SELF-REPORTED NON-CELIAC GLUTEN SENSITIVITY IN ITALIAN YOUNG ADULTS: A CROSS-SECTIONAL STUDY. A DIETARY FAD?

OBJECTIVES: In different countries, the exact prevalence of people that refer symptoms after gluten ingestion is increasing and the unavailability of reliable laboratory tests to diagnose the condition known as non-celiac gluten sensitivity (NCGS) has opened the door to the spread of survey-based studies to hypothesize a prevalence of this condition with highly discordant results. We aim to describe the attitude toward gluten consumption in a large population of young adults in Italy. METHODS: A questionnaire-based cross-sectional study was conducted in thirteen Italian cities to investigate the dietary attitudes of more than 9400 people distributed throughout the country about gluten consumption. Only those referring to gluten-related symptoms with a frequency equal to "always" or "most of the time" were considered self-reported NCGS (SR-NCGS) patients. RESULTS: Five thousand two hundred and thirty-four of 9432 eligible participants (55.5%) fully completed the questionnaire. Excluding those with previous gastrointestinal diagnoses of celiac disease and wheat allergy, we have finally analyzed 4987 questionnaires. Four hundred and eighty-seven participants indicated gluten-related symptoms "always" or "most of the time" (SR-NCGS subjects), while 121 already had a medical diagnosis of NCGS. The minimum prevalence figure of SR-NCGS is 6.4% (95%CI: 6.0-6.9), with a higher prevalence in females (79.9%). The most frequent gluten-related symptoms were bloating, abdominal pain and tiredness. CONCLUSIONS: The high prevalence of people reporting symptoms after gluten ingestion requires that the diagnosis of NCGS should be ascertained with a double-blind controlled study to limit the number of people who improperly approach a gluten-free diet.

Novel Bacteroides Vulgatus strain protects against gluten-induced break of human celiac gut epithelial homeostasis: a pre-clinical proof-of-concept study.

BACKGROUND AND AIMS: We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions. METHODS: We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS). RESULTS: Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS. CONCLUSIONS: We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming. IMPACT: Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.

Gastrointestinal involvement in STEC-associated hemolytic uremic syndrome: 10 years in a pediatric center.

BACKGROUND: The gastrointestinal (GI) tract represents one of the main targets of typical hemolytic uremic syndrome (HUS) in children. In this observational study, we tried to establish (1) the main features of GI complications during STEC-HUS and (2) the relationship between Escherichia coli serotypes and Shiga toxin (Stx) variants with hepatopancreatic involvement. METHODS: A total of 79 STEC-HUS patients were admitted to our pediatric nephrology department between January 2012 and June 2021. Evidence of intestinal, hepatobiliary, and pancreatic involvements was reported for each patient, alongside demographic, clinical, and laboratory features. Frequency of gastrointestinal complications across groups of patients infected by specific E. coli serotypes and Stx gene variants was evaluated. RESULTS: Six patients developed a bowel complication: two developed rectal prolapse, and four developed bowel perforation which resulted in death for three of them and in bowel stenosis in one patient. Acute pancreatitis was diagnosed in 13 patients. An isolated increase in pancreatic enzymes and/or liver transaminases was observed in 41 and 15 patients, respectively. Biliary sludge was detected in three, cholelithiasis in one. Forty-seven patients developed direct hyperbilirubinemia. Neither E. coli serotypes nor Shiga toxin variants correlated with hepatic or pancreatic involvement. CONCLUSIONS: During STEC-HUS, GI complications are common, ranging from self-limited elevation of laboratory markers to bowel perforation, a severe complication with a relevant impact on morbidity and mortality. Hepatopancreatic involvement is frequent, but usually short-lasting and self-limiting.

Early Antibody Dynamics in a Prospective Cohort of Children At Risk of Celiac Disease.

INTRODUCTION: The purpose of this study was to identify possible serum biomarkers predicting celiac disease (CD) onset in children at risk. METHODS: A subgroup from an ongoing, international prospective study of children at risk of CD was classified according to an early trajectory of deamidated gliadin peptides (DGPs) immunoglobulin (Ig) G and clinical outcomes (CD, potential CD, and CD autoimmunity). RESULTS: Thirty-eight of 325 children developed anti-tissue transglutaminase IgA antibody (anti-tTG IgA) seroconversion. Twenty-eight of 38 children (73.6%) showed an increase in anti-DGPs IgG before their first anti-tTG IgA seroconversion. DISCUSSION: Anti-DGPs IgG can represent an early preclinical biomarker predicting CD onset in children at risk.

Twelve Months with COVID-19: What Gastroenterologists Need to Know.

Corona virus disease-19 (COVID-19) is the latest global pandemic. COVID-19 is mainly transmitted through respiratory droplets and, apart from respiratory symptoms, patients often present with gastrointestinal symptoms and liver involvement. Given the high percentage of COVID-19 patients that present with gastrointestinal symptoms (GIS), in this review, we report a practical up-to-date reference for the physician in their clinical practice with patients affected by chronic gastrointestinal (GI) diseases (inflammatory bowel disease, coeliac disease, chronic liver disease) at the time of COVID-19. First, we summarised data on the origin and pathogenetic mechanism of SARS-CoV-2. Then, we performed a literature search up to December 2020 examining clinical manifestations of GI involvement. Next, we illustrated and summarised the most recent guidelines on how to adhere to GI procedures (endoscopy, liver biopsy, faecal transplantation), maintaining social distance and how to deal with immunosuppressive treatment. Finally, we focussed on some special conditions such as faecal-oral transmission and gut microbiota. The rapid accumulation of information relating to this condition makes it particularly essential to revise the literature to take account of the most recent publications for medical consultation and patient care.

Functional Abdominal Pain Disorders and Constipation in Children on Gluten-Free Diet.

BACKGROUND & AIMS: We studied the prevalence of functional abdominal pain disorders (FAPDs) and functional constipation (FC) in a large prospective cohort of children with celiac disease on a strict gluten-free diet (GFD). METHODS: We performed a prospective cohort study, from 2016 through 2018, in a tertiary care center in Italy, of 417 patients (37% male; mean age, 13.7 y) with a diagnosis of celiac disease (European Society for Paediatric Gastroenterology Hepatology, and Nutrition criteria) who had been on a strict GFD for more than 1 year and had negative results from serologic tests after being on the GFD. Parents and children (>10 y) were asked to fill in a questionnaire on pediatric gastrointestinal symptoms, according to Rome IV criteria. Patients' closest siblings (or cousins) who had negative results from serologic test for celiac disease were used as controls (n = 373; 39% male; mean age, 13.5 y). RESULTS: We found a higher prevalence of FAPDs among patients with celiac disease (11.5%) than controls (6.7%) (P < .05); the relative risk (RR) was 1.8 (95% CI, 1.1-3.0). Irritable bowel syndrome (IBS) and FC defined by the Rome IV criteria were more prevalent in patients with celiac disease (7.2% for IBS and 19.9% for FC) than controls (3.2% for IBS and 10.5% for FC) (P < .05 and P < .001, respectively); the RR for IBS was 2.3 (95% CI, 1.1-4.6) and the RR for functional constipation was 2.1 (95% CI, 1.4-3.2). We found no differences in the prevalence of other subtypes of FAPDs. A logistic regression showed that younger age (P < .05) and a higher level of anti-transglutaminase IgA at diagnosis (P < .04) were associated with FAPDs (in particular for IBS) irrespective of GFD duration. CONCLUSIONS: Celiac disease is associated with an increased risk of IBS and FC. Strategies are needed to manage IBS and FC in patients with celiac disease.

Limosilactobacillus reuteri Strains as Adjuvants in the Management of Helicobacter pylori Infection.

Helicobacter pylori (HP) is a Gram-negative bacterium which finds its suitable habitat in the stomach. The infection affects about half of the global population with high variability in prevalence among regions and for age. HP is the main causative agent of chronic active gastritis, peptic and duodenal ulcers, and may be the primary cause of gastric cancer or MALT lymphoma. Due to the high rate of failure of eradication therapy in various countries and the increase in antibiotic resistance reported in the literature, there is an ever wider need to seek alternative therapeutic treatments. Probiotics seem to be a promising solution. In particular, the Limosilactobacillus reuteri (L. reuteri) species is a Gram-positive bacterium and is commonly found in the microbiota of mammals. L. reuteri is able to survive the gastric acid environment and bile and to colonize the gastric mucosa. This species is able to inhibit the growth of several pathogenic bacteria through different mechanisms, keeping the homeostasis of the microbiota. In particular, it is able to secrete reuterin and reutericycline, substances that exhibit antimicrobial properties, among other molecules. Through the secretion of these and the formation of the biofilm, it has been found to strongly inhibit the growth of HP and, at higher concentrations, to kill it. Moreover, it reduces the expression of HP virulence factors. In clinical trials, L. reuteri has been shown to decrease HP load when used as a single treatment, but has not achieved statistical significance in curing infected patients. As an adjuvant of standard regimens with antibiotics and pump inhibitors, L. reuteri can be used not only to improve cure rates, but especially to decrease gastrointestinal symptoms, which are a common cause of lack of compliance and interruption of therapy, leading to new antibiotic resistance.

Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial.

GOALS: The goals of this study were to evaluate the efficacy and safety of a probiotic mixture in patients with celiac disease (CD) with irritable bowel syndrome (IBS)-type symptoms despite a strict gluten-free diet (GFD). BACKGROUND: About 30% of patients with CD adherent to a GFD suffer from IBS-type symptoms; a possible cause resides in the imbalances of the intestinal microbiota in CD. Probiotics may represent a potential treatment. STUDY: CD patients with IBS-type symptoms entered a prospective, double-blind, randomized placebo-controlled study. A 6-week treatment period was preceded by a 2-week run-in and followed by a 6-week follow-up phase. Clinical data were monitored throughout the study by validated questionnaires: IBS Severity Scoring System (IBS-SSS); Gastrointestinal Symptom Rating Scale (GSRS); Bristol Stool Form Scale (BSFS); and IBS Quality of Life Questionnaire (IBS-QOL). The fecal microbiota were assayed using plate counts and 16S rRNA gene-based analysis. RESULTS: In total, 109 patients were randomized to probiotics (n=54) or placebo (n=55). IBS-SSS and GSRS decreased significantly in probiotics, as compared with placebo [(-15.9%±14.8% vs. 8.2%±25.9%; P<0.001) and (-19.8%±16.6% vs. 12.9%±31.6%; P<0.001)], respectively. Treatment success was significantly higher in patients receiving probiotics, as compared with placebo (15.3% vs. 3.8%; P<0.04). Presumptive lactic acid bacteria, Staphylococcus and Bifidobacterium, increased in patients receiving probiotic treatment. No adverse events were reported. CONCLUSIONS: A 6-week probiotic treatment is effective in improving the severity of IBS-type symptoms, in CD patients on strict GFD, and is associated with a modification of gut microbiota, characterized by an increase of bifidobacteria.

Intervention for Dysbiosis in Children Born by C-Section.

The symbiotic relationship between microbes and human is fundamental for a physiological development and health. The microbiome of the newborn undergoes to dramatic changes during the process of birth and in the first thousand days of life. Mother Nature provided us with the best possible start to achieve eubiosis: vaginal delivery to receive our mother's microbiome and breast milk that favours the establishment of beneficial bacteria. Infants deprived of one or both of these evolutionary gifts undergo to important modification of the microbial communities leading to a state of dysbiosis enhancing the chance of the emergence of a variety of immune, inflammatory and metabolic disorders. Are we able to imitate nature? Is there any intervention for dysbiosis in children born by cesarean section? In this review we will try to answer to this intriguing question on the basis of the most recent scientific evidences.

Long-term outcomes of Heller's myotomy and balloon dilatation in childhood achalasia.

Achalasia is a rare esophageal motility disorder: its optimal treatment in children is still a matter of debate. Records of children treated for achalasia, over an 18-year period, were reviewed.Forty-eight children (median age at diagnosis 10 years; range 3-17 years) were identified. Twenty-eight patients were initially treated with Heller's myotomy (HM) and 20 with balloon dilatation (BD). At last follow-up (median 3 years; range 1-5.5 years), 43.8% (21/48) of children were symptom free. The number of asymptomatic children was significantly higher among those treated initially with HM compared to BD (HM 15/28, 53.6% BD 6/20, 30%, p < 0.05). All children who underwent BD required HM due to symptom recurrence. The median (range) total number of procedures was significantly higher in the BD group (BD 3 (1-7); HM 1 (1-5); p < 0.05) with a shorter time to the second intervention (BD 14 months, 95%CI 4-24; HM 58 months, 95%CI 38-79; p < 0.05). Of 108 procedures, esophageal perforation occurred in two children after HM (two out of 48 HM procedures in total, 4%) and one child after BD (1/60, 1.7%). CONCLUSION: Less than half of children with achalasia are symptom free after initial treatment with either BD or HM. HM, however, when performed as first procedure, provided longer symptom-free period and reduced need for subsequent intervention. What is Known: • Balloon dilatation (BD) and Heller's myotomy (HM) are safe and effective treatment options for achalasia. • Controversy, however, exists regarding the most effective initial therapeutic approach. What is New: • HM with or without fundoplication may represent the initial therapeutic approach of choice. • Initial BD may negatively affect the outcome of a subsequent HM.

Indications and Recommendations by Societies and Institutions for the Use of Probiotics and Prebiotics in Paediatric Functional Intestinal Disorders.

PURPOSE OF REVIEW: To report the indications and/or recommendations by Societies and Institutions for the use of probiotics and prebiotics in functional intestinal disorders in childhood. RECENT FINDINGS: A position by Societies and Institutions is available only for infant colic, irritable bowel syndrome and constipation. Supplementation with the probiotic L reuteri DSM 17938 in breastfed term infants with colic appears to be effective in reducing crying, while still debated is its role in the prevention of colic. Irritable bowel syndrome is a common disorder in children and at present no specific treatments are available; existing data show that although high-quality studies are still needed, some evidence support the efficacy of LGG and VSL#3 in paediatric IBS. At present there is no evidence for the use of pre- or probiotics in childhood constipation. SUMMARY: Probiotics in a near future may have a definite role is some FGIDs of infants and children. The main limitations for the recommendation by Societies and Institutions are the methodological issues that limit the quality of the evidence and the heterogeneity of treatments (probiotic strain and dose, mode, dose and duration of supplementation, primary outcomes, etc). Some specific strains are promising for infant colic (L. reuteri DSM 17938) and irritable bowel syndrome (LGG) while at present there is no indication for their use in the treatment of childhood constipation.

Clinical relevance of esophageal baseline impedance measurement: just an innocent bystander.

OBJECTIVE: The clinical relevance of esophageal baseline impedance (BI) remains to be determined. In the present study, we explored the impact of gastroesophageal reflux disease (GERD) and esophageal dysmotility on BI. METHODS: A total of 18 children with esophageal atresia, 26 children with GERD, and 17 controls prospectively underwent esophagogastroduodenoscopy and pH-impedance monitoring. BI was measured in both proximal and distal esophagus. Gastroesophageal reflux (GER) and bolus transit indicators were defined according to published criteria. RESULTS: Patients with esophageal atresia showed significantly lower proximal and distal BI values (952 [716-1811] Ω; 895 [284-1189] Ω; respectively) compared with those with GERD (3015 [2368-3975] Ω; 2231 [1770-3032] Ω, P < 0.001 and <0.001, respectively) and controls (3699 [3194-4358] Ω; 3522 [2927-3994] Ω, P < 0.001 and <0.001, respectively). Using linear regression, proximal BI strongly correlated with total bolus transit time (r(2) = 0.61, P < 0.001) and bolus presence time (BPT; r(2) = 0.63, P < 0.001). Distal BI weakly correlated with acid exposure time (r(2) = 0.16, P < 0.01) and longstanding reflux episodes (r(2) = 0.17, P < 0.01), and strongly correlated with total bolus transit time (r(2) = 0.53, P < 0.001) and BPT (r(2) = 0.58, P < 0.001). By logistic regression, BPT predicted low proximal BI values (odds ratio [OR] 1.052; P < 0.05), whereas both GER indicators (acid exposure time: OR 1.56, P < 0.05; longstanding reflux episodes: OR 2.8, P < 0.05) and BPT (OR 1.66, P < 0.01) predicted low distal BI values. CONCLUSIONS: Along the length of esophagus, both bolus transit variables and GER significantly affect BI. This suggests that BI may merely mirror phenomena occurring within the esophageal lumen or wall, limiting its value as a discrete clinical entity to replace variables already used for assessing both GERD and esophageal dysmotility.

Clinical, serologic, and histologic features of gluten sensitivity in children.

OBJECTIVE: To describe the clinical, serologic, and histologic characteristics of children with gluten sensitivity (GS). STUDY DESIGN: We studied 15 children (10 males and 5 females; mean age, 9.6 ± 3.9 years) with GS who were diagnosed based on a clear-cut relationship between wheat consumption and development of symptoms, after excluding celiac disease (CD) and wheat allergy, along with 15 children with active CD (5 males and 10 females; mean age, 9.1 ± 3.1 years) and 15 controls with a functional gastrointestinal disorder (6 males and 9 females; mean age, 8.6 ± 2.7 years). All children underwent CD panel testing (native antigliadin antibodies IgG and IgA, anti-tissue transglutaminase antibody IgA and IgG, and anti-endomysial antibody IgA), hematologic assessment (hemoglobin, iron, ferritin, aspartate aminotransferase, erythrocyte sedimentation rate), HLA typing, and small intestinal biopsy (on a voluntary basis in the children with GS). RESULTS: Abdominal pain was the most prevalent symptom in the children with GS (80%), followed by chronic diarrhea in (73%), tiredness (33%), bloating (26%), limb pain, vomiting, constipation, headache (20%), and failure to thrive (13%). Native antigliadin antibodies IgG was positive in 66% of the children with GS. No differences in nutritional, biochemical, or inflammatory markers were found between the children with GS and controls. HLA-DQ2 was found in 7 children with GS. Histology revealed normal to mildly inflamed mucosa (Marsh stage 0-1) in the children with GS. CONCLUSION: Our findings support the existence of GS in children across all ages with clinical, serologic, genetic, and histologic features similar to those of adults.

Celiac Disease: The Importance of Studying the Duodenal Mucosa-Associated Microbiota.

There is increasing evidence indicating that changes in both the composition and functionality of the intestinal microbiome are closely associated with the development of several chronic inflammatory diseases, with celiac disease (CeD) being particularly noteworthy. Thanks to the advent of culture-independent methodologies, the ability to identify and quantify the diverse microbial communities residing within the human body has been significantly improved. However, in the context of CeD, a notable challenge lies in characterizing the specific microbiota present on the mucosal surfaces of the intestine, rather than relying solely on fecal samples, which may not fully represent the relevant microbial populations. Currently, our comprehension of the composition and functional importance of mucosa-associated microbiota (MAM) in CeD remains an ongoing field of research because the limited number of available studies have reported few and sometimes contradictory results. MAM plays a crucial role in the development and progression of CeD, potentially acting as both a trigger and modulator of the immune response within the intestinal mucosa, given its proximity to the epithelial cells and direct interaction. According to this background, this review aims to consolidate the existing literature specifically focused on MAM in CeD. By elucidating the complex interplay between the host immune system and the gut microbiota, we aim to pave the way for new interventions based on novel therapeutic targets and diagnostic biomarkers for MAM in CeD.

Mucoadhesive Budesonide Solution for the Treatment of Pediatric Eosinophilic Esophagitis.

Eosinophilic Esophagitis is an antigen-mediated inflammatory disease characterized by thickening of the esophageal wall, leading to dysphagia, vomiting, reflux, and abdominal pain. This disease can be treated with a therapeutic approach ranging from diet to pharmacological therapy. Jorveza® (budesonide) and Dupixent® (dupilumab) are treatments for Eosinophilic Esophagitis approved by the European Medicines Agency in adults but not in children. Budesonide-based extemporaneous oral liquid suspensions could be prepared for pediatric use. The main limit of this formulation is that budesonide needs a longer residence time on the esophageal mucosa to solubilize and diffuse in it to exert its local anti-inflammatory effect. Herein, we propose the development of an extemporaneous mucoadhesive oral budesonide solution for the pediatric population. A liquid vehicle containing hydroxypropyl-beta-cyclodextrin as a complexing agent and carboxymethylcellulose sodium as a mucoadhesive excipient was used to prepare budesonide-based formulations. A stable solution at a concentration of 0.7 mg/mL was successfully prepared and characterized. The formulation showed rheological and mucoadhesive properties suitable for an Eosinophilic Esophagitis local prolonged treatment. In this way, pharmacists can prepare stable budesonide-based mucoadhesive solutions, providing both patients and physicians with a new therapeutic option for Eosinophilic Esophagitis pediatric treatment.

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial.

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.

Diagnostic Delay of Celiac Disease in Childhood.

Importance: The extent and factors associated with risk of diagnostic delay in pediatric celiac disease (CD) are poorly understood. Objectives: To investigate the diagnostic delay of CD in childhood, and to assess factors associated with this delay. Design, Setting, and Participants: Multicenter, retrospective, cross-sectional study (2010-2019) of pediatric (aged 0-18 years) patients with CD from 13 pediatric tertiary referral centers in Italy. Data were analyzed from January to June 2023. Main Outcomes and Measures: The overall diagnostic delay (ie, the time lapse occurring from the first symptoms or clinical data indicative of CD and the definitive diagnosis), further split into preconsultation and postconsultation diagnostic delay, were described. Univariable and multivariable linear regression models for factors associated with diagnostic delay were fitted. Factors associated with extreme diagnostic delay (ie, 1.5 × 75th percentile) and misdiagnosis were assessed. Results: A total of 3171 patients with CD were included. The mean (SD) age was 6.2 (3.9) years; 2010 patients (63.4%) were female; and 10 patients (0.3%) were Asian, 41 (1.3%) were Northern African, and 3115 (98.3%) were White. The median (IQR) overall diagnostic delay was 5 (2-11) months, and preconsultation and postconsultation diagnostic delay were 2 (0-6) months and 1 (0-3) month, respectively. The median (IQR) extreme overall diagnostic delay (586 cases [18.5%]) was 11 (5-131) months, and the preconsultation and postconsultation delays were 6 (2-120) and 3 (1-131) months, respectively. Patients who had a first diagnosis when aged less than 3 years (650 patients [20.5%]) showed a shorter diagnostic delay, both overall (median [IQR], 4 [1-7] months for patients aged less than 3 years vs 5 [2-12] months for others) and postconsultation (median [IQR], 1 [0-2] month for patients aged less than 3 years vs 2 [0-4] months for others). A shorter delay was registered in male patients, both overall (median [IQR], 4 [1-10] months for male patients vs 5 [2-12] months for female patients) and preconsultation (median [IQR], 1 [0-6] month for male patients vs 2 [0-6] months for female patients). Family history of CD was associated with lower preconsultation delay (odds ratio [OR], 0.59; 95% CI, 0.47-0.74) and lower overall extreme diagnostic delay (OR, 0.75; 95% CI, 0.56-0.99). Neurological symptoms (78 patients [21.5%]; OR, 1.35; 95% CI, 1.03-1.78), gastroesophageal reflux (9 patients [28.1%]; OR, 1.87; 95% CI, 1.02-3.42), and failure to thrive (215 patients [22.6%]; OR, 1.62; 95% CI, 1.31-2.00) showed a more frequent extreme diagnostic delay. A previous misdiagnosis (124 patients [4.0%]) was more frequently associated with gastroesophageal reflux disease, diarrhea, bloating, abdominal pain, constipation, fatigue, osteopenia, and villous atrophy (Marsh 3 classification). Conclusions and Relevance: In this cross-sectional study of pediatric CD, the diagnostic delay was rather short. Some factors associated with risk for longer diagnostic delay and misdiagnosis emerged, and these should be addressed in future studies.