Sirolimus to treat chronic and steroid-resistant allograft rejection-related fibrosis in pediatric liver transplantation.

This study aimed to report our experience with the use of sirolimus in pediatric liver transplant patients with chronic rejection or steroid-resistant rejection with hepatic fibrosis, focusing on their histological evolution. All pediatric liver transplant recipients who received off-label treatment with sirolimus for chronic ductopenic rejection or cortico-resistant rejection between July 2003 and July 2022 were included in the study. All nine patients included in the study showed improvement in liver enzymes and cholestasis parameters as soon as 1-month after postsirolimus introduction. A decrease in fibrosis stage was observed in 7/9 (77.7%) patients at 36 months. All but one patient experienced an improvement in the Rejection Activity Index and ductopenia at 12 months. A single patient had to discontinue sirolimus treatment owing to nephrotic proteinuria. In conclusion, sirolimus may be a safe and effective treatment for chronic and steroid-resistant rejection and may improve allograft rejection-related fibrosis and ductal damage.

A Better Understanding of Pediatric Autoimmune Pancreatitis: Over 13 Years of Experience.

OBJECTIVES: Pediatric autoimmune pancreatitis (P-AIP) is an uncommon disease whose diagnosis requires strong clinical suspicion. Late diagnosis increases morbidity. We aimed to compare the usefulness of the 2011 International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis with the 2018 INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) criteria. METHODS: We retrospectively analyzed demographics and clinical, laboratory, radiological, and histological findings at diagnosis and during long-term follow-up in children diagnosed with AIP in 2 tertiary hospitals between 2008 and 2021. RESULTS: We included 11 patients [6 girls; median age at diagnosis, 12.5 (range 2.8-15.7) years]. The most common symptom was abdominal pain. Pancreatic enzymes were elevated in 10 patients, and serum immunoglobulin G4 was elevated in 1. Magnetic resonance imaging showed enlargement of the pancreatic head in 10 patients and general pancreatic enlargement in 1. Pancreatic and papilla tissue were obtained from 9 patients. All patients received corticosteroids (prednisolone), and 4 also received azathioprine. According to the ICDC, all patients were classified as probable or non-otherwise specified AIP. According to INSPPIRE criteria, all patients were classified as AIP. Using the INSPPIRE criteria would have avoided biopsies in 6 patients who responded well to corticosteroids. CONCLUSIONS: The INSPPIRE criteria are useful. Using the ICDC in pediatric patients can delay diagnosis and result in unnecessary invasive tests.

Delayed sequential abdominal wall closure in pediatric liver transplantation to overcome "large for size" scenarios.

BACKGROUND: Primary abdominal wall closure after pediatric liver transplantation (PLT) is neither always possible nor advisable, given the graft-recipient size discrepancy and its potential large-for-size scenario. Our objective was to report the experience accumulated with delayed sequential closure (DSC) guided by Doppler ultrasound control. METHODS: Retrospective analysis of DSC performed from 2013 to March 2020. RESULTS: Twenty-seven DSC (26.5%) were identified out of 102 PLT. Transplant indications and type of grafts were similar among both groups. In patients with DSC, mean weight and GRWR were 9.4 ± 5.5 kg (3.1-26 kg) and 4.7 ± 2.4 (1.9-9.7), significantly lower and higher than the primary closure cohort, respectively. The median time to achieve definitive closure was 6 days (range 3-23 days), and the median number of procedures was 4 (range 2-9). Patients with DSC had longer overall PICU (22.5 ± 16.9 vs. 9.1 ± 9.7 days, p < .05) and hospital stay (33.4 ± 19.1 vs 23, 9 ± 19.8 days (p < .05). These differences are less remarkable if the analysis is performed in a subgroup of patients weighing less than 10 kg. Two patients presented vascular complications (7.4%) within DSC group. No differences were seen when comparing overall, 3-year graft and patient survival (96% and 96% in the DSC group). CONCLUSIONS: DSC is a simple and safe technique to ensure satisfactory clinical outcomes to overcome "large for size" scenarios in PLT. In addition, we were able to avoid using a permanent biological material for closing the abdomen.

Epstein-Barr virus-associated risk factors for post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre-LT EBV status and post-LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. METHODS: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre-LT primary infected cohort and EBV post-LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. RESULTS: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical-Hodgkin's lymphoma). Patients of the EBV post-LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre-LT primary infected cohort (2.2-133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89-0.98). In EBV post-LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7-241.1; p < 0.001). CONCLUSIONS: The combination of pretransplant EBV serological status with EBV post-transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients.

Endoscopic variceal ligation as primary prophylaxis for upper GI bleeding in children.

BACKGROUND AND AIMS: Variceal hemorrhage can be a life-threatening adverse event of chronic liver disease. In contrast to the well-described guidelines for the management of portal hypertension (PH) in adults, there is limited evidence about the optimal prophylactic management of variceal bleeding in children. This study was carried out to assess the efficacy of endoscopic variceal ligation (EVL) as primary prophylaxis to prevent upper GI bleeding in children with PH. METHODS: From January 2014 to April 2018, all pediatric patients with PH disease and medium to large esophageal varices or reddish spots, regardless of the grade of the varix, were prospectively included in the protocol of primary prophylaxis with EVL. A second retrospective group of patients was made after reviewing medical records of 32 pediatric patients with PH that presented esophageal varices in the upper endoscopy and had received propranolol as primary prophylaxis. RESULTS: Twenty-four patients (75%) reached varices eradication in the EVL group, with a median of 2 procedures (range, 1-4) before eradication and a median time to eradication of 3.40 months (range, 1.10-13.33). No EVL-related adverse events were observed. Statistically significant differences were observed in the bleeding rate at 3 years between propranolol and EVL groups (6/32 [21.9%] vs 1/32 [3.2%], P < .02). The hazard ratio for bleeding for patients treated with propranolol compared with those treated with EVL was 2.6 (95% confidence interval, 1.53-3.67). CONCLUSIONS: EVL is a safe and effective treatment to prevent upper GI bleeding in pediatric patients with PH. (Clinical trial registration number: NCT03943784.).

Prevalence of prenatal exposure to substances of abuse: questionnaire versus biomarkers.

Alcohol and drugs of abuse consumption in young adults, including women of childbearing age, has experienced significant increase over the past two decades. The use of questionnaires as the only measure to investigate prenatal alcohol and drugs of abuse exposure underestimates the real prevalence of exposure and could mislead to wrong conclusions. Therefore, the aim of this article was to compare reported rates of prenatal alcohol and drugs of abuse consumption with biomarkers of exposure by a comprehensive review of the available literature. We searched MEDLINE and EMBASE databases for articles catalogued between 1992 and 2015. We identified relevant published studies that assessed the comparison between prenatal exposure to alcohol and drugs of abuse assessed by self-reported questionnaire of consumption versus biomarkers of exposure. Thirteen studies were included regarding alcohol consumption, and seven of them about drugs of abuse. Women who admitted consumption during pregnancy by questionnaire varied from 0 to 37% for alcohol, from 0 to 4.3% for cocaine, and 2.9% for tetrahydrocannabinol (THC). Positive biomarkers results ranged from 16 to 44% for alcohol, 15.4% for cocaine, and from 4 to 12.4% for THC. Biomarkers should always complement questionnaires, as it has been shown that self-report may underestimate prenatal exposure to substances of abuse.

Infectious complications of non-surgical biliary tract manipulation in paediatric patients. Role of antibiotic prophylaxis.

BACKGROUND: Infections related to non-surgical manipulation of the biliary tract (NSMBT) are common events despite periprocedural antibiotic prophylaxis (PAP). Since June 2017, our local protocol has indicated a 24-h regimen of intravenous piperacillin-tazobactam for this purpose. OBJECTIVE: We aimed to describe the incidence and characteristics of NSMBT-related paediatric infections, define risk factors for their development, and analyse adherence to our PAP protocol. MATERIALS AND METHODS: Epidemiological, clinical, and microbiological data were collected in consecutive NSMBT procedures performed in paediatric patients (<18 years) in our centre (2010-2019). RESULTS: 113 procedures in 37 patients, median age 4 years (IQR 1-8), were included. Main underlying diseases were biliary atresia (32%) and cancer (14%). Sixty-eight percent had undergone liver transplant and 70% hepaticojejunostomy. In 44 procedures (39%), the intervention was performed during the course of infection and previously prescribed antibiotic treatment was maintained. In the other 69, PAP was specifically indicated for NSMBT; antibiotic adequacy increased from 35% to 100% after June 2017. In total, 32 NSMBT-related infections (28%) occurred, mainly in the first 24h post-procedure (72%); no deaths happened. Causative pathogens were Gram-negative rods (64%), Gram-positive cocci (28%), and Candida spp. (8%). Main related risk factors were hepaticojejunostomy, biliary obstruction, and liver transplant. CONCLUSIONS: NSMBT in children entails a significant infection risk, even under antibiotic prophylaxis, being hepaticojejunostomy the main risk factor. Infectious complications mainly occurred immediately after the procedure. After establishing a PAP protocol, 100% of interventions received appropriate prophylaxis, decreasing antibiotic exposure time and potentially, the length of hospital stay.

Diagnostic action against hypertransaminasemia in paediatrics: Consensus document of Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP), Asociación Española de Pediatría de Atención Primaria (AEPap) and Sociedad Española de Pediatría de Atención Primaria (SEPEAP).

Hypertransaminasemia is a frequent finding in pediatrics, which could reflect potentially treatable serious disease. The aim of this document is to establish, by reviewing the available evidence, a consensus for an adequate management of hypertransaminasemia, from its detection until the study is complete. To this end, a working group was formed with the participation of members of the Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP), the Spanish Association of Primary Care Pediatrics (AEPap) and the Spanish Society of Primary Care Pediatrics (SEPEAP). Twenty-one recommendations are established with a marked practical component that will be useful in hospital clinical practice and primary care.

Infectious complications of non-surgical biliary tract manipulation in paediatric patients. Role of antibiotic prophylaxis.

BACKGROUND: Infections related to non-surgical manipulation of the biliary tract (NSMBT) are common events despite periprocedural antibiotic prophylaxis (PAP). Since June 2017, our local protocol has indicated a 24-h regimen of intravenous piperacillin-tazobactam for this purpose. OBJECTIVE: We aimed to describe the incidence and characteristics of NSMBT-related paediatric infections, define risk factors for their development, and analyse adherence to our PAP protocol. MATERIALS AND METHODS: Epidemiological, clinical, and microbiological data were collected in consecutive NSMBT procedures performed in paediatric patients (<18 years) in our centre (2010-2019). RESULTS: 113 procedures in 37 patients, median age 4 years (IQR 1-8), were included. Main underlying diseases were biliary atresia (32%) and cancer (14%). Sixty-eight percent had undergone liver transplant and 70% hepaticojejunostomy. In 44 procedures (39%), the intervention was performed during the course of infection and previously prescribed antibiotic treatment was maintained. In the other 69, PAP was specifically indicated for NSMBT; antibiotic adequacy increased from 35% to 100% after June 2017. In total, 32 NSMBT-related infections (28%) occurred, mainly in the first 24h post-procedure (72%); no deaths happened. Causative pathogens were Gram-negative rods (64%), Gram-positive cocci (28%), and Candida spp. (8%). Main related risk factors were hepaticojejunostomy, biliary obstruction, and liver transplant. CONCLUSIONS: NSMBT in children entails a significant infection risk, even under antibiotic prophylaxis, being hepaticojejunostomy the main risk factor. Infectious complications mainly occurred immediately after the procedure. After establishing a PAP protocol, 100% of interventions received appropriate prophylaxis, decreasing antibiotic exposure time and potentially, the length of hospital stay.

Successful Treatment with Rituximab and Immunoadsorption for an Auto-Antibody Induced Bile Salt Export Pump Deficiency in a Liver Transplanted Patient.

We present an 8 years old girl who was diagnosed at 6 months of age of Progressive Familial Intrahepatic Cholestasis type 2. Although liver transplantation (LT) was classically considered curative for these patients, cholestasis recurrence with normal gamma-glutamyl transpeptidase (GGT), mediated by anti-bile salt export pump (BSEP) antibodies after LT (auto-antibody Induced BSEP Deficiency, AIBD) has been recently reported. Our patient underwent LT at 14 months. During her evolution, patient presented three episodes of acute rejection. Seven years after the LT, the patient presented pruritus with cholestasis and elevation of liver enzymes with persistent normal GGT. Liver biopsy showed intrahepatic cholestasis and giant-cell transformation with very low BSEP activity. Auto-antibodies against BSEP were detected therefore an AIBD was diagnosed. She was treated with Rituximab and immunoadsorption with resolution of the AIBD. As a complication of the treatment she developed a pneumocystis infection successfully treated with corticoids, cotrimoxazol and anidulafungin.

Transition to Adult Care for Pediatric Liver Transplant Recipients.

In recent years a growing number of pediatric liver transplant recipients are reaching adulthood and are transferred to an adult team. Because pediatric to adult transition has become a common event with many particularities, specific clinical protocols are needed to guide professionals in this process. Transition must be seen as a complex process of high vulnerability for the patient. The incorrect assumption that the transition process is only a bureaucratic transfer of information leads to inappropriate transition procedures that result in young patients not ready to move to adult units with guaranteed success. To ensure this success, a correct coordination and transmission of the information, accompaniment by the health professional during the whole process, and the empowerment of the patient are required. To have a successful transition, a person within the pediatric team must be in charge of the process (named worker).

[Ledipasvir/sofosbuvir combination for chronic hepatitis C infection in children and adolescents]. / Combinación de ledipasvir/sofosbuvir como tratamiento de la infección crónica por hepatitis C.

INTRODUCTION: Hepatitis C virus infection is world health problem. The aim of this study was to assess the safety and efficacy of ledipasvir/sofosbuvir combination in chronic Hepatitis C Virus (HCV) genotype 1 and 4 infection in paediatric patients. METHODS: Eligible patients to be treated with ledipasvir/sofosbuvir were patients from 6 to 18 years old with a chronic HCV genotype 1 or 4 infection. The duration and doses of antiviral drugs were changed depending on patient age, fibrosis stage, and PEGylated interferon+ribavirin experience status. The primary efficacy endpoint was the percentage of patients with a sustained virological response 12 weeks post-treatment. RESULTS: A total of nine patients (7 males) with a median age of 14.8 years (8.48-17.91) were treated with ledipasvir/sofosbuvir combination. Five patients received previous treatment with PEGylated interferon+ribavirin during a median of 8.5 months (3-12 months). Eight patients had some degree of fibrosis (1 patient presented with F1, three patients F2, 2 patients F3, and 2 patients F4). The median pre-treatment viral load was 6.2 Log [5.9-6.8] with the HCV RNA becoming negative six weeks after starting the treatment in 100% of the patients. All patients maintained a sustained viral response at 12 weeks. Three patients (33.3%) had some type of adverse effect (2 headache and one oral thrush). The median post-treatment follow-up was 24 weeks (12-104). CONCLUSIONS: Treatment with ledipasvir/sofosbuvir in paediatric patients with chronic HCV infection genotype 1 and 4 is safe and effective with SVR12 and similar to those reported in adults.

[Probiotic associations in the prevention of necrotising enterocolitis and the reduction of late-onset sepsis and neonatal mortality in preterm infants under 1,500g: A systematic review]. / Asociaciones de probióticos para la prevención de la enterocolitis necrosante y la reducción de la sepsis tardía y la mortalidad neonatal en recién nacidos pretérmino de menos de 1.500g: una revisión sistemática.

INTRODUCTION AND OBJECTIVE: Necrotising enterocolitis (NEC) is one of the most common and serious acquired bowel diseases a premature newborn can face. This meta-analysis was performed comparing different probiotic mixtures to ascertain their benefits as a routine tool for preventing necrotising enterocolitis and reducing late-onset sepsis and mortality in premature neonates of less than 1500g. MATERIAL AND METHODS: A systematic review of randomised controlled trials, between January 1980 and March 2014, on MEDLINE, the Cochrane Central Register of Controlled Trials, together with EMBASE, was carried out. Studies with infants <1500g or <34 weeks were selected, discarding those with Jadad scores lower than 4. RESULTS: 9 studies were selected for further investigation, pooling a total of 3521 newborns. Probiotics were found to reduce the NEC incidence (RR 0.39; 95%CI: 0.26-0.57) and mortality (RR 0.70; 95%CI: 0.52-0.93), with no difference to placebo regarding late-onset sepsis (RR 0.91; 95%CI: 0.78-1.06). Finally, when analysing the different strands, the use of a 2-probiotic combination (Lactobacillus acidophilus with Bifidobacterium bifidum) proved to be statistically significant in reducing all-cause mortality when compared to other probiotic combinations (RR 0.32; 95%CI: 0.15-0.66, NNT 20; 95%CI: 12-50). CONCLUSIONS: Probiotics are a beneficial tool in the prevention of NEC and mortality in preterm neonates. Moreover, the combination of 2 probiotics (Lactobacillus acidophilus with Bifidobacterium bifidum) seems to produce the greatest benefits. However, due to the differences in probiotic components and administration, it would be wise to perform a randomised controlled trial comparing different probiotic mixtures.