Early steroids after pediatric liver transplantation protect against T-cell-mediated rejection: Results from the ChilSFree study.

Steroid-free immunosuppression protocols gained popularity in pediatric liver transplantation (pLT) after the introduction of IL-2-receptor blockade for induction therapy. We analyzed the clinical and immunologic outcome data of the multicenter prospective observational ChilSFree study to compare the impact of steroid-free versus steroid-containing immunosuppressive therapy following pLT in a real-life scenario. Two hundred forty-six children [55.3% male, age at pLT median: 2.4 (range: 0.2-17.9) y] transplanted for biliary atresia (43%), metabolic liver disease (9%), acute liver failure (4%), hepatoblastoma (9%), and other chronic end-stage liver diseases (39%) underwent immune monitoring and clinical data documentation over the first year after pLT. Patient and graft survival at 1 year was 98.0% and 92.7%, respectively. Primary immunosuppression was basiliximab induction followed by tacrolimus (Tac) monotherapy (55%), Tac plus steroid tapering over 3 months (29%), or cyclosporine and steroid tapering (7%). One center used intraoperative steroids instead of basiliximab followed by Tac plus mycophenolate mofetil (7% of patients). N = 124 biopsy-proven T-cell-mediated rejections were documented in n = 82 (33.3%) patients. T-cell-mediated rejection occurred early (median: 41 d, range: 3-366 d) after pLT. Patients initially treated with Tac plus steroids experienced significantly fewer episodes of rejection than patients treated with Tac alone (chi-square p <0.01). The use of steroids was associated with earlier downregulation of proinflammatory cytokines interferon (IFN)-γ, Interleukin (IL)-6, CX motif chemokin ligand (CXCL)8, IL-7, and IL-12p70. Both primary immunosuppression with Tac plus steroids and living donor liver transplantation were independent predictors of rejection-free survival 1 year after pLT on logistic regression analysis. Adjunctive steroid therapy after pLT leads to earlier suppression of the post-pLT proinflammatory response and significantly reduced rejection rates during the first year after pLT (15.9%). Fifty-one percent of patients initially treated without steroids remain steroid-free over the first 12 months without rejection.

Diagnosing Acute Cellular Rejection after Paediatric Liver Transplantation-Is There Room for Interleukin Profiles?

BACKGROUND: The current gold standard to diagnose T-cell-mediated acute rejection (TCMR) requires liver histology. Using data from the ChilSFree study on immune response after paediatric liver transplantation (pLT), we aimed to assess whether soluble cytokines can serve as an alternative diagnostic tool in children suspected to have TCMR. METHODS: A total of n = 53 blood samples obtained on the day of or up to 3 days before liver biopsy performed for suspected TCMR at median 18 days (range 7-427) after pLT in n = 50 children (38% female, age at pLT 1.8 (0.5-17.5) years) were analysed for circulating cytokine levels using Luminex-based Multiplex technology. Diagnostic accuracy of cytokine concentrations was assessed using a multivariable model based on elastic net regression and gradient boosting machine analysis. RESULTS: TCMR was present in 68% of biopsies. There was strong evidence that patients with TCMR had increased levels of soluble CXCL8, CXCL9, CXCL10, IL-16, IL-18, HGF, CCL4, MIF, SCGF-ß, and HGF before biopsy. There was some evidence for increased levels of sCD25, ICAM-1, IL-6, IL-3, and CCL11. Diagnostic value of both single cytokine levels and a combination of cytokines and clinical markers was poor, with AUROCs not exceeding 0.7. CONCLUSION: Patients with TCMR showed raised levels of cytokines and chemokines reflective of T-cell activation and chemotaxis. Despite giving insight into the mechanisms of TCMR, the diagnostic value of soluble cytokines for the confirmation of TCMR in a clinical scenario of suspected TCMR is poor.

International registry of congenital porto-systemic shunts: a multi-centre, retrospective and prospective registry of neonates, children and adults with congenital porto-systemic shunts.

BACKGROUND: Congenital portosystemic shunts (CPSS) are rare vascular malformations associated with the risk of life-threatening systemic conditions, which remain underdiagnosed and often are identified after considerable diagnostic delay. CPSS are characterized by multiple signs and symptoms, often masquerading as other conditions, progressing over time if the shunt remains patent. Which patients will benefit from shunt closure remains to be clarified, as does the timing and method of closure. In addition, the etiology and pathophysiology of CPSS are both unknowns. This rare disorder needs the strength of numbers to answer these questions, which is the purpose of the international registry of CPSS (IRCPSS). METHOD: A retrospective and prospective registry was designed using secuTrial® by the ISO certified Clinical Research Unit. Given that a significant number of cases entered in the registry are retrospective, participants have the opportunity to use a semi-structured minimal or complete data set to facilitate data entry. In addition, the design allows subjects to be entered into the IRCPSS according to clinically relevant events. Emphasis is on longitudinal follow-up of signs and symptoms, which is paramount to garner clinically relevant information to eventually orient patient management. The IRCPSS includes also three specific forms to capture essential radiological, surgical, and cardiopulmonary data as many times as relevant, which are completed by the specialists themselves. Finally, connecting the clinical data registry with a safe image repository, using state-of-the-art pseudonymization software, was another major focus of development. Data quality and stewardship is ensured by a steering committee. All centers participating in the IRCPSS have signed a memorandum of understanding and obtained their own ethical approval. CONCLUSION: Through state-of-the-art management of data and imaging, we have developed a practical, user-friendly, international registry to study CPSS in neonates, children, and adults. Via this multicenter and international effort, we will be ready to answer meaningful and urgent questions regarding the management of patients with CPSS, a condition often ridden with significant diagnostic delay contributing to a severe clinical course.

Perioperative Complications after Kasai Hepatoportoenterostomy: Data from the Swiss National Biliary Atresia Registry.

INTRODUCTION: Hepatoportoenterostomy (HPE) is the first-line treatment for biliary atresia (BA) patients. This study aims to describe perioperative complications after HPE and to analyze their impact on outcome. MATERIALS AND METHODS: Patients with HPE (Swiss National Biliary Atresia Registry, 1994-2017) were retrospectively analyzed. Perioperative complications were defined as complications occurring up to 30 days after surgery. Surgical complications were defined as directly related to the surgical act; medical complications were defined as any other deviation from the uneventful postoperative course. RESULTS: Sixty-two patients were included. Median age at HPE was 63 days (18-126). Twenty six patients out of 62 (42%) had ≥ 1 complications: 6/62 (10%) surgical, 24/62 (39%) medical, that is, we observed 7 surgical and 28 medical complications. As for medical complications, cholangitis was the most frequent: 19/28 (68%). Lower gestational age at birth correlated with more overall complications (p = 0.02). Age, weight at HPE, syndromic BA, and postoperative steroid administration were not significantly correlated. There were no perioperative deaths. Perioperative complications did not correlate with overall survival (p = 0.14) and survival with native liver (p = 0.55). CONCLUSION: HPE is often associated with perioperative medical complications. Lower gestational age at birth was significantly associated with more complications. Perioperative complications had no impact on overall outcome.

Newborn biliary atresia screening with the stool colour card: a questionnaire survey of parents.

PURPOSE: Biliary atresia can easily be screened using a stool colour card (SCC) and has shown to significantly reduce time to diagnosis, improving children's outcome. Despite the general approval of the clinical usefulness of the SCC, physicians remain reluctant: it might unnecessarily worry parents. This study aimed to analyse the parental reaction to this screening method and if it evokes parental stress. METHODS: A semistructured questionnaire was sent to parents with one or more healthy child to inquire about reactions on receipt and use of the SCC. RESULTS: 109/256 questionnaires were returned and evaluated (43%). 107/107 parents considered the SCC as helpful, a simple screening method and easy to use (100%). 26/43 were reassured when receiving the SCC (60%), 2 were worried (5%) and 9 had no particular feelings (21%). In 41/49, emotions experienced during its use were positive or neutral (84%), and 3 were worried (6%). In 41/50, the discussion with the paediatrician about stool colour-linked pathologies was neutral (82%), and 9 felt uneasy (18%). CONCLUSION: A vast majority of parents appreciate the SCC. It creates uneasiness in a minority of parents. Our results are encouraging and argue in favour of implementing the regular distribution of the SCC in antenatal, postnatal and newborn infant clinics.

Intestinal permeability and effects of Lactobacillus rhamnosus therapy in children with short bowel syndrome.

BACKGROUND: The present study was conducted to investigate the effects of Lactobacillus rhamnosus (also known as LGG) on intestinal permeability (IP) in children with short bowel syndrome (SBS). PATIENTS AND METHODS: In a double-blind, placebo-controlled crossover clinical trial, baseline IP (ie, lactulose-to-mannitol ratio) was measured in subjects with SBS and healthy control subjects. Subjects with SBS received LGG or placebo for 4 weeks, followed by a 3-week washout before therapy was crossed over for another 4 weeks. IP, quantitative fecal cultures for Lactobacillus species (in colony-forming units [cfu] per gram of stool) and hydrogen breath test (HBT) were performed during LGG and placebo phases of therapy. RESULTS: Twenty-one children (SBS, n = 9; control, n = 12) with a median age of 4.5 years (range 1.6-16.4 years) enrolled. Baseline IP measurements were similar in patients with SBS and control subjects: 0.08 +/- 0.06 (mean +/- SD) versus 0.07 +/- 0.05 (P = 1.0). IP was correlated with age in control subjects (r = -0.83, P = 0.001) but not among patients with SBS (r = -0.55, P = 0.16). Fecal colonization with Lactobacillus species did not differ during LGG versus placebo therapy (median 1.4 x 10(9) cfu/g [range 4.0 x 10(5) to 4.0 x 10(9) cfu/g] vs 6.0 x 10(9) cfu/g [1.0 x 10(3) to 1.0 x 10(10) cfu/g], respectively; P = 0.83). LGG therapy had no consistent effects on IP (P = 0.58) or its relationship with age (r = -0.40, P = 0.29), and was associated with conversion to positive HBT results in 1 subject. CONCLUSIONS: In this sample of children with SBS, the IP was within normal limits but did not correlate with age. LGG therapy had no consistent effects on IP. These findings do not support empiric LGG therapy to enhance IP in children with SBS.