At the time of going to press in The Lancet Infectious Diseases , more than 300 probable cases of acute hepatitis in previously healthy children were being investigated worldwide. The majority of cases were reported in the United Kingdom (163 as of May 3), but smaller numbers of cases were reported in 20 countries. On May 5, the U.S. Centers for Disease Control and Prevention announced that it was investigating 109 cases of pediatric hepatitis of unknown cause reported in the past 7 months in 25 states and territories. So far, more than 20 children have required liver transplants and several have died. Research is underway to identify a cause, but the most common causes of acute hepatitis in children, including hepatitis A–E viruses, have been ruled out.
Adenoviruses have become the main focus of investigations, as a considerable number of cases (around 70% according to a WHO press conference on May 10) have tested positive for them. Adenoviruses are common pathogens that typically cause mild respiratory symptoms, although in the past they have been implicated in hepatitis in immunocompromised children and, more recently, in an immunocompetent adult.
Several hypotheses have been proposed as to how the pathogenesis of adenoviruses might have changed to cause hepatitis in otherwise healthy children. These include that an immune deficit in children as a result of lack of exposure to pathogens during the COVID-19 pandemic has made them more susceptible to adenovirus infection and rarer outcomes from the infection. Alternatively, as has been seen with other respiratory viruses, the relaxation of pandemic restrictions could have led to a massive wave of adenovirus infections, allowing a rarer outcome of infection to be detected. Another hypothesis is that past infection or coinfection (with SARS-CoV-2 or an alternative pathogen), or exposure to a toxin, drug, or environmental factor, has altered the host response to adenovirus infection.
Alternatively, what we are seeing is a new adenovirus capable of causing serious liver disease in children.
The main suspect is adenovirus subtype 41 . A May 6 UK Health Security Agency (UKHSA) technical report reported that all 18 cases in the UK that underwent adenovirus typing had subtype 41. Similarly, Baker and colleagues reported that Five children with hepatitis of unknown cause identified at a children’s hospital in Alabama between October 2021 and February 2022, had adenovirus subtype 41 at typing.
Not everyone is convinced of the adenovirus hypothesis. Adenovirus subtype 41 has previously only been linked to mild to moderate gastrointestinal symptoms. Not all children have tested positive for adenovirus, those who have tested positive have often done so only in whole blood (liver and plasma samples have been largely negative ) and whole blood concentrations have been low , which prevents complete genome sequencing from being carried out. to better characterize the virus and any genomic changes that may explain this new phenomenon. Adenoviruses are a common cause of infection and therefore may be an incidental finding ; An ongoing case-control study in the UK seeks to address this.
Other infectious causes are being investigated, including the role of SARS-CoV-2. In the United Kingdom, a decrease in reports of new cases of pediatric hepatitis of unknown cause in the 2 weeks to May 6 coincided with a decrease in SARS-CoV-2 cases. However, the UKHSA warned of delays in reporting hepatitis cases, saying new cases are still being recorded in Scotland and many cases in England are awaiting triage. Furthermore, few of the cases reported so far have tested positive for SARS-CoV-2 infection. It is unclear how extensively past infection has been investigated; UKHSA reported that serological investigations were ongoing, and Baker and her colleagues reported that none of the children in Alabama had a documented history of SARS-CoV-2 infection.
Much attention is being paid to the cause of the outbreak. Conspiracy theories abound on social media, with some attributing cases to COVID-19 vaccines. However, COVID-19 vaccines have been categorically ruled out , as most children with unexplained hepatitis are too young to receive a COVID-19 vaccine. While it is important to identify the underlying cause, considering the health status of the children and that liver transplant is only possible in highly specialized centers, it is also important to focus on early identification of cases and find effective treatments that can stop the progression. of the illness.
Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens
Petter Brodin, Moshe Arditi
The Lancet IGastroenterology and Hepatology
DOI: https://doi.org/10.1016/S2468-1253(22)00166-2
Recently, there have been reports of children with a severe acute form of hepatitis in the UK, Europe, the US, Israel and Japan. Most patients present with gastrointestinal symptoms and then progress to jaundice and, in some cases, acute liver failure. So far, no common environmental exposures have been found and an infectious agent remains the most plausible cause. Hepatitis viruses A, B, C, D and E have not been found in these patients, but 72% of children with severe acute hepatitis in the United Kingdom who were tested for an adenovirus had a adenovirus detected, and of 18 cases subtyped in the United Kingdom, all were identified as adenovirus 41F. This is not an uncommon subtype and predominantly affects young children and immunocompromised patients. However, to our knowledge, adenovirus 41F has not been previously reported to cause severe acute hepatitis.
SARS -CoV-2 was identified in 18% of reported cases in the United Kingdom and in 11 (11%) of the 97 cases in England with available data testing positive for SARS-CoV-2 on admission; Three other cases had tested positive in the 8 weeks prior to admission. Ongoing serological testing is likely to reveal a higher number of children with severe acute hepatitis and previous or current SARS-CoV-2 infection.
Eleven of the 12 Israeli patients were reported to have had COVID-19 in recent months and most of the reported hepatitis cases were in patients too young to be eligible for COVID-19 vaccines.
SARS-CoV-2 infection can lead to the formation of a viral reservoir . Viral persistence of SARS-CoV-2 in the gastrointestinal tract can lead to repeated release of viral proteins through the intestinal epithelium, leading to immune activation. Such repeated immune activation could be mediated by a superantigen within the SARS-CoV-2 spike protein that resembles staphylococcal enterotoxin B, triggering broad, nonspecific activation of T cells. This superantigen-mediated immune cell activation has been proposed as a causal mechanism of multisystem inflammatory syndrome in children.
Acute hepatitis has been reported in children with multisystem inflammatory syndrome, but coinfection with other viruses has not been investigated. We hypothesized that the recently reported cases of severe acute hepatitis in children could be a consequence of adenovirus infection with intestinal trophism in children previously infected with SARS-CoV-2 and carrying viral reservoirs.
In mice , adenovirus infection sensitizes to subsequent staphylococcal enterotoxin B-mediated toxic shock, leading to liver failure and death. This result was explained by adenovirus-induced type 1 immune bias, which, upon subsequent administration of staphylococcal enterotoxin B, led to excessive production of IFN-γ and IFN-γ-mediated apoptosis of hepatocytes.
Translated to the current situation, we suggest that the persistence of SARS-CoV-2 in feces, T cell receptor skewing and upregulation of IFN-γ be investigated in children with acute hepatitis, because this could provide evidence of a SARS-CoV-2 superantigen mechanism in a host sensitized with adenovirus-41F. If evidence of superantigen-mediated immune activation is found, immunomodulatory therapies should be considered in children with severe acute hepatitis.
