Hepatitis of unknown etiology in children: Current evidence and association

Table 1 Possible causes of acute hepatitis of unknown etiology in children

Etiological speculation	Possible causes	Ref.
Association with adenovirus infection
Adenovirus infection	Adenovirus was detected by PCR in 209 (20.7%) patients with AHUCD.	World Health Organization[4]
Adenovirus mutation	Adenoviruses generate new viruses exhibiting various tissue tropism and increased virulence through molecular mutations of homologous recombination.	Tian X et al[22]
Secondary adenovirus infection "superantigen hypothesis"	Viral reservoirs emerge in the intestine after COVID-19 infection, followed by adenovirus infection, which triggers aberrant host immune-mediated hepatitis.	Brodin P et al[20]
Association with COVID-19 infection
COVID-19 infection	SARS-CoV-2-specific CD4+ and CD8+ memory T cells can be detected not only in patients recovering from COVID-19, but also in close contacts. Memory T-cell response after close contact with SARS-CoV-2 infection. During reinfection with SARS-CoV-2, a dysregulated immune response leads to rapid liver damage and acute liver failure.	Wang Z et al[26]; Zhu M et al[27]
Secondary multisystem inflammatory syndrome in children	Hepatitis is common in children with multisystem inflammatory syndrome, and MIS-C appears after COVID-19 infection, resulting in liver sequelae.	Cantor A et al[25]; Yasuhara J et al[21]
Pathogen exposure reduction	Children are not exposed to the viruses that children are generally exposed to; therefore, when they are first exposed to these viruses, it has an unexpected and serious impact.	Samarasekera U[28]
Association with vaccination against COVID-19	Vaccination against COVID-19 induces antigen-specific immune responses in children.	Sergi CM[29]
Adenovirus and SARS-CoV-2 co-infection
Co-infection ofadenovirus and SARS-CoV-2 or other pathogens	Adenovirus-associated hepatitis mainly occurs in immunosuppressed patients. Co-infection with adenovirus and SARS-CoV-2 or other pathogens leads to immune dysfunction, increasing the likelihood of adenovirus-associated hepatitis infection.	Lion T[18]; Li L et al[19]; Mendez-Sanchez N et al[9]

AHUCD: Acute hepatitis of unknown etiology in children; MIS-C: Multi-system inflammatory syndrome in children; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PCR: Polymerase chain reaction.