Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Novel insights into the assessment of risk of upper gastrointestinal bleeding in decompensated cirrhotic children.

OBJECTIVES: Cirrhotic children wait-listed for liver transplant are prone to bleeding from gastrointestinal varices. Grade 2-3 esophageal varices, red signs, and gastric varices are well-known risk factors. However, the involvement of hemostatic factors remains controversial because of the rebalanced state of coagulation during cirrhosis. METHODS: Children suffering from decompensated cirrhosis were prospectively included while being on waitlist. Portal hypertension was assessed by ultrasound and endoscopy. Coagulopathy was evaluated through conventional tests, thromboelastometry, and platelet function testing. The included children were followed up until liver transplantation, and all bleeding episodes were recorded. Children with or without bleeding were compared according to clinical, radiological, endoscopic, and biological parameters. In addition, validation of a predictive model for risk of variceal bleeding comprising of grade 2-3 esophageal varices, red spots, and fibrinogen level <150 mg/dL was applied on this cohort. RESULTS: Of 20 enrolled children, 6 had upper gastrointestinal bleeding. Significant differences were observed in fibrinogen level, adenosine diphosphate, and thrombin-dependent platelet aggregation. The model used to compute the upper gastrointestinal bleeding risk had an estimated predictive performance of 81.0%. Platelet aggregation analysis addition improved the estimated predictive performance up to 89.0%. CONCLUSIONS: We demonstrated an association between hemostatic factors and the upper gastrointestinal bleeding risk. A low fibrinogen level and platelet aggregation dysfunction may predict the risk of bleeding in children with decompensated cirrhosis. A predictive model is available to assess the upper gastrointestinal bleeding risk but needs further investigations. Clinicaltrials.gov number: NCT03244332.

Hepatitis C virus in children: the global picture.

Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma and end-stage liver disease. One hundred thirty million to 150 million people have chronic HCV infection, among them 11 million are younger than 15 years of age. This review summarises the epidemiology and characteristics of HCV infection in children, and highlights the role of the new upcoming therapies in HCV-related liver complications.

Turning Regenerative Medicine Breakthrough Ideas and Innovations into Commercial Products.

The TERMIS-Europe (EU) Industry committee intended to address the two main critical issues in the clinical/commercial translation of Advanced Therapeutic Medicine Products (ATMP): (1) entrepreneurial exploitation of breakthrough ideas and innovations, and (2) regulatory market approval. Since January 2012, more than 12,000 publications related to regenerative medicine and tissue engineering have been accepted for publications, reflecting the intense academic research activity in this field. The TERMIS-EU 2014 Industry Symposium provided a reflection on the management of innovation and technological breakthroughs in biotechnology first proposed to contextualize the key development milestones and constraints of allocation of financial resources, in the development life-cycle of radical innovation projects. This was illustrated with the biofuels story, sharing similarities with regenerative medicine. The transition was then ensured by an overview of the key identified challenges facing the commercialization of cell therapy products as ATMP examples. Real cases and testimonies were then provided by a palette of medical technologies and regenerative medicine companies from their commercial development of cell and gene therapy products. Although the commercial development of ATMP is still at the proof-of-concept stage due to technology risks, changing policies, changing markets, and management changes, the sector is highly dynamic with a number of explored therapeutic approaches, developed by using a large diversity of business models, both proposed by the experience, pitfalls, and successes of regenerative medicine pioneers, and adapted to the constraint resource allocation and environment in radical innovation projects.

Assessment of risk of bleeding from esophageal varices during management of biliary atresia in children.

OBJECTIVES: The management of esophageal varices (EV) in children experiencing biliary atresia (BA) remains controversial. Recent studies in children proposed initiating a prophylactic treatment in patients with severe (grade III) EV and/or EV associated with red color signs. Our study was aimed at assessing the risk of bleeding from EV in a series of patients with BA, identifying risk factors for bleeding to develop a predictive model of bleeding. METHODS: This was a retrospective study including 83 eligible patients with BA. Clinical, ultrasonographic, endoscopic, and laboratory parameters were studied from the beginning of medical management up to the occurrence of upper gastrointestinal bleeding. In patients not presenting any bleeding, data were analyzed until liver transplantation, endoscopic treatment of EV was performed, or last follow-up. Risk factors were investigated using univariate and multivariate statistical analyses. RESULTS: Seventeen of 83 patients (20%) presented gastrointestinal bleeding, with a median age of 9.5 months (6-50 months). In univariate and multivariate analyses, high-grade EV, red color signs on endoscopic examination, and low fibrinogen levels, at first endoscopy, were identified as risk factors for bleeding. When tested in >10,000 different models, these 3 variables appeared to play the most significant role in predicting bleeding. CONCLUSIONS: Our study confirmed that grade III EV and red color signs are risk factors for bleeding in patients followed up for BA. We identified low fibrinogen levels as an additional risk factor. The relevance of these 3 factors to predict bleeding from EV requires validation in a prospective study.

Steroid-free, tacrolimus-basiliximab immunosuppression in pediatric liver transplantation: clinical and pharmacoeconomic study in 50 children.

Corticosteroid-free immunosuppression (IS) may be potentially beneficial for transplanted patients, particularly children. The purpose of this study was to evaluate the efficacy and cost of such strategy in primary pediatric liver transplantation (LT). Fifty pediatric LT recipients were prospectively treated with a steroid-free, tacrolimus-basiliximab-based IS (group TB). A group of 34 children transplanted under a conventional tacrolimus-steroids regimen served as control series (group TS). Groups TB and TS were compared regarding patient and graft survival, rejection incidence, infectious complications, and growth, as well as cost of the transplant procedure. Patient and graft survivals at 3 years were 96% and 94% in group TB, versus 91% and 88% in group TS (P = 0.380 and P = 0.370, respectively). Rejection-free graft survival at 3 years was 72% in group TB, versus 41% in group TS (P = 0.007). Patients in group TB had significantly less viral infections than patients in group TS (P = 0.045). Height standard deviation score was significantly enhanced in children from group TB, when compared to group TS. Medical care costs were similar in both groups. Steroid avoidance together with basiliximab immunoprophylaxis was not harmful in terms of allograft acceptance, and even seemed to be beneficial in the long term.

PELD score and posttransplant outcome in pediatric liver transplantation: a retrospective study of 100 recipients.

BACKGROUND: Pediatric End-stage Liver Disease (PELD) score is proposed as an objective tool to prioritize children awaiting liver transplantation (LT), higher PELD being associated with increased pre-LT mortality. This study investigated whether PELD may also impact on post-LT results. METHODS: PELD was retrospectively analyzed in 100 pediatric recipients of a primary LT from living-related (n = 49) or postmortem donors (PMD, n = 51). The main pre-LT diagnosis was biliary atresia (n = 64), hepatic malignancy and fulminant hepatitis cases being excluded. PELD was calculated in all patients at the time of pre-LT assessment. Considering the median delay of 117 days between listing and LT in the PMD subgroup, a second PELD was calculated at the time of LT, allowing the determination of a delta PELD during the waiting period. PMD grafts were allocated using an allocation system taking into account waiting times as well as medical urgency, operative at EuroTransplant. RESULTS: Overall 5-year actuarial patient and graft survivals were 96% and 91%, respectively. PELD at listing (13.3 +/- 9.7) showed a normal statistical distribution. PELD scores at listing and at LT were not found to significantly impact on post-LT outcome (NS). In contrast, higher delta PELD might be associated with lower posttransplant patient survival (p = 0.094). CONCLUSIONS: The results of this retrospective analysis suggest that giving priority to high PELD recipients may not result in worsening post-LT outcome. Accordingly, these data support such "sickest children first" allocation policy, which should contribute to reduce pre-LT mortality without worsening post-LT results and increasing organ waste.

Engraftment assessment in human and mouse liver tissue after sex-mismatched liver cell transplantation by real-time quantitative PCR for Y chromosome sequences.

Transplanted hepatocytes can engraft, proliferate, and function permanently in host animals. After one cell infusion, however, engrafted hepatocytes constitute only between 1 in 200 to 1 in 3,000 host liver cells. Although transplanted cells can be identified using biochemical and molecular techniques, more accurate methods are needed to evaluate interventions that could improve cell engraftment rates. Real-time polymerase chain reaction (PCR) was done using primers and probes complementary to human testis determining gene (SRY) and mouse testis-specific Y-encoded protein (TSPY) pseudogene. Tissue samples from human or mouse recipients of liver cell transplantation were used to determine the test ability to detect transplanted cell DNA. Real-time PCR for the human SRY and mouse TSPY were species- and sex-specific. These two tests were sensitive in the detection of male DNA. Test sensitivity was consistently found at minimum 1:10,000 of male and female DNA mixing curve in both human SRY and mouse TSPY assays. The optimal amount of sample DNA per reaction to produce the highest sensitivity was 300 ng to 1 microg. Real-time PCR gave similar results whether standard male-female mixtures were prepared from liver cells or mononuclear cells. Engraftment of male liver cells in female liver tissues in mice and humans ranging from 0.125% to 0.257% was successfully measured using this method. Real-time PCR for SRY and TSPY affords a specific, sensitive, and reproducible tool for chimerism analysis in transplanted human and mouse liver tissues. This method could be used to optimize current models of cell transplantation.