Acute hepatitis in children of unknown cause spreads to Singapore: a 10-month-old baby boy who was infected with COVID-19

One more case of acute hepatitis in unexplained children: The Singapore Ministry of Health reported similar symptoms in a 10-month-old baby boy. Singapore's Health Ministry said it was investigating to determine if the case was similar to the case from the recent global outbreak.

Singapore's Ministry of Health said the case was seen in the emergency department of the Women's and Children's Hospital a week ago and that the baby boy and his family are currently in good condition. Laboratory tests in Singapore have determined that the baby boy is negative for hepatitis A, B, C and E viruses. The baby boy was infected with COVID-19 in December 2021. Singapore's Ministry of Health said, "There is currently no evidence that acute hepatitis in unexplained children is associated with COVID-19. ”

As of 1 May, more than 200 cases of unexplained childhood acute hepatitis have been reported in 17 countries worldwide. This round of unexplained childhood acute hepatitis was first detected in the UK. On 12 April 2022, Scotland detected 13 cases of severe acute hepatitis in unexplained children aged 11 months to 10 years (median age 3.9 years, IQR: 3.6 to 4.6 years), with the earliest case occurring in January 2022.

THE WHO (World Health Organization) previously reported that as of 21 April 2022, a total of 169 cases of unexplained acute hepatitis had been reported from 11 countries in the European region and 1 country in the Americas, including 114 cases in the United Kingdom, 13 cases in Spain, 12 cases in Israel, 9 cases in the United States, 6 cases in Denmark, 5 cases in Ireland, 4 cases in the Netherlands, 4 cases in Italy, 2 cases in Norway, 2 cases in France, 1 case in Romania and 1 case in Belgium; the case age is 1 month old - 16 years old, With acute hepatitis with significantly elevated levels of liver enzymes as the main sign, accompanied by jaundice and symptoms such as gastrointestinal tract, 17 children (about 10%) need liver transplantation, and at least 1 death is reported.

The common hepatitis virus (hepatitis A, B, C, D, E) that causes acute viral hepatitis was not detected in any of these cases, while human adenovirus (HAdV) was detected in at least 74 cases, of which 18 were identified as F subtype HAdV-41; and severe acute respiratory syndrome was detected in 20 cases coronavirus 2, SARS-CoV-2; in addition, 19 cases were found to be infected with both SARS-CoV-2 and HAdV.

The Chinese Journal of Preventive Medicine, a subsidiary of the Chinese Medical Association, published a paper entitled "Reflections on the Current Cases of Severe Acute Hepatitis in Unexplained Children in Some Countries Around the World" online on April 27. The corresponding author of the paper is Xu Wenbo, director of the Institute for Viral Disease Prevention and Control of the Chinese Center for Disease Control and Prevention, and director of the WHO Polio and Measles/Rubella Reference Laboratory in the Western Pacific Region. The etiological studies that cause acute hepatitis in these children are still being investigated and studied, and the researchers have hypothesized the following etiology:

(1) Certain auxiliary factors lead to common HAdV (human adenovirus) infection in the liver of children caused by severe inflammatory or immunopathological reactions, possible auxiliary factors include pre-SARS-CoV-2 infection, toxin, drug or environmental exposure, increased susceptibility, etc.;

(2) HAdV mutations may lead to increased virulence or changes in tissue appetite;

(3) Unknown pathogen infection;

(4) Caused by infection with a new variant of SARS-CoV-2;

(5) Caused by factors such as drugs, toxins or environmental exposures;

(6) Autoimmune hepatitis caused by SARS-CoV-2 mRNA vaccine caused by T cells.

As currently widely discussed in the scientific and clinical community, the paper also mentions, "The current etiology mainly points to HAdV infection." "Adenovirus is a common virus that usually causes respiratory or gastrointestinal disorders and usually does not cause hepatitis in healthy children.

The paper also provides an in-depth discussion of HAdV. HAdV is an important viral pathogen in humans, first discovered in the 1950s, and has been divided into 7 subgenera (A-G) and at least 113 types (due to the different tissue habits of different types of HAdV, it can lead to a variety of diseases, including pneumonia, ocular conjunctivitis, cystitis and gastrointestinal diseases). Among them, HAdV is an important pathogen of respiratory infection and acute conjunctivitis, and the detection rates in children's pneumonia cases and viral conjunctivitis cases are 4%-10% and 65%-90%, respectively.

However, HAdV rarely infects the liver and HAdV hepatitis is rare. In immunocompetent patients, most HAdV infections are usually self-limiting, whereas in immunocompromised patients, HAdV can cause severe infections of multiple organs, including the liver. Data from the 1960-2012 study show that of the 89 reported cases of HAdV hepatitis worldwide, 43 (48%) were liver transplant recipients, 19 (21%) were bone marrow transplant recipients, and 11 (12%) were cases of recent chemotherapy for malignant tumors.

The paper believes that the existing research data show that HAdV hepatitis is mainly limited to immunosuppressed patients, and because the clinical manifestations are non-specific, it is of great significance to carry out early pathogen identification and reduce the intensity of immunosuppression, which is of great significance for clinical treatment.

The paper also points out that genetic homology recombination is the main driving force for the evolution of HAdV molecules, and at least 60 new HAdV (HAdV-53-113) have been discovered internationally. It is worth noting that HAdV may change the original tissue habit of the virus after genetic recombination, and form a new virus with stronger virulence and transmissibility to humans, which can cause new outbreaks of infectious diseases in the population.

Some cases have been identified as positive for HAdV-41 nucleic acid in this global outbreak of unexplained hepatitis, but there is no report on whether HAdV-41 and its whole genome sequence have been detected in the liver of the children, so it is not possible to judge at this stage whether the HAdV-41 detected in this outbreak has undergone important genetic mutations, or a new type of recombinant HAdV formed by genetic recombination with different serotypes or genotype viruses. The authors note that whether HAdV-41 is the main pathogen triggering this severe hepatitis outbreak in children requires additional etiology, genomics, liver pathology, and immunohistochemical analysis to determine or exclude.

Xu Wenbo et al. stressed that at present, there is no systematic monitoring study of hepatitis caused by HAdV, and there are very few reports of HAdV-related hepatitis in mainland children's hospitals, so it is impossible to judge whether there are similar cases of hepatitis in mainland China. They also reminded that the potential risks of HAdV hepatitis in the mainland should be studied and judged, so as to provide scientific and technological support for the prevention and control of HAdV-related diseases in the mainland, prediction and early warning, and the research and development of vaccines and drugs.