PHOTO: WIDDERS FAMILY906 27 MAY 2022 • VOL 376 ISSUE 6596 science.org SCIENCENEWS | IN DEPTHP
hysicians at pediatric liver centers in
the United Kingdom have been meet-
ing regularly to work out how best to
care for children with a mysterious
hepatitis that has afflicted at least
197 youngsters in the United King-
dom and more than 600 worldwide.
But they can’t agree.
“It’s proving immensely difficult to get
everyone to agree how on Earth to manage
these children,” says Will Irving, a virologist
at the University of Nottingham.
At the center of the debate are conflict-
ing theories about what is causing healthy
young children to suddenly become jaun-
diced and fall seriously ill with acute liver
inflammation. One hypothesis suggests
the damage is being done by adenovirus, a
common childhood infection that normally
causes coldlike symptoms and could be
treated with an antiviral drug. Another sug-
gests the cause is a rogue immune response
to previous infection by SARS-CoV-2—which
could be treated with immune-suppressing
drugs such as steroids. A third hypothesis
proposed this month brings them together,suggesting adenovirus infection forms a de-
structive partnership with SARS-CoV-2 that
sets the immune system loose on the liver.
“The clinicians have got a really difficult
dilemma,” Irving says. “With a sick child, do
you give steroids? Do you give [an antiviral
drug]? Do you give both?”
Cases remain rare but some children be-
come seriously ill: About 9% of 180 cases in
the United States have required liver trans-
plants, the U.S. Centers for Disease Control
and Prevention (CDC) said on 18 May; six
children have died. In the United Kingdom,
11 children have needed transplants, with
no deaths as of 16 May.
Official bodies including CDC and the
UK Health Security Agency (UKHSA) have
elevated the adenovirus hypothesis. Infec-
tion with adenovirus can cause hepatitis in
immune-suppressed children but is not
known to do so in healthy kids. But CDC says
adenovirus had been found in nearly half of
the U.S. cases as of 18 May “and continues to
be a strong lead.” The agency’s most recent
physician alert urges testing of suspected
cases for adenovirus. Adenovirus was also
found in 68% of U.K. children with hepatitis
who were tested for it through 16 May. AndUKHSA, in an announcement on 20 May,
said pointedly, “The investigation continues
to suggest an association with adenovirus.”
“The fact you have it in [nearly] 70% of
cases does suggest that it must have a role,”
says Deirdre Kelly, a pediatric hepatologist
at Birmingham Children’s Hospital, one of a
group of experts advising UKHSA.
But other scientists say adenovirus could
be an innocent bystander. The key ques-
tion, says Isabella Eckerle, a virologist at
the University of Geneva, is “how specific is
this finding of low amounts of adenovirus?
Would we also find it in healthy kids?”
The skeptics note that liver biopsies from
the children have failed to find cells stuffed
with adenovirus, a classic sign of adeno-
viral hepatitis. They say, sometimes heat-
edly, that the agencies are overlooking a
more likely culprit, SARS-CoV-2.
“It is profoundly embarrassing that ma-
jor scientific bodies in U.S. and U.K. are
using such weak circumstantial evidence,”
tweeted Farid Jalali, an adult hepatologist
in Laguna Hills, California. He accused
them of downplaying the “likely possibility
that recent SARS-CoV-2 infection may be
driving the increase in cases.”
Jalali and others suggest SARS-CoV-2
may trigger an immune-mediated attack on
the liver several weeks after infection, just
as other organs can be attacked weeks later
in the condition called multisystem inflam-
matory syndrome in children (MIS-C).
Only some of the children were known
to be infected with SARS-CoV-2 around the
time their hepatitis was diagnosed—15%
in the United Kingdom. But a recent CDC
study estimated that 75% of all U.S. chil-
dren under 12 have been infected, 31% of
them between December 2021 and Febru-
ary. The European Centre for Disease Pre-
vention and Control on 20 May reported
evidence of prior SARS-CoV-2 infection in
19 of 26 children with hepatitis. It also
showed that most cases in Europe occurred
during a large Omicron wave. Only a tiny
minority of the affected children were vacci-
nated against SARS-CoV-2; vaccines are not
available for children under 5 years old, the
age group in which most cases occur.
The debate is not academic. It “has every-
thing to do with whether [a] patient stays
alive or not,” Jalali said in an interview. If
adenovirus is damaging the liver, the pow-
erful antiviral drug cidofovir could be de-
ployed. But if the liver damage results from
a sustained immune reaction, immune-
suppressing drugs could be lifesaving. You
had better not be wrong, Jalali says. “If you
mistakenly assume some infectious processLiviah Widders, 4, of Cincinnati, Ohio, awaited
a liver transplant in December 2021.Researchers scramble for data on the cause—and therefore
the treatment—of liver disease in children
INFECTIOUS DISEASE
By Meredith WadmanCoronavirus, adenovirus, or
both? Hepatitis poses mystery