Hypothesis that hepatitis of unknown cause in children is caused by adeno-associated virus type 2
I would like to state the hypothesis that acute hepatitis of unknown cause in children is caused by adeno-associated virus type 2.
Gastrointestinal symptoms such as diarrhea and nausea were commonly reported prior to admission, which is consistent with the typical clinical presentation of type41 infection, an intestinal adenovirus [1,2]. Adenovirus DNA levels in blood and serum have been noted to be approximately 12 times higher in liver transplant recipients than in non-transplant recipients. Normally, however, adenoviruses do not cause hepatitis in children with healthy immunity. In immunodeficiency, some serotypes of adenovirus have been reported to cause hepatitis, but even then, serotype 41 is not common. In the case of adenovirus, there is a "threshold effect" that prevents the virus from reaching the hepatocyte unless adenovirus capture by liver Kupffer cells is saturated. Therefore, a small amount of adenovirus in the blood does not easily infect hepatocytes, and if it does, there should be at least a finding that the Kupffer cells are saturated with adenovirus. However, liver biopsies from six U.S. patients showed no immunohistochemical evidence of adenovirus and no electron microscopic evidence of viral particles. Therefore, it is unlikely that the adenovirus is infecting the hepatocytes and causing hepatitis.
On the other hand, metagenomic analyses of blood and liver tissue have detected large amounts of adeno-associated virus type 2 (AAV-2) . Adeno-associated virus (AAV) is used as a vector for gene therapy targeting hepatocytes and has the property of reaching hepatocytes efficiently. AAVs are generally considered non-pathogenic, but in a high-dose gene therapy trial with the AAV type 8 vector, two patients died due to progressive liver dysfunction. Temporary liver inflammation and transient elevation of liver enzymes following intravenous administration of AAV-2 are reported.
Possible mechanisms of hepatotoxicity following high-dose intravenous administration of AAV may point to complement activation. It is possible that inadequate immunity to AAV-2 or large amounts of AAV-2 can cause liver dysfunction. Since AAV is a virus that can multiply only in the presence of helper viruses such as adenovirus, it is reasonable to assume that AAV-2, detected in large quantities in blood and liver, multiplied as a result of adenovirus type 41 infection.
Adenovirus type 41 is transmitted through the fecal-oral route. Countries where hepatitis of unknown origin in children is seen tend to be those with good sanitary conditions, such as Europe, the United States, and Japan. Prevalence of serum neutralizing antibodies to adenovirus type 41 in Chinese children is associated with age and sanitary conditions. The younger the age and the better the sanitary conditions, the lower the prevalence. The difference in adenovirus 41 neutralizing antibody titers diminished in children over 3 years of age. These results indicate that childhood sanitary conditions is an important factor affecting adenovirus 41 neutralizing antibody titers. Neutralizing antibodies Prevalence of AAV-2 in adults is also low in the United States (30%) and Europe (about 35%), where sanitary conditions are considered good, and as high as 70% in Africa . Positive rates of neutralizing antibodies to AAV-2 have also been reported to increase with age[11,12].
A possible link between waned immunity to respiratory syncytial virus in the COVID-19 pandemic and the interseasonal re-emergence of RSV cases seen worldwide has been raised. . In countries with good sanitation, the proportion of children with low immunity to adenovirus and AAV-2 was originally high and may have been further exacerbated by the measures taken against COVID-19. If an outbreak of adenovirus 41 and AAV-2 were to occur among such children, it is possible that some children would develop hepatitis.
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Competing interests: No competing interests