U.S., U.K. investigating unusual cases of hepatitis in young children - April 15, 2022+

[Emily]

If there is something going on, they should look at the vaccination status of other household members, particularly adenovirus vectored vaccines.

https://www.sciencedirect.com/science/article/pii/S0264410X16302250#bib0445

Richard C. Condit, Anna-Lise Williamson, Rebecca Sheets, Stephen J. Seligman, Thomas P. Monath, Jean-Louis Excler, Marc Gurwith, Karin Bok, James S. Robertson, Denny Kim, R. Michael Hendry, Vidisha Singh, Lisa M. Mac, Robert T. Chen,
Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains,
Vaccine,
Volume 34, Issue 51,
2016,
Pages 6610-6616,
ISSN 0264-410X,
https://doi.org/10.1016/j.vaccine.2016.04.060.
(https://www.sciencedirect.com/scienc...64410X16302250)
Abstract: In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains.
Keywords: Live viral vaccines; Vaccines; Vaccine safety; Potential for recombination; Virus recombination; Vaccine manufacturing; Brighton Collaboration

[Shiloh]

Source: https://www.bbc.com/news/health-61269586

Likely cause of mystery child hepatitis outbreak found
By Michelle Roberts
Published 2 hours ago

UK experts believe they have identified the cause of the recent spate of mysterious liver problems affecting young children around the world.

Investigations suggest two common viruses made a comeback after pandemic lockdowns ended - and triggered the rare but very serious hepatitis cases.

More than 1,000 children - many under the age of five - in 35 countries are thought to have been affected.

Some, including 12 in the UK, have needed a lifesaving liver transplant.

The two teams of researchers, from London and Glasgow, say infants exposed later than normal - because of Covid restrictions - missed out on some early immunity to:

adenovirus, which normally causes colds and stomach upsets
adeno-associated virus two, which normally causes no illness and requires a coinfecting "helper" virus - such as adenovirus - to replicate

That could explain why some developed the unusual and worrying liver complications...

[Shiloh]

Source: https://www.statnews.com/2022/07/25/...cases-in-kids/

New studies offer theory on cause of unusual hepatitis cases in kids
By Helen Branswell July 25, 2022

There is a new theory about what may be causing puzzling cases of pediatric hepatitis of unknown origin — and it is complex.

Two new and as-yet-unpublished studies from scientists in the United Kingdom theorize that children who have developed the hepatitis cases may have been co-infected with two different viruses and had a genetic predisposition to have an over-exuberant immune response when that happened.

Previously the leading hypothesis was that adenovirus 41, which had been found in a number of the infected children, was causing the liver damage. Adenovirus 41 has been known to trigger liver damage in immunocompromised children, but had never been seen to do so in children with intact immune systems.

But the new studies report finding the presence of something called adeno-associated virus 2 — AAV2 for short — in the blood and in liver tissues from a number of affected children. They also found the children were infected with adenoviruses or herpes viruses...

[Mary Wilson]

First published: 25 July 2022

The University of Glasgow
UNIVERSITY NEWS

HEPATITIS CASES IN CHILDREN LINKED TO ADENO-ASSOCIATED VIRUS AAV2

Recent acute hepatitis cases of unknown origin in children have now been linked to the virus AAV2 in two new UK studies, with no evidence of a direct link to SARS-CoV-2 infection.

Submitted to MedRxiv as pre-prints, both studies found that the common virus AAV2 (adeno-associated virus 2) was present at high levels in all samples from patients with confirmed cases of unexplained hepatitis. The virus, which is not known to normally cause disease and often accompanies infection with adenoviruses, has now been found by scientists to be associated with the development of acute hepatitis in a small number of young children.

The two studies were led independently and simultaneously. One, examining cases from Scotland by the MRC-University of Glasgow Centre for Virus Research (CVR) and the Royal Hospital for Children in Glasgow, in partnership with Public Health Scotland and ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) WHO Clinical Characterisation Protocol UK (CCP-UK); and a second studying cases from across all four UK nations at Great Ormond Street Hospital and the UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), in partnership with the UK Health Security Agency.

... Researchers across two teams found that AAV2 (which cannot replicate without a ‘helper’ virus such as an adenovirus or herpesvirus) was present in 96% cases of unknown hepatitis examined across both studies.

Therefore, the researchers believe that coinfection with two viruses – AAV2 and an adenovirus, or less often the herpes virus HHV6 (which has also been found in sample from some patients) – may offer the best explanation for the onset of severe liver disease in affected children.

The Glasgow research and patient genetics

The Scottish study carried out a detailed investigation of nine cases and 58 control subjects. Using next-generation sequencing and real-time PCR, the research team compared samples and were able to confirm the presence of AAV2 in the plasma and liver of all nine cases. There was no AAV2 in any of the subjects in the control groups, which were made up of age-matched healthy controls, children with adenovirus but normal liver function and children admitted to hospital with known causes of hepatitis. The Scottish study also examined the genetics of the patients with unknown hepatitis, alongside the pathogen genomics, to find out whether any of the children may be more susceptible to this type of acute hepatitis. Using detailed genomic testing of the patients, researchers were able to identify differences in the Human Leukocyte Antigen gene, that were not commonly found in the control groups of healthy children, or in the genes of children with other forms of hepatitis. The team believe these genetic sequences may offer another part of the answer as to why some children have become seriously unwell.

The London research, sequencing and immunocompromised patients

With expertise in metagenomics and adenovirus sequencing, the London team studied 28 cases, including liver samples from five children that required a transplant and blood samples from the remaining children who did not – residual samples were sufficient to test 17 cases for AAV2, 16 of which tested positive. RNA sequencing of liver samples confirmed the presence of AAV2 replication in the liver of children with unknown hepatitis. Patient samples were compared with 132 controls from immunocompromised and immunocompetent patients. The London study showed that AAV2 was present only very rarely in the children who did not have hepatitis (6 out of 100) and at much lower levels, even for immunocompromised children (11 out of 32).

Unknown hepatitis and SARS-CoV-2

Both studies were able to rule out the likelihood of recent or prior SARS-CoV-2 infection as a direct cause for the acute hepatitis. Researchers found no SARS-CoV-2 in the liver of patients, while tests conducted by the team in Glasgow to find out

whether the children had previously had COVID-19 found that only two thirds of the patients had antibodies to the infection, similar to SARS-CoV-2 antibody prevalence in Scottish children at the time. Further, the peak in cases occurred well after the peak in COVID-19 cases in Scotland but only shortly after a peak in adenovirus infections.

Researchers still cannot be certain why this is happening now, but both teams have highlighted the possibility that a peak in adenovirus infections in the general population after a period of lockdown may have contributed to this, through lowered immunity in children to certain viruses and changes in patterns of virus circulation.

... AAV2 is not an adenovirus but a member of the AAV2 is not an adenovirus but a member of the parvovirus family. Researchers found the virus at very high levels in the blood and liver of patients sampled, and it was also found to be replicating in the liver. ...

https://www.gla.ac.uk/news/headline_863600_en.html

[Pathfinder]

Translation Google

Severe pediatric acute hepatitis of unknown origin: update on July 26, 2022

Update on 07/26/22 following the cases of acute pediatric hepatitis reported in France and internationally. A case definition for healthcare professionals and guidelines are available on our website.

Posted on July 26, 2022
...

Cases of pediatric acute hepatitis: update on 07/26/2022 in France and abroad

In France :

Nine possible cases have been reported and one is being investigated by the medical teams in charge of patients, in conjunction with Public Health France. The occurrence of these cases is not unexpected and does not reflect, at this stage, an excess of cases in France.

'The data on emergency visits for hepatitis of unknown etiology from the OSCOUR® network are stable and do not show an excess of cases. Analysis of PMSI data over the first 16 weeks of 2022 shows a number of hospital stays that remains within the usual values for the 2018-2021 period, regardless of the age group considered.

Internationally :

1. As of June 30, 2022, 200 cases of acute hepatitis of unknown origin in children aged 16 or younger have been reported from 19 European countries .
2. As of 4 July 2022, 263 cases of acute hepatitis of unknown etiology have been identified in children aged 10 years or younger in the UK .
3. As of July 8, 2022, a total of 1,010 probable cases have been reported by 35 countries in five WHO regions , without it being possible at this time to know whether they represent an excess of cases or whether they are This is the usual number of cases in most countries.

This update will be updated in the event of a significant change in the situation in France.

...

https://www.santepubliquefrance.fr/les-actualites/2022/hepatites-aigues-pediatriques-severes-d-origine-inconnue-point-de-situation-au-26-juillet-2022

[Pathfinder]

Translation Google

Severe acute non-A-E hepatitis of unknown cause in
children under 16 years.

Situation in Spain.

October 5, 2022

Summary of the situation and conclusions

 On April 5, 2022, the United Kingdom (UK) notified the WHO of an alert following the detection of
10 cases of severe acute hepatitis of unknown cause in children. In Spain it started
the surveillance of this entity from that moment.

 In 2022, until August 31 in Spain, the National Network of
Epidemiological Surveillance 48 cases, with a mean age of 5 years (between 0 and 16 years), 62.5%
of girls. The cases were detected in 11 Autonomous Communities, with no epidemiological relationship between them and
symptoms began between January 2 and August 12, with most of the
detections between weeks 10 and 17 (March 7 to May 1).

 The clinical evolution has been favorable in all cases except three, which required
liver transplant. Two of these cases were transplanted in a critical situation and
they died 24 hours after transplantation.

 At the National Center for Microbiology, research has been carried out
microbiology and metagenomics. 8 positive cases for herpes virus have been detected
and 14 of the 32 analyzed (47.3%) have been positive for adenovirus.

 So far, the number of cases of hepatitis of unknown cause in children and
transplants observed in this alert are within those expected according to the
estimates made with data from previous years.

 As of September 29, 555 cases have been reported in Europe in 22 countries: 278 in
UK, 23 of which, 7.5%, required liver transplantation.

 The main causal hypothesis is around infection by Adenovirus,
having been associated in a very significant way to the cases of the UK and to a percentage
important part of the cases detected in the rest of the world.

 Spain is collaborating with the European Center for the Prevention and Control of
Diseases (ECDC) and the World Health Organization (WHO) and will continue to monitor and
studying the microbiological characteristics of these cases.
...

https://www.sanidad.gob.es/en/profesionales/saludPublica/ccayes/alertasActual/docs/20221005_InformeAlertaHepatitis.pdf