Charna Albert
October 2023—With respiratory virus season near, those with a close eye on it in August gave the lay of the land for test algorithms, technologies, and forecasts, even as SARS-CoV-2 and RSV cases were rising in parts of the country.
Roche Diagnostics is emphasizing to customers the importance of multiplex testing in differentiating between pathogens that cause overlapping respiratory symptoms. “But also we need to be closely monitoring what’s happening in the U.S.,” says Alesia McKeown, PhD, scientific partner at Roche, “because indications might be that we’re going to have an early season.”
What’s certain, Dr. McKeown says, and what forecasting from the Southern hemisphere confirms, is that three viruses will be co-circulating. “It looks like flu, SARS-CoV-2, and RSV. Those viruses are here to stay.”
Less certain is how SARS-CoV-2 will behave, particularly with new and emerging variants in the mix. Manoj Gandhi, MD, PhD, senior director of medical and scientific affairs at Abbott Molecular, says COVID-related hospitalizations remained low last year, though influenza-related hospitalizations were significantly higher than in the previous two years. “But we need to remain vigilant this year,” Dr. Gandhi says. “We don’t know yet how the COVID variants are going to behave and we can’t let our guard down.”
As for flu, says Matthew J. Binnicker, PhD, D(ABMM), director of clinical virology at Mayo Clinic and professor of laboratory medicine and pathology, Mayo Clinic College of Medicine and Science, early signs from the Southern hemisphere and particularly Australia indicate this year’s season might be “at least average, if not above average, here in the United States.”
Influenza activity last year came early, says Dr. Binnicker, who is also vice chair of practice, Department of Laboratory Medicine and Pathology, Mayo Clinic. “In the upper Midwest we saw peak numbers of influenza in November and December, and then by January the flu season had wrapped up.” Otherwise, the flu season was fairly typical. “I wouldn’t say it was remarkable in terms of high numbers, but it wasn’t completely absent either, like we saw in 2020 and 2021. So the theory that the few years off from influenza was going to lead to this tremendous surge in cases—that didn’t pan out.” RSV, however, was elevated even earlier in the year than influenza, and RSV-related hospitalizations spiked among pediatric patients last fall.
By the end of 2022, SARS-CoV-2 was on the overall decline, though transmission continued through the winter months. “It didn’t necessarily overlap with influenza,” Dr. Binnicker says. It may be that a COVID surge suppresses influenza, “likely because the body mounts an immune response to one virus, and it may prevent infection with other viruses. So we see not overlapping surges but one before the other, and that seemed to be the case this past respiratory season. It will be interesting to see if that plays out again this upcoming respiratory season.”
With SARS-CoV-2 cases rising in late summer, Dr. McKeown says, laboratories were preparing for heightened testing demand while making decisions about post-pandemic resource management. “We’ve heard from customers that they’re seeking to simplify their respiratory testing algorithms to make sure they’re thinking about diagnostic stewardship, but it’s hard to prepare for something when you don’t know what’s going to happen,” she says. “They want to simplify, but they also want to have contingency plans so they’re capable of responding to surges.” Staffing issues, too, add to the unpredictability. “There are all these new uncertainties that you just have to manage.”
Dr. McKeown is optimistic that the upcoming respiratory season, “however you want to define that, is going to be our new normal. But people may not be able to commit to that being our new normal yet.” Though some customers are consolidating testing platforms brought on for SARS-CoV-2 at the height of the pandemic, or planning to consolidate, “there’s a hesitancy to make big decisions because they don’t know how those decisions are going to impact the availability of testing, especially if confronted with a surge.”
Mayo Clinic has downsized since 2021, Dr. Binnicker says, “when we had as many as 10 different COVID tests running at the same time.” This year, they will run their SARS-CoV-2, flu A/B, and RSV assays on a high-throughput automated platform, as well as a commercially available multiplex panel. “We also use a point-of-care molecular test with a more rapid turnaround time in our express care sites and the emergency department,” he says. The laboratory has discontinued tests that require heavy personnel involvement. “We’ve brought up sample-to-answer high-throughput systems, and we’ve tried as much as possible to bring up systems that are walkaway and highly automated.”
Dr. Binnicker advises a site-specific approach to developing a respiratory testing algorithm, one that is based on the tests available and types of patients seen. “Are you able to use small panels? Do you have just a large multiplex panel? Do you have access to antigen tests for your employees or your patients? Based on what you have available, work with infectious diseases and occupational health to determine the best way to utilize those testing resources.” There’s no “one-size-fits-all” approach to developing a respiratory testing algorithm, he says. “But in general, if someone is otherwise healthy—adult or child—starting with either a [SARS-CoV-2] antigen test or a COVID/flu PCR makes sense.” For the elderly or those with an underlying health condition, beginning with a SARS-CoV-2, influenza A/B, and RSV panel or a large multiplex panel is a sound strategy.
Some physicians may lean toward ordering large panel testing to cast a broad net, Dr. Binnicker says. “My concern with that is twofold: One is the cost that’s going to be passed on to the patient—those tests are expensive. And two, by casting a broad net you may get a result that is unexpected, and you may not know how to take action on that result.” Unexpected results are more common with some of the other large panels, he notes, such as the gastrointestinal and meningitis/encephalitis panels. “But it is possible to get a result back on a large respiratory panel that the physician may question, ‘What do I do with this information?’ because of the number of organisms that often are included on these panels.”
Alan Wright, MD, chief medical officer in North America for BioMérieux, sees keeping track of patient comorbidities as key to managing respiratory testing resources.
“It requires a bit of behavior change with clinical laboratories to understand what the comorbidities are for patients as they come in, and to tailor the testing to suit the patient,” Dr. Wright says. Staying abreast of local trends in infection also should be a focus. “Often trends differ locally from nationally, and understanding those so you can keep your community of clinicians informed is another thing laboratories are just beginning to adopt. They’re moving to a philosophy of delivering precise and accurate results with a much more interactive community engagement with clinicians.”
BioMérieux is “committed to syndromic testing,” he says. “We’re developing a portfolio of laboratory tests where we have smaller panels for patients who are less ill and in an ambulatory context, and larger panels for patients with significant comorbidities who could be affected not only by COVID-19 but any upper respiratory infection.” Traditionally, the company’s assays have required nasopharyngeal swabs. “Now we are looking at all sample types and developing our clinical information around that.”
Also new for BioMérieux is Spotfire, a CLIA-waived and FDA-approved device that runs a mini panel with five targets—influenza A/B, RSV, SARS-CoV-2, and rhinovirus—and a large panel with 15 targets. “We increase the diagnostic yield tremendously by adding rhinovirus to the panel, and also diagnostic certainty,” he says of the decision to include rhinovirus. “Patients like to be told exactly what’s affecting them, more so than what is not causing their problems.”
For Roche, preparing for the eventual termination of the SARS-CoV-2 emergency use authorization is a focus, Dr. McKeown says. “We want to make sure we are on the leading edge of that—that most of our EUA solutions are going to be transitioned to 510(k)-cleared in vitro diagnostic and/or CLIA waiver,” depending on the setting. This summer, Roche received 510(k) clearance for its SARS-CoV-2 qualitative test. “That’s our high-throughput assay,” she says. “And at the end of July we got 510(k) clearance and CLIA waiver for our SARS-CoV-2 and Influenza A/B assay on the Liat.”
The Liat can detect and differentiate SARS-CoV-2 and influenza A/B or A/B and RSV in 15 to 20 minutes, she says. “But what we’ve identified is that during the pandemic, people brought these on to live in hospital labs,” where they were used to run stat testing for high-risk emergency department patients. “And stat is not 20 minutes; it’s within the hour plus, because you still have to process through that hospital lab. So what we’re seeing from our customers is an interest to get those instruments out of those semi-centralized settings and into decentralized settings that are truly at the point of care.”
Dr. McKeown anticipates increased demand at the point of care this season. “Patients want to have their results at their visit and walk out with a prescription, or at least some direction. And that’s where we’re going to see more demand, because patients are taking control of their health. They know what to ask for.” Demand is less certain for the reference and core laboratories, she says. “How is testing going to be divided between these two complementary but distinct testing settings—that’s still to be determined based on the amplitude of what we’re going to see for activity.”
For innovation, Roche is looking to multiplex testing. “Multiplex is the future. And we’re trying to figure out all the different avenues by which we can leverage multiplex to offer that more personalized testing solution.”
Though influenza, RSV, and SARS-CoV-2 didn’t peak simultaneously last season, she says, “if you look at their occurrence, all three were at a relatively significant level, all the way from November to February. And that demonstrates the need to test for multiple pathogens at once.” With that in mind, laboratories are beginning to implement multiplex testing as the first step in their respiratory testing algorithms, and the aim is to avoid loss to follow-up of the patient who tests negative for flu and is unlikely to return for another test. “That’s how they’re reevaluating,” she says. “It’s not just changing what pathogens we should be testing for and which patients we should be testing, but also trying to figure out that simplified workflow so that the patient is getting the result they need when they need it.”
She notes that multiplex testing comes with its own set of challenges, at least for now. “One of the number one issues is reimbursement.” With multiplex still in its early days and the pressures of the pandemic just beginning to diminish, publication of findings demonstrating clinical utility and economic impact has been slowed. “So there’s a bit of an evidence gap,” she says, one they’re digging into now.
Another challenge: understanding the value of multiplex testing outside the test-to-treat paradigm. “Test to treat is part of why we want to do multiplex testing, but not all our respiratory viruses have a treatment. For the ones that don’t, there’s still action within a negative or positive result, even if that action is not prescription of an antiviral. It could be not prescribing an antibiotic,” or tracking disease prevalence or protecting the elderly and others at risk of severe disease from transmitted infection. “So what we’re trying to do at Roche is build that value proposition.”
BioMérieux’s Dr. Wright views the public health value proposition as an expectation that payers haven’t incorporated. “Payers pay for the diagnosis of disease. They don’t pay for epidemiology or incidental contact, and yet society expects that. So there’s a gap in expectation,” he says. “And that is an interface in public health needs and broader payer philosophy that we need to talk about.”
A number of companies are interested in developing molecular point-of-care and at-home tests for SARS-CoV-2, influenza, and RSV, Dr. Binnicker says.
“That’s what we’re going to see over the next several years—for sure within five years. You’ll be able to go to a local drugstore or have a prescription from a physician for an at-home test that has high sensitivity like a lab-based PCR test.”
The Food and Drug Administration on June 6 granted marketing authorization for the Cue Health COVID-19 Molecular Test, the first at-home over-the-counter test for SARS-CoV-2 to be granted such authorization using the traditional premarket review pathway. Now under review through the EUA pathway is Cue’s SARS-CoV-2 and influenza A/B at-home and over-the-counter molecular panel test. The company also has applied for de novo classification for an OTC molecular RSV test for point-of-care and home use; if approved, it will be the first FDA-approved RSV test for home use. And in August, Cue Health was awarded a grant from the Biomedical Advanced Research and Development Authority—part of the Department of Health and Human Services—to develop an at-home multiplex panel test for SARS-CoV-2, influenza A/B, and RSV.
The challenge in designing the tests, says David Tsay, MD, PhD, Cue’s chief medical officer, is that they’re technologically complex but must be simple to use. “And simple to use not just by those who may be trained, but simple to use by the average person,” Dr. Tsay says.
The Cue test platform leverages microfluidic technology with the molecular chemistry of nucleic acid amplification; the tests don’t require mixing of fluids or calibration, he says. “We avoided that by putting all those reactions using microfluidics and all the other design within the [test] cartridge itself.” Users of the Cue platform can download an app on a smartphone to view their results. “It clearly tells you positive and negative between these different analytes and what it might mean for you in terms of next steps,” he says. “There’s not a lot of interpretation that has to go on by users—it’s easily understandable.”
How it works: Once the test sample is collected and the wand with the nasal swab is inserted into the Cue cartridge, the test automatically begins. “Within the single reaction chamber the sample is eluted off the wand tip and any virus present is lysed.” The enzymes and labeled primers then amplify the target sequence, he says. “It also amplifies an internal control target for nasal epithelial cells to make sure there’s enough sample within the reaction for a valid test.” Once the heating, mixing, and amplification have taken place, the reaction ensures the amplified product flows over a series of electrodes that bind to sensors. “The system then measures the signal as a current difference, which is used to determine the test result,” he says.
The FDA said in its June 6 news release that in a study it reviewed, the test correctly identified 98.7 percent of negative and 92.9 percent of positive samples in individuals with signs and symptoms of upper respiratory infection.
Dr. Tsay is optimistic that the FDA will move quickly on the company’s submissions. “We continue to work closely with FDA on all these fronts, and we remain on track to have a robust respiratory care offering for the ’23–’24 respiratory season.” With the approval of Cue’s SARS-CoV-2 at-home test, he says, “the FDA made a public statement that the marketing authorization represented ‘a new era of consumer access to diagnostic tests that can be performed entirely at home.’ In our view this is a positive signal for the at-home molecular testing space and FDA’s commitment to supporting consumer access to fast and accurate molecular diagnostics.”
As at-home molecular testing moves into the mainstream, Dr. Binnicker’s main concern is that results be communicated to the patient’s care team and to public health. “One thing we saw over the last 18 months or so is most people are testing for COVID with an at-home antigen test now. And we’ve lost a bit of that tracking and knowledge of where the virus is surging from when we were doing all the testing in central laboratories. So those are important factors: connection with the physician, making sure patients who test positive get treated if possible, and tracking with public health.”
For at-home testing to scale, Dr. Tsay says, “it needs to be connected to virtual care clinical pathways,” and Cue offers its own telehealth service that can be used in conjunction with its home tests. “But it also can be seamlessly integrated with health systems, if that’s the preferable route,” he says, noting that Cue worked with Memorial Hermann Health System in Texas to integrate use of the Cue platform into the system’s electronic health record. “The advantage of our platform is that we are digitally connected, so we’re able to seamlessly transfer data as long as there are places that want to receive it, whether that’s public health authorities or within health care systems.” During the pandemic, “we built infrastructure to be able to seamlessly send anonymized public health reporting directly to public health authorities and had that in place for COVID when it was required.” In the future, he says, “getting data from at-home testing would complement the existing reporting structure, enabling a more 360 [degree] view of test positivity in cases from the hospital all the way to the home.”
Even as home testing becomes routine, says Dr. Gandhi, of Abbott Molecular, lab-based and point-of-care PCR tests will remain the mainstay for diagnosis. “At-home over-the-counter tests may become common but won’t fundamentally change the landscape for the clinical lab,” he says. “They’ll coexist and play different roles.”
“Offering tests to more people in more settings is what we continue to work on,” he says.
As for BioMérieux, Dr. Wright calls home testing “the next step of bringing diagnostics closer to the patient.”
“Through technology and improved tests,” he adds, “we see the extension of the testing environment into the home as inevitable.”
Charna Albert is CAP TODAY associate contributing editor.