Shan Shan, Ji-Dong Jia

Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing 10 0 050, China

On April 6, 2022, the United Kingdom Health Security Agency(UKHSA) released an alert on cases of hepatitis of unknown etiology in children[1].On April 15, 2022, World Health Organization(WHO) published the first notice of this condition[2].

Later on, similar cases were reported from the UK, other European countries, and other parts of the world.Consequently, the European Center for Disease Prevention and Control (ECDC), the United States (US) Center for Disease Control and Prevention (CDC)and WHO have issued and updated alerts and provided working case definitions of severe acute hepatitis of unknown etiology in children[3–6].

As per ECDC notification, as of May 19, 2022, approximately 614 cases have been reported worldwide, including 176 cases from the UK, 125 from 14 European Union/European Economic Area countries, 180 from the United States, and at least 119 from other countries (9 in Argentina, 44 in Brazil, 11 in Canada, 2 in Costa Rica, 14 in Indonesia, 12 in Israel, 12 in Japan, 11 in Panama, 1 in Palestine, 1 in Serbia, 1 in Singapore, and 1 in Korea), with 14 of them dying[5].

Limited data published in peer-reviewed journals or the official websites of the national or international health organizations demonstrated the following clinical pictures [4,5,7-9].Most of the cases were under 16 years old.The majority of them presented with gastrointestinal symptoms including abdominal pain,diarrhea, and vomiting, with only a few of them having respiratory symptoms or fever.Laboratory tests revealed marked elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (greater than 500 IU/L) and bilirubin, with some cases having aminotransferase over 20 0 0 IU/L[9].A higher proportion of the patients have developed acute liver failure or even required liver transplantation[3].Check-up for the regular etiology of acute hepatitis including hepatitis viruses A through E was not positive in any of these cases.Notably, in cases of England and Scotland,75.5% and 50.0% were tested positive for adenovirus, respectively;subtyping of 11 cases from the UK investigation found that these were all type 41F, which was the same subtype identified among several cases reported from the US.In addition, around 16% of the patients were positive for SARS-CoV-2, and 4.9% were positive for both adenovirus and SARS-CoV-2[10].Epidemiological information generally yielded no hint of case clustering.None of the patients had a history of COVID-19 vaccination.

Currently, the etiology is not established but the hypotheses focus on adenovirus, especially type 41F.In line with this hypothesis is the fact that adenovirus DNA has been detected in most of the patients.Further support to this notion is that severe acute hepatitis due to adenovirus does occur in immunocompetent infants and adults although it occurs mostly in immunocompromised hosts [11,12].It could be a newhepatotropic variant causing more severe clinical manifestations, or a common variant causing more severe manifestations in children who are adenovirus-na?ve due to being restricted from social contact during the epidemics of COVID-19[9].

However, the hypothesis of adenovirus infection has been challenged by the following points.

Firstly, it still needs to make certain that the increasing number of reported cases worldwide truly reflects a real increase in such cases.Actually, acute hepatitis or acute liver failure of unknown etiology in both children and adults has been well reported in previous literature [13,14].Two recent multi-national surveys showed that there was no remarkable increase in the number of such cases when compared with the previous 3-5 years in most of the responded European centers [15,16].Therefore, the possibility still needs exclusion that the increased case number would be due to increased awareness and effort for case-finding and notification.

Secondly, the positive rate of adenovirus in children with severe acute hepatitis has not been directly compared with age-matched children living in the same region and with similar hygiene conditions.Indeed, compared to positive tests in previous years there is a marked recent exceedance in adenovirus detections in fecal samples among children aged 1-4 years in the UK[7].

Thirdly, adenoviruses are common pathogens that usually lead to self-limited infections mainly causing acute febrile respiratory disease, gastroenteritis, or conjunctivitis in immunocompetent children and adults.Specifically, adenovirus type 41F typically causes diarrhea, vomiting, fever, as well as respiratory symptoms, and does not cause hepatitis in immunocompetent subjects[6].

Fourthly, limited data on the cases of severe acute hepatitis in children showed that the viral load was generally lowin the circu-lation and that adenovirus has not been detected in the liver tissue[17].Therefore, adenovirus might be a coincidental bystander rather than a real offender.

Hypotheses related to side effects from the COVID-19 vaccines can be excluded since most of the children with severe acute hepatitis had no history of COVID-19 vaccination.Therefore, other biological, toxicological, or environmental factors need to be fully elucidated[3].The role of SARS-CoV-2 alone or in conjunction with adenovirus infection still needs further clarification.Although SARS-CoV-2 usually causes mild liver injury, severe acute hepatitis or even liver failure did occur in children with COVID-19[18].Indeed, some of the reported cases had evidence of recent or ongoing SARS-CoV-2 infection, although fever and respiratory symptoms were generally lacking.An interesting hypothesis recently proposed by Brodin and Arditi is that SARS-CoV-2 superantigen induced augmented nonspecific response to adenovirus[19].In brief,in children previously infected by SARS-CoV-2 and carrying viral reservoirs, the superantigen motif within the SARS-CoV-2 spike protein mediates a persistent, broad, and nonspecific immune activation, which would lead to a strong immune response to intestinal trophic adenovirus, thereby releasing interferon-gamma and inducing hepatocyte apoptosis[20].However, this hypothesis needs to be proven by solid clinical and immunological evidence.

In summary, it is still premature to say whether adenovirus is a guilty offender or just an innocent bystander.In the clinical encounter of children presenting acutely with gastrointestinal symptoms and jaundice or elevated aminotransferase, a careful history and routine check-up for conventional hepatotropic and non-hepatotropic viruses (especially adenovirus) is highly recommended.Prompt supportive therapy and close monitoring of biochemical, hematological, and immunological/inflammatory biomarkers, would be highly valuable.If the etiology is still undetermined, the physicians should collect and properly store the blood, urine, feces, respiratory samples, and liver tissue if available,for further investigation.Finally, promptly notify such cases to the public health authorities following the local and national regulatory requirements.

Acknowledgments

None.

CRediT authorship contribution statement

Shan Shan:Writing –original draft.Ji-Dong Jia:Conceptualization, Funding acquisition, Supervision, Writing –review & editing.

Funding

This study was supported by a grant from the National Natural Science Foundation of China (820 0 0569).

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.