When to fire up large multiplex PCR?

Alexander McAdam, MD, PhD, associate professor of pathology at Harvard Medical School, was Dr. Schreckenberger’s interlocutor during the point-counterpoint session at the AMP meeting as well as in the pages of JCM. He tells CAP TODAY he is not persuaded that multiplex PCR panels will yield a great improvement in patient satisfaction.

“To me, that’s a relatively small gain—telling a patient that they’re infected with a virus they’ve never heard of, and for which there’s no treatment. It’s of some value because they know they don’t have something worse,” says Dr. McAdam, director of the infectious diseases diagnostic laboratory at Boston Children’s Hospital.

“The emergency room visit can be very valuable if the clinician tells the patient, ‘Based on your history and physical exam, you have a respiratory virus. You’re going to get better, and you’re not going to get desperately ill. If you get really sick, come back and we’ll be here for you,’” he says. “There’s tremendous value in that patient-physician interaction. And there’s only a little bit added by naming the specific pathogen.”

Laying out his views before the AMP crowd, Dr. McAdam said, “Will multiplex PCR panels achieve certain ends—improve patient satisfaction, reveal mixed infections, etc.? Yes, yes, yes. I don’t like these tests; I love them. The question is whether to use them as first-line tests.”

He noted, for one, that the tests are expensive. The cost per cassette is between $80 and $130, and laboratories also must account for other costs such as testing controls, capital expenses, and service contracts. He estimates that annual expenses for multiplex PCR panels as first-line tests at Boston Children’s would be about $200,000 for stool pathogens, $180,000 for respiratory pathogens, and $160,000 for blood-culture identification.

Dr. McAdam says his objection to first-line use of multiplex PCR panels is not entirely about cost.

“That’s certainly part of it,” he says, “but it’s also about the clinical utility of the tests and the difficulty that clinicians may have appropriately utilizing these tests and interpreting the results. The diagnostics have jumped ahead and we’re now detecting organisms that might or might not be true pathogens. People will struggle to understand the results of these tests. It’s important that normal microbiota not be treated as pathogens.”

His biggest concern is not that physicians will prescribe antibiotics to treat a viral pathogen. Rather, Dr. McAdam worries that physicians receiving a positive result for C. difficile on a GI panel may wrongly interpret that information.

“C. diff. is an important pathogen but it’s also found as a member of the normal flora. There’s a risk people will treat based on a positive test result when C. diff. may not be the cause of the patient’s symptoms.”

Boston Children’s Hospital will implement a rapid respiratory panel this year, but is holding off on GI and blood-culture identification panels for now.

“The big mistake,” Dr. McAdam added, “would be to introduce a large multiplex PCR test for syndromic diagnosis without having a careful conversation with the clinicians beforehand, so they understand what organisms the tests will detect as well as the clinical sensitivity and specificity. The goal is that they be prepared to deliver appropriate care when they get the results of the test.”
Without doing that necessary legwork with clinicians, it is possible that unintended outcomes, such as more misuse of antibiotics, could be seen.

“There’s no data either way,” he says. “There aren’t data on outcome studies based on these tests. We don’t know what actions clinicians take as a result of these reports, and we don’t know what effect there is on patients. It’s a real hole in the literature.”

Robin Patel, MD, says she is excited about the availability of multiplex GI panels but shares Dr. McAdam’s concern about their cost and the potential for unintended consequences. She chairs the Division of Clinical Microbiology at Mayo Clinic in Rochester, Minn., and presented data on the performance of panels from BioFire, Luminex, and Verigene. At Mayo, Dr. Patel and her colleagues evaluated the Luminex and BioFire GI panels.

“We found that they were both very good,” she says. Mayo opted for BioFire’s GI panel (which went live Oct. 12, 2015), in part because the laboratory already uses the FilmArray platform for blood-culture identification.

Despite excellent analytical performance of the GI panel, Dr. Patel said her laboratory encourages first-line use of the panel in only certain patients.

She cautions about the diagnostic uncertainty they can create. “These tests pick up targets that we haven’t been able to detect in the past,” Dr. Patel says. “That sounds like it should be an incontrovertibly good thing, but it’s not necessarily always so—when you detect something that you couldn’t detect before, it can be hard to know what to do with that result.”

The FilmArray GI panel can detect 22 pathogens in stool.

“Stool contains a large number of different organisms, some of which can be pathogens but most of which are beneficial for us,” she says. “There can also be a transient presence of pathogens or organisms that could be pathogens in one person and not in another, depending on what’s going on with them.” This situation wouldn’t necessarily warrant treatment, she says.

Dr. Patel offers as a hypothetical the case of a patient who tests positive for C. difficile, and whose stool also tests positive for enteroaggregative E. coli.

“That’s an organism we’ve not had a routine assay for in clinical microbiology,” she says. “So we have to look at the literature to try to figure out what the significance of this finding might be. Now we have a situation where the clinician knows how to handle C. diff.-associated diarrhea, but they have to deal with a report telling them that the patient also has enteroaggregative E. coli.

We’ve added confusion because we don’t necessarily know what the role of this E. coli might be in this patient. The clinician has the option of not changing the patient’s management based on this result, either because they don’t know what it means or they don’t think it should change their patient’s management. Or they may decide they need to treat the enteroaggregative E. coli, potentially using an antibiotic which, when given to the patient, may worsen their C. diff.-associated disease. Or they may decide to perform further testing. Overall, this situation shows that GI panels may add confusion to clinical care,” Dr. Patel says. The hypothetical patient case could unfold with repeat tests to see whether the enteroaggregative E. coli has resolved.

“This is because sometimes results of GI panel testing provide too much information and this is not a good thing, at least until we determine what actions should be taken or not taken based on the results.”

To help clinicians navigate this potential minefield, Mayo Clinic has developed a testing algorithm for infectious causes of diarrhea that recommends the GI panel only for cases of community-acquired diarrhea that have persisted for more than a week. For patients with health-care–associated diarrhea, Mayo recommends physicians order a C. difficile toxin PCR test alone. Mayo Clinic also provides interpretive comments in its laboratory report when certain targets are detected by the GI panel.

Kimberle Chapin, MD, director of microbiology and infectious diseases molecular diagnostics at Brown University-affiliated Lifespan Academic Medical Centers in Rhode Island, agrees in part with points made in the AMP session. “Multiplex technology has provided a solution to issues the lab has been screaming for help with—time-consuming, costly, and nonsensitive techniques for diseases such as viral respiratory pathogens and detection of stool pathogens. Now that we have syndromic panels, a few more issues have emerged that were not fully anticipated,” she says.

“Does this mean we should not use the technology? No,” she insists. “But it does mean we might have to find the best fit and be willing to adjust as we learn more after implementation.”

Right now, all labs are using a workaround solution to address their own issues with current multiplex systems as they relate to lab or patient costs or both, interpretation, volumes, and provider ordering, Dr. Chapin says. “Respiratory panels were the first multiplex panels to be cleared, and we have gained immense knowledge from our experiences.”

For some health care organizations, use of a rapid respiratory panel as a first-line test is not feasible because of the high volume of testing. Dr. Chapin says Lifespan expects to see about 5,000 acute respiratory cases during the flu season. “That volume cannot be handled by the only truly rapid respiratory panel where the provider could have clinically impactful results, the BioFire instrument, because a single instrument can perform only one test at a time, and I would need several instruments. That assay is not going to work for every patient, unfortunately,” says Dr. Chapin, who spoke at an AMP corporate workshop titled “What’s Missing in Molecular Diagnostics,” sponsored by GeneWeave, which was recently acquired by Roche. “While other truly rapid RVP diagnostics—two hours or less—are pending, the technology is lacking for another, faster, higher-volume RVP that could be clinically helpful in our setting.”

To address some of what laboratories face, Dr. Chapin says she wants to see the capability for flexibility, if necessary, from a multiplex panel from one specimen, from the same vendor. “One test panel performed a single time based on provider requests, but with the ability to pull additional results if needed.” That might be to reflex from a narrow panel to a broader panel, to increase the number of pathogens based on the severity or immune status of the patient or if a patient is admitted and infection control needs to know the true pathogen for isolation or cohorting, she says. “I can’t do an RVP assay on every single respiratory disease patient currently as test systems are set up, basically because of the cost to the patient in the outpatient setting and the time it takes to report the assay to be clinically useful. So what do we do? And what do most places do?

“We come up with a workaround. A rapid influenza test, and then potentially a reflex to an RVP if the patient gets admitted and the flu was negative. And it would be really nice if a company or our information systems could do both of these things together so we would not have to run a second assay.” Maybe Luminex—a single vendor with Magpix and Aries—will be an answer, she says. “Maybe there’s something else out there that will be the answer. But, essentially, I have gone to two different vendors to accomplish our clinical needs, and this makes things a little bit difficult for our lab as well as confusing to providers.”

Dr. Chapin argues that more outcomes data should be collected at the time the trials are conducted to secure FDA approval or clearance. That would enable a more informed comparison of the clinical and financial costs and the benefits of new molecular diagnostics.

“There’s a major disconnect, now, between trying to get the higher-quality test for someone but not being clear on what benefits some of the results will actually provide, either in the care of the patient or for the overall health care system. For outpatients, where panels might be used because they are more sensitive and less expensive for the lab, it ends up being really costly for the patient if they are paying out of pocket for lab testing,” she says. “Providers will want to know and be able to tell patients that there is a real benefit to the test.”

But, Dr. Chapin notes, device manufacturers lack the “deep pockets” of pharmaceutical companies. The vast majority of expenses associated with the outcome data-collection process involve patient enrollment, the informed-consent process, and follow-up, she says, where a lot of the outcome data would need to be collected prospectively at the time of the trial. “That’s the unfortunate component, and that’s where the diagnostic companies are not going to be able to really do this on their own,” Dr. Chapin says. “Unique partnering of diagnostics with NIH or other foundations, and/or changes in how trials are performed to gather this information, has started to address this need on outcomes from the get-go.”

“As we learn more about the pathogenesis of syndromic disease and pathogens that we are identifying, then we are going to find value, absolutely, in multiplex methods,” she adds. “The diagnostics are ahead of the clinical picture.”
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Kevin B. O’Reilly is CAP TODAY senior editor.