Here comes again, children with unexplained hepatitis

Author | South Wind Window reporter Zhang Danjun

In the context of the global outbreak of the new crown epidemic, the emergence of an unexplained acute hepatitis has once again tightened the nerves of public health departments around the world.

World Health Organization spokesman Yasharevic said on May 3 that as of May 1, at least 228 cases of hepatitis of unknown etiology had been reported from 20 countries and more than 50 more cases were being investigated. Yasarevich said most of the existing cases have been found in Europe, with cases also reported in Asia, the Americas and Oceania. For China, it is particularly alarming that the disease has spread in neighboring countries, and cases have been detected in Japan, Singapore and Indonesia. On 2 May, the Indonesian Ministry of Health reported three cases of hepatitis deaths in children of unknown etiology, bringing the number of deaths from the disease worldwide to at least four.

Will this unexplained hepatitis become the next major disease that plagues humanity?

01

The alarm goes off

In March 2022, the Royal Children's Hospital of Glasgow in Scotland, England, received five children with acute severe hepatitis in three weeks, sounding the alarm of the local public health department.

The children, who were between the ages of three and five, collectively showed vomiting and jaundice, and most had alanine transferase (ALT) levels of more than 2,000 IU/L, compared to the normal range of 10 to 40 IU/L. Due to their serious condition, three children were transferred to England to await liver transplant evaluation, and one of them underwent a transplant.

They have not detected a common virus that causes acute viral hepatitis, and due to technical limitations, it is normal to find no cause clinically. However, hepatitis is not a very common disease in children, and in the past, there were usually no more than 4 cases of hepatitis of unknown etiology per year in the entire Scotland region.

Sensing the unusualness, on 5 April, the UK reported to the World Health Organization 10 cases of hepatitis in children of unknown etiology found throughout the UK.

The World Health Organization said on April 23 local time that as the number of cases of acute hepatitis of unknown origin increased among children, it has now led to the death of a child

Subsequently, the data grew rapidly in a short period of time, and 3 days after the report, a total of 74 cases that met the definition were further detected across the UK. As of 29 April, the UK Health Security Agency reported that the cumulative number of cases had reached 145.

Countries began to strengthen the detection of similar diseases, and after the United Kingdom, the European countries of Ireland and Spain also reported the existence of suspected cases. At the other end of the Atlantic, the United States reported that Alabama Children's Hospital hosted five children with hepatitis of unknown etiology between October and November last year, earlier than the cases detected in the UNITED Kingdom.

According to information provided by the U.S. Centers for Disease Control and Prevention, from October 2021 to February 2022, Alabama Children's Hospital had a total of nine patients with hepatitis of unknown etiology, with a median age of 2 years and 11 months at admission, of which 8 developed scleral jaundice, and 7, 6, and 3 reported vomiting, diarrhea, and upper respiratory tract symptoms, respectively.

On April 29, the U.S. Centers for Disease Control and Prevention released a report showing that nine young children in Alabama developed unexplained hepatitis

Similar to the cases that emerged at the Royal Children's Hospital in Glasgow, UK, all 9 patients tested negative for the common hepatitis virus and ruled out several other causes of paediatric hepatitis. The patients were in a more severe condition, with 3 developing acute liver failure, two of whom underwent liver transplants.

In addition to Alabama, 5 other states, including Wisconsin in the United States, have also reported confirmed cases. On 27 April, the United States reported the first case of hepatitis death in children of unknown etiology.

At the same time, there were also children with hepatitis of unknown etiology in the Asian region. On April 25, Japan's Ministry of Health, Labor and Welfare reported the first suspected case in Asia, and three days later, the number of cases in Japan rose to three. On 30 April, the Ministry of Health of Singapore notified that a 10-month-old infant was suffering from acute hepatitis of unknown etiology.

On April 26, the European Centre for Disease Control and Prevention reported that more than 190 cases have been reported from more than 10 countries since the UK reported the detection of cases of hepatitis in children of unknown etiology (CCTV News screenshot)

In addition to the countries mentioned above, countries that have reported confirmed and suspected hepatitis of unknown cause include Israel, Denmark, the Netherlands, Italy, Norway, France, Romania, Belgium, Portugal, Greece, Cyprus and Canada. According to the World Health Organization, as of April 21, the age of these confirmed and suspected patients was as young as one month and the maximum was 16 years old, and about 10% of patients needed liver transplantation.

02

Where is the pathogen

The World Health Organization defines the global "confirmed case" of hepatitis as a child aged 10 years and under who has acute hepatitis (not caused by hepatitis A, B, C, D, and E virus) and whose aspartate aminotransferase (AST) or alanine transaminase (ALT) is greater than 500 IU/L since 1 January 2022.

An infectious disease expert who did not want to be named told the South Wind Window that the current emergence of hepatitis in children with unknown etiology in the world has two characteristics, one is that it has a sporadic and epidemic trend, and the other is that the patient's condition is more serious and the disease progresses rapidly. The scholar speculated that severely ill patients showed signs of liver failure more quickly after infection or liver damage due to non-infectious factors.

Hepatitis is inflammation of the liver, and it occurs for a variety of reasons, the most common is viral hepatitis caused by hepatitis viruses such as hepatitis A, B, and C. However, after medical testing, these viruses were not found in the children who were affected this time, and other causes such as toxins, immune systems, and familial inheritance were also ruled out. The current important challenge for health systems in countries is to find the pathogen of unexplained hepatitis.

Because hepatitis patients in different regions exhibit different characteristics, the hypotheses given by local medical experts are also different.

One theory is that hepatitis of unknown etiology is associated with the new crown virus. A recently reported case in Singapore has been infected with the new crown virus, and 11 of the 12 children with hepatitis of unknown etiology reported in Israel have been infected with the new crown virus, and Moser Glasberg, director of the Pediatric Liver Transplant Center at Schneider Children's Medical Center, handled 7 of the cases, and she said in an interview with the Israeli newspaper Haaretz that all 7 children were infected with the new crown virus about three and a half months before the emergence of hepatitis.

But she also said that this does not mean that hepatitis of unknown etiology is a "post-covid-19" phenomenon.

Globally, as of 21 April, 20 of the 169 patients with hepatitis of unknown etiology counted by the World Health Organization (WHO) were detected in the body with SARS-CoV-2 (i.e., the new coronavirus), which is not too high compared to the number of patients detected with adenovirus.

A growing number of professionals believe that hepatitis of unknown etiology is associated with adenovirus. A report released by the U.S. Centers for Disease Control and Prevention showed that nine patients from Alabama tested positive for adenovirus; the World Health Organization said at least 74 cases have detected adenovirus.

According to a report released by the US Centers for Disease Control and Prevention, 9 patients from Alabama tested positive for adenovirus

Adenovirus is a non-enveloped double-stranded DNA virus, which is common in nature, it can be transmitted through contact with droplets, and after entering the human body, it binds to different recipient cells to cause infection, which can cause acute gastroenteritis, conjunctivitis, respiratory infections, etc., and occasionally can cause hepatitis and encephalitis.

According to the Guardian, Bowen, co-chair of the Infectious Diseases Association of Australia, said the adenovirus theory was by far the most likely explanation, but "there is still considerable uncertainty as to whether this is an absolute causative factor."

As the vast majority of patients are too young to be vaccinated against COVID-19, the UK Health Security Agency notes in the document that hepatitis of unknown etiology is not related to the COVID-19 vaccine.

03

Changes in the immune system

Even if adenovirus is considered a pathogen of unknown hepatitis, there are still some problems to be explained.

In general, adenovirus is less harmful to people with normal immunity, and healthy people will only show mild self-limiting symptoms after infection with adenovirus. Its serious consequences are more affected by immunocompromised people who have experienced tissue and organ transplantation, AIDS and other immune-impaired people, and it is extremely rare to cause hepatitis in immune-healthy children.

Greg De Mury, a professor at the University of Wisconsin's School of Medicine and Public Health, said in an interview that he had only seen a handful of such cases, "The latest thing about this is that it infects healthy children, and it is more numerous than we expected." ”

In this regard, a common view is that it may be that the lockdown and epidemic prevention policies implemented in the early days of the new crown epidemic have caused young children's immune systems to develop less than their pre-epidemic children during this period, and adenovirus has triggered a more violent immune response.

Li Tong and Zhuang Hui, scholars from the Department of Pathogenic Biology and the Center for Infectious Diseases research at Peking University School of Basic Medical Sciences, explained this on the "Chinese Journal of Liver Disease" public account: "Due to the prevention and control measures of the new crown epidemic and better personal protection, young children have a reduced risk of contracting various pathogenic microorganisms during their growth, possibly due to the lack of trained immunity, compared with children of the same age before the epidemic, their immune systems may not be mature and sound enough. Therefore, common adenovirus infections can lead to acute severe hepatitis. ”

At the same time, the UK found a significant increase in adenovirus in the community (especially detected in stool samples from children) after experiencing a low-level cycle in the early stages of COVID-19 prevention and control, and the Netherlands also reported an increase in community adenovirus transmission.

In addition to the affected immune system in young children, genomic changes in the adenovirus itself are another cause that cannot be ruled out. On April 29, Xie You and others wrote on the "Huashan Infection" public account that if the pathogen is a new variant of adenovirus, it needs to be considered 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 (a new crown vaccine).

From this point of view, for whatever reason, unknown hepatitis is like a major test that people will face in the post-epidemic era.

To prevent acute hepatitis of unknown etiology, the World Health Organization says care should be paid to children's handwashing and respiratory hygiene. Although most of the patients currently have no epidemiological association, the above experts told the South Wind Window that if it is indeed adenovirus-induced hepatitis, it is contagious. If similar unexplained childhood hepatitis occurs in China, genetic testing or liver aspiration biopsy can be used to identify the pathogen.

Experts also said that similar to the new crown virus pneumonia, the spread of adenovirus is in line with the spread of infectious diseases, the initial stage of the disease is often more serious, in the middle and late stages of the epidemic, the symptoms will be alleviated.

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