Is the pediatric hepatitis outbreak real? A top WHO physician weighs in | Science
It has been 3 months since the United Kingdom reported severe, unexplained hepatitis was sending young children to hospitals in unusual numbers. The initial handful of cases reported in Scotland on 31 March were soon joined by dozens and then hundreds, primarily from Europe, the United States, and the United Kingdom. As of 22 June, the global total, from 33 countries, has swollen to 920 probable cases, the World Health Organization (WHO) reported on 24 June. The U.S. Centers for Disease Control and Prevention (CDC) reported the same day that U.S. cases through 15 June numbered 296.
Yet after weeks of intensive effort by scientists, the cause of the acute liver inflammation that has killed 18 of the children globally and led to liver transplants in 41 others remains unclear. Adenovirus infection, SARS-CoV-2 infection or a delayed reaction to it, or a combination of both, are on the list of possible culprits.
Recent data raise questions as to whether these cases constitute a true outbreak. One survey published by the European Centre for Disease Prevention and Control in May found elevated case numbers in some countries, but another survey did not. Researchers at CDC this month reported no increase, compared with prepandemic levels, in pediatric liver transplants, U.S. emergency room visits, or hospitalizations for pediatric hepatitis between October 2021 and March. Nor did they find more adenovirus in stool samples from children during this period, compared with before the pandemic.
To discover whether a true outbreak is unfolding, a WHO team led by infectious disease physician Philippa Easterbrook this week aims to launch a survey of hepatologists at pediatric liver units and intensive care units around the globe, asking for case counts and data from the prepandemic era as well as from recent months. Science spoke with Easterbrook last week.
This interview has been edited for brevity and clarity.
Q: What have you learned in the 4 weeks since WHO last reported in depth on the status of the outbreak?
A: The positive news is the U.S., the U.K., and Europe seem to have a declining trajectory of new case reports. … It’s reassuring. The working hypotheses [for what’s behind the outbreak] are pretty much the same [ones] that emerged early. … The adenovirus, and current or past COVID-19 infection, either operating independently or working as cofactors in some way together.
Adenovirus is still the most detected pathogen where there is available data: 52% positivity in Europe, 65% in the U.K., and about 45% in the U.S.
Q: What about the coronavirus as the possible culprit?
A: Currently [active] COVID-19 is detected in about 10% of cases … [that are tested by] PCR [polymerase chain reaction] in Europe and the U.S.
The information that is really missing is on past COVID infection in these children. … [That’s] difficult to get and difficult to interpret because there was so much COVID transmission going on in late December 2021 and early 2022. [CDC recently reported that an estimated 75% of U.S. children had been infected by February.] Most children will be positive [when tested for antibodies that indicate a previous SARS-CoV-2 infection.] So, it’s difficult to prove a point there.
Q: How do you reconcile the CDC report indicating no apparent U.S. outbreak with the apparently large numbers in the United Kingdom and the ambiguousness of data from other countries?
A: We have always known there is this phenomenon of acute hepatitis of unknown [cause] in children. It is really important that we tease out: Is this just more of the same and because of greater awareness and greater reporting we are just seeing more of this? Or is there definitely something new—something above the background rate?
There are often not good records where you can easily pull out these cases that occur every year.
Q: Are new data expected soon?
A: Hopefully we will get some better information with the global survey we are launching soon.
A key result will be from a case/control study [in the United Kingdom] looking at adenovirus infection rates in children hospitalized with and without hepatitis. … If we see the same rates in those populations, [adenovirus] is just a bystander infection; it’s not likely to be causal. Or it could be a cofactor, but on its own it wouldn’t be causal. [The UK Health Security Agency plans to publish the case/control study results on 7 July, according to a spokesperson.]
Most of the [other] in-depth scientific investigations are inevitably going to be done in the high-income countries with a lot more cases, that have access to genetic sequencing, to host genomics, metagenomics, and toxicology studies. We are asking countries that are reporting cases to … please store samples. … [WHO this month] launched a minimum data set for reporting cases and separate guidance on collecting samples for laboratory testing.
It has been 3 months since the United Kingdom reported severe, unexplained hepatitis was sending young children to hospitals in unusual numbers. The initial handful of cases reported in Scotland on 31 March were soon joined by dozens and then hundreds, primarily from Europe, the United States, and the United Kingdom. As of 22 June, the global total, from 33 countries, has swollen to 920 probable cases, the World Health Organization (WHO) reported on 24 June. The U.S. Centers for Disease Control and Prevention (CDC) reported the same day that U.S. cases through 15 June numbered 296.
Yet after weeks of intensive effort by scientists, the cause of the acute liver inflammation that has killed 18 of the children globally and led to liver transplants in 41 others remains unclear. Adenovirus infection, SARS-CoV-2 infection or a delayed reaction to it, or a combination of both, are on the list of possible culprits.
Recent data raise questions as to whether these cases constitute a true outbreak. One survey published by the European Centre for Disease Prevention and Control in May found elevated case numbers in some countries, but another survey did not. Researchers at CDC this month reported no increase, compared with prepandemic levels, in pediatric liver transplants, U.S. emergency room visits, or hospitalizations for pediatric hepatitis between October 2021 and March. Nor did they find more adenovirus in stool samples from children during this period, compared with before the pandemic.
To discover whether a true outbreak is unfolding, a WHO team led by infectious disease physician Philippa Easterbrook this week aims to launch a survey of hepatologists at pediatric liver units and intensive care units around the globe, asking for case counts and data from the prepandemic era as well as from recent months. Science spoke with Easterbrook last week.
This interview has been edited for brevity and clarity.
Q: What have you learned in the 4 weeks since WHO last reported in depth on the status of the outbreak?
A: The positive news is the U.S., the U.K., and Europe seem to have a declining trajectory of new case reports. … It’s reassuring. The working hypotheses [for what’s behind the outbreak] are pretty much the same [ones] that emerged early. … The adenovirus, and current or past COVID-19 infection, either operating independently or working as cofactors in some way together.
Adenovirus is still the most detected pathogen where there is available data: 52% positivity in Europe, 65% in the U.K., and about 45% in the U.S.
Q: What about the coronavirus as the possible culprit?
A: Currently [active] COVID-19 is detected in about 10% of cases … [that are tested by] PCR [polymerase chain reaction] in Europe and the U.S.
The information that is really missing is on past COVID infection in these children. … [That’s] difficult to get and difficult to interpret because there was so much COVID transmission going on in late December 2021 and early 2022. [CDC recently reported that an estimated 75% of U.S. children had been infected by February.] Most children will be positive [when tested for antibodies that indicate a previous SARS-CoV-2 infection.] So, it’s difficult to prove a point there.
Q: How do you reconcile the CDC report indicating no apparent U.S. outbreak with the apparently large numbers in the United Kingdom and the ambiguousness of data from other countries?
A: We have always known there is this phenomenon of acute hepatitis of unknown [cause] in children. It is really important that we tease out: Is this just more of the same and because of greater awareness and greater reporting we are just seeing more of this? Or is there definitely something new—something above the background rate?
There are often not good records where you can easily pull out these cases that occur every year.
Q: Are new data expected soon?
A: Hopefully we will get some better information with the global survey we are launching soon.
A key result will be from a case/control study [in the United Kingdom] looking at adenovirus infection rates in children hospitalized with and without hepatitis. … If we see the same rates in those populations, [adenovirus] is just a bystander infection; it’s not likely to be causal. Or it could be a cofactor, but on its own it wouldn’t be causal. [The UK Health Security Agency plans to publish the case/control study results on 7 July, according to a spokesperson.]
Most of the [other] in-depth scientific investigations are inevitably going to be done in the high-income countries with a lot more cases, that have access to genetic sequencing, to host genomics, metagenomics, and toxicology studies. We are asking countries that are reporting cases to … please store samples. … [WHO this month] launched a minimum data set for reporting cases and separate guidance on collecting samples for laboratory testing.
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