Why a Coronavirus-Influenza Twindemia Can Never Happen

An intriguing theory may help explain why the flu and Covid-19 never caught the nation simultaneously: the so-called twindemia that many public health experts had feared.

The idea is that it wasn’t just masks, social distancing, or other pandemic restrictions that caused the flu and other respiratory viruses to fade as the coronavirus reigned and resurface as it receded.

Rather, exposure to a respiratory virus can put the body’s immune defenses on high alert, preventing other intruders from entering the airways. This biological phenomenon, called viral interference, can limit the amount of respiratory virus circulating in a region at any given time.

“My gut feeling, and my feeling based on our recent research, is that viral interference is real,” said Dr. Ellen Foxman, an immunologist at Yale School of Medicine. “I don’t think we’re going to see the flu and the coronavirus at the same time.”

On an individual level, he said, there may be some people who end up infected with two or even three viruses at a time. But at the population level, according to this theory, one virus tends to outperform others.

However, he warned: “The health system can be overloaded long before the upper limit of traffic is reached, as the Omicron wave has shown.”

Viral interference can help explain the patterns of infection observed in large populations, including those that may arise as the coronavirus becomes endemic. But research is in its infancy and scientists are still struggling to understand how it works.

Before coronavirus became a global threat, the flu was one of the most common serious respiratory infections each year. The 2018-2019 season, for example, was responsible for the flu 13 million medical visits, 380,000 hospitalizations and 28,000 deaths.

The 2019-2020 flu season was coming to an end before the coronavirus began to rage around the world, so it was unclear how the two viruses could influence each other. Many experts feared the viruses would crash next year in a hospital storm and flood.

Those worries were not realized. Despite a weak effort to increase flu vaccines, cases remained unusually low during the 2020-2021 flu season as the coronavirus continued to circulate, according to the Centers for Disease Control and Prevention.

Only 0.2 percent of samples were positive for the flu from September to May, compared with 30 percent in recent seasons, and hospitalizations for the flu were the lowest since the agency went started collecting this data in 2005.

Many experts attributed the flu-free season to masks, social distancing, and restricted movements, especially young children and older adults, both at higher risk for severe flu. Influenza figures rose a year later, in the 2021-2022 season, when many states had waived restrictions, but the numbers were still below the pre-pandemic average.

So far this year, the nation has recorded about five million cases, two million medical visits and less than 65,000 hospitalizations and 5,800 flu-related deaths.

In contrast, coronavirus has continued to dominate winters, much more common than influenza, respiratory syncytial virus, rhinovirus, and common cold viruses.

Respiratory syncytial virus, or RSV, usually comes to the surface in September and reaches its peak in late December to February, but the pandemic distorted its seasonal pattern. It remained low throughout 2020 and peaked in the summer of 2021, when the coronavirus had fallen to its lowest levels since the start of the pandemic.

The idea that there is a kind of interaction between viruses first arose in the 1960s, when polio vaccines, which contain weakened poliovirus, significantly reduced the number of respiratory infections. The idea gained new ground in 2009: Europe seemed ready for an increase in swine flu cases later this summer, but when schools reopened, rhinovirus colds seemed to somehow disrupt the epidemic of grip.

“This caused a lot of people at the time to speculate on this idea of ​​viral interference,” Dr. Foxman said. Even in a typical year, rhinovirus peaks in October or November and then again in March, at either end of the flu season.

Last year, a team of researchers set out to study the role of an existing immune response in the fight against the flu virus. Because it would not be ethical to deliberately infect children with the flu, the Gambian children were given a vaccine with a weakened strain of the virus.

Virus infection triggers a complex cascade of immune responses, but the first defense comes from a set of nonspecific defenders called interferons. The team found that children who already had high levels of interferon ended up with far fewer flu viruses in their bodies than those who had lower levels of interferon.

The findings suggested that previous viral infections prepared children’s immune systems to fight the flu virus. “Most of the viruses we saw in these children before the vaccine was given were rhinoviruses,” said Dr. Thushan de Silva, an infectious disease specialist at the University of Sheffield in England, who led the study.

This dynamic may explain in part why children, who tend to have more respiratory infections than adults, appear to be less likely to become infected with coronavirus. The flu can also prevent coronavirus infections in adults, said Dr. Guy Boivin, a virologist and infectious disease specialist at Laval University in Canada.

Recent studies have shown that flu and coronavirus co-infections are rare, and people with an active flu infection were nearly 60 percent less likely to test positive for coronavirus, he said.

“We are now seeing an increase in flu activity in Europe and North America, and it will be interesting to see if it leads to a decrease in the circulation of SARS-VOC-2 in the coming weeks,” he said.

Technological advances over the last decade have made it feasible to show the biological basis of this interference. Dr. Foxman’s team used a tissue model of the human airway to show that rhinovirus infection stimulates interferons that can then defend the coronavirus.

“Protection is transient for a certain period of time while you have this rhinovirus-induced interferon response,” said Pablo Murcia, a virologist at the MRC Virus Research Center at the University of Glasgow. find similar results.

But Dr. Murcia also discovered a twist in the theory of viral interference: an attack with coronavirus did not appear to prevent infection with other viruses. This may have something to do with the coronavirus’s ability to evade the immune system’s initial defenses, he said.

“Compared to the flu, it tends to activate less of these antiviral interferons,” Dr. de Silva said of the coronavirus. This finding suggests that in a given population, it may matter which virus appears first.

Dr. de Silva and his colleagues have compiled additional data from the Gambia, which had no pandemic-related restrictions that could have affected the viral patterns they were observing, indicating that rhinovirus, influenza and coronavirus reached their peak in different times between April 2020 and June. 2021.

These data “have made me a little more convinced that interference could play a role,” he said.

However, the behavior of viruses can be greatly influenced by their rapid evolution and by social restrictions and vaccination patterns. Therefore, the potential impact of viral interference is unlikely to become apparent until the coronavirus settles into a predictable endemic pattern, experts said.

RSV, rhinovirus, and the flu have coexisted for years, said Dr. Nasia Safdar, an expert in healthcare-associated infections at the University of Wisconsin-Madison.

“Eventually, this will also happen with this one: it will become one of the many circulating,” Dr. Safdar said of the coronavirus. Some viruses may attenuate the effects of others, he said, but the patterns may not be easily obvious.

As for common cold coronaviruses, some researchers have predicted that SARS-CoV-2 will turn into a seasonal winter infection that could coincide with the flu. But the pandemic coronavirus has already been shown to be different from its cousins.

For example, it is rarely seen in coinfections, while one in four common cold coronaviruses is often seen as a coinfection with the other three.

“This is the kind of interesting example that makes anyone hesitant to make generalizations among various viruses,” said Jeffrey Townsend, a biostatistician at Yale School of Public Health who has studied coronavirus and its seasonality. “It seems a bit specific to the virus how these things happen.”

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