American Scientist

In the wake of the COVID-19 pandemic, we are now seeing a highly unusual pattern of seasonal respiratory infections. The influenza and respiratory syncytial virus (RSV) seasons started earlier and spiked higher than usual in 2022. Hospitalization rates for flu are the highest seen in a decade in the United States, and pediatric hospitals in particular have been at or near capacity. The COVID-19 pandemic has changed so much in public health. “We’ve never studied respiratory viruses, especially the common respiratory viruses, in such great detail before,” says Vijay Dhanasekaran of the University of Hong Kong.

The cumulative load of infections that would have happened over three years have hit all at once. As people changed their behaviors to avoid transmitting SARS-CoV-2, rates of flu and RSV dropped to near zero over the past two to three years. “Before the pandemic, I don’t think I ever would have guessed that in the absence of vaccines or therapeutics, that based on changes to our behavior alone, we could basically wipe out two flu seasons,” epidemiologist Stephen Kissler of Harvard University says. As human populations and viral populations come together again after this unprecedented period of separation, we’re seeing new patterns of infection. That creates complex issues from a public health perspective, but also unwitting case studies that reveal new lessons and information about how these viruses operate.

Flu and RSV usually follow a seasonal pattern, peaking in the winter when conditions are cold and dry in temperate locations, and peaking close to the rainy season in tropical locations. RSV mostly affects children under two years old and the elderly; for most other people, getting infected feels like a common cold. First infections in young children, before they’ve developed immunity through an exposure, can be more severe. Epidemiologist Rachel Baker of Brown University says that, absent the weird dynamics introduced by the COVID-19 pandemic, “RSV is a very regular disease in terms of the timing and the size of the seasonal outbreak, at least compared to something like influenza, where we always have this slight surprise each year of how severe the outbreak is going to be and how well the particular strain that’s circulating matches what we prepare for the vaccines. RSV’s evolution doesn’t tend to play as much of a key role as it does for influenza.”

Hong Kong hasn’t experienced a flu outbreak since February 2020.

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The two-year break in human exposure to influenza has had notable effects on the flu virus. Flu infects many adults and children every year, evolving quickly and traveling efficiently around the world. “Influenza viruses would behave a certain way before the pandemic because they migrate really quickly,” Dhanasekaran says. “Now the biggest issue is the unpredictability of the evolution.” As travel declined during the pandemic, flu strains diversified. Rather than one strain that dominated globally, different strains evolved and circulated in particular locations, as Dhanasekaran and coauthors documented in a March 2022 paper in Nature Communications. This unpredictability has made vaccine development more challenging. Three separate strains lost genetic diversity and were largely confined to outbreak hot spots in South and Southeast Asia, China, and West Africa, and one strain that was already declining before the COVID-19 pandemic seems to have gone extinct. Nevertheless, this year’s vaccine targeting four major flu strains is effective and the best protection at our disposal during this epidemic. In the future, mRNA vaccine technology could circumvent these problems.

Hong Kong hasn’t experienced a flu outbreak since February 2020, providing an interesting case. Dhanasekaran points to widespread mask wearing as the reason why. “By February, we had almost 99 percent of people wearing face masks in public,” he says. “So, in Hong Kong we immediately saw a complete decrease in influenza much earlier than the rest of the world.” Wearing masks in public continues to be nearly unanimous and unpolitical there, even though it is not mandatory. These big drops in flu prevalence surprised many epidemiologists, and we now know far more about medical face masks, improved ventilation, and other mitigation measures.

Among young children, a large group who had never gotten RSV has now been getting the virus all at once. “When you have a large susceptible population like we have right now, then more kids are getting infected,” Baker says. “Those kids are spreading it to more of their peers. And so there’s this ripple effect through exponential growth that happens, a multiplier effect.” Importantly, all these kids would have gotten RSV anyway—what’s unusual is that they’re all getting it at once, rather than spread out over several years (see the figure below).

Baker contributed to papers that warned of the coming surges, including one in the Proceedings of the National Academy of Sciences of the USA in November 2020, and another in Lancet in September 2022. Hospitals and health departments struggled to prepare at a time when the pandemic was in full force and health care workers were quitting their jobs in record numbers.

There are always regional variations in these viral spikes, and this year’s unusual pattern offers an opportunity to understand them better. Factors that seem to affect this variation, for RSV, include absolute humidity and past and current patterns of nonpharmaceutical interventions, according to Baker’s research. RSV normally follows a latitudinal pattern, with warmer places tending to see spikes first and for longer. For flu, regional variation may be affected by what strain is circulating, vaccine uptake, the prevalence of wearing masks and taking other precautions, and winter or rainy season onset. Those seasonal rhythms can be shifted off course when other dynamics increase transmission. “When you have a larger pool of kids who don’t have immunity to the disease, that tends to override seasonality,” Baker says. “Much like in a pandemic, you can get outbreaks at any time of year.”

Not every state has had a problematic RSV outbreak so far. Places heavily hit include Colorado, New York, Oregon, Pennsylvania, Rhode Island, and Washington. Researchers like Baker are trying to understand why—how much this variation is because of human behaviors that currently reduce transmission, variations in immunity because of how long nonpharmaceutical interventions were in place and how they were lifted, and climate effects.

The surges seen in the United States have occurred in other places in the world, too. For example, RSV swept through parts of Australia in late 2020 as schools reopened and other mitigations were lifted, documented in a May 2022 paper in Nature Communications led by the Australian RSV study group. “When children don’t mix with each other, viruses can be carried in smaller groups of children,” explains Dhanasekaran, one of the authors on that paper. “And then once things open up, an epidemic gets going really quickly. That’s what we saw in Australia.” A study about what happens when a large, uninfected population suddenly mixes with a wild virus would never be ethical or feasible in a lab; studies like this one are significant, because of the unique situation the COVID-19 pandemic imposed.

This unfortunate situation is allowing researchers to answer another big question about RSV: What affects the severity of the infection? Data show that, after the COVID-19 pandemic, children are getting RSV for the first time at older ages. Now researchers can investigate: Are older children less likely to be hospitalized, or is the same proportion of children at any age at a heightened risk of hospitalization when they are infected with RSV for the first time? That information could help caregivers and health care workers make better informed decisions about protecting children. And in the coming years, preventing many severe RSV cases will be possible. Two vaccines and a monoclonal antibody injection for RSV are on the horizon, with pharmaceutical companies GSK and Pfizer hoping to roll out vaccinations for pregnant people and the elderly in 2023.

An important tool for responding quickly to outbreaks and pandemics is genomic and serological surveillance of pathogens. Here, the COVID-19 pandemic has also been an impetus for improvements. “I’m hoping that people use the capacity that was built for COVID-19 and then transform it toward other pathogens,” Dhanasekaran says. “Sequencing technology has become cheaper and cheaper, and lots of middle income countries are moving toward that.” Twenty or so years ago, a handful of genomes would have been available for coronaviruses or influenza, monitored only in major cities in the richest nations. “Now we have millions and millions of genomes for analysis,” Dhanasekaran says. We’ve come a long way, and as we learn lessons from these outbreaks, it will be possible to do far better next time.