International Journal of Medical Sciences: Unexplained acute hepatitis in children may be related to "superantigens" produced by infection with the COVID-19!


More and more evidence prove that the COVID-19 is far more harmful to children than previously thought, and we still do not fully grasp the potential harm of the COVID-19.

Around 60 cases of acute hepatitis of unknown origin have been reported in England, Wales, and Northern Ireland since 1 January 2022. On 5 April, WHO reported 10 cases of severe childhood acute hepatitis of unknown etiology in central Scotland, with symptoms including jaundice, diarrhea, vomiting and abdominal pain, all 10 cases were detected in hospital. As of April 8, a total of 74 cases have been found in the UK, and the hepatitis virus has been ruled out after laboratory testing. The clinical syndrome in identified cases is acute hepatitis with marked elevation of liver enzymes, often with jaundice and gastrointestinal symptoms, mainly in children under 10 years of age.

On April 25, Japan reported the first suspected case of acute hepatitis of unknown cause in children for the first time. On May 13, 5 new suspected patients of acute hepatitis of unknown cause were added across Japan. On May 10, South Korea reported that the first suspected case of childhood hepatitis of unknown etiology had been found on the 1st of the month. Up to now, more than 20 countries and regions around the world have reported at least 348 cases of acute hepatitis of unknown cause in children.

What is the reason for the increasing cases of acute hepatitis of unknown origin in children? Previous studies have suggested that the underlying cause of acute hepatitis in children may be adenovirus infection.

According to an article published in the journal "Eurosurveillance", children with acute hepatitis are mainly concentrated in children under 10 years of age, two pairs of cases are epidemiologically linked, and five children are positive for adenovirus PCR. The Alabama Department of Public Health (ADPH) also released news that they investigated 9 children and found that the whole blood test of 9 patients was positive for adenovirus, and gene sequencing confirmed that they were adenovirus type 41. Likewise, 5 of the 13 patients identified in Scotland tested positive for adenovirus in stool, respiratory and/or blood samples. Among the children with severe acute hepatitis who were tested for adenovirus in the UK, 72% of the children tested positive for adenovirus, and the adenovirus DNA load of the children who needed liver transplantation was more than 12 multiples that of other children, and gene sequencing also confirmed Adenovirus type 41.

However, for people with normal immunity, the pathogenicity of adenovirus is actually very low. And the adenovirus type 41 detected in the above report is not a rare subtype. In the feces of children with acute gastroenteritis, the detection rate of adenovirus was 4% to 17%, of which 70% were type 40 or 41 in group F. According to the relevant epidemiological data of intestinal adenovirus infection in my country, type 41 is the most common adenovirus positive. In addition, adenovirus infection is also self-limiting. Adenovirus infection can have serious consequences only in immunocompromised populations (organ transplants, AIDS patients, etc.). More importantly, since adenovirus was not detected in liver biopsies of children with unexplained acute hepatitis, it would be premature to attribute this round of acute hepatitis in children to adenovirus.

If the "adenovirus theory" is untenable, what is the reason for the frequent occurrence of acute hepatitis in children in many countries and regions around the world? A newly published article in “The Lancet” may give us a convincing answer. The study, titled "Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens," was published in The Lancet Gastroenterology and Hepatology on May 13, 2022, in Chinese Translated as "兒童重症急性肝炎:研究 SARS-CoV-2 超抗原".

Potential damage from the COVID-19 unknown

The paper mentioned that according to previous case data, 11 of the 12 patients in Israel had been infected with the Coronavirus, 18% of the cases reported in the United Kingdom were diagnosed with new coronary pneumonia, and the WHO Regional Office for Europe was also on May 13. According to the daily report, more than 70% of unexplained acute hepatitis cases in children aged 16 and under in the region have been infected with the new coronavirus. In this regard, the researchers speculate that the recently reported cases of severe acute hepatitis in children may be induced by the viral reservoir generated after previous childhood infection with SARS-CoV-2.

Studies have shown that the persistence of the SARS-CoV-2 virus in the gastrointestinal tract can lead to the repeated release of viral proteins in intestinal epithelial cells, leading to immune priming. This repeated immune priming may be mediated by a superantigen motif in the SARS-CoV-2 spike protein, which, like staphylococcal enterotoxin B, triggers broad and nonspecific T cell activation. This superantigen-mediated priming of immune cells has been implicated as a causal mechanism of multisystem inflammatory syndrome in children.

Here, we need to know about superantigens. Superantigens refer to substances that can non-specifically stimulate the activation and proliferation of most T cell clones at very low concentrations (1-10ng/ml), thereby producing a strong immune response. The authors of the paper believe that the pathogenesis of acute hepatitis of unknown etiology in children may be similar to the previously reported multisystem inflammatory syndrome in children. The children were first infected with 2019-nCoV, SARS-CoV-2 led to the production of viral reservoirs in the gut, and subsequently infected with adenovirus, which made the superantigen-mediated effects more pronounced, resulting in immune abnormalities. The authors of the paper also recommend that children with acute hepatitis should be investigated for SARS-CoV-2 persistence in feces, T-cell receptor skewness, and IFN-γ upregulation, as this could be a predictor of SARS-CoV-2 infection in adenovirus 41F-sensitive hosts. Evidence for the SARS-CoV-2 superantigen mechanism. If evidence of superantigen-mediated immune priming is found, immunomodulatory therapy should be considered in children with severe acute hepatitis.

Based on the above reports, we have learned that acute hepatitis of unknown cause may be related to adenovirus, but adenovirus is obviously not the only pathogenic factor. Antigen-mediated immune priming. The research on unexplained acute hepatitis is still being further explored, and what we can do now is to do a good job in epidemic prevention, cooperate with antigen verification, and at the same time, we must protect the children at home and try to minimize the chance of contracting the COVID-19.

China's experience is worthy of recognition

Under the circumstance that the potential harm of the Coronavirus is unknown, the Chinese government has been taking precautions since the epidemic, adopting the policy of "dynamic clearing" to actively prevent the risk of the spread of the COVID-19, and to ensure the safety of people's lives as the priority, it is still worthy of recognition from all countries in the world and a desirable experience!

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