Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Neonatal Cholestasis: Updates on Diagnostics, Therapeutics, and Prevention.

Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.

Barriers to Pretransplant Immunization: A Qualitative Interview Study of Pediatric Solid Organ Transplant Stakeholders.

OBJECTIVES: To describe the experiences and beliefs of pediatric transplant stakeholders regarding factors that contribute to low pretransplant immunization rates. STUDY DESIGN: Semistructured interviews were conducted with transplant team members (hepatologists, cardiologists, nephrologists, transplant nurse coordinators, and transplant infectious diseases physicians), primary care physicians, and parents of heart, liver, and kidney transplant recipients at 3 geographically diverse large pediatric transplant centers in the US. Interviews were conducted between July 2017 and February 2020 until thematic saturation was reached within each stakeholder subgroup. Content analysis methodology was used to identify themes. RESULTS: Stakeholders participated in 30- to 60-minute interviews (16 transplant subspecialists, 3 transplant infectious diseases physicians, 11 transplant nurse coordinators, 12 primary care physicians, and 40 parents). Five central themes emerged: (1) gaps in knowledge about timing and safety of pretransplant immunizations, (2) lack of communication, coordination, and follow-up between team members regarding immunizations, (3) lack of centralized immunization records, (4) subspecialty clinic functioning as the medical home for transplant candidates but unable to provide all needed immunizations, and (5) differences between organ type in prioritization and completion of pretransplant immunization. CONCLUSIONS: There are multiple factors that contribute to low immunization rates among pediatric transplant candidates. New tools are needed to overcome these barriers and increase immunization rates in transplant candidates.

Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1.

Spinal muscular atrophy is a neurodegenerative disease resulting from irreversible loss of anterior horn cells owing to biallelic deletions/mutations in the survival motor neuron (SMN) 1 gene. Gene replacement therapy using an adeno-associated virus vector containing the SMN gene was approved by the US Food and Drug Administration in May 2019. We report 2 cases of transient, drug-induced liver failure after this therapy.

The Importance of Prioritizing Pre and Posttransplant Immunizations in an Era of Vaccine Refusal and Epidemic Outbreaks.

Vaccine-preventable infections are occurring at epidemic rates both nationally and internationally. At the same time, rates of vaccine hesitancy and refusal are increasing across the country leading to decreased herd immunity. For immunosuppressed transplant recipients, this situation poses great risk. Currently, 1 in 6 pediatric solid organ transplant recipients is hospitalized with a vaccine-preventable infection in the first 5 years posttransplant. For many recipients, these infections result in significant morbidity, mortality, and increased hospitalization costs. Surprisingly, despite this risk many transplant recipients are not up-to-date on age appropriate immunizations at the time of transplant and thereafter. As a transplant community, we must prioritize immunizations in both pre and posttransplant care. Research is needed to understand how to monitor immune response to vaccines in immunosuppressed patients and when to optimally immunize patients posttransplant. Finally, recommendations about administration of live vaccines posttransplant may need to be reevaluated in the setting of measles outbreaks and decreased herd immunity.

Under-immunization of pediatric transplant recipients: a call to action for the pediatric community.

Vaccine-preventable infections (VPIs) are a common and serious complication following transplantation. One in six pediatric solid organ transplant recipients is hospitalized with a VPI in the first 5 years following transplant and these hospitalizations result in significant morbidity, mortality, graft injury, and cost. Immunizations are a minimally invasive, cost-effective approach to reducing the incidence of VPIs. Despite published recommendations for transplant candidates to receive all age-appropriate immunizations, under-immunization remains a significant problem, with the majority of transplant recipients not up-to-date on age-appropriate immunizations at the time of transplant. This is extremely concerning as the rate for non-medical vaccine exemptions in the United States (US) is increasing, decreasing the reliability of herd immunity to protect patients undergoing transplant from VPIs. There is an urgent need to better understand barriers to vaccinating this population of high-risk children and to develop effective interventions to overcome these barriers and improve immunization rates. Strengthened national policies requiring complete age-appropriate immunization for non-emergent transplant candidates, along with improved multi-disciplinary immunization practices and tools to facilitate and ensure complete immunization delivery to this high-risk population, are needed to ensure that we do everything possible to prevent infectious complications in pediatric transplant recipients.

Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure.

OBJECTIVES: To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. STUDY DESIGN: Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. RESULTS: Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. CONCLUSIONS: A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00986648.

Hospitalizations for Respiratory Syncytial Virus and Vaccine-Preventable Infections in the First 2 Years After Pediatric Liver Transplant.

OBJECTIVES: To examine in liver transplant recipients at centers participating in the Pediatric Health Information System dataset the number of hospitalizations for respiratory syncytial virus (RSV) and vaccine-preventable infections (VPIs) in the first 2 years after transplantation, morbidity and mortality associated with these hospitalizations, and costs associated with these hospitalizations. STUDY DESIGN: A retrospective cohort study of patients <18 years of age who underwent liver transplantation at a Pediatric Health Information System center between January 1, 2004, and December 31, 2012. Hospitalizations for RSV/VPIs during the first 2 years post-transplant were ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Data were collected on clinical care, outcomes, and costs during these hospitalizations. RESULTS: There were 2554 liver transplant recipients identified; 415 patients (16.3%) had 544 cases of RSV/VPIs. RSV, rotavirus, and influenza were the most common infections resulting in hospitalization. Ninety-two patients (3.6%) had RSV/VPI during their transplant hospitalization. Transplant hospitalizations complicated by RSV/VPI were longer (44 days vs. 21 days; P < .001), had higher rejection rates (37% vs. 26%; P = .02), and were more expensive ($259 697 vs. $190 860; P < .001). Multivariate analyses identified age <2 years at transplant (P < .001) and multivisceral recipient (P = .04) as predictors of a hospitalization for RSV. CONCLUSIONS: VPIs occurred in 1 of 6 liver transplant recipients in the first 2 years post-transplant, a significantly higher rate than in the general pediatric population. These hospitalizations had substantial morbidity, mortality, and costs, demonstrating the importance of vaccinating patients before transplantation.

Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care.

Biliary atresia (BA) is a progressive, fibro-obliterative disorder of the intrahepatic and extrahepatic bile ducts in infancy. The majority of affected children will eventually develop end-stage liver disease and require liver transplantation (LT). Indications for LT in BA include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as hepatopulmonary syndrome and portopulmonary hypertension, are also indications for LT. Optimal pretransplant management of these potentially life-threatening complications and maximizing nutrition and growth require the expertise of a multidisciplinary team with experience caring for BA. The timing of transplant for BA requires careful consideration of the potential risk of transplant versus the survival benefit at any given stage of disease. Children with BA often experience long wait times for transplant unless exception points are granted to reflect severity of disease. Family preparedness for this arduous process is therefore critical. Liver Transplantation 23:96-109 2017 AASLD.

Impaired physical function following pediatric LT.

The purpose of this article is to investigate the spectrum of physical function of pediatric liver transplantation (LT) recipients 12-24 months after LT. Review data were collected through the functional outcomes group, an ancillary study of the Studies of Pediatric Liver Transplantation registry. Patients were eligible if they had survived LT by 12-24 months. Children ≥ 8 years and parents completed the Pediatric Quality of Life Inventory™ 4.0 generic core scales, which includes 8 questions assessing physical function. Scores were compared to a matched healthy child population (n = 1658) and between survivors with optimal versus nonoptimal health. A total of 263 patients were included. Median age at transplant and survey was 4.8 years (interquartile range [IQR], 1.3-11.4 years) and 5.9 years (IQR, 2.6-13.1 years), respectively. The mean physical functioning score on child and parent reports were 81.2 ± 17.3 and 77.1 ± 23.7, respectively. Compared to a matched healthy population, transplant survivors and their parents reported lower physical function scores (P < 0.001); 32.9% of patients and 35.0% of parents reported a physical function score <75, which is > 1 standard deviation below the mean of a healthy population. Physical functioning scores were significantly higher in survivors with optimal health than those with nonoptimal health (P < 0.01). There was a significant relationship between emotional functioning and physical functioning scores for LT recipients (r = 0.69; P < 0.001). In multivariate analysis, primary disease, height z score < -1.64 at longterm follow-up (LTF) visit, > 4 days of hospitalization since LTF visit, and not being listed as status 1 were predictors of poor physical function. In conclusion, pediatric LT recipients 1-2 years after LT and their parents report lower physical function than a healthy population. Findings suggest practitioners need to routinely assess physical function, and the development of rehabilitation programs may be important.

Neonatal Cholestasis.

Cholestatic jaundice is a common presenting feature of neonatal hepatobiliary and metabolic dysfunction. Any infant who remains jaundiced beyond age 2 to 3 weeks should have the serum bilirubin level fractionated into a conjugated (direct) and unconjugated (indirect) portion. Conjugated hyperbilirubinemia is never physiologic or normal. The differential diagnosis of cholestasis is extensive, and a step-wise approach based on the initial history and physical examination is useful to rapidly identify the underlying etiology. Early recognition of neonatal cholestasis is essential to ensure timely treatment and optimal prognosis. Even when specific treatment is not available, infants who have cholestasis benefit from early medical management and optimization of nutrition. Future studies are necessary to determine the most reliable and cost-effective method of universal screening for neonatal cholestasis.