A year ago, the European health authorities and the World Health Organization warned about an outbreak of severe acute hepatitis of unknown origin that affected children – most of whom were previously healthy – under 16 years of age in more than 35 countries, including Spain, and that it was characterized by elevated transaminases, often presenting with jaundice, and sometimes including gastrointestinal symptoms such as vomiting.
Pediatric hepatitis is infrequent and therefore the alarms went off. So far there have been around 1,000 cases, 50 of those affected have required a liver transplant, and at least 22 have died. Now, a study has linked this disease to coinfections with several common viruses, and especially with a strain of adeno-associated virus type 2 (AAV2). Their results have been published in Nature.
The research has been carried out by scientists from the University of California-San Francisco (UCSF), who have explained that AAVs would not have the capacity to cause hepatitis on their own and that they would need to use other ‘helper’ viruses, such as the adenoviruses that cause colds and flu, to replicate in the liver.
A statement with which I would not agree Marina Berenger Haym, from the Hepatology and Liver Transplant group, IIS La Fe, coordinator of the group Center for Biomedical Research in the Network of Liver and Digestive Diseases (CIBEREHD) and president of the International Transplant Society Hepático, which has declared to SMC Spain that “these viruses replicate without ‘helper’ and produce hepatitis, but it has only been seen in immunocompromised children.
The outbreak of severe acute hepatitis in children “may have been an unintended consequence of what we have experienced over the past two to three years of the pandemic”
Following the restrictions and social distancing imposed during the COVID-19 pandemic, children became more susceptible to contracting these common microbes when they returned to school, and the study findings suggest that contracting more than one viral infection at the same time Time may have made a small subset of these children more vulnerable to severe hepatitis.
“We were surprised by the fact that the infections we detected in these children were not caused by an unusual emerging virus, but by common childhood viral pathogens,” said Dr. Charles Chiu, professor of laboratory medicine and medicine in the Division of Infectious Diseases, director of the UCSF Clinical Microbiology Laboratory and lead author of the article.
“That’s what led us to speculate that the timing of the outbreak was probably related to the really unusual situations we were going through with COVID-19-related school and daycare closures and social restrictions,” Chiu says. “It may have been an unintended consequence of what we have experienced over the last two or three years of the pandemic.”
Viral coinfections that can cause hepatitis in children
The new study has been supported by the US Centers for Disease Control and Prevention (CDC). The researchers used polymerase chain reaction (PCR) in conjunction with various metagenomic sequencing methods and molecular tests to analyze plasma, whole blood, nasal swabs, and stool samples from 16 pediatric cases in six states: Alabama, California, Florida, Illinois, North Carolina, and South Dakota, between October 1, 2021, and May 22, 2022, and compared the samples to 113 control samples.
In the genotyping of the 14 available blood samples, adeno-associated virus 2 (AAV2) was detected in 93% of the cases and human adenoviruses (HAdVs) in all cases; in 11 cases they found a specific type of adenovirus related to gastroenteritis (HAdV-41), and in 85.7% of the cases additional coinfections with Epstein-Barr, herpes, and enteroviruses were found.
Chiu explained that the results have shown the findings of two simultaneous studies carried out in the United Kingdom, which identified the same AAV2 strain. All three studies have found co-infections with multiple viruses, and 75% of children in the US study had three or four viral infections.
AAVs are not considered pathogenic by themselves, and therefore a direct causal link with severe acute hepatitis has not yet been established, but the study indicates that children may be especially vulnerable to more severe hepatitis caused by co-infections. Although adeno-associated virus infections can occur at any age, the peak is usually between one and five years, and the median age of affected children in the study was three years.
Outbreaks of severe acute hepatitis in children have been on the decline recently, but Chiu says the best protective measures against this disease are frequent proper handwashing and staying home when contracting a viral infection.
In Spain, this infectious outbreak affected more than 60 children in 12 autonomous communities, 49 of them under 11 years of age, three of whom died. Although this generated social alarm, these figures do not represent an anomaly compared to other years regarding severe childhood hepatitis of unknown origin, and last December the Ministry of Health concluded the special surveillance that it had been carrying out since the Kingdom Kingdom reported an increase in cases and deaths in April 2022.
In her statements to SMC Spain, Marina Berenger Haym, concludes that, as indicated in a News & views article that accompanies the three studies, they are ‘retrospective studies’, and that “at the moment there is no confirmation in in vitro studies (with organoids, for example, to confirm the potential direct effect of the virus on the hepatocyte), nor prospective studies that show that hepatitis is produced by the interaction between a generally low pathogenic virus with an altered or deficient immune system ( both due to genetic polymorphism and not being adequately developed due to the measures taken against covid-19).
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