ESPGHAN Position Paper On Management and Follow Up.29

Societal Paper: Gastroenterology: Celiac Disease
ESPGHAN Position Paper on Management and Follow-

up of Children and Adolescents With Celiac Disease
*‡‡‡‡‡‡
Maria Luisa Mearin, MD, PhD, †‡Daniel Agardh, MD, PhD, §||¶Henedina Antunes, MD, PhD,
#
Abdul Al-toma, MD, PhD, **Renata Auricchio, MD, PhD, ††Gemma Castillejo, MD, PhD,
‡‡
Carlo Catassi, MD, PhD, §§Carolina Ciacci, MD, **Valentina Discepolo, MD, PhD,
||||
Jernej Dolinsek, MD, PhD, ¶¶##Ester Donat, MD, PhD, ***Peter Gillett, MbChB,
†††
Steffano Guandalini, MD, PhD, ‡‡‡Steffen Husby, MD, DMSc, §§§||||||Sibylle Koletzko, MD,
¶¶¶
Tunde Koltai, BEng, ###****Ilma Rita Korponay-Szabó, MD, PhD, ††††‡‡‡‡§§§§Kalle Kurppa, MD, PhD,
‡‡
Elena Lionetti, MD, PhD, ||||||||¶¶¶¶Karl Mårild, MD, PhD, ####Eva Martinez Ojinaga, MD, PhD,
*
Caroline Meijer, MD, ‡‡Chiara Monachesi, MSc, PhD, ####Isabel Polanco, MD, PhD,
*****
Alina Popp, MD, PhD, †††††Maria Roca, BSc, PhD, ‡‡‡‡‡Alfonso Rodriguez-Herrera, MD, PhD,
§§§§§
Raanan Shamir, MD, ||||||||||Ketil Stordal, MD, PhD, **Riccardo Troncone, MD, PhD,
¶¶¶¶¶
Francesco Valitutti, MD, PhD, #####Anita Vreugdenhil, MD, PhD, ******Margreet Wessels, MD, PhD,
††††††
Penny Whiting, MSc, PhD; on behalf of the ESPGHAN Special Interest Group on Celiac Disease
ABSTRACT
There is a need for consensus on the recommendations for follow-up of What Is Known
children and adolescents with celiac disease.
Objectives: To gather the current evidence and to offer recommendations • There is a need for consensus on the methods
for follow-up and management. regarding follow-up children and adolescents with
Methods: The Special Interest Group on Celiac Diseases of the European celiac disease.
Society of Paediatric Gastroenterology Hepatology and Nutrition formu-
lated ten questions considered to be essential for follow-up care. A literature
What Is New
search (January 2010–March 2020) was performed in PubMed or Medline.
Relevant publications were identified and potentially eligible studies were
assessed. Statements and recommendations were developed and discussed • The Special Interest Group on Coeliac Diseases of
by all coauthors. Recommendations were voted upon: joint agreement was the European Society of Paediatric Gastroenterol-
set as at least 85%. ogy Hepatology and Nutrition (ESPGHAN) formu-
Results: Publications (n = 2775) were identified and 164 were included. lated 10 questions considered to be essential for the
Using evidence or expert opinion, 37 recommendations were formulated follow-up care.
on: The need to perform follow-up, its frequency and what should be • Based on the available evidence from the litera-
assessed, how to assess adherence to the gluten-free diet, when to expect
ture or on expert opinion, 37 recommendations to
catch-up growth, how to treat anemia, how to approach persistent high
improve follow-up were formulated.
serum levels of antibodies against tissue-transglutaminase, the indication
• Gaps in knowledge were identified that should be
to perform biopsies, assessment of quality of life, management of children
investigated to further improve follow-up.
with unclear diagnosis for which a gluten-challenge is indicated, children
with associated type 1 diabetes or IgA deficiency, cases of potential celiac
disease, which professionals should perform follow-up, how to improve the
communication to patients and their parents/caregivers and transition from Key Words: celiac disease, children and adolescents, follow-up, position
pediatric to adult health care. paper European Society of Paediatric Gastroenterology Hepatology and
Conclusions: We offer recommendations to improve follow-up of children Nutrition (ESPGHAN)
and adolescents with celiac disease and highlight gaps that should be inves-
tigated to further improve management. (JPGN 2022;75: 369–386)
Received December 22, 2021; accepted June 10, 2022. Clinical Center (2CA Braga), Hospital de Braga, the ||Life and Health Sci-
From the *Willem-Alexander Children’s Hospital, Leiden University Medical ences Research Institute (ICVS), the ¶ICVS/3B’s Associate Laboratory and
Centre, Leiden, The Netherlands, the †Unit of Celiac Disease and Diabe- School of Medicine, University of Minho, Braga, Portugal, the #Department
tes, Department of Clinical Sciences, Lund University, Lund, Sweden and of Internal Medicine and Gastroenterology, St. Antonius Hospital, Nieu-
Unit of Pediatric Gastroenterology, Department. of Pediatrics, Skåne Uni- wegein, The Netherlands, the **Department of Translational Medical Sci-
versity Hospital, Malmö, Sweden, the ‡Unit of Pediatric Gastroenterology, ences, European Laboratory for the Investigation of Food-Induced Diseases,
Department of Pediatrics, Skåne University Hospital, Malmö, Sweden, the University of Naples Federico II, Naples, Italy, the ††Pediatric Gastroenter-
§Paediatric Gastroenterology Hepatology and Nutrition Unit, Academic ology Unit, Hospital Universitario Sant Joan de Reus, Institut d’Investigació
JPGN • Volume 75, Number 3, September 2022 369

Mearin et al JPGN • Volume 75, Number 3, September 2022
I t is generally accepted that clinical follow-up of children and ado-

lescents with celiac disease (CD) is necessary to assess growth and
development, resolution of their symptoms and possible complications
consisted of pediatric gastroenterologists, a methodologist (PW), two
adult gastroenterologists (CCi, AAT), a biologist (MR), and a repre-
sentative of the Association of European Celiac Societies (AOECS)
and monitor compliance to the treatment with a gluten-free diet (GFD). (TK). During several group meetings, 10 focused clinical ques-
However, the current follow-up approach is largely based on local tions considered to be essential for follow-up care were formulated
practice and opinion with lack of evidence-based approaches. The (Table 1). Smaller working groups, consisting of 3 to 5 coauthors,
responses to an enquiry of the Special Interest Group (SIG) on CD of focused on each clinical question. All questions were then discussed
the European Society of Paediatric Gastroenterology Hepatology and jointly at two face-to-face meetings and at eight videoconferences.
Nutrition (ESPGHAN) among pediatricians and pediatric gastroenter-
ologists across Europe showed significant variation in the methods of Search for and Inclusion of Studies
following-up their patients and offered scope for improvement (1). Eligibility Criteria
The aim of this position paper was to therefore gather and eval- We searched in PubMed or in Medline for articles published in
uate the current evidence for the management and follow-up of CD English from January 2010 to March 2020, relevant to children and
in children and adolescents and offer recommendations on this topic. adolescents (<18 years) diagnosed with CD according to the ESP-
GHAN criteria (2,3). However, if a paper published before or after
these dates was considered particularly important for an individual
METHODS question, it was also included and this information was specified in
In 2019, ESPGHAN established a working group within the the corresponding search results for the question, both in the Sum-
SIG on CD to develop a position paper on the management and mary Table of the Literature (Appendix, Supplemental Digital Con-
follow-up of children and adolescents with CD. The working group tent, http://links.lww.com/MPG/C861) and in the individual section
Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Tarragona, Spain, Disease are given in https://www.espghan.org/our-organisation/council-
the ‡‡Department of Specialized Clinical Sciences and Odontostomathol- and-committees/gastroenterology-committee.
ogy, Polytechnic University of Marche, Ancona, Italy, the §§Center for Address correspondence and reprint requests to Maria Luisa Mearin,
Celiac Disease, Gastrointestinal Unit, AOU San Giovanni di Dio e Ruggi Department of Paediatrics, Willem-Alexander Children’s Hospital,
D’Aragona, University of Salerno, Salerno, Italy, the ||||Gastroenterology, Leiden University Medical Center, PO 9600, 2300 RC Leiden, The
Hepatology and Nutrition Unit, Department of Pediatrics, University Medi- Netherlands (e-mail: l.mearin@lumc.nl).
cal Centre Maribor, Maribor, Slovenia, the ¶¶Pediatric Gastroenterology The guideline was funded by ESPGHAN and was developed in collabora-
and Hepatology Unit, Hospital Universitari i Politècnic La Fe, the ##Celiac tion with AOECS.
Disease and Digestive Immunopathology Unit, Instituto de Investigación Disclaimer: ESPGHAN is not responsible for the practices of physicians
Sanitaria La Fe, Valencia, Spain, the ***Department of Paediatric Gas- and provides guidelines and position papers as indicators of best prac-
troenterology, Royal Hospital for Children and Young People, Edinburgh, tice only. Diagnosis and treatment is at the discretion of physicians.
United Kingdom, the †††Department of Pediatrics, Section of Gastro- Mearin received receipt of grants/research supports from Research Grant Euros-
enterology, Hepatology and Nutrition, University of Chicago Medicine, pital, ThermoFisher and BioHit and served as member of advisory board
Chicago, IL, the ‡‡‡Hans Christian Andersen Children’s Hospital, Odense and consultancy and speaker from ThermoFisher. Agardh received receipt of
University Hospital, Odense, Denmark, the §§§Department of Pediatrics, grants/research supports from Novo Nordisk Foundation and served as mem-
Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s ber of advisory board from Takeda and ThermoFischer. Antunes received
Hospital, University Hospital, LMU Klinikum Munich, Munich, Germany, receipt of payment/honorarium for lectures from Danone, Catassi received
the ||||||Department of Pediatrics, Gastroenterology and Nutrition, School of receipt of payment/honorarium for consultation from Dr Schar Food. Dolin-
Medicine Collegium Medicum University of Warmia and Mazury, Olsz- sek received receipt of payment/honorarium for lectures from Medis, Abbot,
tyn, Poland, the ¶¶¶Association of European Coeliac Societies (AOECS), Merit. Guandalini served as member of advisory board from ExeGIPharma,
Imaware. Koletzko received receipt of grants/research supports from Mead-
the ###Heim Pál National Paediatric Institute, Budapest, Coeliac Disease
Johnson, Biogaia; served as member of advisory board from Abbvie,
Center, the ****Department of Paediatrics, University of Debrecen, Debre-
Danone, Jannsen, Sanofi, Takeda; receipt of payment/honorarium for lec-
cen, Hungary, the ††††Tampere Center for Child, Adolescent and Maternal
tures from Danone, Mead-Johnson, Nestlé Nutrition, Pfizer, Takeda; receipt
Health Research, Tampere University, the ‡‡‡‡Department of Pediatrics,
of payment/honorarium for consultation from Danone. Korponay-Szabó
Tampere University Hospital, Tampere, Finland, the §§§§University Con-
other support from patent on celiac disease rapid test licensed to Labsystems
sortium of Seinäjoki, Seinäjoki, Finland, the ||||||||Department of Pediatrics,
Oy, Vantaa, Finland. Kurppa received receipt of grants/research supports
Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden, from Finnish Pediatric Foundation, Päivikki, and Sakari Sohlberg Founda-
the ¶¶¶¶Department of Pediatric Gastroenterology, Queen Silvia Children’s tion; served as member of advisory board from Finnish Coeliac Society;
Hospital, Gothenburg, Sweden, the ####Department of Pediatric Gastro- receipt of payment/honorarium for lectures from Thermo Fisher; and receipt
enterology and Nutrition, La Paz University Hospital, Madrid, Spain, the of payment/honorarium for consultation from Takeda. Rodriguez-Herrera
*****University of Medicine and Pharmacy “Carol Davila,” National Insti- received other support from Patent and detecting gluten peptides in human
tute for Mother and Child Health, Bucharest, Romania, the †††††Celiac fluids, March 29, 2019—Universidad de Sevilla. Shamir received receipt of
Disease and Digestive Immunopathology Unit, Instituto de Investigación grants/research supports from Helmsley Foundation; served as member of
Sanitaria La Fe, Valencia, Spain, the ‡‡‡‡‡Department of Paediatrics, Saint advisory board: Nestle Nutrition Institute, Teva; receipt of payment/hono-
Luke’s General Hospital, Kilkenny, Ireland, the §§§§§Institute for Gastro- rarium for lectures from Abbott, Nutricia, Nestle Nutrition Institute; receipt
enterology, Nutrition and Liver Diseases, Schneider Children’s Medical of payment/honorarium for consultation from Abbott, Else, Nutricia, Nestle
Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Nutrition Institute and Stock shareholder from NGS. Ciacci received receipt
the ||||||||||Department of Pediatric Research, Division of Paediatric and of honoraria or consultation fees from Takeda, GSK, Mediserve, Biogen
Adolescent Medicine, Oslo University Hospital, University of Oslo, Oslo, Celltrion. The remaining authors report no conflicts of interest.
Norway, the ¶¶¶¶¶Pediatric Unit, Salerno University Hospital, Salerno, Supplemental digital content is available for this article. Direct URL cita-
Italy, the #####Department of Paediatrics, NUTRIM School of Nutrition tions appear in the printed text, and links to the digital files are provided
and Translational Research in Metabolism, Maastricht University Medical in the HTML text of this article on the journal’s Web site (www.jpgn.org).
Centre, Maastricht, The Netherlands, the ******Department of Pediatrics, Copyright © 2022 by European Society for European Society for Pediatric
Rijnstate Hospital, Arnhem, The Netherlands, and the ††††††Population Gastroenterology, Hepatology, and Nutrition and North American Soci-
Health Sciences, Bristol Medical School, University of Bristol, Bristol, ety for Pediatric Gastroenterology, Hepatology, and Nutrition.
England.‡‡‡‡‡‡The details of ESPGHAN Special Interest Group on Celiac DOI: 10.1097/MPG.0000000000003540
370 www.jpgn.org
JPGN • Volume 75, Number 3, September 2022 ESPGHAN Among Children and Adolescents With Celiac Disease
TABLE 1. Questions and recommendations on the follow-up of children and adolescents with celiac disease
Questions and recommendations
1. Is follow-up and management of celiac disease needed?
We recommend follow-up for children and adolescents after the diagnosis of CD has been established.
2. Who should do the follow-up of which patients and which is the role of the dietitian? What is the role of self-care and E-health?
The regular follow-up visits of children with CD are preferably carried out by a physician or a dietitian experienced in managing the disease. Local conditions and
practices may determine how to apply these recommendations, but self-care treatment without access to adequate health care and dietitians is not recommended.
3. What should be the frequency of follow-up and what should be assessed?
3.1. The first follow-up visit should be scheduled 3–6 months after CD diagnosis, but with easy access to the celiac service if earlier advice is needed, and
sooner review if there are concerns regarding how the family is coping with the diet, if there are ongoing issues with growth or persistent symptoms or a
need to repeat bloodwork earlier. Subsequent visits should be every 6 months until normalization of TGA levels, and every 12–24 months thereafter.
3.2. During follow-up patients should be evaluated for:
3.2.I. Gastrointestinal and extraintestinal signs and symptoms.
3.2.II. Anthropometric measurements and growth parameters.
3.2.III. IgA-TGA using the same assay as at diagnosis as a surrogate marker for improvement/healing of the small-bowel mucosa. IgG based tests and RIA
based IgA-TGA measurements are not suitable for follow-up in IgA sufficient patients. IgA insufficient patients with CD should be followed with IgG
based tests.
3.2.IV. A complete blood cell count, micronutritional status (eg, hemoglobin, iron, vitamin B12, and vitamin D levels) and ALT measurements, should
be performed after clinical evaluation at time of diagnosis. Any abnormality should be followed and deficiencies corrected until normalization. If
abnormalities persist, additional diagnoses should be considered and appropriately investigated.
3.2.V. Screening for thyroid disease with TSH and thyroxine (and autoantibodies if indicated) may be considered during follow-up after clinical evaluation
at the discretion of the clinician.
3.2.VI. Routine bone-density screening is not recommended.
3.2.VII. HBV antibody levels may be measured in previously immunized patients if this is considered important in the population. A booster dose should be
given if inadequate levels are present.
4. Adherence to the gluten-free diet
4.1. Should the adherence to the diet be assessed during follow-up and if so, how?
Since a gold standard method is still missing, adherence to the GFD should be assessed multidimensionally through a careful evaluation of symptoms,
dietary interview, or dietary questionnaires and laboratory tests.
4.2. What is the role of detection of gluten immunogenic peptides (GIPs) in the assessment of the compliance to the gluten-free diet?
Further data are needed before a recommendation on stool/urinary GIPs determination to assess compliance to the GFD in clinical practice can be formulated.
5. Common issues during follow-up and management of CD
5.1. When to expect catch-up growth?
In the prepubertal/pubertal child, if significant catch-up growth in height is not reached within 1 year after initiating the GFD, despite strict dietary
adherence, additional investigations, and consultation with a pediatric endocrinologist are recommended to rule out other causes of short stature.
5.2. Is a lactose-free diet necessary?
We recommend a trial with lactose-reduced diet only in CD patients with symptoms suggestive of lactose intolerance (such as ongoing diarrhea, abdominal
pain, or gassiness) despite adhering to the GFD.
5.3. Chronic tiredness in well-controlled celiac disease?
There are no specific recommendations for chronic fatigue in CD except to follow a GFD.
5.4. Irritable bowel syndrome (IBS) in celiac disease?
IBS in children with CD on a GFD should be treated similarly as in children without CD.
5.5. How to treat anemia and/or sideropenia?
Young children with anemia due to iron, folate, or vitamin B12 deficiency should receive supplementation in addition to the GFD, since improvement over
time may take too long in these children in a critical period of brain development and rapid catch-up growth. A low threshold for supplementation may
also be considered for older children. The disappearance of anemia should be confirmed in all cases. Adherence to the GFD should be checked, and
other causes for anemia should be excluded in children who do not recover despite a strict GFD. Concerning sideropenia without anemia, an expectant
attitude may be appropriate on GFD as long as there is improvement in iron stores without supplementation.
6. Specific issues during follow-up and management
6.1. How to approach persistent high serum levels of antibodies against tissue-transglutaminase (TGA)?
Lack of decreasing IgA-TGA levels after 6–12 months on a GFD or persisting positive IgA-TGA levels should be assessed by carefully reviewing dietary
compliance and testing IgA-TGA using the same test from the same manufacturer.
6.2. When is it necessary to (re)biopsy?
Routine assessment of mucosal healing by small-bowel biopsies is not recommended in children with CD following a GFD. We recommend considering (re)
biopsy only in selected CD cases; based on specific clinical grounds, for example, when doubts about the original diagnosis or suspicion of occurrence
of an additionalcondition.
6.3. Refractory celiac disease in children: does it exist?
We recommend properly investigating other causes of an apparent “refractory CD” in children, including ongoing inadvertent ingestion of gluten and other
possible concomitant enteropathies, such as Crohn’sdisease, autoimmune enteropathy, small-bowel bacterial overgrowth, cow’s milk protein allergy and
pancreatic insufficiency.
7. Should the quality of life (QOL) be assessed during the follow-up and if so, how?
We recommend assessing the HRQOL of children and adolescents with CD during follow-up by means of validated, CD-specific HRQOL questionnaires.
These questionnaires may be administrated during or before the follow-up consultations, either on paper or by e-consultation. The results should be
interpreted by the physician together with the parents/care givers, and if age adequate, also with the child.
8. Should follow-up of children with special situations be different from the one in the average CD patient?
www.jpgn.org 371
TABLE 1. Continued
Questions and recommendations
8.1. In cases of unclear diagnosis
In cases of uncertain CD diagnosis, HLA typing should be performed before gluten-challenge to detect children in whom the occurrence of CD is
unlikely.
8.1.1. How to perform a gluten-challenge?
8.1.1.II. To avoid unnecessary exposure to gluten in CD children with an early response to the challenge serum IgA-TGA determination may be considered
1 month after starting and this should be measured every 3 months during daily ingestion of 10–15 g of gluten for 12 months. Earlier evaluation is
recommended in case of suggestive symptoms.
8.1.1.IV. In the absence of symptoms or specific CD-antibodies after 1 year of formal gluten-challenge, the child should be allowed to have a normal
gluten-containing diet and follow-up visits with measurement of specific celiac-antibodies should be offered annually or every other year. Earlier
evaluation is recommended in case of suggestive symptoms.
8.2. In children with associated type 1 diabetes (T1D)?
8.2.I. We recommend the same frequency and follow-up tests in children with CD and T1D as inchildren with isolated CD, with (additional) special
attention to test for thyroid involvement and diabetic retinopathy.
8.2.II. We recommend developing the follow-up plan in conjunction with an endocrinologist/diabetologist and a dietitian, also considering the need for
psychological and social support.
8.3. In children with associated IgA deficiency?
8.3.I. We recommend the same follow-up practice in IgA deficient children with CD than in IgA sufficient children with CD.
8.3.II. At follow-up visits CD-specific IgG antibodies(TGA, EMA or DGP)should be assessed.
8.4. In cases of potential CD?
8.4.I. In the presence of symptoms attributable to gluten, a trial of a GFD should be discussed with the family.
8.4.II. If left on a regular diet, we recommend annual follow-up visits, with attention towards growth and nutritional status, including bone health.
8.4.III. Duodenal biopsies should be performed in case of appearance of symptoms and/or of increased elevation of the CD antibody levels. In other cases
with persistent serological positivity, on individual basis and in dialogue with the patient/caregivers, duodenal biopsies may be considered during
follow-up.
9. How to improve communication: To parents? To patients?
9.1. Communication of diagnostic certainty to parents and children
The pediatric gastroenterologist/pediatrician should communicate to the patient and the parents/caregivers that the CD diagnosis is made with certainty
and according to current evidence-based guidelines. All results (serology, histopathology, HLA if done) with dates of performance should be provided in
writing for later proof of CD diagnosis.
9.2. Patient empowerment
9.2.I. The pediatric gastroenterologist/pediatrician and dietitian should communicate the need for a lifelong GFD and regular monitoring and facilitate
access to professional dietary counseling knowledgeable on GFD.
9.2.II. We recommend providing education using oral and written information (leaflets, E-learnings etc.)about the disease and benefits of adhering to the
diet. Later health risks should be brought into perspective without inducing fear or anxiety considering the patient’s age and complications at the time of
diagnosis and compliance with dietary recommendations.
9.3. Emotional and social support
9.3.I. Emotional and practical support from personal contact with other individuals with CD (Celiac/parent support groups, patient organizations, etc.)
should be provided to reduce eventual feelings of social isolation.
9.3.II. Patients, especially adolescents, perceiving lifestyle changes related to CD diagnosis, including the GFD and emotional coping, as difficult warrant
particular attention and support.
10. How to organize the transition from pediatric care to adult health care?
Even though current data is insufficient, we recommend a formal transfer of medical care of an adolescent with CD to facilitate the transition to adult care.
The transfer should be structured and, at minimum, include a transition letter or “celiac passport” providing data on the basis of diagnosis, follow-up,
anthropometric data, possible comorbidities and dietary adherence level.
CD = celiac disease; GFD = gluten-free diet; GIPs = gluten immunogenic peptides; HLA = human leukocyte antigen; HRQOL = health-related quality of
life; IBS = irritable bowel syndrome; RIA = radio immune assay; TGA = antibodies against tissue-transglutaminase; T1D = type 1 diabetes.
of the question. The basic search strategy with emphasis on CD in including study design (prospective or retrospective, cross-sectional,
children was shared by all groups and broadening of the inclusion or case-control), age of the study population, sample size, study objec-
of publications was allowed according to the specific question. Full tives, and main findings (Summary Table of the Revised Literature,
search strategies for each question are presented in the Summary Table Supplemental Digital Content, http://links.lww.com/MPG/C861).
of the Revised Literature (Supplemental Digital Content, http://links.
lww.com/MPG/C861). We excluded single case reports, commentar- Strength of Recommendations
ies, abstracts, nonsystematic reviews of the literature such as narra- A recommendation was given for each (sub)question after
tive reviews and expert opinions and studies performed exclusively an open discussion involving all coauthors, followed by a close
in adults. In particular, if a narrative review was considered especially individual voting. Agreement was set at 85% for each recommen-
important or if no pediatric studies were available, this information dation. When no agreement was reached, another round of discus-
was also included and specified for the corresponding single question sions was performed to formulate a new recommendation upon
as well as in the Summary Table of the Revised Literature (Supple- which a final vote was taken. The recommendations are presented
mental Digital Content, http://links.lww.com/MPG/C861). Relevant in Table 1.
papers were identified by review of their title and abstract contents. In
case of potentially eligible studies, full texts were assessed. The final Ethics and Regulations
choice of studies was agreed upon by discussion and consensus. For All guideline members’ conflicts of interest have been noted
each question, a short summary of the selected papers was provided, and registered on the ESPGHAN website. The development of the
372 www.jpgn.org
position paper was funded by ESPGHAN and was performed in expert in the field of celiac, general doctor, dietitian, and e-health. The
collaboration with AOECS. search identified a total of 111 records, of which 4 were included: 2 pri-
mary observational studies (381 children) and 2 randomized clinical tri-
als (RTC) in both children and adults (17, 18) (365 patients <25 years).
RESULTS Children with CD have traditionally been followed by pediat-
Overall, 2775 publications were identified of which 164 ric gastroenterologists or pediatricians and sometimes after a period
informed these recommendations (Summary Table of the Literature, of a GFD by a dietitian (3). The indicated person to conduct the fol-
Supplemental Digital Content, http://links.lww.com/MPG/C861). low-up of children with CD differs substantially between countries
and even regionally within countries applying the same health care
system. The general recommendation by most studies indicates that
Question 1: Is Follow-up and Management of access to a dietitian or a physician with an interest in CD is impor-
CD Needed? tant for adequate treatment and evaluation of adherence to the GFD
A search was conducted in Medline using the search terms (see question 1). There is, however, a paucity of studies that compare
celiac, celiac, children, adherence, and follow-up. The search iden- long-term effects of dietary compliance depending on who conducts
tified a total of 356 records, of which 12 were included for this the follow-up. The only study investigating compliance to the diet in
question: 8 primary observational studies (7509 children) and children followed by a dietitian or a by a physician showed no differ-
4 systematic reviews (640 studies). We included 1 study in both ences in outcome, albeit dietitian-led visits being less expensive (16).
adults and children (6), 1 systematic review until the age of 20 years A cornerstone of successful treatment of children with CD
(12), and another one without an age specification (13). is how they adapt to the GFD. Educating children, adolescents, par-
One goal of short-and medium-term follow-up is the moni- ents, and guardians (and extended family) about the GFD constitutes
toring of the improvement of symptoms after starting the GFD. In an important component of the follow-up visits (see question 9).
patients with inadequate improvement (symptoms, catch-up growth, Whether education in self-care of children with CD should be sepa-
serology) after short-medium-term adherence to the diet, it is neces- rated from physical follow-up visits may depend on local conditions
sary to investigate hidden sources of gluten in the diet and to consider and practices. Communication over the internet offers new opportu-
the presence of other pathologies. Complications should be checked nities to connect to the patient and families and are under develop-
for. Another general goal is to ensure education on the condition and ment. E-learning is defined as all forms of electronically mediated
social support and to motivate the child with CD and their family teaching. Electronic health technologies (E-health) is the use of
(4,5), reinforcing at each visit the importance of dietary compliance information and communication technologies, such as smartphone
which may vary between 4% and 90% (6–9). Strict adherence to applications, in support of health and disease management. Utiliz-
GFD has a positive impact on the improvement of symptoms (10) ing E-learning and E-health as a replacement for physical follow-up
and it may also allow prevention of CD-associated complications. visits of children with CD has recently been evaluated. Three studies
Whether the risk for associated autoimmune diseases can be reduced of which two were RCTs (17,18) have investigated E-health in the
by early diagnosis and treatment of CD remains controversial (11). follow-up of patients with CD. Haas et al studied the influence of
During one of the first visits after the diagnosis, information on the Text Message intervention in newly diagnosed children and young
increased risk of CD among first degree relatives and their indica- adults. Vriezinga et al compared online consultation versus in-office
tion of CD screening according to the ESPGHAN diagnostic guide- outpatient visits. Both interventions positively affected self-man-
lines (3), should be part of the family education. Information on new agement, QoL, patient satisfaction, and in one study reduced health
treatment avenues should also be given during follow-up. care costs compared with conventional in-office standard of care.
Current recommendations on follow-up are largely based on Another RCT by Connan et al prospectively studied a small number
expert opinion (12,13). Reports have emerged that may help shape of participants (n = 33) and found an improvement in knowledge
the follow-up content of the follow-up visits (14). The chronic and about CD by introducing interactive E-learning methods (19).
systemic nature of CD makes a multidisciplinary team advanta-
geous for follow-up, including a pediatric gastroenterologist, dieti- Statement
tian-nutritionist, and in some cases, an immunologist, pathologist, There is evidence that the follow-up of children with CD
and psychologist. Consultation with a pediatric gastroenterologist should be performed by a physician and a dietitian with experience
or a pediatrician with expertise in CD is recommended for diagnos- in managing and evaluating patients on a GFD. While a dietician-
ing the disease. They should likewise be involved in the monitoring led follow-up of CD has shown promising results and may come
and adequate interpretation of the laboratory test results requested at a lower cost, more research is needed before stating whether a
during follow-up, as well as in the identification and management dietitian, a physician, or both should conduct the long-term follow-
of possible associated complications. During adolescence, the up. E-health interventions seem promising tools in CD-care, which
transfer to adult health care is initiated and organized, depending on utilization and effectiveness in CD-care should be further explored.
the patient’s understanding of the condition, readiness and required
maturity to transition into adult services (15). Recommendations
The regular follow-up visits of children with CD are prefer-
Statement and Recommendation ably carried out by a physician or a dietitian experienced in manag-
We recommend follow-up for children and adolescents after ing the disease. Local conditions and practices may determine how
the diagnosis of CD has been established. 100% Agreement. to apply these recommendations, but self-care treatment without
access to adequate health care and dietitians is not recommended.
Question 2: Who Should Do the Follow-up of 93% Agreement.
Which Patients and Which Is the Role of the
Dietitian? What is the Role of Self-care and Question 3: What Should Be the Frequency of
E-Health? Follow-up and What Should Be Assessed?
A search was conducted in PubMed using the search terms celiac, A search was conducted in Pubmed using the search terms
celiac, children, follow-up, gluten-free diet, pediatrician, pediatric celiac, celiac, children, and follow-up. The search identified a total
www.jpgn.org 373
of 382 records, of which 30 were included for this question: 17 The risk of autoimmune thyroid disease is increased in CD
primary observational studies (1,599,387 children) and 13 reviews patients as reported by a large population study (37) and several
(772 studies). We included 1 guideline in adults (30), one pub- case-control studies (38–40). However, other studies show no added
lication in adults and children (23) and one systematic review benefit of thyroid disease testing in CD children in the absence of
(35) in adults. We also included 5 studies published before 2010 symptoms (14). Based on the current literature, there is no evidence
(38,39,45,46) and 1 after March 2020 (36). to advise whether assessment of thyroxin or thyroid stimulating
Current literature does not provide solid evidence on the hormone (TSH) blood levels should be monitored during follow-
optimal frequency of follow-up. Despite a lack of high-quality stud- up, and in which frequency.
ies, a first follow-up visit scheduled 3–6 months after CD diagnosis Concerning immunization, HBV vaccine has been shown to
is recommended, but with easy access to the celiac service if earlier potentially have a reduced response, with 50% of patients with CD
advice is needed and with earlier clinic review depending on family having a poor antibody response versus 11% of controls in case of
knowledge, concerns and difficulties with the diet, and importantly, vaccination within the first 6 months of life (41–43). In addition,
if symptoms persist or worsen despite strict adherence to GFD, or if one study reported reduced protection after HAV vaccination (42).
clinical presentation (eg, malnutrition) or laboratory abnormalities Whether this is related to genetic host susceptibility or to other fac-
at diagnosis require earlier follow-up. Intervals for further follow- tors has not been clarified. Based on the above, screening for HBV
up visits should also take the “above mentioned” issues under con- immunization status has been suggested in newly diagnosed CD
sideration, and be scheduled at a 6–12 months interval and every children (12). There is no current evidence indicating that response
12–24 months afterwards. to HBV vaccine should be evaluated during follow-up. However,
Pediatric patients on a strict GFD usually show rapid reso- if a poor antibody response is detected, revaccination should be
lution of CD-related gastrointestinal symptoms, such as bloating, performed (43). A second dose effectively induces protective levels
diarrhea, abdominal pain, weight loss, as well as of extraintesti- in those CD children (41–44). Several studies detected no differ-
nal manifestations such as anemia, delayed puberty, and stomatitis ences between CD children and controls in the immune response
(20). Inconsistent or no follow-up is associated with poor dietary to poliomyelitis, diphtheria, mumps, and pertussis (45), rubella,
adherence (10). tetanus (45,46), haemophilus influenzae type b (46) and measles
Normalization of serology is widely used during follow-up (45,47). There is therefore currently no evidence to support routine
as a proxy for mucosal healing in children with high positive and checking of vaccine response during follow-up.
negative predictive values (21–23). A significant reduction in lev- The question about who should follow-up the patient is the
els of IgA against tissue-transglutaminase (TGA) is already seen subject of question 2 in this paper. In general, and based on the
after 3 months of GFD if measured with the same assay. However, resources available in each national system, a pediatric gastroen-
TGA levels remained above 1× the upper level of normal (ULN) terologist or a pediatrician with special interest/experience in pedi-
in 83.8% and above 10× ULN in 26.6% of studied children after 3 atric gastroenterology or an experienced dietitian could follow the
months on GFD (24). Full normalization of both TGA levels and patient with CD.
histopathology may take over 2 years, particularly in those with
severe small-bowel lesions and high TGA levels at diagnosis (25– Statements
27). IgG based tests and radio immune assay (RIA) based TGA
measurements are not suitable for monitoring response to a GFD in 1. The current literature does not provide evidence on the opti-
IgA sufficient patients with CD. mal frequency of follow-up or what should be assessed during
Bone health may be compromised in CD patients (28) and in visits.
children bone disease is mostly asymptomatic and associated with 2. Normalization of IgA-TGA levels is widely used as a proxy for
decreased growth and bone quality (29). In contrast to that observed mucosal healing in children.
in adults (30), CD in children does not seem to be associated with an 3. Nutritional deficiencies may be present at the time of CD
increased fracture risk (31). A reduced bone mineral density (BMD) diagnosis.
may be present at CD diagnosis in children and adolescents (29,32). 4. Children with CD have an elevated risk of autoimmune thyroid
Although a longer follow-up might be needed in some cases to diseases.
ensure a proper BMD recovery (33), in most cases, 1 year on a strict 5. A reduced BMD may be present at CD diagnosis.
GFD is sufficient to restore bone mass (12,14,28). Therefore, rou- 6. Vaccine responses in children with CD are identical to those of
tine BMD testing is neither required nor cost-effective. When bone the general population, except for a moderate level of evidence
loss has been identified for clinical reasons serial bone-density tests of poor seroconversion in response to HBV vaccination.
should be conducted every 1 to 2 years until normalization (12).
Vitamin D levels have been investigated in CD children
in several studies that are heterogeneous in their design and out- Recommendations
comes. Some of these demonstrate low vitamin D levels at diag- 1. The first follow-up visit should be scheduled 3–6 months after
nosis (12,14,34–36), but the impact of the GFD on vitamin levels CD diagnosis, but with easy access to the celiac service if ear-
remains uncertain. Although the evidence is not strong, assessment lier advice is needed, and sooner review if there are concerns
of vitamin D status, in case of abnormal levels at CD diagnosis, and regarding how the family is coping with the diet, if there are
correction of any ongoing deficiency should be considered good ongoing issues with growth or persistent symptoms or a need
patient care to optimize bone health. to repeat bloodwork earlier. Subsequent visits should be ev-
The liver is a common site of extraintestinal manifestations of ery 6 months until normalization of the TGA levels, and every
CD, usually presenting with raised aminotransferases. Liver function 12–24 months thereafter. 93% Agreement.
should be monitored during follow-up if abnormal at diagnosis (12). 2. During follow-up patients should be evaluated for:
As CD children may present with micronutrient deficiencies,
investigations for iron (commonest), folate, and vitamin B12 defi- I. Gastrointestinal and extraintestinal signs and symptoms.
ciencies are relevant at diagnosis and, if abnormal, these should be 100% Agreement.
monitored until normalization, either via the GFD or supplementa- II. Anthropometric measurements and growth parameters.
tion in case of anemia or depleted iron stores. 100% Agreement.
374 www.jpgn.org
III. IgA-TGA using the same assay (ELISA or EIA) as at di- Question 4.2: What is the role of detection of Gluten
agnosis, as a surrogate marker for improvement/healing of Immunogenic Peptides (GIPs) in the assessment of
the small-bowel mucosa. IgG based tests and RIA based compliance to the gluten-free diet?
IgA-TGA measurements are not suitable for follow-up in A search was conducted in Medline using the search terms
IgA sufficient patients. IgA insufficient patients with CD celiac, celiac, children, adherence, follow-up, gluten immunogenic
should be followed with IgG based tests. 100% Agreement. peptides, gluten-free diet, compliance, adherence, diet, monitor,
IV. A complete blood cell count, micronutritional status (eg, aftercare, secondary care and health care. The search identified a
hemoglobin, iron, vitamin B12, and vitamin D levels) and total of 28 records, of which 7 were included: 5 primary observa-
ALT measurements, should be performed after clinical tional studies (1 in children, 2 in both adults and children, and 2 in
evaluation at time of diagnosis. Any abnormality should be adults) (129 children) and 2 systematic reviews (990 publications).
followed and deficiencies corrected until normalization. If We included studies in adults (57, 58) and in both adults and chil-
abnormalities persist additional diagnoses should be con- dren (53, 54, 56). We included Silvester (58) and Stefanolo (57)
sidered and appropriately investigated. 91% Agreement. published after March 2020.
V. Screening for thyroid disease with TSH and thyroxine A small fraction of ingested gluten peptides is excreted in urine
(and autoantibodies if indicated) may be considered dur- and in stools, thereby revealing recent gluten exposure. Measurement
ing follow-up after clinical evaluation at the discretion of of GIPs in stool or urine has been introduced as a tool to detect gluten
the clinician. 91% Agreement. ingestion in patients adhering to a GFD (53,54,56–58). GIPs may be
VI. Routine bone-density screening is not recommended. 93% detected using specific monoclonal antibodies, A1 or G12, recogniz-
Agreement. ing gluten epitopes by lateral flow immunochromatography (LFIA)
VII. HBV antibody levels may be measured in previously im- (stool or urine) or ELISA (stool). Compared with other methods to
munized patients if this is considered important in the evaluate adherence, GIP testing disclosed the lowest adherence rate
population. A booster dose should be given if inadequate to the GFD (75%), suggesting that this assay is more sensitive than
levels are present. 91% Agreement. others to detect cases occasionally exposed to inadvertent gluten
ingestion (9). Repeated GIP positivity over a span of multiple days
Question 4: Adherence to the Gluten-free has been reported to correlate with intestinal mucosa damage (49,54).
Diet. Now that GIPs are available for use in clinical settings and for disease
self-managing by the patient, some questions remain to be answered,
Question 4.1: Should the Adherence to the Diet Be as the indication for urine or stool testing, the latency between gluten
Assessed During Follow-up and If So, How? exposure and appearance in stool/urine, the relationship between the
A search was conducted in Medline using the search terms quantity of ingested versus eliminated gluten in stool/urine and the
celiac, celiac, children, adherence, follow-up, gluten-free diet, dietitian, role of these tests in the assessment of long-term adherence to GFD.
teenagers, questionnaires, score, E-Health/App. The search identified a
total of 54 records, of which 9 were included for this question: 6 primary Statement and Recommendation
observational studies (306 children) and 3 systematic reviews (15,470
Further data are needed before a recommendation on stool/
studies). We included 2 studies in adults and children (53, 54) and 2 in
urinary GIPs determination to assess compliance to the GFD in
adults (50, 55). We included Harder et al published after March 2020.
clinical practice can be formulated. 93% Agreement.
There is general consensus about the need to assess adherence
to the GFD during the follow-up of CD patients (48–50). Despite the
absence of a gold standard to assess dietary compliance, a dietary Question 5: Common Issues During Follow-up
evaluation by a trained dietitian is considered the best method, as it is and Management of CD
the cornerstone of dietitians to asses and manage diets, but this is time- A search was conducted in Medline using the search terms
consuming and requires expert personnel. Short dietary questionnaires celiac, celiac, children, follow-up, catch-up, growth and develop-
and TGA determinations in serum fail to detect dietary transgressions ment, lactose intolerance, chronic tiredness, fatigue, irritable bowel
in children and adolescents with CD, showing poor sensitivity to iden- syndrome, anemia and iron deficiency. The search identified a total
tify all patients who consume gluten (51–53). There is a limited range of 58 records, of which 18 were included: all primary observational
of questionnaires specific for children. Long questionnaires specific studies (1,590,861 children). Two papers on adults and children
for children may be useful to assess diet compliance, especially in set- were included (64, 67).
tings with no dietitian consultation available (51).
In spite of the wide use of determination of specific CD- Question 5.1: When to Expect Catch-up Growth?
antibodies, especially TGA in serum as a surrogate marker of GFD Four original studies were included (29, 59–61). All studies
adherence, negative TGA results do not correlate well with dietary but one were retrospective and with a limited sample size. Only
compliance (21,54). one study assessed the correlation between recovery of growth
Further development of E-Health resources for assessment velocity and decrease in CD antibody levels (61). Maximum catch-
of adherence to the GFD are needed, as most available CD smart- up growth in weight and (in the prepubertal child) also in height,
phone apps lack clinical validation (55). is expected within the first six months on a GFD (61) and it can
continue for 2–3 years, at which time the child is predicted to reach
Statement the expected height. Age at diagnosis may influence final/target
The assessment of adherence to the GFD is one of the pri- height (59), but it is controversial whether it is possible to prevent
mary goals of CD follow-up. permanent height reduction by early dietary treatment. Negative
TGA is associated with a rapid weight recovery but does not seem
Recommendation to have the same long-term effect on catch-up of height (29,59,60).
Since a gold standard method is still missing, adherence to
the GFD should be assessed multidimensionally through a careful Statement
evaluation of symptoms, dietary interview and/or dietary question- In a child with impaired growth at the time of CD diagnosis,
naires and laboratory tests. 100% Agreement. catch-up growth in weight and height is usually expected within
www.jpgn.org 375
six months after starting the GFD, after which, depending on the Question 5.5: Anemia or sideropenia
patient’s age and continuance of the diet for 1–2 years, expected Seventeen studies were evaluated and ten pediatric studies
height is reached. were included (14,37,64,67–73). Only one study was prospec-
tive (71). Anemia is a frequent finding (12–24%) in children with
Recommendation untreated CD (64,67–70). It is usually caused by iron deficiency,
In the prepubertal/pubertal child, if significant catch-up but also vitamin B12 and folate deficiencies and anemia of chronic
growth in height is not reached within 1 year after initiating GFD, disease may contribute. In one large nationwide study, anemia,
despite strict dietary adherence, additional investigations and con- regardless of the underlying etiology, was significantly more com-
sultation with a pediatric endocrinologist are recommended to rule mon in adolescents with CD compared to controls (37). However,
out other causes of short stature. 93% Agreement. prevalence of subclinical iron deficiency is rarely reported during
follow-up. In most cases (84%-96%) anemia improves or recovers
Question 5.2: Is a Lactose-free Diet Necessary? on a GFD (14,64,67,70,72). Poor compliance to GFD may hamper
Untreated CD may cause secondary lactose intolerance due recovery (70,73). Evidence is lacking regarding the incremental
to villous damage, but this is not a consistent finding. The prevalence benefit of routinely adding iron supplementation.
of genotypes predisposing to adult-onset primary hypolactasia in CD
patients is comparable to the rate within the general population (62,63). Statement
CD is a common cause of anemia and associated nutritional
Statement deficiencies in children. Abnormal values should be monitored until
CD patients may develop primary lactose intolerance over normalization on a GFD. An adequate response can be expected
time, similar to the general population. Patients can also have sec- within one year from initiating GFD, although more prospective
ondary lactase deficiency due to villous damage, but are usually evidence is needed. Poor dietary compliance and/or reduced nutri-
lactose-tolerant and there is no evidence of the benefits of tempo- tional iron-content predispose to non-recovery of anemia.
rary lactose-free diet on top of the GFD, unless clinical symptoms
are highly suggestive of concomitant lactose intolerance (such as Recommendation
ongoing diarrhea, abdominal pain, or gassiness after starting GFD). Young children with anemia due to iron, folate or vitamin
B12 deficiency should receive supplementation in addition to the
Recommendation GFD, since improvement over time may take too long in these in
We recommend a trial with lactose-reduced diet only in CD children in a critical period of brain development and rapid catch-
patients with symptoms suggestive of lactose intolerance (such as up growth. A low threshold for supplementation may also be con-
ongoing diarrhea, abdominal pain and/or gassiness) despite adher- sidered for older children. The disappearance of anemia should be
ing to the GFD. 93% Agreement. confirmed in all cases, adherence to the GFD should be checked,
and other causes for anemia should be excluded in children who do
Question 5.3: Chronic Tiredness in Well-controlled not recover despite a strict GFD. Concerning sideropenia without
Celiac Disease? anemia, an expectant attitude may be appropriate on the GFD as
Only two papers (64,65) were found, both reporting that long as there is improvement in iron stores without supplementa-
children had greater and more significant improvements of chronic tion. 95% Agreement.
tiredness on a GFD compared to adults with CD. Fatigue improved
significantly in 81% of children on a strict GFD and only 3 of the Question 6: Specific Issues During Follow-up
40 children had persistent chronic fatigue after one year on the diet. and Management.
Question 6.1: How to Approach Persistent High TGA
Statement
Levels During Follow-up?
CD children on GFD have a significant improvement in A search was conducted in PubMed using the search terms
chronic fatigue. celiac, celiac, children, follow-up, persistent or elevated transgluta-
minase, antibody, and gluten-free diet. The search identified a total
Recommendation of 167 records, of which 17 were included: all primary observa-
There are no specific recommendations for chronic fatigue tional studies (2128 children). We included one article published
in CD except to follow a GFD. 97% Agreement. after March 2020 (26).
Although CD serology markers (IgA-TGA and endomysial
Question 5.4: Irritable Bowel Syndrome (IBS) in Celiac autoantibodies (EmA)) work very well for diagnosis, these are less
Disease? accurate for dietary monitoring (74,75). Dynamics of CD-antibod-
Similar prevalence of abdominal pain and functional gastro- ies after diagnosis may vary according to the adherence to the GFD,
intestinal disorders have been demonstrated in CD on a GFD for the timeframe of testing, type of antibodies, age at diagnosis, coex-
at least six months vs. controls on a regular diet (66). In both CD isting diseases (IgA deficiency, type 1 diabetes), antibody levels at
patients and in controls, the most common functional gastrointesti- diagnosis, and by assays used (25,26,76–83).
nal disorder was IBS. During follow-up, continuous decreasing levels of IgA-TGA,
until values below cutoff of normality are reached, and a negative
Statement EmA cautiously reflects sufficient dietary compliance (84,85). On a
No increased frequency of IBS has been demonstrated in GFD, IgA-TGA levels decrease over time and are expected to nor-
children with CD on a GFD. malize by 18–24 months after starting the diet (84) depending on
the serology kit used. No data are available on how slightly elevated
Recommendation IgA-TGA at follow-up should be addressed. However, it is reason-
IBS in children with CD on a GFD should be treated simi- able to suspect that persistently slightly elevated IgA-TGA levels
larly as in children without CD. 93% Agreement. imply inadequate dietetic compliance in most patients with CD.
376 www.jpgn.org
Different methods are available to detect CD-antibodies in detection of persistent villous atrophy, but the authors did not specify
serum: enzyme-linked immunosorbent assay (ELISA); chemilumi- the levels of antibodies (only positive or negative) (21).
nescence; radioimmunoassay (RIA). For decades, the most widely
used CD serology assessment method has been ELISA and the Statements
majority of clinical evidence available has been addressed by this
technique. Persistent positivity of chemiluminescence IgA-TGA 1. There are few and heterogeneous studies addressing the ques-
should be interpreted with caution since it has a slower decrease tion “if and when” to perform (re)biopsy.
over time (26) and should be better integrated with ELISA assay 2. Slightly elevated IgA-TGA levels in CD children on a GFD are
since more follow-up data are available on this latter technique with unlikely to be correlated with mucosal injury.
regards to dietary monitoring. Nevertheless, it should be clear that
CD-specific antibody measurement does not suffice to evaluate Recommendation
compliance to a GFD and to establish complete recovery of mucosal Routine assessment of mucosal healing by small-bowel
healing. Gastrointestinal symptoms, with or without slightly ele- biopsies is not recommended in children with CD following a GFD.
vated CD-antibodies, may persist in a small percentage of children We recommend considering (re)biopsy only in selected CD cases;
claiming optimal dietary adherence (86,87) (see also question 6.2). based on specific clinical grounds, for example, when doubts about
Statements the original diagnosis or suspicion of occurrence of an additional
IgA-TGA levels are expected to normalize by 18–24 months condition. 100% Agreement.
following the start of a strict GFD.
Question 6.3: Refractory Celiac Disease in Children:
Recommendation Does It Exist?
Lack of decreasing IgA-TGA levels after 6–12 months on a A search was conducted in PubMed using the search terms
GFD or persistently positive IgA-TGA levels should be assessed by celiac, celiac, children, follow-up, unresponsive, refractory, non-
carefully reviewing dietary compliance and testing IgA-TGA using responsive, and nonresponsive. The search identified a total of
the same test from the same manufacturer. 93% Agreement. 69 records, of which 7 were included: 6 observational studies
(252 children) and 1 systematic review (5 studies in children). We
Question 6.2: When Is it Necessary to (Re)biopsy? included studies in both adults and children ( 21,64,92,93).
A search was conducted in PubMed using the search terms celiac, Refractory celiac disease is defined by persistent or recurrent
celiac, children, follow-up, repeated, biopsy and follow-up biopsy. The villous atrophy and malabsorptive symptoms in CD patients despite
search identified a total of 225 records, of which 8 were included: 6 pri- adherence to a strict GFD. Although well described and character-
mary observational studies (592 children) and 2 systematic reviews (87 ized in adults, the occurrence of refractory CD in children is very
studies). We included 3 studies in both adults and children (21, 89, 90). rare. Our search did not find any report on refractory CD in chil-
After CD diagnosis, duodenal biopsies to assess mucosal dren in 6 of the 7 papers (21,56,64,91–93). Only one paper (94)
healing may be considered as an ultimate option to discuss thor- described 3 cases of celiac children “not responding to the GFD.”
oughly with the family and to dismiss any further doubt about However, 2 of the patients were negative at immunohistochemistry
compliance and responsiveness to the GFD. This may be of clini- for CD3 changes consistent with refractory CD and in addition they
cal value even in those asymptomatic children whose parents claim eventually responded to a strict GFD. In the third patient, who was
strict dietary adherence but with still, mostly slightly, elevated IgA- apparently permanently nonresponsive, specific immunochemical
TGA after 24 months on a GFD. Following this path, in the case of testing for refractory CD was not performed. The paucity of these
normal duodenal mucosa (Marsh 0 and Marsh 1) the family can be challenging cases underline the importance of referring suspected
reassured (75). In case of persisting major mucosal abnormalities child/adolescent cases to tertiary care centers (with available expert
(ie, Marsh 2 (crypt hyperplasia) and/or Marsh 3 (villous atrophy)), pathologists) and the duty of reporting cases of pediatric refractory
better dietary compliance should be encouraged. CD in the medical literature.
In the scarce literature regarding persisting villous atrophy in
CD children on a GFD, we found a prevalence of 2%-19% at 1–3 Statement
years after CD diagnosis (75,85–89). The discrepancy in frequencies There is very poor evidence for the existence of refractory
is possibly due to the heterogeneity in study design of the different CD in children.
studies, including the inclusion criteria, duration of the GFD and
methods of assessment of dietary compliance. A meta-analysis dem- Recommendation
onstrated that children had higher frequency of complete histologi- We recommend properly investigating other causes of an
cal recovery (65%) and regression of abnormal villous/crypt depth apparent “refractory CD” in children, including ongoing inad-
ratio (74%) than adults (24% and 58%, respectively) (90). Moreover, vertent ingestion of gluten and other possible concomitant enter-
younger age at diagnosis was related to less severe initial histologic opathies, such as Crohn’s disease, autoimmune enteropathy,
damage; and male gender predisposed for achieving mucosal recov- small-bowel bacterial overgrowth, cow’s milk protein allergy, and
ery. Vécsei et al concluded that antibody tests are of limited value in pancreatic insufficiency. 100% Agreement.
predicting the mucosal status in the early post-diagnosis years but that
they perform better after a longer period of time on GFD. The study
also found that negative EmA most reliably predicts mucosal healing Question 7: Should the Quality of Life (QOL)
(85). These results are in accordance with a prospective longitudinal Be Assessed During Follow-up and If So, How?
study performed in Australia in which no persistent villous atrophy A search was conducted in Medline using the search terms
was found in 97 negative IgA-TGA CD children with a median time celiac, celiac, children, follow-up, and quality of life/QoL. The
to re-biopsy of 1.4 years on a GFD (range 1.0–12.4 years) (75). How- search identified a total of 89 records, of which 18 were included:
ever, in the retrospective study performed by Leonard et al, serology 16 primary observational studies (16,043 children) and 2 system-
as predictor of Marsh 3 histology at repeat biopsy was poor (86). A atic reviews (39 studies). The study from (110), published after
recent meta-analysis concluded that IgA-TGA has low sensitivity in March 2020, was also included.
www.jpgn.org 377
Most of the included studies assessed the health-related Due to its high negative predictive value, HLA-DQ2 and
quality of life (HRQOL) in CD during follow-up after starting DQ8 typing is the most reliable test to select those children in
treatment with a GFD (4,82,95–109). Ten studies used generic which the CD diagnosis is extremely unlikely (3). However, in
HRQOL questionnaires: SF-12; KIDSSCREEN-52, Nowicki- HLA-DQ2 and/or DQ8 positive children, the uncertain diagnosis
Strickland Locus of Control Scale, KINDL, Pediatric QoL may be assessed by gluten reintroduction, followed by monitor-
Inventory Test, PedsQL, Kidscreen, EQ-5D test, General Pur- ing of symptoms, measurements of CD-specific antibodies and
pose HRQOLScale for Children, Inventory of Life Quality in small-bowel mucosal biopsy in selected cases. ESPGHAN 2012
Children and Adolescents; Berner Subjective Well-being Inven- CD diagnosis guidelines provided indications on how to perform
tory. Nine of these studies found similar HRQOL in children a gluten-challenge (2). However, the amount of gluten to be used
with CD as in control children (4,82,95,96,99,100,102,103,10 and the appropriate duration of the challenge remains a matter
6). However, five of the six studies using CD-specific HRQOL of debate. In general, the amount of gluten in one slice of bread
questionnaires (CDDUX, CDQL, CDQOL Scale-KINDL, is about 3–5 g and the regular daily gluten intake has been esti-
CDPQOL) found that the HRQOL of children and adolescents mated to be 10–20 g/day in adults and about 5–15 g/day in chil-
with CD was poor or neutral (82,96,100,105,109). A model of dren, depending on the age (2,111,112). In practice, 10–15 g/day
a questionnaire for assessment of CD-specific HRQOL is proof gluten followed by first clinical and serological assessment
vided in Annex 1 (Supplemental Digital Content, http://links. after 3 months of challenge is usually used for CD diagnosis. As
lww.com/MPG/C861). Parents gave lower HRQOL scores as a rule, CD may be considered less probable in children without
compared to their children (96,97). These findings are in agree- specific CD-antibodies in serum and normal small-bowel mucosa
ment with those from studies reported in a recent systematic after up to 2 years of gluten-challenge. However, cases of chil-
review and meta-analysis of the literature (110). Food situations dren relapsing after gluten-challenge as long as 19 years after the
at school, meals at home and meals outside home are factors challenge have been reported (113). Gluten-challenge studies in
repeatedly found to have a negative impact on emotions, social children using a gluten amount of 5–10 g/day resulted in sero-
relationships, and management of the daily life of CD children logical relapse in 66% of 134 CD children after 3 months and
and adolescents. These factors include feeling different at times, in 89.9% after 6 months. The challenge duration for histologi-
feeling unhappy when eating, feeling angry about having to fol- cal relapse was about 6 months (114). One study reported 71%
low a GFD and in general difficulties in accepting the diet. In of 41 CD children developing gastrointestinal symptoms after a
the only study on the subject, physicians were found to overesti- gluten-challenge with 1–3 slices of wheat bread per day during
mate the HRQOL of children and young adults with CD during 3 consecutive days (115). A previous study demonstrated duode-
follow-up (109). While a little-studied area of CD-care, when nal mucosal deterioration and positive celiac autoimmunity in 10
indicated, one can consider it as good clinical practice to refer long-term treated CD children after a challenge with 14 g gluten/
to a psychologist, preferably with knowledge of CD and coping day for 3–12 months (112).
strategies. As CD causes malabsorption and attenuated growth, glu-
ten-challenge is usually avoided in toddlers and adolescents. In
Statement adults, randomized blinded gluten-challenges were performed
When assessed by CD-specific questionnaires, the HRQOL as part of several CD pharmaceutical trials. Different amounts of
of children and adolescents with CD on a GFD is reported to be gluten were given, concluding that 2 g of daily gluten ingested
neutral or poor. for 6 weeks induced small-bowel injuries and symptoms in
most of the patients, and that 2–4 g of daily gluten for 10 weeks
Recommendation induces symptoms as well as serological and histological relapse
We recommend assessing the HRQOL of children and ado- in the majority of CD patients (116–119). Even shorter chal-
lescents with CD during follow-up by means of validated, CD-spe- lenges of 2–10 weeks with 2–4 g or 3 g of gluten/day have been
cific HRQOL questionnaires. 87% Agreement. These questionnaires proposed (120,121). However, it has been argued that short
may be administrated during or before the follow-up consultations, gluten-challenges of 2 weeks are prone to false negative conclu-
either on paper or by e-consultation. The results should be inter- sions when only conventional histology is used for the mucosal
preted by the physician together with the parents/care givers, and if assessment (122).
age adequate, also with the child.
Statements
Question 8: Should Follow-up of Children
I. Gluten-challenge is indicated in children suspected of
With Special Situations Be Different From the CD but in whom a GFD was initiated before the CD di-
One in the Average CD Patient? agnosis was certain. Challenge should be avoided dur-
ing periods of accelerated growth. The gluten-challenge
Question 8.1: In Cases of Uncertain Diagnosis: When should be performed under the supervision of a pediatric
and How to Perform Gluten-challenge? gastroenterologist.
A search was conducted in Pubmed using the search terms celiac, II. Gluten ingestion of 10–15 g/day for 3–6 months is expected
celiac, children, follow-up, and gluten-challenge. The search identified to induce small-bowel abnormalities in the majority of CD
a total of 850 records, of which 20 were included: 9 RCT (1 in children: children.
23 children) and 8 primary observational studies (2 in children: 194 III. The optimal amount of daily gluten intake and the shortest
children). We included 14 studies in adults (116–122, 159–165) and 2 time for an effective gluten-challenge are still unknown.
studies in both adults and children (3, 111). We included 4 studies pub-
lished before 2010 (111–114) and 1 after March 2020 (161).
In situations where a GFD was started before the diagnosis Recommendations
was completed, the reintroduction of gluten into the diet, or the so- In cases of uncertain CD diagnosis, HLA typing should be
called gluten-challenge is currently the only method to secure the performed before gluten-challenge in order to detect children in
diagnosis. whom the occurrence of CD is unlikely. 100% Agreement.
378 www.jpgn.org
Question 8.1.1: How to Perform a Gluten-Challenge? II. We recommend developing the follow-up plan in conjunction
with an endocrinologist/diabetologist and a dietitian, also con-
I. In children with HLADQ2 and/or DQ8 positivity with an in- sidering the need for psychological and social support. 100%
dication for gluten-challenge, intestinal biopsies before start- Agreement.
ing the challenge may be considered at the discretion of the
clinician and in dialogue with the patient/caregivers. 77%
Agreement. As this recommendation did not reach threshold Question 8.3: Follow-up of Patients With CD and IgA
for agreement (85%) it is not included in the recommendations Deficiency
in this paper (Table 1). A search was conducted in PubMed using the search terms
II. To avoid unnecessary exposure to gluten in CD children with celiac, celiac, children, follow-up and IgA deficiency. The search
an early response to the challenge serum IgA-TGA determina- identified a total of 24 records, of which 2 were included: 2 primary
tion may be considered 1 month after starting, and this should observational studies (191 children), one of them prospective. We
be measured every 3 months during daily ingestion of 10–15 g included 1 article published after March 2020 (132).
of gluten for 12 months. Earlier evaluation is recommended in Selective IgA deficiency is the most prevalent primary
case of suggestive symptoms. 100% Agreement. immunodeficiency in the general population (1:300–700). Chil-
III. In case of symptoms suggestive of CD and/or specific CD- dren with selective IgA deficiency are at a 10- to 15-fold higher
antibodies, small-bowel biopsies should be performed. 82% risk of developing CD. Limited data on the follow-up of children
Agreement. As this recommendation did not reach threshold with CD and selective IgA deficiency is available, with low num-
for agreement (85%) it is not included in the recommendations ber of affected children (88). Studies show prolonged recovery time
in this paper (Table 1). of serological and mucosal changes after the introduction of GFD
IV. In the absence of symptoms and/or specific CD-antibodies af- during follow-up, with half of IgA deficient CD patients having
ter 1 year of formal gluten-challenge, the child should be al- elevated serum IgG specific CD-antibodies after 2 years on a GFD
lowed to have a normal gluten-containing diet and follow-up (132). No other findings were found to be specific during follow-up
visits with measurement of specific CD-antibodies should be of selective IgA deficient CD patients.
offered annually or every other year. Earlier evaluation is rec-
ommended in case of suggestive symptoms. 93% Agreement. Statement
Data from the literature on patients with selective IgA defi-
ciency indicate a longer recovery time for serum IgG CD-antibod-
Question 8.2: Follow-up of Patients With CD and T1D
ies after starting a GFD.
A search was conducted in PubMed using the search terms
celiac, celiac, children, follow-up and diabetes. The search identi- Recommendation
fied a total of 151 records, of which 10 were included: 7 studies in
children (3295 children) and 3 studies in both adults and children I. We recommend the same follow-up practice in IgA deficient
(123–125). children with CD than in IgA sufficient children with CD. 93%
There are few studies focusing on the follow-up of children Agreement.
with CD and T1D, and they are mostly retrospective in nature. II. At follow-up visits CD-specific IgG antibodies (TGA, EMA or
Most of the authors compared outcomes in patients with T1D and DGP) should be assessed. 100% Agreement.
CD to patients with T1D only (123–127). Few compared patients
with both diseases to patients with CD only (79,128,129). Some
studies are nationwide, multicentric, registry-based focusing Question 8.4: Potential Celiac Disease
on a single country (123–126); others are single-center stud- A search was conducted in PubMed using the search terms
ies (130). The number of patients in most of the studies is low. celiac, celiac, children, follow-up and potential celiac disease. The
Most patients with CD and T1D are detected through screening search identified a total of 80 records, of which 9 were included:
and are usually asymptomatic, with some having potential CD. 8 performed in children (835 children) and 1 in both adults and
Data on long-term follow-up of patients with both diseases show children (137).
that they have an increased risk of thyroid pathology compared Potential CD is defined as the presence of CD-specific anti-
with isolated T1D (124) or to isolated CD (128) and of diabetic bodies and compatible HLA, but normal duodenal architecture. It
retinopathy compared with isolated T1D (123). It has also been can either be asymptomatic or symptomatic. The patient may or
shown that growth can be affected for a prolonged time despite may not develop villous atrophy later. Once diagnosed, the most
strict GFD (126). On the other hand, the risk of fractures and important decision to be taken is whether to treat it with a GFD or
nephropathy was not found to be higher in patients with both not. That decision depends on the predictable evolution, the allevia-
CD and T1D compared to isolated T1D (125,128,131). The long- tion of possible symptoms by GFD and the possible risk inherent to
term outcome of CD in T1D patients is similar to the one in CD a long-term regular diet, including bone health, because the pres-
without T1D in terms of compliance with the GFD and achiev- ence of alterations may represent a valid reason to start a GFD, oth-
ing remission of CD (129,130). However, some patients who erwise not prescribed if the subject is asymptomatic. Bone health
perceived themselves to be asymptomatic had more problems should be monitored by assessment of serum levels of calcium,
with compliance with a GFD, warranting a stricter follow-up in phosphate, alkaline phosphatase, vitamin D, and eventually miner-
selected cases (79). alometry performed at the discretion of the physician. The first two
issues find some evidence in the literature (133–140). All studies
Recommendations but one (133) indicate that the evolution to villous atrophy occurs
in a minority (5–20%) of the cases with a cumulative incidence of
I. We recommend the same frequency and follow-up tests in chil- approximately 50%. The majority remain as “potential CD,” with
dren with CD and T1D as in children with isolated CD, with a significant percentage of those normalizing their CD-antibodies,
(additional) special attention to test for thyroid involvement which is frequently observed in younger children. Factors predict-
and diabetic retinopathy. 93% Agreement. ing evolution to villous atrophy are genetic profile, intraepithelial
www.jpgn.org 379
lymphocytic infiltration, and intestinal CD-antibodies deposits “suspected CD,” and action should be taken to confirm or reject
(138). A GFD does not always improve symptoms (141). No infor- the diagnosis.
mation is available on the long-term risks if left on a regular gluten-
containing diet. Statement
Communication and documentation of the CD diagnosis
Statement based on evidence-based guidelines are crucial to avoid later doubts
In the literature there is insufficient data for evidence-based about the diagnosis, both by the patient or other caring physicians.
management of patients with potential CD.
Recommendations
Recommendation The pediatric gastroenterologist/pediatrician should commu-
nicate to the patient and the parents/caregivers that the CD diagno-
I. In the presence of symptoms attributable to gluten, a trial of a sis is made with certainty and according to current evidence-based
GFD should be discussed with the family. 90% Agreement. guidelines. All results (serology, histopathology, HLA if done) with
II. If left on a regular diet, we recommend annual follow-up visits, dates of performance should be provided in writing for later proof
with attention towards growth and nutritional status, including of CD diagnosis. 97% Agreement.
bone health. 97% Agreement.
III. Duodenal biopsies should be performed in case of appearance Question 9.2: Patient Empowerment at Diagnosis and
of symptoms and/or of increased elevation of the CD antibody
levels. In other cases with persistent serological positivity, on
During Follow-up
an individual basis and in dialogue with the patient/caregivers, The diagnosing physician should communicate the benefits
duodenal biopsies may be considered during follow-up. 95% of an early diagnosis in childhood as compared to undiagnosed and
Agreement. untreated disease until adulthood in a structured way. To patients
with symptoms affecting their QoL, this is obvious (immediate ben-
efit). For screening-detected persons with minor or no symptoms
Question 9: How to Improve Communication: (144,145) or those who do not remember their symptoms due to
To Parents? To Patients? young age at diagnosis, the motivation to adhere to a GFD is based
A search was conducted in Medline using the search terms on internalizing the risks/possible consequences to later health (146)
celiac, celiac, children, follow-up, gluten-free diet, communica- and enduring beliefs of being spared negative consequences (146).
tion, patient satisfaction, caregivers/education, education, consul- Knowledge about the disease may be provided using dif-
tants/education, consultants/organization, and administration. The ferent tools, including information leaflets, web-based documen-
search identified a total of 46 records and 14 publications were tation, or E-learnings (19,147). A modular E-learning tool for
included: 12 primary observational studies (638 children) and patients and their household members has been developed within
2 literature reviews (34 studies). We included 4 studies in adults an EU-funded project and is freely available in 6 languages: https://
(143,145,149,150), 1 in both adults and children (148) and 2 pub- celiacfacts-onlinecourses.eu/?lang=en. Although children diag-
lished before 2010 (142,147). nosed early in life usually accept the GFD as normal, they need to
Communication between the caring physician and other be informed, reassured and empowered for autonomy and taking
health care professionals with the parents and patients includes responsibility for their CD, particularly during adolescence (148).
much more than providing information on the disease. Commu- A well-informed patient is more likely to adhere to the GFD and to
nication shapes the patient’s/parent’s relationship with the caring reconstruct normality (149,150). Better knowledge of the risks and
medical team and the trust in evidence-based medicine. Commu- benefits of the disease may also reduce anxiety. Informed patients
nication in pediatrics is generally triadic and should be addressed with trust in evidence-based medicine are less likely to follow
towards both the parents and the child with language appropriate unproven, sometimes risky treatments and intervention or spend
to the age of the child (142). How the physician communicates money on these treatments or diagnostics of unproven value.
the initial diagnosis to the patient/parents affects the degree of
acceptance of the diagnosis and may influence the impact of the Statements and recommendations
disease on the intrafamily relationship. In adults with CD, it has
I. The pediatric gastroenterologist/pediatrician and dietitian
been shown that negative perceptions of having CD were associ-
should communicate the need for a lifelong GFD and regular
ated with dissatisfaction with the quality of doctor-patient com-
monitoring and facilitate access to professional dietary coun-
munication (143).
seling knowledgeable on GFD. 100% Agreement.
II. We recommend providing education using oral and written
Question 9.1: Communication of Diagnostic Certainty information (leaflets, E-learnings etc.) about the disease and
to Parents and Children benefits of adhering to the diet. Later health risks should be
The information at all times, but most importantly at the brought into perspective without inducing fear or anxiety con-
time of the diagnosis, should be given to the patient/family in sidering the patient’s age and complications at the time of di-
lay terms in a relaxed atmosphere. It should include explana- agnosis and compliance with dietary recommendations. 97%
tions of the results of the diagnostic work-up and the implica- Agreement.
tions of the lifelong disease for the patient’s life and the family.
The documentation of confirmed diagnosis is important, par-
ticularly if the child was diagnosed early in life, to avoid later Question 9.3: Emotional and Social Support
doubt by the patient and future caring physicians. Ideally, a Patients and parents should be informed about the value of
celiac passport should be used for documentation (in Germany the national or local celiac patients’ associations where they can
free available from the German Celiac Society DZG: https:// meet families, participate in different programs and collect valuable
www.dzg-online.de/der-zoeliakiepass.1074.0.html). If the and updated information about the disease, gluten-free products or
diagnostic criteria were not fulfilled, and there is doubt about even practical hints on reorganizing the household. Members of
the diagnosis, the physician should not name it as “CD,” but as CD patients’ associations may benefit by receiving psychosocial
380 www.jpgn.org
support by peer groups, which in turn may ensure better adherence on the basis of CD diagnosis and a summary of important follow-
to the diet and outcome (10). The CD patients‘ organizations in up information such as serology, growth data, comorbidities, and
Europe usually are members of the AOECS: http://aoecs.org/mem- dietary adherence.
bers and encourage to name the condition in the social environ- Young adults should have the chance to trust and improve
ment as something, which is “quite common,” and “most people are their own abilities to cope with their disease burden and the nec-
aware of CD” (151). In their daily life, many individuals suffering essary dietary restrictions (153). Furthermore, although there is
from a chronic disease may not like to be considered a “patient,” but little evidence, as for other diseases, building a good relationship
as a person affected with a certain disease or condition. This is par- between the young adult and the treating medical team may be rel-
ticularly true for CD, as the GFD reverts the enteropathy and alle- evant to ensure good management of the disease (153).
viates most, if not all, signs and symptoms that may be present at There is no evidence in the literature about the exact age to
the time of diagnosis. Children in particular may be sensitive to the start the transition process in pediatric celiac patients. Physician
word “patient” which implies feeling “sick.” Therefore, the word- organizations from the United States had suggested that the transition
ing used should be carefully chosen and may be mutually decided be commenced at age 12–13 years, developing a transition plan at
upon with the affected child, including the wording she/he will use age 14–15 years, with the actual transfer taking place at ≥18 years of
describing CD to their friends, peers and other social contacts in age (158). This proposed timeline is based on expert opinion, as the
their daily life. Particularly, some screening identified adolescents quality indicators and metrics used to evaluate transition outcomes
perceive the change of their lifestyle (GFD) more as a burden than are still being developed. The transition should start according to the
as potential benefit (152). This feeling of stigmatization and social general health care organization in a given country, taking into con-
isolation needs to be addressed in the patient-physician communi- sideration the adolescent’s physical, mental, psychosocial develop-
cation and requires particular attention and support (107). ment, and other factors, such as the level of disease activity, dietary
adherence, and the patient’s autonomy in disease management.
Statements and recommendations
Statements
I. Emotional and practical support from personal contact with
other individuals with CD (Celiac/parent support groups, pa- 1. There are no prospective studies on the transfer of care from
tient organizations, etc.) should be provided to reduce eventual pediatric to adult medical care in CD.
feelings of social isolation. 97% Agreement. 2. Retrospective data show that the transition to adult care is in-
II. Patients, especially adolescents, perceiving lifestyle changes consistent, particularly among asymptomatic patients.
related to CD diagnosis, including the GFD and emotionally 3. There is no evidence in the literature about the age to start the
coping, as difficult warrant particular attention and support. transition process in pediatric celiac patients.
100% Agreement.
Recommendation
Question 10: How to Organize the Transition Even though current data are insufficient, we recommend a
From Pediatric Care to Adult Health Care? formal transfer of medical care of an adolescent with CD to facilitate
A search was conducted in PubMed using the search terms the transition to adult care. The transfer should be structured and, as
celiac, celiac, children, follow-up, childhood celiac, and transi- a minimum, include a transition letter or “celiac passport” provid-
tion of care. The search identified a total of 85 records, of which ing data on the basis of diagnosis, follow-up, anthropometric data,
7 were included: 4 primary observational studies (17,172 children) possible comorbidities, and dietary adherence level. 93% Agreement.
and 3 reviews/guidelines (156 (10 studies), 15,157). Two studies on
adults were included (154,155).
The transition between pediatric and adult care for young DISCUSSION
people with chronic illness, including CD, is often poorly organized, In this paper, we present a summary of the literature on the
with potential negative consequences on the QoL. There is a gen- follow-up of children and adolescents with CD and we provide rec-
eral agreement that adolescent services need to be improved. Still, ommendations on how to approach it. Although the searched and
there is little empirical data on which policies can be used (153). The identified literature encompass an impressive representation of
organization of transition from the pediatric to adult care for indi- the pediatric population with CD, most of the included studies are
viduals with CD is necessary to prevent gaps in management (15). observational and retrospective, as shown in the Summary Table of
Studies on the transition process in CD are scarce. We identi- the Revised Literature (Supplemental Digital Content, http://links.
fied nine relevant original papers, several of which were performed lww.com/MPG/C861). In addition, the exclusion of case reports
in young adults after transition. These provided only retrospective, by the methods may have had an impact on the underestimation
descriptive data without any long-term follow-up. Importantly, of refractory CD, which is such a rare event in pediatrics. For this
there are gaps in follow-up care after transition. Dietary compliance reason, we stress the importance of referring suspected cases to
tends to be low in young adults and surprisingly, there are sugges- specialized centers and of reporting cases in the medical literature.
tions that follow-up care is not associated with a higher compliance Although some of the provided recommendations have been
and good quality of health (154). Moreover, the transition of care based on available evidence (Table 1: 1; 3.2.II–VI; 4.1, 4.2; 5.1–5.4;
in CD appears often to be inconsistent, particularly among asymp- 6.1–6.3; 7; 8.1, 8.2.1, 8.2.II, 8.3.I, 8.3.II; 9.2.I, 9.3.1), others have
tomatic patients (155). been based on expert opinion (Table 1: 2; 3.1, 3.2.IV, V, VII; 5.5;
A systematic review of the literature on the transfer of care 8.1.1.II, 8.1.1.IV, 8.4.I–8.4.III; 9.1, 9.2.II, 9.3.I; 10). Nevertheless,
among different chronic diseases suggested that the most commonly upon voting, agreement was present for 95% of the 39 statements
used strategies in successful programs were patient education and and 37 recommendations were formulated.
specific transition clinics jointly staffed by pediatric and adult phy- Gaps in knowledge were identified indicating fields for
sicians or dedicated young adult clinics within adult services (156). future prospective research.
The pediatrician should write a transition letter to facilitate care These include the frequency of follow-up visits and the
transition (15,35,157),. The transition letter should contain details laboratory tests that should be performed, including vitamin D
www.jpgn.org 381
determinations and control of thyroid disease. Also, how to treat 3. Husby S, Koletzko S, Korponay-Szabó I, et al. European society paedi-
sideropenia and how to address persistent slightly elevated levels atric gastroenterology, hepatology and nutrition guidelines for diagnos-
of serum IgA-TGA in children adhering to the GFD are knowledge ing coeliac disease 2020. J Pediatr Gastroenterol Nutr 2020;70:141–56.
gaps that were addressed based on expert opinion and available 4. Bellini A, Zanchi C, Martelossi S, et al. Compliance with the glu-
ten-free diet: the role of locus of control in celiac disease. J Pediatr
evidence. The need for a reliable method to assess adherence to 2011;158:463–466.e5.
the GFD was identified, as well as the importance of studying the 5. Rimárová K, Dorko E, Diabelková J, et al. Compliance with gluten free
performance of GIPs determinations in clinical practice. diet in a selected group of celiac children in the Slovak republic. Cent
Although some evidence supports the assessment of QOL Eur J Public Health 2018;26:S19–24.
during follow-up, it remains unknown what the frequency of 6. Kurppa K, Lauronen O, Collin P, et al. Factors associated with
assessments should be, taking into account the time-consuming and dietary adherence in celiac disease: a nationwide study. Digestion
economic aspects of follow-up. 2012;86:309–14.
Although three recommendations are provided on how to 7. Charalampopoulous D, Panayiotou J, Chouliaras G, et al. Determinants
perform a gluten-challenge in children with uncertain diagnosis of adherence to gluten-free diet in Greek children with coeliac disease:
A cross-sectional study. Eur J Clin Nutr 2013;67:615–9.
of CD adhering to a gluten-free diet (Table 1: 8.1, 8.1.1.II and 8. Tapsas D, Fälth-Magnusson K, Högberg L, et al. Swedish children with
8.1.1.IV), these are mainly based on expert opinion, since there is celiac disease comply well with a gluten-free diet, and most include
little evidence on this topic. This was also the reason to avoid for- oats without reporting any adverse effects: a long-term follow-up study.
mulating a recommendation on the quantity of gluten that should Nutr Res 2014;34:436–41.
be ingested during a gluten-challenge, even if, as stated, gluten 9. Myléus A, Reilly NR. Green PHR. Rate, risk factors, and outcomes
ingestion of 10–15 g/day for 3–6 months is expected to induce of nonadherence in pediatric patients with celiac disease: a systematic
small-bowel abnormalities in the majority of CD children. In addi- review. Clin Gastroenterol Hepatol 2020;18:562–73.
tion, no consensus was reached on whether intestinal biopsies 10. Barnea L, Mozer-Glassberg Y, Hojsak I, et al. Pediatric celiac disease
should be performed before starting or after the gluten-challenge patients who are lost to follow-up have a poorly controlled disease.
Digestion 2014;90:248–53.
(8.1.1.I and 8.1.1.III), since a substantial number of the coauthors 11. Hagopian W, Lee HS, Liu E, et al; TEDDY Study Group. Co-occurrence
found that serum IgA-TGA levels ≥ 10× ULN should be enough of Type 1 Diabetes and Celiac Disease Autoimmunity. Pediatrics
to confirm a relapse of CD after gluten-challenge. All these rea- 2017;140:e20171305.
sons make future prospective research on gluten-challenge in chil- 12. Snyder J, Butzner D, DeFelice AJ, et al. Evidence-informed expert
dren necessary. Surrogate biomarkers of CD-specific small-bowel recommendations for the management of celiac disease in children.
damage, such as cytokines and gliadin-specific T cells recruited Pediatrics 2016;138:e20153147.
in peripheral blood after short-time gluten exposure, are promis- 13. Valitutti F, Trovato CM, Montuori M, et al. Pediatric celiac disease:
ing tools to develop less invasive forms of gluten-challenge. This follow-up in the spotlight. Adv Nutr 2017;8:356–61.
may involve new immunohistochemical markers of morphologi- 14. Wessels M, van Veen II, Vriezinga SL, et al. Complementary serologic
investigations in children with celiac disease is unnecessary during
cal changes of the mucosa such as APOA4:Ki67 ratios (159,160), follow-up. J Pediatr 2016;169:55–60.
detection of the HLA-DQ-gluten tetramer and increase in IL2 15. Ludvigsson JF, Agreus L, Ciacci C, et al. Transition from childhood
in peripheral blood (122) or changes in gut-homing CD8T-cells, to adulthood in coeliac disease: the Prague consensus report. Gut
HLA-DQ restricted gluten-specific CD4 T cells, all proposed as 2016;65:1242–51.
markers of T-cell response in CD patients after short-term gluten 16. Johansson K, Malmberg Hard af Segerstad E, Martensson H, et al.
intake (161–165). Dietitian visits were a safe and cost-effective form of follow-up care for
Similarly, there is little information available on how to fol- children with celiac disease. Acta Paediatr 2019;108:676–680.
low children with potential CD and long-term studies on this topic 17. Haas K, Martin A, Park KT. Text Message Intervention (TEACH)
are needed. In addition, there is a paucity of studies that compare improves quality of life and patient activation in celiac disease: a ran-
domized clinical trial. J Pediatr 2017;185:62–67.e2.
long-term effects on dietary compliance depending on who does the 18. Vriezinga S, Borghorst A, van den Akker-van Marle E, et al.
follow-up and more studies are warranted to evaluate if physical E-Healthcare for celiac disease—A multicenter randomized controlled
follow-up visits can be replaced by E-health services. trial. J Pediatr 2018;195:154–160.e7.
Finally, there are few studies on the effect of communi- 19. Connan V, Marcon MA, Mahmud FH, et al. Online education for gluten-
cation between the physician and the patient/parents/caregivers free diet teaching: Development and usability testing of an e-learning
on the long-term health status of CD children and no prospec- module for children with concurrent celiac disease and type 1 diabetes.
tive studies on the transfer of care from pediatric to adult medical Pediatr Diabetes 2019;20:293–303.
care in CD. In conclusion, we present here an update of the pres- 20. Sansotta N, Amirikian K, Guandalini S, et al. Celiac disease symptom
ent knowledge on the follow-up of children and adolescents with resolution: effectiveness of the Gluten-free diet. J Pediatr Gastroenterol
Nutr 2018;66:48–52.
CD and provide recommendations accordingly. Furthermore, we 21. Silvester JA, Kurada S, Szwajcer A, et al. Tests for serum transgluta-
have identified and highlighted gaps in knowledge that warrant minase and endomysial antibodies do not detect most patients with
more research to improve further follow-up of CD children and celiac disease and persistent villous atrophy on gluten-free diets: a
adolescents. meta-analysis. Gastroenterology 2017;153:689–701.e1.
22. Husby S, Bai JC. Follow up of coeliac disease. Gastroenterol Clin N Am
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ESPGHAN Position Paper On Management and Follow Up.29

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Societal Paper: Gastroenterology: Celiac Disease

ESPGHAN Position Paper on Management and Follow-

JPGN • Volume 75, Number 3, September 2022 369

I t is generally accepted that clinical follow-up of children and ado-

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