When previously healthy little kids started showing up in hospitals with failing livers last fall and this spring, startled doctors and public health authorities didn’t know what was behind what they were seeing. They also didn’t know if what they were seeing was new.
There have always been cases of hepatitis in children for which a cause cannot be found — such cases are labeled pediatric hepatitis of unknown etiology. But these cases occur in very low numbers and they aren’t well-studied or tracked. So when doctors in Alabama and Scotland reported seeing more of these cases over a few weeks then they would normally see in a year, they didn’t have reliable statistics against which to compare the seeming surge.
Now scientists at the Centers for Disease Control and Prevention have come up with some estimates for the normal rate of this condition, at least in the United States. Their findings, published earlier this week in the online journal Morbidity and Mortality Weekly Report, may come as a surprise.
Their research suggests there has not been an increase in cases of pediatric hepatitis of unknown origin, at least in the United States. Nor has there been a rise in the number of pediatric liver transplants, which a portion of these children have needed. Likewise, the rate of detections of infections caused by adenovirus 41 — a stomach bug virus that has been implicated as a potential trigger of these hepatitis cases — has not changed over time, the CDC scientists reported.
(They note that authorities in the United Kingdom believe they may have seen a small increase in pediatric hepatitis cases, but the report they point to says the lack of pre-pandemic data there makes it hard to be certain.)
The CDC findings don’t identify what is causing the cases of pediatric hepatitis of unknown origin, 290 of which are under investigation in this country. Elsewhere, about three dozen countries have detected cases since the United Kingdom raised the alarm in early April. As of June 6, the World Health Organization had been notified of over 800 probable and suspected cases.
But the CDC findings may help to rule some things out. With rates unchanged since before the Covid-19 pandemic, a theory espoused by scientists from Israel — that this is some sort of post-Covid condition — becomes harder to argue.
“It doesn’t mean that Covid still can’t have some collateral role with all of this. But I think these kind of data helps support that that’s probably not the cause,” explained veteran epidemiologist Michael Osterholm, who was not involved in the CDC work.
The CDC researchers drew data from four different sources looking at emergency department visits and hospitalizations for hepatitis of unknown etiology in kids under age 11, from January 2018 to March 2022 for the former and January 2019 and March 2022 for the latter.
They also compared monthly liver transplant figures for children under the age of 18 for whom the diagnosis was hepatic necrosis — liver failure — of unknown etiology from October 2017 through March 2022. Finally, they studied lab data on stool samples tested for adenovirus 40 or 41 during the period from October 2017 to March 2022 from Labcorp, a large commercial laboratory network.
There were no statistically significant increases in hospitalizations for hepatitis of unknown origin in the period after the start of the Covid-19 pandemic; nor was there a statistically significant increase in the number of liver transplants per month, the researchers found. The number of positive adenovirus stool tests varied — within a range — before the pandemic and it did after the pandemic as well. But the positivity rate from last October, when the Alabama cases were detected through March, when Scotland started to report cases, did not exceed pre-pandemic rates.
“The cases that we’re currently describing, at least the trends, do not seem to be different to what we described prior to the pandemic,” senior author Jacqueline Tate, lead of the epidemiology team in CDC’s viral gastroenterology branch, told STAT in an interview.
“I think that does point out that with all the changes that we’ve undergone with the pandemic … that does not seem to have had the same impact on the trends in hepatitis, if it was a driving factor.”
The work was done to establish baseline rates, she said.
“We’re trying to look at what the landscape is. Is there something that’s dramatically changed? We don’t think so. But I think in looking at this and just realizing that we have improved diagnostics, improved accessibility to information, we may be able to explain better what’s going on with this hepatitis,” Tate said.
The fact that baseline rates haven’t changed doesn’t mean there’s nothing going on with pediatric hepatitis of unknown etiology, said Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy. Rather, a couple of clusters of cases — in Alabama and in Scotland — may be giving the scientific community an opportunity to figure out what has been responsible for some of the cases all along.
In disease detective work, having baseline data is crucial to differentiate something new from something newly recognized, said Jeffrey Duchin, health officer for the Seattle and King County public health department and an infectious diseases professor at the University of Washington.
The seeming increase in cases could be “enhanced ascertainment” — increased detection, he said, adding that the CDC analysis is reassuring, suggesting we’re not seeing a major increase in pediatric hepatitis.
When medical events happen at very low levels — an unexplained case here, another there — it can be very tough to get to the bottom of what is going on, said Osterholm, who has been involved in cracking a number of public health mysteries.
But sooner or later, by fluke, there will be a cluster of cases. And if the cluster is spotted and the clinicians involved work it up thoroughly and report their findings, as both groups did, other physicians will start looking and realizing that they too saw cases that fit that definition, he said.
“It’s not unusual at all to see new conditions where somebody gets a case series of five or six cases, somebody else will look carefully and get a case series of five or six and pretty soon those five and six and five and six grow to 700,” Osterholm said.
“With really comprehensive information, like the CDC just presented here … the bottom line is this very well could have been going on for some time before Covid ever occurred at this low level,” he said.
The current attention to pediatric hepatitis may help to move some of these cases out of the “unknown etiology” column. But it will take more and different types of studies to identify what is causing them. Tate said the CDC currently has such a study underway. So does the U.K. Health Security Agency, which has repeatedly said that adenovirus infection — possibly in combination with some other factor — appears to be linked to these cases.