Acute hepatitis of unknown origin in children is currently being
reported around the world, especially in Europe and the United States.
Of the 163 cases in the UK outbreak, 126 were tested for adenovirus, 91
were detected, and 18 of the 33 cases with adenovirus in the blood were
successfully subtyped, all of which were type 41, a well-known cause of
acute gastroenteritis in children[1].
In the United Kingdom, positive adenovirus test reports in children aged
1-4 years decreased in the year beginning April 2020 compared to the
previous 5 years, but have increased significantly since November 2021
compared to the previous 5 years[1]. The timing of this increase
coincides with the occurrence of acute hepatitis of unknown origin. An
increase in adenovirus circulation in the community has also been
reported in the Netherlands recently [2]. Gastrointestinal symptoms
such as diarrhea and nausea were commonly reported prior to admission,
which is consistent with the typical clinical presentation of type 41
infection, an intestinal adenovirus [1,3].
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[4].
Normally, however, adenoviruses do not cause hepatitis in children with
healthy immunity[1]. In immunodeficiency, some serotypes of
adenovirus have been reported to cause hepatitis, but even then,
serotype 41 is not common[5].
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[6]. Therefore, a small amount of
adenovirus in the blood does not readily 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[3]. 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) [1].
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[7].
Temporary liver inflammation and transient elevation of liver enzymes
following intravenous administration of AAV-2 are reported[8].
Possible mechanisms of hepatotoxicity following high-dose intravenous
administration of AAV may point to complement activation[9].
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[10]. 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[10]. 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 [11]. Positive rates of neutralizing
antibodies to AAV-2 have also been reported to increase with
age[12,13].
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. [14].
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.
Adenovirus and AAV are non-enveloped viruses, and alcohol disinfection
is less effective. Considering the above possibilities, it would be
appropriate for facilities where children congregate to use
disinfectants effective against non-enveloped viruses, such as
hypochlorous acid, and to increase the frequency of hand washing under
running water, as a precautionary principle. Also, as was the case with
the re-emergence of RSV cases seen worldwide, if this hepatitis in
children were caused by the above, the epidemic could form a peak and
converge in 2-3 months. Closure of child care facilities for short
periods of time during the most prevalent epidemics may also be a
consideration. It may also be useful to investigate whether the child’s
attendance at day care centers or other facilities is a risk factor.
During lockdown, it may be advisable to investigate the prevalence of
adenovirus type 41 and AAV-2 antibodies in children, especially in
countries with good original sanitary conditions.
1. UK Health Security Agency. Investigation into acute hepatitis of
unknown aetiology in children in England Technical briefing 2. London,
United Kingdom: Department of Health and Social Care, UK Health Security
Agency; 2022.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1073704/acute-hepatitis-technical-briefing-2.pdf
2. World Health Organization. Multi-Country – acute, severe hepatitis
of unknown origin in children. Geneva, Switzerland: World Health
Organization; 2022. Accessed April 23, 2022.https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON376
3. Baker JM, Buchfellner M, Britt W, et al. Acute Hepatitis and
Adenovirus Infection Among Children - Alabama, October 2021-February
2022. MMWR Morb Mortal Wkly Rep. 2022 May 6;71(18):638-640. doi:
10.15585/mmwr.mm7118e1. PMID: 35511732.
https://www.cdc.gov/mmwr/volumes/71/wr/mm7118e1.htm
4. UK Health Security Agency. Investigation into acute hepatitis of
unknown aetiology in children in England Technical briefing. London,
United Kingdom: Department of Health and Social Care, UK Health Security
Agency; 2022.
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1071198/acute-hepatitis-technical-briefing-1_4_.pdf
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