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Covid Protections Kept Other Viruses at Bay. Now They’re Back

In the middle of June, staffers at the Centers for Disease Control and Prevention sent out a bulletin to state health departments and health care providers, something they call a Health Advisory—meaning, more or less, that it contains information that’s important but not urgent enough to require immediate action. (”Health Alerts” are the urgent ones.)

The advisory told epidemiologists and clinicians to be on the lookout for respiratory syncytial virus, usually known as RSV, an infection that puts about 235,000 toddlers and senior citizens in the hospital each year with pneumonia and deep lung inflammation. RSV was cropping up in 13 southern and southeastern states, the agency warned, and clinicians should be careful to test for the virus if little kids showed up sneezing, wheezing, or with poor appetites and inflamed throats.

Normally, this bulletin would be no big deal: The CDC frequently sends out similar warnings. What made it odd was the timing. RSV is a winter infection. By June, it should be gone. Instead, it was spreading—and has since continued to spread up the East Coast.

You can think of the bulletin, and the virus it flagged, like an alarm bell. We already know that the things we did to defend against Covid disrupted the viral landscape over the past 16 months, suppressing infections from almost every winter pathogen. Now RSV’s out-of-season return tells us that we could be headed into viral havoc this winter, and no one knows just yet how that might play out.

“RSV has sprung back quicker than we predicted,” says Rachel E. Baker, an associate research scholar at the Princeton Environmental Institute. She was the first author on a study published last December that predicted lockdowns, masking, and social distancing would suppress RSV and flu in the US by at least 20 percent. “The idea was that, because we have a lack of population immunity—a build-up of susceptibility—things would spread fast, even outside the typical RSV season. And that’s what we’re starting to see right now,” she says. (It turns out, she adds, that the 20 percent was conservative; data is still being gathered, but depending on location, up to 40 percent might have been suppressed.)

To understand why what’s happening now is so off-track, imagine a normal winter. We talk about “flu season,” but, in fact, winter (in either hemisphere) contains overlapping epidemics from a range of respiratory infections—not just flu but RSV, parainfluenza, human metapneumovirus, enteroviruses, adenoviruses, other long-known coronaviruses that don’t cause Covid, and rhinoviruses, which are responsible for at least a third of what we think of as everyday colds.

Despite being common, those viruses aren’t necessarily benign. Flu can cause ear infections, pneumonia, and inflammation of the brain and heart, and has killed anywhere from 12,000 to 61,000 Americans in past seasons. RSV kills up to 500 kids younger than 5 each year. One variety of enterovirus, known as EV-D68, is linked to a floppy paralysis resembling polio. Rhinovirus causes asthma flare-ups.

So it was excellent news when researchers began to notice that the normal cycles on which these viruses occur had been disrupted during Covid. In cities, in counties and provinces, in nations, and broadly across the world, most of the viruses that should have been circulating effectively vanished. Infections caused by them were detected only sporadically, if at all.

Of course, they didn’t actually go away. They just couldn’t get to us: The things we did that protected us from Covid protected us from them, too. But they’re still out there—and now that we’re relaxing our protective behaviors, they are finding us again.

The US isn’t the only place to experience an out-of-season RSV surge. Australia, South Africa, Iceland, and various European countries did also. In France, RSV arrived four months late—April instead of December—according to Jean-Sébastien Casalegno, a physician and virologist at the Institut des Agents Infectieux of the Hospices Civils in Lyon and first author on a March preprint describing the outbreak.

There are not a lot of models to indicate what might happen next. Will RSV return again this year and have a smaller, weaker season in its normal time slot? Will it slowly rotate around the calendar til it ends up back where it belongs? “Seasonality will probably come back after several seasons,” Casalegno says. “What’s complicated is next season, what will happen.”

Viruses are seasonal for complicated reasons, not just because they have evolutionary preferences for particular temperatures and humidity, but because winters tend to be the time when people crowd together indoors. But they are also seasonal because it takes a while to build up a sufficiently large number of vulnerable people—those who have not previously been exposed, or vaccinated if a vaccine exists—to provide a virus with enough territory to reproduce and pass copies of itself to new hosts.

Just how that group of “susceptibles” expands is slightly different for each virus. For RSV, which usually observes an annual cycle, the youngest children are at most risk. By school age, most kids have gained immunity from infection, or from repeated exposures that didn’t cause symptoms but still allowed their immune systems to create a defense.

Children may be susceptible not just because they themselves weren’t exposed, but because their mothers also were not. A national study of RSV antibodies in pregnant women is finding lower levels in their blood than were recorded in past years, which means they may not possess the same degree of protection to pass on. This could mean that, when RSV bounces back, more children might contract the virus or become sicker than they otherwise would, or catch it earlier in their lives, in their most vulnerable months.

EV-D68 is also seasonal, but in a more complicated way. First, its outbreaks occur in summer, not winter. Second, as demonstrated in the first analysis of its seasonality, published in March in Science Translational Medicine, both the respiratory illness it causes and that floppy paralysis seems to recur every two years. That analysis found that the cycles are driven by climate conditions, but also by the immune system: Women who are exposed to EV-D68 while pregnant pass antibodies against it to their infants. Thus, for their first 6 months, babies are protected against the disease, and become vulnerable as that passive immunity wanes. That later vulnerability, combined with seasonality, seems to drive the slower accumulation of susceptibles.

The last EV-D68 outbreak was predicted to occur last summer, in 2020. Just as with RSV and flu, it did not arrive, and for similar reasons: Masking, distancing, hand-washing, and staying home protected kids who would have been vulnerable then. And as with RSV, no one is sure what will happen next.

“There’s nothing about enteroviruses that makes them love even years—they don’t have a lucky number,” says Kevin Messacar, an associate professor of pediatrics at the University of Colorado and Children's Hospital Colorado who was a coauthor on that March analysis. “The model for this whole family of viruses, which is well-described, would not predict that we would wait until 2022 for an outbreak because we missed a cycle. It would say we are continually growing the pool of susceptibles who haven’t seen that virus.”

And then there’s flu—always the most unpredictable of the respiratory infections, because it mutates nonstop to evade our immune defenses, periodically swaps its dominant strains for new ones, and sometimes triggers mild disease years and sometimes devastating ones. Flu is also, right now, the future infection that is causing the most anxiety. Without some dramatic return to social distancing, “I am expecting an inordinately bad flu season,” says Sarah Cobey, an immunologist and associate professor of ecology and evolution at the University of Chicago. “I expect more people to get infected with flu. I also expect there to be a lot of really bad flu infections.”

If more people are susceptible, more are likely to get sick, unless something intervenes. (More on that in a minute.) And as more people get sick, there will be more people passing on the virus to other susceptibles.

But also: Not everyone who gets exposed to the flu gets really sick. Some people have a transient brush with it—just enough to boost their existing immunity, sort of like a top-up. In 2020, not only did few people get severe flus, but few received this immune system refresher. So now the population’s ability to defuse the flu’s attack is out of practice—and those who would normally be somewhat susceptible when a new season begins may be more likely to become seriously ill.

About that intervention: That would be the influenza vaccine. It doesn’t work equally well every year—sometimes its annual recalibration to anticipate flu’s latest mutations misses the target—and not everyone takes it. Still, the shot is the best defense against contracting the flu and becoming seriously ill. But every year, flu shots barely arrive on time; the process that begins with strain selection and ends up with vaccine vials on trucks is always a race to the finish. If the next flu season begins early, it could arrive before the vaccine.

“It’s not uncommon to see small clusters of infection when schools and colleges go back into session,” congregating in close quarters just as cooling temps become flu-friendly, says Emily Toth Martin, an associate professor of epidemiology at the University of Michigan School of Public Health. “Take that and put it into a scenario where we have low population immunity—more dry wood in the forest. If one of those fall clusters starts to take off, the timing of the vaccine could miss it.”

Further complications could arise. The vaccine could be less effective than normal. Its composition every year arises through predictions made from viruses isolated from patients during the previous season, but with so few cases last year, the strain selection might have been skewed. And the flu could cause even more serious illness than it normally does—because it might be contracted by people recovering from Covid-19, who have been left with long-term breathing or lung-clearance problems.

None of this sounds good, but there is a potential bright spot. It's possible that a quirk in how viruses encounter our biology may undercut these dire predictions of illnesses to come. If overlapping waves of different viruses wash over us next winter, our bodies’ responses to the first-arriving infections might excite our immune systems enough to protect us against later ones.

Immediately after the 2009 H1N1 avian flu, Casalegno and colleagues launched a study asking why that epidemic seemed to start later in France than in other European countries. They concluded that an early, intense wave of rhinovirus got in the way of the flu. It triggered immune responses in rhinovirus-infected people that effectively bounced the flu virus off their airway cells.

Last year, Ellen Foxman of Yale Medical School and colleagues showed how that phenomenon, known as viral interference, might work. They demonstrated that rhinovirus infection in cultured cells taken from human airways triggered the release of interferon, an immune system protein, which protected the cells from being entered by the 2009 virus. This June, they showed that the same response could also protect cells against the Covid coronavirus, by keeping it from latching on and replicating. In between those two papers, Pablo Murcia and team at the University of Glasgow confirmed the same result in cell cultures, and also modeled that the interaction could be meaningful for an entire population as well as for individuals. Under certain circumstances, lots of colds could keep Covid from spreading.

All of that is speculative—or at least insufficiently modeled. The population dynamics of seasonal infections are intricate in the best of times, and there is not yet enough data to say what multiple, possibly off-kilter, waves of them will do to people, especially those with lesser immunity or damaged health.

But there is this: We already know how to prevent those infections, or at least how to mitigate them. Much of the world kept them mostly at bay for more than a year through fairly simple actions. Keeping up with wearing masks, staying home when sick, and washing hands could make a difference in how the next viral season unfolds.

“All of these viruses will come back at some point—but if we still have some measures in place, they may come back in a more gradual way,” Messacar says. “If we stop everything simultaneously, there’s a high chance that those pathogens could resurge with even more spread than would typically be seen.”

Update 7-6-2021 5:22 PM: This story was updated to correct the spelling of Kevin Messacar's name and to clarify that the study of antibodies in pregnant women refers to antibodies against the RSV virus, not EV-D68.

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