Steven Lobritto

Background: Hepatic graft‐versus‐host disease (GVHD) is a rare but life‐threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Steroid‐refractory hepatic GVHD carries a high risk of mortality with limited salvage options. Liver transplantation after HSCT poses unique challenges due to dual alloimmunity and is rarely pursued, particularly in pediatric patients. We report a pediatric patient with steroid‐refractory chronic hepatic GVHD successfully treated with living donor liver transplantation (LDLT) from a parental donor. Case Presentation: A 13‐year‐old male underwent allogeneic HSCT for idiopathic severe aplastic anemia and developed progressive chronic hepatic GVHD characterized by ductopenia and severe cholestasis. His disease was refractory to corticosteroids and multiple additional therapies, including ruxolitinib, mesenchymal stromal cells, infliximab, sirolimus, anti‐thymocyte globulin, alpha‐1 antitrypsin, cyclophosphamide, and emapalumab. His course was complicated by Epstein–Barr virus (EBV) associated post‐transplant lymphoproliferative disorder (PTLD), successfully treated with rituximab. Fifteen months after HSCT, and seven months after clearance of EBV viremia, he underwent LDLT from a parental donor. Donor selection preserved the option for future donor‐derived EBV‐specific cytotoxic T lymphocyte therapy if needed. Eleven months following LDLT, the patient remains clinically well, with normal liver function, sustained full donor chimerism, and no evidence of recurrent GVHD or PTLD. Conclusion: LDLT may represent a viable option in select pediatric patients with irreversible chronic hepatic GVHD. This case underscores the importance of early multidisciplinary planning and highlights the absence of liver‐specific biomarkers or targeted therapies to guide management. Dedicated research into preventive and regenerative strategies is warranted.

Background: The Starzl Network for Excellence in Pediatric Transplantation, a learning health network focused on pediatric liver transplantation, identified optimizing immunosuppression as a priority challenge. There remains significant variability in immunosuppression practices across transplant centers and a need for comparative effectiveness research to clarify best practices. As a prelude, we aimed to develop a composite outcome that focuses on immunosuppression‐related morbidity and to characterize its baseline prevalence at 1 year post‐liver transplant. Methods: We developed a composite transplant primary outcome, based on a previously described “ideal outcome” definition utilized by the Society of Pediatric Liver Transplantation registry studies, with components reflecting liver and child health. We used retrospective data from Starzl Network centers to calculate the prevalence of achieving the composite outcome among children who underwent a liver transplant in 2023. Results: In 2023, 19 participating centers transplanted a total of 267 children. Of the 250 with complete data available, 46% were < 2 years of age at transplant, 25% were 2–8 years, 22% were > 8 years, and 7% were missing age data. Seventy‐eight children (31%) achieved the composite outcome at 1 year, including 35% of < 2‐year‐olds, 32% of 2–8 year‐olds, 29% of > 8 year‐olds, and 11% without age available. The most common failed composite outcome criterion was having ALT > 50 IU/L at 1 year. Conclusions: Only 31% of pediatric liver transplant recipients achieved the composite outcome by 1 year. Our network will aim to develop evidence‐based best practices to increase achievement of the composite outcome by “right‐sizing” immunosuppression for each child.

Background: Patient‐reported outcomes are increasingly recognized as essential complements to biological indices in chronic disease including pediatric liver transplantation. However, clinicians lack clear thresholds to determine when changes in patient‐reported outcome measure (PROM) scores represent clinically meaningful change. Establishing minimal clinically important difference (MCID) values is critical to interpret longitudinal PROM data and guide action. The Starzl Network Patient Reported Outcomes (SPaRO) study provided a unique opportunity to derive MCID estimates of the Pediatric Liver Transplant Quality of Life (PeLTQL) questionnaire. Methods: In SPaRO, English‐ or Spanish‐speaking pediatric LT recipients aged 8–18 years and at least 1 year post‐LT were recruited from 7 Starzl Network for Excellence in Pediatric Transplantation (SNEPT) sites. Participants and caregivers completed the PeLTQL (self‐ and proxy‐report) questionnaire twice via a mobile application or web‐based platform. MCIDs were estimated using anchor‐based and distribution‐based methods including predictive modeling. Results: A total of 98 patients and 86 caregivers completed two PeLTQL assessments between March 2022 and October 2023. Triangulated MCID values for the total score (TS) were 6.4 (self‐report) and 5.6 (proxy‐report). Predictive modeling yielded estimates of 7.7 (self) and 6.8 (proxy). Conclusions: In this multicenter cohort, MCID thresholds for the PeLTQL TS were approximately 6–8 points (self‐report) and 6–7 points (proxy‐report), consistent with prior single‐center estimates. Changes in the PeLTQL TS of greater than 6 points may help clinicians identify patients who warrant closer attention. Prospective validation using an independent anchor is underway. Trial Registration: ClinicalTrials.gov Identifier: NCT05241847

Background: Activated T-cell pediatric acute liver failure (TC-PALF) is the most common cause of non-acetaminophen PALF, with poor transplant-free survival. Livers in TC-PALF are infiltrated by effector cytotoxic T lymphocytes with markers of tissue-resident memory function (CD8 Trm) and an interferon gamma (IFNγ) transcriptional signature. The PALF-Immune Response Network (PALF-IRN) and the prospective TReatment for ImmUne-Mediated PathopHysiology (TRIUMPH) clinical trial (NCT04862221) aim to characterize the TC-PALF immune pathology and utility of T-cell directed therapy to improve transplant-free survival. Methods: TRIUMPH patients with TC-PALF were compared with healthy children and disease controls utilizing multiparameter flow cytometry and 3′ single-cell RNA sequencing from peripheral blood mononuclear cells. TC-PALF patient serum was compared with healthy children and those with PALF from other causes, utilizing the Olink Inflammation I 384 protein assay. Results: Two distinct endotypes of TC-PALF were identified, which differed in flow cytometry CD8+ Perforin1 (Prf) expression and liver biopsy staining of Prf. TC-PALF patients with high CD8+ Prf (TC-PALF High Prf) had monocytosis, with a unique circulating CD8 IFNγ+ Trm-like population and IFNγ-responsive CD14/CD16 monocyte ligand–receptor interaction. TC-PALF patients with normal CD8+ Prf expression had hypergammaglobulinemia, an increase in class-switched B-cells, and a decrease in serum inflammatory proteins associated with myeloid activation. Conclusions: TC-PALF high Prf patients have a unique circulating CD8+ IFNγ+ Trm-like population accompanied by monocyte proliferation and activation. Further understanding of the role of IFNγ in TC-PALF High Prf may provide a therapeutic target for this endotype to improve transplant-free survival. Export

Background: The Society of Pediatric Liver Transplantation (SPLIT) has undergone tremendous growth with > 45 sites contributing data focusing on improving outcomes in pediatric liver transplantation (LT). We report and compare outcomes from the SPLIT Registry. Methods: Patients < 18 years with first‐time LT only enrolled into the SPLIT Registry between 2011 and 2023 were included. Data was stratified into eras from the last published registry update (era 1: 2011–2018, era 2: 2018–2023). Results: Three thousand five hundred four participants from 47 centers were included (era 1: n = 2159; era 2: n = 1345). Age distribution differed with more children < 1 year. of age at LT in era 2 (era 1: 29% vs. era 2: 33%, p = 0.01). Indications for LT were similar, with biliary atresia (38.8%) and metabolic disease (16.0%) being most common. Exception point use was higher in era 2 (era 1: 45% vs. era 2: 56%, p < 0.001). No difference in graft type (deceased: 81% era 1 vs. 78% era 2, p = 0.78), patient survival at 90 days (era 1: 98.7% vs. era 2: 98.3%), 1 year (era 1: 97.2 vs. era 2: 96.8%), or 3 years (era 1: 95.3% vs. era 2: 95.2%) was noted. Rate of hepatic artery thrombosis was lower in era 2 (era 1: 7% vs. era 2: 5%, p = 0.02). Conclusions: Trends in pediatric LT within SPLIT note similar LT indications and graft type, higher utilization of exception points, and lower HAT rates despite transplanting more children < 10 kg. This data underscores the evolution of pediatric LT toward higher survivability and overall patient outcomes.

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Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).

Background: Patient‐reported outcome measures (PROMs) are not routinely used in clinical care by pediatric liver transplant (LT) teams. The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) assessed feasibility of using a disease‐specific Quality of Life (QoL) questionnaire in the ambulatory setting at 10 SNEPT sites.Methods: A mixed methods feasibility project assessing administration processes, barriers, and user experiences with the Pediatric Liver Transplant Quality of Life (PeLTQL) tool. Iterative processes sought stakeholder feedback across four phases (Pilot, Extended Pilot, Development of a Mobile App PeLTQL version, and Pilot App use).Results: A total of 149 patient–parent dyads completed the PeLTQL during LT clinic follow‐up. Clinicians, parents, and patients evaluated and reported on feasibility of operationalization. Only two of 10 SNEPT sites continued PeLTQL administration after the initial two pilot phases. Reasons include limited clinical time and available personnel aggravated by the COVID‐19 pandemic. In response, a mobile application version of the PeLTQL was initiated. Providing PeLTQL responses electronically was “very easy” or “easy” as reported by 96% (22/23) parents.Conclusions: Administration of a PROM into post‐pediatric LT clinical care was feasible, but ongoing utilization stalled. Use of a mobile app towards facilitating completion of the PeLTQL outside of clinic hours may address the time and work‐flow barriers identified.