Eighteen months into the covid-19 pandemic, with the delta variant fueling a massive resurgence of disease, many hospitals are hitting a heartbreaking new low. They're now losing babies to the coronavirus.
The first reported covid-related death of a newborn occurred in Orange County, Florida, and an infant has died in Mississippi. Merced County in California lost a child under a year old in late August.
"It's so hard to see kids suffer," said Dr. Paul Offit, an expert on infectious diseases at Children's Hospital of Philadelphia, which — like other pediatric hospitals around the country — has been inundated with covid patients.
Until the delta variant laid siege this summer, nearly all children seemed to be spared from the worst ravages of covid, for reasons scientists didn't totally understand.
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Although there's no evidence the delta variant causes more severe disease, the virus is so infectious that children are being hospitalized in large numbers — mostly in states with low vaccination rates. Nearly 30% of covid infections reported for the week that ended Sept. 9 were in children, according to the American Academy of Pediatrics.
Doctors diagnosed more than 243,000 cases in children in the same week, bringing the total number of covid infections in kids under 18 since the onset of the pandemic to 5.3 million, with at least 534 deaths.
Experts say it's a question of basic math. "If 10 times as many kids are infected with delta than previous variants, then, of course, we're going to see 10 times as many kids hospitalized," said Dr. Dimitri Christakis, director of the Center for Child Health, Behavior and Development at the Seattle Children's Research Institute.
But the latest surge gives new urgency to a question that has mystified scientists throughout the pandemic: What protects most children from becoming seriously ill? And why does that protection sometimes fail?
"This is an urgent and complex question," said Dr. Bill Kapogiannis, senior medical officer and infectious disease expert at the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
"We are doing everything we can to address it, using all the tools we have available," Kapogiannis said. "Answers can't come soon enough."
Investigating Immune Systems
For much of the pandemic, doctors could only guess why children's immune systems were so much more successful at rebuffing the coronavirus.
Despite the alarming number of hospitalized children in the recent surge, young people are much less likely to become critically ill. Fewer than 1% of children diagnosed with covid are hospitalized and about 0.01% die — rates that haven't changed in recent months, according to the American Academy of Pediatrics. Most children shrug off the virus with little more than a sniffle.
A growing body of evidence suggests that kids' innate immune systems usually nip the infection early on, preventing the virus from gaining a foothold and multiplying unchecked, said Dr. Lael Yonker, an assistant professor of pediatrics at Massachusetts General Hospital.
In a series of studies published in the past year, the husband-and-wife team of Drs. Betsy and Kevan Herold found that children have particularly strong mucosal immunity, so called because the key players in this system are not in the blood but in the mucous membranes that line the nose, throat and other parts of the body that frequently encounter germs.
These membranes act like the layered stone walls that protected medieval cities from invaders. They're made of epithelial cells — these also line many internal organs — which sit side by side with key soldiers in the immune system called dendritic cells and macrophages, said Betsy Herold, chief of the division of pediatric infectious diseases at the Albert Einstein College of Medicine.
Significantly, these cells are covered in proteins — called pattern recognition receptors — that act like sentries, continuously scanning the landscape for anything unusual. When the sentries notice something foreign — like a new virus — they alert cells to begin releasing proteins called interferons, which help coordinate the body's immune response.
In an August study in Nature Biotechnology, Roland Eils and his colleagues at Germany's Berlin Institute of Health found that kids' upper airways are "pre-activated" to fight the novel coronavirus. Their airways are teaming with these sentries, including ones that excel at recognizing the coronavirus.
That allows kids to immediately activate their innate immune system, releasing interferons that help shut down the virus before it can establish a foothold, Eils said.
In comparison, adults have far fewer sentinels on the lookout and take about two days to respond to the virus, Eils said. By that time, the virus may have multiplied exponentially, and the battle becomes much more difficult.
When innate immunity fails to control a virus, the body can fall back on the adaptive immune system, a second line of defense that adapts to each unique threat. The adaptive system creates antibodies, for example, tailored to each virus or bacterium the body encounters.
While antibodies are some of the easiest pieces of the immune response to measure, and therefore often cited as proxies for protection, kids don't seem to need as many to fight covid, Betsy Herold said. In fact, the Herolds' research shows that children with covid have fewer neutralizing antibodies than adults. (Both kids and adults usually make enough antibodies to thwart future coronavirus infections after natural infection or vaccination.)
While the adaptive immune system can be effective, it can sometimes cause more harm than good.
Like soldiers who kill their comrades with friendly fire, a hyperactive immune system can cause collateral damage, triggering an inflammatory cascade that tramples not just viruses, but also healthy cells throughout the body.
In some covid patients, uncontrolled inflammation can lead to life-threatening blood clots and acute respiratory distress syndrome, which occurs when fluid builds up in the air sacs of the lung and makes it difficult to breathe, Betsy Herold said. Both are common causes of death in adult covid patients.
Because kids typically clear the coronavirus so quickly, they usually avoid this sort of dangerous inflammation, she said.
Research shows that healthy children have large supplies of a type of peacekeeper cell, called innate lymphoid cells, that help calm an overactive immune system and repair damage to the lungs, said Dr. Jeremy Luban, a professor at the University of Massachusetts Medical School.
Kids are born with lots of these cells, but their numbers decline with age. And both children and adults who are sick with covid tend to have fewer of these repair cells, Luban said.
Men also have fewer repair cells than women, which could help explain why males have a higher risk of dying from covid than females.
Both children and adults can develop "long covid," the lingering health issues experienced by about 10% of younger adults and up to 22% of those 70 and older. Studies suggest that 4% to 11% of kids have persistent symptoms.