In flu season management, POC molecular to the fore

Anne Paxton

May 2017— Stacked against some of the nation’s previous bouts with influenza—such as the 2014–15 season—the 2016–17 flu season didn’t break records for drama.

To be sure, every flu season is different, and regional variation was prominent. In Central Texas, some outbreaks appeared to start later than usual, but the dominant viruses were the same as last year’s—H1N1, H3N2, and influenza B—says Bob Fader, PhD, chief of the virology and microbiology laboratory at Baylor Scott & White Health, Temple, Tex. The strains identified were a good match with this year’s trivalent and quadrivalent vaccine. Testing volume was up, as were positive PCRs.

From her vantage point in the northeast, “I’d say this season was about average,” says Donna M. Wolk, MHA, PhD, D(ABMM), system director of clinical and molecular microbiology for Geisinger Health System, Danville, Pa. “We had a diverse mixture of viruses throughout the entire respiratory season—nothing like two years ago when influenza predominated and the vaccine mismatch for flu strains was partly responsible for testing volumes five times that of our usual respiratory virus season.”

In Southern California, the outbreak was more substantial. “We had a heavy flu season,” says Omai Garner, PhD, D(ABMM), associate director of clinical microbiology and director of point-of-care testing for the UCLA Health System. “We counted a lot of positive PCRs this year, and our urgent cares and ERs were full. There were a lot of patients.”

But there was something more dramatic to note about this flu season, Dr. Garner says: Influenza testing technology has taken a big step forward.

For most clinicians, “Before this year, if you weren’t doing antigen testing for influenza, you were either using clinical discretion to diagnose, or you were sending the specimen to the lab and getting the result outside of the time frame that was clinically useful,” he says. But the recent approval of new CLIA-waived molecular influenza tests has triggered a whole new ball game. “You can now have a very sensitive test at the point of care. Before this flu season, that didn’t exist.”

In his dual role, helping to lead microbiology and point-of-care testing at UCLA, Dr. Garner says, “We’ve been thinking about how to improve our infectious disease testing for a long time. We completed an in-house evaluation, and we think that waived molecular influenza testing is going to represent a great solution for us.” The UCLA system plans to go live this fall with waived molecular testing in both of its emergency departments and most of its outpatient areas and study how it affects turnaround time and patient and physician satisfaction.

UCLA, which serves two 400–500-bed hospitals and 200 outpatient clinics, currently uses the Simplexa A/B & RSV PCR test in-house. “But in our very extended outreach network, we can’t turn around same-day results, so in a lot of our outpatient areas, we’re still using the poor antigen tests that are available.” The clinicians don’t trust them, and for inpatients they’ve been eliminated across the board.

Especially during the flu season, Dr. Garner notes, doctors’ clinical diagnoses based solely on patients’ presenting symptoms have a higher sensitivity than the antigen tests. “If it looks like flu during flu season, it’s probably the flu. And the challenge is if you have a test with bad sensitivity, you may accurately think it’s flu but the test tells you it’s not. Then your sensitivity can drop below 50 percent, depending on how much flu virus is present.” Given the rapid antigen test’s potential for misleading results, he adds, “It’s almost better not to test at all.” The FDA has issued a reclassification for some influenza antigen tests amid serious concerns about their sensitivity, he notes.

In the past, antigen testing hit closer to the mark. “When the antigen test in influenza got its approval from the FDA in 2005 or 2006, the tests were actually pretty good for the strains that were there. It’s just that there’s been so much antigenic drift that has gone on over time, the sensitivity gets worse and worse.” During the H1N1 pandemic in 2014–15, the numbers showed antigen testing’s worsened performance, Dr. Garner adds.

UCLA may or may not be ahead of the curve in moving to waived molecular testing. But it’s had special cause to feel the need. “The reason waived testing is important is that we have a very large network of outpatient facilities, some of them 50 to 60 miles away from the microbiology lab.” With Los Angeles’ notorious traffic, that can be a 10- to 15-hour delay in specimen transport. “So because we have such a big outpatient footprint, we represent a key area where the waived technology can really come into play.”

Next year, Dr. Garner says, waived instruments will occupy the space where the clinics are now performing rapid antigen testing. He estimates that 50 to 75 of the 200 clinics could end up with a molecular platform for flu testing. Those available are the Alere i Influenza A & B, the Roche Cobas Liat Influenza A/B, and Cepheid’s GeneXpert Xpress test; BioMérieux’s BioFire is now promoting an FDA-approved, CLIA-waived panel, the FilmArray Respiratory Panel EZ, as well.

He expects the cost per testing instrument to be between $1,000 and $10,000. “And paying for that will represent a struggle in the outpatient area because it used to cost $15 to $20 a test for a lateral flow test that has no instrumentation with it whatsoever. But it depends on your perspective,” Dr. Garner says. “In the laboratory, all the instrumentation costs far more than $10,000, but for point of care, where a dipstick reader is usually $500 to $1,000, the price for dozens of rapid molecular test instruments is going to mean a much more sizable up-front investment than is customary.”

In some conversations about cost, he has steered physicians to look at the bigger picture: “Think about what you’ve been paying for the antigen test that hasn’t been able to provide you with relevant clinical information.”

Some companies may find a way to make their antigen test more sensitive, Dr. Garner says. “But projecting over the long term, if I had to predict, over the next three to five years I’d say the molecular testing will take over, at least for infectious diseases such as flu and RSV.”

Still, he cautions, there’s no comparison between what the laboratory can perform and what the platforms at the point of care can do. “With waived testing, you do one test in about 20 minutes. In the lab we can perform, in an hour and a half, 400 to 500 tests. That’s why you have to be a bit judicious about a rollout of waived testing.” So if a site is within a certain distance of the central microbiology lab, “it still makes sense to run the tests in the central lab, from a batching and efficiency perspective.”

UCLA is different from systems like Cedars Sinai and Kaiser, Dr. Garner points out. “They build localized hospitals where you go for health care, so you don’t have this issue of clinics operating 75 miles away from the laboratory. That’s the reason that at UCLA we’re trying to get on board with waived testing as fast as possible. But the way health care systems are expanding, with the direction of health care right now, I think more point-of-care waived testing will be the solution, especially because the FDA has changed the way it looks at point-of-care testing. I do think you’re going to see an expansion of waived molecular testing.”

Patients are becoming more savvy, he says, but not about everything. “More patients understand the difference between a viral infection and a bacterial infection. But if you’re the treating physician and you don’t have proof that a patient has a virus, then potentially the pressure is higher to prescribe an antibiotic.”

Laboratory directors try to provide the most accurate data points possible, but ultimately it’s up to the clinician to diagnose disease, and a lot of other factors may come into play. Often, Dr. Garner says, “I do know [using the antigen tests] they’re now getting a data point of a negative that isn’t truly negative. I try to give them as much data as possible that’s correct, and then if they want to call the microbiology lab and are asking about follow-up testing, we love to make that clinical consultation. But again, that’s difficult too, if we don’t have solid data.”

He doesn’t know how many others are considering large rollouts of waived molecular testing for flu, but he predicts it’s coming, regardless of institution. “Antigen testing is on its way out the door,” he asserts.

Dr. Fader is not quite convinced that antigen testing will become a relic of the past anytime soon. Recent rapid growth in the Baylor Scott & White Health system has left influenza testing in a transitional phase, he says. “We have a huge system here. Just within Central Texas, we have more than 100 outpatient clinics and 13 hospitals. A lot of our outpatient clinics are still with the rapid EIA tests that are waived and can be done in clinical doctors’ offices.”

The system’s hospital-based labs have switched to molecular testing, and some of the smaller hospitals may follow, but many of the labs are in a holding pattern. “We’re kind of waiting to see on a couple of things.” The price of the molecular instrumentation is an obstacle. “At a huge organization like this, we can’t go out and buy a BioFire for every hospital or every clinic. So we kind of let everybody decide what testing modality they want to use during the course of the year.”

To date, Baylor Scott & White has not moved to the CLIA-waived molecular-based assays. “I know other places that have, and they’ve had good success.” But Dr. Fader does see molecular testing steadily increasing. In the Temple hospital, the main hospital in Central Texas, for example, EIA is no longer performed on anyone over age 18. “That test gets reflexed to either the influenza PCR or the Luminex xTAG respiratory pathogen panel, which we use a lot.”

The steep increase in cost is offset by the test’s higher sensitivity, he says. “Although you’re not getting results in 10 or 15 minutes, as you would with an EIA, you can get them in an hour or so. And some molecular assays are down to the 20- to 40-minute range.”