Unusual venous collateral pathways allow for reperfusion of the intrahepatic portal venous system in children with portal vein thrombosis after split liver transplantation: Clinical relevance and management implications.

PVT is the most frequent vascular complication after LT in small children, and a higher incidence has been observed in those transplanted for biliary atresia or with a LLSG. Thrombosis of the PV causes extrahepatic portal hypertension and is associated with splenomegaly and the development of venous neo-collaterals, including gastro-oesophageal varices and splenorenal shunts. It has also been incidentally suggested in the literature that patients who have had a Roux-en-Y loop for a biliary reconstruction may present with a cavernomatous transformation of the distal portion of the loop. In this study, 13 children with CEPH caused by thrombosis of the PV after LT were analysed. The study evidenced the development of two types of hepatopetal venous networks: (a) a large cavernoma along the Roux loop and around the biliary anastomosis, and (b) a network of neo-collaterals in the gastro-duodeno-pancreatic area that connected to the intrahepatic portal branches directly through the liver capsule. These hepatopetal venous networks between the venous system of the surrounding organs or the omentum and the intrahepatic portal branches can be identified by radiologists. The relevance for the transplanting physician and the transplant surgeon is discussed.

Immune monitoring after pediatric liver transplantation - the prospective ChilSFree cohort study.

BACKGROUND: Although trough levels of immunosuppressive drugs are largely used to monitor immunosuppressive therapy after solid organ transplantation, there is still no established tool that allows for a validated assessment of functional degree of immunosuppression or the identification of clinically relevant over- or under-immunosuppression, depending on graft homeostasis. Reliable non-invasive markers to predict biopsy proven acute rejection (BPAR) do not exist. Literature data suggest that longitudinal measurements of immune markers might be predictive of BPAR, but data in children are scarce. We therefore propose an observational prospective cohort study focusing on immune monitoring in children after liver transplantation. We aim to describe immune function in a cohort of children before and during the first year after liver transplantation and plan to investigate how the immune function profile is associated with clinical and laboratory findings. METHODS: In an international multicenter prospective approach, children with end-stage liver disease who undergo liver transplantation are enrolled to the study and receive extensive immune monitoring before and at 1, 2, 3, 4 weeks and 3, 6, 12 months after transplantation, and whenever a clinically indicated liver biopsy is scheduled. Blood samples are analyzed for immune cell numbers and circulating levels of cytokines, chemokines and factors of angiogenesis reflecting immune cell activation. Statistical analysis will focus on the identification of trajectorial patterns of immune reactivity predictive for systemic non-inflammatory states, infectious complications or BPAR using joint modelling approaches. DISCUSSION: The ChilSFree study will help to understand the immune response after pLTx in different states of infection or rejection. It may provide insight into response mechanisms eventually facilitating immune tolerance towards the graft. Our analysis may yield an applicable immune panel for non-invasive early detection of acute cellular rejection, with the prospect of individually tailoring immunosuppressive therapy. The international collaborative set-up of this study allows for an appropriate sample size which is otherwise difficult to achieve in the field of pediatric liver transplantation.

Surgical anterior cavoplasty for managing a case of early acute outflow obstruction after liver transplantation.

HVOO following liver transplantation is rarely treated surgically because it tends to debut subacutely. However, acute HVOO is a surgical emergency that compromises the viability of the graft. We report a case of HVOO diagnosed intra-operatively during surgical revision for a suspected arterial thrombosis in a 10-month-old male recipient of a second graft (segments II-III) for familial intrahepatic cholestasis. HVOO was related to a stenosis at the first transplant hepato-caval anastomosis, left in place to obtain longer venous cuffs for retransplantation. An anterior cavoplasty was necessary to resolve the issue. The new anastomosis was created under total vascular exclusion after gaining control of the supradiaphragmatic vena cava, because the inferior vena cava was unsuitable for further surgery. This approach (normally used as a means to avoid sternotomy in patients with hepatic or renal tumours associated with venous thrombosis) allows adequate vascular control and, in selected cases, offers a surgical alternative for treating HVOO.

A European International Multicentre Survey on the Current Practice of Perioperative Antibiotic Prophylaxis for Paediatric Liver Transplantations.

(1) Background: Postoperative infections are major contributors of morbidity and mortality after paediatric liver transplantation (pLTX). Evidence and recommendations regarding the most effective antimicrobial strategy are lacking. (2) Results: Of 39 pLTX centres, 20 responded. Aminopenicillins plus ß-lactamase inhibitors were used by six (30%) and third generation cephalosporins by three (15%), with the remaining centres reporting heterogenous regimens. Broad-spectrum regimens were the standard in 10 (50%) of centres and less frequent in the 16 (80%) centres with an infectious disease specialist. The duration ranged mainly between 24-48 h and 3-5 days in the absence and 3-5 days or 6-10 days in the presence of risk factors. Strategies regarding antifungal, antiviral, adjunctive antimicrobial, and surveillance strategies varied widely. (3) Methods: This international multicentre survey endorsed by the European Liver Transplant Registry queried all European pLTX centres from the registry on their current practice of perioperative antibiotic prophylaxis and antimicrobial strategies via an online questionnaire. (4) Conclusions: This survey found great heterogeneity regarding all aspects of postoperative antimicrobial treatment, surveillance, and prevention of infections in European pLTX centres. Evidence-based recommendations are urgently needed to optimise antimicrobial strategies and reduce the spectrum and duration of antimicrobial exposure.

The Impact of Thrombophilic Factors on Disease Progression in Children with Biliary Atresia-A Single-Centre Cohort Study.

Epidemiological evidence suggests that thrombophilic factors, including male sex, non-O blood type, MTHFRnt677TT mutation, factor V Leiden G1691A mutation, and prothrombin G20210A polymorphism, may contribute to the progression of fibrosis and occurrence of portal vein thrombosis in liver disease. We retrospectively investigated the effect of potentially thrombophilic factors on native liver survival as a patient-relevant endpoint of disease progression in a cohort of 142 children being followed up for biliary atresia at Hannover Medical School from April 2017 to October 2019. No significant association could be determined. There was no evidence for relevant differences in native liver survival for the Factor V Leiden G1691A mutation (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.38-1.98, p = 0.73), prothrombin G20210A polymorphism (HR = 0.96, 95%CI 0.24-3.65, p = 0.96), non-O blood type (HR = 0.79, 95%CI 0.51-1.21, p = 0.28) or MTHFRnt677TT mutation (HR = 1.24, 95%CI 0.60-2.56, p = 0.56). A certain, albeit not strong, evidence of reduced native liver survival in male patients after Kasai hepatoportoenterostomy, particularly during the first 2000 days (42%; HR = 1.41, 95%CI 0.92-2.18, p = 0.11) was found. All children with pre-transplant portal vein thrombosis (n = 7) had non-O blood types. Larger multi-centre studies are necessary to show if the male sex or other thrombophilic factors could be potentially associated with reduced native liver survival.

Early postoperative duplex ultrasound findings of the hepatic artery in postoperative vascular complications from paediatric liver transplantation.

PURPOSE: To evaluate duplex US findings of the HA in all three postoperative vascular (HA, PV, HV and IVC) complications of paediatric LT for early detection and some helpful secondary signs to determine these vascular complications. MATERIALS AND METHODS: We collected data from 44 post-LT paediatric patients who underwent daily duplex US for seven consecutive days and three months after LT during January 2017-June 2020. Four duplex US parameters of the HA (extrahepatic PSV, intrahepatic PSV, RI and AT) were compared in patients with and without complications. RESULTS: The PSV of the extrahepatic HA in patients with HA complications was higher than that in patients without complications (P value = 0.019). The PSV at 107.7 cm/s is the optimal cut-off parameter associated with HA complications [a sensitivity of 88.9% and a specificity of 80.0% (ROC area is 0.84)]. The intrahepatic RI was higher on the first day than on the last day and gradually decreased in patients without vascular complications (P value = 0.000). The intrahepatic PSV significantly decreased with time when comparing the first and last days in patients without PV and HV-IVC complications (P value = 0.014 and 0.038). In contrast, patients with vascular complications showed no significant decrease. CONCLUSION: The extrahepatic PSV relates to HA complications after paediatric LT but not PV and HV-IVC complications. Non-significantly decreased intrahepatic RI and PSV from the first day to the day of complication diagnosis may correlate with the occurrence of vascular complications.

Hepatitis A Immunity and Paediatric Liver Transplantation-A Single-Centre Analysis.

Following paediatric solid organ liver transplantation, risk of infection is high, both in the short and long term. Even though an infection with hepatitis A virus (HAV) is often asymptomatic and self-limited in children, some case studies describe severe cases leading to death. Vaccinations offer simple, safe and cheap protection. However, data on vaccination rates against hepatitis A in children with liver disease are scarce. Moreover, the vaccine is only approved from the age of one year old. At the same time, up to 30% of children with liver disease are transplanted within the first year of life, so the window of opportunity for vaccination is limited. This retrospective, observational, single-centre study examines the HAV immunity in paediatric liver transplant recipients before and after the first year of transplantation. Vaccination records of 229 of 279 (82.1%) children transplanted between January 2003 and June 2021 were analysed. Of 139 eligible children aged ≥ 1 year old, only 58 (41.7%) were vaccinated at least with one HAV dose prior to transplantation. In addition, seven patients received the vaccine below one year of age. After one or two doses, 38.5% or 90.6% of 65 patients were anti-HAV-IgG positive, respectively. This percentage remained stable up to the first annual check-up. For children vaccinated only once, a shorter interval from vaccination to transplantation is a risk factor for lack of immunity. Thus, HAV immunisation should be started earlier in liver transplant candidates to improve immunity in this high-risk group.

Parental Disease Specific Knowledge and Its Impact on Health-Related Quality of Life.

OBJECTIVE: Structured education programs have been shown to improve somatic outcome and health-related quality of life (HRQOL) in a variety of chronic childhood diseases. Similar data are scarce in paediatric liver transplantation (pLTx). The purpose of this study was to examine the relationship of parental disease-specific knowledge and psychosocial disease outcome in patients after pLTx. METHODS: Parents of 113 children (chronic liver disease n = 25, after pLTx n = 88) completed the transplant module of the HRQOL questionnaire PedsQL, the "Ulm quality of life inventory for parents of children with chronic diseases" ULQUI, and a tailor-made questionnaire to test disease-specific knowledge. RESULTS: Parental knowledge was highest on the topic of "liver transplantation" and lowest in "basic background knowledge" (76% and 56% correct answers respectively). Knowledge performance was only marginally associated with HRQOL scores, with better knowledge being related to worse HRQOL outcomes. In contrast, self-estimation of knowledge performance showed significant positive correlations with both PedsQL and ULQUI results. CONCLUSION: Patient HRQOL and parental emotional wellbeing after pLTx are associated with positive self-estimation of parental disease-specific knowledge. Objective disease-specific knowledge has little impact on HRQOL. Parental education programs need to overcome language barriers and address self-efficacy in order to improve HRQOL after pLTx.

Long-Term Varicella Zoster Virus Immunity in Paediatric Liver Transplant Patients Can Be Achieved by Booster Vaccinations-A Single-Centre, Retrospective, Observational Analysis.

Varicella is one of the most common vaccine-preventable infections after paediatric solid organ transplantation; thus, vaccination offers simple and cheap protection. However, children with liver disease often progress to liver transplantation (LT) before they reach the recommended vaccination age. As a live vaccine, varicella zoster virus (VZV) vaccination after transplantation is controversial; however, many case series demonstrate that vaccination may be safe and effective in paediatric liver transplant recipients. Only limited data exists describing long-term vaccination response in such immunocompromised patients. We investigated retrospectively vaccination response in paediatric patients before and after transplantation and describe long-term immunity over ten years, including the influence of booster-vaccinations. In this retrospective, single-centre study, 458 LT recipients were analysed between September 2004 and June 2021. Of these, 53 were re-transplantations. Patients with no available vaccination records and with a history of post-transplant lymphoproliferative disease, after hematopoietic stem cell transplantation and clinical chickenpox were excluded from this analysis (n = 198). In total, data on 207 children with a median annual follow-up of 6.2 years was available: 95 patients (45.9%) were unvaccinated prior to LT. Compared to healthy children, the response to vaccination, measured by seroconversion, is weaker in children with liver disease: almost 70% after one vaccination and 93% after two vaccinations. One year after transplantation, the mean titres and the number of children with protective antibody levels (VZV IgG ≥ 50 IU/L) decreased from 77.5% to 41.3%. Neither diagnosis, gender, nor age were predictors of vaccination response. Booster-vaccination was recommended for children after seroreversion using annual titre measurements and led to a significant increase in mean titre and number of protected children. Response to vaccination shows no difference from monotherapy with a calcineurin inhibitor to intensified immunosuppression by adding prednisolone or mycophenolate mofetil. Children with liver disease show weaker seroconversion rates to VZV vaccination compared to healthy children. Therefore, VZV-naïve children should receive basic immunization with two vaccine doses as well as those vaccinated only once before transplantation. An average of 2-3 vaccine doses are required in order to achieve a long-term seroconversion and protective antibody levels in 95% of children.

Paediatric Liver Transplantation During COVID-19 Pandemic: Lessons Learned and Unanswered Questions.

COVID-19 pandemic has imposed many challenges on paediatric liver transplantation (PLT) services and has necessitated several adaptations in different stages of the process to ensure transplant centres can still deliver the proposed services in addition to protecting patients and staff against infection. This review article digs through the current literature to clarify the challenges imposed by SARS-CoV2 on PLT centres globally. It provides an overview of current practice as well as suggestions from experts in the field to overcome multiple obstacles. In paediatrics, the reaction to SARS-CoV2 may be less severe than that seen in the adult population, but this can change in view of newly discovered virus strains. Response of transplant centres to the current pandemic was variable depending on the anticipated risk and available resources. Telemedicine has helped PLT programmes to continue their activities while protecting patients, as well as staff against the risk of SARS-CoV2 virus. Further studies are needed to guide immunosuppression management in post-transplant infected candidates; answering this critical question will help PLT centres solve this dilemma.

Interventional Radiological Treatment of Paediatric Liver Transplantation Complications.

PURPOSE: To assess the efficacy of percutaneous techniques in managing paediatric liver transplantation complications. MATERIAL AND METHODS: We carried out 105 paediatric cadaveric donor liver transplantations at our centre from 2001 to 2018. Percutaneous techniques were used to treat 25 cases involving transplantation complications in 23 patients. Biliary complications were treated in 14 cases (13.3%): 10 patients had bile duct obstruction, and 4 had biliary leaks. Vascular complications were treated in 11 cases (10.5%): 5 hepatic artery (HA) stenoses/occlusions, 2 inferior vena cava (IVC) stenoses, and 1 portal vein (PV) stenosis. Other interventions involved embolisation of the superior mesenteric artery branch to manage gastrointestinal bleeding in 2 patients and embolisation of an arteriobiliary fistula in 1 patient. RESULTS: Biliary: We carried out external-internal drainage and balloon dilatation of stenoses in 12 cases. The external-internal drainage catheter was removed after 6-8 weeks in 7 patients, with the remaining 5 patients with persisting stenosis assigned for retransplantation. We failed to cross anastomotic occlusions in 2 patients before completing the procedures using external drainage; both individuals subsequently underwent retransplantation. Vascular: We performed PTA/stenting of HA stenoses/occlusions in 4 out of 5 patients. After the procedure, all 4 patients showed liver function normalisation. All 3 cases of embolisation were technically and clinically successful. Both IVC and PV stenoses treated with dilatation/stenting were also successful. CONCLUSIONS: Percutaneous techniques used to treat biliary and vascular complications after liver transplantation in paediatric patients are safe and efficient.

Perioperative monitoring of intracranial pressure using optic nerve sheath diameter in paediatric liver transplantation.

An elevation of intracranial pressure (ICP) secondary to cerebral oedema is a major contributor to morbidity and mortality in acute liver failure (ALF). We present a case of ICP monitoring with ocular ultrasonography in a 2-year-old child with ALF for liver transplantation. Since invasive ICP monitoring was risky considering the level of coagulopathy, optic nerve sheath diameter (ONSD) monitoring was done by ultrasound. A value of 4.5 mm was chosen as the cut-off for an ICP >20 mmHg in this child and was checked at regular intervals during the surgery. Ultrasonographic ONSD assessment can be a useful modality in liver transplant recipients, with severe coagulopathy and high ICP. In our specific patient scenario, ocular ultrasound proved to be a valuable safe and noninvasive monitoring tool in this paediatric patient.