When medical professionals think they’re seeing something new, or an unusual spike in cases of something known, disease detectives — epidemiologists — are generally tasked with solving the mysteries of the case. Some of these seeming events turn out to be nothing more than coincidence. Some, however, are very real and teach us more about what a known disease agent can do or introduce us to a new bug that poses a hitherto unrecognized threat.
Increasingly, it appears that the mounting reports of unusual pediatric hepatitis cases will turn out to be the latter type of event. As of May 1, at least 20 countries reported 228 cases of pediatric hepatitis of unknown etiology or origin, with more than 50 suspected cases still under investigation. At least 18 of the children have required liver transplants and at least one has died, the World Health Organization said Wednesday. The question is no longer “Is this real?” but “What is triggering severe liver inflammation in previously healthy little kids?”
The usual suspects — the hepatitis viruses labeled A through E — were quickly ruled out. But that leaves a number of options on the table. The good news is there are hypotheses and there are clues and there are public health experts and scientists in a number of countries trying hard to crack the case. But solid answers will take time.
Here’s a glimpse at the different kinds of work being done to come up with those answers.
Epidemiologists train for just such a moment. But they do not work alone. Teams that investigate outbreaks are often composed of people whose expertise spans a range of specialties — toxicologists, microbiologists, laboratory experts, and medical professionals to properly collect the medical samples that may make or break an investigation, explained Eric Pevzner, chief of the famed Epidemic Intelligence Service at the Centers for Disease Control and Prevention.
When the CDC is asked for help in a disease investigation — it must wait for an invitation, from state or local authorities, or from health officials overseas — job one is to figure out what types of experts should be placed on the case.
“The first thing we look at is: What do we think we might be dealing with? And what are the skill sets that we need for the team of people we might send?” Pevzner told STAT. “If it’s something that might involve transmission of something from animals to humans, we’re going to make sure we include someone who’s a veterinarian…. If it’s something that is potentially … an environmental exposure, we might send someone who has that type of background, who has a toxicology background, and we might send some microbiologists.”
With something like hepatitis, having people from various backgrounds is crucial. Multiple pathogens can induce liver inflammation but so can contaminants and medications and excess consumption of alcohol. This kind of search requires a broad set of skills.
Pathologists are needed, to study biopsies taken from the livers of affected children as well as the failed livers that were removed from the children who received transplants. Needed, too, are people who can conduct genetic sequencing of viruses, and can compare any viral findings to previously known versions of those bugs, to see if genetic changes in a known virus might explain why something that has been seen before appears now to be acting in different ways.
Toxicologists are also involved here, though the wide geographic dispersal of the cases — reported from Japan and Indonesia, Scandinavia and the Middle East, North America and Western Europe — makes the notion of common exposure to a toxin not impossible, but perhaps less likely.
Early on in epidemiological investigations, work focuses on a trio of factors that in the field’s shorthand are described as person, place, and time. Who got sick? Where did they get sick? And when?
That information helps investigators focus their efforts as they design a key tool of outbreak investigations — detailed questionnaires that are put to affected people, or in the case of young children, likely their parents, to try to determine what they might have been exposed to, consumed, or experienced. Most of these cases are kids under the age of 5 — the median age of the Alabama cases was just under 3 years old — though some have been as old as 16.
“One of the initial things that we do is what we call trawling questionnaires,” said Richard Pebody, head of the high threats pathogen team at the World Health Organization’s European regional office, which has taken the lead on the investigation for the WHO. “That’s a common tool epidemiologists use to generate hypotheses — where they just ask questions or gather information from cases on a wide range of possible potential exposures to then see which ones are the ones that sort of pop up frequently which might then be explaining what’s going on.”
These questionnaires can be incredibly time-consuming to administer. Julia Petras, an EIS officer at the CDC who led an investigation into four cases of melioidosis — two of which were fatal — in the United States last year, recounted the work that went into scouring one of the victim’s household for a possible source. (The bacteria that causes melioidosis, Burkholderia pseudomallei, isn’t found in the U.S., and the cases hadn’t traveled abroad, so the source had to have been something bought locally.)
“I mean the number of products in any given U.S. household is mindboggling,” Petras said. An aromatherapy room spray imported from India was eventually found to be the source.
Once hypotheses have been generated, a case control study may be performed, where people who had the condition are compared to similar people who did not.
If all the cases in an investigation are tightly focused in a single area, suspicion will mount that there’s a single source, a so-called point source outbreak, CDC’s Pevzner explained. A toxic leak into a water supply. A shipment of spoiled food.
If there are cases in lots of places, as is the situation with the unexplained hepatitis cases, it makes some things easier and others harder, he suggested. Cases reported from a number of countries make it appear that this is truly a new phenomenon. But there’s always the chance that all the jurisdictions are not seeing the exact same thing. Or that the attention being paid to an unusual increase in cases of condition X elsewhere leads countries to report cases that actually fall within their normal numbers, he said.
There’s also a possibility that what’s known as detection bias may be clouding the picture. A place may be finding more cases because it is now using newer, more sensitive tests. But the actual number of cases that are occurring has not changed.
While this strange episode first came to the public’s attention in mid-April, in reality the effort to solve this mystery began six months ago, when four young kids who had turned yellow with jaundice showed up at Children’s of Alabama in Birmingham over a two-week stretch.
Neither the hospital’s gastroenterology team nor its pediatric infectious diseases team could figure out what had triggered hepatitis in these previously healthy children. In the run of a normal year, the hospital would see four or five such pediatric patients, who they would eventually label as having hepatitis of unknown etiology or origin when they could not find a cause. Now, they had seen a year’s worth of cases in the last half of October.
“They all came in one after the other,” Helena Gutierrez, a liver transplant specialist and an assistant professor at the University of Alabama at Birmingham, told STAT. “It was very concerning to me and my partner.”
The Children’s doctors tested the children for a spate of things — the aforementioned hepatitis viruses A through E, SARS-CoV-2 (the virus that causes Covid-19), the Epstein-Barr virus, cytomegalovirus, and adenoviruses. The latter normally cause colds, but some members of the large family can cause gastrointestinal problems and some have been seen to cause hepatitis in immunocompromised children.
The hospital eventually saw nine cases of pediatric hepatitis of unknown etiology between October and February. None of the kids had active Covid infections at the time they were in hospital. But all nine tested positive for adenoviruses; in five of the cases, those viruses were identified as adenovirus type 41. “That seems like too much to be just chance,” said Markus Buchfellner, a pediatric infectious diseases specialist at Children’s.
Buchfellner said the hospital tested these patients for adenovirus because there had been cases of adenovirus-triggered hepatitis in Alabama in the past. “But what we have not seen before is adenovirus 41 causing hepatitis.”
In March, 4,000 miles away, Rachel Tayler experienced the shock Gutierrez had faced six months earlier.
A pediatric gastroenterologist, Tayler is the resident expert on hepatitis at the Royal Hospital for Children in Glasgow, Scotland. If children in western Scotland develop hepatitis, they turn up at her hospital.
Acute hepatitis in previously healthy little kids is rare, though every year there are some and every year a few of the cases are labeled hepatitis of unknown etiology. In a typical year, Scotland had about eight pediatric hepatitis cases, with half being attributed to a known cause and the remainder being of unknown etiology. On average, two of those mystery cases would end up in Tayler’s care.
But suddenly, boom-boom-boom, there was an influx of kids with liver inflammation — eight in the last two weeks of March alone. Going back through hospital records, the team found another five. On March 31, Tayler reached out to Public Health Scotland, to alert the agency of what she and colleagues were seeing. “To go from that” — the previous average of two unknown etiology cases a year — “to then suddenly have 13 is why we’ve recognized that there was something going on,” she said in a recent interview. (Scotland has since diagnosed a total of 17 cases.)
And these kids were sick.
“The severity of that illness was one of the other things we were concerned about. Because children do present and will have mild evidence of liver inflammation with lots of common viral infections. But the degree of it was the thing that was concerning to us,” Tayler said.
One of the Scottish children required a liver transplant, as had two of the Alabama children.
Five of the Scottish children tested positive for adenoviruses. Several tested negative and results are still pending on a few. Later, when the United Kingdom Health Security Agency alerted hospitals across England, Wales, and Northern Ireland to be on the lookout for unexplained pediatric hepatitis cases, numbers started to rise quickly.
In a recently published report on the situation, the UKHSA reported that 40 of 53 affected children tested for adenovirus were positive. Preliminary work to further identify the viruses indicated many were consistent with type 41, it said.
As they tried to home in on what was making their tiny charges so sick, doctors and public health authorities looked for clues in who was getting sick, and who wasn’t — a standard epidemiological approach.
There was no evidence of clustering of cases in households, which pushed down the list of potential hypotheses any notion that they might be linked to contaminated food or household product. Likewise, authorities in Scotland noted the affected children didn’t live along a single waterway or linked waterways. Contaminants in water slipped down the list of possible causes.
The Alabama children hailed from different parts of the state, which lessened the likelihood that they had all been exposed to a common toxin that could explain their mysterious illnesses.
Though the finding of adenovirus type 41 is enticing and seems, as Buchfellner put it, too consistent to be by chance, investigators know they can’t stop searching. Getting too invested in an idea about the possible cause of an outbreak is a rookie mistake. You have to remain open to what the evidence reveals, said Petras, the EIS officer at the CDC.
“There’s that fine balance, I think, that we had to achieve between keeping an open mind, but also trying to look for themes and pursuing the search,” Petras said in an interview. “It is a difficult balance but it’s so critical because if you don’t do that, you’re probably going to miss your smoking gun.”
Buchfellner said the team in Alabama knew they couldn’t jump to conclusions. “The workup [of cases] continued looking into other causes of hepatitis, such as things like toxins, autoimmune hepatitis, underlying genetic, or metabolic conditions that cause hepatitis — which there are a lot,” he said.
“They all got pretty comprehensive workups in addition to the infection testing.”
Many armchair epidemiologists on Twitter feel Covid infection — current or previous — could explain the hepatitis and seem to feel the idea has gotten short shrift, though that is still very much on the list of working hypotheses listed in the UKHSA report. Some think that perhaps a previous infection triggered the inflammatory condition known as multisystem inflammatory syndrome in children or MIS-C. But Buchfellner said the Alabama children didn’t meet the case definition for MIS-C.
Still another theory is that the public health measures employed over the past couple of years to reduce spread of Covid-19 may have set up some children to have more severe illness when they contracted a bug that might previously have been innocuous. Masking, online schooling, and social distancing have dramatically reduced transmission of viruses that cause colds or influenza.
Buchfellner isn’t convinced. “For me, I don’t know how that explains ‘Why hepatitis?’ I think that’s the key that we really need to figure out. Why is adenovirus 41 causing hepatitis when it really hasn’t before?”
This article has been updated with new global totals of reported cases.
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