Cholangioscopy in Children and Adolescents: Utilization, Outcomes, and Safety.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is increasingly utilized for management of biliary disorders in children and adolescents. Practice patterns surrounding cholangioscopy in pediatric patients, however, are largely uncharacterized. METHODS: We retrospectively analyzed all ERCPs in which cholangioscopy was performed on patients 18 and under at our tertiary care children's hospital from 2015 to 2020 using our institution's paper and electronic medical record system. Patient demographics, procedure indications, interventions, and associated adverse events were analyzed. RESULTS: Over the study period, 307 ERCPs were performed on 282 patients at our children's hospital. Cholangioscopy was performed in 36 procedures (11.7%) using the SpyGlass cholangioscope (Boston Scientific). Antibiotics to cover biliary organisms were administered to all patients precholangioscopy. Mean patient age was 13.6 years (range 7-18 years). The 2 most common indications for cholangioscopy included electrohydraulic lithotripsy for biliary stone disease and evaluation of biliary stricture (with incidental finding of biliary web in 2 patients and retained suture material in 2 patients). Adverse events were less prevalent in patients who underwent cholangioscopy relative to those who underwent ERCP. 0/36 (0%) developed post-ERCP pancreatitis, one patient had self-limited melena (possible self-limited postsphincterotomy bleeding). Patient care was enhanced by cholangioscopy in 30/36 (83.3%) of these patients. CONCLUSIONS: These data attest to the safety and clinical utility of cholangioscopy in children and adolescents. Cholangioscopy was performed in just over 11% of pediatric patients who underwent ERCP at our academic medical center-rates similar to those reported in adult patients. The radiation-sparing nature of cholangioscopy, coupled with these data supporting its safety, make it particularly appealing for use in children. Further multi-institution evaluation of the utility, safety, and range of indications for cholangioscopy in other practice settings would be of great interest and help guide endoscopic care.

Nationwide Evolution of Pediatric Endoscopic Retrograde Cholangiopancreatography Indications, Utilization, and Readmissions over Time.

OBJECTIVES: To analyze outcome and utilization trends over time of pediatric endoscopic retrograde cholangiopancreatography (ERCP) in an all-capture US population-level study. STUDY DESIGN: Using the National Inpatient Sample (2005-2014) and National Readmission Database (2010-2014), we identified pediatric (age <20 years) hospitalizations during which ERCP was performed and assessed ERCP-associated readmissions. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify hospitalization diagnoses, comorbidities, and patient/hospital characteristics. Multivariate logistic regression analyses were performed to determine significant predictors (P < .05) of 30-day readmission. RESULTS: A total of 11 060 hospitalized pediatric patients underwent ERCP between 2005 and 2014. Most were female (n = 8859; 81%), aged 14-20 years (n = 9342; 84%), and white (n = 4230; 45%). Most (85%) of ERCPs were therapeutic, and leading indications were biliary (n = 5350; 48%) and pancreatitis (n = 3218; 29%). Thirteen pecent of patients were readmitted post-ERCP. Odds for 30-day readmission were highest for patients with a history of liver transplantation, age 0-4 years, male sex, and obesity (P < .001 for each). Patients in both urban teaching and urban hospitals had much lower odds than those in rural hospitals for prolonged length of stay associated with ERCP. CONCLUSIONS: These data represent a comprehensive study of nationwide trends in age-specific volumes and outcomes following ERCP in the pediatric population and provide important insights into trends in pediatric pancreaticobiliary disease management, as well as practice setting, patient characteristics, and patient comorbidities associated with pediatric post-ERCP outcomes, including readmission and length of stay.

Fluoroscopy Time During Endoscopic Retrograde Cholangiopancreatography Performed for Children and Adolescents is Significantly Higher With Low-volume Endoscopists.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a fluoroscopy and endoscopy-based procedure important for diagnosis and management of pediatric pancreaticobiliary disorders. Patient, procedure, endoscopist, and facility characteristics have been shown to influence ERCP complexity and procedure outcomes as well as fluoroscopy utilization in adults; however, the extent to which this is true in pediatric patients remains under-studied and there are minimal data regarding fluoroscopy utilization in pediatric ERCP. METHODS: We retrospectively analyzed ERCPs performed on patients <18 years of age at our tertiary care children's hospital from 2002 to 2017 using our institution's paper and electronic medical record system along with a prospectively maintained radiation exposure database. Procedure complexity was graded using the Stanford Fluoroscopy Complexity Score and the American Society of Gastrointestinal Endoscopy Complexity scale. High-volume endoscopists (HVE) were defined as having a cumulative annual ERCP volume >100 and low-volume endoscopists (LVE) as <100 (pediatric + adult) ERCPs/year. RESULTS: Three hundred eighty-five ERCPs performed on 321 patients were included in this analysis. The mean patient age was 13.4 years (+/- 4.2 years), 77% were index ERCPs (native ampullas), and 81% were performed with therapeutic intent (87% for biliary indication and 13% for pancreatic indication). Fluoroscopy times (FTs) varied between procedures and providers. Median FT was 4.85 (+/- 2.68) minutes. Endoscopist annual ERCP volume was the strongest predictor of FT (P < 0.001). In addition to endoscopist volume, procedure-specific predictors of increased FT included pancreatic indication for the procedure, biliary or pancreatic duct stricture, patient age <4 years or >16 years at the time of ERCP (P < 0.01 for each), and native ampulla. ERCP complexity rating based on the Stanford Fluoroscopy Complexity Score correlated with FT. CONCLUSIONS: Radiation exposure is higher than desirable for pediatric ERCP and varies with endoscopist as well as patient and procedure-specific factors. HVE perform ERCP with lower FT relative to LVE even though HVE procedure complexity was higher. The Stanford Fluoroscopy Score predicted FT for pediatric ERCP, but the ASGE ERCP complexity scale did not. Adaptation and refinement of pediatric-specific ERCP complexity scales including factors, such as patient size and age and indications/interventions more consistent with those encountered in pediatrics could be beneficial.

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

BACKGROUND: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. METHODS: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

Pediatric Endoscopy Practice Patterns in the United States, Canada, and Mexico.

BACKGROUND AND AIMS: Endoscopic procedures are important for diagnosis and management of many gastrointestinal, liver, and biliary conditions in children. Therapeutic endoscopy procedures, including endoscopic retrograde cholangiopancreatography (ERCP), are performed less frequently in children relative to adults. A formal study to evaluate institutional volumes and practice patterns for advanced therapeutic pediatric endoscopy procedures has, however, not been previously undertaken. METHODS: A self-administered 16-question (5-minute) online survey assessing practice patterns for performance of pediatric endoscopy procedures was distributed to all registered North American Society for Pediatric Gastroenterology, Hepatology and Nutrition programs. Results were analyzed using descriptive statistics and thematic analysis of free-text comments. RESULTS: Respondents from 82.9% of North American Society for Pediatric Gastroenterology, Hepatology and Nutrition centers completed this survey. Responses revealed that esophagogastroduodenoscopy/colonoscopy are performed at the vast majority of centers (>90%), with most performing >50/year. Therapeutic endoscopy procedures are performed less frequently in the pediatric population, with 18.97% reporting that ERCP is not performed at their institution. Where ERCP is performed, 91.38% reported <25/year. Endoscopic ultrasound is not performed at more than half (53.33%) of institutions. Approximately 71.67% of respondents do not believe their institution's current arrangement for performing pediatric therapeutic endoscopy procedures is adequate. CONCLUSIONS: Although the range of endoscopic procedures performed in children parallels that performed in adults, there are notable differences in pediatric and adult gastroenterologists' endoscopy training and procedure volumes. Our results and respondent comments suggest that pediatric patients would benefit from a partnership between pediatric and adult gastroenterologists, with adult gastroenterologists performing more complex therapeutic endoscopic procedures.

Prenatal treatment of ornithine transcarbamylase deficiency.

PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation.

Long-term IS in transplant patients has significant morbidity, poorer quality of life, and substantial economic costs. TOL, defined as graft acceptance without functional impairment in the absence of IS, has been achieved in some pediatric LT recipients. Using mass cytometry, peripheral blood immunotyping was performed to characterize differences between tolerant patients and patients who are stable on single-agent IS. Single-cell mass cytometry was performed using blood samples from a single-center pediatric LT population of operationally tolerant patients to comprehensively characterize the immune cell populations in the tolerant state compared with patients on chronic low-dose IS. Specific T-cell populations of interest were confirmed by flow cytometry. This high-dimensional phenotypic analysis revealed distinct immunoprofiles between transplant populations as well as a CD4+ TOT (CD4+ CD5+ CD25+ CD38-/lo CD45RA) that correlates with tolerance in pediatric LT recipients. In TOL patients, the TOT was significantly increased as compared to patients stable on low levels of IS. This TOT cell was confirmed by flow cytometry and is distinct from classic Treg cells. These results demonstrate the power of mass cytometry to discover significant immune cell signatures that have diagnostic potential.

Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure.

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

Immunophenotyping of peripheral eosinophils demonstrates activation in eosinophilic esophagitis.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE. METHODS: Eosinophils and CD3+ lymphocytes were identified directly from 50 µL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset. RESULTS: Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05). CONCLUSIONS: Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

Long-term outcome following pediatric liver transplantation for metabolic disorders.

In order to determine long-term outcome, including survival, growth and development, following liver transplantation in children with metabolic disorders, we retrospectively reviewed charts of 54 children with metabolic disorders evaluated from 1989-2005 for presenting symptoms, transplantation timing and indications, survival, metabolic parameters, growth, and development. Thirty-three patients underwent liver transplantation (12 received combined liver-kidney transplants) at a median age of 21 months. At a median follow-up of 3.6 yr, patient survival was 100%, and liver and kidney allograft survival was 92%, and 100%, respectively. For the group as a whole, weight Z scores improved and body mass index at follow-up was in the normal range. Two yr post-transplantation, psychomotor development improved significantly (p < 0.01), but mental skills did not; however, both indices were in the low-normal range of development. When compared to patients with biliary atresia, children with metabolic disorders showed significantly lower mental developmental scores at one and two yr post-transplantation (p < 0.05), but psychomotor developmental scores were not significantly different. We conclude that, in patients with metabolic disorders meeting indications for transplantation, liver transplantation or combined liver-kidney transplantation (for those with accompanying renal failure) is associated with excellent long-term survival, improved growth, and improved psychomotor development.

Combined liver-kidney transplantation in children: indications and outcome.

Although it remains a relatively infrequent procedure in children, CLKT has become a viable option for a select group of pediatric patients with severe liver and kidney disease. Most are performed for rare primary diseases such as PH1, but a selected few are performed in the setting of concomitant hepatic and renal failure of uncertain etiology and prognosis. This article reviews the indications for and outcomes following CLKT in children. While it focuses on the specific primary diseases which impact liver and kidney function simultaneously, it addresses the indications based on concomitant hepatic and renal failure, such as seen in the hepatorenal syndrome, as well.

Non-adherence to post-transplant care: prevalence, risk factors and outcomes in adolescent liver transplant recipients.

This study examined the prevalence, demographic variables and adverse outcomes associated with non-adherence to post-transplant care in adolescent liver transplant recipients. We conducted a retrospective chart review of 111 adolescent patients (age 12-21 yr) greater than six months post-transplantation and defined non-adherence as not taking the immunosuppressive(s) or not attending any clinic visit in 2005. Fifty subjects (45.0%) were non-adherent and 61 (55.0%) were adherent. Twenty percent of the subjects did not attend clinic and 10.9% did not complete laboratory tests. Non-adherence was significantly associated with fewer completed laboratory tests (p < 0.0001), single parent status (p < 0.0186), and older age and greater years post-transplantation by both univariate and multivariate analyses (p < 0.008, p < 0.0141 and p < 0.0012, p < 0.0174, respectively). Non-adherence to medication was significantly associated with a rejection episode in 31 patients (p < 0.0069) but not in the subgroup of seven patients who stopped their immunosuppression completely. Non-adherence to post-transplant care is a prevalent problem in adolescents particularly of an older age and greater years post-transplantation. Rejection was a significant consequence of medication non-adherence except in a subgroup with presumed graft tolerance who discontinued their immunosuppression. These results emphasize the need for strict monitoring of adherence to post-transplant care to improve long-term survival and quality of life in adolescent transplant patients.

Initial experience with peroral endoscopic myotomy for treatment of achalasia in children.

BACKGROUND: Achalasia is a primary esophageal motility disorder characterized by aperistalsis of the esophagus and failed relaxation of the lower esophageal sphincter that presents rarely in childhood. The peroral endoscopic myotomy (POEM) procedure is an emerging treatment for achalasia in adults that has recently been introduced into pediatric surgical practice. METHODS: This is a prospective case series of all children referred to Stanford University Lucile Packard Children's Hospital with manometry-confirmed achalasia who underwent a POEM procedure from 2014 to 2016. RESULTS: We enrolled 10 subjects ranging in age from 7 to 17years (M=13.4). The mean pre- and 1-month post-procedure Eckardt scores were 7 (SD=2.5) and 2.4 (SD=2) (p<0.001), respectively. The median procedure time for the entire cohort was 142min (range 60-259min) with ongoing improvement with increased experience (R2=0.6, p=0.008). There were no major adverse events. CONCLUSION: The POEM procedure can be successfully completed in children for the treatment of achalasia with demonstrated short-term post-operative improvement in symptoms. The adoption of advanced endoscopic techniques by pediatric surgeons may enable development of unique intraluminal approaches to congenital anomalies and other childhood diseases. LEVEL OF EVIDENCE: Treatment Study - Level IV.

Parenteral nutrition-associated cholestasis related to parental care.

Parenteral nutrition-associated cholestasis (PNAC) is a complication not uncommon in the pediatric population. In severe cases, patients require a liver transplant. To our knowledge, we report the only case of PNAC with end-stage liver failure in a child with short bowel syndrome that resolved with a change in caretaker. Until his care was transferred from his abusive parents, he was frequently admitted for infection and sepsis. His liver function vastly improved from aspartate aminotransferase (AST) 3139 units/L, conjugated bilirubin 25.9 mg/dL to AST 47 units/L, direct bilirubin 0.3 mg/dL under the care of his attentive foster mother, and a liver transplant was no longer necessary. Bacterial infection and sepsis are risk factors correlated with patients with PNAC requiring liver transplant. Prevention of infection by a good caregiver may be a means to reduce the incidence of PNAC.

Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

Text Messaging Improves Participation in Laboratory Testing in Adolescent Liver Transplant Patients.

BACKGROUND: In solid organ transplant patients, non-participation in all aspects of the medical regimen is a prevalent problem associated with adverse consequences particularly in the adolescent and young adult (AYA) age group. This study is the first to evaluate the feasibility, utility and impact of a text messaging (TM) intervention to improve participation in laboratory testing in adolescent liver transplant patients. METHODS: AYA patients, aged 12 to 21 years, were recruited for a prospective pilot trial evaluating a TM intervention delivered over a 1-year period. The intervention involved automated TM reminders with feedback administered according to a prescribed laboratory testing frequency. Participation rate in laboratory testing after the intervention was compared to the year prior. Patient responses and feedback by text and survey were used to assess feasibility, acceptability and use of the intervention. RESULTS: Forty-two patients were recruited and 33 patients remained enrolled for the study duration. Recipients of the TM intervention demonstrated a significant improvement in participation rate in laboratory testing from 58% to 78% (P<.001). This rate was also significantly higher than in non-intervention controls (P=.003). There was a high acceptability, response rate and a significant correlation with reported versus actual completion of laboratory tests by TM. CONCLUSIONS: TM reminders significantly improved participation in laboratory testing in AYA liver transplant patients. The intervention demonstrated feasibility, acceptability, and use with a high proportion of patients who engaged in and perceived a benefit from using this technology.

One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience.

BACKGROUND: Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease. METHODS: Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg. RESULTS: At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation. CONCLUSIONS: Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.