Assessing vaccine-induced immunity against pneumococcus, hepatitis A and B over a 9-year follow-up in pediatric liver transplant recipients: A nationwide retrospective study.

Pediatric liver transplant recipients are particularly at risk of infections. The most cost-effective way to prevent infectious complications is through vaccination, which can potentially prevent infections due to hepatitis B (HBV) virus, hepatitis A virus (HAV), and invasive pneumococcal diseases. Here, we performed a retrospective analysis of HBV, HAV, and pneumococcal immunity in pediatric liver transplant recipients between January 1, 2009, and December 31, 2020, to collect data on immunization and vaccine serology. A total of 94% (58/62) patients had available vaccination records. At transplant, 90% (45/50) were seroprotected against HBV, 63% (19/30) against HAV, and 78% (18/23) had pneumococcal immunity, but immunity against these 3 pathogens remained suboptimal during the 9-year follow-up. A booster vaccine was administered to only 20% to 40% of patients. Children who had received >4 doses of HBV vaccine and > 2 doses of HAV vaccine pretransplant displayed a higher overall seroprotection over time post-solid organ transplant. Our findings suggest that a serology-based approach should be accompanied by a more systematic follow-up of vaccination, with special attention paid to patients with an incomplete vaccination status at time of transplant.

Long-term persistence of seroprotection against measles following measles-mumps-rubella vaccination administered before and after pediatric liver transplantation.

Liver transplant (LT) recipients are susceptible to infections, including measles. Concerns about the safety and efficacy of live-attenuated vaccines, such as the measles-mumps-rubella (MMR) vaccine, have led to hesitancy among providers in administering them to immunocompromised patients. This 9-year interventional study assessed seroprotection against measles following MMR vaccination in pediatric LT recipients. Of 119 participants enrolled, 60 (50%) were seroprotected against measles after transplantation. Among the 59 non-seroprotected participants, 56 fulfilled safety criteria and received MMR vaccination with a seroprotection rate of 90% (95%CI 73-98%) after a first dose, 95% (95%CI 85-99%) after primary vaccination with 1 to 3 doses, comparable to non-immunocompromised populations. However, measles antibodies declined over time, suggesting the need for regular monitoring, and booster doses. Half of the vaccinees (26/53, 49%) subsequently lost seroprotection. Among them, 23 received additional doses of MMR, with high seroconversion rate. At their last follow up (median 6.1 years, IQR 3.0-8.1 after inclusion), 63% (95%CI 49-75%) of all vaccinees were seroprotected against measles. In conclusion, MMR vaccination in pediatric LT recipients offers seroprotection against measles, but long-term immunity should be monitored closely. CLINICAL TRIAL REGISTRATION: The trial is registered at the US National Institutes of Health (Clinicaltrials.gov) number NCT01770119.

Predictors for pathological bone fractures in children undergoing liver transplantation: A retrospective cohort study.

BACKGROUND: Hepatic osteodystrophy refers to bone disorders associated with chronic liver disease, including children undergoing liver transplantation (LT). The aim of this study was to quantify the prevalence of pathological fractures (PF) in children before and after LT and to identify associated factors for their occurrence. METHODS: Children aged 0-18 years who underwent LT from 1/2005 to 12/2020 were included in this retrospective study. Data on patient demographics, types and anatomical locations of fracture and biological workups were extracted. Variables were assessed at 3 time points: T - 1 at the moment of listing for LT; T0 at the moment of LT and T + 1 at 1-year post-LT. RESULTS: A total of 105 children (49 [47%] females) were included in this study. Median age at LT was 19 months (range 0-203). Twenty-two patients (21%) experienced 65 PF, 11 children before LT, 10 after LT, and 1 before and after LT. The following variables were observed as associated with PF: At T - 1, low weight and height z-scores, and delayed bone age; at T0, low weight and height z-scores, high total and conjugated bilirubin; at T + 1, persistent low height z-score. Patients in the PF-group were significantly more under calcium supplementation and/or nutritional support at T - 1, T0 and T + 1. CONCLUSION: More than one in five children needing LT sustain a PF before or after LT. Patients with low weight and height z-scores and delayed bone age are at increased risk for PF. Nutritional support remains important, even if to date it cannot fully counteract the risks of PF.

Anatomic parameters of omphaloceles and their association with anatomic, genetic, or syndromic malformations: a retrospective study.

PURPOSE: This retrospective study aims to describe anatomical parameters of omphaloceles and to analyze their association with anatomical, genetic, or syndromic malformations. METHODS: Cases were selected from digital records of two university centers, a certified regional registry and personal records. Patients from 1998 to 2018 with omphalocele and live birth (LB), termination of pregnancy due to fetal anomaly (TOPFA) and fetal death (FD) were included. Cases born outside Western Switzerland and/or with upper or lower coelosomy were excluded. RESULTS: We analyzed 162 cases with the following distribution: 57 (35%) LB, 91 (56%) TOPFA and 14 (9%) FD. TOPFA was significantly more frequently performed in cases with non-isolated omphalocele, i.e., omphaloceles with associated major malformations (especially cardiovascular and genitourinary), genetic/chromosomal anomalies, or syndromes. For LB, associated anatomical malformations, genetic or chromosomal anomalies were not significantly associated with the size of the omphalocele or the liver involvement. CONCLUSIONS: The proportion of cases resulting in TOPFA was higher among fetuses with major malformations, genetic or chromosomal anomalies. Despite the large size of this cohort, and in contrary to previous publications, the size of the omphalocele and/or liver involvement does not allow for conclusions regarding the presence or number of associated malformations, genetic or chromosomal anomalies.

Impact of length of donor ICU stay on outcome of patients after pediatric liver transplantation with whole and ex situ split liver grafts.

BACKGROUND: Patients who have a prolonged stay in the intensive care unit (ICU) are often excluded for organ donation because of supposed deleterious effects of a lengthy ICU stay. We aimed to determine the effects of a prolonged donor stay in the ICU on the outcome of liver transplantation (LT) in children. METHODS: Retrospective review of 89 pediatric LT patients, age 0-18 years, period 2003-2018, including patients having undergone whole organ or in situ split LT. The patients were divided into two groups according to the donor length of stay in the ICU. A prolonged stay was defined as >5 days. Recipient, graft, and donor characteristics were compared; outcome parameters included recipient and graft survival rates and postoperative complications. RESULTS: Group short (donor ICU stay <5 days) included 75 patients, group long (donor ICU stay >5 days) 14 patients. Baseline characteristics between recipients did not differ. Donors in group long had significantly more infectious complications and a higher gamma glutamyl transferase (gGT) the day of organ recovery. Incidence of biliary complications post-LT was significantly higher in group long (p = .029). Patient and graft survival rates did not differ significantly between groups. CONCLUSIONS: Donors with a prolonged stay in the ICU should still be considered for liver donation if they fulfill most other selection criteria. Recipients from donors having stayed in ICU >5 days may be at increased risk of biliary complications.

Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes.

The liver is an organ with strong regenerative capacity, yet primary hepatocytes have a low amplification potential in vitro, a major limitation for the cell-based therapy of liver disorders and for ex vivo biological screens. Induced pluripotent stem cells (iPSCs) may help to circumvent this obstacle but often harbor genetic and epigenetic abnormalities, limiting their potential. Here, we describe the pharmacological induction of proliferative human hepatic progenitor cells (HPCs) through a cocktail of growth factors and small molecules mimicking the signaling events involved in liver regeneration. Human HPCs from healthy donors and pediatric patients proliferated vigorously while maintaining their genomic stability and could be redifferentiated in vitro into metabolically competent cells that supported the replication of hepatitis B and delta viruses. Redifferentiation efficiency was boosted by three-dimensional culture. Finally, transcriptome analysis showed that HPCs were more closely related to mature hepatocytes than iPSC-derived hepatocyte-like cells were. Conclusion: HPC induction holds promise for a variety of applications such as ex vivo disease modeling, personalized drug testing or metabolic studies, and development of a bioartificial liver.

Multimodal safety assessment of measles-mumps-rubella vaccination after pediatric liver transplantation.

Live-attenuated vaccines are currently contraindicated in solid-organ transplant recipients. However, the risk of vaccine-preventable infections is lifelong, and can be particularly severe after transplantation. In this prospective interventional national cohort study, 44 pediatric liver transplant recipients with measles IgG antibodies <150 IU/L (below seroprotection threshold) received measles-mumps-rubella vaccine (MMR) at a median of 6.3 years posttransplantation (interquartile range, 4.0 to 10.9). A maximum of two additional doses were administered in nonresponders or when seroprotection was lost. Vaccine responses occurred in 98% (95% confidence interval [CI], 88-100) of patients. Seroprotection at 1-, 2-, and 3-year follow-up reached 62% (95% CI, 45-78), 86% (95% CI, 70-95), and 89% (95% CI, 67-99), respectively. All patients responded appropriately to the booster dose(s). Vaccinations were well tolerated and no serious adverse event attributable to vaccination was identified during the 8-week follow-up period (or later), using a multimodal approach including standardized telephone interviews, diarized side effect reporting, and monitoring of vaccinal virus shedding. We conclude that live attenuated MMR vaccine can be administered in liver transplant recipients fulfilling specific eligibility criteria (>1 year posttransplantation, low immunosuppression, lymphocyte count ≥0.75 G/L), inducing seroprotection in most subjects. (Clinicaltrials.gov number NCT01770119).

International survey on anticoagulation and antiplatelet strategies after pediatric liver transplantation.

In pediatric LT, anticoagulants and antiplatelet agents are regularly used to reduce the risk of vascular thrombosis. As evidence for optimal strategy is lacking, local practices vary greatly. The present survey aimed to compile an international overview of anticoagulation and antiplatelet strategies in pediatric LT. An online survey was sent to 98 pediatric LT centers in North and South America, Europe, Asia, and Australia. Twenty-four centers answered the survey. 20/24 (83%) use some sort of anticoagulation and antiplatelet therapy, yielding 20 different strategies. Perioperative vascular problems, size of the hepatic artery, and patient weight were the most frequent determinants of changes in anticoagulant and antiplatelet strategy. Early HAT rates were reported to be 5% or less in 79% of responding centers. Anticoagulation and antiplatelet strategies were not significantly associated with early HAT rates (P = 0.63), or with the number of pediatric LTs performed per year and center (P = 0.92). Internationally, there is a wide variety in anticoagulation and antiplatelet strategies after pediatric LT. Efforts must be made to design a prospective multicentric trial to identify the optimal antithrombotic strategy.

Congenital Portosystemic Shunts: Current Diagnosis and Management.

Congenital portosystemic shunts are increasingly recognized in several settings and at any age. The following are some of the most common presentations: prenatal ultrasound, neonatal cholestasis, incidental finding on abdominal imaging, or systemic complications such as unexplained cardiopulmonary or neurological disease, or the presence of liver nodules in a noncirrhotic liver. The purpose of the present review is to summarize clinical presentation and current recommendations for management, and highlight areas of future research. Illustrative examples from the veterinary literature complement our current lack of knowledge of this rare malformation often masquerading as a multisystem disease.

Pulmonary complications after liver transplantation in children: risk factors and impact on early post-operative morbidity.

Liver transplantation (LT) is associated with high post-operative morbidity, despite excellent survival rates. With this retrospective study, we report the incidence of early and late pulmonary complications (PC) after LT, identify modifiable risk factors for PC and analyzed the role of PC in post-operative ventilation duration and hospital length of stay. In a series of 79 children (0-16 years) with LT over a 12 years period, early (<3 months post-LT) and/or late (>3 months post-LT) PC occurred in 68 patients (86%). Sixty-four percent (64%) developed early major complications such as pulmonary edema, atelectasis, or pleural effusion. Atelectasis requiring an intervention (P ≤ .02), pulmonary edema (P ≤ .02), or elevated PELD/MELD scores (P = .05) were associated with an increase in total ventilation duration and length of stay in the ICU. Risk factors for early PC included preoperative hypoxemia (P = .005), low serum albumin at LT admission (P = .003), or early rejection (P = .002). About 20% of patients experienced late PC of which 81% were infections. Risk factor assessment prior to LT may ultimately help reduce early PC thereby possibly minimizing post-operative morbidity and ICU length of stay.

Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency.

Endogenous retroelements (EREs) account for about half of the mouse or human genome, and their potential as insertional mutagens and transcriptional perturbators is suppressed by early embryonic epigenetic silencing. Here, we asked how ERE control is maintained during the generation of induced pluripotent stem cells (iPSCs), as this procedure involves profound epigenetic remodeling. We found that all EREs tested were markedly up-regulated during the reprogramming of either mouse embryonic fibroblasts, human CD34(+) cells, or human primary hepatocytes. At the iPSC stage, EREs of some classes were repressed, whereas others remained highly expressed, yielding a pattern somewhat reminiscent of that recorded in embryonic stem cells. However, variability persisted between individual iPSC clones in the control of specific ERE integrants. Both during reprogramming and in iPS cells, the up-regulation of specific EREs significantly impacted on the transcription of nearby cellular genes. While transcription triggered by specific ERE integrants at highly precise developmental stages may be an essential step toward obtaining pluripotent cells, the broad and unspecific unleashing of the repetitive genome observed here may contribute to the inefficiency of the reprogramming process and to the phenotypic heterogeneity of iPSCs.

Procalcitonin for infections in the first week after pediatric liver transplantation.

BACKGROUND: Procalcitonin (PCT) has become a commonly used serum inflammatory marker. Our aim was to describe the kinetics and usefulness of serial post-operative PCT measurements to detect bacterial infection in a cohort of children immediately after pediatric liver transplantation (pLT). METHODS: We performed a retrospective chart review of a cohort of pLT recipients with serial serum PCT measurements in the first week following pLT. The presence of infection was determined on clinical and biological parameters. Normal PCT was defined as < 0.5 (ng/ml). RESULTS: Thirty-nine patients underwent 41 pLT. PCT was measured daily during the first week post pLT. Values first increased following surgery and then decreased, nearing 0.5 ng/ml at day seven. Peak PCT reached a median of 5.61 ng/ml (IQR 3.83-10.8). Seventeen patients were considered to have an infection. There was no significant difference in daily PCT or peak PCT between infected and non infected patients during the first post-operative week. AUC of ROC curve for PCT during first week was never higher than 0.6. CONCLUSIONS: We conclude that serial PCT measurements during the first week after pLT is not useful to identify patients with bacterial infections. Rather, we propose that serum PCT may be useful after the first week post pLT.

Early complications after liver transplantation in children and adults: Are split grafts equal to each other and equal to whole livers?

Split-liver transplantation (LT) allows transplantation of two recipients from one deceased donor, thereby increasing pool of grafts. However, split LT may be hampered by technical problems, and split grafts are still considered suboptimal organs in some centres. We analysed the outcomes in split- and whole-liver recipients in a combined adult-to-paediatric transplantation programme. Records of paediatric and adult patients having undergone LT from 1999 to 2013 were analysed retrospectively. All splits were performed in situ. Adult split-graft recipients were matched 1:2 with whole-graft recipients (matching criteria: BMI, MELD, year of transplantation, age), and matched to the paediatric recipient transplanted from the same donor. Post-LT complications were classified according to the Clavien scale. Among children, 32 split- and 31 whole-graft recipients were analysed. Among adults, 20 split- and 40 matched whole-graft recipients were analysed. In both populations, the post-operative complications did not differ between split- and whole-graft recipients. There was no difference in 1-year graft and patient survival between split- and whole-graft recipients in paediatric (90% vs. 97%, 94% vs. 97%, respectively) and in adult recipients (89% in both, 89% vs. 92%, respectively). In the analysis of both recipients issued from the same donor, there was no association in the prevalence and severity of complications. A case-by-case analysis showed that split mortality was unrelated to LT in all but one patient (small-for-size left split graft). In the setting of careful donor selection, recipient matching and surgical skill, in situ split LT is an effective and safe technique to increase the number of available organs, and split livers should no longer considered marginal grafts.

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

Complications of indwelling central venous catheters in pediatric liver transplant recipients.

In pLT recipients, the advantages of ICVCs need to be weighed against the risk of complications. This single-center retrospective study aimed to review ICVC complications in our cohort of pLT recipients. We performed chart reviews of pLT patients having undergone transplant between 01/2000 and 03/2014 and who underwent ICVC placement either before or after LT. We identified 100 ICVC in 85 patients. Overall observation time was 90 470 catheter-days. There was no difference in catheter lifespan between those inserted pre- or post-transplant; 46% of ICVC presented a complication. Most frequent complications were MD and infection. The infection rate was 0.09 per 1000 catheter-days, and MD rate was 0.36 per 1000 catheter-days. Patients having received technical variant grafts were more at risk of complications. To the best of our knowledge, this is the first study examining ICVC complications in pLT recipients. We conclude that ICVC have a high rate of MD. Children receiving technical variants may be more at risk of complications. By removing ICVC in a select number of patients at six months post-insertion, we might avoid as much as 60% of complications.

Acoustic radiation force impulse sonography in assessing children with biliary atresia for liver transplantation.

BACKGROUND: Children with biliary atresia are prone to developing progressive hepatic fibrosis and biliary cirrhosis following the Kasai operation. The only treatment is liver transplantation. OBJECTIVE: To assess liver fibrosis by acoustic radiation force impulse elastography (ARFI) in children who had Kasai operation, with the goal of identifying an ARFI value cut-off for children requiring liver transplantation. MATERIALS AND METHODS: Of the 32 post-Kasai children included, 19 were transplanted or listed for transplantation (group A), while 13 were not on the list during their follow-up (group B). We recorded biopsies, blood samples and ARFI values over time, including at Kasai operation and at transplantation. We estimated an association between groups and continuous variables using generalized estimating equations, and we compared categorical variables using the Fisher exact test. RESULTS: Portal hypertension signs were similar in both groups, whereas ARFI values were higher in group A (mean±standard deviation=3.3±1.2 m/s) than in group B (2.0±0.7 m/s; P=.0003). Eighteen of 19 (94.7%) children in group A and 6/13 (46.2%) children in group B presented with two consecutive ARFI values ≥2 m/s (sensitivity=7%, specificity=53.8%; P=0.003). CONCLUSION: We found that children who were transplanted had two consecutive ARFI values ≥2 m/s during follow-up. ARFI for evaluation of post-Kasai liver fibrosis may assist the long-term assessment of biliary atresia and may even guide treatment decisions.

The Seatbelt Syndrome-Do We Have a Chance?: A Report of 3 Cases With Review of Literature.

The seatbelt syndrome represents an injury pattern seen after motor vehicle accidents. It is secondary to either the misplacement of seatbelts over the abdomen or the misuse of the restraint systems. This syndrome is infrequent in the pediatric population and occurs mostly in school-aged children because recommended lap-shoulder belts and booster seats are often not used in this age group, so that the seatbelt lies over the abdomen. Sudden deceleration bends the child around the lap belt causing injuries to the viscera, head, and spine (Chance fracture), often associated with paraplegia. Because not all patients have an abdominal seatbelt sign, this syndrome can easily not be recognized with potentially life-threatening consequences.We report on 3 patients with the seatbelt syndrome and review the literature regarding prevalence, diagnosis, treatment, and prognosis of the different injuries and discuss the diagnostic challenges of intestinal lesions and their management.Following this accident pattern, in hemodynamically stable patients with a normal abdominal computed tomography scan, close surveillance is warranted to rule out intestinal lesions manifesting with progressive peritoneal irritation. In hemodynamically unstable patients, or if there is evidence of free air on the computed tomography scan, emergency abdominal exploration is required.

Donor hypernatremia before procurement and early outcomes following pediatric liver transplantation.

The demand for transplantable organs far outweighs the supply. Recently, efforts have been made to increase the donor pool by adopting extended criteria for livers, including those from hypernatremic donors. Currently, there is no clear evidence that the use of organs from hypernatremic donors has detrimental effects on pediatric liver transplantation (LT) recipients. Our aim was to use the Scientific Registry of Transplant Recipients database to evaluate the effects of donor hypernatremia on 30-day outcomes in pediatric LT recipients. We performed an analysis of 2325 children who underwent whole or partial LT between 2005 and 2010. First, we sought to determine a donor sodium threshold for increased mortality following pediatric LT. Second, we examined rates of mortality and graft failure at 30 days after LT in patients receiving grafts from hypernatremic donors compared to patients receiving grafts from normonatremic donors. Hypernatremia was defined as a donor sodium level of ≥160 µmol/L. The primary outcome measure was mortality at 30 days after transplant. The secondary outcome measure was graft failure at 30 days after transplant. There was no threshold sodium level for increased 30-day mortality following pediatric LT. Mean recipient ages/weights, Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease scores, and mean cold and warm ischemia times were similar between the 2 study groups. There were no significant differences in mortality rates (3.9% versus 4.5%; P = 0.87) and graft failure rates (2.2% versus 1.9%; P = 1.00) in patients receiving grafts from hypernatremic donors compared to patients receiving grafts from normonatremic donors at 30 days after LT. In conclusion, donor hypernatremia just before procurement does not appear to have negative effects on mortality and graft failure rates at 30 days following pediatric LT.