Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Catheter salvage from central line-related bloodstream infections in pediatric intestinal failure.

OBJECTIVES: Patients with intestinal failure require central venous access which puts them at risk for central line-associated bloodstream infections (CLABSI). Maintaining vascular patency is critical for this population to receive nutrition support. When CLABSIs occur line salvage can help maintain vascular access. The aim of this study is to assess factors associated with safe and successful central venous catheter salvage. METHODS: Retrospective cohort study of patients with intestinal failure at two tertiary care institutions between 2012 and 2020. The study examined the rates of attempted salvage, factors associated with successful salvage, and complications associated with salvage attempts. RESULTS: Over the study period, 76 patients with intestinal failure were include while central venous access was in place. There were a total of 94 CLABSIs. Salvage was more likely to be attempted when patients were under the direct care of an intestinal rehabilitation service (95% vs. 68%, p = 0.04). The overall successful salvage rate was 91.6% (n = 77). Gram-positive, Gram-negative, and polymicrobial infections had successful salvage rates of 97%, 92%, and 94% respectively. The successful salvage rate for fungal infections was 40%. There was no difference in 30-day complication rates for hospital readmission, intensive care unit admission, and death between patients who underwent salvage attempt and those who did not. CONCLUSIONS: Central line salvage can be safely attempted for many infections in patients with intestinal failure, leading to vascular access preservation.

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

NASPGHAN Nutrition University (N2U): A Survey of its Efficacy as Continuing Nutrition Education for North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

The North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) developed NASPGHAN Nutrition University (N2U) in 2012 to improve nutrition education for pediatric gastroenterology providers. A total of 543 providers (physicians, registered dietitians, and advanced practice nurses) have applied to N2U and 285 have attended this 2-day course. We used survey methodology to compare attendees to applicants who did not attend. Course attendees reported more confidence than nonattendees in the nutritional management of patients with short bowel syndrome, feeding disorders, and gastrointestinal allergies, even though they were seen at similar frequency in both groups. Eighty-eight percent of attendees disseminated the information they learned at N2U through venues such as grand rounds or guideline/policy development. These results demonstrate the benefit of N2U in enhancing nutrition education for pediatric gastroenterology practitioners.

Pediatric retransplantation of the liver: A prognostic scoring tool.

Few prognostic models have been created in children that receive liver retransplantation (rLT). We examined the SRTR database of 731 children that underwent second liver transplant between 2002 and 2018. Proportional hazards models using backward variable selection were used to identify recipient, donor, and surgical characteristics associated with survival. A simple prognostic scoring system or nomogram (ie, each risk factor was weighted on a five-point scale) was constructed based on the fitted model. Recipient age (P < .001), MELD/PELD (P < .001), recipient ventilated (P = .003), donor cause of death (P = .024), graft type (P = .045), first graft loss due to biliary tract complications (P = .048), and survival time of the first graft (P = .006) were significant predictors of retransplant survival. The bias-corrected Harrell's C-index for the multivariable model was 0.63. Survival was significantly different (P < .001) for those at low risk (0-4 points), medium risk (5-7 points), and high risk (8+ points). Survival was equivalent between low risk pediatric second transplant recipients and pediatric primary liver transplant recipients (P = .67) but significantly worse for medium- (P < .001) and high-risk (P < .001) recipients. With simple clinical characteristics, this scoring tool can modestly discriminate between those children at high risk and those children at low risk of poor outcomes after second liver transplant.

Failure to Thrive: A Prospective Study in a Pediatric Gastroenterology Clinic.

OBJECTIVES: We aimed to describe the clinical characteristics, diagnostic work-up, interventions, and outcomes of children referred to a pediatric gastroenterology clinic with the diagnosis of failure to thrive (FTT). METHODS: We prospectively enrolled 110 children seen for the first time in our pediatric gastroenterology clinic for FTT. Standard demographic information, history, and anthropometric data were collected at initial and follow-up visits. We also obtained data about diagnostic workup, therapeutic interventions, and growth outcomes. RESULTS: Seventy patients (63.6%) were boys with a median age of 0.79 years (interquartile range 0.36-1.98). Of the 91 children with follow-up data, 81 (89%) were found to have nonorganic etiologies of their FTT. The majority of children (56.4%) underwent laboratory evaluation. Imaging and endoscopic evaluations were performed in fewer patients (29.6 and 10.2%, respectively). Endoscopic intervention yielded a diagnosis in 16.7% of patients while the positive result rates for laboratory testing and imaging were 3.2% and 3.1%, respectively. The most common therapeutic interventions included increasing calories (71.8%), avoiding grazing (71.8%), and structuring meals and snacks (67.3%). Compared with nonadherent children, children who were adherent with standard behavioral and nutritional interventions showed a higher positive change in z scores for weight (0.36 vs -0.01, P = 0.001) and body mass index (0.58 vs -0.18, P = 0.031). CONCLUSIONS: The majority of children in a pediatric gastroenterology clinic with FTT have nonorganic etiologies of their failure to thrive. Laboratory, imaging, and endoscopic evaluation are rarely positive and should be judiciously performed. Adherence to standardized interventions leads to improved growth.

Langerhans cell histiocytosis of the digestive tract identified on an upper gastrointestinal examination.

Langerhans cell histiocytosis (LCH) with involvement of the gastrointestinal tract is rare and typically identified in patients with systemic disease. We describe a 16-month-old girl who initially presented with bilious vomiting, failure to thrive and a rash. An upper gastrointestinal (GI) examination revealed loss of normal mucosal fold pattern and luminal narrowing within the duodenum, prompting endoscopic biopsy. Langerhans cell histiocytosis of the digestive tract was confirmed by histopathology. A skeletal survey and skin biopsy identified other systemic lesions. Although uncommon, it is important to consider LCH in the differential diagnosis for gastrointestinal symptoms of unclear origin, especially when seen with concurrent rash. Findings of gastrointestinal involvement on upper GI examination include loss of normal mucosal fold pattern and luminal narrowing in the few published case reports.

Use of upper gastrointestinal series before gastrostomy tube placement.

We studied the use of a preoperative upper gastrointestinal series in children with and without major congenital anomalies undergoing gastrostomy tube (G-tube) placement. Of 1163 children evaluated, 743 had major anomalies and a total of 39 episodes of malrotation were found. All of the children with malrotation had either major congenital anomalies or cystic fibrosis. Our study suggests that an upper gastrointestinal series may be unnecessary before G-tube placement in children without other congenital anomalies or cystic fibrosis.

Pediatric Acute Liver Failure.

Pediatric acute liver failure is a rare process that results from many different diseases including toxin ingestion and drug overdose, infections, metabolic and genetic disorders, immune-mediated diseases, and ischemia. Up to 50% of children with acute liver failure will never have an underlying cause found. Early identification, supportive care, and disease-directed therapy are critical. For some children liver transplantation is needed for survival, but many children will recover with appropriate therapy, without the need for transplantation. Nonetheless, overall survival is approximately 50% without liver transplantation. Opportunities for improvement in the care of children with acute liver failure still exist.

Body composition assessment after pediatric liver transplant.

BACKGROUND: Pediatric liver transplantation generally restores metabolic function; yet after transplantation, some children remain malnourished, have increased adiposity, and develop obesity. Measurement of body composition in the assessment of nutrition status could reduce adverse consequences in children. METHODS: Anthropometric measurements, multiple-frequency bioelectrical impedance analysis, air displacement plethysmography, and ultrasound measurements were conducted on children recruited from the liver transplant program at the University of Minnesota Masonic Children's Hospital. A cross-sectional study was conducted to describe the quality of weight gain in post-liver transplant children between the ages of 2 and 17 years using multiple assessment tools (air displacement plethysmography, multiple-frequency bioelectrical impedance analysis, and ultrasound) and to determine whether multiple-frequency bioelectrical impedance analysis and ultrasound accurately describe body composition and quality of weight gain. RESULTS: Mean percent body fat by air displacement plethysmography and multiple-frequency bioelectrical impedance analysis was 18.4% (±3.3) and 19.0% (±3.9), respectively (P > .99). There were insufficient data to examine the relationship between summed muscle and adipose thickness measures by ultrasound and percent body fat determined by air displacement plethysmography or multiple-frequency bioelectrical impedance analysis. CONCLUSION: Percent body fat, fat mass, and fat-free mass measures determined by air displacement plethysmography and multiple-frequency bioelectrical impedance analysis were not statistically different, which suggests the stand-on device used in this study could be a useful body composition assessment tool for the pediatric population.

Use of Cidofovir for Safe Transplantation in a Toddler with Acute Liver Failure and Adenovirus Viremia.

Background: Since October 2021, there have been more than 500 cases of severe hepatitis of unknown origin in children reported worldwide, including 180 cases in the U.S. The most frequently detected potential pathogen to date has been adenovirus, typically serotype 41. Adenovirus is known to cause a self-limited infection in the immunocompetent host. However, in immunosuppressed individuals, severe or disseminated infections may occur. Method: We present the case of a two-year-old female who presented with cholestatic hepatitis and acute liver failure (ALF). Work up for etiologies of ALF was significant for adenovirus viremia, but liver biopsy was consistently negative for the virus. The risk for severe adenoviral infection in the setting of anticipated immunosuppression prompted us to initiate cidofovir to decrease viral load prior to undergoing liver transplantation. Result: Our patient received a successful liver transplant, cleared the viremia after 5 doses of cidofovir, and continues to maintain allograft function without signs of infection at the time of this report, 5 months posttransplant. Conclusion: Recent reports of pediatric hepatitis cases may be associated with adenoviral infection although the exact relationship is unclear. There is the possibility of the ongoing SARS-CoV-2 environment, or other immunologic modifying factors. All patients presenting with hepatitis or acute liver failure should be screened for adenovirus and reported to state health departments. Cidofovir may be used to decrease viral load prior to liver transplantation, to decrease risk of severe adenoviral infection.

Body Composition Post Pediatric Liver Transplant: Implications and Assessment.

Liver disease has a negative influence on growth and development of children. Measurement of body composition as a component of nutrition status assessment in children before and after transplant would facilitate tailoring of nutrition therapy. A comprehensive literature search on pediatric liver transplant and body composition assessment was performed using a modified systematic approach. This review includes evidence specific to body composition of children undergoing liver transplant and a discussion of relevant body composition assessment methods for this population. Malnutrition is commonly seen in children with liver disease prior to transplant because of the disrupted metabolic pathways from liver dysfunction; however, malnutrition is not consistently diagnosed. Within 1 year of transplant, children tend to quickly recover with weight gain and linear growth. In some children, obesity and sarcopenia have been observed as long-term posttransplant outcomes. Body composition assessment tools have been utilized in diagnosing nutrition status in adults; yet there are limited studies that use these tools in the pediatric liver-transplant population. Technologies available to assess body composition include air displacement plethysmography, dual-energy x-ray absorptiometry, bioimpedance, and ultrasound. Total body potassium has been used for body composition assessment in adults and children post liver transplant; however, this method is not applicable in a clinical setting. We conclude that understanding posttransplant body composition could help clinicians diagnose and treat malnutrition.

Improving the rate of anthropometric measurements in the pediatric intensive care unit.

BACKGROUND: Malnutrition occurs in approximately 25% of pediatric intensive care patients and correlates with increased length of stay, prolonged ventilation, and mortality. Anthropometric measurements should be obtained at admission and throughout hospitalization to evaluate nutrition status. We aimed to increase documentation, reporting, and discussion of anthropometric measurements, including height/length, weight, and occipital frontal circumference (OFC) within 24 hours of admission and weekly. METHODS: A multifaceted process improvement model was implemented over 1 month. Interventions included education, recruiting nurse champions, process mapping, new equipment, and formal discussion of nutrition status during rounds. A proportions hypothesis test compared frequency of anthropometric measures obtained during each study phase: preintervention, postintervention, and sustainment. RESULTS: In terms of admission metrics over respective study phases, the PICU had fluctuation in weights (91%, 98%, and 97%) and height (49%, 73%, and 71%) and increased rates in OFC (36%, 61%, and 65%). The cardiovascular intensive care unit (CVICU) had stable weights (100%, 100%, and 100%) and increased rates in height (87%, 94%, and 95%) and OFC (28%, 64%, and 86%), respectively. In terms of weekly metrics over study phases, the PICU had fluctuation in weights (91%, 89%, and 93%) and increased rates in heights (38%, 69%, and 76%) and OFC (45%, 76%, and 100%). The CVICU had increased rates in weights (98%, 100%, and 100%) and fluctuations in heights (50%, 83%, and 75%), and OFC (48%, 84%, and 75%). CONCLUSIONS: Interventions increased rates of measurements. During the sustainment phase, there was regression in rates, although these remained above baseline. Additional interventions may increase compliance and foster change in unit culture.

Transient hyperphosphatasemia following pediatric liver transplantation in a patient with hepatic and skeletal abnormalities.

BACKGROUND: We report a unique case of transient hyperphosphatasemia in a pediatric patient with a history of hepatic and skeletal abnormalities. PATIENT AND METHODS: A 2-month old male was diagnosed with progressive familial intrahepatic cholestasis type-2 and osteoporosis after marked increases in liver function tests were noted at 1 month of age. He underwent a second liver transplantation at 1 y. The increased liver function test trend resolved a few weeks post-transplantation. Four months after successful liver transplantation, unexplained significant increases in alkaline phosphatase (ALP) were observed, and they persisted for almost 9 months. Among the etiologies under consideration for the isolated increased ALP activity were viral infections and macro-ALP. RESULTS: A persistent trend in abnormally increased ALP for 9 months was investigated leading to a confirmed diagnosis of transient hyperphosphatasemia (TH). CONCLUSION: Pediatric post-liver transplant patients with skeletal and hepatic abnormalities including isolated markedly increased ALP activities represent a previously undescribed TH patient population. The 4.3% prevalence of TH in pediatric liver transplant recipients within our healthcare system is considerably higher than the previously reported prevalence of 2.1% for patients within the United States.

Neonatal Acute Liver Failure.

Neonatal acute liver failure (NALF) is a rare disease with a few known primary causes: gestational alloimmune liver disease (GALD), viral infections, metabolic diseases, and ischemic injury. Many cases still do not have a known cause. Laboratory evaluation may suggest a diagnosis. Most of the known causes have disease-specific treatments that improve outcomes. Survival is improving with better knowledge about and treatment options for GALD; however, overall mortality for NALF is still 24%. Liver transplant remains an important option for neonates with an indeterminate cause of NALF and those who do not respond to established treatments.

Rapid Infliximab Infusion in the Pediatric Population.

OBJECTIVES: To compare infusion reaction rates between rapid infliximab (REMICADE, Janssen Biotech Inc) infusions and previous standard 2- to 3-hour infusions; additionally, to assess patient satisfaction and reduction in chair time associated with rapid infliximab infusions. METHODS: Pediatric rheumatology and gastroenterology patients receiving maintenance infliximab therapy using a standard 2- to 3-hour titrated infusion had the opportunity to enroll in the non-titrated rapid 1-hour infusion protocol following tolerance of induction dosing at 0, 2, and 6 weeks. Patients were included from December 1, 2017, to March 31, 2018, via retrospective chart review and patient satisfaction surveys. RESULTS: Data were collected on 55 patients receiving a total of 160 rapid infliximab infusions. There were 2 infusion reactions during the enrollment and data collection period, resulting in an overall infusion reaction rate of 1.3%. The patient satisfaction survey results showed all patients were at minimum satisfied with the information provided regarding rapid infliximab, decreased time spent in clinic, ease of scheduling, and overall process. CONCLUSIONS: Our data suggest rapid infliximab infusions are safe in pediatric rheumatology and gastroenterology patients receiving maintenance infliximab infusion therapy. The overall infusion reaction rate of 1.3% in this study is well below the accepted infusion reaction rate of standard-length infliximab infusions of 2% to 3%.

Malnutrition in Children With Chronic Disease.

Malnutrition occurs when nutrient intake does not meet the needs for normal body functions and as a consequence leads to alterations of growth and development in children. Chronic illness puts children at risk for developing malnutrition. Because of children's rapid periods of growth and development, early diagnosis, prevention, and management of malnutrition are paramount. The reasons for malnutrition in children with chronic disease are multifactorial and are related to the underlying disease and non-illness-associated factors. This review addresses the causes, evaluation, and management of malnutrition in pediatric congenital heart disease, chronic kidney disease, liver disease, and cystic fibrosis.