Zhang Wenhong on hepatitis in children of unknown origin: there is an imported risk...

"We also need to be vigilant against unknown pathogens, even if the probability of such an emerging infectious pandemic is not high."

Author| Xie Youhua Chen Jieliang Wang Yongxiang Yuan Zhenghong

The source | the "Huashan Infection" WeChat public account

The "Huashan Infection" WeChat public account published an article on April 29 to introduce the development of hepatitis in children of unknown causes in the United Kingdom and other places and its possible causes. The article pointed out that there is an imported risk of hepatitis in unexplained children, and the mainland should prepare for this early.

Zhang Wenhong, director of the National Center for Infectious Diseases And director of the Department of Infectious Diseases at Huashan Hospital affiliated to Fudan University, commented in the article that cases of hepatitis of unknown cause occur every year, often referring to liver damage caused by known hepatitis viruses or known causes, which is not uncommon in children. However, hepatitis of unknown cause of concern to WHO this time has the characteristics of cluster incidence, and the incidence rate is higher than in previous years. In this case, it makes sense to consider the risk of infectious diseases.

Zhang Wenhong said that there is a certain correlation with adenovirus infection. But adenovirus infection is a very common phenomenon and can cause pneumonia or diarrhea, so why are there so many cases of severe hepatitis this year, and only in children? At present, it is speculated that it is a long period of new crown isolation, children have not been exposed to this virus for a long time, and sudden contact will produce more serious immune damage, which is consistent with the phenomenon that emerging infectious diseases tend to be heavier in the early stages of disease outbreaks.

Zhang Wenhong believes that if it is caused by a long period of new crown isolation, rather than a new virus that has not been discovered before, the subsequent effects of this unexplained hepatitis will gradually decline, but we also need to be vigilant against unknown pathogens, even if the probability of this emerging infectious disease pandemic is not high. In addition, as awareness continues to deepen, the definition of the current confirmed case is also constantly being updated.

The original text is as follows:

Executive Summary

On 31 March 2022, Scotland first reported 5 cases of severe hepatitis of unknown cause. The World Health Organization (WHO) issued guidance on 15 April on hepatitis of unknown cause in children, defining confirmed cases, suspected cases and epidemiologically related cases. As of 21 April, 12 countries have reported 169 cases of unexplained hepatitis in children ranging from 1 month to 16 years of age.

Hepatitis of unknown origin presents clinically as acute hepatitis, with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 500 IU/L, and most children have jaundice, nausea, abdominal pain, fatigue, drowsiness, and gastrointestinal symptoms, including diarrhea and vomiting. Most children are fever-free. Seventeen patients underwent liver transplants and at least one death was reported. Taking into account the epidemiological characteristics and the clinical characteristics of the child, infectious factors are more likely to cause the disease. Laboratory findings in all cases have ruled out hepatitis A, B, C, D, and E, suggesting that adenovirus may be associated with unexplained childhood hepatitis, but other infectious or environmental factors are not completely excluded. This article introduces the development of hepatitis in unexplained children and its possible causes. There is an imported risk of the disease, and the mainland should prepare for this early.

Outbreaks of hepatitis in children of unknown cause in the United Kingdom, the United States and other countries

On 31 March 2022, the Scottish Department of Public Health (PHS) received a report that the Royal Glasgow Hospital had treated five children with unexplained severe hepatitis in the last 3 weeks, aged 3 to 5 years, who were in good health before the onset of illness. Prior to this, there were usually fewer than 4 children with unexplained hepatitis in Scotland each year. However, by 12 April, a total of 13 confirmed cases (age 1 to 10 years, median 3.9 years) had been detected in PHS, one of which dates back to 11 January 2022, and the remaining 12 cases occurred between 4 March and 7 April. On 14 April, PHS questionnaire findings showed that 2 out of 13 cases were epidemiologically linked.

On the other hand, in November 2021, a large children's hospital in Alabama, USA, notified the public health department of 5 pediatric patients with obvious liver damage, and further investigation identified another 4 children with unexplained hepatitis, bringing the total number of cases to 9. These cases were presented from October 2021 to February 2022. All children were in good health prior to the onset of illness and denied a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

On 15 April, the WHO issued a briefing and guidance on acute hepatitis in children of unknown cause, defining confirmed cases, probable cases, and epidemiologically related cases [WHO 20220415].

Confirmed case: Children 10 years and younger with acute hepatitis (not caused by hepatitis A, B, C, D, E virus) and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 500 IU/L from 1 January 2022.

Suspected cases: Children aged 11 to 16 years with acute hepatitis (not caused by hepatitis A, B, C, D, or E virus) and AST or ALT > 500 IU/L as of 1 January 2022.

Epidemiologically relevant cases: Patients with acute hepatitis (not caused by hepatitis A, B, C, D, E) and close contact with confirmed cases since 1 January 2022.

As of 21 April, 12 countries have reported 169 confirmed cases, including 114 in the United Kingdom, 13 in Spain, 12 in Israel, 9 in the United States, 6 in Denmark, 5 in Ireland, 4 in the Netherlands, 4 in Italy, 2 each in Norway and France, and 1 each in Romania and Belgium. The age of the child is 1 month to 16 years old. Seventeen patients underwent liver transplantation and at least one died.

Children present clinically with acute hepatitis, elevated levels of transaminases in the blood (AST or ALT>500 IU/L), and many children have jaundice, nausea, abdominal pain, fatigue, and drowsiness. Some children report gastrointestinal symptoms, including diarrhea and vomiting, in the weeks leading up to admission. Most children do not have fever.

Etiology of hepatitis in children of unknown origin

All children with unexplained hepatitis in the UK have not been vaccinated against SARS-CoV-2, so a direct link between this vaccine and unexplained childhood hepatitis can be ruled out. The UK Health Department's investigation team collected detailed information on the children's diet, drinking water and personal daily habits through questionnaires, and found no common exposure to poisoning factors. Although toxicological investigations are still ongoing, it is speculated based on epidemiological features and the clinical features of the case that infectious factors are more likely to cause the disease.

Laboratory findings in all reported cases excluded hepatitis A, B, C, D and E. Of the 169 cases published by the WHO, 74 children tested positive for adenovirus, of which 18 were identified as adenovirus type 41. SARS-CoV-2 was detected in 20 children, and 19 were co-infected with adenovirus and SARS-CoV-2. Of the 13 cases previously reported in Scotland, 11 tested for adenovirus and 5 were positive, and 5 had been or were infected with SARS-CoV-2. In addition, norovirus, rhinovirus, enterovirus, parainfluenza virus, human cytomegalovirus, human coronavirus NL63 and Sapporo virus have been detected in individual cases (no more than 2 cases). Adenovirus was widely detected in reported cases in the United States, with 5 sample sequencing results showing adenovirus type 41. Laboratory tests suggest that adenovirus may be associated with unexplained childhood hepatitis, but other infectious causes or environmental factors cannot be completely ruled out. Metagenomic sequencing and sequence analysis are still underway, and the results have not yet been published.

Although it has been speculated that adenovirus infection may be one of the potential factors contributing to severe acute hepatitis in children, it is not possible to explain the severity of its clinical symptoms. Adenovirus is a common human pathogen, a double-stranded DNA virus, without envelope, divided into 7 subgroups (A ~ G subgroup) more than 50 serotypes, mainly through the respiratory tract and contact in human-to-human transmission, often causing respiratory diseases. Different serotypes of adenoviruses can cause other diseases such as gastroenteritis (inflammation of the stomach or intestines), conjunctivitis (pink eye), and cystitis. Adenoviruses types 40 and 41 are transmitted mainly through the digestive tract (see Table 1). Adenovirus type 41 infection usually presents with diarrhea, vomiting, and fever with respiratory symptoms. Adenovirus infection is usually self-limiting and causes only mild illness or symptoms. Acute hepatitis caused by adenovirus infection is uncommon, especially in immunocompetent children, although there have been case reports of hepatitis developing after infection with adenovirus in immunocompromised children. It is unclear whether adenovirus type 41 infection is the cause of acute hepatitis in healthy children.

For example, the detection rate of moderate and severe diarrhea samples in children (<5 years old) in Sanjiang Dong Autonomous County, Liuzhou City, Guangxi Zhuang Autonomous Region showed that the detection rate of adenovirus types 40 and 41 was 16.5%, and the detection rate of other adenoviruses was as high as 39.1%, and the detection rate of adenovirus in children's diarrhea samples in Zhengding County, Shijiazhuang City, Hebei Province was also high.

At present, it is speculated that the possible causes of hepatitis in children of unknown origin are as follows:

1. It is a new variant of a known virus, which may be adenovirus, but it cannot rule out the possibility of other pathogens, such as coronavirus, rhinovirus, enterovirus, parainfluenza virus, etc. variants. If it is a new variant of adenovirus, it is worth paying attention to whether it is related to the recombination and mutation of adenovirus under the selection pressure that may occur after mass vaccination of adenovirus vector vaccine.

2. Epidemic prevention and control during the COVID-19 pandemic may result in reduced exposure of some young children to common pathogens, resulting in a different development of their immune systems than children of the same age before the COVID-19 pandemic. When young children are subsequently infected with common pathogens such as adenovirus, they have a different immune response or disease manifestation than their previous peers; it is also possible to have a subsequent infection with adenovirus or other viruses based on previous SARS-CoV-2 infection, or sars-CoV-2 co-infection with adenovirus or other viruses.

3. The presence of a new pathogen that has not yet been discovered.

4. Non-infectious factors, such as environmental toxins and drugs, cannot be completely ruled out.

epilogue

Based on epidemiological investigation information and clinical laboratory test results, it is speculated that unexplained childhood hepatitis in many countries in Europe and the United States is likely to be caused by an infectious pathogen, and its source of infection is temporarily confirmed cases, suspicious cases and epidemiologically related cases. According to current reports, confirmed cases are children under 16 years of age, but in the absence of a pathogen, it cannot be ruled out that people of other age groups will also be infected with the associated pathogen.

The presence of similar unexplained childhood hepatitis on the mainland remains to be investigated. According to the criteria for confirmed cases, the occurrence of hepatitis of unknown cause in the mainland (hepatitis A, B, C, D and E) can be collected since January 1, 2022, compared with the data of previous years, and whether there is also an increase in hepatitis cases in children of unknown cause in the mainland. On the other hand, because of the imported risk of the disease, preparation must be made early. Given the differences in immunization backgrounds and prevalent pathogens in different countries and regions, it is not possible to assess the risk of disease caused by exposure to this pathogen in mainland children at this stage. As far as personal protection is concerned, the mainland is still in an important stage of actively preventing and controlling the COVID-19 epidemic, and in the context of promoting the development of good personal hygiene habits, parents especially need to care about children's hand hygiene.

The WHO predicts that the number of cases of hepatitis in unexplained children is likely to continue to increase in the future, and with the release of more case data and laboratory test results, many questions about the etiology of hepatitis in unexplained children may be answered, so that prevention and control measures can be more targeted.

Professor Zhang Wenhong commented

Cases of unexplained hepatitis occur annually, often referring to liver damage without known hepatitis viruses or of known causes, which is not uncommon in children. However, hepatitis of unknown cause of concern to WHO this time has the characteristics of cluster incidence, and the incidence rate is higher than in previous years. In this case, it makes sense to consider the risk of infectious diseases. Some correlation with adenovirus infection has been found. But adenovirus infection is a very common phenomenon and can cause pneumonia or diarrhea, so why are there so many cases of severe hepatitis this year, and only in children? At present, it is speculated that it is a long period of new crown isolation, children have not been exposed to this virus for a long time, and sudden contact will produce more serious immune damage, which is consistent with the phenomenon that emerging infectious diseases tend to be heavier in the early stages of disease outbreaks. If this is the cause, rather than a new virus that has not been discovered before, the subsequent effects of this unexplained hepatitis will gradually decline, but we also need to be vigilant against unknown pathogens, even if the probability of such an emerging infectious disease pandemic is not high. In addition, as awareness continues to deepen, the definition of the current confirmed case is also constantly being updated. (Original title: Outbreaks and causes of hepatitis in children of unknown cause in the United Kingdom and other places)

END

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