Among the hypotheses, the leading aetiology continues to be HAdV infection, since the overall positive rate of HAdV (47.1%, 209/444) among AHUA cases reported to WHO, largely outweighs other potential aetiologies around the world [2]. For cases in England, by sample type based on the data reported, amongst 258 cases tested for adenovirus, 170 (65.9%) had adenovirus detected [5]. In a UK-wide frequency matched case–control study, multivariable regression analyses with 74 cases and 225 controls indicate that cases have statistically significant higher odds of concomitant HAdV infection compared to controls with an adjusted odds ratio of 35.27 (95% CI 15.23–81.68) [4]. Recent evidence from the UK has indicated a primary association of Adeno-associated virus 2 (AAV2) with AHUA. To present, metagenomics undertaken on blood and liver tissue has detected primarily adeno-associated virus 2 (AAV-2) [5, 6], although AAV is not currently known to cause disease. In the UK study, in 5 cases who underwent liver transplantation, high levels of AAV-2 were detected in the explanted livers. Also, in a case–control investigation of 9 Scottish children hospitalized with AHUA, AAV-2 was identified in the plasma of 9 out of 9 and liver of 4 out of 4 cases, but in 0 out of 13 sera/plasma of age-matched healthy controls, 0 out of 12 children with adenovirus infection without hepatitis and normal liver function, and 0 out of 33 children admitted with hepatitis of other aetiology. This study indicated that 8 out of 9 cases (88.9%) carried the HLA-DRB1*04:01 allele which is also detectable in four out of five liver transplant cases by the UK study.

In comparison, the frequency of HLA-DRB1*04:01 in a control Scottish population (n = 974) is 8.9%. Simultaneously, adenovirus (C or F) was found in 6 out of 9 case samples, including 3 out of 4 liver biopsies, while human herpesvirus 6B was detected in 3 out of 9 case samples, including 2 out of 4 liver biopsies, suggesting that AAV2 typically needs a co-infecting ‘helper’ virus for replication, most commonly adenovirus or a herpes virus.

Notably, HAdV may change its original tissue tropism (even the host type) and acquire stronger virulence and transmission capability after genetic recombination. The fowl adenoviruses (FAdVs), especially FAdV-4, cause inclusion body hepatitis in chickens which is characterized by hepatitis. Under the current knowledge, HAdV‑F41 has been rarely reported to cause liver injury in humans, mainly causing diarrhea, nausea, vomiting, and abdominal pain, while FAdV can cause severe liver injury in poultry or birds. Though less likely, we could not deny the potential given the clinical manifestations of these children with AHUA, that HAdV might experience new recombination from FAdV and have spread around the world. This hypothesis may be supported by a higher prevalence of HAdV (mainly F41 type) reported among children with  diarrhea in 2021 [2, 7] and reduced influence of humans on the living environment of birds due to the COVID-19 pandemic. However, it is reported that HAdV genomics is not unusual among the population in the UK, particularly among AHUA cases. Therefore, continuous investigations on the relationship between HAdV and AHUA should be maintained. Epidemological analyses based on the case–control or ecological studies should be used to explore the association of AUHA with HAdV infection.



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Acute hepatitis of unknown aetiology among children around the world | Infectious Diseases of Poverty

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