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Purpose of reviewGuidelines were recently published highlighting why esophageal atresia (EA) patients are prone to complication risks, and the need for long-term follow-up. In this review, we will focus on how to investigate and treat potential complications, as well as the pros and cons of different investigative and treatment modalities, and what areas continue to need further research.Recent findingsEA patients are at high risk for gastroesophageal reflux and esophageal strictures, and the sequela that result. Extraintestinal manifestations of gastroesophageal reflux disease (GERD) can appear similar to other pathologic diagnoses commonly found in EA patients, such as congenital stricture, eosinophilic esophagitis, esophageal dysmotility, tracheomalacia, recurrent fistula, aspiration, etc. Therefore, it is important to have a standardized way to monitor for these issues. pH impedance allows for detection of nonacid reflux and the height of reflux, which are important in correlating symptoms with reflux episodes. A multidisciplinary approach is beneficial in evaluating and monitoring EA patients in the long term.

BackgroundEsophageal atresia (EA) is one of the most common congenital digestive anomalies. With improvements in surgical techniques and intensive care treatments, the focus of care of these patients has shifted from mortality to morbidity and quality-of-life issues. These children face gastrointestinal (GI) problems not only in early childhood but also through adolescence and adulthood. There is, however, currently a lack of a systematic approach to the care of these patients. The GI working group of International Network on Esophageal Atresia comprises members from ESPGHAN/NASPGHAN and was charged with the task of developing uniform evidence-based guidelines for the management of GI complications in children with EA.MethodsThirty-six clinical questions addressing the diagnosis, treatment, and prognosis of the common GI complications in patients with EA were formulated. Questions on the diagnosis, and treatment of gastroesophageal reflux, management of "cyanotic spells," etiology, investigation and management of dysphagia, feeding difficulties, anastomotic strictures, congenital esophageal stenosis in EA patients were addressed. The importance of excluding eosinophilic esophagitis and associated GI anomalies in symptomatic patients with EA is discussed as is the quality of life of these patients and the importance of a systematic transition of care to adulthood. A systematic literature search was performed from inception to March 2014 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. During 2 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation.

Simple Summary: The brain senses and regulates all internal bodily processes, including the levels of the sugar molecule glucose in the blood stream (systemic regulation) or in specific organs, such as the gut. The contribution of the vagus nerve to this mechanism, the longest nerve connecting the brain with the rest of the body, has not been well understood. Moreover, it has remained unknown how the activity of the vagus nerve contributes to the inflammatory response as may be seen during infections when the immune system is activated. Here, we mechanically and electrically manipulated the vagus nerve activity, decreasing or increasing it selectively, and measuring the degree of change in the glucose levels and of the inflammatory response systemically and in the gut, an important site of neonatal injury. We reported a surprising dual (hormetic) anti- or pro-inflammatory effect of reduced vagal activity combined with increased levels of glucose dependent on the levels of the infectious agent inducing the inflammatory response. We further discussed the implications for future research and clinical practice. BACKGROUND. Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3–54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses. [ABSTRACT FROM AUTHOR]

Purpose: Anorexia Nervosa (AN) is a serious and potentially lethal mental disorder characterised by a deliberate quest to reduce one's weight. It can have multiple physical and psychological consequences. The clinical presentation of AN can include gastrointestinal symptoms, however, the pathophysiology of these symptoms in the context of AN remains uncertain. It is hypothesised that patients with AN may have an increase in intestinal permeability, which could lead to an increase in faecal calprotectin (fCP), a marker of intestinal inflammation. No relation between AN and elevation of fCP has been previously described in literature. Methods: Eight patients hospitalised for AN have a dosage of fCP. Results: Calprotectine was found to be elevated in 50% of cases, with or without any underlying comorbid gastrointestinal disease. Only the duration of illness tended to be associated with the increase in fCP suggesting a greater alteration as a function related to the time of denutrition. Conclusion: Although these findings provide insights in the potential pathophysiology of gastrointestinal symptoms in AN, further studies that evaluate the factors associated with elevated fCP in patients with AN are needed. Key points: What is already known on this subject? To our knowledge, our study is the first to describe faecal calprotectin (fCP) levels in patients who are malnourished due to anorexia nervosa (AN) and describe the patients' clinical characteristics in order to better explain the gastrointestinal tract implication in AN symptoms. What this study adds? This study's finding of a possible elevation of fCP in patients with AN raises interesting questions on the pathophysiology of AN, and the possibility of an underlying inflammatory process in these patients. Although this is a preliminary study, as the sample size is small, it is therefore important for clinicians to acknowledge that fCP can be elevated in patients with AN without any other disease. The literature remains scarce regarding the relationship between the gastrointestinal tract and AN, although it is a predominant aspect of the symptomatology of the disease. This offers opportunities and strengthen the need for further research on the effects of restriction, renutrition and weight gain on the gastrointestinal tract in patients with AN, and the possible role and use of fCP in this disease. [ABSTRACT FROM AUTHOR]

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 (Col6α4) 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., Introduction The enteric nervous system (ENS) is located within the gut wall and is mainly composed of multiple interconnected ganglia organized into two main plexuses: the submucosal plexus and the [...]

This document is a letter to the editor expressing concern about a recent review article on the transition process for patients with neurogastroenterology issues in childhood. The authors of the letter, who are part of the International Network on Esophageal Atresia (INoEA), were surprised that their consensus guidelines on the transition of patients with esophageal atresia were not cited in the review. They believe that their guidelines, which emphasize coordinated multidisciplinary care and patient education, are highly relevant to the broader discussion of transition care for patients with neurogastroenterology and motility (NGM) disorders. The authors respectfully request that their guidelines be included in future revisions or related publications to enhance the comprehensiveness and applicability of the review. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Hirschsprung disease (HSCR) is a complex genetic disorder of neural crest development resulting in incomplete formation of the enteric nervous system (ENS). This life-threatening neurocristopathy affects 1/5000 live births, with a currently unexplained male-biased ratio. To address this lack of knowledge, we took advantage of the TashT mutant mouse line, which is the only HSCR model to display a robust male bias. Our prior work revealed that the TashT insertional mutation perturbs a Chr.10 silencer-enriched non-coding region, leading to transcriptional dysregulation of hundreds of genes in neural crest-derived ENS progenitors of both sexes. Here, through sex-stratified transcriptome analyses and targeted overexpression in ENS progenitors, we show that male-biased ENS malformation in TashT embryos is not due to upregulation of Sry–the murine ortholog of a candidate gene for the HSCR male bias in humans–but instead involves upregulation of another Y-linked gene, Ddx3y. This discovery might be clinically relevant since we further found that the DDX3Y protein is also expressed in the ENS of a subset of male HSCR patients. Mechanistically, other data including chromosome conformation captured-based assays and CRISPR/Cas9-mediated deletions suggest that Ddx3y upregulation in male TashT ENS progenitors is due to increased transactivation by p53, which appears especially active in these cells yet without triggering apoptosis. Accordingly, in utero treatment of TashT embryos with the p53 inhibitor pifithrin-α decreased Ddx3y expression and abolished the otherwise more severe ENS defect in TashT males. Our data thus highlight novel pathogenic roles for p53 and DDX3Y during ENS formation in mice, a finding that might help to explain the intriguing male bias of HSCR in humans. Author summary: Hirschsprung disease (HSCR) is a life-threatening birth defect characterized by the lack of enteric neurons in the colon. HSCR is due to many gene defects, which are only partially understood. In particular, the reason why more boys than girls are affected by this condition is currently unknown. Yet, a better understanding of HSCR at the genetic/molecular level would help to develop more efficient therapies compared to current surgical approaches. Here, we identified a potential molecular cascade involving sequential upregulation of p53 and DDX3Y that, when inhibited, can eliminate the male bias in a HSCR mouse model. We found DDX3Y to be also specifically expressed in enteric neurons of a subset of male HSCR patients, suggesting that manipulation of the putative p53-DDX3Y pathway might eventually have therapeutic value in humans as well. [ABSTRACT FROM AUTHOR]

We investigated activation status, cytotoxic potential, and gut homing ability of the peripheral blood Natural Killer (NK) cells in Crohn disease (CD) patients. For this purpose, we compared the expression of different activating and inhibitory receptors (KIR and non-KIR) and integrins on NK cells as well as their recent degranulation history between the patients and age-matched healthy controls. The study was conducted using freshly obtained peripheral blood samples from the study participants. Multiple color flow cytometry was used for these determinations. Our results show that NK cells from treatment-naïve CD patients expressed higher levels of activating KIR as well as other non-KIR activating receptors vis-à-vis healthy controls. They also showed increased frequencies of the cells expressing these receptors. The expression of several KIR and non-KIR inhibitory receptors tended to decrease compared with the cells from healthy donors. NK cells from the patients also expressed increased levels of different gut-homing integrin molecules and showed a history of increased recent degranulation events both constitutively and in response to their in vitro stimulation. Furthermore, treatment of the patients tended to reverse these NK cell changes. Our results demonstrate unequivocally, for the first time, that peripheral blood NK cells in treatment-naïve CD patients are more activated and are more poised to migrate to the gut compared to their counterpart cells from healthy individuals. Moreover, they show that treatment of the patients tends to normalize their NK cells. The results suggest that NK cells are very likely to play a role in the immunopathogenesis of Crohn disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Scoliosis has been reported after repair of esophageal atresia with or without tracheoesophageal fistula (EA-TEF). This study aims to investigate the prevalence and natural history of scoliosis and associated congenital vertebral anomalies in patients operated for EATEF. A retrospective review of patients operated for EA-TEF with radiological examination for the presence of scoliosis or associated spine congenital anomalies was done on 106 patients (ages 5–19 years). Scoliosis was found in 53 patients (49%) for which 46 of these were in the thoracic region and 33 were right-thoracic curves. After a follow-up ranging from 5 to 14 years, four patients (3.7%) out of 106 were operated for scoliosis. Right-sided thoracotomy (RST) was the identifiable risk factor for scoliosis development; all patients with scoliosis had their EA repaired through RST. Congenital vertebral anomalies were found in 8 of those patients (7.5%). After a median follow-up of 6.5 years, no patients progressed enough to require operation. Scoliosis affects one of every two patients operated for EA; it may progress to the indication of surgery. RST was the identifiable risk factor for scoliosis development. [ABSTRACT FROM AUTHOR]

Background: Killer-cell Immunoglobulin-like Receptor (KIR) genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. There exist six distinct activating KIR genes in humans, who differ from one another with respect to the repertoire of these genes. Because activated NK cells can potentially cause tissue destruction, we hypothesized that variation in the inherited activating KIR genes in humans is associated with their innate susceptibility/resistance to developing Crohn disease (CD). Methods: We performed case control studies on three independent Canadian CD patient cohorts (all of the Western European descent): two comprising children (Montreal having 193 cases and 245 controls, and Ottawa having 93 cases and 120 controls) and the third one comprising predominantly adults (Winnipeg having 164 cases and 200 controls). We genotyped cases and controls for activating KIR genes by PCR with gene-specific primers and investigated associations between the genes and cases using unconditional logistic regression. Results: We observed strong associations between all the six KIR genes and CD in Ottawa children, with the strongest risk observed for the KIR2DS1 (p = 1.7 x10-10). Associations between all but the KIR2DS2 were replicated in the Montreal cohort with the strongest association evident for the KIR2DS5 (8.0 x 10−10). Similarly associations between five genes were observed in the adult Winnipeg cohort. In this cohort, strongest associations were evident with the KIR2DS5 (8.75 x 10−8). An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for the KIR2DS5 (p = 1.35 x 10−17). In the combined analysis for four KIR genes, individuals carrying one or more of the KIR genes were at significantly higher risks for acquiring CD (p = 3.5 x 10−34). Conclusions: Activating KIR genes are associated with risk for developing CD in both children and adults. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. Treatment study. Level III. [ABSTRACT FROM AUTHOR]

This study examines the impact of postoperative noninvasive ventilation strategies on outcomes in esophageal atresia–tracheoesophageal fistula (EA-TEF) patients. A single center retrospective chart review was conducted on all neonates followed at the EA-TEF Clinic from 2005 to 2017. Primary outcomes were: survival, anastomotic leak, stricture, pneumothorax, and mediastinitis. Statistical significance was determined using Chi-square and logistic regression (p ≤.05). We reviewed 91 charts. Twenty-five infants (27.5%) were bridged with postextubation noninvasive ventilation (15 on Continuous Positive Airway Pressure (CPAP), 5 on Noninvasive Positive Pressure Ventilation (NIPPV), and 14 on High-Flow Nasal Cannula (HFNC)). Overall, 88 (96.7%) patients survived, 25 (35.7%) had a stricture, 14 (20%) had anastomotic leak, 9 (12.9%) had a pneumothorax, and 4 (5.7%) had mediastinitis. Use of NIPPV was associated with increased risk of mediastinitis (P =.005). Use of HFNC was associated with anastomotic leak (P =.009) and mediastinitis (P =.036). These data suggest that postoperative noninvasive ventilation techniques are associated with a significantly higher risk of anastomotic leak and mediastinitis. Further prospective research is needed to guide postoperative ventilation strategies in this population. Retrospective study. IV. [ABSTRACT FROM AUTHOR]

Aim: This prospective study evaluated the incidence of functional gastrointestinal disorders (FGIDs) during infancy, on their own or combined with other symptoms.Methods: We asked 273 French paediatricians with a specific interest in FGIDs to provide feedback on 2757 infants aged zero to six months from March 2013 to January 2014. Gastrointestinal health status was assessed by two questionnaires at inclusion and at a four-week follow-up visit. FGIDs were assessed according to the Rome III criteria and quality of life (QoL) was monitored.Results: Combined FGIDs were diagnosed in 2145 (78%) infants: 63% with two disorders and 15% with three or more disorders. The most frequently combined FGIDs were gas/bloating and colic (28%), colic and regurgitation (17.0%) and gas/bloating and regurgitation (8%). Compared to infants with a single FGID, combined FGID were associated with lower body weight (4.63 vs 4.79 kg, p = 0.009), shorter breastfeeding duration (33 vs 43 days, p < 0.001), a decreased QoL score (5.9 vs 6.5, p < 0.001), more frequent drug prescriptions (25% vs 13%, p < 0.001) and significantly greater improvements in QoL scores after four weeks (p = 0.003).Conclusion: Combined FGIDs were extremely common in infants up to six months of age and had a negative impact on breastfeeding, weight gain and QoL. [ABSTRACT FROM AUTHOR]