Paola Stroppa

Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease.

Background. End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver–organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). Methods. Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille’s syndrome (n=12), Byler’s disease (n=8), and other cholestatic diseases (n=8). Results. Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. Conclusions. SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.

Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%. Liver Transpl 12:573–577, 2006.

Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation.

Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis followed by preemptive therapy (10 patients) versus preemptive therapy alone (11 patients) for prevention of human cytomegalovirus (HCMV) disease. In the prophylaxis arm, patients were treated with ganciclovir for 30 days, then preemptive therapy was initiated with virologic monitoring for pp65 antigenemia. In the preemptive therapy arm, patients were treated on reaching 100,000 DNA copies/mL whole blood. An interim analysis showed that, although numbers of both infected and treated patients were comparable in the two arms, the median number of total days of antiviral therapy per patient (30 vs. 18, P<0.01) was significantly higher in the prophylaxis arm. No case of HCMV disease occurred in either arm. Therefore, the trial was interrupted and prophylaxis replaced with preemptive therapy alone. In parallel, the development of T-cell-mediated immune response was found to be comparable in both arms.

Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.

Romano F, Stroppa P, Bravi M, Casotti V, Lucianetti A, Guizzetti M, Sonzogni A, Colledan M, D’Antiga L. Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.
Pediatr Transplantation 2011: 15: 573–579.

Specific autologous cytotoxic T lymphocytes for chronic varicella in a liver transplanted child.

Abstract:  Infections by herpesviruses may have severe complications in liver transplant patients. Although prophylactic varicella zoster virus vaccination is strongly recommended and widely applied, severe infection may still occur. We report the case of systemic chronic varicella, which developed in a liver allograft recipient, unresponsive to antiviral drug treatment, successfully treated by varicella zooster‐specific CTL. Graft failure ensued, likely, because of massive cytolysis of infected hepatocytes. The patient, who was re‐transplanted in the absence of signs of varicella zooster reactivation, is now well and disease free 3 yr after second liver transplant.

Effectiveness of preemptive therapy for Cytomegalovirus disease in pediatric liver transplantation.

Background Most pediatric liver transplantation (LT) centers administer long courses of prophylaxis against cytomegalovirus (CMV) without evidence of benefit and with significant drug exposure and costs. We aimed at evaluating overall outcomes, direct and putative indirect effects of CMV, possible impact of viremia and risk factors for CMV infection in pediatric LT recipients managed with ganciclovir-based preemptive therapy (PET). Methods The records of all the children who underwent LT between 2008 and 2014 were retrospectively analyzed. Results One hundred children were included. Three children had CMV disease; no CMV-related death or graft loss was recorded. The only identified risk factor for CMV infection was the donor/recipient serostatus (odds ratio, 17.23; 95% confidence interval, 1.88-157.87; P = 0.012), while viremia per se did not worsen LT outcomes, such as the incidence of acute rejection, Epstein-Barr virus infection, sepsis, biliary and vascular complications, nor graft dysfunction/loss or death at 3 and 5 years after LT. When compared with a historical cohort of children receiving ganciclovir prophylaxis, PET did not differ from prophylaxis for any of the selected outcomes, but was rather associated with lower antiviral drug exposure (6.4 ± 13 days vs 38.6 ± 14 days, P < 0.0001) and cost per patient (2.2 ± 3.9 k&OV0556; vs 6.6 ± 8.2 k&OV0556;, P = 0.001). Conclusions PET is effective in controlling CMV in children receiving LT, with lower costs and lower exposure to antivirals.

A Randomized Trial For Tacrolimus And Steroids Vs. Tacrolimus And Basiliximab In Pediatric Liver Transplantation

Aims: Basiliximab is a monoclonal antibody against IL-2 receptor. A comparison between immunosuppression carried out with Tacrolimus (TAC) and Steroids (ST) VS. Tacrolimus and Basiliximab (BAS) was performed to evaluate the efficiency and safety of these two drugs association after pediatric liver transplantation. Methods: A randomized prospective trial was started in June 2001 at the Liver Transplantation Center in Bergamo, Italy. Patients receiving primary liver transplantation were enrolled in two groups: group A (TAC ST) or in group B (TAC BAS). A total of 64 patients were recruited in the study, 32 in group A and 32 in group B. Mean age was 3 yrs (0.5-16.9) and mean weight was 13.3 (4-65). The main indication for transplantation was biliary atresia. Primary endpoint of the study was the incidence of acute rejection (ACR) in the first three months. Secondary endpoints of the study were the cumulative incidence and severity of ACR, patient and graft survival, and incidence of adverse events. Tacrolimus was given at an initial dose of 0.08 mg/kg/die and then adjusted to obtain trough levels between 10 and 15 ng/ml during the first three months and of 5/10 ng/ml after the 3 month. ST were administered at the dose of 2 mg/kg and tapered before being stopped after three months. BAS was given at the dose of 20 mg iv on postoperative day 0 and 4. Results: Overall survival rate was 92%, 93% for patients in group A and 90% for patients in group B. 4 patients were excluded from the study (1 in group A and 3 in group B) for early death or discontinuation of immunosuppression. Rejection episodes were 7 in group A (22%) and 2 in group B (7%). Mean RAI score was 6 for group A, while the two patients in group B had a RAI of 4. Rejection occurred after 11 days (mean) in group A and after 20 and 223 days in the two cases in group B. One patient in group B had PTLD. Rates of EBV seroconversion were respectively (group A vs. group B) 25% and 17%. CMV infection rates were 19% vs. 13%. Sepsis occurred in 25% of patients in group A vs. 13% in group B. Conclusions: ACR seems to be less frequent in the BAS group and, even when it occurs, shows a delayed onset and a less severity. Severe infectious episodes are more rare without the use of steroids. Adverse effects of BAS were not observed in this study. Long term follow-up needs to clarify the effect of these results on the occurrence rate of late complications and chronic rejection.

Intestinal Transplantation in Children: The First Successful Italian Series

The preliminary experience of the first Italian program of pediatric intestinal transplantation is presented herein. A multidisciplinary group with broad experience in pediatric solid organ transplantation started the program. Nine children with complications of chronic intestinal failure were listed for transplantation. One child died on the waiting list; one received an isolated liver transplantation; three isolated intestinal; three multivisceral; and one, a combined liver/intestine transplantation. There was no in-hospital mortality, and all children were weaned from parenteral nutrition. The recipient of the multivisceral graft died after 14 months for unknown causes. All other recipients are alive after a median follow-up of 13 months. Patient and graft actuarial survivals for recipients of intestinal grafts were 100% at 1 year and 75% at 2 years.

Determinants of large drain losses early after pediatric liver transplantation

The goal of this study was to evaluate postoperative ascites to correlate it with graft dysfunction and other complications. We therefore reviewed the files of patients transplanted between 2009 and 2014 to correlate drain losses with indication, patient and organ size, PELD, graft type, GRWR, NRBW, NGWD, cold ischemia time, histologically proven graft dysfunction, and surgical complications. Of 120 LTs in 104 patients, 48 (40%) were complicated by graft dysfunction, 43 (36%) by surgical complications, and 25 (21%) by cellular rejection. Large drain losses correlated with younger age (P=.05), graft dysfunction (P<.01), surgical complications (P<.01), chylous ascites (P=.05); there was no association with PELD, GRWR, NRBW, or NGWD. Graft dysfunction was predicted by >20 mL/kg/d of ascites at age 0‐2 years (AUROC 0.671), and >10 mL/kg/d above 2 years (AUROC 0.710). The measurement of drain losses after pediatric LT could be used as a non‐invasive marker of graft dysfunction. Younger recipients tend to develop larger amounts of ascites, and its persistence is associated with early complications.