What sends children to hospitals with hepatitis – coronavirus, adenovirus, or both?

Doctors at Children’s Liver Centers in the UK meet regularly to determine how best to care for children with occult hepatitis, which has affected at least 176 children in the UK and more than 500 children worldwide.

But they cannot agree.

“It has proven to be very difficult to convince everyone how to manage these children on Earth,” says Will Irving, a virologist at the University of Nottingham.

At the center of the debate are conflicting theories about why healthy young children suddenly develop jaundice and become critically ill with acute hepatitis. One hypothesis is that the damage is caused by adenovirus, a common childhood infection that usually causes cold-like symptoms and can be treated with an antiviral drug. Another suggests that the cause is a rogue immune response to a previous SARS-CoV-2 infection — which can be treated with immunosuppressive drugs such as steroids. A third hypothesis was proposed earlier this week, suggesting that adenovirus infection forms a devastating partnership with SARS-CoV-2 that causes the immune system to unwind in the liver.

“Physicians face a really difficult dilemma,” Irving says. “With a sick child, do you give steroids? Do you give [an antiviral drug]? Do you give them both? “

Cases remain rare but some children develop serious illnesses: About 9% of 180 affected children in the United States have required liver transplants, according to figures released today by the US Centers for Disease Control and Prevention (CDC); The agency said earlier that five deaths were under investigation. In the UK, 11 cases required a transplant, and there were no deaths as of May 3.

Doctors say most cases can be managed with supportive care, but they urge parents to seek medical attention immediately if their child shows yellowing of the skin and whites of the eyes.

Official bodies including the CDC and the UK Health Security Agency (UKHSA) have raised the adenovirus hypothesis. Adenovirus infection can cause hepatitis in immunocompromised children but is not known to do so in healthy children. But the CDC says the adenovirus has been found in nearly half of US cases as of May 18 and “remains a strong lead.” The agency’s latest medical alert urges testing for suspected cases of adenovirus. Adenovirus was also found in 72% of UK children with hepatitis tested up to 3 May. Announcing its updated case numbers last week, UKHSA said explicitly: “Our investigations continue to indicate an association with adenovirus.”

“The fact that you have this disease in more than 70% of cases suggests that you should have it,” says Deirdre Kelly, a pediatric hepatologist at Birmingham Children’s Hospital who is one of a group of technical experts advising the UK’s Health and Social Services. Role”.

But other scientists and specialists say the adenovirus can be an innocent bystander. The key question, says Isabella Eckerl, a virologist at the University of Geneva, is “How accurate is this detection of low amounts of adenoviruses? Will we also find them in healthy children?”

UKHSA aims to answer a similar question. The methodology for a study that will compare the prevalence of adenovirus in hospitalized children with occult hepatitis with children hospitalized for other causes is expected to be published today.

Skeptics note that liver biopsies from infected children failed to find cells packed with adenovirus, a classic sign of viral hepatitis. They say, sometimes heartily, that agencies are condoning a potential culprit, SARS-COV-2.

“It is deeply embarrassing that major scientific bodies in the US and UK would use such poor circumstantial evidence to distract the public… [from the] It is possible that the recent SARS-CoV-2 infection is the driver of the increase in cases,” tweeted Fred Jalali, an adult hepatologist in Laguna Hills, California recently.

He and others suggest that SARS-CoV-2 may trigger an immune-mediated attack on the liver after several weeks, just as it can attack other organs several weeks after SARS-CoV-2 infection in a condition called pediatric multisystem inflammatory syndrome (MIS). c).

Only some children with hepatitis are currently infected with SARS-CoV-2; In the UK, the figure was 18%. But a recent study by the Centers for Disease Control and Prevention estimated that 75% of American children under age 12 became infected, 31% of them between December 2021 and February. A publication by the European Center for Disease Prevention and Control last week reported evidence that 14 of 19 children infected with hepatitis A had SARS. It also showed that most cases in Europe occurred this year, during the big Omicron wave. Only a small minority of infected children were vaccinated against SARS-CoV-2; Vaccines are not available for children under 5 years old, which is the age group in which most cases occur.

The discussion is not academic. “It all has to do with whether [a] “The patient survives or not,” Jalali said in an interview. If the adenovirus is damaging the liver, the powerful antiviral drug cidofovir may be used in urgent cases. But if the liver damage is caused by an ongoing immune reaction, immunosuppressive drugs may save lives. Jalali says it is better not to be wrong. “If you mistakenly assume that some infectious process is causing liver failure, you can’t approach that patient with immunosuppressive drugs,” because they can hamper the body’s ability to fight off an active viral infection.

Peter Prudden, a pediatric immunologist and pediatrician at Imperial College London, and Moshe Ardeti, a pediatric infectious disease physician at Cedars-Sinai Medical Center, last week published a hypothesis linking the two viruses together..

They noted that so far, 18 of the 18 cases tested in the UK harbor adenovirus-41, a strain of adenovirus that infects the intestine, and SARS-CoV-2 has been found to create gut reservoirs that persist after infection. acute. Brodin and Arditi suggested that after adenovirus infects the intestine, SARS-CoV-2 may act as a co-leader. A small portion of the SARS-CoV-2 spike protein that has been shown to induce extensive, non-specific activation of T cells may increase the immune response to adenovirus, and the rogue immune response may attack the liver. Such a mechanism, in which a piece of the coronavirus spike protein triggers an exaggerated immune reaction, is implicated in the dangerous inflammation found in MIS-C.

Prudden urges clinicians who see children with unexplained hepatitis to collect stool samples that can confirm intestinal reservoirs of SARS-CoV-2 and test for an overactive immune system. If the hypothesis is confirmed — and Prudden stresses it was not — he says an immunosuppressive treatment would be appropriate. “[If] It’s an out-of-control activation of the immune system, so you have to be very aggressive in stopping the immune response.”

Jalali, for his part, is concerned about a preprint version, which has not yet been revised, was published on May 14 by scientists at Case Western Reserve University. The research paper notes that the cases of hepatitis reported so far are the tip of the iceberg of liver damage in children following COVID-19 infection. Researchers compared the electronic records of 246,000 children ages 1 to 10 who contracted COVID-19 between March 2020 and March 2022 with 551,00 children who developed other respiratory infections in that period. In the months following infection, children with COVID-19 were 2.5 times more likely to have elevated levels of enzymes that indicate liver damage, and 3.3 times more likely to have elevated bilirubin, a byproduct of the liver’s breakdown of red blood cells. It causes jaundice. High levels could be a sign of poor liver function.

Claire Wenham, a global health policy expert at the London School of Economics, whose 4-year-old son was hospitalized with hepatitis earlier this month and treated with supportive care, has been closely following the conflicting theories about causation. “There isn’t enough data to make any firm conclusions yet,” she says. “You’re with your doctors and they’re like: ‘We don’t really know… what the path will be.’ “That’s the scary thing as a father.”

Wenham’s son, who developed symptoms several weeks after she and her daughter contracted COVID-19, did not test positive for SARS-CoV-2 but tested positive for the adenovirus. He walked out of the house on May 15. Wenham says his liver enzymes are still elevated. “He has not yet come out of the woods.”

2022-05-19 15:26:46

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