The Double-Whammy COVID-Flu

In late February 2020, only a couple of weeks after the pandemic coronavirus disease had even received a formal name, a man with a terrible cough and fever showed up at one of the ProHealth Urgent Care centers in Queens, New York. At that point, no COVID-19 cases had yet been confirmed in New York City, but numbers were on the rise in spots across the country, and the man had recently been at a conference.

An ER-trained physician donned protective goggles, a face mask, and gloves, and went in to swab the man’s nose with a giant Q-tip. With any luck at all, this would show he’d gotten sick from some other, more mundane pathogen—and that the timing of his symptoms was just a grim coincidence.

Within a few minutes, the staffers got just the answer they were hoping for: The swab was positive for influenza. But Daniel Griffin, a researcher at Columbia University and the chief of the infectious-disease division at ProHealth, wasn’t ready to let down his guard. “Wait a second,” he says he told the health-care team, as colleagues prepared to shed their protective gear. “How do we know this gentleman isn’t also infected with the pandemic virus?” He suggested that they all assume the worst until they’d had a chance to run some further tests.

In early March, those results finally came in: Yes, the man was positive for the pandemic virus. His wife was, too, and so were their two kids. The whole family had COVID-19 and the flu.

By late summer 2020, many experts were warning of a potential “twindemic” of these two diseases. But their fears were as much about the possibility that COVID-19 and influenza would combine to overwhelm health systems as the possibility that they would combine to overwhelm an individual’s immune system. In 2021, we still don’t know much about how—or how often—the flu virus and SARS-CoV-2 act in tandem within the same body. A very early study from China in January 2020 found zero cases of coinfection of these two pathogens among 99 COVID-19 patients, but a follow-up, conducted a month later at a COVID-19 hospital, concluded that about one in eight had both diseases at the same time. Whatever the historic prevalence of coinfection, the twindemic never happened last winter. Perhaps due to mask wearing and social distancing, flu numbers in the U.S. were much, much lower than normal during the 2020–21 season.

But with pandemic restrictions relaxing, and fewer people getting flu shots, the same warnings have returned. “I actually think it’s more of a risk this year,” Griffin told me. Cases like the ones he saw almost two years ago could become far more common. In fact, new research suggests that getting coinfections—not just of COVID-19 and flu, but of many one-two punches of pathogens—may be far more common than we thought. Doctors’ understanding of what these coinfections mean for care and treatment remains preliminary, but they could well have important consequences.

Some colds feel worse than others. On occasion they can be a terrible ordeal, knocking us out for days, leaving us miserable; other times they are barely a bother at all. This isn’t a great mystery or anything: We know that some cold viruses are nastier than others, and that we can be exposed to larger or smaller amounts of the same virus; we also know that our immune systems can be stronger or weaker at any given time. But what if another, unacknowledged factor is at play? What if the nastiest case of sniffles you ever had was, in fact, two viruses infecting your body at the same time—a double-whammy cold?

Within the past decade, new molecular diagnostics have made such coinfections much easier to identify—and they’ve turned up some disquieting statistics. Recent screening studies have found that 14 to 70 percent of those hospitalized with flu-like illness test positive for more than one viral pathogen.

[Read: We accidentally solved the flu. Now what?]

For COVID-19, the acquisition of multiple infections appears to be associated with bad outcomes. People with severe COVID-19 who ended up in the ICU for many days and sometimes weeks were prone to developing additional illnesses—what’s known as “superinfection”—while in the hospital. It’s hard to shake the images of COVID-19 patients disfigured by mucormycosis, also known as black fungus; but those who end up in the ICU are also susceptible to ventilator-associated pneumonias and sepsis. People sick with flu are similarly prone to bacterial superinfections, which are thought to have caused many of the deaths during the 1918 pandemic, according to Brianne Barker, a professor at Drew University, in New Jersey, who teaches virology and immunology.

Some researchers have estimated that, all told, as many as half of all COVID-19 deaths can be attributed to mixed infections, although others put the number considerably lower. According to an analysis from last spring of more than 100 studies, people who tested positive for both SARS-CoV-2 and a second pathogen had triple the odds of dying compared with those who had only COVID-19. That added risk wasn’t just associated with superinfections that came on during a patient’s hospital stay; according to this analysis, it applied just as well to those who had coinfections from the time they were first diagnosed with COVID-19.

Those data come from studies of acute coinfections such as COVID-19 and flu—diseases that the body typically clears in a matter of days or weeks. Our bodies also hold a soup of chronic coinfections that never really go away. These include a host of herpes viruses such as cytomegalovirus, a lifelong presence in 50 to 80 percent of U.S. adults; and the varicella-zoster virus, which causes chicken pox and shingles. Another one that sticks with us forever is the Epstein-Barr virus, which can cause mononucleosis (“mono”) when a person first is exposed and infects an estimated 90 percent of people worldwide.

These lifelong infections, kept in check by our immune systems, are usually irrelevant to later encounters with a different pathogen. But in certain cases they might be reawakened by a new disease that temporarily weakens our immune defenses. For example, some small studies during the pandemic offered hints that severe COVID-19 is associated with a quickening of latent cytomegalovirus or herpes simplex virus.

On the flip side, chronic infection with lifelong viruses can make people more vulnerable to acute infection. The classic example of this is HIV, which goes after the immune system itself and depletes the body’s T cells. Individuals with the virus are far more likely to get tuberculosis, and as a result tuberculosis is a leading cause of death in people living with HIV.

Coinfections aren’t always bad news for the patient. In some cases, pathogens are pitted against one another, competing for the same host cells. Take human papillomavirus, which causes cervical cancer and genital warts. A 2018 laboratory study found that a single human skin or cervical cell could be infected simultaneously with two different strains of HPV—and that when this happened, one of the strains ended up less able to generate copies of itself that would go on to infect further cells.

Researchers believe that in some situations a viral infection might also protect you by activating the body’s innate immune response, priming it to thwart a second infection that arrives later. In a third scenario, an initial infection might also spark the activation of T cells that happen to recognize a second, similar invading pathogen—an effect known as a “bystander response.” That’s what happens to people who are infected with both dengue virus and Zika virus, although whether this really offers protection (or whether it might even cause some harm) is unclear.

Doctors have tried, on rare occasions, to induce coinfections as a treatment. A century ago, before antibiotic drugs were invented, the Austrian neuropsychiatrist Julius Wagner-Jauregg advocated for the use of malaria parasites as a cure for psychosis caused by syphilis. The treatment caused fever in patients, which Wagner-Jauregg found would ameliorate the psychosis. (Quinine would be administered to treat the malaria as soon as the disease had done its job.) Wagner-Jauregg won a Nobel Prize for this discovery, but his work would be overshadowed by his endorsement of eugenics and eventual support for the Nazis. Later scientists took up the idea of using other pathogens—in particular the common parasitic worm Ascaris lumbricoides—against malaria itself.

It’s possible that even the dreaded collision of coronavirus and influenza might actually have some benefits for individuals. For a study published in 2018, a group of scientists in Moscow, Idaho, squirted a common-cold-type virus, either a rhinovirus or a mouse coronavirus, up the noses of white mice. When they followed these infections, two days later, with a squirt of a mouse-adapted flu virus, the mice fared better—they lived longer and showed fewer symptoms, such as ruffled fur and labored breathing—than other mice that were never given colds. The researchers suggested that the rhinovirus or coronavirus had set off an “early but controlled” inflammatory response in the animals’ lungs, which then helped them defeat the flu virus. For these mice, at least, a lab-induced one-two was protective.

New testing techniques have revealed a combinatorial quagmire of infections in individual patients, even in routine practice. When doctors do a nose or throat swab on a sick child, the results sometimes indicate the presence of multiple pathogens, says Aubrey Cunnington, who is the head of the pediatric-infectious-diseases section at Imperial College London. The kids could turn out to have a mix of rhinovirus, parainfluenza, and respiratory syncytial virus. “We often see two or even three different viruses come up positive,” he told me. “Coexisting infections with different organisms, particularly viruses, are the rule rather than the exception.”

But what, exactly, do these coinfections mean? The implications of smorgasbord results remain unclear. “We have rather limited understanding of how they interact with one another, with bacteria, and other pathogens, to result in the illness affecting each patient,” Cunnington said, adding that children with more than one pathogen don’t necessarily seem sicker than others. In other words, having a double-whammy cold may not be especially bad. The same could be true for certain pandemic coinfections: Some research suggests that many COVID-19 patients have bacteria, fungi, or other viruses in their systems at the time of diagnosis, but with perhaps little reason for concern. One study at a local Chinese hospital, for example, found that about 94 percent of COVID-19 patients tested positive for either acute or chronic coinfections, but that rate was even higher (96 percent) for those with mild or asymptomatic illness. Our immune systems can produce different antibodies simultaneously, so they can typically multitask against different pathogens.

It’s sometimes hard to tell which of several microbes in a patient is the one causing illness. The new molecular tests are so sensitive, they may pick up on harmless genetic fragments that linger in the body after a pathogen has been cleared—identifying a “coinfection” that is no longer even active. Griffin suggested that multiple-pathogen screens should still be used for patients hospitalized with COVID-19, or with any other grave disease, so that treatment can be tailored to the underlying need. If someone has the flu in addition to COVID-19, for example, a doctor might offer Tamiflu, or antibiotics might be given for a hidden bacterial infection. But Griffin warned that when molecular testing implicates multiple culprits, those results should be validated with further lab tests, such as trying to grow the pathogens in the lab. “You still want to do the cultures,” Griffin told me.

Looking for coinfections creates more work for doctors, and interpreting the results when they find multiple pathogens lurking inside someone’s organs makes for an even bigger clinical headache. But more and more studies are finding that coinfections are commonplace, so it’s important not to ignore them—particularly for patients who are very ill. Not everything in biology abides by Ockham’s razor, a principle attributed to the Franciscan friar and philosopher William of Ockham, which argues that, when given several possible solutions, the one with the least complexity is the most likely. “Ockham was not a physician,” Griffin said. “You can have more than one thing going on.”