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BACKGROUND & AIMS: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic. METHODS: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022). RESULTS: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died. CONCLUSIONS: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases. IMPACT AND IMPLICATIONS: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care.

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In medical studies, some therapeutic decisions could lead to dependent censoring for the survival outcome of interest. This is exemplified by a study of paediatric acute liver failure, where death was subject to dependent censoring due to liver transplantation. Existing methods for assessing the predictive performance of biomarkers often pose the independent censoring assumption and are thus not applicable. In this work, we propose to tackle the dependence between the failure event and dependent censoring event using auxiliary information in multiple longitudinal risk factors. We propose estimators of sensitivity, specificity and area under curve, to discern the predictive power of biomarkers for the failure event by removing the disturbance of dependent censoring. Point estimation and inferential procedures were developed by adopting the joint modelling framework. The proposed methods performed satisfactorily in extensive simulation studies. We applied them to examine the predictive value of various biomarkers and risk scores for mortality in the motivating example.

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Following the report of an excess in paediatric cases of severe acute hepatitis of unknown aetiology by the United Kingdom (UK) on 5 April 2022, 427 cases were reported from 20 countries in the World Health Organization European Region to the European Surveillance System TESSy from 1 January 2022 to 16 June 2022. Here, we analysed demographic, epidemiological, clinical and microbiological data available in TESSy. Of the reported cases, 77.3% were 5 years or younger and 53.5% had a positive test for adenovirus, 10.4% had a positive RT-PCR for SARS-CoV-2 and 10.3% were coinfected with both pathogens. Cases with adenovirus infections were significantly more likely to be admitted to intensive care or high-dependency units (OR = 2.11; 95% CI: 1.18-3.74) and transplanted (OR = 3.36; 95% CI: 1.19-9.55) than cases with a negative test result for adenovirus, but this was no longer observed when looking at this association separately between the UK and other countries. Aetiological studies are needed to ascertain if adenovirus plays a role in this possible emergence of hepatitis cases in children and, if confirmed, the mechanisms that could be involved.

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The aetiology of several liver diseases in children is age specific and many of these conditions have significant and potentially long-term clinical repercussions if not diagnosed early and managed in a timely fashion. We address 5 clinical scenarios that cover most of the diagnostic and therapeutic emergencies in children: infants with liver disease; acute liver failure; management of bleeding varices; liver-based metabolic disorders; and liver tumours and trauma. A wide spectrum of conditions that cause liver disease in infants may present as conjugated jaundice, which could be the only symptom of time-sensitive disorders - such as biliary atresia, metabolic disorders, infections, and haematological/alloimmune disorders - wherein algorithmic multistage testing is required for accurate diagnosis. In infantile cholestasis, algorithmic multistage tests are necessary for an accurate early diagnosis, while vitamin K, specific milk formulae and disease-specific medications are essential to avoid mortality and long-term morbidity. Management of paediatric acute liver failure requires co-ordination with a liver transplant centre, safe transport and detailed age-specific aetiological work-up - clinical stabilisation with appropriate supportive care is central to survival if transplantation is indicated. Gastrointestinal bleeding may present as the initial manifestation or during follow-up in patients with portal vein thrombosis or chronic liver disease and can be managed pharmacologically, or with endoscopic/radiological interventions. Liver-based inborn errors of metabolism may present as encephalopathy that needs to be recognised and treated early to avoid further neurological sequelae and death. Liver tumours and liver trauma are both rare occurrences in children and are best managed by a multidisciplinary team in a specialist centre.

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BACKGROUND: Acute liver failure (ALF) is the leading cause for emergency liver transplantation (LT) all over the world. We looked at the profile of cases who required LT for ALF from a single centre to identify the possible predictors of poor outcomes. METHODOLOGY: During the 10-year period starting from 2007, 320 cases of ALF were treated at our institution, of which 70 (median age 24 years, Male:Female 1:2) underwent LT. Retrospective analyses of these 70 patients were performed. RESULTS: Etiology was identifiable in 73% (n = 51) of cases (yellow phosphorous [YP] poisoning [n = 16], Hepatitis A virus [HAV] [n = 15], Hepatitis B virus [HBV] [n = 5], Hepatitis E virus [HEV] [n = 1], anti-tubercular therapy [ATT] induced [n = 6], acute Wilson's [n = 3], and autoimmune [n = 5]]. Upon meeting King's College Hospital criteria, 69 had live donor LT (61 right lobe grafts, three left lobe grafts, five left lateral segment grafts) and one had deceased donor LT. Among these, there were five auxiliary partial orthotopic grafts and four ABO-incompatible transplants. Overall, 90-day mortality was 35.7% (n = 25), predominantly due to sepsis. Significant risk factors for mortality on multivariate analysis included indeterminate etiology, pre-op renal dysfunction, and Grade IV hepatic encephalopathy (HE). Cumulative 10-year survival of the remaining survivors was 95.6% (n = 45). CONCLUSION: LT for ALF carries high perioperative mortality (35.7%) in those presenting with indeterminate etiology, pre-op renal dysfunction, and Grade IV HE. Nevertheless, if they survive the perioperative period, long-term survival is excellent.

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BACKGROUND & AIMS: The outcome of paediatric acute liver failure largely depends on age and aetiology. The aim of this work was to study the aetiological spectrum and outcome of the paediatric acute liver failure cases. METHODS: This prospective observational study included all children (<18 years age) fulfilling paediatric acute liver failure study group definition. Aetiological evaluation was done and predictive factors for poor outcome (death or liver transplantation) were analysed. RESULTS: There were 109 children in total. The commonest aetiology was viral infections (50, 45.8%) followed by metabolic liver diseases (14, 13.2%) and drug-induced liver injury (12, 11%). Viral, indeterminate and drug-induced liver injury group were older in age, had higher international normalized ratio and alanine transaminases in comparison with those with metabolic liver diseases and other aetiologies (P<.05). At 90 days from presentation, 52 (47.7%) children survived with native liver. On multivariate analysis, jaundice to encephalopathy interval >7 days (adjusted OR: 9.16, 95% CI: 1.55-53) and higher paediatric/model for end-stage liver disease scores at 72 hours (adjusted OR: 1.2, 95% CI: 1.08-1.32) were associated with poor outcome. CONCLUSION: Viral infections, indeterminate and drug-induced liver injury-related paediatric acute liver failure usually present in older children with higher international normalized ratio and alanine transaminases. Jaundice to encephalopathy interval >7 days and paediatric/model for end stage liver disease score >24 at 72 hours are associated with poor outcome.

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