Introduction
The global outbreak of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an unexpected challenge for healthcare, requiring unprecedented measures and strategies to prevent diffusion. In Italy, one of the most severely hit countries, public healthcare has been reorganized to limit transmission and accommodate COVID-19 patients. In this new scenario, all elective diagnostic procedures have been suspended, particularly in children [1 2 celiac disease , despite the presence of symptoms. While the Inflammatory Bowel Disease (IBD) Working Group (the Porto group) of the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) published two documents for the management of IBD in children [3 , 4 celiac disease during COVID-19 pandemic.
Currently, the celiac disease diagnosis is based on IgA antitransglutaminase (TGA-IgA) autoantibodies, endomysial antibodies (EMA-IgA) and SB mucosa atrophy [5 6
Unfortunately, children with TGA-IgA <10 ULN still need to undergo endoscopy with biopsies to confirm the presence of an intestinal damage and the final diagnosis [7 celiac disease and TGA-IgA values <10 ULN. Our final goal is to evaluate the utility of the biopsy-free approach during the COVID-19 pandemic.
Methods
In this study cohort, we retrospectively analyzed celiac disease children with TGA-IgA value <10 ULN diagnosed by endoscopy between 2014 and 2019 in our unit. TGA-IgA was normalized in ULN; EMA was investigated by indirect immunofluorescence using monkey esophagus as substrate. At the time of diagnosis, all children were on free diet without gluten restrictions.
All endoscopies were performed under general anesthesia or deep sedation by an expert pediatric endoscopist. Mucosal biopsies (four in duodenum and two in bulb) were obtained and all specimens were oriented and graded according to the Marsh–Oberhuber classification [8
Categorical data were presented as frequency and percentages. The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were evaluated. Symptoms resolution and autoantibodies normalization after gluten-free diet (GFD) were also considered to confirm the celiac disease diagnosis.
Results
Among 430 patients (F: 274; mean age 7.54 years) with a biopsy-confirmed diagnosis of celiac disease at the Pediatric Gastroenterology and Hepatology Unit at the Hospital Umberto I – Sapienza University, we identified 242 children (F: 148; mean age 7.69 years) with serum TGA-IgA ≥5 ULN. Children with TGA-IgA ≥10 ULN and/or EMA negative were excluded, while 84 children (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and EMA positive were analyzed (Table 1 ).
Table 1. -
Characteristics of enrolled children
Number of children
Total
84
Males
38
Females
46
Symptomatic children (diarrhea, constipation, abdominal pain, failure to thrive, bloating, anemia)
74
Asymptomatic children (family screening)
10
EMA positive
84
EMA negative
0
Atrophy
78
No mucosal damage
6
EMA, endomysial antibody.
Seventy-four were symptomatic (gastrointestinal and/or extraintestinal symptoms), while a diagnosis after a family screening was made in 10. Seventy-eight children (92.8%) had a mucosal atrophy compatible with celiac disease , while six children (7.15%) had no sign of mucosal damage and were classified as potential celiac disease (Fig. 1 ). All potential celiac disease children showed HLA compatible with celiac disease .
Fig. 1.: Flow diagram of the study.
The PPV of TGA-IgA between 5 and 10 ULN and positive EMA were 0.93 (95% confidence interval 0.90–0.96).
At 1-year follow-up after the GFD, all children were having negative TGA-IgA and EMA values together with symptoms resolution.
Discussion
A biopsy-free approach with serum TGA-IgA titers ≥ 5 times ULN and positive EMA can accurately predict celiac disease in children. The high PPV of TGA-IgA between 5 and 10 ULN confirms the good correlation of this antibody with the intestinal damage. In our cohort, only six children received a diagnosis of potential celiac disease , which was less frequent than expected and reported in the literature [9 celiac disease diagnosis, especially during the pediatric endoscopy shutdown for COVID-19 pandemic. Not only children were typed for HLA but all showed mucosal atrophy and autoantibodies for celiac disease and their diagnosis was confirmed; therefore, HLA does not seem to increase diagnostic accuracy when low TTG is repeatedly positive and when EMA is also positive. The main role of HLA is to identify subjects who can develop celiac disease in the high-risk group.
Over the years, ESPGHAN guidelines for celiac disease have been continuously revised based on updated evidence. The first ‘biopsy-sparing’ approach was conceptualized in 2012, but it was applicable only for symptomatic children with high TGA-IgA values (>10 ULN) and DQ2 and/or DQ8 genotypes. More recently, these criteria have been also broadened to asymptomatic children [10 , 11 12–14 7
Many studies have demonstrated that TGA-IgA and EMA levels correlate with duodenal villous atrophy in pediatric celiac disease patients even at lower values [15 , 16 et al . [17 18 19 20 , 21
In our cohort, a TGA-IgA value between 5 and 10 ULN has been confirmed accurate to diagnose celiac disease , almost in all patients. The TGA-IgA accuracy was confirmed not only by the histology but also by symptoms resolution and TGA-IgA values normalization after GFD. Because the clinical follow-up plays a pivotal role in celiac disease management [22
A timely and correct diagnosis is extremely important to improve symptoms and prevent complications. An early diagnosis is particularly necessary in children with suspected celiac disease because the complications risk also depends on age at diagnosis [23 24 celiac disease and TGA-IgA < 10 ULN have not been diagnosed because of the current criteria and the lack of endoscopy availability, even though they were having sufficient parameters for diagnosing celiac disease . While this approach might be useful in an emergency setting, findings from our study need to be validated in a larger cohort.
In conclusion, during the COVID-19 outbreak, a temporarily reduction of the TTG-IgA threshold for biopsy-sparing approach seems feasible, avoiding delayed diagnosis and complications. Surely, a strict follow-up of the disease course and serum autoantibodies levels is extremely important to confirm diagnoses over time. In the next future, a critical revision of the ESPGHAN biopsy-free criteria for celiac disease diagnosis seems worthwhile if this approach will be prospectively validated.
Acknowledgements
C.M.T. and S.O. conceptualized the study, coordinated and supervised data collection, drafted the initial manuscript, and critically reviewed the manuscript for important intellectual content. M.M. and S.C. reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflicts of interest
There are no conflicts of interest.
References
1. Gralnek IM, Hassan C, Beilenhoff U, Antonelli G, Ebigbo A, Pellisè M, et al.ESGE and ESGENA position statement on gastrointestinal endoscopy and the COVID-19 pandemicEndoscopy202052483490
2. Ruan W, Fishman DS, Lerner DG, Engevik MA, Elmunzer BJ, Walsh CM, et al.Changes in pediatric endoscopic practice during the COVID-19 pandemic: results from an international surveyGastroenterology2020
3. Turner D, Huang Y, Martín-de-Carpi J, Aloi M, Focht G, Kang B, et al.Paediatric IBD Porto Group of ESPGHANCorona virus disease 2019 and paediatric inflammatory bowel diseases: global experience and provisional guidance (March 2020) from the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology, and NutritionJ Pediatr Gastroenterol Nutr202070727733
4. Turner D, Huang Y, Martin-de-Carpi J, Aloi M, Focht G, Kang B, et al.COVID-19 and paediatric inflammatory bowel diseases: global experience and provisional guidance (March 2020) from the Paediatric IBD Porto Group of ESPGHANJ Pediatr Gastroenterol Nutr202070727733
5. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al.The Oslo definitions for coeliac disease and related termsGut2013624352
6. Werkstetter KJ, Korponay-Szabó IR, Popp A, Villanacci V, Salemme M, Heilig G, et al.ProCeDE Study GroupAccuracy in diagnosis of
celiac disease without biopsies in clinical practiceGastroenterology2017153924935
7. Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-Koninckx C, et al.European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for diagnosing coeliac disease 2020J Pediatr Gastroenterol Nutr202070141156
8. Oberhuber G, Granditsch G, Vogelsang HThe histopathology of coeliac disease: time for a standardized report scheme for pathologistsEur J Gastroenterol Hepatol19991111851194
9. Volta U, Caio G, Giancola F, Rhoden KJ, Ruggeri E, Boschetti E, et al.Features and progression of potential
celiac disease in adultsClin Gastroenterol Hepatol20161468693.e1
10. Trovato CM, Montuori M, Anania C, Barbato M, Vestri AR, Guida S, et al.Are ESPGHAN ‘biopsy-sparing’ guidelines for
celiac disease also suitable for asymptomatic patients?Am J Gastroenterol201511014851489
11. Paul SP, Sandhu BK, Spray CH, Basude D, Ramani PEvidence supporting serology-based pathway for diagnosing
celiac disease in asymptomatic children from high-risk groupsJ Pediatr Gastroenterol Nutr201866641644
12. Landman M, Theuns SDM, van Wering HM, Tramper G, van Ledden M, Rietveld E, et al.Evaluation of the implementation of the 2012 ESPGHAN guideline of coeliac disease in children: results of a retrospective study in the NetherlandsArch Dis Child2020105413
13. Paul SP, Adams HL, Basude DCollaboratorsInterpretation and implementation of the revised European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines on pediatric
celiac disease amongst consultant general pediatricians in Southwest of EnglandIndian J Gastroenterol201938203210
14. Wolf J, Petroff D, Richter T, Auth MKH, Uhlig HH, Laass MW, et al.Validation of antibody-based strategies for diagnosis of pediatric
celiac disease without biopsyGastroenterology2017153410419.e17
15. Donaldson MR, Firth SD, Wimpee H, Leiferman KM, Zone JJ, Horsley W, et al.Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac diseaseClin Gastroenterol Hepatol20075567573
16. Meena DK, Akunuri S, Meena P, Bhramer A, Sharma SD, Gupta RTissue transglutaminase antibody and its association with duodenal biopsy in diagnosis of pediatric celiac diseasePediatr Gastroenterol Hepatol Nutr201922350357
17. Diamanti A, Colistro F, Calce A, Devito R, Ferretti F, Minozzi A, et al.Clinical value of immunoglobulin A
antitransglutaminase assay in the diagnosis of celiac diseasePediatrics2006118e1696e1700
18. Giersiepen K, Lelgemann M, Stuhldreher N, Ronfani L, Husby S, Koletzko S, Korponay-Szabó IRESPGHAN Working Group on Coeliac Disease DiagnosisAccuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence reportJ Pediatr Gastroenterol Nutr201254229241
19. Wessels M, Velthuis A, van Lochem E, Duijndam E, Hoorweg-Nijman G, de Kruijff I, et al.Raising the cut-off level of anti-tissue transglutaminase antibodies to detect
celiac disease reduces the number of small bowel biopsies in children with type 1 diabetes: a retrospective studyJ Pediatr20202238792.e1
20. Tortora R, Imperatore N, Capone P, De Palma GD, De Stefano G, Gerbino N, et al.The presence of anti-endomysial antibodies and the level of anti-tissue transglutaminases can be used to diagnose adult coeliac disease without duodenal biopsyAliment Pharmacol Ther20144012231229
21. Di Tola M, Marino M, Goetze S, Casale R, Di Nardi S, Borghini R, et al.Identification of a serum transglutaminase threshold value for the noninvasive diagnosis of symptomatic adult
celiac disease patients: a retrospective studyJ Gastroenterol20165110311039
22. Valitutti F, Trovato CM, Montuori M, Cucchiara SPediatric
celiac disease : follow-up in the spotlightAdv Nutr20178356361
23. Biagi F, Schiepatti A, Maiorano G, Fraternale G, Agazzi S, Zingone F, et al.Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentationDig Liver Dis201850549552
24. Sansotta N, Amirikian K, Guandalini S, Jericho HCeliac disease symptom resolution: effectiveness of the gluten-free dietJ Pediatr Gastroenterol Nutr2018664852
