Is it COVID or the flu? New combo tests can find out.

In January, a man in his 60s with heart disease and diabetes went to a South Dakota hospital with a cough and fever, worried he had COVID. A nurse swabbed the inside of his nose, and the sample went into a small device resembling an inkjet-printer cartridge, which was then placed into a machine about the size of a printer.

This so-called quad test, now available at thousands of hospitals and clinics around the country, could detect not only the coronavirus, but two types of influenza and the respiratory syncytial virus, or RSV. A little more than a half-hour later, Dr. Blake Gustafson had the patient's result: He had the flu.

"I remember giving myself a fist bump like, 'Yes! It's not COVID. It's the flu,'" said Gustafson, chief of emergency medicine of the Sanford USD Medical Center in Sioux Falls, S.D. He relayed the news to the patient and his wife, happily adding that there was a treatment he could offer right away, Tamiflu. "The relief in their eyes above their masks was very satisfying," Gustafson said.

The patient's situation was somewhat unusual this past winter given that the United States, like many other countries, witnessed a shocking absence of a flu season. But as the country begins to reopen, doctors say that flu and other pathogens might make a comeback this autumn. What's more, even as a growing number of people get vaccinated against COVID, there are still some 40,000 new infections every day in the United States, and a significant number of people who may be resistant to taking the vaccines.

The Sanford Health system, which includes 46 hospitals and 1,400 physicians in South Dakota, carries out 600 to 800 tests for the coronavirus a day in its clinics using antigen tests, which detect proteins made by the virus. But according to Rochelle Odenbrett, the senior executive director of laboratories, the organization is now in the process of replacing all of those tests with the quad tests used in its emergency settings.

Unlike the antigen tests, the quad test looks for a virus's genetic material using a polymerase chain reaction, or PCR for short. The PCR-based method is far more accurate than the antigen approach, Odenbrett says. She notes that PCR sequencing of patient samples used to be more cumbersome and relied on multistep procedures across different laboratory rooms. "It's just amazing how the technology has evolved," she said.

The quad test used by the Sanford system is made by the California-based company Cepheid, which received emergency authorization from the Food and Drug Administration in late September.

Although last year's flu season was nonexistent, Dr. Geoffrey Baird of the University of Washington in Seattle said that a confluence of factors might precipitate its return in the fall: children returning to school buildings, declining use of masks and perhaps a lack of recent immune system exposure to the flu. If more people get sick in the fall, he added, they will want to know if it is flu or the coronavirus.

"We in the laboratory are preparing for another big boom in testing," said Baird, whose team has run more than 2 million coronavirus tests since the beginning of the pandemic. "Even if people are vaccinated, they're going to wonder, 'Am I the breakthrough case?' "

In addition to Cepheid, other companies have developed tests that look for influenza and the coronavirus at the same time, including Roche, which has received emergency use authorization for a test that looks for the coronavirus, influenza A and influenza B at once.

In recent years various hospitals have developed in-house versions of these combination tests as well, some of which look for more than a dozen different respiratory pathogens simultaneously using PCR technology. Those "multiplex" tests are especially helpful in diagnosing illnesses in people with weak immune systems because they allow doctors to swiftly discern what pathogen is making a person sick before it is too late to start the right treatments.

A French company, bioMérieux, sells a PCR test that looks for the coronavirus as well as 21 other viruses and bacteria simultaneously. And Roche recently bought a company that sells a machine that can screen for more than 20 pathogens in one go.

Testing for multiple pathogens does not always lead to a simple treatment, however. Co-infections, in which a person is infected with multiple viruses simultaneously, are more common than doctors expected, and sometimes the multiplex tests might detect a viral infection but miss a bacterial one, said Dr. Daniel Griffin, chief of infectious diseases at ProHealth New York. A patient could carry the influenza virus but also test positive for a bacterium such as pneumococcus, for example.

"We initially thought that every time we identified a virus, we would just be able to stop all antibiotics and just treat the virus if effective antiviral therapy was available," Griffin said. "We now know that we often need to continue antibiotics," he explained, because sometimes the multiplex tests are not sensitive enough to rule out a bacterial culprit.

Doctors and test developers are still grappling with how many pathogens to test patients for in different settings. "A burning question at every company is what panel is best — is it one, two, four, 20?" said Dr. Mark Miller, chief medical officer at bioMérieux. Relatively young and healthy adults might just need a quad test to know if they should start on Tamiflu for influenza, for example, but patients with underlying chronic diseases who are very sick might benefit from receiving the test for 22 different pathogens so that doctors can decide whether they need to be admitted to a hospital.

Before the pandemic, people were not always as curious to know the exact pathogen causing respiratory symptoms, according to Dr. Alexandra Valsamakis, head of clinical development and medical affairs at Roche Diagnostics Solutions.

"I think there was always this perception of 'Oh, whatever it is, it's not going to kill us,' " Valsamakis said. But the terrible toll of COVID-19 has changed that. "There's this need to actually know what's there, more than there ever was before."