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 . Pediatric digestive endoscopy was allowed only for emergency cases , with a strong minimization of the total number of procedures. Most exams were postponed, including upper gastrointestinal endoscopies for children with suspected 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], no specific recommendation was produced for diagnosis and follow-up of pediatric 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 . TGA-IgA is usually normalized in upper limit normal (ULN) to minimize differences between commercial kits. TGA-IgA titers are highly predictive of SB mucosa damage . In 2020, ESPGHAN recommended a biopsy-free approach in children with TGA-IgA ≥10 ULN and positive EMA, regardless of symptoms.
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 . This particular group of children were the most affected by the elective procedures’ interruption during the COVID-19 outbreak. Without endoscopy many symptomatic children remained undiagnosed with potential harmful effects on overall health and growth. Thus, we retrospectively analyzed the feasibility and accuracy of a biopsy-free approach in children with suspected 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.
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  by the same pathologist.
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.
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
|Symptomatic children (diarrhea, constipation, abdominal pain, failure to thrive, bloating, anemia)
|Asymptomatic children (family screening)
|No mucosal damage
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.
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.
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 . For this reason, we believe that the reduction of the proposed ESPGHAN threshold can be feasible for 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], even without HLA status [12–14], by the new ESPGHAN 2020 guidelines .
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]. Diamanti et al.  reported TGA-IgA values >5 ULN as strongly predictive of mucosal atrophy. Combined sensitivities and specificities of positive TGA-IgA and EMA were above 90% . A biopsy-sparing approach has recently been proposed even for children with T1DM , and possibly in adults [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 , a tight monitoring can represent an additional and useful way to confirm the initial diagnosis in these children avoiding endoscopy.
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 ; indeed, an early detection and a strict diet adherence control represent the main factors to improve symptoms, especially in children . Likely, during the COVID-19 pandemic, many children with suspected 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.
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.
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