative result, the
OFC).
- 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.
- Combination of the sIgE and SPT not necessary.
BSACI 201417 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
(continued)
18 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Cow’s milk specific IgE (sIgE) and skin prick tests

(SPT)
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.
SEICAP 201516 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.
AAAAI and I-FPIES 201713 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 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.
GPIFN and MAP 201910 Suspected IgE-mediated CMA: IgE testing,
particularly in children with eczema after a
prolonged period of avoidance.
NICE 201918 Suspected IgE-mediated CMA: SPT or sIgE
recommended. If results not corresponding with
history, or the equivocal history, supervised OFC
recommended.
ISPGHAN 202012 - sIgE and SPT not useful in diagnosis of non-IgE-
mediated CMA.
- SPT can be considered in IgE-mediated CMA: a
positive test do not confirm allergy, a negative
SPT rules out IgE-mediated CMA.
- 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.
Other guidelines8,9,14 Not reported.
Not recommended tests
WAO 20102 Routine use of molecular-component resolved
diagnostics. Allergen microarrays only in research.
ESPGHAN 201211 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
(continued)
Volume 15, No. 2, February 2022 19

Not recommended tests

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.
BSACI 201417 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
SEICAP 201516 Intradermal tests, the patch tests with commercial
antigens, IgG and its components, basophil
activation testing or microarray techniques.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 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.
NICE 201918 Atopy patch testing, serum-specific immunoglobulin
(Ig)G testing, applied kinesiology (muscle strength
testing), hair analysis (assessing mineral content)
and vega testing (electroacupuncture devices).
ISPGHAN 202012 The cow’s milk-related symptom score (CoMiSS).
8–10,13,14
Other guidelines Not reported.
Other recommended tests
AAAAI and I-FPIES 201713 - Assessment of chemistry or blood count in the
acute setting in differential diagnosis of FPIES.
- 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.
ISPGHAN 202012 Sigmoidoscopy and rectal biopsy in patients with
only gastrointestinal manifestation (enterocolitis
presentation).
Other Not reported.
guidelines2,8–11,14–18
Breastfeeding
EWPGAG 20108 - Breast-fed infants: a diagnostic maternal diet
without CM not recommended for mild
symptoms. Infants with bloody stools
(continued)
20 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Breastfeeding
(proctocolitis): recommendation against the
maternal diet without egg and CM.
- Elimination of CMP, eggs, and other foods
recommended in infants with moderate-severe
symptoms only with history of unequivocal
reaction.
- 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.
WAO 20102 Not reported as a recommendation.
- Breast-fed infants: continuation of breast-feeding
while avoiding dairy products.
- Supplementation: calcium (1000 mg/day divided
into several doses) while after a milk-free diet.
- Fully breast-fed children more than 2 years: no
need to substitute CM if an adequate supply of
calcium (600–800 mg/day).
Finnish guidelines 201214 Breastfeeding mothers and to children eating solid
foods: a diet eliminating CMP or egg.
ESPGHAN 201211 - Recommendation for continuation of
breastfeeding with the maternal CMP-free diet.
- Supplementation: calcium supplements (ie,
1000 mg/day spread across the day).
- Referral to dietitian.
- If there is no improvement: child should be
further evaluated.
- CMA confirmed: continuation of breastfeeding
while maintaining a CMP-free diet (referral to
dietitian and supplementation as above)
- 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.
- 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.
BSACI 201417 Not reported as recommendation.
- Continuation of breastfeeding with maternal CMP
elimination diet only if infant is symptomatic.
Assessment of mother’s need for calcium and
vitamin D supplementation.
- All breastfed infants over 6 months vitamin D
supplementation in the form of vitamin drops.
SEICAP 201516 - Exclusively breastfed infants: recommendation for
continuation of breastfeeding with maternal milk
and dairy product exclusion diet elimination diet.
(continued)
Volume 15, No. 2, February 2022 21

Breastfeeding
- Only when breastfeeding not possible: SF, EHF
based on CMP, partially hydrolyzed formulae
based on rice, or AAF started or added.
- Recommendation against maternal elimination
diet in infants with atopic dermatitis.
- Supplementation: Ca (1000 mg per day).
- 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.
AAAAI and I-FPIES 201713 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.
CNSFP 20189 Not reported as recommendation.
- In breastfed infants, maternal elimination diet
without milk and dairy products.
- Supplementation: calcium and vitamin D.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 - Exclusively breastfed children: continuation of
breastfeeding with CMP-free maternal diet.
- 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).
- 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).
- Supplementation with calcium (1 g/day) and
vitamin D (600 IU/day).
GPIFN and MAP 201910 Suspected IgE-mediated and non-IgE-mediated
CMA:
- Exclusively breastfeeding mother: if symptomatic
on breastfeeding only, trial exclusion of all CMP
from her own diet.
- Mixed-fed infant: revert to exclusive
breastfeeding. If infants asymptomatic on
exclusive breastfeeding, recommendation
against maternal elimination diet.
- Infants with severe AD or more severe gut
symptoms: consider seeking specialist advice to
also exclude soy protein/egg.
- 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).
- Supplementation: calcium and vitamin D
following local guidelines.
- Referral to dietitian.
(continued)
22 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Breastfeeding
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.
NICE 201918 - Exclusively breastfed infants: recommendation for
continuation of breastfeeding with maternal
elimination diet without CMP.
- Mixed-fed infant: revert to exclusive
breastfeeding.
- Infants asymptomatic on exclusive breastfeeding:
recommendation against maternal elimination
diet.
- Infants with severe non-IgE-mediated allergy and/
or AD: consider seeking specialist advice to also
exclude soy protein and egg.
- 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.
ISPGHAN 202012 Recommendation for continuation of breastfeeding
with maternal CMP elimination diet.
Supplementation: calcium (1000 mg per day in
divided doses).
Extensively hydrolyzed formula for CMA
EHWF and EHCF were not discussed separately
in any guidelines.
EWPGAG 20108 - Children <12 months and in older children with
severe gastrointestinal symptoms: EHF or AAF.
- Children >12 months with anaphylaxis: CM
substitutes not always required.
- 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).
- 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.
WAO 20102 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.
Finnish guidelines 201214 Children under 6 months: EHF. Children over 6
months: either hydrolysate or soy milk.
ESPGHAN 201211 - Formula-fed infants: EHF with proven efficacy
usually a first-line choice. Choice of formula
(continued)
Volume 15, No. 2, February 2022 23

Extensively hydrolyzed formula for CMA

EHWF and EHCF were not discussed separately
in any guidelines.
depends mostly on the patient age and the other
food allergies.
- Confirmed CMA: the continuation of elimination
diet for at least 6 months or until 9 to 12 months
of age.
- 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.
- Infants with enteropathy, diarrhea, and lactose
intolerance: a lactose-free EHF as first-line.
- 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)
BSACI 201417 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).
SEICAP 201516 - Mixed or formula-fed infant: a substitution
formula with demonstrated efficacy in CMA.
- Symptoms after the intake of EHF: switched to a
different EHF or to AAF.
- Coexisting secondary lactose intolerance,
particularly in infants suffering important
digestive alterations with enteropathy and
diarrhea: evaluation of lactose-free diet.
- 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.
AAAAI and I-FPIES 201713 Formula-fed infants or infants who can no longer
breastfeed diagnosed with CM-FPIES: a
hypoallergenic formula recommended.
CNSFP 20189 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Formula-fed infants with mild to moderate non-IgE-
mediated CMA: casein- or whey-EHF as the first-line
choice.
(continued)
24 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Extensively hydrolyzed formula for CMA

EHWF and EHCF were not discussed separately
in any guidelines.
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.
GPIFN and MAP 201910 Formula-fed or mixed-fed infants:
- 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.
- Mild to moderate non-IgE-mediated CMA: if
mother unable to revert to fully breastfeeding,
EHF.
- 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.
- Exclusively breastfed infants with confirmed mild
to moderate CMA and need of top-up/
supplemental formula: EHF.
NICE 201918 - 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).
- Partially hydrolyzed formulas: not recommended.
- Lactose-free formulas not recommended in
suspected or confirmed CMA.
- 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.
ISPGHAN 202012 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)
ESPGHAN 201211 No evidence of role of probiotics and prebiotics in
the treatment of CMA.
SEICAP 201516 A controversy as to whether supplementing EHF
with certain probiotics accelerates the acquisition of
tolerance.
(continued)
Volume 15, No. 2, February 2022 25

Modified extensively hydrolyzed formula for

CMA (supplemented with pro-, pre- and/or
postbiotics)
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 No sufficient evidence to recommend the routine
use of formulas enriched with prebiotic and/or
probiotics in the management of children with CMA.
Other guidelines2,8–10,12–14,17 Not reported.
Amino acid formula for CMA (supplemented with
pro-, pre- and/or postbiotics)
EWPGAG 20108 Children with gastrointestinal reactions and anemia,
poor growth, or hypoalbuminemia: AAF as first line
and then switched to EHF.
WAO 20102 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.
Finnish guidelines 201214 Recommendation against immediate transfer to
AAF.
ESPGHAN 201211 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.
BSACI 201417 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.
SEICAP 201516 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.
AAAAI and I-FPIES 201713 Not reported as recommendation.
CNSFP 20189 Not reported as recommendation.
(continued)
26 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Amino acid formula for CMA (supplemented with

pro-, pre- and/or postbiotics)
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 AAFs: the first-line treatment in severe cases of
enteropathy or FPIES, also recommended in no
response to treatment with EHF (casein or whey).
GPIFN and MAP 201910 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.
NICE 201918 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.
ISPGHAN 202012 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 CMA
Rice formula
EWPGAG 20108 A choice in selected cases taking into consideration
the taste and the cost.
WAO 20102 In children with IgE-mediated CMA: EHF rather than
extensively hydrolyzed rice formula.
ESPGHAN 201211 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.
SEICAP 201516 Partial rice hydrolysate (long-term nutritional studies
are lacking) is an option.
Hydrolyzed rice protein formula has evidence of
safety and nutritional suitability.
(continued)
Volume 15, No. 2, February 2022 27

Plant-based formula (ie, soya-based, rice-based)

for CMA
Rice formula
CNSFP 20189 Not reported as recommendation.
15
SEGHPN, AEPAP, SEPEAP, and SEICAP 2019 Hydrolyzed rice protein formulas: at any age, an
alternative to patients that refuse or do not respond
to casein or whey EHF.
Other guidelines10,12–14,17,18 Not reported.
Soy formula
EWPGAG 20108 Infants <6 months of age with allergic symptoms
and in those with late gastrointestinal symptoms: not
recommended
WAO 20102 Children with IgE-mediated CMA: EHF rather than
SF.
Finnish guidelines 201214 Recommendation for use of either hydrolysate or
soy milk for children over 6 months.
ESPGHAN 201211 EHF or AAF (if EHF not tolerated) preferable over SF
in infants with CMA. SF may be considered:
- in an infant with CMA older than 6 months if EHF
not accepted or tolerated, or too expensive,
- or if strong parental preferences (ie, vegan diet).
BSACI 201417 - Not the first line choice of substitute milk for
infants <6 months old with CMA.
- If hydrolysates not tolerated, AAF.
- To consider in infants after 6 months of age
because of lower cost or better palatability, after
assessment of tolerance to soy protein.
SEICAP 201516 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.
AAAAI and I-FPIES 201713 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.
CNSFP 20189 Not recommended as first-line treatment in infant
<6 months (an increased risk of cross-reaction and
unclear effect of phytoestrogen on hormonal
balance).
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Recommendation against the use in infants aged
less than 6 months.
(continued)
28 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Soy formula
GPIFN and MAP 201910 May be used over 6 months of age if non-sensitized
on IgE testing
NICE 201918 - Recommendation against the use as a first line
and not in infants less than 6 months of age or in
those with suspected soy allergy
- Recommendation for use in some children over 6
months of age without soy allergy.
- Impact of isoflavones with a weak estrogenic
action and with a theorized hormonal effect on
the reproductive system: no consensus.
ISPGHAN 202012 Infants more than 6 months of age with mild to
moderate reaction: in case of financial constraints.
Other mammalian milk formula (ie, goat’s) for
CMA
SEICAP 201516 Formulas based on extensive soy and meat (pig
collagen) hydrolysates can be used (limited data on
clinical effectiveness and nutritional safety).
CNSFP 20189 Not reported as recommendation. Other
mammalian milk, such as goat’s or ewe’s milk-based
formulas, only after individual testing.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Formulas from other mammals (goat, sheep, buffalo,
mare, camel, donkey) not recommended.
Other guidelines2,8,10–14,17,18 Not reported.
Cow’s milk dietary substitutes for CMA
Other mammalian milk
EWPGAG 20108 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.
WAO 20102 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.
ESPGHAN 201211 Goat’s- and sheep’s-milk protein: strictly avoided
(high cross-reactivity with CMP).
Other mammalian proteins not recommended.
BSACI 201417 Other mammalian milk: not recommended.
SEICAP 201516 The use of unmodified milk from other mammals
(eg, sheep, goat, etc.): not advisable (risk of cross-
reactivity with the CMP).
(continued)
Volume 15, No. 2, February 2022 29

Cow’s milk dietary substitutes for CMA

Other mammalian milk
Equine milk (mare, donkey): an alternative (the fat
contents must be balanced to meet the nutritional
requirements of children).
AAAAI and I-FPIES 201713 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).
CNSFP 20189 Not reported as recommendation.
Goat’s or ewe’s milks: only after individual testing
(higher risk of reacting to other mammalian milk).
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Milks from other mammals (goat, sheep, buffalo,
mare, camel, donkey): should not be used.
NICE 201918 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).
ISPGHAN 202012 Unmodified mammalian milk (cow, buffalo, donkey,
goat or camel): not recommended in infants with
proven CMA.
Other guidelines10,14 Not reported.
Plant-based drinks
ESPGHAN 201211 Industrial juices made of soy, rice, almond, coconut,
or chestnut, improperly called ‘‘milks’: not
recommended (unsuitable to meet infant nutritional
needs).
BSACI 201417 Alternative ‘milks’:
 not a main drink under 1 year of age (can be
used for cooking); a nutritionally complete
formula preferably to 2 years of age,
 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),
 not in families with financial constraints,
 need to ensure that specific ingredients are not
allergenic,
 rice milk: not recommended <4.5 years (natural
inorganic arsenic content)
(continued)
30 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Plant-based drinks
SEICAP 201516 Unmodified soy, as well as non-adapted rice milks:
contraindicated (not meet the necessary metabolic
requirements).
CNSFP 20189 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Plant-based milks (soy, rice, oat, almond, tiger nut
etc.): not recommended.
GPIFN and MAP 201910 Children under 4.5 years: rice milk beverage not
recommended; replacement milks only fortified with
120 mg calcium per serving.
NICE 201918 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).
Other guidelines2,8,12–14 Not reported.
Cow’s milk re-challenge to test for acquired
tolerance
EWPGAG 20108 - 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.
- 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.
- 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.
WAO 20102 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.
Finnish guidelines 201214 Not discussed in CMA section but with regard to
food allergies in general.
(continued)
Volume 15, No. 2, February 2022 31

Cow’s milk re-challenge to test for acquired

tolerance
- 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.
- In milk allergy, a trial with small amount milk
made at home at the age of 18 months.
- 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.
- 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.
BSACI 201417 - Reassessment of individuals at 6–12 monthly
intervals from 12 months of age to assess for
suitability of reintroduction.
- The challenge food in CMA: either baked or fresh
milk. Baked milk for initial use (less allergenic,
reactions less likely severe).
- 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.
AAAAI and I-FPIES 201713 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.
CNSFP 20189 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.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 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.
(continued)
32 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Cow’s milk re-challenge to test for acquired

tolerance
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.
GPIFN and MAP 201910 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.
NICE 201918 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).
(continued)
Volume 15, No. 2, February 2022 33

Cow’s milk re-challenge to test for acquired

tolerance
ISPGHAN 202012 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.
Other guidelines11,16 Not reported.
Introduction of complementary feeding in infants
with CMA
EWPGAG 20108 - Home-made meals a dietary option after 4
months of age.
- 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.
Finnish guidelines 201214 Not discussed in CMA section but with regard to
food allergies in general.
- 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.
- 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.
SEICAP 201516 - Recommendation against delay of the
introduction of complementary feeding.
- Recommendation against elimination of beef
from the diet.
- Tolerance of thoroughly cooked dairy products
by some patients with CMA.
- Possible tolerance of the yoghurt by patients
sensitized only to CM whey proteins.
AAAAI and I-FPIES 201713 - Possible increased risk of having FPIES to other
foods (most commonly rice or oats) in infants with
CM-induced FPIES.
- 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.
- 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
(continued)
34 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Introduction of complementary feeding in infants

with CMA
OFCs to a mixture of several solids, followed by
gradual build up to regular age-appropriate
serving size at home.
- Recommendation for a provision of guidance to
parents during the introduction of
complementary foods and consultation with a
dietitian.
- 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.
- 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.
- Recommendation against routine avoidance of
products with precautionary allergen labelling in
patients with FPIES.
CNSFP 20189 - Regular advice of adequate replacement of dairy
products, if introduced solid foods.
- Diversification not restricted except in cases of
other proven food allergies.
- Need of dietary advice even when CMA is
outgrown.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 - 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.
- No need to elimination of beef and similar meats,
always well cooked.
NICE 201918 - 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.
- 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.
ISPGHAN 202012 Not reported as recommendation.
- Introduction of supplementary foods one at a
time in small quantities, preferably during the
(continued)
Volume 15, No. 2, February 2022 35

Introduction of complementary feeding in infants

with CMA
breastfeeding but not before the infant is at least
17 weeks of age to prevent other allergies.
- No evidence to suggest any protective effect of
delaying introduction of solid foods, or even
potentially allergenic foods, beyond age 4–6
months.
Other guidelines2,10,11,17 Not reported.
Allergen immunotherapy (eg, oral, sublingual,
epicutaneous, baked milk diet)
WAO 20102 Recommendation against administration of OIT with
CM in patients with IgE-mediated CMA outside of
clinical research
BSACI 201417 Oral tolerance induction as a novel treatment option
to the small but clinically significant proportion of
affected individuals whose CMA persists.
SEICAP 201516 - OIT in IgE-mediated CMA: a promising treatment
to achieve desensitization in most cases, inducing
immune modulating changes, and promoting
tolerance.
- Always used in a center with experience in the
management of OIT and with the capacity to deal
with the possible adverse reactions.
- Long-term controlled trials are needed before
general use of OIT in patients with CMA.
- 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).
- 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.
- A need for further exploration of immunotherapy
with food allergens, although especially in
subcutaneous and oral immunotherapy
association with significant adverse effects.
Other guidelines8–15,18 Not reported.
Management of anaphylaxis and other
emergencies (eg, acute FPIES)
WAO 20102 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.
BSACI 201417 If a history of anaphylaxis, prescription of
intramuscular adrenaline for emergency use.
(continued)
36 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Management of anaphylaxis and other

emergencies (eg, acute FPIES)
SEICAP 201516 Diagnosis of patient with anaphylaxis is mentioned,
but not the management. AAF is recommended in
severe cases of anaphylaxis.
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 - 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.
- 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.
GPIFN and MAP 201910 If severe IgE-mediated CMA – anaphylaxis,
emergency treatment and admission.
NICE 201918 - Immediate ambulance transfer to Accident and
Emergency, if systemic symptoms or suspected
anaphylaxis with or without angioedema.
- 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.
- Written advice given to parents/carers on prompt
recognition and management of acute symptoms
following accidental or new exposures.
- Oral antihistamines available at home, in case of a
return of symptoms on reintroduction or any
accidental exposure.
- AAF recommended in management.
Other guidelines8,9,11–14 Not reported.
Nutritional deficiencies in CMA
EWPGAG 20108 Diets must be nutritionally balanced. A
supplementation with Ca must be evaluated.
WAO 20102 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.
ESPGHAN 201211 - Children with CMA beyond the first 12 months of
age need individualized nutritional advice.
Dietetic assessment is required to: (1) assess the
(continued)
Volume 15, No. 2, February 2022 37

Nutritional deficiencies in CMA

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.
- Supervision of the diet by a specialist dietician/
pediatrician trained in pediatric nutrition strongly
recommended.
- Chronic iron-deficiency anemia may be the sole
manifestation of CMA in infants and children.
- Failure to thrive is nonspecific but can have
severe consequences for a growing child.
BSACI 201417 A risk of a deficient calcium intake. Assessment of
Ca intake and advise of dietary or pharmaceutical
supplementation where appropriate, by dietitian.
SEICAP 201516 - A risk of lesser intake of nutrients than
recommended may affect growth and
development.
- 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.
CNSFP 20189 - 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.
- 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).
SEGHPN, AEPAP, SEPEAP, and SEICAP 201915 Growth (weight, length/height, and head
circumference) assessed at regular intervals based
on national standards. Main nutrients of concern:
calcium, protein, fat, vitamin D
NICE 201918 - A risk of inadequate nutritional intake,
malabsorption, and faltering growth in children if
food allergens that contribute essential nutrients
are eliminated (ie, iron).
- 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,
Other guidelines10,12–14 Not reported.
(continued)
38 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Probiotics for CMA

WAO 20102 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.
Finnish guidelines 201214 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.
Other guidelines8–13,15–18 Not reported.
Prebiotics for CMA
Not reported in any guidelines.2,8–18
Synbiotics for CMA
Not reported in any guidelines.2,8–18
Polyunsaturated fatty acids (PUFAs) for CMA
WAO 20102 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.
Other guidelines8–18 Not reported.
Other non-pharmacological treatment methods
(ie, Chinese herbal medicine) for CMA
WAO 20102 Not reported as recommendation. Studies are in the
preclinical stage to treat food allergy with a
traditional Chinese herbal remedy.
Other guidelines8–18 Not reported.
Table 3. (Continued) Summary of specific recommendations. AAAAI, American Academy of Allergy, Asthma and Immunology; AAF, amino acid
formula; AD, atopic dermatitis; AEPAP, Spanish Association of Paediatric Primary Care; BMD, bone mineral density; BSACI, British Society for Allergy and
Clinical Immunology; CM, cow’s milk; CMA, cow’s milk allergy; CMP, cow’s milk protein; CNSFP, Committee of Nutrition of the French Society of Paediatrics;
EHCF, extensively hydrolyzed casein formula; EHF, extensively hydrolyzed formula; EHWF, extensively hydrolyzed whey formula; ESPGHAN, European Society
of Paediatric Gastroenterology; EWGPAG, the Emilia-Romagna Working Group for Paediatric Allergy and that for Paediatric Gastroenterology; FPIES, food
protein-induced enterocolitis syndrome; GOR, gastro-esophagal reflux; GORD, gastro-esophagal reflux disease; 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; OFC, oral food challenge; OIT, oral
immunotherapy; PUFA, polyunsaturated fatty acids; RCT, randomized controlled trial; RDA, recommended dietary allowance; SEGHPN, Spanish Society of
Paediatric Gastroenterology, Hepatology, and Nutrition; SEICAP, Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology; SEPEAP, Spanish
Society of Extra-hospital Paediatrics and Primary Health Care; SF, soy formula; sIgE, specific immunoglobulin E; SPT, skin prick tests, WAO, World Allergy
Organization

not achieve a median score of 60% for this domain. was achieved only by 1 set of guidelines (NICE).18
The main reason for such low scores was a lack of The median score for 8 guidelines8–12,14–16 did
assessment of the views and preferences of the not exceed 44%. The main reasons for low scores
target population (patient, public, etc.). for this domain were unclear description of
strengths and limitations of the body of evidence
Rigor of development (domain 3) and a lack of reporting of the procedures for
For this domain, the median score was 30% (Q1- updating the guidelines.
Q3: 15–67%). The highest median score (100%)
Volume 15, No. 2, February 2022 39

Clarity of presentation (domain 4) oral food challenge (OFC) and/or home

The median score for this domain was 92% reintroduction of baked-milk for diagnosis of
(Q1-Q3: 81–100%). Five guidelines (AAAAI and I- CMA was recommended mostly in cases with
FPIES, BSACI, NICE, Spanish on non-IgE- suspicion of non-IgE-mediated CMA in four
mediated CMA and WAO)2,13,15,17,18 achieved guidelines;10,11,17,18 in 3 guidelines, it was
the highest median score (100%). Only 1 set of advised regardless of IgE-mechanism,8,11,12,14
guidelines14 did not exceed a median score of and, in 4 guidelines,2,13,15,16 in only defined
60%, in which the main reason for the low score specific cases. Skin prick or specific serologic IgE
was the lack of easily identifiable key tests were recommended only if IgE-mediated
recommendations. CMA was suspected according to 9 guide-
lines;2,10–13,15–18 however, in 1 set of guidelines, it
Applicability (domain 5) was recommended regardless of type of CMA
The median score for this domain was 68% (Q1- reaction.8
Q3: 57–75%). Only 1 set of guidelines (NICE)18
achieved the highest possible score (100%). The Maternal elimination of cow’s milk during
median score for 4 guidelines9,12,14,15 did not breastfeeding
exceed 60% (Q1-Q3: 14–58%). The main limita- A continuation of breastfeeding with a maternal
tion was a lack of or not clearly described facilita- cow’s milk elimination diet was recommended in 8
tors and barriers for application of these guidelines.8,10–12,14–16,18 Six of the included
guidelines. guidelines10,11,13,15,16,18 recommended against
a maternal elimination diet if the infant was
Editorial independence (domain 6) asymptomatic on breastfeeding alone; in an
For this domain, the median score was 75% additional one,8 it was recommended against
(Q1-Q3: 69–100%). Five guidelines (AAAAI and I- elimination diet in case of mild symptoms.
FPIES, BSACI, GPIFN and MAP, Indian Society of Supplementation of the maternal elimination diet
Pediatric Gastroenterology [ISPGHAN], and with calcium was recommended in 7
NICE)10,12,13,17,18 achieved the highest possible guidelines,2,10–12,15,16,18 including 3,10,15,18 that
median score (100%). Three guidelines2,9,14 had also recommended supplementation of vitamin D.
a median score below 60%. The low score was
mainly due to the lack of reporting of the Use of cow’s milk formula
competing interests of the guideline Extensively hydrolyzed formulas (EHFs) were rec-
development group members. ommended as a first-line treatment in formula-fed
children with CMA in 5 guidelines;2,11,13,16,18
Overall quality score however, in 3 guidelines,10,12,15 EHFs were only
The median overall score was 70% (Q1-Q3: 58– recommended for infants with mild-to moderate
89%). The maximum possible overall score was CMA. Amino acid formula was recommended in the
100% and it was achieved by four guidelines management of children with severe CMA symp-
(AAAAI and I-FPIES, BSACI, NICE, WAO).2,13,17,18 toms in 6 guidelines,8,10,12,15,17,18 and/or in those
For 3 guidelines,9,10,14 the median overall score with a high risk of anaphylaxis according to 4
did not achieve 60% (Q1-Q3: 17–50%). guidelines,2,11,16,18 and/or in case of no response
to or refusing EHF according to 5
Summary of recommendations guidelines.11,12,15–17

Table 3 provides a summary of specific

recommendations listed separately for each Use of plant-based formula
recommendation or clinical indication. Rice-based formula was recommended as the
treatment of choice in selected infants according
Diagnosis to 3 guidelines,8,11,16 and, in 1 additional set of
Recommendations for clinical history and phys- guidelines,15 hydrolyzed rice formula was
ical examination to establish suspicion of CMA recommended as an alternative if the infant
were presented in 9 guidelines.8,10–13,15–18 Use of refuses or does not respond to EHF. Use of soy
40 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

formula was not recommended in infants below 6 summarized specific recommendations for the
months of age in 10 guidelines.8–12,14–18 diagnosis and management of CMA. While the
quality of the CMA guidelines published in the
Use of plant based beverages and mammalian past 10 years varied, the median score for
milks almost all domains exceeded 60%, except the
rigor of development domain, that had the
Use of other mammalian milks was not recom-
median score 30%; Q1-Q3: 15–67%. The clarity
mended in children with CMA according to 7
of presentation domain had the highest median
guidelines;8,11,12,15–18 however, in 1 of these,16 an
score (92%; Q1-Q3: 81–100%). Three guidelines
exception was made for equine milk with modified
(BSACI, NICE, WAO) achieved the highest rat-
fat content, which could be used as an alternative.
ings (100%) in at least 3 domains and for the
Five guidelines11,15–18 recommended against use
overall score.
of soy plant-based beverage in infants with CMA.
According to 3 guidelines,10,17,18 use of rice plant-
based beverage is not advised in children under Agreement with other systematic reviews
4.5 years of age. Two guidelines,11,15 recommend
Compared to the previous similar systematic
against any plant-based beverages.  ski et al,1 which assessed CMA
review by Ruszczyn
guidelines published from 2010 to November
Acquisition of tolerance 2015, we included fewer full-text articles (12
Eight guidelines8–10,12,13,15,17,18 recommended compared to 15) despite the longer years of
periodic re-assessments of acquisition of tolerance publication inclusion period. This is explained by
with oral food challenges in children with CMA; our decision to only include the guidelines
however, the recommended period varied across endorsed by the recognized scientific societies or
the documents. According to 4 guidelines,8,13,15,16 organizations. Similar to Ruszczyn  ski et al,1 we
complementary feeding should be introduced found the clarity of presentation to be the
similarly as in healthy children. Five guidelines domain with the highest median score. We also
recommended supervision of the elimination diet found an improvement over time in the score for
by a dietitian (ie, assessment of one or more the applicability domain (68%, Q1-Q3: 57–75%)
specific nutrients intake).10,11,16–18 compared to the previous systematic review1
(32%, range: 6–100%).
Pre-, pro- and synbiotic and nutrient In the recent, non-systematic review of CMA
supplementations guidelines by Munblit et al,19 commercial
There were no recommendations with regard to involvement was reported as an important issue;
probiotics, prebiotics, synbiotics, polyunsaturated 81% of authors in nine guidelines had financial
fatty acids, or other non-pharmacological methods conflict of interest with formula manufacturers
(ie, Chinese herbal medicine) for management of and three CMA guidelines were directly
CMA. supported by formula manufacturers. However,

DISCUSSION these 3 guidelines20–22 with financial support

from pharmaceutical companies were not
This systematic review assessed CMA guide-
endorsed by any scientific organizations. In our
line quality using the AGREE II instrument and
review, the editorial independence (domain 6)
Volume 15, No. 2, February 2022 41

was of good quality in the majority of included Some of the authors who contributed to this
guidelines. Sixty-seven percent of authors in six systematic review were also authors of some of
guidelines9–11,13,15,17 declared conflicts of the included guidelines. However, the appraisal of
interest, in two2,14 individual conflict of interest methodological quality using the AGREE II in-
was not reported, in the other four,8,12,16,18 there strument was performed by independent
was nothing to declare. reviewers.

The AGREE-II instrument is widely used to eval- CONCLUSIONS

uate the methodological quality and transparency
of guidelines that are used in clinical practice.6,23 It The majority of the included CMA guidelines
was also designed to inform development and published from 2010 to 2020 were of good or very
reporting requirements for practice guidelines (ie, good quality. However, the weakest domain was
prioritization of the update of high quality the rigor of development, mostly due to the poorly
guidelines and improvement of quality of described strengths and limitations of the body of
guidelines during update, if necessary).5 Rigorous evidence and the procedure for updating the
development and strategies for reporting are key guidelines.
predictors of successful implementation of the
recommendations.24 Although the AGREE-II in- Abbreviations
strument focuses on methodological issues around AAAAI, Adverse Reactions to Food Committee of the
guideline development and reporting, these issues American Academy of Allergy, Asthma and Immunology;
are insufficient to ensure that recommendations are AGREE, Appraisal of Guidelines for Research and
appropriate and valid, as methodological rigor and Evaluation; AHRQ, Agency for Healthcare Research and
Quality; BSACI, British Society for Allergy & Clinical
validity are not necessarily correlated.25 Therefore,
Immunology; CMA, cow’s milk allergy; CI, confidence
when a clinician is choosing guidelines, some other interval; DRACMA, Diagnosis and Rationale for Action
factors may need to be considered according to the against Cow’s Milk Allergy; EAACI, European Academy of
individual clinical situation, including guideline Allergy and Clinical Immunology; EHFs, Extensively
applicability (that may differ with regard to hydrolyzed formulas; ESPGHAN, European Society for
geographical region and/or available resources), Pediatric Gastroenterology, Hepatology, and Nutrition;
FPIES, food protein-induced enterocolitis syndrome; GIM,
scope of guidelines, and year of publication Global Index Medicus; GIN, Guideline International
(preferably updated no later than 2 to 5 years Network; GPIFN, General Practice Infant Feeding Network,
from issue date).5 GRADE, Grading of Recommendations Assessment,
Development and Evaluation; I-FPIES, International FPIES
Association; ICC, intraclass correlation coefficient; ISP-
Strengths and limitations GHAN, Indian Society of Pediatric Gastroenterology; MAP,
The search was limited to guidelines published Milk Allergy in Primary; NICE, National Institute for Health
and Care Excellence; OFC, oral food challenge; PRISMA,
in English only (risk of language bias). No blinding Preferred Reporting Items for Systematic Reviews and
to the authors/organizations was implemented. Meta-Analyses; SIGN, Scottish Intercollegiate Guidelines
However, the review team was well aware of Network; TRIP, Turning Research into Practice; WAO,
available guidelines; thus, blinding, while feasible, World Allergy Organization.
might have been artificial. We used the AGREE II
instrument to appraise all guidelines. However, the Ethics approval
AGREE methodology has its limitations. For Ethics approval was not required for this study as it is a
example, it does not provide a threshold for systematic review.
discrimination between good- and poor-quality
guidelines, thus, the judgment is left to the ap-
Author’s contribution
praisers. Of note, previous reviewers/appraisers,
HS, AS, AH, and MR initially conceptualized the study. AS,
including members of the current panel,1 have AH, MR, and LD contributed to data collection. AS, AH, and
provided input as to an appropriate quality MR also performed data analysis and interpretation. AS
threshold (ie, standardized domain score of and HS drafted the first version of the manuscript. All
above 60%). authors approved the final version of the manuscript.
42 Stró_zyk et al. World Allergy Organization Journal (2022) 15:100613
[Link]

Funding Pharmaceuticals, Novartis. A Fiocchi – Abbott, Danone. G

Medical University of Warsaw. Lack – FARE, National Peanut Board (NPB), The Davis
Foundation, Action Medical Research, UK Food Standards
Agency, Medical Research Council, DBV Technologies,
Informed consent Mission Mighty Me, Novartis, Sanofi-Genyzme, Regeneron,
Not applicable. ALK-Abello, Lurie Children’s Hospital. A Nowak-Wegrzyn –
Nestle, Nutricia, Novartis, Gerber, Aimmune. N
Papadopoulos – Novartis, Nutricia, HAL Allergy, Menarini/
Consent for publication
Faes Farma, Sanofi, Mylan/Meda, Biomay, AstraZeneca,
All authors approved the final version and its submission.
GSK, MSD, ASIT Biotech, Boehringer Ingelheim,
Declaration of competing interest Gerolymatos International SA, Capricare. M Said – Nestle,
AS has no potential conflict of interest to declare. AH has Nutricia, Abbott, Bayer for Anaphylaxis Australia. J Spergel
participated as a speaker for companies manufacturing – DBV Technologies, Regeneron, Sanofi, and Aimmune. H
infant formulas, ie, Danone, Nestle, Nestle Nutrition Szajewska – Ausnutria, Cargill, Danone, Else Nutrition,
Institute, Nutricia, and Mead Johnson. MR has participated Hipp, Nestle, and Nestle Nutrition Institute. Y Vandenplas –
as a speaker for companies manufacturing infant formulas, Abbott Nutrition, Biogaia, Biocodex, By Heart, CHR
ie, Danone, Nestle, Nestle Nutrition Institute, Nutricia, and Hansen, Danone, ELSE Nutrition, Friesland Campina, Hero,
Mead Johnson. LD have no conflicts of interest to declare. Hypocrata, Nestle Health Science, Nestle Nutrition Institute,
AF reports currently sponsored research by Danone/ Nutricia, Mead Johnson Nutrition, Orafti, Phacobel,
Nutricia, the Netherlands, Sanofi/Regeneron, U.S.A., Hipp, Phathom Pharmaceuticals, Sari Husada, United
Germany, Ferrero, Italy. He is on advisory boards of Pharmaceuticals (Novalac), Wyeth, Yakult. C Venter –
Danone, Stallergenes, France, Menarini, Italy, Abbott, Reckitt Benckiser, Nestle Nutrition Institute, Danone,
U.S.A., DBV, U.S.A. - France, Novartis, Switzerland, and Abbott Nutrition, Else Nutrition, and Before Brands, DBV
Hipp. ANW has participated as consultant and/or speaker Technologies. S Waserman – Novartis-basic science work
for companies manufacturing infant formulas, ie, Danone, on peanut allergy, Aimmune-peanut OIT trial, Medical
Nestle, and Nestle Nutrition Institute. RS has participated as Advisor to Food Allergy Canada, and Pfizer, Bausch, Kaleo
consultant and/or speaker for companies manufacturing consultant for epinephrine autoinjectors. GWK Wong –
infant formulas, ie, Abbott, Danone, Else Nutrition, Nestle, Nestle, Danone.
Nestle Nutrition Institute. JMS has participated as
consultant for Abbott Nutrition and Nutricia. YV has Acknowledgements
participated as a clinical investigator, and/or advisory We thank Urszula Malinowska for her help with statistical
board member, and/or consultant, and/or speaker for analysis.
Abbott Nutrition, Biogaia, By Heart, CHR Hansen, Danone,
ELSE Nutrition, Friesland Campina, Nestle Health Science,
Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, Appendix A. Supplementary data
Phathom Pharmaceuticals, United Pharmaceuticals Supplementary data to this article can be found online at
(Novalac), Wyeth. CV has participated as a speaker for [Link]
companies manufacturing infant formulas, ie, Danone,
Nestle, Nestle Nutrition Institute, Nutricia, and Mead
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