Since the UK first notified WHO of 10 cases of acute severe hepatitis of unknown cause in children in Scotland on April 5, 12 EU countries including the UK, the US, Israel, Japan and Spain, Denmark, the Netherlands and Sweden have More than 300 cases have been reported.
As of the beginning of May, 18 children have been treated with liver transplantation, and more than 5 cases have died.
The possibility of hepatitis virus infection, exposure to toxic substances or drug-induced hepatitis has been ruled out, however, 72% of UK cases tested positive for adenovirus, and 18 of them were subtyped for adenovirus. All without exception are adenovirus type 41.
February-April is the peak period of adenovirus epidemics, and children are also susceptible to adenovirus, but adenovirus 41-infected patients usually present with diarrhea, vomiting and fever, accompanied by respiratory symptoms, almost Does not cause liver failure.
Not only that, in the case of Alabama, USA, adenovirus was only found in the blood of the child, and the presence of adenovirus was not detected in the liver.
Therefore, some medical experts believe that adenovirus infection is not the direct cause of severe hepatitis. The real killer of severe hepatitis is someone else, and adenovirus is only an accomplice or innocent person involved in the storm (just right catch up with the peak of the adenovirus epidemic).
Recently, Petter Brodin, a pediatric immunologist from Imperial College London, UK, published his latest hypothesis in the journal “The Lancet Gastroenterology and Hepatology”, proposing that the new coronavirus superantigen may cause children The real cause of acute severe hepatitis.
The relationship between the new coronavirus and acute hepatitis
During the new crown epidemic, most of the infected children showed asymptomatic or mild symptoms , only a small proportion of children develop multisystem inflammatory syndrome (MIS) 1-2 months after infection with the new coronavirus, and one of the comorbidities of MIS is acute hepatitis.
In a single-center study in 2020, 44 children developed a multisystem inflammatory syndrome after Covid-19 infection, of which 19 had acute hepatitis symptoms and 1 had liver disease. exhaustion.
It is worth noting that more than half of the children with MIS had a negative nucleic acid test (56.8%) and a positive antibody test (92.3%) on admission, indicating that patients with multisystem inflammatory syndrome are likely to have Have been infected with the new crown virus, not necessarily during the new crown infection.
Only 18% of children with acute hepatitis of unknown cause in the UK recently tested positive for the new crown nucleic acid, and further serological testing can determine whether these children have ever been infected with the new crown virus.
The mechanism of MIS caused by SARS-CoV-2
There is a superantigen motif on the spike protein (S) of SARS-CoV-2, which is related to the sequence of staphylococcal enterotoxin B superantigen highly similar in structure. If ordinary antigens can only activate T cells with corresponding receptors, the principle of superantibody can widely activate a large number of T cells, generate inflammatory storms, and damage multiple organs, including the liver.
Why is severe hepatitis only seen in children?
This question is equivalent to asking why MIS is more common in children? As mentioned earlier, most children have mild symptoms after being infected with the new crown virus. In the first year of the new crown epidemic, only about 2 deaths per million new crown deaths in the UK were from patients under the age of 18, but the new crown virus caused more MIS. Seen in children and rarely in adults.
A very interesting explanation is the energy distribution trade-off theory, which says that children who are in the growing stage tend to devote more energy to their own development, and if they are infected with a virus, they will have a severe inflammatory response and consume a lot of energy. If so, the body will choose to coexist with the virus, rather than immediately launch an immune response to attack the virus.
On the 34th day after the child was infected with the new crown, the new crown nucleic acid fragment can still be detected in the stool (only 19 days for adults), if the new crown virus persists In the intestine, superantigens are continuously released, resulting in an inflammatory response, which in turn leads to damage to the intestinal mucosal barrier, and superantigens enter the blood circulation, causing the occurrence of MIS.
Another explanation is that a virus commonly found in children can synergize with the SARS-CoV-2 superantigen to cause MIS, which The virus is adenovirus type 41.
A study in 2005 demonstrated that adenovirus infection in mice increased the sensitivity of mice to staphylococcal enterotoxin B superantigen, resulting in liver failure and death in mice. If a child is infected with adenovirus and then infected with the new coronavirus, or if the new coronavirus exists in the body for a long time, MIS may theoretically occur, resulting in severe hepatitis.
How to verify that SARS-CoV-2 superantigen causes severe hepatitis
Petter Brodin recommends stool testing for SARS-CoV-2 in these children with severe hepatitis, and The presence of T cell receptor skew and IFN-γ upregulation consistent with superantigen activation was detected in the children.
If the hypothesis that the new coronavirus superantigen causes severe hepatitis is true, these children with severe hepatitis may be rescued by steroids and immunoglobulins or other immunomodulatory treatments. References
1. Brodin P, Arditi M. Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens [published online ahead of print, 2022 May 13]. Lancet Gastroenterol Hepatol. 2022;S2468- 1253(22)00166-2. doi:10.1016/S2468-1253(22)00166-2
2. Brodin P. SARS-CoV-2 infections in children: Understanding diverse outcomes. Immunity. 2022;55(2):201-209. doi:10.1016/j.immuni.2022.01.014
3.Cantor A, Miller J, Zachariah P, DaSilva B, Margolis K, Martinez M. Acute Hepatitis Is a Prominent Presentation of the Multisystem Inflammatory Syndrome in Children: A Single-Center Report. Hepatology. 2020;72(5):1522-1527. doi:10.1002/hep.31526
4.Yarovinsky TO, Mohning MP, Bradford MA, Monick MM, Hunninghake GW. Increased sensitivity to staphylococcal enterotoxin B following adenoviral infection. Infect Immun. 2005;73(6):3375-3384. doi:10.1128/IAI.73.6.3375-3384.2005
5.Cheng MH, Zhang S, Porritt RA, et al. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc Natl Acad Sci U S A. 2020;117(41):25254-25262. doi:10.1073/pnas.2010722117