Roberta DeBiasi, chief of infectious disease for the hospital, knew she couldn’t conclude anything from one case. But it set off alarm bells. And as the researchers delved further into the mystery, they found evidence that a variant with a mutation called N679S may be circulating in the Mid-Atlantic region.
No one knows whether the infant, who was seen in September and has since recovered, represents a chance case, a sign of things to come, or worrisome changes already in motion as new, more transmissible variants race across the Earth.
“It could be a complete coincidence,” DeBiasi said. “But the association is pretty strong. If you see a patient who has exponentially more virus and it’s a completely different variant, it is probably related.”
Jeremy Luban, a virologist at the University of Massachusetts Medical School, said the viral load in the infant’s nose “in itself, is shocking and noteworthy.” However, he was cautious in speculating that it “could be because of N679S, or simply because it is a [newborn] with an immature immune system, permitting the virus to replicate out of control.”
As the world heads into a new stage of the pandemic where the virus is changing in significant ways, the United States is just starting to understand its growing family tree because of the lack of a coordinated national effort to sequence and monitor variants. The White House announced last week that it will invest an additional $200 million into genomic sequencing to help track new variants — making it possible to analyze 25,000 per week. But experts say it will be weeks, if not months, before this boosts the understanding of how the virus is changing within U.S. borders.
Until then, findings like the one from Children’s National remain single puzzle pieces that may be important in determining the direction of the pandemic — or merely transient scientific curiosities.
The question of the new variants’ effect on children is especially important as school systems across Europe, in countries besieged by the variant first identified in the United Kingdom, have closed and in some cases begun reopening at the same time that the top U.S. health authority has declared that it is largely safe to reopen. Under pressure from President Biden and state officials, numerous districts that had remained fully virtual — including D.C. Public Schools — are now reopening for the first time this month.
Kids in general do not get sick from the coronavirus the way adults do. The rate of severe illness is low, and about 270 children have died from covid-19, the disease caused by the virus, or an associated illness in a sea of 500,000 U.S. deaths. It is still not known why. It could be something about the biology of youth, some scientists have said, or perhaps a higher likelihood of being exposed to a similar pathogen more recently.
There’s no evidence that the variant with N679S, or others from the United Kingdom, South Africa and Brazil, are more dangerous to children. But health officials in the United Kingdom have said they are monitoring an unusual surge in infections, especially among children ages 6 to 9, that is disproportionate to their share of the population. In Italy, officials have been puzzled by a spike in cases in the northern town of Corzano among those in elementary school and even younger.
And according to a Feb. 9 report in the medical journal the BMJ, Israel also has experienced “a sharp rise in covid-19 infections among young people, with more than 50,000 children and teens testing positive in January — more than Israel saw in any month during the first and second waves.”
In the United States, doctors at several major medical centers reported a holiday surge in hospitalizations of children that paralleled what happened in adults, and a January and February spike in cases of MIS-C — a rare but potentially fatal post-viral syndrome associated with covid-19 that occurs four to six weeks after a coronavirus infection.
Those increases are in line with what would be expected given the waves of community spread of the virus nationwide. But at Children’s National, DeBiasi said the hospital has been surprised to find that more MIS-C patients have needed intensive care-level support than last year. About 40 to 60 percent were in the ICU last year, she said, and now it’s closer to 90 percent.
Some other institutions, however, reported no change in the severity of cases. Doctors at Boston Children’s and UCLA Health said the MIS-C cases have been more numerous because of the surge in community infections, but the course of the illness appears similar to before.
A doctor at Intermountain Primary Children’s Hospital in Salt Lake City also reported no change in the severity of cases, but said physicians have noticed that more children with MIS-C have active infections than in the past, when nearly all tested negative for the virus — prompting the group to send samples off for sequencing in recent days.
“It’s hard to say what is out of the ordinary, because with covid, we’re always finding something new,” said Ngan Truong, a pediatric cardiologist. “But we’ve wondered, ‘Is this because of new strains? Is virus shedding longer than previous strains?’ ”
Why hospitals in different parts of the country are seeing a divergence in these cases is unclear.
DeBiasi said it could be pure happenstance. Perhaps another virus — maybe a cold or flu — circulating in the D.C. area last year resulted in a milder disease that was mistaken for MIS-C, or perhaps there was another regional difference unrelated to the coronavirus.
However, the team cautioned in a paper posted on Feb. 10 that the critical location of the newly documented variant in the infant — in the spike protein area that researchers think gives it an advantage in attaching to receptors in bodies — as well as evidence that it is infecting other patients in the region, “underscores the need for increased viral sequencing to monitor variant prevalence and emergence, which may have a direct impact on recommended public health measures and vaccination strategies.”
Genomic sequencing in kids
As of Feb. 11, more than 3 million children in the United States had tested positive for the virus since the beginning of the pandemic. The biggest surges have occurred since mid-November, when cases increased at a rate of 100,000 to 200,000 each week. But the nation’s scant genomic sequencing has focused almost exclusively on adults.
Harvard researcher Adrienne Randolph, who is leading an international research effort on children and the coronavirus, said that in the early days of the pandemic, fewer children were infected, so they were not prioritized for sequencing. But now that cases are surging in the youngest Americans, and the virus is evolving, the need to expand sequencing is urgent, she said.
“A couple of hospitals saying their cases are more severe in kids doesn’t mean nationally this a problem,” Randolph said. “But we have to investigate. With new variants, it could be some of these kids were infected with them.”
Variants being closely tracked from South Africa, Brazil and the United Kingdom have a change in their spike protein that affects how it binds to cells, which scientists fear is making the variants more transmissible or possibly able to reinfect. Another in California appears to be potentially be more resistant to treatment with monoclonal antibodies.
“There are likely other variants of concern we’re not aware of right now,” said Neville Sanjana, a geneticist at the New York Genome Center and New York University who studies coronavirus mutations. “That’s the real worry.”
Sanjana, whose team was among the first to document the effect of the D614G mutation that is all over the world today, said that as more adults get vaccinated, it becomes even more important to watch how mutations affect children, who will be among the last to be vaccinated, with clinical studies still ongoing. Experts also think sequencing in children could provide an early warning of more infectious strains, because kids appear more resistant to infection.
A study in Open Forum Infectious Diseases in June, for example, found that 95 percent of children seen at hospitals in Southern California were infected with virus with the D614G mutation as early as April. At that time, only 60 percent of the state’s infected population had strains containing that mutation.
“If you’re not capturing what’s happening in young individuals, that is shortsighted and we wouldn’t be able to fully understand how the virus may be different in people of different ages,” said Jennifer Dien Bard, director of the virology lab at Children’s Hospital Los Angeles and one of the study’s co-authors.
Another big finding in the paper, which looked at 35 children, is the sheer diversity in the variants infecting them — 97 unique changes from the original virus first identified in Wuhan, China, were sequenced — but no particular variant appeared to correlate with disease severity. That provided important evidence to researchers that it probably was something about the children, their environment or the way they were infected that determined who got very sick and who had a milder case.
DeBiasi’s Children’s National study involved 76 patients, 27 of whom had their full genomes analyzed. The researchers found evidence similar to the Southern California study that most variants did not seem to affect the severity of disease. Most notably, they found five children with identical viral genomic profiles — but the course of their illnesses looked very different. And on the flip side, the hospital saw two children with similar-seeming MIS-C cases, but each had very different viral genotypes.
The newborn with the high viral load was an anomaly.
The initial measures of the amount of virus were so unbelievably high that the researchers ran them again on a different type of machine and found similar results. Genomic sequencing revealed that the virus infecting the child had the D614G spike variant mutation, as well as something they hadn’t seen before: the N679S mutation. The finding was so unusual that they reran this analysis on another platform with the same results.
DeBiasi and the other authors noted that the particular change appears to be related to how the virus enters the body.
William Hanage, an epidemiologist at the Harvard School of Public Health, speculated that “the spike mutation might have something to do with why that [viral load] was so high, but I think it is premature to draw strong conclusions.”
Hanage urged caution when interpreting the significance of children with high viral loads: “It is probable that in order for infection in kids to be noticed at all, the viral loads have to be very high.”
At Children’s National, no other patients had the same variant, but when researchers queried an emerging international database used by scientists worldwide to compare genomic sequences, they were surprised to find six other samples in the Maryland and Virginia area, and two more in Delaware.
Alan Beggs, a Boston Children’s genomics expert, said the fact that N679S appears in the database — which represents a tiny portion of the virus circulating in the world — suggests that “this variant is present in some significant percentage of the population in this area.” He also said there was evidence that the eight cases had a common genetic background, suggesting that all “were originated from one patient initially somewhere in the region.”
There were four additional cases in Australia and Japan and one in Brazil. Medical information about them was not available in the database.
Like other researchers, Beggs emphasized that the paper “does not have evidence this new variant has anything to do with making little babies sicker.” However, he added, when so many millions of people have active infections, anything can happen in terms of mutations.
“The take-home message is that as a country or society, we are doing poorly in identifying worrisome changes in the evolving virus,” he said, “and this is just more evidence that needs to change.”
Joel Achenbach contributed to this report.
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