Aetiology of acute hepatitis of unknown in children, association with AAV2 and controversies.
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ABSTRACT:
SUBMITTER: Qi Y
PROVIDER: S-EPMC10425936 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
Publications
Aetiology of acute hepatitis of unknown in children, association with AAV2 and controversies.
Qi Yong Y Lu Nianhong N Chen Leru L Li Yuexi Y
JHEP reports : innovation in hepatology 20230509 9
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Project description:Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.
2023-04-04 | PXD035925 | Pride
Project description:BackgroundThe cause of acute paediatric hepatitis of unknown aetiology (2022) has not been established despite extensive investigation.ObjectiveTo summarise the evidence for and against a causal role for human adenovirus (HAdv), adeno-associated virus 2 (AAV-2) and SARS-CoV-2 in outbreaks of paediatric hepatitis in 2022.MethodsWe appraised and summarised relevant evidence for each of the Bradford Hill criteria for causality using quantitative (statistical modelling) and qualitative (narrative coherence) approaches. Each team member scored the evidence base for each criterion separately for HAdv, AAV-2 and SARS-CoV-2; differences were resolved by discussion. We additionally examined criteria of strength and temporality by examining the lagged association between SARS-CoV-2 positivity, respiratory HAdv positivity, positive faecal HAdv specimens and excess A&E attendances in 1-4 years for liver conditions in England.ResultsAssessing criteria using the published literature and our modelling: for HAdv three Bradford Hill criteria (strength, consistency and temporality) were partially met; and five criteria (consistency, coherence, experimental manipulation, analogy and temporality) were minimally met. For AAV-2, the strength of association criterion was fully met, five criteria (consistency, temporality, specificity, biological gradient and plausibility) were partially met and three (coherence, analogy and experimental manipulation) were minimally met. For SARS-CoV-2, five criteria (strength of association, plausibility, temporality, coherence and analogy) were fully met; one (consistency) was partially met and three (specificity, biological gradient and experimental manipulation) were minimally met.ConclusionBased on the Bradford Hill criteria and modelling, HAdv alone is unlikely to be the cause of the recent increase in hepatitis in children. The causal link between SARS-CoV-2, and to a lesser degree AAV-2, appears substantially stronger but remains unproven. Hepatitis is a known complication of multisystem inflammatory syndrome in children following COVID-19, and SARS-CoV-2 has been linked to increased susceptibility to infection post-COVID-19, which may suggest complex causal pathways including a possible interaction with AAV-2 infection/reactivation in hosts that are genetically susceptible or sensitised to infection.
| S-EPMC11628968 | biostudies-literature
Project description:On 5 April 2022, the United Kingdom reported an increase of cases of severe acute hepatitis of unknown aetiology in children, several needing hospitalisation and some required liver transplant or died. Thereafter, 35 countries reported probable cases, almost half of them in Europe. Facing the alert, on 28 April, Portugal created a multidisciplinary Task Force (TF) for rapid detection of probable cases and response. The experts of the TF came from various disciplines: clinicians, laboratory experts, epidemiologists, public health experts and national and international communication. Moreover, Portugal adopted the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) case definition and recommendations. By 31 December 2022, 28 probable cases of severe acute hepatitis of unknown aetiology were reported: 16 male and 17 aged under 2 years. Of these cases, 23 were hospitalised but none required liver transplant or died. Adenovirus was detected from nine of 26 tested cases. No association was observed between adenovirus infection and hospital admission after adjusting for age, sex and region in a binomial regression model. The TF in Portugal may have contributed to increase awareness among clinicians, enabling early detection and prompt management of the outbreak.
| S-EPMC10515495 | biostudies-literature
Project description:The World Health Organization has issued a global alert on Acute Severe Hepatitis of Unknown Aetiology (AS-HEP-UA) since 23 April 2022,and there was still uncertainty regarding the association of AS-HEP-UA with SARS-CoV-2 as well as adenovirus. This study aimed to summarize the infection of SARS-CoV-2 and co-infections with adenovirus, as well as clinical features and outcomes in patients with AS-HEP-UA. PubMed, Embase, Web of Science, and the Cochrane Library were searched from 1 October 2021 to 8 December 2022 for studies about patients with AS-HEP-UA. This study was registered in the PROSPERO database (CRD42023385056). We has included 14 eligible articles. The main clinical features of AS-HEP-UA were jaundice (65%) and vomiting (59%), while other clinical features included diarrhea (45%), abdominal pain (37%), and fever (31%), roughly 10% of the children required liver transplantation. The overall positivity rate for SARS-CoV-2 was 21.6% (95% CI: 0.126-0.319), with 25.5% (95% CI: 0.161-0.358) for previous infections. The positivity rate for adenovirus infection was 58.6% (95% CI:0.429-0.736) while co-infection with SARS-CoV-2 was 17.5% (95% CI: 0.049-0.342). Moreover, we found that the positive rate of SARS-CoV-2 for this hepatitis outbreak was correlated with region by subgroup analysis. In conclusion, the positive rate of adenovirus was higher than SARS-CoV-2, and the relationship between AS-Hep-UA and COVID-19 is not significant. However, it cannot be excluded that the COVID-19 epidemic is an indirect causative agent of AS-Hep-UA, which requires a larger cohort of AS-Hep-UA patients to uncover additional findings.
| S-EPMC11620374 | biostudies-literature
Project description:BackgroundAdenovirus is a known cause of hepatitis in immunocompromised children, but not in immunocompetent children. In April, 2022, following multiple reports of hepatitis of unknown aetiology and adenovirus viraemia in immunocompetent children in the USA and UK, the US Centers for Disease Control and Prevention (CDC) and jurisdictional health departments initiated national surveillance of paediatric acute hepatitis of unknown aetiology. We aimed to describe the clinical and epidemiological characteristics of children identified with hepatitis of unknown aetiology between Oct 1, 2021, and Sept 30, 2022, in the USA and to compare characteristics of those who tested positive for adenovirus with those who tested negative.MethodsIn this national surveillance investigation in the USA, children were identified for investigation if they were younger than 10 years with elevated liver transaminases (>500 U/L) who had an unknown cause for their hepatitis and onset on or after Oct 1, 2021. We reviewed medical chart abstractions, which included data on demographics, underlying health conditions, signs and symptoms of illness, laboratory results, vaccination history, radiological and liver pathology findings, diagnoses and treatment received, and outcomes. Caregiver interviews were done to obtain information on symptoms and health-care utilisation for the hepatitis illness, medical history, illness in close contacts or at school or daycare, diet, travel, and other potential exposures. Blood, stool, respiratory, and tissue specimens were evaluated according to clinician discretion and available specimens were submitted to CDC for additional laboratory testing or pathology evaluation.FindingsSurveillance identified 377 patients from 45 US jurisdictions with hepatitis of unknown aetiology with onset from Oct 1, 2021, to Sept 30, 2022. The median age of patients was 2·8 years (IQR 1·2-5·0) and 192 (51%) were male, 184 (49%) were female, and one patient had sex unknown. Only 22 (6%) patients had a notable predisposing underlying condition. 347 patients (92%) were admitted to hospital, 21 (6%) subsequently received a liver transplant, and nine (2%) died. Among the 318 patients without notable underlying conditions, 275 were tested for adenovirus. Of these 116 (42%) had at least one positive specimen, and species F type 41 was the most frequent type identified (19 [73%] of 26 typed specimens were HAdV-41). Proportions of patients who had acute liver failure, received a liver transplant, and died were similar between those who tested positive for adenovirus compared with those who tested negative. Adenovirus species F was detected by polymerase chain reaction in nine pathology liver evaluations, but not by immunohistochemistry in seven of the nine with adequate liver tissue available. Interviews with caregivers yielded no common exposures.InterpretationAdenovirus, alone or in combination with other factors, might play a potential role in acute hepatitis among immunocompetent children identified in this investigation, but the pathophysiologic mechanism of liver injury is unclear. To inform both prevention and intervention measures, more research is warranted to determine if and how adenovirus might contribute to hepatitis risk and the potential roles of other pathogens and host factors.FundingNone.
| S-EPMC11088931 | biostudies-literature
Project description:BackgroundIn spring 2022, a series of reports from the United Kingdom and the United States identified an increase in the incidence of acute severe hepatitis in children. The Public Health Agency of Canada (PHAC) collaborated with provincial/territorial health partners to investigate in Canada. Clinical hepatitis, or inflammation of the liver, is not reportable in Canada, so to determine if an increase was occurring above historical levels, the baseline incidence in Canada was estimated. This article estimates the pre-existing baseline incidence of acute severe hepatitis of unknown origin in children in Canada using administrative databases. It further summarizes the outbreak investigation using information from the national case report forms.MethodsA committee with representatives from PHAC and provincial/territorial health partners was established to investigate current cases in Canada. A national probable case definition and case report form were developed, and intentionally created to be highly sensitive to capture all potential cases for etiological investigations. To estimate a nationally representative baseline incidence, hospitalization data were extracted from the Discharge Abstract Database and was combined with data from Québec from the Ministère de la Santé et des Services sociaux.ResultsTwenty-eight probable cases of acute severe hepatitis of unknown origin in children were reported between October 1, 2021, to September 23, 2022, by six provinces: British Columbia=1; Alberta=5; Saskatchewan=1; Manitoba=3; Ontario=14; and Québec=4. The estimated national baseline incidence was an average of 70 cases annually, or 5.8 cases per month.ConclusionThere was no apparent increase above the estimated historical baseline levels.
| S-EPMC10907059 | biostudies-literature
Project description:BackgroundAn outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children during 2022 was subsequently linked to infections with adenovirus-associated virus 2 and other 'helper viruses', including human adenovirus. It is possible that evidence of such an outbreak could be identified at a population level based on routine data captured by electronic health records (EHR).MethodsWe used anonymised EHR to collate retrospective data for all emergency presentations to Oxford University Hospitals NHS Foundation Trust in the UK, between 2016-2022, for all ages from 18 months and older. We investigated clinical characteristics and temporal distribution of presentations of acute hepatitis and of adenovirus infections based on laboratory data and clinical coding. We relaxed the stringent case definition adopted during the AS-Hep-UA to identify all cases of acute hepatitis with unknown aetiology (termed AHUA). We compared events within the outbreak period (defined as 1st Oct 2021-31 Aug 2022) to the rest of our study period.ResultsOver the study period, there were 903,433 acute presentations overall, of which 391 (0.04%) were classified as AHUA. AHUA episodes had significantly higher critical care admission rates (p < 0.0001, OR = 41.7, 95% CI:26.3-65.0) and longer inpatient admissions (p < 0.0001) compared with the rest of the patient population. During the outbreak period, significantly more adults (≥ 16 years) were diagnosed with AHUA (p < 0.0001, OR = 3.01, 95% CI: 2.20-4.12), and there were significantly more human adenovirus (HadV) infections in children (p < 0.001, OR = 1.78, 95% CI:1.27-2.47). There were also more HAdV tests performed during the outbreak (p < 0.0001, OR = 1.27, 95% CI:1.17-1.37). Among 3,707 individuals who were tested for HAdV, 179 (4.8%) were positive. However, there was no evidence of more acute hepatitis or increased severity of illness in HadV-positive compared to negative cases.ConclusionsOur results highlight an increase in AHUA in adults coinciding with the period of the outbreak in children, but not linked to documented HAdV infection. Tracking changes in routinely collected clinical data through EHR could be used to support outbreak surveillance.
| S-EPMC11251388 | biostudies-literature
Project description:Hepatitis is a general term meaning inflammation of the liver, which can be caused by a variety of viruses. However, a substantial number of cases remain with unknown aetiology. We analysed the serum of patients with clinical signs of hepatitis using a metagenomics approach to characterize their viral species composition. Four pools of patients with hepatitis without identified aetiological agents were evaluated. Additionally, one pool of patients with hepatitis E (HEV) and pools of healthy volunteers were included as controls. A high diversity of anelloviruses, including novel sequences, was found in pools from patients with hepatitis of unknown aetiology. Moreover, viruses recently associated with gastroenteritis as sapovirus GV.2 and astrovirus VA3 were also detected only in those pools. Besides, most of the HEV genome was recovered from the HEV pool. Finally, GB virus C and human endogenous retrovirus were found in the HEV and healthy pools. Our study provides an overview of the virome in serum from hepatitis patients suggesting a potential role of these viruses not previously described in cases of hepatitis. However, further epidemiologic studies are necessary to confirm their contribution to the development of hepatitis.
| S-EPMC5628893 | biostudies-literature
Project description: Not available
| S-EPMC10106159 | biostudies-literature
Project description:Can you diagnose this patient with vision problems? https://bit.ly/3vGe5qy.
| S-EPMC8291921 | biostudies-literature