Intended for healthcare professionals
Rapid response to:
We process your data to deliver content or advertisements and measure the delivery of such content or advertisements to extract insights about our website. We share this information with our partners on the basis of consent and legitimate interest. You may exercise your right to consent or object to a legitimate interest, based on a specific purpose below or at a partner level in the link under each purpose. These choices will be signaled to our vendors participating in the Transparency and Consent Framework. Privacy and cookie policies
List of IAB VendorsThese cookies are necessary for the website to function and cannot be switched off in our systems. They are usually only set in response to actions made by you which amount to a request for services, such as setting your privacy preferences, logging in or filling in forms. You can set your browser to block or alert you about these cookies, but some parts of the site will not then work. These cookies do not store any personally identifiable information.
These cookies allow us to count visits and traffic sources so we can measure and improve the performance of our site. They help us to know which pages are the most and least popular and see how visitors move around the site. All information these cookies collect is aggregated and therefore anonymous. If you do not allow these cookies we will not know when you have visited our site, and will not be able to monitor its performance.
These cookies enable the website to provide enhanced functionality and personalisation. They may be set by us or by third party providers whose services we have added to our pages. If you do not allow these cookies then some or all of these services may not function properly.
These cookies may be set through our site by our advertising partners. They may be used by those companies to build a profile of your interests and show you relevant adverts on other sites. They do not store directly personal information, but are based on uniquely identifying your browser and internet device. If you do not allow these cookies, you will experience less targeted advertising.
Cookies, device identifiers, or other information can be stored or accessed on your device for the purposes presented to you.
Ads can be shown to you based on the content you’re viewing, the app you’re using, your approximate location, or your device type.
A profile can be built about you and your interests to show you personalised ads that are relevant to you.
Personalised ads can be shown to you based on a profile about you.
A profile can be built about you and your interests to show you personalised content that is relevant to you.
Personalised content can be shown to you based on a profile about you.
The performance and effectiveness of ads that you see or interact with can be measured.
The performance and effectiveness of content that you see or interact with can be measured.
Market research can be used to learn more about the audiences who visit sites/apps and view ads.
Your data can be used to improve existing systems and software, and to develop new products
Your precise geolocation data can be used in support of one or more purposes. This means your location can be accurate to within several meters.
Your device can be identified based on a scan of your device's unique combination of characteristics.
Your data can be used to monitor for and prevent fraudulent activity, and ensure systems and processes work properly and securely.
Your device can receive and send information that allows you to see and interact with ads and content.
Data from offline data sources can be combined with your online activity in support of one or more purposes
Different devices can be determined as belonging to you or your household in support of one or more of purposes.
Your device might be distinguished from other devices based on information it automatically sends, such as IP address or browser type.
Allowing third-party ad tracking and third-party ad serving through Google and other vendors to occur. Please see more information on Google Ads https://policies.google.com/privacy?hl=en-US
We and our partners store and/or access information on a device, such as unique IDs in cookies to process personal data. You may accept or manage your choices by clicking below, including your right to object where legitimate interest is used, or at any time in the privacy policy page. These choices will be signaled to our partners and will not affect browsing data.Cookie policy
Store and/or access information on a device, Personalised ads and content, ad and content measurement, audience insights and product development, Use precise geolocation data, Actively scan device characteristics for identification List of Partners (vendors)
Rapid Response:
Hypothesis that hepatitis of unknown cause in children is caused by adeno-associated virus type 2
Dear Editor
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[3]. 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[4]. 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[5]. 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[2]. 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[6]. Temporary liver inflammation and transient elevation of liver enzymes following intravenous administration of AAV-2 are reported[7].
Possible mechanisms of hepatotoxicity following high-dose intravenous administration of AAV may point to complement activation[8]. 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[9]. 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 [10]. 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. [13]. 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.
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/uploa...
2. 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
3. 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/uploa...
4. Hierholzer JC. Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992;5:262–74. https://doi.org/10.1128/CMR.5.3.262external icon
5. Tao N, Gao GP, Parr M, et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther. 2001 Jan;3(1):28-35. doi: 10.1006/mthe.2000.0227. PMID: 11162308.
6. Morales L, Gambhir Y, Bennett J, Stedman HH. Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys following Systemic High-Dose AAV. Mol Ther. 2020;28(8):1753-1755. doi:10.1016/j.ymthe.2020.07.009
7. Wang L, Wang H, Bell P, et al. Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2010;18(1):118-125. doi:10.1038/mt.2009.246
8. Flotte TR Editor-in-Chief. Revisiting the "New" Inflammatory Toxicities of Adeno-Associated Virus Vectors. Hum Gene Ther. 2020 Apr;31(7-8):398-399. doi: 10.1089/hum.2020.29117.trf. PMID: 32302233.
9. Yang WX, Zou XH, Jiang SY, et al. Prevalence of serum neutralizing antibodies to adenovirus type 5 (Ad5) and 41 (Ad41) in children is associated with age and sanitary conditions. Vaccine. 2016 Nov 4;34(46):5579-5586. doi: 10.1016/j.vaccine.2016.09.043. PMID: 27682509; PMCID: PMC7115419.
10. Roberto Calcedo, Luk H. Vandenberghe, Guangping Gao, et al. Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses, The Journal of Infectious Diseases, Volume 199, Issue 3, 1 February 2009, Pages 381–390, https://doi.org/10.1086/595830
11. Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol. 2011;18(9):1586-1588. doi:10.1128/CVI.05107-11
12. Mimuro J, Mizukami H, Shima M, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. J Med Virol. 2014 Nov;86(11):1990-7. doi: 10.1002/jmv.23818. Epub 2013 Oct 17. PMID: 24136735.
13. Frederic Reicherz, Rui Yang Xu, Bahaa Abu-Raya, et al. Waning immunity against respiratory syncytial virus during the COVID-19 pandemic, The Journal of Infectious Diseases, 2022;, jiac192, https://doi.org/10.1093/infdis/jiac192
Competing interests: No competing interests