A new idea explains unexplained cases of paediatric hepatitis of unknown aetiology, and it’s complex.
Two new, undisclosed studies from the UK suggest that infants with hepatitis may have been co-infected with two viruses and had a genetic tendency to have an over-exuberant immune response when that happened.
The dominant hypothesis was that adenovirus 41, present in many sick youngsters, caused liver injury. Adenovirus 41 causes liver damage in immunocompromised children but not in those with healthy immune systems.
The new investigations found AAV2 in the blood and liver tissues of some affected children. Children also have adenoviruses or herpes viruses.
A2 is a dependoparvovirus. Without another virus, it can’t multiply in host cells.
If right, this explanation doesn’t rule out adenovirus 41’s role in the instances, said Angela Rasmussen, a virologist at the University of Saskatchewan’s Vaccine and Infectious Disease Organization.
It shows AdV 41 (or another helper virus) is necessary but not sufficient, she told STAT.
“If this is correct,” she said, “you need all three” — a helper virus like adenovirus 41, adeno-associated virus 2, and a genetic predisposition.
In fact, Judy Breuer, senior author of one of the articles, said the group thinks adenovirus 41 is implicated. Breuer, a clinical virologist at University College London and consultant at Great Ormond Street Hospital for Children, told STAT the adenovirus is playing a role.
Adeno-associated viruses haven’t been considered hazardous, therefore clinicians don’t check for them. But her research cast a wide net when investigating samples from certain outbreak youngsters, not hunting for a specific virus but for all possible disease agents.
She noted that AAV2 may be a bystander in these hepatitis cases.
Second set of experts, largely from Scotland, looked at genetic makeup of impacted infants there. 8 of 9 children evaluated have a genetic variation that impacts immune system response. 16% of Scottish blood donors have this mutation. Doctors in Scotland were the first to report odd hepatitis cases in the spring.
Breuer said the children’s immunological genetic constitution made them prone to a novel reactivity to one or both infections.
Mario Koopmans, chief of viroscience at Erasmus Medical Center in Rotterdam, Netherlands, said the notion deserves additional study but is not conclusive. It “suggests a link between AAV2 and Adeno or other viruses,” she wrote.
The new studies need peer evaluation. If they are right, they will help explain why several medical centres that treat children with liver problems have observed an exceptional number of unexplained hepatitis cases since fall and into spring.
Over 1,000 cases from 35 countries were reported to WHO. 22 died and 46 required liver transplants. In the US, the CDC is investigating 355 suspected cases. Late in June, 20 of the children needed liver transplants and 11 had died.
Studies also suggested that the pandemic’s disruption of normal life may have contributed to greater transmission of adeno-associated virus 2 and adenoviruses when Covid-19 control measures dropped, because more children would have been susceptible. It would have led to more incidences of hepatitis among children.
“The recent incident followed relaxation of pandemic restrictions and was one of many diseases, including norovirus, that occurred in UK children after normal [social] mixing,” Breuer and her co-authors wrote.
Yes, said Koopmans. “The combination of two viruses and a genetic susceptibility factor fits the theory that the rise in cases was due to the atypical occurrence of ‘common’ infections, as the patterns for numerous endemic viruses were interrupted by COVID 19 control methods.”
Alasdair Munro, a paediatric infectious disease researcher at University Hospital Southampton, considered the papers persuasive.
“Everything seems to fit, will be interesting to see if further examination can establish this as the cause,” he remarked on Twitter.
But Rasmussen stressed that there are other pieces to the picture, including how this trio of events caused the damage.
She wrote, “This is correlation, not causation.” To prove this is the cause, the mechanism must be determined.
She urged other groups duplicate the findings of these two U.K. children. I hope all investigators outside the U.K. who have reported on these instances are reviewing their sequence data for AAV2 sequences and genotyping.
The unexplained cases of paediatric hepatitis have sparked a passionate and sometimes nasty debate on Twitter, with many scientists and medics saying that those researching the outbreak were ignoring what seemed evident – that the sickness was likely a result of past Covid infection.
Data from the US showed no increase in paediatric hepatitis of unknown origin, liver transplants for paediatric hepatitis, or adenovirus 41 infections in the past year compared to before the pandemic. That doesn’t mean there hasn’t been an increase in cases caused by this constellation of triggers, but that the overall number of paediatric hepatitis cases without a reason has not changed.