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 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.

Epidemiology, clinical features and management of autoimmune hepatitis in Switzerland: a retrospective and prospective cohort study.

BACKGROUND AND AIMS: The Swiss Autoimmune Hepatitis Cohort Study is a nationwide registry, initiated in 2017, that collects retrospective and prospective clinical data and biological samples from patients of all ages with autoimmune hepatitis treated at Swiss hepatology centres. Here, we report the analysis of the first 5 years of registry data. RESULTS: A total of 291 patients with autoimmune hepatitis have been enrolled, 30 of whom were diagnosed before 18 years of age and composed the paediatric cohort. Paediatric cohort: median age at diagnosis 12.5 years (range 1-17, interquartile range (IQR) 8-15), 16 (53%) girls, 6 (32%) with type 2 autoimmune hepatitis, 8 (27%) with autoimmune sclerosing cholangitis, 1 with primary biliary cholangitis variant syndrome, 4 (15%) with inflammatory bowel disease and 10 (41%) with advanced liver fibrosis at diagnosis. Adult cohort: median age at diagnosis 54 years (range 42-64, IQR 18-81), 185 (71%) women, 51 (20%) with primary biliary cholangitis variant syndrome, 22 (8%) with primary sclerosing cholangitis variant syndrome, 9 (4%) with inflammatory bowel disease and 66 (32%) with advanced liver fibrosis at diagnosis. The median follow-up time for the entire cohort was 5.2 years (IQR 3-9.3 years). Treatment in children: 29 (97%) children were initially treated with corticosteroids, 28 of whom received combination treatment with azathioprine. Budesonide was used in four children, all in combination with azathioprine. Mycophenolate mofetil was used in five children, all of whom had previously received corticosteroids and thiopurine. Treatment in adults (data available for 228 patients): 219 (96%) were treated with corticosteroids, mostly in combination with azathioprine. Predniso(lo)ne was the corticosteroid used in three-quarters of patients; the other patients received budesonide. A total of 78 (33%) patients received mycophenolate mofetil, 62 of whom had previously been treated with azathioprine. Complete biochemical response was achieved in 13 of 19 (68%) children and 137 of 182 (75%) adults with available follow-up data. All children were alive at the last follow-up, and none had undergone liver transplantation. Five (2%) adults underwent liver transplantation, two of whom had a fulminant presentation. Four (2%) adults with autoimmune hepatitis died (two from liver-associated causes). CONCLUSION: Patients with autoimmune hepatitis in Switzerland had clinical features similar to those in other cohorts. The proportion of patients diagnosed with primary biliary cholangitis variant syndrome was higher than expected. Autoimmune hepatitis was managed according to guidelines, except for the use of budesonide in a small proportion of paediatric patients. The outcomes were excellent, but the findings must be confirmed over a longer follow-up period.

Constipation in Children and Adolescents.

BACKGROUND: According to a population-based study, approximately 6.8% of children and adolescents in Germany suffer from acute or chronic constipation. It can be of organic or functional origin and may be associated with comorbid disturbances, particularly fecal incontinence. METHODS: We selectively searched the PubMed and Google Scholar databases for articles with the keywords "constipation," "children and adolescents," and "incontinence". Recommendations are based on the AWMF guideline on constipation and fecal incontinence and on international guidelines and reviews. RESULTS: More than 90% of cases of chronic constipation are of functional origin. Organic causes vary with age and call for targeted differential diagnosis. Invasive tests are only rarely necessary. Functional constipation may be associated with fecal and urinary incontinence, and the relative risk of urinary tract infections is 2.2 to 6.5. There may be associated psychological symptoms and mental disorders in 30-50% of cases. The cornerstone of treatment is patient and parent education, along with laxative medication and toilet training. Instructional programs have been found effective in otherwise refractory cases. CONCLUSION: The treatment of constipation in childhood should begin as soon as the differential diagnostic evaluation is completed. The education of parents, follow-up at close intervals, and drug treatment and behavioral therapy that are adapted to the symptoms can improve quality of life.

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.

Newborns with Bloody Stools-At the Crossroad between Efficient Management of Necrotizing Enterocolitis and Antibiotic Stewardship.

The onset of bloody stools in neonates often results in antibiotic treatment for suspected necrotizing enterocolitis (NEC). Food protein-induced allergic proctocolitis (FPIAP) is an often-neglected differential diagnosis. We performed a retrospective analysis of antibiotic exposure at our tertiary center from 2011 to 2020 that included three time periods of differing antimicrobial stewardship goals. We compared these data with the conventional treatment guidelines (modified Bell's criteria). In our cohort of 102 neonates with bloody stools, the length of antibiotic exposure was significantly reduced from a median of 4 to 2 days. The proportion of treated neonates decreased from 100% to 55% without an increase in negative outcomes. There were 434 antibiotic days. Following a management strategy according to modified Bell's criteria would have led to at least 780 antibiotic days. The delayed initiation of antibiotic treatment was observed in 7 of 102 cases (6.9%). No proven NEC case was missed. Mortality was 3.9%. In conclusion, with FPIAP as a differential diagnosis of NEC, an observational management strategy in neonates with bloody stools that present in a good clinical condition seems to be justified. This may lead to a significant reduction of antibiotic exposure. Further prospective, randomized trials are needed to prove the safety of this observational approach.

Critically Ill Children in a Swiss Pediatric Emergency Department With an Interdisciplinary Approach: A Prospective Cohort Study.

Objective: Delivery of prompt and adequate care for critically ill and injured children presenting to the pediatric emergency department (PED) is paramount for optimal outcomes. Knowledge of the local epidemiology, patient profile, and presentation modes are key for organizational planning, staff education strategy, and optimal care in a PED. Our aim was to analyze the profile of critically ill and injured children admitted to a tertiary, non-academic Swiss PED, to investigate potential risk factors associated with admission to the pediatric intensive care unit (PICU), and the outcomes mortality and PICU admission. Methods: Prospective cohort study of critically ill and injured children presenting to the PED over a two-year period (2018-2019). Inclusion criteria were Australasian triage scale category (ATS) 1, trauma team activation (TTA), medical emergency response (MER) activation, additional critical care consult, and transfer to an outside hospital. Results: Of 42,579 visits during the two-year period, 347 presentations matched the inclusion criteria (0.81%). Leading presentations were central nervous system (CNS) disorders (26.2%), trauma (25.1%), and respiratory emergencies (24.2%). 288 out of 347 cases (83%) arrived during the day or evening with an even distribution over the days of the week. 128 out of 347 (37%) arrived unexpectedly as walk-ins. 233 (67.15%) were ATS category 1. 51% of the cohort was admitted to PICU. Australasian triage scale category 1 was significantly more common in this group (p = 0.0001). Infants with respiratory disease had an increased risk of PICU transfer compared to other age groups (OR 4.18 [95%CI 2.46, 7.09] p = 0.0001), and this age group presented mainly as walk-in (p = 0.0001). Pediatric intensive care unit admissions had a longer hospital stay (4 [2, 8] days vs. 2 [1, 4] days, p = 0.0001) compared to other patients. 0.045% of all PED patients had to be transferred out. Three deaths (0.86%) occurred in the PED, 10 patients died in the PICU (2.9%). Conclusions: High acuity presentations in the PED were rare, more likely to be young with CNS disorders, trauma and respiratory diseases. A significant proportion were unexpected walk-in presentations, mainly during day and evening shifts. Low exposure to high-acuity patients highlights the importance of deliberate learning and simulation for all professionals in the PED.

Nutritional Aspects of Pediatric Gastrointestinal Diseases.

In the last decade, the role of nutritional management in pediatric gastrointestinal diseases has gained increasing popularity. Disease-specific diets have been introduced as conventional treatments by international guidelines. Patients tend to more willingly accept food-based therapies than drugs because of their relatively "harmless" nature. Apart from a diet's therapeutic role, nutritional support is crucial in maintaining growth and improving clinical outcomes in pediatric patients. Despite the absence of classical "side effects", however, it should be emphasized that any dietary modification might have negative consequences on children's growth and development. Hence, expert supervision is always advised, in order to support adequate nutritional requirements. Unfortunately, the media provide an inaccurate perception of the role of diet for gastrointestinal diseases, leading to misconceptions by patients or their caregivers that tends to overestimate the beneficial role of diets and underestimate the potential adverse effects. Moreover, not only patients, but also healthcare professionals, have a number of misconceptions about the nutritional benefits of diet modification on gastrointestinal diseases. The aim of this review is to highlight the role of diet in pediatric gastrointestinal diseases, to detect misconceptions and to give a practical guide for physicians on the basis of current scientific evidence.

Corrigendum: Microbial Colonization From the Fetus to Early Childhood-A Comprehensive Review.

[This corrects the article DOI: 10.3389/fcimb.2020.573735.].

New Parents Experienced Lower Parenting Self-Efficacy during the COVID-19 Pandemic Lockdown.

Background: The COVID-19 pandemic is a global issue which affects the entire population's mental health. This study evaluates how restrictions to curtail this pandemic change parenting self-efficacy, depressive symptoms, couple satisfaction and health-related quality of life in parents after delivery of a newborn. Methods: In this prospective single center evaluation of parental self-efficacy and quality of life, four validated questionnaires were used to repeatedly assess parenting self-efficacy (Tool to measure Parental Self-Efficacy, TOPSE), depressive symptoms (Edinburgh Postnatal Depression Scale, EPDS), couple satisfaction (Couple Satisfaction Index, CSI) and health-related quality of life (short form 12, SF12). Fifty-three parents of 50 infants answered a total number of 63 questionnaires during the lockdown period to limit the spread of COVID-19. These questionnaires were matched with 63 questionnaires of 58 other parents that had answered them before or after strong pandemic related measures. Results: Parents experienced lower parenting self-efficacy during the strict pandemic measures as compared to before and after (p = 0.04). In terms of age, socioeconomic, marital status and duration of hospitalization we detected no significant difference between both groups. On univariate linear regression, TOPSE scores were associated with gestational age (p = 0.044, parameter estimate 1.67, 95% CI: 0.048 to 3.301), birth weight (p = 0.035, parameter estimate 0.008, 95% CI: 0.001 to 0.015), number of newborns' siblings (p = 0.0554, parameter estimate 7.49, 95% CI: -0.174 to 15.145) and distance of home from hospital (p = 0.043, parameter estimate -0.38, 95% CI: -0.745 to -0.011). Interestingly, there was a positive correlation between quality of life and TOPSE scores, suggesting that those who experience a higher self-efficacy also have a higher quality of life. Conclusions: When implementing a lock-down period psychological effects such as lower experience of parental self-efficacy have to be considered.

The Assessment of Steroid Injections as a Potential Risk Factor for Osteochondral Lesions in Children with Juvenile Idiopathic Arthritis.

OBJECTIVE: Intra-articular corticosteroid injections (IACIs) are frequently used to suppress local inflammation, that is, in children with juvenile idiopathic arthritis (JIA). While systemic high-dosage corticosteroids are known to trigger osteonecrosis and result in osteochondral (OC) lesions, the effect of IACIs on joint cartilage and subchondral bone remains unclear. This study was conceived to analyze the coincidence of IACI and the subsequent manifestation of osteochondral lesions in a large cohort of pediatric JIA patients. DESIGN: Retrospective data assessment and comparative analysis of skeletally immature JIA patients treated with IACIs between 1993 and 2017. RESULTS: A total of 280 JIA patients were included in the analysis, the majority were girls (64%). Osteochondral lesions were present in 16 patients (5.7%) at a mean age of 10.7 years (range 4-14 years) and appeared on average after 63-month duration of disease. The majority was present at atypical locations such as the lateral femoral condyle. Multivariable analysis using cox regression showed that steroid injections were a risk factor to develop an OC lesion (hazard ratio [95%CI] for number of steroid injections per year, 8.20 [3.18, 21.16]). CONCLUSIONS: Pediatric patients with JIA show a relatively high incidence of osteochondritic lesions, which present at an early age and in rather atypical locations and repetitive steroid injection need to be considered an associated risk factor.

Microbial Colonization From the Fetus to Early Childhood-A Comprehensive Review.

The development of the neonatal gastrointestinal tract microbiota remains a poorly understood process. The interplay between neonatal (gestational age, genetic background), maternal (mode of delivery, nutritional status) and environmental factors (antibiotic exposure, available nutrition) are thought to influence microbial colonization, however, the exact mechanisms are unclear. Derangements in this process likely contribute to various gastrointestinal diseases including necrotizing enterocolitis and inflammatory bowel disease. As such, enhanced understanding of microbiota development may hold the key to significantly reduce the burden of gastrointestinal disease in the pediatric population. The most debatable topics during microbial seeding and possible future treatment approaches will be highlighted in this review.

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.

Dysmotility in Esophageal Atresia: Pathophysiology, Characterization, and Treatment.

Esophageal dysmotility is almost universal after esophageal atresia (EA) repair and is mainly related to the developmental anomaly of the esophagus. Esophageal dysmotility is involved in the pathophysiology of numerous symptoms and comorbidities associated with EA such as gastroesophageal reflux disease, aspiration and respiratory complications, and symptoms of dysphagia and feeding disorders. High-resolution esophageal manometry (HREM) has facilitated the characterization of the dysmotility, but there is an incomplete correlation between symptoms and manometrical patterns. Impedance coupled to HREM should help to predict the clinical outcome and therefore personalize patient management. Nowadays, the management of esophageal dysmotility in patients with EA is essentially based on treatment of associated inflammation related to peptic or eosinophilic esophagitis.

A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. Here, we report the generation of a mouse model for HSCR--named Holstein--that contains an untargeted transgenic insertion upstream of the collagen-6α4 (Col6a4) gene. This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. Increased collagen VI levels during development mainly result in slower migration of eNCCs. This appears to be due to the fact that collagen VI is a poor substratum for supporting eNCC migration and can even interfere with the migration-promoting effects of fibronectin. Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.