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.

Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy.

BACKGROUND AND AIMS: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. APPROACH AND RESULTS: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n  = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 µmol/L ( n  = 43) or >40 µmol/L ( n  = 94) groups. At 2 years of age, the ≤40 µmol/L compared with >40 µmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 µmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 µmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 µmol/L group ( p  = 0.001). CONCLUSIONS: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.

Determining the minimally clinically important difference for the pediatric liver transplant quality of life questionnaire.

PURPOSE: The Pediatric Liver Transplant Quality of Life (PeLTQL) questionnaire is a disease-specific patient reported outcome measure for pediatric liver transplant (LT) recipients. To-date, threshold values above which a change in PeLTQL score is considered meaningful to patients are unavailable. This study proposes the first values for the minimally clinically important difference (MCID) for the PeLTQL. METHODS: In this retrospective cohort study, anchor and distribution-based methods were used to estimate the MCID for the PeLTQL. Questionnaires completed between March 2013, and July 2022 were included if data from two sequential visits were available. An internal anchor question was used for anchor-based determination of the MCID. A final MCID estimate was ascertained from triangulation of all methods. RESULTS: PeLTQL data from 65 LT recipients (26 [40%] male, 17 [42%] biliary atresia, median age at LT 3.08 years [interquartile range 0.99-7.30]), and their caregivers were included for analysis. Median patient age at time of baseline PeLTQL completion was 13.84 (10.90-15.86) years. The MCID for self-PeLTQL total scores ranged from 4.53 to 8.46, and from 4.47 to 8.85 for proxy responses. By triangulation, the MCID of the PeLTQL total score was 6.45 and 6.78 for self and proxy responses respectively. CONCLUSION: A change in PeLTQL score of 6.5 or more points suggests a change in health status that is meaningful to the patient, providing the clinical team an opportunity to engage the patient's voice in reassessing current health status and management strategies.

Biodegradable biliary stents placement using a "kissing-stent" technique for management of a recalcitrant stricture post-live donor liver transplant.

BACKGROUND: Biliary complications are common in pediatric liver transplant. Strictures resistant to interventional radiology procedures can be extremely challenging to manage and may result in the need of surgery or retransplantation. METHODS: This case report illustrates the use of biodegradable stents post left lateral segment live donor liver transplant in a pediatric patient with a recalcitrant chronic stricture of the biliary-enteric anastomosis. The patient developed a high stricture requiring multiple interventions and eventual access of both the segment II and segment III ducts of the graft. RESULTS: To ensure adequate biliary drainage, two biodegradable stents were deployed using a "kissing-stent" technique. The stents were successfully deployed and allowed the patient to remain free from an internal-external biliary drain for 11 months, with eventual redeployment of an additional biodegradable stent. CONCLUSION: In patients with recalcitrant stenosis of the biliary anastomosis, biodegradable stents may provide durable drainage, optimizing graft function and delaying retransplantation in addition to keeping patients without external devices, thus improving quality of life.

Impact of early immunosuppression on pediatric liver transplant outcomes within 1 year.

OBJECTIVES: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. METHODS: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. RESULTS: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. CONCLUSIONS: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia.

BACKGROUND AND AIMS: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study. APPROACH AND RESULTS: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH. CONCLUSIONS: The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.

Health Care Transition for Adolescents and Young Adults With Pediatric-Onset Liver Disease and Transplantation: A Position Paper by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

Advances in medical therapies and liver transplantation have resulted in a greater number of pediatric patients reaching young adulthood. However, there is an increased risk for medical complications and morbidity surrounding transfer from pediatric to adult hepatology and transplant services. Health care transition (HCT) is the process of moving from a child/family-centered model of care to an adult or patient-centered model of health care. Successful HCT requires a partnership between pediatric and adult providers across all disciplines resulting in a transition process that does not end at the time of transfer but continues throughout early adulthood. Joint consensus guidelines in collaboration with the American Society of Transplantation are presented to facilitate the adoption of a structured, multidisciplinary approach to transition planning utilizing The Six Core Elements of Health Care Transition TM for use by both pediatric and adult specialists. This paper provides guidance and seeks support for the implementation of an HCT program which spans across both pediatric and adult hepatology and transplant centers.

An appraisal of technical variant grafts compared to whole liver grafts in pediatric liver transplant recipients: Multicenter analysis from the SPLIT registry.

BACKGROUND: Shortages of liver allografts for children awaiting transplantation have led to high LT waitlist mortality. Prior studies have shown that usage of TVG can reduce waiting time and waitlist mortality, but their use is not universal. We sought to compare patient and graft survival between WLG and TVG and to identify potential associated risk factors in a contemporary pediatric LT cohort. METHODS: We performed a retrospective analysis of patient survival, graft survival, and biliary and vascular complications for LT recipients <18 years old entered into the Society of Pediatric Liver Transplantation prospective multicenter database. RESULTS: Of 1839 LT recipients, 1029 received a WLG and 810 received a TVG from either a LD or a DD. There was no difference in patient survival or graft survival by graft type. Three-year patient survival and graft survival were 96%, 93%, and 96%, and 95%, 89%, and 92% for TVG-LD, TVG-DD, and WLG, respectively. Biliary complications were more frequent in TVG. Hepatic artery thrombosis was more frequent in WLG. Multivariate analysis revealed primary diagnosis was the only significant predictor of patient survival. Predictors for graft survival included time-dependent development of biliary and vascular complications. CONCLUSIONS: There were no significant differences in patient and graft survival based on graft types in this North American multi-center pediatric cohort. Widespread routine use of TVG should be strongly encouraged to decrease mortality on the waitlist for pediatric LT candidates.

Findings in percutaneous trans-hepatic cholecysto-cholangiography in neonates and infants presenting with conjugated hyperbilirubinemia: emphasis on differential diagnosis and cholangiographic patterns.

BACKGROUND: Biliary atresia (BA) is one of the causes of conjugated hyperbilirubinemia in infants which if untreated leads to end-stage liver disease and death. Percutaneous Trans-hepatic Cholecysto-Cholangiography (PTCC) is a minimally invasive study which can be utilized in the diagnostic work-up of these patients. This study's purpose is to describe the experience with PTCC in neonates, the imaging findings encountered, and the abnormal patterns which warrant further investigation. METHODS: A 16-year single-center retrospective study of patients with persistent neonatal cholestasis (suspected BA) undergoing PTCC. Patient demographics, laboratory values, PTCC images, pathology and surgical reports were reviewed. RESULTS: 73 patients underwent PTCC (68% male, mean age 8.7 weeks, mean weight 4.0 Kg). The majority of studies were normal (55%). Abnormal patterns were identified in 33 cases, 79% were diagnosed with BA and 12% with Alagille syndrome. Non-opacification of the common hepatic duct with a narrowed common bile duct (42%) and isolated small gallbladder (38%) were the most common patterns in BA. CONCLUSION: PTCC is a minimally invasive study in the diagnostic work-up of infants presenting with conjugated hyperbilirubinemia (suspected BA). Further invasive investigations or surgery can be avoided when results are normal.

Development and validation of a multivariable prediction model in pediatric liver transplant patients for predicting intensive care unit length of stay.

BACKGROUND: Liver transplantation is the life-saving treatment for many end-stage pediatric liver diseases. The perioperative course, including surgical and anesthetic factors, have an important influence on the trajectory of this high-risk population. Given the complexity and variability of the immediate postoperative course, there would be utility in identifying risk factors that allow prediction of adverse outcomes and intensive care unit trajectories. AIMS: The aim of this study was to develop and validate a risk prediction model of prolonged intensive care unit length of stay in the pediatric liver transplant population. METHODS: This is a retrospective analysis of consecutive pediatric isolated liver transplant recipients at a single institution between April 1, 2013 and April 30, 2020. All patients under the age of 18 years receiving a liver transplant were included in the study (n = 186). The primary outcome was intensive care unit length of stay greater than 7 days. RESULTS: Recipient and donor characteristics were used to develop a multivariable logistic regression model. A total of 186 patients were included in the study. Using multivariable logistic regression, we found that age < 12 months (odds ratio 4.02, 95% confidence interval 1.20-13.51, p = .024), metabolic or cholestatic disease (odds ratio 2.66, 95% confidence interval 1.01-7.07, p = .049), 30-day pretransplant hospital admission (odds ratio 8.59, 95% confidence interval 2.27-32.54, p = .002), intraoperative red blood cells transfusion >40 mL/kg (odds ratio 3.32, 95% confidence interval 1.12-9.81, p = .030), posttransplant return to the operating room (odds ratio 11.45, 95% confidence interval 3.04-43.16, p = .004), and major postoperative respiratory event (odds ratio 32.14, 95% confidence interval 3.00-343.90, p < .001) were associated with prolonged intensive care unit length of stay. The model demonstrates a good discriminative ability with an area under the receiver operative curve of 0.888 (95% confidence interval, 0.824-0.951). CONCLUSIONS: We develop and validate a model to predict prolonged intensive care unit length of stay in pediatric liver transplant patients using risk factors from all phases of the perioperative period.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

BACKGROUND AND AIMS: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Motor outcomes in young children pre-and one-year post-liver transplant.

BACKGROUND: Motor skill acquisition plays an important role in physical activity participation and overall social and physical health. Limited studies have examined motor development in children pre-and post-liver transplant (LT). METHODS: Retrospective review of motor outcomes in children <6 years old with cholestatic liver disease assessed pre-and 1-year post-isolated LT. Measures include Alberta Infant Motor Scale and Peabody Developmental Motor Scales (gross motor quotient (GMQ), fine motor quotient (FMQ), and total motor quotient (TMQ)). Association of medical variables with motor outcomes was explored. RESULTS: Participants included 33 (58% male) children with diagnoses of biliary atresia (70%), Alagille syndrome (21%), and others (9%). Median age at LT was 10 (IQR 7.0-20.5) months. Pre-LT >75% of children were at risk for motor delay (≤10th percentile on AIMS/ ≥1SD below mean GMQ). Post-LT, 52% scored ≥1 SD below the mean GMQ compared with 22% FMQ. Children at risk/delayed pre-LT had an increased risk of motor delay on GMQ post-LT (odds ratio 11.43, 95% CI 1.12-116.7, p = .017). Higher INR pre-LT correlated with lower TMQ post-LT (r = -.51, p = .003). Longer waitlist time correlated with lower FMQ post-LT (r = .41, p = .03). GMQ post-LT and height z-scores pre-LT (r = .46, p = .02) and post-LT (r = .45, p < .01) were positively correlated. There was no correlation with presence of ascites, weight z-score, length of hospitalization, and age at LT. CONCLUSIONS: Young children have increased risk of motor delay pre-LT, which may persist post-LT. Severity of liver disease and growth delays may impact motor development, highlighting the need for ongoing rehabilitation pre- and post-LT.

The Impact of Severe Acute Respiratory Syndrome Coronavirus Type 2 on Children With Liver Diseases: A Joint European Society for Pediatric Gastroenterology, Hepatology and Nutrition and Society of Pediatric Liver Transplantation Position Paper.

ABSTRACT: Children are seldom affected by severe forms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) infection; however, the impact of comorbidities in the clinical presentation and outcome of SARS-CoV2 in children is poorly characterized including that of chronic liver disease (CLD) and those taking immunosuppressive medications for autoimmune liver disease or following liver transplantation (LT). Although not the main target organ, a spectrum of liver involvement has been described in children infected with SARS-CoV2 and those presenting with Multisystem Inflammatory Syndrome in Children (MIS-C). The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the Society of Pediatric Liver Transplantation (SPLIT) present an evidence-based position paper on liver involvement in children with SARS-CoV2 infection and its impact on those with CLD as well as LT recipients. All children may exhibit acute liver injury from SARS-CoV2 infection, and those with CLD and may experience hepatic decompensation. Preventative and therapeutic measures are discussed.

Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver.

OBJECTIVE: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment. METHODS: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease. RESULTS: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ. CONCLUSIONS: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.

Pediatric Acute Liver Failure: A Clinicopathological Perspective.

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

Sarcopenia in Children With End-Stage Liver Disease on the Transplant Waiting List.

Sarcopenia predicts morbidity and mortality in adults with end-stage liver disease (ESLD) and is determined by total psoas muscle area (tPMA) measurement from computed tomography (CT) imaging. Recently developed pediatric age- and sex-specific tPMA growth curves provide the opportunity to ascertain prevalence and impact of sarcopenia in children awaiting liver transplantation (LT). This retrospective single-center study evaluated sarcopenia in children between 1 and 16 years with ESLD and a clinically indicated abdominal CT less than 3 months before first isolated LT. Sarcopenia was defined as tPMA z score less than -2 measured at the intervertebral L4-5 level. Patient demographic, biochemical, and outcome data were recorded. tPMA was compared with other measures of nutritional status using univariate and multivariate logistic analyses. Outcome measures included 1-year morbidity events and mortality after LT. CT images from 25 (64% female) children with median age of 5.50 (interquartile range [IQR], 3.75-11.33) years were reviewed. Ten children (40%) had a tPMA z score less than -2. Sarcopenia was associated with lower z scores for weight (odds ratio [OR], 0.38; P = 0.02), height (OR, 0.32; P = 0.03), and nutritional support before LT (OR, 12.93; P = 0.01). Sarcopenic children had a longer duration of pediatric intensive care unit (PICU) stay (3.50 [IQR, 3.00-6.00] versus 2.00 [IQR, 2.00-3.50] days; P = 0.03). Sarcopenia was prevalent in 40% of children with ESLD awaiting LT, and lower tPMA z score was associated with deficient anthropometrics and need for nutritional support before LT. Post-LT PICU duration was increased in children with sarcopenia, reflecting adverse outcomes associated with muscle loss. Further studies are needed to elucidate the underlying mechanisms of sarcopenia in children with ESLD.

The effects of child anxiety and depression on concordance between parent-proxy and self-reported health-related quality of life for pediatric liver transplant patients.

BACKGROUND: HRQOL is a key outcome following pediatric LT. Parent-proxy reports may substitute for patients unable to report their own HRQOL. This study compared parent-proxy and self-reported HRQOL in children who have undergone LT. METHODS: Pediatric LT recipients between the ages of 8 and 18 years, and a parent, completed self and proxy versions of the PeLTQL questionnaire, PedsQL Generic and Transplant modules, and standardized measures of depression and anxiety. RESULTS: Data from 129 parent-patient dyads were included. Median parent age was 44 years, and most (89%) were mothers. Median patient age was 2.5 years at LT and 13.6 years at the time of study participation. Parents had significantly lower scores than patients on PedsQL total generic (70.8 ± 18.5 and 74.3 ± 19.0, p = .01), PeLTQL coping and adjustment (63.0 ± 15.6 and 67.3 ± 16.2, p < .01), and social-emotional (66.3 ± 14.9 and 71.9 ± 15.6, p < .001) domains. Higher patient anxiety and depression were related to larger absolute differences between parent-proxy and self-reported scores on all HRQOL measures (all p < .05). In this disparity, parents reported higher HRQOL scores than their child as self-reported anxiety and depression scores increased. CONCLUSIONS: Differences in concordance between parent-proxy and self-reported HRQOL scores can be more prominent when children have more symptoms of anxiety and depression. Children's mental health symptoms should be queried, if feasible, when interpreting differences in parent and child reports of HRQOL.

Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study.

OBJECTIVES: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. METHODS: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. RESULTS: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). CONCLUSIONS: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.

A Learning Health System for Pediatric Liver Transplant: The Starzl Network for Excellence in Pediatric Transplantation.

OBJECTIVE: Learning health systems (LHS) integrate research, improvement, management, and patient care, such that every child receives "the right care at the right time...every time," that is, evidence-based, personalized medicine. Here, we report our efforts to establish a sustainable, productive, multicenter LHS focused on pediatric liver transplantation. METHODS: The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant families and providers to develop shared priorities and a shared agenda for innovation in clinical care. This report outlines SNEPT's structure, accomplishments, and challenges as an LHS. RESULTS: We prioritized 4 initial projects: immunosuppression, perioperative anticoagulation, quality of life, and transition of care. We shared center protocols/management to identify areas of practice variability between centers. We prioritized actionable items that address barriers to providing "the right care at the right time" to every pediatric liver transplant recipient: facilitating transparency of practice variation and the connection of practices to patient outcomes, harnessing existing datasets to reduce the burden of tracking outcomes, incorporating patient-reported outcomes into outcome metrics, and accelerating the implementation of knowledge into clinical practice. This has allowed us to strengthen collaborative relationships, design quality improvement projects, and collect pilot data for each of our priority projects. CONCLUSIONS: The field of pediatric liver transplantation can be advanced through application of LHS principles. Going forward, SNEPT will continue to unite patient advocacy, big data, technology, and transplant thought leaders to deliver the best care, while developing new, scalable solutions to pediatric transplantation's most challenging problems.

Severe Acute Respiratory Syndrome Coronavirus-2 Infection in Children With Liver Transplant and Native Liver Disease: An International Observational Registry Study.

OBJECTIVE: Increased mortality risk because of severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) infection in adults with native liver disease (LD) and liver transplant (LT) is associated with advanced age and comorbid conditions. We aim to report outcomes for children with LD and LT enrolled in the NASPGHAN/SPLIT SARS-CoV2 registry. METHODS: In this multicenter observational cohort study, we collected data from 91 patients <21 years (LD 44, LT 47) with laboratory-confirmed SARS-CoV2 infection between April 21 and September 17, 2020. RESULTS: Patients with LD were more likely to require admission (70% vs 43% LT, P = 0.007) and pediatric intensive care unit (PICU) management (32% vs 4% LT, P = 0.001). Seven LD patients required mechanical ventilation (MV) and 2 patients died; no patients in the LT cohort died or required MV. Four LD patients presented in pediatric acute liver failure (PALF), 2 with concurrent multisystem inflammatory syndrome in children (MIS-C); all recovered without LT. Two LD patients had MIS-C alone and 1 patient died. Bivariable logistic-regression analysis found that patients with nonalcoholic fatty LD (NAFLD) (odds ratio [OR] 5.6, P = 0.02) and LD (OR 6.1, P = 0.01, vs LT) had higher odds of severe disease (PICU, vasopressor support, MV, renal replacement therapy or death). CONCLUSIONS: Although not directly comparable, LT recipients had lower odds of severe SARS-CoV2 infection (vs LD), despite immunosuppression burden. NAFLD patients reported to the registry had higher odds of severe SARS-CoV2 disease. Future controlled studies are needed to evaluate effective treatments and further stratify LD and LT patients with SARS-CoV2 infection.