COVID-19 & influenza testing algorithm arms Mayo Clinic for the upcoming flu season

Flu season is just now unfolding. But this time, it’s piggy-backed with a pandemic, which threatens to spike with the colder weather as people huddle indoors. Adding to this conundrum is the unsettling fact that, for both COVID-19 and the flu, the symptoms overlap.

Matthew Binnicker, Ph.D.

“It’s almost impossible to distinguish between COVID-19 and influenza because, in the early parts of both diseases, people can have a fever, cough, sore throat, and body aches,” says Matthew Binnicker, Ph.D., director of the Clinical Virology Laboratory and vice chair of Practice in Mayo Clinic’s Department of Laboratory Medicine & Pathology. “Infections caused by these viruses have to be confirmed through testing.”  

In light of this unprecedented health threat, Mayo has designed an algorithmic approach by which each patient can be more accurately assessed when calling in symptoms to the clinic’s nurse hotline. There are two versions of the algorithm, the more complex version being for in-house use only, and a more simplified version (launched on October 13) meant for Mayo Clinic Laboratories’ external clients, which include the top medical centers and multidisciplinary clinics in the United States.

“The external version is focused more on testing recommendations rather than treatment or management,” says Joseph Yao, M.D., director of Mayo’s Hepatitis/HIV Laboratory in the Division of Clinical Microbiology. “We wanted our Mayo Clinic Laboratories clients to have this more simplified testing algorithm as a resource to guide them on testing decisions for flu and COVID.”   

For both versions, the testing platform is supported by three types of tests:

  1. SARS-CoV-2 (the virus that causes COVID-19) alone
  2. SARS-CoV-2 testing + Influenza A/B
  3. SARS-CoV-2 + Influenza A/B + RSV—respiratory syncytial virus, a commonvirus that usually causes mild, cold-like symptoms, but can sometimes be serious, especially for infants and adults with underlying health conditions (This third option is being validated at Mayo Clinic Laboratories and should be available later in 2020.) *Now available as HPFLU starting 10-31-2023
Joseph Yao M.D.

“The internal version is actually meant for our triage nurses to use to advise patients, so it’s more detailed and has more paths,” says Dr. Yao. “The algorithm is based on input from our primary care practice groups, our infectious diseases practice groups, and also the Clinical Virology Laboratory. Representatives from these three groups came together to look at the current specialty practice guidelines then adapted and operationalized it for clinical practice at Mayo.”      

By using the algorithm, triage nurses can then direct individuals to have appropriate testing based on their described symptoms.

“With this testing strategy,” says Dr. Binnicker, “if the caller describes an influenza-like illness, during the time of year when influenza is known to be circulating in their community, we will need to test for influenza A and B, and also COVID-19, to determine which virus they’re infected with, and to help determine the best management strategy.”

There will likely be several collection sites—similar to drive-thru collection sites that were used over the summer for COVID-19—both in Rochester, Minnesota, and near Mayo’s other affiliated health systems. This way, most patients won’t have to come into a facility to have their sample collected (via nasal swab). Samples will then be sent to Mayo’s testing lab.

Navigating test results

If a patient tests positive for COVID-19, that result is forwarded to a team of physicians and nurses who review it and then inform the patient of the result, give recommendations, and answer any questions the patient may have related to self-care. If the result is positive for influenza, and negative for COVID-19, then the patient may be considered for antiviral therapy.

“There are antiviral options for influenza if the disease is diagnosed within 48 hours of the onset of symptoms,” says Dr. Binnicker. “For COVID-19, we mainly communicate the positive result and discuss the importance of isolation.”

Mayo Clinic Laboratories also launched a multiplex assay, which covers 22 pathogens that can cause a respiratory infection. “The multiplex panel is reserved mainly for hospitalized or immunocompromised patients,” says Dr. Yao. “So this test is different and for a more complicated patient population.”

Aaron Tande, M.D.

Aaron Tande, M.D., an associate professor of Medicine and Associate Chair for Infectious Diseases Outpatient Practice at Mayo, chimes in: “We wanted the algorithm to include people who are at high risk of complications from influenza, who will be especially considered for empiric antiviral treatment, such as our transplant patients, leukemia lymphoma patients, and young children with certain at-risk conditions.”

If a person tests negative for both COVID-19 and influenza, it doesn’t mean they don’t have a viral infection. It means they most likely have one of these 21 other infections that commonly cause flu-like illnesses. “So it could be parainfluenza (HPIV),” says Dr. Yao, “or it could be adenovirus, or metapneumovirus. These are other infections that we can diagnose, but we don’t have treatments for them. So we don’t recommend testing for these less common viruses, unless the patient falls within a high-risk group. For example, a transplant patient could die from one of these—what we call ‘puny’ viruses.”      

Importance of testing early for both flu and COVID-19

One of the factors triage nurses will have to assess is how long each patient has had flu-like symptoms. COVID-19 testing is best done during the early stages of symptoms, according to Dr. Binnicker.

“The likelihood of detecting SARS-CoV-2 is highest when testing is performed during the first few days after someone develops symptoms,” he explains. “That being said, you can still test someone at later stages of their disease (e.g., >7 days after symptom onset), but a negative result would have to be interpreted carefully. If someone with COVID-19 or influenza presents during a later stage of disease and tests negative using an upper respiratory swab sample (i.e., nasopharyngeal swab), then we typically recommend collecting a lower respiratory specimen, like a sputum or tracheal secretion, because the virus tends to be more prevalent in the lower respiratory tract as the disease progresses.”

The ideal window for being tested is within 24 hours after symptoms appear. There is more virus in the early stages of symptoms, which will better show up via a nasal swab. On the other hand: “If you tough it out and wait at home four or five days before you go get tested, the amount of virus in your respiratory tract drops off and you may get a false-negative test result,” says Dr. Binnicker.    

Timeframe of symptoms also helps clinicians determine if patients who are positive for influenza should be treated or not. Because, for patients who have had the flu longer than four days or so, the treatment isn’t as effective and may not be worth the resources—which is why one of the first questions the triage nurse will ask callers is “How long have you had your symptoms?”

Anticipating a potential increase in testing & hospitalizations

As flu season unfolds, one might say the Mayo team is hoping for the best but preparing for the worst, which means conserving resources. To that end, the testing algorithm will help mitigate spreading those resources too thin.

“Historically, we’ve only tested people at high risk for influenza complications when they’re displaying these common symptoms, who would be considered for treatment,” says Dr. Tande. “But this year is different. If someone comes in with that set of symptoms, we can test them to confirm if their illness is influenza, or COVID, or another virus. It not only answers the question of why they’re having those symptoms, but it also helps prevent someone from coming back repeatedly or being seen unnecessarily. So this testing platform is a way to optimize health care resources.”     

From a nationwide perspective, laboratory resources might be strained as testing collection sites ramp up.

“The staff needed to perform testing is likely going to be a limiting factor because labs across the country will be doing more testing,” says Dr. Binnicker. “And the availability of test reagents is also going to be a concern.”

Dr. Tande sums it up this way: “We will have to be careful about anticipating hospital capacity, and also the laboratory capacity, for the addition of flu cases on top of COVID-19 cases. It’s just something that every health care institution will have to keep in mind.”

How bad could it get this flu season?

There’s still quite a bit of uncertainly about what we’ll experience in the United States this fall and winter. Could it be a perfect storm that spikes COVID-19 and influenza cases like we’ve not yet seen?

Dr. Binnicker envisions one of two scenarios: “We could see a very significant resurgence of COVID-19 with influenza also circulating, because during winter we typically see higher rates of viral and respiratory infections,” he says. “People are indoors in closer proximity. Our immune systems aren’t usually functioning as well as they are during the warmer months. And it’s less humid outside, so these viruses can spread more easily. That’s what we’re preparing for in terms of the worst possible outcome.

“But if we look at countries in the Southern Hemisphere, they’re actually seeing very low rates of influenza as they come off of what should be peak influenza season there. Those low rates are likely because of all the precautionary measures that have put in place to help reduce COVID-19 transmission. So those countries that have universally adopted masking and social distancing are not only protecting their citizens from COVID-19, but also influenza. If we take those precautionary measures for COVID-19 to heart here in the U.S., we may actually see a significant reduction of influenza cases.”

The only hitch is, the United States has not yet embraced these precautionary measures on a universal level, not like certain countries around the globe. Governors and citizens, state by state, are not always on the same page about masking and social distancing. And this could inhibit how well we get through the coming flu season.   

“If you look at countries like Australia and New Zealand, which have somewhat comparable health structures to ours, they’ve had incredibly low influenza years,” says Dr. Tande. “So we’re hopeful that masking and physical distancing and hygiene will lead to a lighter than expected season. However, those two countries also have a comprehensive national strategy for COVID that we do not have. So we’ll have to wait and see if the lack of a coordinated approach here in the U.S. will have the same results. I anticipate it will probably be somewhere in between historical levels in the U.S. and what they’re seeing in the Southern Hemisphere.”

Chris Bahnsen

Chris J. Bahnsen covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.