Children in many countries suffer from hepatitis of unknown cause, the cause of which remains to be investigated

A child photographed on a street in London, England, on March 13. (Xinhua News Agency reporter Li Ying/photo)

On 15 April 2022, the World Health Organization (WHO) website published a message that acute hepatitis of unknown etiology had been found in the UK, and some cases were positive for COVID-19 and adenovirus.

Found in multiple countries

The WHO said it was informed on 5 April of 10 cases of severe acute hepatitis of unknown etiology among children under 10 years of age in central Scotland, some of which tested positive for both the new coronavirus (SARS-CoV-2) and adenovirus that caused COVID-19 (COVID-2019). Of the 10 cases, nine developed symptoms in March and one in January. Symptoms include jaundice, diarrhea, vomiting, and abdominal pain, all of which were detected during hospitalization. As of 8 April, a total of 74 such patients have been identified across the UK. Six children with severe illness in the UK received liver transplants.

Following the discovery of unexplained hepatitis in the UK, the Madrid region of Spain also announced on 13 April that madrid, Aragón and Castilla-La Mancha had reported a case of severe hepatitis in young children of unknown origin, one of whom had undergone a liver transplant. In addition, the European Centre for Disease Control and Prevention (ECDC) said that countries such as Denmark, Ireland and the Netherlands have also reported cases of unexplained acute hepatitis in children.

Unexplained childhood hepatitis also occurs in the United States. Over time span, unexplained hepatitis began in the fall of 2021. On April 14, 2022, the U.S. Centers for Disease Control and Prevention (CDC) reported that since fall 2021, nine cases of hepatitis infection in children ages 1 to 6 have been detected in Alabama. 2 out of 9 patients require a liver transplant. The CDC said it is currently working with the Alabama Department of Public Health and other state departments to investigate the causes of the hepatitis outbreak.

Although the countries in which hepatitis is found is unknown, this acute hepatitis has some common features and symptoms, mostly in children under 13 years of age, with common symptoms of significant elevation of liver enzymes, usually accompanied by jaundice (yellowish skin), discoloration of urine or stool, itchy skin, fever, nausea, and abdominal pain.

There have been no deaths to date from patients with unexplained hepatitis in all countries.

Associated with an adenovirus infection?

Hepatitis is a contagious disease that is usually transmitted only through contact with hepatitis patients and virus carriers, however, there is currently only one UK case of close contact with a patient with hepatitis, i.e. it may be transmitted through close contact with a patient with hepatitis.

The WHO's preliminary judgment is that the cause of hepatitis is unknown. According to the report, laboratory tests exclude hepatitis A, B, C, D and E viruses. Therefore, the WHO's risk assessment is that while some cases have tested positive for COVID-19 and adenovirus, the virus should be genetically identified to identify any potential associations between cases.

However, based on the situation in each country, the researchers first speculated that unexplained hepatitis may be related to adenovirus infection. In Spain and the UK, as many as half of infected children test positive for adenovirus when they enter hospitals. Five of the 9 children in Alabama, USA, tested positive for adenovirus and were confirmed to be adenovirus type 41. To that end, researchers in Alabama are conducting genetic testing to determine if there is a link between adenovirus type 41 and liver disease that infects local children.

Although many adenoviruses can infect humans, they mainly cause respiratory diseases. Adenoviruses are a large family with six subfamily A-F, with many more branches in the subfamily. The main sites of infection of serotypes of adenoviruses are different, and the symptoms are different. Adenovirus mainly infects the human mucosa, most of which can cause respiratory symptoms such as cough, runny nose, sore throat and fever, and in severe cases, pneumonia, diarrhea, eye inflammation and rash.

Even if adenovirus can cause gastrointestinal symptoms such as diarrhea in the past, it generally does not cause hepatitis, but it is easy to secondary or complicated by myocarditis, toxic hepatitis and heart failure after severe pneumonia caused by adenovirus. However, whether adenoviruses can now cause hepatitis requires repeated studies to prove that, at a minimum, to meet koch's principles.

Related to COVID-19 infection?

Some of the patients with unexplained hepatitis have tested positive for the new crown virus, is the latter related to hepatitis?

The original strain of the new coronavirus only infected the upper respiratory tract and lower callus and lungs, and in severe cases can cause pneumonia, while the mutated virus, such as the Now China and the world's main infection of the Omilon BA.2 branch, has not caused pneumonia symptoms, only upper respiratory tract symptoms. The reason is both that they mutate and that the human cells they excel at invading have different structures and compositions.

The new crown virus is mainly combined with the cell surface of angiotensin converting enzyme 2 (ACE2) to invade human tissue cells, ACE2 is not only present in the lungs, kidneys, cardiovascular and other organs, but also in the human conjunctiva, cornea, aqueous humor and retina is also expressed, but the expression in the kidneys, liver and muscle tissue is low, therefore, so far, the new crown virus infected people rarely appear kidney and liver symptoms.

In addition, the distribution of ACE2 is species- and tissue-specific, and ACE2 is actually the highest expression in human testicles, but there are fewer patients with reproductive system problems after infection. This shows that the new crown virus still selectively invades cells mainly by targeting ACE2 on the cells of respiratory tissues and harming human health.

Moreover, the harm of the new crown virus to people also lies in the path of its invasion of the human body, mainly through the respiratory tract into human tissues and organs, so it mainly hurts the respiratory system, as for the damage to other tissues and organs, it may be through the blood, lymphatic circulation to reach other organs caused, due to the small amount of virus, thus causing other tissues and organs the damage is also low. Therefore, strong evidence is also needed to prove that the new crown virus is related to unknown hepatitis, or even causes hepatitis.

Even though 5 children with hepatitis recently tested positive for COVID-19, the timing varied. 2 people were admitted to the hospital 3 months before admission, 2 people were admitted to the hospital within 11 days, and 1 person was admitted to the hospital with a rapid antigen test positive. These circumstances do not indicate that hepatitis is directly related to the new crown virus.

In addition, the researchers also believe that hepatitis in children is not related to the new crown vaccine, because all children with hepatitis are not vaccinated against the new crown.

Other analyses

Different pathogens can also cause the same or similar conditions, so there is a special link in clinical differential diagnosis. Multiple pathogens and symptoms of the disease can be present in the same person at the same time, such as people with pneumonia can also be tested positive for hepatitis B virus. Now many countries of unknown hepatitis patients have both the new crown virus and adenovirus positive may indicate that these people are infected with the new crown virus and adenovirus, but did not show symptoms, they did not perceive, in the discovery of unexplained hepatitis only incidentally found positive for the new crown virus and adenovirus.

In addition, the researchers speculate that isolation during the COVID-19 pandemic may make children's immune systems weak and more susceptible to serious illnesses due to viral infections. If you are infected with the new crown virus, you will suffer from other diseases such as hepatitis at the same time as the loss of immunity, that is, hepatitis is one of the complications of the new crown, but this speculation also needs evidence to confirm.

From the discovery and diagnosis of hepatitis, it can also show how important scientific rigor is for the diagnosis and prevention of diseases. After the discovery of hepatitis A and hepatitis B, people thought that all hepatitis was these two types of hepatitis, but researchers found out after 10 years of efforts that there is also a blood-induced hepatitis - hepatitis C, before the doctor diagnosed hepatitis has a common feature, liver enzymes are significantly elevated, generally jaundice. However, the researchers found that after ruling out hepatitis A virus and hepatitis B virus infection, there were still a large number of cases of hepatitis, and that the virus was also detected from chimpanzee blood after genetic engineering techniques were injected into the chimpanzee liver with an unknown RNA variant of hepatitis, and its pathological changes were similar to those of human patients with chronic hepatitis. At this point, it was confirmed that there was non-A and non-B hepatitis, that is, hepatitis C. The three discoverers, Harvey Alter, Charles Rice and Michael Horton, also jointly won the 2020 Nobel Prize in Physiology or Medicine.

These circumstances suggest that the relationship between unexplained hepatitis and adenovirus coronavirus cannot be confirmed and needs to be studied to reveal the truth. WHO encourages Member States to identify, investigate and report potential cases that meet the case definition, as well as investigate biological, chemical or other pathogen causes of unexplained hepatitis. Furthermore, the WHO does not recommend any restrictions on travel and trade in the UK or any other country where cases of unexplained hepatitis have been found.

Zhang Tiankan