It all started when the United Kingdom launched an international alert, on April 5, 2022, to the rest of the countries. They had detected a mysterious outbreak of severe acute hepatitis in children, mostly healthy, just after the confinement measures were “loosened” by the Covid-19. Pediatric hepatitis is very rare, and doctors were alarmed to see the increase in severe and unexplained cases. Finally, the alert was lifted in more than 35 countries and Spain began to track cases retrospectively to see if they found a similar increase. Finally, there were around 1,000 cases in the world; 50 of them required liver transplants and at least 22 died.
Multiple causes were studied: from a possible link between dogs and childhood hepatitis cases to its association with the Omicron variant. Now, three studies published in the journal Nature They believe they have established the cause of the “outbreak” and point out that the disease was related to the coinfections of multiple common viruses, particularly with a strain of adeno-associated virus type 2 (AAV2). The University of California-San Francisco (UCSF) researchers explain that although these AAVs are not known to cause hepatitis on their own, they do they can be with “helper” viruses. For example, adenoviruses which are very common childhood pathogens that often cause infections such as colds and the flu.
But Marina Berenger Haym, head of the IIS La Fe Hepatology and Liver Transplant group, coordinator of the Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD) and president of the International Liver Transplant Society, says that this is not entirely true. . “These viruses replicate without an assistant and cause hepatitis, although it has only been seen in immunocompromised children.
The work associates adenoviruses very significantly with severe cases in the United Kingdom and the United States. The researchers point out that children who had returned to school after the end of the Covid-19 lockdowns were more susceptible to these serious infections caused by common pathogens. In a small subgroup of these children, they suggest, contracting more than one infection at the same time could have made them more vulnerable to severe hepatitis.
“We were surprised by the fact that the infections we detected in these children were caused not by an unusual emerging virus, but by common childhood viral pathogens,” said study senior author Dr. Charles Chiu, director of the UCSF Clinical Microbiology Laboratory. .
This led them to speculate that the timing of the outbreak was likely related to the closure of schools and day care centers, as well as social distancing measures, related to Covid-19. “Maybe it was an accidental consequence than what we have experienced during the last two to three years of the pandemic,” Chiu says.
The epidemic affected 61 children in Spain in 12 autonomous communities, 49 of them under 11 years of age. Three needed a transplant, two of them died and a third died without being transplanted. These are figures that do not represent an anomaly with respect to other years Regarding severe childhood hepatitis of unknown origin, however, the social alarm that unleashed the possibility of a hepatitis “pandemic” led the Ministry of Health to initiate this special surveillance from April to December 23, 2022.
To try to find the relationship, the researchers used polymerase chain reaction (PCR) tests, along with metagenomic sequencing and a molecular screening method. They examined plasma, whole blood, nasal swab, and fecal samples from 16 pediatric cases in Alabama, California, Florida, Illinois, North Carolina, and South Dakota from October 1, 2021, to May 22, 2022.
The researchers compared these specimens with 113 “control” samples. They detected the presence of adeno-associated virus type 2 (AAV2) in 93% of the cases, and in all cases human adenoviruses were found. A specific type of adenovirus associated with gastroenteritis was found in 11 of the cases. Additional coinfections with viruses including Epstein-Barr, herpes, and enterovirus were found in 86% of cases.
The findings mirrored the results of two concurrent studies conducted in the UK, which identified the same AAV2 strain. All three studies identified multiple virus co-infections. About 75% of the children in the US study with severe hepatitis had three or four simultaneous viral infections. However, although the study authors concluded that children with coinfections might be particularly vulnerable to more severe hepatitis, the papers do not settle the issue.
Berenger Haym concludes that “studies (published) in Nature are credible”, but they have “limitations”. Thus, in the article by News & views that accompanies the three studies, are qualified. “They are retrospective studies. 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 demonstrate that hepatitis is produced by the interaction between a generally low pathogenic virus with an altered or deficient immune system (both due to the genetic polymorphism as not being adequately developed by the measures taken against Covid-19)”. Therefore, new studies will be required to test the hypothesis.
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