BACKGROUND & AIMS: The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. METHODS: We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. RESULTS: Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00). CONCLUSIONS: Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Celiac Disease Center Heim Pál Children's Hospital Budapest and Department of Pediatrics University of Debrecen Debrecen Hungary

Celiac Disease Center Heim Pál Children's Hospital Budapest and Department of Pediatrics University of Debrecen Debrecen Hungary; Center for Child Health Research University of Tampere and Tampere University Hospital Tampere Finland

Center for Child Health Research University of Tampere and Tampere University Hospital Tampere Finland

Center for Child Health Research University of Tampere and Tampere University Hospital Tampere Finland; University of Medicine and Pharmacy Carol Davila and National Institute for Mother and Child Health Alessandrescu Rusescu Bucharest Romania

Department of Clinical Immunology Odense University Hospital Odense Denmark

Department of Pediatric Gastroenterology Addenbrookes Hospital Cambridge United Kingdom

Department of Pediatric Gastroenterology and Hepatology Children's Medical Center Tehran University of Medical Sciences Tehran Iran

Department of Pediatric Gastroenterology and Hepatology La Fe University Hospital Valencia Spain

Department of Pediatric Gastroenterology and Nutrition Hospital Universitari Sant Joan Reus Spain

Department of Pediatric Gastroenterology Hepatology and Nutrition Ghent University Hospital Ghent Belgium

Department of Pediatric Gastroenterology Hepatology and Nutrition Hôpital Necker Enfants Malades Paris France

Department of Pediatric Gastroenterology Hospital S João Porto Portugal

Department of Pediatric Gastroenterology Royal Manchester Children's Hospital Manchester United Kingdom

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine and General Teaching Hospital Charles University Prague Czech Republic

Department of Pediatrics Jessa Hospital Hasselt Belgium

Department of Pediatrics Leiden University Medical Center Leiden the Netherlands

Department of Pediatrics Medical University of Graz Graz Austria

Department of Pediatrics Sapienza University of Rome Rome Italy

Department of Pediatrics St Marien Hospital Bonn Germany

Department of Pediatrics University Medical Center Maribor Slovenia

Department of Translational Medical Sciences and European Laboratory for the Investigation of Food Induced Diseases University Federico 2 Naples Italy

Division of Gastroenterology Hepatology and Nutrition 1st Department of Pediatrics Children's Hospitals Agia Sophia University of Athens Athens Greece

Dr von Hauner Children's Hospital Department of Pediatrics University Hospital LMU Munich Munich Germany

Gastroenterology Outpatient Clinic St Anna Children's Hospital Medical University Vienna Vienna Austria

Hans Christian Andersen Children's Hospital Odense University Hospital Odense Denmark

Institute of Gastroenterology Nutrition and Liver Diseases Schneider Children's Medical Center of Israel Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Institute of Pathology Spedali Civili Brescia Italy

Queen Mary's Hospital for Children Carshalton United Kingdom

Université Catholique de Louvain IREC PEDI Cliniques universitaires Saint Luc Brussels Belgium

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