Outcome in pediatric celiac disease is independent of the diagnostic approach in patients with high antibody levels.

OBJECTIVES: European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines enable the diagnosis of celiac disease (CD) without biopsies in patients with immunoglobulin A (IgA)-antibodies against tissue transglutaminase (TGA-IgA) ≥ 10× the upper limit of normal (ULN) and positivity of endomysial antibodies in a second blood sample. Limited data exist comparing the biopsy versus the nonbiopsy diagnostic approach regarding long-term outcomes in CD patients. Our study aimed to investigate the influence of the diagnostic approach on adherence to gluten-free diet (GFD), serological remission (defined as normalization of TGA-IgA during follow-up (FU)) and clinical remission in CD patients with TGA-IgA ≥ 10× ULN. METHODS: Retrospective multicenter study. Patients with CD and TGA-IgA ≥ 10× ULN at diagnosis were included in the study. Patients with confirmed diagnosis by biopsy were compared to patients diagnosed by nonbiopsy approach using univariate analysis, Kaplan-Meier survival curve, and logistic regression models. RESULTS: A total of 282 CD patients (192 [68.1%] in the biopsy group; 90 [31.9%] in the nonbiopsy group) were analyzed. The median time to normalization of TGA-IgA was 16.5 months [interquartile range, IQR: 13, 28] in the biopsy and 15 months [IQR: 12, 26] in the nonbiopsy group; p = 0.14). Rates of normalized TGA-IgA at first to third-year FU were comparable between both groups. Adherence to GFD did not seem to be influenced by the diagnostic approach. CONCLUSIONS: The nonbiopsy approach is not inferior to the biopsy approach in terms of adherence to GFD and serological remission in patients with CD.

Drug-Related Adverse Events Necessitating Treatment Discontinuation in Pediatric Inflammatory Bowel Disease Patients.

OBJECTIVES: Inflammatory bowel disease (IBD) requires long-term drug therapy in most patients, posing a risk for adverse drug events with the need for discontinuation. In this study, we investigated adverse events (AE) necessitating drug discontinuation in pediatric and adolescent IBD patients. METHODS: We used data prospectively collected from IBD patients below the age of 18 enrolled in the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), namely demographic variables, medical characteristics, drug treatments, and related AE. We analyzed the frequency, type, and risk factors for AE necessitating drug discontinuation. RESULTS: A total of 509 pediatric IBD patients fulfilled the inclusion criteria of which 262 (51.5%) were diagnosed with Crohn disease (CD), 206 (40.5%) with ulcerative colitis (UC), and 41 (8%) with IBD-unclassified (IBD-U). In total, 132 (25.9%) presented with at least 1 drug-related AE that required drug cessation. Immunomodulators [methotrexate 29/120 (24.2%), azathioprine 57/372 (15.3%)] followed by tumor necrosis factor (TNF)-alpha antagonists [adalimumab 8/72 (11.1%), infliximab 22/227 (9.7%)] accounted for the highest proportions of AE necessitating treatment discontinuation. Treatment schemes with at least 3 concomitant drugs significantly amplified the risk for development of drug-related AE [odds ratio = 2.50, 95% confidence interval (1.50-4.17)] in all pediatric IBD patients. CONCLUSIONS: Drug-related AE necessitating discontinuation are common in pediatric and adolescent IBD patients. Caution needs to be taken in the case of concomitant drug use.

Characterization of the Transition Zone in Short Segment Hirschsprung Disease Using Calretinin Immunostaining.

Introduction: The detailed expression pattern of calretinin immunohistochemistry in the transition zone (TZ) of Hirschsprung disease (HSCR) has not yet been reported. This study aims to examine the value of calretinin immunohistochemistry for more accurately determining the distal and proximal border of the TZ in short segment HSCR. Methods: Specimens of pull-through surgery from 51 patients with short form of HSCR were analyzed on two longitudinal strips using hematoxylin and eosin (H&E) staining and calretinin immunohistochemistry. Results: In all but two patients, the first appearance of calretinin expression was seen on mucosal nerve fibers before the appearance of any ganglion cells, indicating the distal border of the TZ. The maximum distance between the distal border of the TZ and the proximal border of the TZ, defined by ganglion cells in a normal density on H&E stained sections, a strong calretinin expression on mucosal nerve fibers and in >80% of submucosal and myenteric ganglion cells, with no nerve hypertrophy and absence of ganglionitis was 60 mm. Conclusion: The distal border of the TZ is characterized by calretinin positive intramucosal neurites in nearly all of short form of HSCR and not by calretinin expression on ganglion cells.

Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improves Colon Structure and Function in Mouse Models of Hirschsprung Disease.

BACKGROUND & AIMS: Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR. METHODS: We performed studies with four mouse models of HSCR: Holstein (HolTg/Tg, a model for trisomy 21-associated HSCR), TashT (TashTTg/Tg, a model for male-biased HSCR), Piebald-lethal (Ednrbs-l//s-l, a model for EDNRB mutation-associated HSCR), and Ret9/- (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis. RESULTS: GDNF significantly prolonged mean survival times of HolTg/Tg mice, Ednrbs-l//s-l mice, and male TashTTg/Tg mice, compared with control mice, but not Ret9/- mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from HolTg/Tg mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of HolTg/Tg mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons. CONCLUSIONS: GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.

Should Proton Pump Inhibitors be Systematically Prescribed in Patients With Esophageal Atresia After Surgical Repair?

OBJECTIVE: To evaluate outcomes of patients with esophageal atresia (EA) on systematic treatment with proton pump inhibitors (PPI) since the neonatal period and to determine factors associated with successful discontinuation of PPI. STUDY DESIGN: Longitudinal cohort study with prospective data collection of 73 EA patients, over 11 years systematically treated with PPI. Outcome and predictive factors for discontinuation of PPI treatment were evaluated at study end in February 2017. The incidence of anastomotic strictures was compared with a historical cohort of 134 EA patients followed in the same institution between 1990 and 2005 before the era of systematic PPI treatment. RESULTS: PPI treatment was discontinued definitively in 48% of patients during follow-up. Prematurity, longer initial hospitalization, moderate-to-severe tracheomalacia, anastomotic leak and anastomotic stricture had a significant negative association with PPI discontinuation on univariate analysis (P < 0.05). On adjusted multivariable Cox regression analysis, moderate-to-severe tracheomalacia and anastomotic leak were negatively associated with discontinuation of PPI treatment (hazard ratio 0.26 [95% CI 0.12-0.59]; P = 0.001 and hazard ratio 0.38 [95% CI 0.16-0.93]; P = 0.03, respectively). There was no significant difference in the incidence of anastomotic strictures in the present cohort compared with the historical cohort (44% vs 39%); (P > 0.05). CONCLUSIONS: PPI treatment does not prevent the formation of anastomotic strictures and appears to be over-prescribed in children with airway symptoms because of tracheomalacia. This suggests that PPI treatment could be prescribed more selectively. Close monitoring and long-term follow-up, however, of these vulnerable patients in specialized multidisciplinary clinics is imperative.

Factors influencing the incidence of Hirschsprung associated enterocolitis (HAEC).

PURPOSE: This study aims to characterize risk factors for Hirschsprung-associated enterocolitis (HAEC). We hypothesize that earlier pull-through surgery is associated with lower risks of developing postoperative HAEC. METHODS: A comparative study of 171 Hirschsprung patients treated from 1990 to 2017 was performed. Patients without HAEC were compared to patients with preoperative and/or postoperative HAEC. Results are presented as median [IQR] or frequency (%). Pearson's χ2 test and Wilcoxon rank sum test were performed with a significance level at p < 0.05. Multivariable logistic regression analysis was used to adjust for potential confounders. A subanalysis was done to evaluate laparoscopic, laparotomy, and transanal surgeries. RESULTS: Risk of developing preoperative HAEC was significantly associated with congenital malformations (OR 2.63 [1.11, 6.24]; p = 0.02). Birth weight was lower in patients with preoperative HAEC (OR 0.48 [95% CI 0.25, 0.93]; p = 0.03). On regression analysis, intestinal obstruction after surgery was significantly associated with postoperative HAEC (OR 8.2 [3.18, 21.13]; p < 0.0001). Patients with earlier pull-through surgery did not have a lower risk of developing postoperative HAEC. CONCLUSIONS: Timing of surgery does not seem to be associated with a higher risk of developing pre- and postoperative HAEC. Predisposing factors for preoperative HAEC included associated malformations and lower birth weight, whereas intestinal obstruction was found to be associated with postoperative HAEC. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III.

Prevalence and Predictive Factors of Histopathological Complications in Children with Esophageal Atresia.

OBJECTIVES: Endoscopic follow-up after esophageal atresia (EA) tracheoesophageal fistula (TEF) repair is recommended to detect esophageal histopathological complications. We investigated the prevalence of histopathologically proven esophageal complications (peptic esophagitis, gastric metaplasia, and eosinophilic esophagitis) and assessed the predictors of these complications in children with EA-TEF. MATERIALS AND METHODS: This is a prospective longitudinal cohort study performed between September 2005 and December 2014 comprising 77 children with EA-TEF followed-up until February 2017. Univariate analysis was performed using the Wilcoxon's rank-sum test for continuous variables and the Pearson's chi-square test for categorical variables. Multivariable analysis was performed using a Cox regression hazard model. The association between clinical factors and histopathologically proven complications was estimated using a Cox regression hazard model with time until the appearance of complications as the time scale. RESULTS: All 77 children received proton pump inhibitors (PPIs) (n = 73) or H2 receptor antagonists (H2RA). A total of 252 endoscopies were performed in 73 children (median 2.6/child, range: 1-29). Median age at study completion was 4.9 years (range: 2.3-11.5 years). Histopathologically proven complications occurred in 38 children (52%): peptic esophagitis (n = 32, 44%), eosinophilic esophagitis (n = 15, 21%), and gastric metaplasia (n = 9, 12%). A total of 82% patients were on PPI or H2RA at the time of diagnosis of histological complication. Multivariable Cox regression analysis showed that patients with recurrent anastomotic strictures (>3 dilations) had a higher risk of occurrence of histopathologically proven complications over time (hazard ratio: 3.11, 95% confidence interval [CI]: 1.53-6.34). On univariate analysis, the result of the first endoscopy was not associated with the occurrence of histopathologically proven complications (odds ratio: 0.8, 95% CI: 0.16-3.95). CONCLUSION: Histopathologically proven complications with potential long-term consequences occurred in approximately 50% of children after EA-TEF repair. A history of recurrent anastomotic strictures is associated with the occurrence of these complications. The result of the first endoscopy does not predict the histopathological outcome. Children with EA-TEF warrant close and systematic long-term follow-up at specialized multidisciplinary clinics with endoscopic evaluation.

PR3-ANCA and panel diagnostics in pediatric inflammatory bowel disease to distinguish ulcerative colitis from Crohn's disease.

BACKGROUND: Accurate classification of patients with inflammatory bowel disease into the subtypes ulcerative colitis (UC) and Crohn's disease (CD) is still a challenge, but important for therapy and prognosis. OBJECTIVES: To evaluate the diagnostic utility of anti-neutrophil cytoplasmic antibodies specific for proteinase-3 (PR3-ANCA) for ulcerative colitis (UC) and the value of an antibody panel incorporating PR3-ANCA to differentiate between Crohn's disease (CD) and UC. STUDY DESIGN: In this cohort study, 122 pediatric and adolescent individuals were retrospectively included (61 IBD patients of two clinical centers, 61 non-IBD controls). All subjects had a comprehensive antibody profile done from stored sera taken close to time of diagnosis. By employing quasi-exhaustive logistic regression the best discriminative model for UC and CD,subjects was determined in a training cohort and confirmed in a validation cohort. RESULTS: PR3-ANCA was specifically associated with UC (odds ratio (OR), 17.6; 95% confidence interval (CI); 3.6, 87); P < .001). A four antibody-panel including PR3-ANCA had an AUC of 90.81% (95%CI; 81.93, 99.69) to distinguish between UC and CD in the training cohort. In a smaller external validation cohort, the AUC was 84.13% (95%CI; 64.21, 100) for accurate diagnosis of CD and UC. CONCLUSION: PR3-ANCA is highly specific for UC. The differentiating capability of a panel, which contains PR3-ANCA and weighs broadly available antibodies, is superior and utilization of the panel can support accurate classification in the work-up of pediatric and adolescent patients with IBD patients.

High-resolution Esophageal Manometry Patterns in Children and Adolescents With Rumination Syndrome.

BACKGROUND: Rumination is defined by effortless regurgitation within seconds or minutes of ingested food. The aim of this study was to determine the high-resolution esophageal manometry (HREM) pattern in children with rumination syndrome. METHODS: HREM was evaluated in 15 pediatric patients with rumination syndrome according to the Rome criteria and compared with 15 controls. Primary rumination was defined as a clinical rumination episode associated with a rise of gastric pressure above 30 mmHg. Secondary rumination was defined as a clinical rumination episode associated with a rise of gastric pressure above 30 mmHg during a transient lower esophageal sphincter relaxation (TLESR). RESULTS: Ninety-two episodes of rumination were demonstrated during HREM study in 12 of the 15 patients (80%; 1-29 episodes per patient; median intragastric pressure 49.6 mmHg). Primary rumination occurred in 3 patients and secondary rumination in 5 patients. One patient had primary and secondary rumination episodes. In 3 patients, classification of rumination episodes was not possible due to repetitive swallowing leading to lower esophageal sphincter relaxation. In the control group, no episodes of rumination occurred. The sensitivity and the specificity of the HREM study (association of a clinical rumination episode with a rise in gastric pressure >30 mmHg) to confirm the diagnosis of rumination were 80% and 100%, respectively. CONCLUSIONS: HREM allows confirming diagnosis of rumination syndrome and to differentiate between primary and secondary rumination in the presence of objective rumination episodes. Further research is needed to study whether HREM results may influence treatment and outcome of children with rumination syndrome.