Immunologic and Survival Benefits of Combined Heart-liver Transplantation in Children

Combined heart-liver transplant (CHLT) in adults has been increasingly reported in the United States, with long-term outcomes that match liver or heart transplant alone (HTA).1 In pediatrics, a tiny experience has proven feasibility, with short-term outcomes that demonstrate the potential for excellent long-term survival, particularly in patients with univentricular congenital heart disease (CHD).2,3 In the face of continued challenges managing pediatric patients with failed palliation for CHD, transplant centers are increasingly considering CHLT in children in whom HTA is not expected to be successful. Fontan-associated liver disease (FALD) has emerged as an important comorbidity in this population, with nearly a universal histologic presence of liver fibrosis by adolescence.4 There is much discussion about the severity of chronic liver disease and the potential for disease regression in FALD following HTA, especially in children. In parallel, these patients have the potential for high levels of preexisting alloantibody due to prior surgeries and transfusion. Up to 60% of HTA recipients experience rejection across a positive crossmatch, with reduced graft survival.5 Listing highly sensitized patients for HTA is futile given the rarity of compatible donors. It has long been recognized that multivisceral transplants that include livers result in lower rates of rejection. Indeed, low rates of rejection have been observed in adult CHLT, even in the presence of preexisting allosensitization and positive crossmatch.6 Thus, multiple factors suggest that a subset of pediatric patients with CHD and FALD may benefit from CHLT. To explore CHLT outcomes in children, we analyzed the US Scientific Registry Transplant Recipients (SRTR). Fourteen pediatric CHLT were performed through December 2019, with only 1 case occurring before 2006 (Table 1). Most patients had CHD and a primary liver diagnosis likely related to FALD (“cardiac cirrhosis,” “cardiogenic liver failure,” and “protein-losing enteropathy”), with familial lipid disorders representing the underlying pathology in the remaining patients. All but 1 patient was listed status 1A or 1B for heart transplant, and the median MELD/PELD was 10 (IQR 8–12). The median waiting time was 79.5 d. Most patients received either nondepleting (anti-IL2R, N = 6) or depleting (ATG, N = 6) induction immunosuppression. The median peak PRA was 11%, and only 1 patient had an acute rejection episode (heart and liver), followed by the development of PTLD within the first 2 y posttransplant. The only reported death occurred in the first case from 1997, in a patient with CHD and biliary atresia who died from a brain hemorrhage and sepsis at 1-mo posttransplant. The overall patient survival was 92.9% with a median follow-up of 7.1 y, which compares favorably with outcomes for heart or liver transplant alone in children.5 TABLE 1. - Patient characteristics CHLT (N = 14) Recipient characteristics Age (y), median [IQR] 14 [10, 15] Male, N (%) 9 (64.3) Race/ethnicity, N (%) White 11 (78.6) Asian 1 (7.1) Native 1 (7.1) Black 1 (7.1) Liver diagnosis, N (%) Cardiogenic/cirrhosisa 7 (50.0) Familial hypercholesterolemia/hyperlipidemia II 5 (35.7) Biliary atresia: extrahepatic 1 (7.1) Hepatoma and cirrhosis 1 (7.1) Heart diagnosis, N (%) Congenital heart defect 9 (64.3) Coronary artery disease/familial hypercholesterolemia 5 (35.7) Preoperative comorbidities BMI (kg/m2), median [IQR] 19.4 [18.4, 23.2] Hypertension, N (%) 2 (14.3) Portal vein thrombosis at transplant, N (%) 1 (7.1) Laboratory MELD/PELD at transplant, median [IQR] 10 [8, 12] Status 1A/1B 9 (64.2) Panel Reactive Antibody, peak percent, median [IQR] 11% [0–95] Medical condition at transplant, N (%) ICU 7 (50) Hospitalized, not in ICU 3 (21.4) Not hospitalized 4 (28.6) Requiring dialysis in the week before transplant 0 (0) Requiring ventilator 1 (7.1) Waitlist time (d), median [IQR] 79.5 [27, 144.5] Donor characteristics Donor age (y), median [IQR] 16 [10.25, 17] Heart total ischemia time (h), median [IQR] 4.2 [2.9, 5.7] Liver cold ischemia time (h), median [IQR] 5.3 [3.7, 7.3] Induction immunosuppression, N (%)b Steroids 2 (14.3) Anti-IL2R + steroids 6 (42.9) ATG + steroids 5 (35.7) ATG + rituximab + steroids 1 (7.1) Acute rejection episode in the first 2 y posttransplantc Heart, N (%) 1 (7.1) Liver, N (%) 1 (7.1) Posttransplant lymphoproliferative disorder, N (%) 1 (7.1) Survival 1/5 y patient survival % (Kaplan–Meier) 92.9/92.9% Follow-up, y, median [IQR] 7.1 [2.5, 9.2] aCardiac cirrhosis (3), chronic heart failure (1), chronic passive congestion with bridging fibrosis (1), and chronic PLE (1).bAnti-IL2R includes daclizumab and basiliximab.cRejection data were missing for 2 patients. It was not possible to assess missingness for PTLD due to limitations of the SRTR.ATG, antithymocyte globulin; CHLT, combined heart-liver transplantation; PTLD, posttransplant lymphoproliferative disorder; SRTR, Scientific Registry of Transplant Recipients. CONCLUSIONS Given the feasibility of CHLT and excellent long-term outcomes, it is possible that the perceived perioperative risk and increased resource utilization for CHLT are justified in pediatric patients with heart failure and underlying chronic liver disease. As well, this analysis and others suggest immunologic benefit for CHLT recipients when compared to HTA.6 While spontaneous operational tolerance has rarely been reported for HTA, studies examining immunosuppression withdrawal have observed that 30%–60% of LT recipients can achieve operational tolerance, particularly among children.7 Moving forward, it is possible that CHLT, especially in children, will enable transplant with preexisting donor-specific alloantibodies, immunosuppression minimization, and perhaps even operational tolerance that would not be possible in the setting of HTA.8 We would encourage those who embark on this life-saving procedure to consider the collection of prospective immunologic data and blood and tissue specimens for future studies. These data support the continued expansion of CHLT in the pediatric population. ACKNOWLEDGMENTS This study was approved by the USC Institutional Review Board. The data reported here have been supplied by the Hennepin Healthcare Research Institute as the contractor for the SRTR. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government. This study used data from the SRTR. The SRTR data system includes data on all donors, waitlisted candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network. The Health Resources and Services Administration, US Department of Health and Human Services provides oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors.