Chronic hepatitis B virus (HBV) infection in children remains a dynamic condition with an incompletely defined natural history. We conducted a multicenter, retrospective cohort study across six Italian paediatric centers to characterize disease progression, evaluate the applicability of adult-derived classification systems, and identify predictors of HBeAg seroconversion. Children aged 0-18 years with chronic HBV diagnosed between January 2006 and August 2024 were included. The primary outcome was spontaneous HBeAg seroconversion, while secondary outcomes included the applicability of the 2017 EASL phase classification and the characterization of children requiring antiviral therapy. Of 248 children included, 45% were unclassifiable by 2017 EASL criteria at baseline. HBeAg seroconversion occurred in 129 children (52%): 34 (26%) were HBeAg-negative at baseline and 95 (74%) seroconverted during follow-up. Higher baseline ALT levels were significantly associated with seroconversion (p < 0.001), whereas HBV DNA levels were not. Seroconversion was less frequent among children of Asian origin (p < 0.001). Fourteen children (6%) received antiviral therapy with 50% achieving seroconversion; all treatments were well tolerated. Applying 2024 WHO guidelines retrospectively, 81 children (33%) would have met treatment criteria. Despite this, most children were not treated, reflecting a cautious clinical approach that may be justified by the high rates of spontaneous viral control. These findings underscore the limitations of adult-derived classification systems in paediatric populations and highlight the need for paediatric-specific management frameworks and prospective studies to optimize treatment strategies.

Hepatitis B virus (HBV) infection remains a global health challenge, with more than 250 million people chronically infected worldwide and >2000 daily deaths from HBV-related disease. Early-life acquisition is the primary driver of chronic infection; up to 90% of infants infected perinatally progress to chronic HBV infection compared with markedly lower rates in older children and adults. Universal infant immunization, including the birth-dose, has been central to global elimination, resulting in a substantial reduction in chronic HBV infection, cirrhosis, and hepatocellular carcinoma. Recent statements from the Centers for Disease Control and Prevention question the evidence-base for early-life vaccination and recommend deferring HBV immunization until later in childhood. These claims reflect misconceptions about HBV epidemiology and reference a perceived association between infant vaccination and autism. This communication summarizes evidence demonstrating the risks of early-life HBV transmission leading to chronic infection. We argue that delaying or foregoing immunization would leave infants at unnecessary risk. We reference two decades of research in which large-scale studies have not identified an association between vaccination, including HBV vaccination, and autism.

Importance:Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children, imposing a substantial burden on health care systems. Nirsevimab, a long-acting monoclonal antibody, has shown high efficacy in clinical trials, and modeling studies suggest it may be cost-effective; however, real-world evidence on its cost-effectiveness in European health care settings remains limited. Objective:To evaluate the real-world cost-effectiveness of nirsevimab immunization in preventing pediatric hospitalizations due to RSV. Design, Setting, and Participants:This multicenter, observational, real-world cost-effectiveness analysis was conducted between October 1, 2022, and March 31, 2025. Precampaign data were modeled using Poisson regression models to estimate expected hospitalizations in the absence of immunization. Data were gathered from 19 pediatric hospitals distributed across 11 Italian regions, from northern to southern areas. Included were all pediatric hospitalizations with RSV-specific International Classification of Diseases, Ninth Revision, Clinical Modification discharge diagnoses recorded at participating hospitals between October 1, 2022, and March 31, 2025. Exposures:Regional nirsevimab immunization campaigns with varying start dates and eligibility criteria, implemented between October 2024 and January 2025. Main Outcomes and Measures:Effectiveness, expressed as hospitalizations averted (ΔE), and incremental costs (ΔC) were estimated from the Italian National Health Service perspective. Cost-effectiveness ratios (CERs = ΔC/ΔE) were calculated for each center. Results:During the 2024 to 2025 season, 5924 RSV-related hospitalizations were recorded in children 18 years and younger across 19 centers. Observed admissions were consistently lower than model-based counterfactual predictions in most centers. Immunization averted between 6 and 151 admissions per center, corresponding to a rate of 83 and 1162 per 100 000 children. Incremental costs were negative in most centers, indicating cost savings ranging from -€10 924 (US $12 562.60) to -€266 954 (US $306 997.10) per center. Corresponding cost-effectiveness ratios were negative (-€1071 [US $1231.65] and -€1682 [(US $1934.30]), reflecting a cost-saving intervention. In 2 centers with late initiation and restricted eligibility, immunization was associated with higher costs relative to the number of hospitalizations prevented, with incremental costs of €19 715 (US $22 672.25) and €81 454 (US $93 672.10). Sensitivity analyses confirmed the robustness of results. Conclusions and Relevance:Results of this Italian multicenter, real-world economic evaluation suggest that nirsevimab immunization was both clinically effective and cost saving from a health system perspective. Timing and eligibility of immunization strongly influenced cost-effectiveness, highlighting the importance of early and broad rollout strategies to maximize clinical and economic benefits.

OBJECTIVES:To describe paediatric RSV-hospitalisation trends over six seasons and changes following regional nirsevimab strategies in Italy. METHODS:A Retrospective study across 19 Italian paediatric units was conducted analysing RSV-related hospitalisations in patients aged <18 years from January 2019 to March 2025. Centres were grouped by regional nirsevimab eligibility criteria (Groups A-G). Group-level ratios of 2024-2025 to pre-immunisation hospitalisations were estimated with a negative-binomial model. Influenza was analysed as a negative control RESULTS: 10,915 RSV hospitalisations were recorded. In 2024-2025 RSV season, hospitalisations decreased 43.6% overall. The largest reductions were in groups with broader eligibility and earlier initiation (Group B: ratio 0.28, 95% CI 0.22-0.36; Group A: 0.40, 95% CI 0.22-0.74) and Group F (0.24; single centre, interval indicative). Groups C, D, and E showed more modest reductions (ratios 0.58-0.70), with Group C spanning unity (0.58, 95% CI 0.27-1.25). Group G showed no clear change once baseline instability was accounted for (1.84, 95% CI 1.15-2.94). CONCLUSIONS:These population-level study describe a temporal association between the 2024-2025 nirsevimab rollout and reduced RSV hospitalisations, particularly with broader eligibility and timely rollout. The study design cannot establish causation or compare the effectiveness of regional strategies.

OBJECTIVES:The hepatology committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to provide education on key aspects of paediatric hepatology. Here we provide recent developments in the understanding, diagnosis and clinical consequences of portal hypertension (PHT) in children and young people, an area in which evidence remains scarce and fragmented. METHODS:In 2024, an EPSGHAN 3-day monothematic conference on paediatric PHT, held in Dublin (Ireland), brought together international experts in PHT. The first sessions of the conference were dedicated to PHT classification, pathophysiology, epidemiology, diagnostic dilemmas and major complications. Lectures have been integrated to provide an up-to-date overview of clinical practice. RESULTS:Opening sessions addressed the definition and classification of paediatric PHT, highlighting key differences between cirrhotic and non-cirrhotic causes. Advances in diagnostic imaging, the role of non-invasive tests and biopsy limitations are reviewed. Subsequent discussions focused on the mechanisms and management of major complications, including renal impairment, encephalopathy, cardiopulmonary dysfunction and endocrine consequences. Nutritional challenges and the interaction between PHT and gut-liver axis were emphasised as possible determinants of outcomes. CONCLUSIONS:This report summarises the key learning points of the first part of the meeting. These discussions set the foundation for defining research priorities and improving early recognition and multidisciplinary care strategies.

OBJECTIVES:To describe national patterns of management, outcomes, and prognostic factors in infants with biliary atresia (BA) in Italy. METHODS:This retrospective study used data from the Italian BA Registry from January 2012 to December 2021. Overall, 309 infants with BA were identified. Clearance of jaundice (CoJ) was defined as total bilirubin <1.2 mg/dL within 6 months. Univariate and multivariate analyses were used to identify prognostic factors for native liver and patient survival. RESULTS:Kasai portoenterostomy (KPE) was performed in 272 infants (88%) at a median age of 68.5 days (interquartile range 52-83). The CoJ rate after KPE was 39%. Multivariate analysis confirmed that CoJ was significantly associated with younger age and lower total bilirubin at referral (p = 0.0446 and p = 0.0144, respectively), younger age at KPE (p = 0.0345), and postoperative corticosteroid use (p = 0.0036). Multiple logistic regression confirmed the major effect of steroid use: the odds ratio for steroid use was 2.51 (95% confidence interval 1.38-4.58; p = 0.0027), whereas the odds ratio for age at KPE was 0.987 (95% CI: 0.975-0.999; p = 0.0371). Liver transplantation was performed in 212/309 patients, and overall 5-year actuarial patient survival was 97.4%. CONCLUSIONS:This retrospective analysis confirms that age at KPE and postoperative corticosteroid use are key favorable factors for successful CoJ, with steroid use showing the strongest association. The excellent overall patient survival highlights the critical role of management in expert centers, even within a decentralized model.

PURPOSE:Elevated transaminases have been associated with increased severity in adult influenza cases, but data in the pediatric population are limited. This study aims to evaluate the prevalence, clinical characteristics and prognostic value of elevated transaminases in children hospitalized for influenza. METHODS:A multicentre retrospective cohort study was conducted on 543 children hospitalized for acute viral respiratory infections. Demographic, clinical, biochemical, radiological features, and outcome were collected and analyzed, comparing children with influenza to those with other respiratory viruses. The association between elevated transaminases and clinical severity, complications, and intensive care unit (ICU) admission was assessed. RESULTS:Among 543 children, 127 (23.4%) had laboratory-confirmed influenza, with 24.4% showing elevated transaminases versus 7.2% in noninfluenza infections (p < 0.001). Influenza B was associated with a higher prevalence of hypertransaminasemia (40%) than influenza A (20.6%, p = 0.042). Asthenia, myalgia, and hypovolemic shock were more common in the elevated transaminase group (p < 0.05). Biochemical markers indicated muscular rather than hepatic origin of hypertransaminasemia. Elevated transaminases correlated with length of hospital stay (10.2 vs. 5.8 days, p < 0.001), ICU admission (OR 4.4, p = 0.035), high-flow oxygen need (OR 4.6, p = 0.005), and intravenous fluids (OR 6.2, p = 0.001). Two deaths occurred, both in the elevated transaminase group. CONCLUSION:Elevated transaminases occur in one fourth of children hospitalized for influenza and are associated with more severe disease, systemic complications, and worse outcomes. The findings suggest that transaminase elevation reflects systemic and muscular involvement rather than primary liver injury. Monitoring transaminases provides an early, easy marker to identify children at risk of severe influenza.

Leniolisib, a selective phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, is approved in several countries for the treatment of activated PI3Kδ syndrome (APDS) in patients 12 years of age and older. We report the first successful compassionate use of leniolisib in another inborn error of immunity, protein kinase C δ deficiency. In addition to infectious complications, the 14-year-old patient experienced lymphoproliferation in the form of splenomegaly, lymphadenopathy, and thymic hyperplasia; trilineage cytopenia; multiple forms of autoimmunity; and interstitial lung disease. Decision to initiate treatment with leniolisib was based on multiorgan-disease progression, lack of therapeutic alternatives, molecular evidence, overlap with APDS manifestations, and mammalian target of rapamycin hyperactivity. We observed improvement in lymphoproliferation, cytopenias, hepatic cytolysis, skin manifestations, pulmonary function, favorable changes in immunophenotypes, and no known drug-related adverse events. This experience supports expanding Leniolisib’s potential indications to appropriately selected patients and conditions. Broader repurposing strategies for targeted therapies in diseases involving dysregulated PI3K signaling should be systematically evaluated in clinical trials.

OBJECTIVE:To summarise current evidence and expert perspectives on the management of paediatric portal hypertension, primarily focusing on portal hypertensive varices and gastrointestinal bleeding in children, as discussed during the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) monothematic conference meeting on portal hypertension. METHODS:In 2024, an EPSGHAN 3-day monothematic conference on paediatric portal hypertension was held in Dublin (Ireland), gathering international experts in portal hypertension. The second part of the meeting focused on clinical algorithms for acute variceal bleeding, minimally invasive radiological treatments, surgical shunts, and indications for liver transplantation. Additional sessions examined methodological constraints affecting paediatric clinical trials, supported by case-based discussions and expert panel debates. RESULTS:Faculty outlined updated approaches to emergency management for upper gastrointestinal bleeding, including stabilisation, pharmacotherapy and endoscopy treatment. Minimally invasive radiological procedures and surgical treatments were reviewed. Sessions highlighted indications for transplantation and management of post-transplant portal vein thrombosis. Presentations on registries underscored their value in rare diseases. The final session detailed the statistical, ethical and logistical challenges inherent in paediatric clinical trials and specific challenges in portal hypertension trials. CONCLUSIONS:Current management strategies across medical, endoscopic, radiological and surgical fields were reviewed, recognising the scarcity of paediatric-specific evidence. Enhanced collaboration, harmonised registries, and standardised study designs were identified as vital next steps towards optimising outcomes in children with portal hypertension.

BACKGROUND Chronic hepatitis B (CHB) is a significant public health problem. Most of the global burden of CHB is due to mother-to-child transmission, since perinatal infections lead to a high rate of chronicity. Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) in CHB happens at a rate of 1% per year. Treatment options for CHB in children are available starting at 1 year of age. Current paediatric guidelines recommend treating children with hepatitis B envelope antigen (HBeAg) positive hepatitis with elevated serum transaminases levels for at least 6 months. Treatment is not indicated for children with HBeAg positive infection and normal transaminases. In 2024, the World Health Organization unified criteria for initiating antiviral treatment in children older than 12 years and in adults. Recent, preliminary evidence showed that antiviral therapy in infants and children younger than 2 years to 3 years of age with CHB infection led to higher rates of HBsAg loss than in adults and older children. AIM To evaluate the available evidence about treatment of CHB in young children and discuss the potential impact of early treatment. METHODS We searched the literature to identify studies reporting cases of HBsAg loss in children treated with antiviral drugs. We included only studies in which treatment-naïve patients started treatment before 2 years of age. RESULTS We identified 6 studies reporting results of CHB treatment, particularly HBsAg loss rates, hepatitis B virus DNA undetectability, and HBeAg loss. CONCLUSION Studies conducted on young children showed a higher HBsAg loss rate compared to those reached in older children and adults, offering new perspectives on the treatment of CHB. Further studies are needed to assess the effect of early treatment in larger populations and over a longer follow-up period.

ABSTRACT Background and Aim Alagille syndrome (ALGS) is a rare disorder characterised by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, we evaluated whether SBA predicts liver disease outcomes in ALGS. Methods Patients were ascertained from the G lobal AL agille A lliance (GALA) cohort. A prognostic threshold of SBA 102 μmol/L was assessed as a time‐dependent covariate in Cox regression analyses for native liver survival (NLS) and event‐free survival (EFS), while adjusting for total bilirubin (TB) levels. Results 570 GALA patients were included (348 [61%] male). There was a moderate positive correlation between SBA and TB (Pearson correlation = 0.47, p < 0.001). SBA below 102 μmol/L was a significant predictor of outcomes (NLS: HR = 3.78, 95% CI 2.39–5.99, p < 0.001; EFS: HR = 3.44, 95% CI 2.35–5.04, p < 0.001). SBA remained a significant predictor for improved EFS after adjusting for TB clearance at 1 year (TB < 2 mg/dL; HR = 2.00, 95% CI 1.10–3.65, p = 0.02). Median SBA in the first year of life above 102 μmol/L, predicted lower NLS (67.2% vs. 83.5% at 7 years p = 0.05) and EFS (63.4% vs. 80.9% at 7 years, p = 0.02). Conclusion Lower SBA in children with ALGS liver disease predicts improved NLS and EFS. SBA is also associated with NLS in children with ALGS who clear their bilirubin, that is, those with anicteric cholestasis. Although the patients studied here did not receive IBAT inhibition, these data suggest that lowering SBA may improve important clinical outcomes.