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Objective The aim of this study was to summarise the evidence from 2004 to September 2009 on the performance of laboratory-based serological and point of care (POC) tests for diagnosing coeliac disease (CD) in children using histology as reference standard. Patients and methods We searched MEDLINE and EMBASE for studies reporting on children for tests based on IgA and IgG anti-gliadin (AGA), endomysial (EmA), anti-transglutaminase-2 (TG2), and anti-deamidated gliadin peptides (DGP) antibodies or POC tests. For inclusion, histological analysis of duodenal biopsies and sensitivity and specificity for index tests had to be reported. Data were pooled and summary measures calculated for sensitivity, specificity, positive and negative likelihood ratios ("LR+", "LR-"), and diagnostic odds ratios (DOR). In case of elevated statistical heterogeneity, studies reaching 90% sensitivity or specificity were reported. Results A total of 2510 articles were reviewed; 16 entered meta-analysis, reporting on 3110 patients (1876 with CD, 1234 without CD). For IgA-EmA, sensitivity was ≥90% in 7/11 studies and pooled specificity 98.2%. For IgA-anti-TG2, 11/15 studies yielded sensitivities ≥90% and 13/15 specificities ≥90%. For IgA-DGP, sensitivity ranged between 80.7% and 95.1% (specificity 86.3%-93.1%); for IgG-DGP between 80.1% and 98.6% (specificity 86.0-96.9%). IgA-EmA had the highest pooled DOR (554) and LR+ (31.8) for a laboratory test, followed by IgA-anti-TG2, IgG-DGP, IgA-DGP and IgA-AGA. POC tests showed a pooled sensitivity of 96.4% for IgA-TG2 (specificity 97.7%). Conclusions IgA-EmA and IgA-anti-TG2 tests appear highly accurate to diagnose CD. IgG-anti-DGP tests may help in excluding CD. IgA-AGA and IgA-DGP tests show inferior accuracy. POC tests may achieve high accuracy in the hands of experienced readers, but IgA-anti-TG2/EmA were superior.

Objectives Use of deamidated gliadin peptide (DGP) test kits as adjunctive to Tissue-transglutaminase IgA (TTG-IgA) for the diagnosis of celiac disease (CD) has been a controversial issue. The objectives of our study were to evaluate the diagnostic performance of DGP antibodies compared to TTG-IgA and to evaluate the correlation between DGP-antibodies titers and degree of enteropathy. Methods We included children who underwent endoscopy and biopsies because of positivity of any of the serology tests in the "celiac profile" (TTG-IgA, DGP-IgA, and DGP-IgG), from 2012 to 2019. We divided children into clinically suspected cases of CD (Group 1) and asymptomatic cases screened because they were from a high risk-group (Group 2). Results Group 1 constituted 52 children and group 2 included 81 children [76 type1-diabetes (T1D)]. The sensitivity and positive predictive value (PPV) of DGP-IgG in group 1 (90%, 98%) and group 2 (91%, 85.5%) were comparable to TTG-IgA (98%, 92% in group 1; 100%, 80% in group 2). By adding DGP-IgG to TTG-IgA, the performance of TTG-IgA has improved marginally in group 1 (sensitivity 100%, PPV 92.3%). All cases with DGP-IgG titer 2 times ULN in group 1, and > 4 times ULN in group 2 had villous atrophy. All T1D patients with TTG IgA > 10 times ULN had villous atrophy. Conclusion DGP-IgG assay did not add to the performance of TTG-IgA. DGP-IgG titer correlated with enteropathy. The diagnosis of CD can be made in asymptomatic T1D child with TTG-IgA titer > 10 times ULN and positive endomyseal antibodies.

Objectives Villous atrophy (VA) is not pathognomonic of celiac disease (CD). We aimed at reporting distribution, clinical, and immunohistochemical features of seronegative VA (SNVA) in a pediatric population. Methods We retrospectively collected data from patients who underwent intestinal biopsies between 2010 and 2017 and showed VA without serum CD-associated autoantibodies. Marsh-Oberhuber grading was used. Density of intraepithelial lymphocytes (IELs) expressing CD3 or TCRγδ+ receptor and of lamina propria CD25+ cells was assessed by immunohistochemistry. Intestinal deposits of anti-tissue tranglutaminase2 (anti-TG2) were also investigated by double immunofluorescence. Results Over a 7-year period, 64 out of 1282 patients with VA had negative serum CD serology. Diagnoses were: inflammatory bowel diseases (IBD) (21/64), Gastro-Esophageal Reflux Disease (GERD) (12/64), food allergy (8/64), infections (7/64, of which 3 HIV infections), immune deficiency (3/64), short bowel syndrome (3/64), congenital diarrhea (2/64), other/inconclusive diagnosis (8/64). Forty-four, 15, and 5 showed Marsh 3a, 3b, and 3c lesion, respectively. The latter category included 2 patients with Crohn disease, 2 with immunodeficiencies, 1 with lymphohistiocytosis. In 41/46 (89%) patients, mononuclear CD25+ cells were above the cut-off, indicating mucosal inflammation but only 18/46 (39%) had IELs and TCRγδ + IELs above limits of normality. In 10 of 46 (22%) patients, a positive immunofluorescence indicated the presence of anti-TG2 mucosal antibodies. Conclusions SNVA is not rare representing up to 5% of the cases of VA. Most patients have a Marsh 3a lesion. Immunohistochemical analysis may be helpful in excluding CD, whereas the finding of mucosal anti-TG2, particularly with a weak staining, shows no absolute specificity for CD.

Since the conception of an idea of a few paediatric gastroenterologists in Europe to create a society for Paediatric Gastroenterology in 1967, and its foundation in 1968, half a century has passed. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) now celebrates its 50th anniversary and its utmost success in combining clinical and scientific expertise in the fields of paediatric gastroenterology, haepatology, and nutrition. To describe this success story 14 of the still living presidents of ESPGHAN recount their impressions of the steady growth of ESPGHAN with all the historical facets from their own points of view. This historical view of ESPGHAN over the last 5 decades provides personal accounts of the development of all activities and creations of this great European Society. The Society started as a small family of experts in the field into a global working open society involved in a large variety of activities within the subspecialties, becoming a leading organisation in Europe and beyond. This unique view gives also a wonderful insight into the famous clinicians and researchers from all over Europe who have helped in the growth and development of ESPGHAN. By describing all these activities and collaborations it becomes clear that this astonishing pan-European enterprise was achieved by people who put considerable effort and time into the development of this society. Their statements serve as a historical source and reference for future evaluation of the first 50 years of ESPGHAN. In depicting different time episodes, and by assembling all the historical pieces of a puzzle together, the statements help to illustrate how a highly structured society such as ESPGHAN has evolved over the last 50 years, for what it stands for today and what is to be expected in the future.

Children comprise one-fifth of Europe's population. Promoting child health and development is of key importance for society and its future. This position paper highlights opportunities of investing in gastrointestinal, liver, and nutritional research to promote child health and delineates priorities for research. Investing in child health plays a key role in the promotion of population health, well-being, and disease prevention lifelong, with large health economic benefits. Major opportunities for improving knowledge and translational application arise from recent scientific and technological developments, for example, the long-term impact of early environmental cues interacting with genes. Personalised approaches to therapy and prevention should be enhanced. Deciphering the microbiome and its effects on functions can help in promoting long-term health. Epigenetic research can help to understand how early environmental factors influence later gastrointestinal and hepatic health and disease. A linked nutrition and physical activity strategy can promote health and prevent nutritional deficiencies, inactivity, and chronic noncommunicable diseases, such as diabetes, to ensure optimal health and cognition. Special attention should be devoted to populations with low socioeconomic status, migrant background, and ethnic minorities, and to critical life periods, including pregnancy, lactation, infancy, and childhood. Improved understanding of optimal nutrition and on maintaining gut and liver homeostasis throughout childhood will help prevent chronic diseases in later life.

Objective To assess the effectiveness of the combined use of fecal calprotectin (FC), anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear staining antineutrophil antibody (pANCA), small intestinal permeability test (IP), and bowel wall ultrasonography measurement (BWUS) in the diagnostic work-up of children with suspected inflammatory bowel disease (IBD). Methods All children referred for initial assessment of possible IBD were eligible. Patients with symptoms or signs (right-lower quadrant mass, perianal disease, or hematochezia) mandating a complete work-up for IBD were excluded. All enrolled patients underwent a clinical, laboratory, radiographic, and endoscopic evaluation including biopsy examinations. The immunoglobulin (Ig)G and IgA ASCA, IgG pANCA, FC, IP, and BWUS were tested in all patients at the initial assessment. Results A final diagnosis of IBD was made in 27 patients: 17 Crohn disease and 10 ulcerative colitis. Eighteen children had other gastrointestinal diagnoses (8 functional bowel disorders, 5 food allergy-mediated diseases, 4 infectious enterocolitis, 1 familial Mediterranean fever). In patients with simultaneous abnormal values of FC, BWUS, and ASCA/pANCA, the estimated probability of having IBD was 99.47%. Patients with negative results on all tests had a 0.69% of probability of IBD. Conclusions The incorporation of noninvasive diagnostic tests into the initial diagnostic approach may avoid unnecessary invasive procedures and facilitate clinical decision-making when the diagnosis of IBD in children is initially uncertain.

OBJECTIVES: Celiac disease (CD) represents a spectrum, which includes cases with minor histological abnormalities (potential CD). The aim of this work is to evaluate the contribution of immunohistochemical analysis of duodenal biopsies to the diagnosis of gluten-related minor enteropathy. METHODS: Duodenal biopsies from 56 patients with untreated CD and 56 controls were analyzed for CD3 and γδ intraepithelial lymphocyte number, γδ/CD3 ratio, and density of CD25+ lamina propria cells. A discriminant equation was obtained by which 61 more biopsies with normal villous architecture were blindly evaluated. RESULTS: All of the immunohistochemical parameters were significantly different between patients with CD and controls. None of the single parameters showed sufficient specificity for CD. The combination of all of the 4 markers resulted in the following discriminant equation: discriminant score (Dscore) = (CD3 × 0.06) - (γδ × 0.119) + (CD25 × 0.012) + (γδ/CD3 × 0.131) - 4.709. Using this Dscore, patients were correctly classified as celiac or controls in 97.3% of the cases. When this equation was applied to a validation set of 61 patients with normal villous architecture and unknown diagnosis, 92.9% of those with a positive score turned out to be patients with potential CD. A normal score, however, did not exclude this condition. CONCLUSIONS: Immunohistochemistry represents a specific tool for the diagnosis of CD, but does lack sensitivity in detecting all of the potential CD cases.

Celiac disease (CD) has a multifactorial etiology with complex genetics and frequently occurs in association with other autoimmune disorders. Even though triggered by a dietary antigen, it shows many autoimmune features, the most peculiar being the presence of high titers of anti-tissue transglutaminase 2 autoantibodies, produced in the small intestinal mucosa since the early stages of the disease. More than 60% of CD-associated susceptibility loci are shared with at least another autoimmune condition, suggesting common pathogenic mechanisms. In particular, recognition of peptides by HLA molecules, posttranslational modifications required for optimal peptide binding and immune mechanisms leading to tissue damage have been found in CD as well as in other autoimmune diseases. This review briefly summarizes the main autoimmune features of CD, underlining the similarities with other autoimmune disorders, in particular with type 1 diabetes mellitus. Furthermore, the role of gluten and microbiome in driving autoimmunity is discussed.

The aim of this study was to investigate the current implementation of the 1990 ESPGHAN criteria for the diagnosis of celiac disease (CD) in Italy to form a foundation for their revision. From September 2006 to March 2007 a nationwide questionnaire concerning current diagnostic methods was sent by mail to 54 Italian centres for the diagnosis of CD, which were distributed across the entire national territory. The questionnaire investigated the tests performed, diagnostic criteria currently used, and the management of some special cases in each centre. Eighty percent of the centres use anti-tissue transglutaminase to diagnose CD and anti-endomysium antibodies to confirm the results. Fifty-five percent still use anti-gliadin antibodies. A total of 87.5% of centres perform HLA typing, especially in first-degree relatives and in unclear diagnosis. Regarding histology, 67.5% of centres consider an infiltrative lesion consistent with diagnosis of CD. The majority of centres (85%) use the 1990 ESPGHAN criteria for both symptomatic and asymptomatic patients, but 80% do not perform a second biopsy in asymptomatic cases or a gluten challenge in children younger than 2 years of age. Furthermore, most centres (72.5%) do not prescribe a gluten-free diet to asymptomatic patients with positive serology and normal bowel architecture (ie, potential cases), but they do program a careful follow-up. In conclusion, ESPGHAN criteria are widely followed by Italian CD centres. However, their revision may be useful, but it should be evidence based. Large, multicentre studies are greatly needed.

The colon is a site of allergic reaction to food proteins. The most common manifestation is allergic proctocolitis. Although frequent in infancy, it may also affect older children. The diagnosis of allergic proctocolitis is mainly based on clinical and histological grounds, but there is a risk of overdiagnosis; challenge is strongly recommended to avoid unnecessary and expensive formula or changes in maternal diet that may discourage continuation of breast-feeding. The benign clinical course and the spontaneous resolution in most infants suggest the need for further prospective studies to validate markers that allow the identification of those children needing a dietary approach. It remains to be assessed whether lymphoid nodular hyperplasia of the colon is a manifestation of food allergy. Finally, allergic proctitis may present clinically with refractory constipation; the true prevalence of food allergy-related constipation remains to be assessed.

A longitudinal (10-22 month) evaluation of intestinal symptoms and function was performed in five children with symptomatic human immunodeficiency virus (HIV) infection. All received cotrimoxazole, ketoconazole, and immunoglobulins. A search for enteric pathogens and intestinal function tests were repeatedly performed in all patients. Mild episodes of diarrhea were observed in two children. One had cow's milk protein intolerance. Giardia lamblia was found in an asymptomatic carrier. Evidence for impaired intestinal function was found in all patients. These consisted of positive D-xylose and iron oral loads, increased steatorrhea, increased fecal excretion of alpha 1-antitrypsin, abnormal intestinal permeability, and increased food antibody levels. Our results suggest that severe diarrhea may be uncommon in children with HIV infection receiving antimicrobial prophylaxis, but that the intestinal function is frequently, and often markedly, impaired.

Objectives Anti-tissue transglutaminase (anti-TG2) immunoglobulin A (IgA) autoantibodies are detectable in the serum of most patients with untreated celiac disease (CD). Their deposits in the intestine of patients with CD with severe enteropathy are considered specific for this condition. The histological spectrum of CD includes cases with normal villous architecture. The aim of this study was to look for anti-TG2 IgA deposits in the intestine of children with normal villous architecture and to relate them with other markers of gluten sensitivity. Patients and methods A total of 57 children with normal duodenal villous architecture and markers of gluten sensitivity were considered. Of those, 39 showed positive serum anti-endomysium antibodies and/or high levels of anti-TG2 antibodies (group 1), and 18 were seronegative with only a greater density of gammadelta intraepithelial lymphocytes (group 2). Thirty-four children with no markers of gluten sensitivity and a normal mucosa represented the control group (group 3). The duodenal sections of all patients were investigated for deposited anti-TG2 IgA by double immunofluorescence. Human lymphocyte antigen molecular typing was performed. Results In group 1 and in group 2, 33 of 39 children (85%) and 12 of 18 children (66%) showed subepithelial anti-TG2 IgA intestinal deposits, respectively. Only in 3 of 34 (8.8%) children with no markers of gluten sensitivity were anti-TG2 IgA deposits noted. Conclusions A subgroup of children with no serum CD-associated autoantibodies, but greater density of gammadelta intraepithelial lymphocytes, shows a clear anti-TG2 IgA deposition in the duodenal mucosa. These children must be investigated further for possible gluten sensitivity.