Pediatric Gastroenterology, Hepatology, and Nutrition Entrustable Professional Activities: Development of an Assessment Tool and Curricular Resources.

BACKGROUND: Entrustable professional activities (EPAs) are critical activities performed by medical professionals, which can be observed and assessed. Adding on to common EPAs for all pediatric subspecialty trainees, specialty-specific EPAs for pediatric gastroenterology, hepatology, and nutritional fellowship were developed by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) EPA Task Force. METHODS: Having developed specialty-specific EPAs, building EPA assessments is the next logical step, as EPAs are included under a larger umbrella of competency-based assessment. Thus, the NASPGHAN EPA Task Force and Training Committee collaborated on an assessment tool and associated curricular resources to aid in tracking trainees' progression to entrustment within individual EPAs and readiness for independent practice. RESULTS: This manuscript reports the development of an EPA assessment tool, including guiding principles and the theory behind the assessment tool, with a focus on simple, meaningful assessments that can provide crucial performance feedback to trainees. In addition, curricular resources were developed, based on the assessment tool, to support training. Ultimately, it is the hope of the NASPGHAN EPA Task Force and Training Committee that this tool can aid training programs in providing formative feedback for trainees, and can be used by training programs and clinical competency committees for summative evaluation.

Expanding and characterizing esophageal epithelial cells obtained from children with eosinophilic esophagitis.

BACKGROUND: The role of epithelial cells in eosinophilic esophagitis (EoE) is not well understood. In this study, our aim was to isolate, culture, and expand esophageal epithelial cells obtained from patients with or without EoE and characterize differences observed over time in culture. METHODS: Biopsies were obtained at the time of endoscopy from children with EoE or suspected to have EoE. We established patient-derived esophageal epithelial cell (PDEEC) lines utilizing conditional reprogramming methods. We determined integrin profiles, gene expression, MHC class II expression, and reactivity to antigen stimulation. RESULTS: The PDEECs were found to maintain their phenotype over several passages. There were differences in integrin profiles and gene expression levels in EoE-Active compared to normal controls and EoE-Remission patients. Once stimulated with antigens, PDEECs express MHC class II molecules on their surface, and when co-cultured with autologous T-cells, there is increased IL-6 and TNF-α secretion in EoE-Active patients vs. controls. CONCLUSION: We are able to isolate, culture, and expand esophageal epithelial cells from pediatric patients with and without EoE. Once stimulated with antigens, these cells express MHC class II molecules and behave as non-professional antigen-presenting cells. This method will help us in developing an ex vivo, individualized, patient-specific model for diagnostic testing for causative antigens.

Retrospective Comparison of Fluticasone Propionate and Oral Viscous Budesonide in Children With Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is treated with dietary modification and/or pharmacologic management with swallowed topical steroids. Swallowed fluticasone propionate (FP) and oral viscous budesonide (OVB) have proven to be effective in resolving symptoms and reversing histologic changes in children and adults with EoE. There are minimal comparative studies between the 2 agents. OBJECTIVE: The aim of the study was to retrospectively compare endoscopic and histologic outcomes after FP versus OVB therapy in children with EoE in our center. METHODS: We performed a retrospective chart review of subjects diagnosed with EoE at a tertiary care center between 2010 and 2015. Inclusion criteria were FP or OVB therapy for ≥8 weeks along with pre- and post-treatment endoscopic evaluation. Demographic and clinical features and endoscopic and histologic assessment were recorded for comparative analysis. Histologic response was defined as <15 eos/hpf and remission as <5 eos/hpf. RESULTS: The study included 68 EoE patients (20 FP and 48 OVB) with a mean age of 10.6 ±â€Š5.2 years (range 1-20 years); 81% were boys and 68% were Caucasian. No significant demographic or clinical differences were noted between the 2 study groups. Overall histologic response to topical steroids was seen in 44 of 68 (65%) patients. A significantly greater number of patients achieved histologic response with OVB (36/48, 75%) than with FP (8/20, 40%) (P = 0.0059). Mean pretreatment peak eos/hpf was 46 ±â€Š19 in the FP group versus 45 ±â€Š23 in the OVB group. Mean post-treatment peak eos/hpf was 20 ±â€Š29 in the FP group versus 12 ±â€Š16 in the OVB group (P = 0.002). There was also a significantly greater difference in the change of absolute eos/hpf from pre- to post-treatment in the OVB group (-33) versus FP (18) (P = 0.047). A greater number of OVB-treated patients without asthma had a histologic response compared to those with asthma (P = 0.031). The response to OVB was not affected by the delivery vehicle, namely sucralose (Splenda) versus Neocate Duocal. CONCLUSIONS: Our data suggest that treatment with OVB leads to better endoscopic and histologic outcomes than FP. Adherence to treatment and history of asthma are major determining factors in the response to treatments. Using Neocate Duocal as the OVB delivery vehicle is just as effective as sucralose.

Characterization of Initial Gastrointestinal Evaluation of Children with Autism Spectrum Disorder: A Descriptive Study.

Autism spectrum disorder (ASD) is a multifactorial, pervasive neurodevelopmental disorder affecting 1 in 36 children in the United States. Given the rising prevalence and significant economic and social costs associated with ASD, it is critical that continued efforts be made towards better understanding the underlying etiology as well as management of the condition and its commonly associated comorbidities. It has been estimated that upwards of 70% of children with ASD have a positive history of gastrointestinal (GI) symptoms. In this retrospective, descriptive study, we identified 131 patients with diagnosis of autism spectrum disorder who presented for initial evaluation by pediatric gastroenterology at the Baystate Children's Specialty Center. We collected data from chart review of these patients with a particular focus on reason for referral, components of evaluation as well as results of said evaluation. Of the 131 patients, the most frequent reason for referral included constipation (42.7%), abdominal pain (27.5%), and feeding difficulties (26.7%). After completion of the evaluation, 60.3% of patients were ultimately diagnosed with a functional gastrointestinal condition. Of patients who completed endoscopic evaluation, 40% of patients were found to have grossly abnormal and 40% were found to have pathologically abnormal EGD. The majority of patients were recommended to have diagnostic evaluation; however, a large proportion of them were unable to complete said evaluation. The majority of patients were found to have abnormal testing; however, the majority of patients were additionally diagnosed with a functional gastrointestinal condition.

Concurrent, New-Onset Autoimmune Hepatitis, Celiac Disease, and Hashimoto's Thyroiditis Following COVID-19: A Case Report.

Here we describe a 13-year-old adolescent female diagnosed with concurrent autoimmune disorders including Grave disease, Celiac disease, and autoimmune hepatitis within 3 months after infection with severe acute respiratory syndrome coronavirus 2. The patient initially presented to her pediatrician with complaints of epistaxis, cessation of menses, palpitations, and weight loss. Initial evaluation showed evidence of hyperthyroidism, elevated liver enzymes, and abnormal Celiac disease serologies. Additional testing including laboratory tests, liver biopsy, and an upper endoscopy with biopsies confirmed the diagnosis of Grave disease, Celiac disease, and type 1 autoimmune hepatitis. This case highlights the importance of recognizing the risk of autoimmune disorders associated with the novel coronavirus disease 2019.

Severe Necrotizing Pancreatitis in a Pediatric Patient with COVID-19: A Case Report.

We describe a 15-year-old female diagnosed with necrotizing pancreatitis in the setting of coronavirus disease 2019 with severe complications including splenic vein and portal vein thromboses, pleural effusion requiring chest tube, acute hypoxic respiratory failure requiring noninvasive positive-pressure ventilation, and new-onset insulin-dependent diabetes mellitus, requiring over a month-long hospitalization. Following discharge, the patient experienced a prolonged loss of appetite, nausea, and extreme weight loss., During her prolonged hospitalization, she was diagnosed with necrotizing pancreatitis with walled-off collection which was ultimately treated with transgastric endoscopic ultrasound-guided drainage, multiple endoscopic necrosectomies, lumen-apposing metal stents, and double-pigtail plastic stent. Nine months after her initial presentation, patient's clinical symptoms improved, and her weight stabilized. This case highlights the importance of recognizing acute and necrotizing pancreatitis and its morbidities as complications associated with coronavirus disease 2019.

Preoperative immunosuppression is not associated with increased postoperative complications following colectomy in children with colitis.

OBJECTIVES: The aim of the present study was to review postoperative complications of pediatric patients undergoing colectomy for ulcerative colitis (UC) or inflammatory bowel disease-unspecified (IBD-U) with a focus on preoperative immunosuppression including exposure to infliximab. METHODS: We performed a retrospective chart review of all of the children with UC or IBD-U undergoing colectomy at our institution from 1996 to 2010. Data collected included indication for colectomy, immunosuppressive medications taken within 30 to 90 days of colectomy, surgical techniques and staging, and early and late postoperative complications. RESULTS: A total of 51 patients underwent colectomy (45 UC, 6 IBD-U) (55% male, 63% pancolitis at diagnosis, mean age at diagnosis 10.8 ± 3.8 years, mean age at colectomy 13.1 ± 3.8 years). Indications for colectomy were fulminant colitis in 26% and medically refractory chronic disease in 74%. Patient exposure to immunosuppression in the 30 days before colectomy included corticosteroids (88%), thiopurines (51%), and calcineurin inhibitors (4%). Within 90 days before colectomy, 65% of patients were exposed to infliximab. Small bowel obstruction was the most common postoperative complication, occurring in 19% (treated surgically in 30%), followed by wound infection in 8% and intraabdominal abscess in 6%. One patient developed postoperative sepsis. There was no increased incidence of early or late infectious or noninfectious complications in those patients taking or not taking thiopurines or calcineurin inhibitors (within 30 days), or infliximab (within 90 days). CONCLUSIONS: Preoperative exposure to thiopurines or calcineurin inhibitors (within 30 days) or infliximab (within 90 days) was not associated with increased postoperative complications in our cohort undergoing colectomy for UC or IBD-U.

Incidental Hepatic Granulomata as the Initial Presentation of Crohn's Disease in a Pediatric Patient.

We describe a 9-year-old girl who presented with abdominal pain, found incidentally to have multiple liver granulomata. Extensive autoimmune and infectious workup was negative. The patient had esophagogastroduodenoscopy and colonoscopy, confirming the diagnosis of Crohn's disease. Hepatic granulomata are a rare complication of Crohn's disease and are often secondary to pharmacotherapy or infection in immunosuppressed patients. This case, to our knowledge, is the first reported case of a pediatric patient diagnosed with Crohn's disease after initially presenting with hepatic granulomata as an extraintestinal manifestation of the disease.

Pediatric Patient With Concurrent Eosinophilic Esophagitis, Erosive Reflux Esophagitis, and Barrett's Esophagus.

Eosinophilic esophagitis and Barrett's esophagus are believed to be separate disease processes, with erosive esophagitis leading to Barrett's esophagus. We report a rare case of concurrent diagnoses in a pediatric patient and examine the relevant genetic profiles in the esophagus.

Efficacy of Dairy Free Diet and 6-Food Elimination Diet as Initial Therapy for Pediatric Eosinophilic Esophagitis: A Retrospective Single-Center Study.

PURPOSE: Management of eosinophilic esophagitis (EoE) varies from center to center. In this study, we evaluated the effectiveness of a dairy-free diet (DFD) and the 6-Food Elimination Diet (SFED) as initial therapies for the treatment of EoE in our practice. METHODS: This was a retrospective study of children who had been treated for EoE at Connecticut Children's Medical Center, Hartford, CT, USA. Pre- and post-treatment endoscopy findings and histology results of patients treated with DFD or SFED were examined. RESULTS: One hundred fifty-two patients (age 9.2±5.2 years, 76.3% male, 69.7% caucasian) met the inclusion criteria for initial treatment with DFD (n=102) or SFED (n=50). Response for DFD was 56.9% and for SFED was 52.0%. Response based on treatment duration (<10, 10-12, and >12 weeks) were 81.8%, 50.0%, and 55.1% for DFD, and 68.8%, 50.0%, and 40.0% for SFED. Response based on age (<6, 6-12, and >12 years) were 59.3%, 42.9%, and 67.5% for DFD, and 36.4%, 58.8%, and 72.7% for SFED. In patients treated with DFD, concomitant proton pump inhibitor (PPI) administration resulted in improved outcomes (p=0.0177). Bivariate regression analysis showed that PPI with diet is the only predictor of response (p=0.0491), however, there were no significant predictors on multiple regression analysis. CONCLUSION: DFD and SFED are effective first line therapies for EoE. DFD should be tried first before extensive elimination diets. Concomitant therapy with PPI's may be helpful.

Treatment with high-dose proton pump inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is a clinical entity that is recognized increasingly in children. The treatment of EE has been debated since its identification as a clinical entity separate from reflux esophagitis. We hypothesize that the treatment with a high-dose proton pump inhibitor (HDPPI) helps differentiate EE from noneosinophilic esophagitis (NEE). PATIENTS AND METHODS: Retrospective review of 2221 patients who underwent esophagogastroduodenoscopy (EGD) with biopsies was undertaken. Sixty-nine patients had more than or equal to 15 eosinophils/high-power field (eos/HPF) in 1 or more esophageal levels. Of those, 36 were initially treated with HDPPI for 3 months followed by repeat EGD. Patients who demonstrated histologic response were classified as NEE. Patients with no histologic response were diagnosed as having EE and treated with HDPPI+swallowed fluticasone for 3 months followed by repeat EGD. RESULTS: Of the 36 patients, histologic response was seen in 14 (39%) after treatment with HDPPI; 95% confidence interval (0.23-0.54). Swallowed fluticasone was added to the treatment of the 22 patients who did not show histologic response to HDPPI alone. Of those, 15 patients underwent repeat endoscopies. Seven patients were lost to follow-up or did not have repeated EGDs. Histologic response was observed in 9 of 15 (60%) patients. Of the nonresponders (6 of 15), 5 of 6 (83%) self-reported noncompliance with the swallowed fluticasone. Patients with more than or equal to 15 eos/HPF at all 3 levels (25 of 36) were less likely to respond to HDPPI alone and more likely to be categorized as EE (18 of 25), P=or<0.043. Symptomatically, 28 of 36 patients reported resolution of symptoms after HDPPI therapy alone, P=or<0.0001, regardless of histology. Visual endoscopic findings during the first and second EGDs did not show any significance in differentiating EE from NEE, P=0.625 and P=0.2405, respectively. CONCLUSIONS: The study demonstrates that HDPPI can be used to help differentiate EE from NEE histologically. Moreover, patients with more than or equal to 15 eos/HPF at all 3 levels are less likely to respond to HDPPI than patients with more than or equal to 15 eos/HPF at fewer than 3 levels. Therefore, having more than or equal to 15 eos/HPF at 1 or 2 biopsy levels does not necessarily establish the diagnosis of EE. Symptomatic response to HDPPI does not correlate with histologic findings. Clinical management guided by EGD with biopsy helps distinguish patients with EE from those with NEE.

Polyurethane scaffolds seeded with autologous cells can regenerate long esophageal gaps: An esophageal atresia treatment model.

BACKGROUND: Pediatric patients suffering from long gap esophageal defects or injuries are in desperate need of innovative treatment options. Our study demonstrates that two different cell sources can adhere to and proliferate on a retrievable synthetic scaffold. In feasibility testing of translational applicability, these cell seeded scaffolds were implanted into piglets and demonstrated esophageal regeneration. METHODS: Either porcine esophageal epithelial cells or porcine amniotic fluid was obtained and cultured in 3 dimensions on a polyurethane scaffold (Biostage). The amniotic fluid was obtained prior to birth of the piglet and was a source of mesenchymal stem cells (AF-MSC). Scaffolds that had been seeded were implanted into their respective Yucatan mini-swine. The cell seeded scaffolds in the bioreactor were evaluated for cell viability, proliferation, genotypic expression, and metabolism. Feasibility studies with implantation evaluated tissue regeneration and functional recovery of the esophagus. RESULTS: Both cell types seeded onto scaffolds in the bioreactor demonstrated viability, adherence and metabolism over time. The seeded scaffolds demonstrated increased expression of VEGF after 6 days in culture. Once implanted, endoscopy 3 weeks after surgery revealed an extruded scaffold with newly regenerated tissue. Both cell seeded scaffolds demonstrated epithelial and muscle regeneration and the piglets were able to eat and grow over time. CONCLUSIONS: Autologous esophageal epithelial cells or maternal AF-MSC can be cultured on a 3D scaffold in a bioreactor. These cells maintain viability, proliferation, and adherence over time. Implantation into piglets demonstrated esophageal regeneration with extrusion of the scaffold. This sets the stage for translational application in a neonatal model of esophageal atresia.

Conditional Reprogramming of Pediatric Human Esophageal Epithelial Cells for Use in Tissue Engineering and Disease Investigation.

Identifying and expanding patient-specific cells in culture for use in tissue engineering and disease investigation can be very challenging. Utilizing various types of stem cells to derive cell types of interest is often costly, time consuming and highly inefficient. Furthermore, undesired cell types must be removed prior to using this cell source, which requires another step in the process. In order to obtain enough esophageal epithelial cells to engineer the lumen of an esophageal construct or to screen therapeutic approaches for treating esophageal disease, native esophageal epithelial cells must be expanded without altering their gene expression or phenotype. Conditional reprogramming of esophageal epithelial tissue offers a promising approach to expanding patient-specific esophageal epithelial cells. Furthermore, these cells do not need to be sorted or purified and will return to a mature epithelial state after removing them from conditional reprogramming culture. This technique has been described in many cancer screening studies and allows for indefinite expansion of these cells over multiple passages. The ability to perform esophageal screening assays would help revolutionize the treatment of pediatric esophageal diseases like eosinophilic esophagitis by identifying the trigger mechanism causing the patient's symptoms. For those patients who suffer from congenital defect, disease or injury of the esophagus, this cell source could be used as a means to seed a synthetic construct for implantation to repair or replace the affected region.

Outcome of medical management of intraabdominal abscesses in children with Crohn disease.

INTRODUCTION: Crohn disease (CD) is a chronic inflammatory condition of the gastrointestinal tract that is complicated by fistulas, strictures, and intraabdominal abscesses (IAA) in 10%-30% of patients. To avoid surgical resection of the bowel, medical therapy with antibiotics (Ab) with or without percutaneous drainage (PD) is first undertaken. Our objectives are to examine the outcome of IAA in CD patients treated with antibiotics alone vs antibiotics and PD, and to identify risk factors for medical therapy failure. METHODS: Charts for patient with CD who were diagnosed between 2004 and 2016 at the Women and Children's Hospital of Buffalo were retrospectively reviewed. We compared the two modalities of medical therapy (Ab + PD vs Ab alone) in terms of abscess resolution and the need for surgical intervention. RESULTS: Twenty-nine patients, ages ranging from 12 to 18years, mean 15.5±2.5, 48% Male with IAA were identified. Overall, 69% of abscesses failed medical therapy including 87% of the drained abscesses and 50% of nondrained abscesses, p=0.04. The abscesses that failed medical therapy were more likely to have been drained (P=0.03) as they were larger in size (P = 0.03), patients were more likely to have a known CD on immunosuppression (P=0.016), and more likely to have an associated upper GI disease (P=0.002), when compared to those that were successful with medical therapy alone. CONCLUSION: Our results show that the majority of our patients required surgical intervention for abscess treatment and resolution of associated findings despite drainage. Risk factors include big drainable abscesses, developing IAA while on immunosuppression, and a more extensive disease with associated fistulae and strictures. Small undrainable abscesses are likely to resolve with antibiotics alone, therefore early detection and treatment are essential. TYPE OF STUDY: Level 2, retrospective study.

Advanced Glycation End Products Induce Obesity and Hepatosteatosis in CD-1 Wild-Type Mice.

AGEs are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and/or nucleic acids. AGEs have been shown to play a role in various conditions including cardiovascular disease and diabetes. In this study, we hypothesized that AGEs play a role in the "multiple hit hypothesis" of nonalcoholic fatty liver disease (NAFLD) and contribute to the pathogenesis of hepatosteatosis. We measured the effects of various mouse chows containing high or low AGE in the presence of high or low fat content on mouse weight and epididymal fat pads. We also measured the effects of these chows on the inflammatory response by measuring cytokine levels and myeloperoxidase activity levels on liver supernatants. We observed significant differences in weight gain and epididymal fat pad weights in the high AGE-high fat (HAGE-HF) versus the other groups. Leptin, TNF-α, IL-6, and myeloperoxidase (MPO) levels were significantly higher in the HAGE-HF group. We conclude that a diet containing high AGEs in the presence of high fat induces weight gain and hepatosteatosis in CD-1 mice. This may represent a model to study the role of AGEs in the pathogenesis of hepatosteatosis and steatohepatitis.

Characterizing the inflammatory response in esophageal mucosal biopsies in children with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an emerging allergic, IgE- and non-IgE (Th2 cell)-mediated disease. There are major gaps in the understanding of the basic mechanisms that drive the persistence of EoE. We investigated whether esophageal biopsies from children with EoE demonstrate an inflammatory response that is distinct from normal controls. We prospectively enrolled 84 patients, of whom 77 were included in our analysis, aged 4-17 years (12.8±3.8 years; 81% males). Five esophageal biopsies were collected from each patient at the time of endoscopy. Intramucosal lymphocytes were isolated, phenotyped and stimulated with phorbol 12-myristate 13-acetate/ionomycin to measure their potential to produce cytokines via flow cytometry. We also performed cytokine arrays on 72-h biopsy culture supernatants. CD8(+) T cells, compared with CD4(+) T cells, synthesized more TNF-α and interferon (IFN)-γ after mitogen stimulation in the EoE-New/Active vs EoE-Remission group (P=0.0098; P=0.02) and controls (P=0.0008; P=0.03). Culture supernatants taken from explant esophageal tissue contained 13 analytes that distinguished EoE-New/Active from EoE-Remission and Controls. Principal component analysis and cluster analysis based on these analytes distinctly separated EoE-New/Active from EoE-Remission and Controls. In summary, we have identified a previously unappreciated role for CD8(+) T lymphocytes with potential to produce TNF-α and IFN-γ in EoE. Our results suggest that CD8(+) T cells have a role in the persistence or progression of EoE. We have also identified a panel of analytes produced by intact esophageal biopsies that differentiates EoE-New/Active from EoE-Remission and controls. Our results suggest that esophageal epithelial cells may have specific immune effector functions in EoE that control the type and amplitude of inflammation.