Katharina Julia Werkstetter1, Ilma Rita Korponay-Szabó2, Alina Popp3, Vincenzo Villanacci4, Marianna Salemme4, Gabriele Heilig1, Søren Thue Lillevang5, Maria Luisa Mearin6, Carmen Ribes-Koninckx7, Adrian Thomas8, Riccardo Troncone9, Birgit Filipiak1, Markku Mäki10, Judit Gyimesi11, Mehri Najafi12, Jernej Dolinšek13, Stine Dydensborg Sander14, Renata Auricchio9, Alexandra Papadopoulou15, Andreas Vécsei16, Peter Szitanyi17, Ester Donat7, Rafaella Nenna18, Philippe Alliet19, Francesca Penagini20, Hélène Garnier-Lengliné21, Gemma Castillejo22, Kalle Kurppa10, Raanan Shamir23, Almuthe Christine Hauer24, Françoise Smets25, Susana Corujeira26, Myriam van Winckel27, Stefan Buderus28, Sonny Chong29, Steffen Husby14, Sibylle Koletzko30. 1. Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany. 2. 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. 3. 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. 4. Institute of Pathology, Spedali Civili, Brescia, Italy. 5. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark. 6. Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands. 7. Department of Pediatric Gastroenterology and Hepatology, La Fe University Hospital, Valencia, Spain. 8. Department of Pediatric Gastroenterology, Royal Manchester Children's Hospital, Manchester, United Kingdom. 9. Department of Translational Medical Sciences & European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy. 10. Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland. 11. Celiac Disease Center Heim Pál Children's Hospital, Budapest and Department of Pediatrics, University of Debrecen, Debrecen, Hungary. 12. Department of Pediatric Gastroenterology & Hepatology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 13. Department of Pediatrics, University Medical Center (UMC), Maribor, Slovenia. 14. Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. 15. Division of Gastroenterology, Hepatology and Nutrition, First Department of Pediatrics, Children's Hospitals "Agia Sophia," University of Athens, Athens, Greece. 16. Gastroenterology Outpatient Clinic, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria. 17. Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic. 18. Department of Pediatrics, Sapienza University of Rome, Rome, Italy. 19. Department of Pediatrics, Jessa Hospital, Hasselt, Belgium. 20. Department of Pediatric Gastroenterology, Addenbrookes Hospital, Cambridge, United Kingdom. 21. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hôpital Necker-Enfants Malades, Paris, France. 22. Department of Pediatric Gastroenterology and Nutrition, Hospital Universitari Sant Joan, Reus, Spain. 23. Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 24. Department of Pediatrics, Medical University of Graz, Graz, Austria. 25. Université Catholique de Louvain, IREC, PEDI, Cliniques universitaires Saint Luc, Brussels, Belgium. 26. Department of Pediatric Gastroenterology, Hospital S. João, Porto, Portugal. 27. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium. 28. Department of Pediatrics, St. Marien Hospital, Bonn, Germany. 29. Queen Mary's Hospital for Children, Carshalton, United Kingdom. 30. Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany. Electronic address: sibylle.koletzko@med.uni-muenchen.de.
Abstract
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.
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.
Authors: Govind K Makharia; Prashant Singh; Carlo Catassi; David S Sanders; Daniel Leffler; Raja Affendi Raja Ali; Julio C Bai Journal: Nat Rev Gastroenterol Hepatol Date: 2022-01-03 Impact factor: 46.802