Diagnostic companies shift attention to multiplex tests for COVID-19, flu

NEW YORK ─ Even as the country continues to grapple with various problems associated with COVID-19 testing, another event is about to hit that could complicate the coronavirus pandemic further and prove devastating to patients, providers, and the entire U.S. healthcare system: the flu season.

With the start of the season roughly a month away, many healthcare experts have voiced concerned that a healthcare system, that at various times has buckled from the strain of triaging COVID-19 patients, could collapse from the additional burden of caring for flu cases.

In particular, because symptoms for the coronavirus and the flu can be similar, being able to differentiate between the two will be crucial to properly and quickly care for and manage patients.

A number of firms, though, are working to meet that need, and several companies have launched, or plan to, multiplex molecular tests to help providers determine which virus a patient may have and then treat them appropriately.

"Going into a full flu season that overlaps with the pandemic, without a treatment or vaccine for SARS-CoV-2, there are real concerns that there will not be enough testing supplies or testing," said Eric Shapiro, senior VP of global marketing at diagnostic test developer Luminex. "That's why getting this under control earlier rather than later is such a high priority."

To prepare for an anticipated rise in demand, manufactures are developing multiplex RT-PCR panels that include targets for SARS-CoV-2, flu, and other respiratory pathogens. Most of them are adding the panels to product portfolios that already include tests to detect SARS-CoV-2.

According to diagnostic industry executives, rapid, inexpensive antigen tests are also expected to play a role in helping satisfy demand as the flu season approaches.

Because healthcare providers will likely be confronted with patients presenting symptoms associated with any of the most prevalent respiratory ailments, "The challenge will be to identify the pathogen responsible for the respiratory infection … and to make rapid and accurate decisions for which treatment is best, which infection control and isolation to implement, as well as whether contact tracing is necessary," BioMérieux Chief Medical Officer Mark Miller said in an interview.

As manufacturers and labs continue to scramble to satisfy demand and COVID-19 cases remain high worldwide, the upcoming flu season, also known as the respiratory season, could further complicate matters, according to industry executives. The flu season brings unknown variables that affect testing, including when the season will begin and end. Additionally, there is no surefire way of knowing beforehand how severe the season may be.

In the Northern Hemisphere, the flu season can begin as early as October and last as late as May, according to the US Centers for Disease Control and Prevention.

In a recent statement, the World Health Organization noted that it is critical this year that countries monitor flu activity and reinforce routine surveillance efforts to include the flu and SARS-CoV-2. It further emphasized the importance of protecting hospital and health workers already coping with COVID-19, from being overwhelmed.

"There has been speculation … that social distancing and infection control measures being implemented to address COVID-19 could lead to a very quiet flu season," said Charles Cooper, a physician and VP of medical affairs for Becton Dickinson's integrated diagnostics solutions business. "On the other hand, it is really anyone's guess what's going to happen. Dealing with COVID-19 in the spring or summer as we just have, when there are fewer respiratory viruses circulating, certainly makes it easier to manage patients."

To test for flu in recent years, healthcare providers have been increasingly turning to point-of-care rapid antigen tests that can return results in 15 minutes or less and, less frequently, to single-plex molecular diagnostic tests that provide higher levels of sensitivity.

Normally, healthcare practitioners complete between 35 million and 40 million flu tests each year in the US, according to diagnostic industry executives. Rapid antigen tests that detect influenza proteins have become the method of choice for many clinicians, and in the past have accounted for about 75 percent to 80 percent of the annual $300 million to $350 million market for respiratory testing in the US.

With the collision of the pandemic with the upcoming flu season, performing just flu tests or just SARS-CoV-2 tests will not be a viable option.

"Given that COVID-19 has brought a further level of complexity to the influenza-like illness differential diagnosis, it is very likely that there will be a shift away from simple flu screening towards more confirmative multi-target PCR assays," said Davide Manissero, chief medical officer, infection and immune diagnostics at Qiagen. "Syndromic testing approaches … will be helpful in the upcoming flu season to not only diagnose or rule out COVID-19 with a single test from a single sample but to help guide treatment decisions when other infections are detected without additional testing and lab time."

PCR-based single-plex and multiplexed tests that address a combination of potential etiologies will remain the confirmatory test of choice for SARS-CoV-2, flu, and the other respiratory pathogens, Manissero added.

Meanwhile, clinicians are likely to continue to rely on rapid antigen-based tests for the diagnosis of flu, and SARS-CoV-2 tests utilizing the same technology could see wide adoption for the differential diagnosis of coronavirus and flu, especially as such tests are seen as a cheaper and quicker alternative to molecular tests.

"The demand for the SARS-CoV-2 antigen testing is absolutely through the roof and going to stay that way during flu season, especially with back-to-school, back-to-work initiatives popping up," Canaccord Genuity analyst Max Masucci said in an interview.

At the same time, the role and acceptance of multiplex molecular panels has improved during the pandemic, he added. In previous flu seasons, clinicians looking to do molecular testing have been comfortable ordering single-target tests, Masucci said, adding, "What we're seeing here is quite different ─ a confusing presentation of symptoms with differences from one person to another ─ so multiplexed panels are now seen as more valuable."

Testing demand is such that almost all of the competitors offering multiplex panels are likely to see adoption and growth during flu season, Masucci said. Many of the companies supplying multiplexed molecular diagnostic tests are likely to "sell everything they can manufacture just because the supply is so constrained," he said. "This principle will probably carry over to the flu season because the US is still not where it needs to be in terms of satisfying SARS-CoV-2 testing demand."

Indeed, even smaller molecular diagnostic companies, such as GenMark Diagnostics, have "disproportionately benefited" from the increase in SARS-CoV-2 testing demand, he noted.

Based in Carlsbad-California, GenMark has developed a test that integrates a SARS-CoV-2 viral target with the firm's FDA-cleared ePlex Respiratory Pathogen panel, which identifies 21 respiratory pathogens, including SARS-CoV-2, flu A, and flu B.

The company received $749,000 from the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) in March to develop the panel. It submitted the panel for FDA EUA in June and, in parallel, began distributing the product in the US for clinical use.

While different respiratory ailments may present similar symptoms in patients, their severity and the danger they pose to patients can vary widely, underscoring the importance of highly multiplexed tests, said Scott O'Brien, GenMark Diagnostics' senior vice president of global marketing and international sales. "To diagnose patients, especially those that will have signs or symptoms of respiratory illness, molecular assays will continue to be the Cadillac of tests and the primary choice for clinicians."

The firm said recently that it is increasing capacity for the upcoming flu season and expects to exit 2020 producing up to 150,000 tests per month. GenMark has three manufacturing lines and expects to add a fourth in the middle of the fourth quarter.

Meantime, Waltham, Massachusetts-based Thermo Fisher Scientific is developing multiplex panels that it believes will be ready for the current respiratory seasons. A three-target panel for the US market includes tests for SARS-CoV-2, flu A, and flu B, and a second panel for the European market includes targets for SARS-CoV-2, RSV, and flu A and flu B, but doesn't differentiate between the flu subtypes. The company anticipates applying the same manufacturing ramp-up approaches for the multiplex panels as for its current authorized SARS-CoV-2 tests, said Rachel Formosa. who leads Thermo Fisher's marketing initiatives associated with its COVID-19 and flu products.

Multiplex testing is important for labs because it can add efficiencies to workflows and reduce consumption of components such as swabs, said Israel Figueroa, product manager for Thermo Fisher's COVID-19 multiplex kits. "The alternative option is to run separate kits that are specific for each condition, but that increases testing complexity and consumption of components."

Qiagen's Manissero said that during past flu seasons, rapid flu antigen testing and single-plex PCR tests for influenza-like illness have played a screening role at the point-of-care, but in the coming flu season, "molecular testing and particularly PCR-based assays are most likely to continue driving testing."

Late in March, Hilden, Germany-based Qiagen received FDA EUA for its QiaStat-Dx Respiratory SARS-CoV-2 Panel for use in diagnosing patients infected with the coronavirus that causes COVID-19. The panel detects 22 viral and bacterial respiratory targets including SARS-CoV-2, flu A, flu B, and RSV.

Austin, Texas-based Luminex has been marketing its NxTag CoV Extended Panel since March when it received FDA EUA, and laboratories are running that test in parallel with the Luminex NxTag Respiratory Pathogen panel to simultaneously detect 20 respiratory pathogens, including multiple influenza subtypes.

The company said recently that it expects to soon obtain FDA EUA for additional tests that it has developed and that it intends to market during the upcoming respiratory season. One is a consolidated respiratory panel that includes a coronavirus target called the NxTag RPP plus SARS-CoV-2. The second is a standalone SARS-CoV-2 assay running on the Verigene I instrument that can be run alongside the current Verigene respiratory pathogens flex-testing panel.

Luminex also plans to apply for FDA EUA for a respiratory panel with a SARS-CoV-2 target running on its next-generation Verigene II molecular instrument. The Verigene II test is a fully automated, sample-to-answer system with 23 respiratory targets, including influenza and SARS-CoV-2.

The "all-in-one" panels reduce the number of samples, lowering patient discomfort, and providing for faster, more comprehensive testing while cutting down on the number of required suppliers, Shapiro said.

In July, Miller's BioMérieux announced that its all-in-one BioFire Respiratory Panel 2.1 plus, which tests for SARS-CoV-2 and other respiratory infections, received CE marking. The panel tests for 23 pathogens encompassing 19 viruses, including SARS-CoV-2 and Middle East Respiratory Syndrome coronavirus, and four bacteria that result in the most frequent respiratory tract infections. An earlier version of the test received FDA EUA in May.

The CDC, which was first to receive EUA for a coronavirus test in February, also nabbed one for a molecular SARS-CoV-2-flu test in July.

Further, Cepheid, part of Washington, DC-based Danaher, has plans to launch a rapid 4-in-1 test for detection of the coronavirus, flu A, flu B, and RSV from a single patient sample, and Roche announced Friday that its Cobas SARS-CoV-2 & Influenza A/B test received FDA EUA. The multiplex test is also available in countries accepting the CE mark

On Monday, three companies announced the development of multiplex respiratory panels. Laboratory Corporation of America said it has developed a single-panel molecular test to detect COVID-19, influenza A/B, and RSV infections, available to patients in the US through doctors, hospitals, and other authorized healthcare providers. LabCorp has submitted an application to the FDA to enable it to offer the combined test through its Pixel by LabCorp at-home test collection kit, which uses a short swab that is inserted into the lower nostril.

Further, Seoul, South Korea-based Seegene said it has introduced a single tube real-time RT-PCR assay, the Allplex SARS-CoV-2/FluA/FluB/RSV test, that simultaneously detects and differentiates flu A, flu B, RSV A/B, and three different target genes of COVID-19 ─ the S gene, RdRP gene, and N gene.

Additionally, CerTest Biotec, based in Zaragoza, Spain, announced it has developed the Viasure SARS-CoV-2, Flu & RSV Real-Time PCR detection kit.

To date, multiplexed tests for the coronavirus and flu are molecular-based, but rapid antigen tests for COVID-19 may also impact flu testing, according to Cornelius Clancy, a physician and chief of infectious diseases at the US Department of Veterans Affairs Pittsburgh Healthcare System.

Only four firms, Quidel, BD, LumiraDx, and Abbott, so far, have received EUAs for SARS-CoV-2 rapid antigen tests. Basel, Switzerland-based Roche recently also announced that it expects a SARS-CoV-2 rapid antigen test that it is developing will receive CE marking in late September, and the firm plans to pursue EUA. The point-of-care test is intended for use in both symptomatic and asymptomatic patients without an instrument.

In general, antigen tests are not as sensitive as molecular tests for flu or SARS-CoV-2. Nonetheless, millions of antigen flu tests are used each respiratory season, said Tamara Ranalli, VP of marketing for San Diego-based Quidel.

Some patients with symptoms indicating they could have flu or COVID-19 may rush to take a SARS-CoV-2 antigen test, according to industry executives. With a negative result from such a test, patients would need to then take a second test for flu, a step eliminated by multiplex testing.

Though such multiplexed molecular tests are available, no multiplex antigen tests are on the market currently to detect both SARS-CoV-2 and influenza in a single test, but some are under development.

Ranalli said that Quidel is developing a multiplexed flu and SARS-CoV-2 antigen assay for its Sofia immunoassay platform that it hopes to have ready for this respiratory season. Brisbane, Australia-based AnteoTech, a developer of surface chemistry technology, is combining SARS-CoV-2, flu A, and flu B on a single multiplex test strip with a reader, which it believes could be ready for launch with Australian Therapeutic Goods Administration (TGA) and US FDA approvals and CE marking in less than nine months.

By combining nanobinding technology with europium nanoparticles, the firm has driven higher levels of sensitivity in preliminary internal studies than that offered by currently available COVID-19 antigen tests, AnteoTech CEO Derek Thomson, said in an interview. Its test has the potential to help reduce the stress anticipated by health systems that need to test patients for COVID-19 but who actually have only the flu, he added.

Not all diagnostic industry executives believe that antigen testing will be a cure-all for the nation's supply and demand challenges as the flu season overlaps with the pandemic.

According to Robert Boorstein, medical director for oncology and esoteric testing at Brooklyn-based Lenco Diagnostic Laboratories, overcoming supply-chain constraints continues to be a priority for his company, but he is not seeing a surge in requests for antigen tests. His laboratory's main challenges stem from sourcing supplies to enable expansion. "Expanding and implementing a comprehensive testing solution becomes very difficult when you have to source various components from different companies," he said. The companies "may not have the capacity, or they may not want to work with you because you have traditionally worked with another company."

Overall, antigen and molecular testing for flu and SARS-CoV-2 and other respiratory conditions are likely to be in demand as the flu season overlaps with the pandemic. "One can easily view all of the COVID-19 molecular tests and antigen tests as complementary to each other, depending on the situation and the need," BioMérieux's Miller said.

Antigen tests that are cheaper and have quicker turnaround times than molecular tests "could be positioned as alternatives" for large population screening, contact tracing, and patient triaging, Qiagen's Manissero said. "For multiplex testing, clinicians will order a combination of targets that depend on epidemiological and clinical considerations."

Manoj Gandhi, senior medical director at Thermo Fisher, said that he believes multiplex panels with a few targets are likely to be in greatest demand during the respiratory season.

"From a clinical perspective, we have never seen this number of patients present to hospitals with these kinds of symptoms and when you add flu, the patient load is going to further increase," he said. "Rather than running highly-multiplexed, high-complexity panels, you need targeted, smaller multiplex panels to help you deal with that increased patient load."

The other consideration is running highly-multiplexed panels can be expensive, and there is no need to run them when only the identification of a few specific pathogens is required, Gandhi said.

This story first appeared in Modern Healthcare's sister publication GenomeWeb.