Infectious Disease

Virus pairing creates ‘perfect storm’ for unexplained hepatitis surge in children

August 12, 2022

5 min read


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Fagan reports no relevant financial disclosures.


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New research has linked the incidence of unexplained hepatitis in pediatric patients to a pair of viruses — adenovirus type F41 and adeno-associated virus 2 — as well as potential markers of genetic mutation.

From October 2021 to July 2022, the WHO reported 1,010 probable cases of severe acute hepatitis of unknown etiology across 35 countries, including the Unites States (33% of global cases) and the United Kingdom (27%). The first cases reported were an unusual cluster of nine patients aged 2 to 11 years in Alabama.

“What we currently believe is that the adenovirus F41 initially detected is only part of the story.  One or more additional viruses, when added to adenovirus 41, create the 'perfect storm' where they help each other in making the situation worse.

According to a report from Gutierrez Sanchez and colleagues in The New England Journal of Medicine, these initial cases were severe, with only a few days between symptom onset, ICU admission and, for some, liver transplantation. At the time, it was unclear whether adenovirus infection alone, or in combination with other factors, contributed to disease.

“There have been similar incidents described in the past where patients with severe hepatitis had adenovirus in the blood but not detected in the liver biopsies,” Henry Shiau, MD, a pediatric hepatologist at the University of Alabama at Birmingham and Children’s of Alabama, said in a university press release. “It’s unclear if the biopsies missed evidence of adenovirus presence due to sampling error or if the infection could be playing an indirect role, such as triggering a dysregulated immune response.”

While adenovirus type F41 is commonly found in children, it typically does not induce severe symptoms in otherwise healthy children, Elizabeth A. Fagan, MD, adjunct professor of internal medicine and pediatrics at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, told Healio.

“Most experts felt that wasn’t the whole story,” Fagan said. “We were struck with this group of children, both in the US and in the UK, where researchers found a vast majority had adenovirus F41, but that virus tends not to cause liver upsets very much in ordinarily healthy children. The question is: Was it just a coincidence?”

Genetic link, COVID-19 connection

Further investigation has uncovered coinfection with other viruses — specifically, adeno-associated virus 2 as well as a family of herpes viruses (eg, HHV6).

“What we currently believe is that the original adenovirus was F41,” Fagan said. “With those other two viruses, the view is that it was ‘the perfect storm’ where they help each other in making the situation worse.”

According to Fagan, an investigation that included 28 children with hepatitis in the UK, five of whom underwent LT, detailed findings from blood, liver tissue, microscopic, genomic and genetic molecular sample studies. Their analysis ruled out the usual causes of viral hepatitis and instead revealed high levels of adeno-associated virus 2 in the blood and liver of these sick pediatric patients. Researchers also uncovered a genetic marker that was associated with an increased immune response in these children. The marker was not activated in most study participants who had hepatitis but did not test positive for adeno-associated virus 2.

“The other interesting finding is this coincided with the SARS-CoV-2 pandemic,” Fagan said. “The general view is that the SARS-CoV-2 virus is not specifically involved. Also, none of these children were vaccinated, so we cannot blame vaccine involvement either.”

Fagan noted that quarantine during the pandemic initially may have had a protective effect on children. Infants are usually exposed to high levels of adenoviruses shortly after birth but sequestering during the pandemic largely prevented this. As parents became more comfortable allowing their children to interact freely with others, there was an increase in viral exposure and subsequent infection in children aged 2 to 5 years.

Warning signs, preventive measures

In this outbreak, the focus has been on children younger than 10 years with typical signs and symptoms of hepatitis that include upset stomach, gastroenteritis, malaise, fever and jaundice. However, this “perfect storm” has created more severe symptoms of liver dysfunction which has led to ICU admission, LT within a few days of symptom onset and, in some cases, death.

A WHO report on 100 probable cases described nausea and vomiting (60%), jaundice (53%), general weakness (52%) and abdominal pain (50%) as the most common symptoms upon presentation. Further, in 167 cases with available data, the median number of days between symptom onset and hospitalization was four.

A complicating feature of this outbreak is that the symptoms in children are often nonspecific but progress rapidly. “Although these cases are very uncommon,” Fagan said, “the pathway is very quick and very severe.”

She continued, “What we tell parents now is that you have to be vigilant. With a typical stomach upset and a little bit of malaise, watch the child carefully. If the child isn’t improving after 2 or 3 days, they should be checked out by a pediatrician or family doctor and, in particular, should be tested for these viruses by what we call whole blood testing, not just typical serum testing.”

Fagan emphasized that these recommendations are for children who are typically healthy. “If, however, the child is immunocompromised for any reason, awareness should be heightened.”

She further noted with no specific “magic treatment” for this unexplained hepatitis, basic standards of hygiene, including handwashing and contamination avoidance, are recommended.

New technology, testing

According to Fagan, current knowledge is limited on the extent of liver damage in affected children because so few had a biopsy. “We do not accurately know the amount of inflammation and fibrosis, or scarring, in the liver tissue, especially in the children who didn’t receive transplants,” she said. “Also, we do not know how the livers are healing in the patients who survived without a transplant.”

Noninvasive imaging technology would allow physicians to better assess these patients and monitor them throughout the course of their disease. “New technology, like LiverMultiScan (Perspectum), measures inflammation, as well as fibrosis, and may provide an ongoing and accurate portrayal of what’s happening inside a child’s liver,” Fagan said.

Genetic testing also may be a consideration, as it could supply a mechanism of action, identify vulnerable children and eventually pave the way for antiviral therapies and vaccines.

“Genetic testing may not help the individual, but on a population level, if we can find out who are the susceptible children that might be a way of targeting children in the future,” she said.

Vigilance is key

Although Fagan is quick to point out that cases of unexplained pediatric hepatitis remain rare, she emphasized the importance of vigilance and swift action. “These children need expert care,” she said. “The timeline between onset of illness and severe illness requiring intensive care and transplantation is literally a few days. One cannot wait around.”

If a physician suspects a case of pediatric hepatitis, Fagan recommends transferring the child to a specialized care facility, preferably a pediatric hepatology center that has transplant and intensive care capabilities.

As the CDC, the American Academy of Pediatrics and various gastroenterological and medical societies continue to investigate and monitor this outbreak, tracking cases becomes paramount and is aided by physicians who diligently report clinical data to public health officials.

“As a country and global population as a whole, we need to get to the bottom of this,” Fagan said.



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