Flu mounts COVID’s bustling stage

Karen Titus

October 2020—Barely a half year into the pandemic’s presence in the United States, history has already begun pressing down on SARS-CoV-2 testing. Like an actor playing Hamlet, it’s been difficult not to feel the burden of past performances when preparing for the months ahead.

Now, at the start of fall, that also means readying for the return of influenza. Here, even longer experience has shown that each new season is, indeed, a new season.

As in the theater world itself these days, planning for what lies ahead feels tempest-tossed. Plans are being laid. Discussions continue. Creativity abounds, and hard work persists. The season shall unfold. But no one knows how it will look until the curtain—or whatever is passing for one this year—goes up.

Poor Hamlet is troubled enough to fill the stage for hours—it is, in fact, Shakespeare’s longest play. Yet he’s just one man. Laboratories this fall are absorbing the slings and arrows of two roles simultaneously. Can they prepare for both parts (think Richard II and III sparring on the same stage) with confidence? What will a pandemic-based flu season entail?

The influenza season is always unpredictable, says John Waugh, system vice president, Pathology and Laboratory Medicine, Henry Ford Health System. “And layering one respiratory illness on top of a pandemic illness is something that we haven’t seen before. So I think we’re all going to school on this one,” he says, using an especially apt metaphor. (When Waugh spoke with CAP TODAY, the University of Notre Dame was making headlines with its plans to return to in-person teaching. Waugh eyed the school’s confidence warily. “They have Touchdown Jesus,” he laughed, referring to the large mural visible from the football stadium. “Maybe that’s going to be a factor.”)

At Mayo Clinic, “We really are doing two things,” says Bobbi Pritt, MD, chair, Division of Clinical Microbiology, and professor of laboratory medicine and pathology. First, she and her colleagues intend to offer standalone COVID-19 testing. Second, they’re planning to use multiplex platforms to test for SARS-CoV-2, influenza A, influenza B, and in some cases respiratory syncytial virus for patients who are at risk for more than one virus.

Behind those offerings lie many conversations between the lab and their patient-facing clinical colleagues, she says. One Mayo task force has been meeting multiple times a week, involving top-level leaders in pathology, surgery, outpatient, inpatient—“you name it,” says Dr. Pritt. “We’re all trying to hypothesize what might happen this fall. None of us has the answers.”

It may be helpful to consider COVID-19 and non-COVID respiratory illnesses separately as labs prepare, Waugh says, at least to start.

“I kind of have a clock in my head that says about Dec. 1 every year is when we should start looking for flu,” he explains. “So we tend to line up testing supplies in the October/November time frame.” At the very least, he says, they want to be ready for the start of flu season, regardless of how it might end.

The COVID situation has its own trajectory. “I think of it as kind of a roller coaster,” Waugh says. “We went up a big hill and then came down, but then we’ve got the smaller hills”—the result of reopenings and closings, and the loosening and tightening (or sometimes start) of social distancing, restricted gatherings, and mask requirements. “We’ll continue to see that as different parts of the country, different states, approach this differently.”

The disease distinction is helpful only up to a point, however. “The great concern is the coexistence of COVID-19 with seasonal influenza,” Waugh says. Will this be a relatively harmonious blended family? (If nothing else, the pandemic is giving observers a chance to trot out a lot of metaphors.) Or will this be a Montague/Capulet-type family gathering?

As labs consider the tests they’ll need, Christine Ginocchio, PhD, MT(ASCP), vice president, global medical affairs, BioMérieux/BioFire Diagnostics, sounds a note of caution. “You can’t lump everything into one bucket.” Testing done in the outpatient setting in a mildly ill patient will differ from testing patients sick enough to come to the ED or those being intubated.

At Mayo Clinic, physicians who work primarily with outpatients by and large prefer a multiplex test that detects SARS-CoV-2, influenza A, and influenza B, says Dr. Pritt. “RSV, to them, is not necessarily as important in all patients. Which is good, because some of the rapid tests performed in the outpatient setting don’t include RSV,” she says. RSV is important for children, of course, but most physicians are primarily interested in differentiating between flu and COVID-19 in adults, she says.

The inpatient setting is different, Dr. Pritt continues, as is dealing with patients who are immunocompromised. RSV takes on heightened importance in those situations, so physicians “want all the options.”

“Thankfully,” Dr. Pritt says, “we are seeing tests coming on the market that offer those different combinations. But, well,”—she pauses, then sighs, before continuing—“like everyone, we are not immune to the supply chain shortages.”

Standalone influenza tests come, like Instacart orders, in a variety of sizes and shapes, and often with the same uneasy anticipation. Some are point of care; the Roche Liat, for example, is a real-time, highly sensitive PCR assay that can be performed at the patient’s bedside in less than 20 minutes, says Dr. Pritt. Others allow 96 tests to be run simultaneously but require upfront RNA extraction and have four- to six-hour turnaround times. Specimens are usually batched, so TATs can extend to 12 to 24 hours. In between are tests that are considered relatively rapid but take one to three hours for results, including larger panels, such as BioFire’s respiratory panel, Dr. Pritt says, with its more than 20 analytes for viruses and some bacteria.

In the best-case scenario, Dr. Pritt says, laboratories could turn to any of these options as needed, but supply chain issues make that unlikely. “We’re all hoping we can get the number of kits and reagents we need,” she says.

“Usually you have one, maybe two tests for a given virus,” she adds. Trying to line up half a dozen tests would have had the makings of a French farce at the start of the 2019–2020 flu season, but now demand has outstretched what any one company can provide. “So we’ll do as much as we can with one manufacturer, but then we’ll have to bring in a test by another manufacturer to make up the difference.” Even small academic labs are running four or five tests. By the end of August, Mayo Clinic planned to implement its eighth test. “All for the same virus!” Dr. Pritt marvels.

Using multiple tests means more than shoehorning analyzers into tight spaces. (Though that, too, can be a challenge.) CLIA has its requirements. Staff have to be trained and evaluated for competency. “And we have to figure out how to do proficiency testing for all eight tests.”

Sample management requires new tactics, too. When Mayo initially began offering SARS-CoV-2 testing through its reference lab, clients were signed up for a specific test. But as reagents fell short, and clients were moved to a new test system, Dr. Pritt says, “we had to manually convert the original test order. That was just a nightmare.” Eventually the lab created a universal code for SARS-CoV-2 molecular testing, “but it just shows you how complicated this is.”

Mayo plans to use the Liat in its outpatient setting, although supply constraints will limit the number of patients who can be tested by the device. Dr. Pritt also anticipates using Roche’s multiplex Liat test that combines influenza A/B and SARS-CoV-2 and offers a similar TAT. “That’s an ideal test for that environment—you collect a single specimen, test it once, and you get three different answers.”

The test also has the potential to address supply chain concerns, one of which was foreshadowed years ago in “The Graduate,” as movie fans of a certain age might recall. A single test uses fewer reagents—and, of course, fewer plastics.

Stan Schofield has plenty to say on that matter (and others) from his perch as president of the regional laboratory NorDx, which is part of the Portland-based MaineHealth integrated health care system. “Everybody wants to go back to work or back to school, and we can’t get pipette tips. Can you imagine? I mean, a little piece of plastic and you’re crumbled. I can do a thousand more tests a day, if I could get the pipette tips.”

He has similar supply concerns about the Roche Liat, which he’s planning to use at each of his system’s hospitals. “I don’t know the availability of the cartridges,” he frets. “We have all the little machines. But without the cartridges it’s just a fancy toaster on the shelf with no bread.

“Early indications are we’re going to have a very tight allocation of cartridges,” Schofield continues, “which will not even come close to meeting the needs of my emergency departments on a daily basis. We might get 200 tests a week for 11 hospitals. One medical center can blow through that in a day.”

So as with COVID-19 testing, the NorDx core lab will remain the backbone for the majority of testing. By running the lab 24/7, nearly all patients have been getting their COVID-19 results in less than 24 hours. “Flu will be the same,” Schofield predicts. The Liat cartridges will be saved for patients who show up at more distant hospitals at odd hours, well past the last courier run. If cartridge availability does increase, then the POC tests would play an expanded role in the hospitals.

Flu testing has its own short-ish history.

Up until 10 to 12 years ago, Waugh recalls, physicians typically assumed flu was the culprit in patients with respiratory illnesses in the winter months. Testing for influenza A and B became more the norm with the advent of antiretrovirals such as Tamiflu and Relenza. Their widespread use in more vulnerable patients required fairly quick TATs, since the medications are most effective within 48 hours of symptom onset.

With COVID-19, the questions become harder for patient-facing physicians, says Dr. Pritt. Do they give Tamiflu? Enroll them in a clinical trial for COVID-19? Or is it a completely different story—does the patient have a bacterial infection that requires antibiotics?

Dr. Ginocchio frets that the presence of multiple illnesses will create “a huge diagnostic dilemma.” In patients coming to the hospital especially, “It’s going to be difficult to say specifically if this is COVID or not.”

Early on, because of the severe lung damage seen in many COVID-19 patients, “Everybody felt, Well, a CT scan is super-diagnostic,” Dr. Ginocchio says. Recent data now suggest a different story: CT scans appear to be only 75 to 80 percent accurate, she says. Without rapid SARS-CoV-2/flu tests, “If we do see flu reemerge, it’s going to be a really difficult diagnosis.”

Stepping back a bit, Dr. Ginocchio talks about how COVID-19 develops and the broader implications for testing. Most people who become severely ill from COVID-19 don’t do so until the second week. Most people head to the hospital around day seven or eight and land in the ICU around day eight or nine. So the rapid decline isn’t as sudden as it once seemed. Severe lung damage is indeed a tipping point, as are other, underlying comorbidities. Says Dr. Ginocchio: “As a result of having these secondary comorbidities, you develop a secondary, bacterial superinfection at home, which is what pushes them to the emergency room, to the ICU, and then to intubation.” Five to 10 days into mechanical ventilation, a second group of patients may develop another infection, such as ventilator-associated pneumonia. “And sepsis is very, very common.”

Given all these factors, says Dr. Ginocchio, “Syndromic testing is so critically important in this patient population.” BioFire’s pneumonia panel covers bacteria, viruses, and resistance markers, but, she adds, “I’m not saying this as a manufacturer; I’m saying it as someone who would think clinically, What do we need to do to treat our patients correctly?” Although the data are variable on coinfections, emerging studies suggest that up to 30 percent of patients coming into the ICU to be intubated already may have a secondary bacterial infection, she says. “I think everyone, on admission to the ICU, needs to have a comprehensive pneumonia panel” to avoid inappropriate empirical treatment. “We want to target that initial therapy without guesswork.” In some cases—sepsis or a bacterial superinfection, say—therapy may need to be escalated. “You need to test them again the minute they show signs of a potential ventilator-associated pneumonia,” she says. But just as important, she adds, is using testing to deescalate therapy, if need be, to practice good antimicrobial stewardship to avoid C. difficile disease or other adverse events.

Long story short: In the hospital setting, “you need to know what they have when you admit them,” Dr. Ginocchio argues. “They don’t necessarily just have COVID.” Some studies from China report that 50 percent of COVID-19 patients had a secondary bacterial infection, she says, with high mortality rates in that group. “So much higher that we presume it adds to severity of the overall illness.”

SARS-CoV-2 testing alone may not be sufficient in communities where flu is circulating, Dr. Ginocchio says, though she acknowledges that “Some people will argue, ‘What’s the big deal? Just give them Tamiflu and send them home.’”

That might work in an outpatient environment. But that patient population can include those with complicating issues, such as chemotherapy, immunosuppression, transplants, chronic lung disease, or cystic fibrosis.

“So I think we have to be able to make that diagnosis,” Dr. Ginocchio says. “I’m a proponent of diagnostic stewardship—test the right patient at the right time.”

That’s why her company decided to incorporate SARS-CoV-2 testing into its routine respiratory panels. As of mid-August, it had an EUA for its RP2.1 panel with the SARS-CoV-2 addition; the company was working on adding it to its POC respiratory testing as well as its pneumonia panel. Not everyone will need comprehensive testing—“not everybody in the outpatient setting, absolutely not,” she says—but it needs to be available for patients who will be at risk if given a misdiagnosis.

NorDx used its own laboratory-developed test for SARS-CoV-2, which served them well, Schofield says, given what he calls the scavenger hunt other labs went on to track down reagents and supplies. It intends to use a combination LDT when flu season starts. RSV will likely remain a standalone test, he says. “I’m not sure I want to put that in the combination. I’ll let my PhDs and medical directors chew on that a little bit.”

COVID-19 will still be prevalent when flu hits, he says, so the combination test will be done automatically. “It’s just going to be the standard of care.” He suspects that will be the CDC’s recommendation. “You just can’t differentiate the clinical symptoms very well,” Schofield says. “It’s going to take the molecular differentiation.”

Most worrisome to Waugh are patients who are coinfected with SARS-CoV-2 and flu. “I’m very confident we will see those kinds of situations,” he says, particularly in patients with risk factors such as exposure, age, and immunosuppression.

Dr. Pritt has a related concern. Since COVID-19 tends to be top of mind for patients who present with any of the various, nonspecific symptoms, such as diarrhea, “Once you get that first lab result that shows a patient has COVID, it’s easy to focus on that” and use it to explain all the symptoms. “We have to continue to be careful and not get so hung up on COVID that we miss something else that’s also important.”

If the questions are becoming thornier for patient-facing physicians, the answers are also becoming harder for labs to provide. Says Dr. Pritt: “We’re often coming to the table with limitations, saying, ‘We only have these two tests.’ Or we say to them, ‘This is the test we have the most of—will that be sufficient?’ And if they want something else, we may not be able to provide that.”

Those hard decisions get made daily at Mayo Clinic, according to Dr. Pritt. She and her colleagues have established a command center in the lab for daily meetings with key representatives in various departments. “Every day we’re assessing how we’re doing with the supply chain. If we have shortages, how are we going to accommodate that? Are we going to perform one test versus another? Every part of the supply chain is vulnerable now.”

Mayo pathologists and clinical microbiologists are also serving on institutional boards to address such matters, including, in one instance, issues related to preprocedure/presurgical COVID-19 testing. The lab initially performed this testing using an assay Dr. Pritt says was highly sensitive, with a rapid TAT. Then “something happened with that test,” she says, “and the manufacturer all of a sudden wasn’t able to provide the kits they promised us.” It’s the perplexing, repeating, pandemic plot line. “So we very quickly had to shift gears and come up with a backup plan.” The new test is relatively fast, she says, but it did increase TAT slightly.

She fears similar scenes could play out with flu tests, with physicians forced to make equally tough, daily decisions. She uses the Roche Liat as an example. If the test is in high demand, what happens if there’s a big outbreak elsewhere in the country and kits are sent to that spot instead?

“There are so many different reasons why all of a sudden supplies may not be available,” Dr. Pritt says.

Schofield calls the ongoing supply chain problems “a disaster. It’s almost criminal.” As his system catches up in one area—reagents, say—it falls behind in another, as outbreaks in other parts of the country effectively commandeer supplies he’d been counting on. “Things that were on trucks disappeared—big pieces of equipment that I ordered a year ago were delayed again, because they got redirected to Houston.”

While the national narrative continues to refer to the pandemic’s “testing problem,” laboratories tell a more nuanced tale: They actually have a backup testing problem.

It’s a story devoid of cliffhangers. Yes, there will be supply chain problems. Again. Still.

Flu season will only add to the pain, Schofield predicts, as manufacturers shift from producing cartridges for SARS-CoV-2 testing alone to combination cartridges.

“In other words, if I needed COVID cartridges today,” he says, speaking in mid-August, “I could probably get it. I don’t think I could get it next month or the month after.”

It remains a worldwide issue, Waugh says. Many of the products that will be in demand are made abroad, and, in manufacturing’s version of sheltering in place, “They tend to stay in their home countries.” Even if a product is manufactured in the United States, the parent company may be European-based, with obligations to ship product back to the country where it’s headquartered. “So that creates constraint right out of the gate.”

The pandemic has pushed everyone into a crash course on economic and manufacturing basics.

Ramping up production, for example, sounds easy but isn’t.

“Factories take a year to build,” Schofield says. “And the raw materials have not been worked out in a global-friendly way.”

Despite the Herculean efforts of manufacturers, “Nobody can make enough tests,” Dr. Ginocchio says.