ObjectivesData driven strategies for acute pancreatitis (AP) in pediatrics are limited; adult data suggests lactated ringers (LR) compared to normal saline (NS) resulted in favorable outcomes, but has not been studied in pediatrics. Our objective was to evaluate the efficacy of LR during the first 48 h of an AP episode compared with NS.Study DesignA multisite randomized controlled clinical trial, from 2015 to 2020 (Clinical NCT03242473). Patients were randomized to exclusively LR or NS for the first 48 h. Primary outcomes were serial C-reactive protein (CRP) values. Secondary outcomes included other lab values, time to feeds, length of stay (LOS), systemic inflammatory response syndrome (SIRS) development, and progression to severe AP (SAP).ResultsWe studied 76 patients (38 LR, 38 NS). CRP at 24 and 48 h were not significantly different between LR or NS group. Additionally, there were no differences in trends of BUN, amylase, lipase, SIRS status, or SAP development between the LR and NS group at 24 and 48 h. A higher proportion of LR patients (32%, 12/38) were discharged before 48 h compared to NS (13%, 5/38). The LR group had a significantly higher rate of discharge within the first 72 h compared to the NS group (p = 0.02).ConclusionThe use of LR was associated with a faster rate of discharge during the intervention period and in the first 72 h, but no other differences compared to NS. This reduction in length of hospitalization has significant implications for patients and healthcare costs. What is Known Fluid resucistation with isotonic fluids has been shown to be helpful in pediatric acute pancreatitis (AP). Adult literature has favored lactated ringers (LR), but this has not been evaluated in pediatric AP.What is New This study shows that patients who exclusively received LR were discharged faster than patients who received normal saline. There were no other benefits or harms associated with the use of LR.

Introduction: Acute cellular rejection (ACR) is a common adverse event in the early period post intestinal transplantation, occurring in up to 80% of patients. Identifying ACR early is imperative as timely diagnosis and treatment can help prevent morbidity and mortality related to intestinal ACR, including development of exfoliative rejection. Methods: We performed a single-center retrospective cohort study evaluating children age <18 years who received an isolated intestinal transplant or combined intestinal and liver transplant from 2000-2021 at Cincinnati Children’s Hospital Medical Center. Patients were divided into 3 groups based on development of no ACR, mild or moderate ACR, and exfoliative rejection within the first 45 days post-transplant. Baseline demographics and operative characteristics were compared between the 3 groups. Bivariate analysis was used to compare risk factors for development of ACR including differences in immunosuppression regimen, infections, and absolute lymphocyte count (ALC). Results: Using univariate and bivariate analysis, baseline demographic and operative characteristics were similar between all groups (p > 0.05). There were also no differences between infections pre- and post-transplant (including EBV/CMV mismatch between donor and recipient). No differences between the 3 groups were noted with regards to the immunosuppression regimen including total dose of anti-thymocyte globulin induction, time to achieve tacrolimus (TAC) trough > 10, and TAC trough at time of rejection. However, patients with mild to moderate ACR had significantly higher ALC at time of their rejection compared to those who had exfoliation (1460 vs 462) or never developed early ACR (1460 vs 642) with ALC at day 45 post-transplant being used for comparison in this group (p = 0.0025). During further analysis of those patients with exfoliative rejection, it was found that these patients also had elevated ALC at time of their initial mild or moderate rejection which decreased at time of exfoliation. Conclusion: Elevated ALC may be an early sign of mild or moderate ACR in intestinal transplant patients. Further prospective studies are needed to validate these findings.

Tacrolimus (TAC)‐mediated renal disease occurs in up to 70% of pediatric liver transplant (LT) recipients. The safety and efficacy of renal‐sparing immunosuppression using anti‐thymocyte globulin (ATG) induction and delayed TAC administration has not been studied in children. We evaluated the safety and efficacy of ATG induction on preserving renal function in children within the first year (Y1) post‐LT in a single‐center retrospective cohort study.

Intestinal failure is the anatomic or functional loss of intestinal function below the minimum required to absorb nutrients to maintain health and growth. Parenteral nutrition is the main supportive therapy for children with intestinal failure, but if serious complications develop, intestinal transplantation may be needed to sustain life. Referral to a multidisciplinary intestinal rehabilitation team and an extensive evaluation are necessary steps before listing for transplantation. Immunosuppression is part of life-long therapy after transplantation, and children continue to have high medical needs. Serious complications include acute cellular rejection, graft-versus-host disease, infection, and post-transplant lymphoproliferative disease. However, intestinal transplantation has led to improved outcomes in recent years and is a viable life-saving option for many children with intestinal failure.

BackgroundLate acute cellular rejection (ACR) is associated with donor-specific antibodies (DSA) development, chronic rejection, and allograft loss. However, accurate predictors of late ACR treatment response are lacking. ACR is primarily T-cell mediated, yet B cells and plasma cells (PC) also infiltrate the portal areas during late ACR. To test the hypothesis that the inflammatory milieu is associated with delayed response (DR) to rejection therapy, we performed a single-center retrospective case-control study of pediatric late liver ACR using multiparameter immunofluorescence for CD4, CD8, CD68, CD20, and CD138 to identify immune cell subpopulations. MethodsPediatric liver transplant recipients transplanted at <17 years of age and treated for biopsy-proven late ACR between January 2014 and 2019 were stratified into rapid response (RR) and DR based on alanine aminotransferase (ALT) normalization within 30 days of diagnosis. All patients received IV methylprednisolone as an initial rejection treatment. Immunofluorescence was performed on archived formalin-fixed paraffin embedded (FFPE) liver biopsy tissue. ResultsLiver biopsies from 60 episodes of late ACR in 54 patients were included in the analysis, of which 33 were DR (55%). Anti-thymocyte globulin was only required in the DR group. The frequency of liver-infiltrating CD20(+) and CD8(+) lymphocytes and the prevalence of autoantibodies were higher in the DR group. In univariate logistic regression analysis, serum gamma-glutamyl transpeptidase (GGT) level at diagnosis, but not ALT, Banff score or presence of DSA, predicted DR. ConclusionsHigher serum GGT level, presence of autoantibodies, and increased CD8(+) T-cell infiltration portends DR in late ACR treatment in children.

Objective To evaluate whether the nature and severity of non-A-E severe acute hepatitis in children noted by the World Health Organization from late 2021 through early 2022 was indeed increased in 2021-2022 compared with prior years. Study design We performed a single-center, retrospective study to track the etiology and outcomes of children with non-A-E severe acute hepatitis in 2021-2022 compared with the prior 3-year periods (2018-2019, 2019-2020, and 2020-2021). We queried electronic medical records of children <= 16 years of age with alanine or aspartate aminotransferase levels of >500 IU. Data were analyzed for the periods of October 1, 2021, to May 1, 2022, and compared with the same time periods in 2018-2021. Results Of 107 children meeting entry criteria, 82 cases occurred from October to May of 2018-2022. The average annual case number was 16.3 in 2018-2021 compared with a 2-fold increase (to 33) in 2021-2022 (P = .0054). Analyses of etiologies showed that this increase was associated with a higher number of children who tested positive for viruses (n = 16) when compared with the average of 3.7 for 2018-2021 (P = .018). Adenovirus (26.1%) and severe acute respiratory syndrome coronavirus-2 (10.3%) were the most frequently detected viruses in 2021-2022. Despite evidence of acute liver failure in 37.8% of children in the entire cohort and in 47% of those with viral infection, the overall survival rate was high at 91.4% and 88.9%, respectively. Conclusions The number of children with severe acute hepatitis in our center increased from 2021 to May 2022, with a greater frequency of cases associated with adenovirus, yet transplant-free survival remains high.

BACKGROUND:Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors. METHODS:In this retrospective analysis, 20 consecutive infants underwent HPE for BA and were compared to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint. RESULTS:Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225). Sixteen of 20 patients in the new protocol have reached 2 years of age or required liver transplantation. Among the sixteen, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). CONCLUSION:This preliminary report suggests the potential benefit of tailored use of postoperative antibiotics and corticosteroids in improving biliary drainage after HPE. LEVEL OF EVIDENCE:III.

Objectives: To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery. Background: The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia. Methods and Results: We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation. Conclusions: In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.

BACKGROUND:Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia. METHODS:We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children's of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing. RESULTS:A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care. CONCLUSIONS:Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.).

Background Primary non-function (PNF) in the early post-LT period in children leads to prolonged hospitalization, high graft loss, and significant mortality. However, there is a paucity of data available on the natural history of children relisted for LT due to PNF, including those who recover graft function and survive with their original allograft. Methods We interrogated the United Network of Organ Sharing (UNOS) database for pediatric LT recipients who were relisted with a primary diagnosis of PNF from 2000 to 2020. Patients >21-year-old and multiple organ transplants were excluded. Logistic regression and Cox proportional hazard models were employed to identify risk factors for early re-transplantation (within 30 days of relisting) and mortality after adjusting for baseline clinical characteristics. Results One hundred and eight patients were relisted for LT for PNF during the study period. Twenty-five patients survived beyond 30 days from relisting with their original LT, 76 underwent early re-transplantation, and 7 did not survive. Having a high-risk EBV mismatch (OR 2.03, 95% CI 0.66-6.27) and an elevated donor serum creatinine (OR: 2.19, 95% CI 0.54-8.84) were associated with increased odds of a patient requiring early re-transplantation. Donor characteristics including age, final total bilirubin, final AST/ALT, and final serum sodium, as well as vasopressor use prior to procurement, were not associated with increased odds of early re-transplantation (p > 0.05). Operative characteristics including allograft type and cold-ischemia time were also not associated with early re-transplantation (p > 0.05). Patients undergoing early re-transplantation showed a trend toward improved 1-year graft survival (69% vs 55%, p = 0.24). On multivariable Cox proportional hazards modeling, early re-transplantation was associated with reduced risk of overall patient mortality compared to those who survived with their original LT (HR 0.27, 95% CI 0.12-0.67). Conclusion Early re-transplantation for PNF is associated with improved patient survival compared with patients who survive with their original LT.

Chronic hepatitis C virus (HCV) infection presents a significant global public health burden. In 2015, over 400000 deaths worldwide were attributed to HCV infection. This led the World Health Organization (WHO) in 2016 to set the ambitious goal of eliminating HCV by 2030. Adult-centered guidelines have been established in order to provide direction for healthcare professionals, allowing integration of the newest screening policies and therapeutic strategies into their practices. However, for children and adolescents, HCV is a significant, unrecognized public health problem. HCV infection rates in the United States in women of childbearing age and those who are pregnant have increased in parallel with the rising opioid epidemic. An estimated 29000 women with HCV infection gave birth each year from 2011 to 2014 in the United States, with approximately 1700 of their infants being infected with HCV. Newer HCV-specific therapeutics, namely direct acting antivirals (DAA), has brought a new and highly successful approach to treatment of hepatitis C. Recent studies have confirmed similar levels of effectiveness and safety of DAA therapies in the pediatric population. Thus, an enhanced cascade of care, which should include the population under 18 years of age, can help achieve the WHO goal by focusing on elimination in the youngest populations. This review will present an overview of the natural history, clinical features, and management of HCV in children and adolescents.

The majority of patients with chronic liver disease (CLD) experience malnutrition. There are multiple complex mechanism by which chronic liver disease leads to malnutrition, including anorexia and malabsorption. Assessing malnutrition in CLD is also difficult at this time as there are no standardized methods for quantifying nutritional status in this group of patients. However, newer methods are being developed to help ensure better diagnosis and thus start treatment earlier.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health-related quality of life and debilitating symptoms. These experiences can be defined as patient-reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty-nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health-related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient-driven study outcomes.

Figure 1.Liver biochemistries in primary biliary cirrhosis

Background In adults, the time of day for LT does not affect post-transplant outcomes. Whether this is true or not in children is unknown. In this study, we aimed to evaluate if weekend and weeknight liver transplants are associated with worse patient and graft survival in children. Methods We interrogated the UNOS database for outcomes of pediatric liver transplants that occurred between 1988 and 2018. We excluded liver transplants in patients >17 years as well as all multiple organ transplants. We compared weeknight and weekday, as well as weekend transplant operations. We used Cox proportional hazard ratios to determine patient and graft survival by 7, 30, 90, and 365 days post-transplant after controlling for confounding factors. Results In total, 12,610 pediatric liver transplants were included in the analysis. A total of 4590 transplants occurred during weekdays, 3671 transplants occurred during weeknights, and 4349 occurred during weekends. After controlling for confounding variables, 1-year patient survival was not associated with worse outcomes if the transplant occurred on the weeknight (HR 0.94, 95%CI 0.74-1.21) or weekend (HR 0.95, 95%CI 0.75-1.20) compared to the weekday. One-year graft survival was also not associated with worse outcomes if the transplant occurred on the weeknight (HR 0.91, 95%CI 0.76-1.09) or weekend (HR 0.91, 95%CI 0.77-1.09) compared to the weekday. Conclusion Weekday, weeknight, and weekend procedures resulted in similar 1-year survival rates. Pediatric patient and graft survival outcomes are not affected by the time or day of surgery.

Congenital defects of bile acid synthesis are rare disorders that cause progressive liver dysfunction. Prolonged neonatal hyperinsulism (PNH) is a separate entity that leads to persistent hypoglycemia secondary to stress. We present a 4-month-old infant who presented with liver failure secondary to a bile acid synthesis defect. The patient's liver failure resolved with oral cholic acid therapy. This patient also developed PNH, which slowly resolved over time. This case illustrates a possible relationship between cholestatic liver failure and PNH. This relationship may help define specific stressors that increase the likelihood of developing PNH.