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<div><p>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.</p></div>