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Q&A: Intermountain's Bert Lopansri Shares Perspective on PCR-Based Syndromic MDx Panels

Bert Lopansri

NEW YORK (GenomeWeb) – The clinical microbiology lab at Intermountain Healthcare serves as a routine lab for 16 hospitals — including a few with more than 350 beds — as well as some medium-sized hospitals, and it serves as a back-up lab for other hospitals in the system.

Bert Lopansri is the medical director of the lab, but also does epidemiology research, teaches, trains residents, and, for a few months a year he also sees patients. He is therefore in a unique position to evaluate impacts and trends in multiplex PCR-based syndromic panels, and has consulted for a few diagnostics firms on the subject.

GenomeWeb recently spoke with Lopansri about panels — the pros and cons, implications for infection control, and what he looks for when bringing on new tests. Below is an edited transcript of the conversation.

What information do you use when deciding to bring new tests into your lab?

First, I look at our clinical needs, and what my colleagues are asking for. Is there a particular clinical program that has articulated the need for a test? As novel tests get approved, we also look at the targets involved and ask whether it applies to our patient population. Once we bring it online, the volume of testing validates the need. Many years ago we brought on a molecular test we thought docs would need but it never got ordered, so we had to take it off the menu.

We also look at performance characteristics and test complexity. In this day and age, one of the important things is the pre-analytical steps, such as the number of sample prep steps, whether we have to batch the tests or whether they can be run in real time. The complexity of the test is an important thing to consider.

Finally, I consider the benefits and downsides to the test. What if we see a whole lot of a certain target we don't normally see, how will that influence the clinical side? And of course we look at the cost of the testing, how it will impact the overall cost of a patient's care, and any outcome studies that have been published.

What is your overall opinion of syndromic panels?

I think there is a role for them. If you are seeing a patient and you have no clue ... for example, if I am dealing with a patient with a solid organ or bone marrow transplant or a patient with respiratory tract infection. The targets on a panel have different meanings in that population. If the patient is going to be admitted to the hospital there are also implications to staff and other patients. In that setting, where the clinical manifestations can be varied, there is definitely a role.

Some manufacturers make panels with different kingdoms or types of pathogens, while others are pushing to separate viral and bacterial — can you give an example of a nuanced case where too much information may have been detrimental?

Yes. A couple years ago I was involved in the care of a patient who was admitted septic with a clinical syndrome that was consistent with community-acquired bacterial pneumonia, as indicated by globar consolidation on chest X-ray and lab tests. The clinical scenario favored bacterial infection, a respiratory panel was run, and it was positive for metapneumovirus.

Because everyone was on the same page thinking the signs were pointing to bacterial pneumonia, we were not confident enough in the metapneumovirus target to stop antibiotics. So we kept her on broad-spectrum antibiotics but the patient still wasn't doing well. She underwent a broncoscopy, and the long and short of it was, she had methicillin-resistant Staphylococcus aureus pneumonia. She improved once we targeted for MRSA.

Many people might have thought, 'OK, metapneumovirus,' and taken her off the antibiotics, but the clinical presentation was so consistent with a bacterial process that we didn't stop looking, and we didn't stop treating.

It highlights how important the clinical scenario is. You can put any target in a panel, but it may not apply to all the patients that you are taking care of. A bacterial/viral panel would have applied to this patient, but it may not apply to an outpatient with a milder case of pneumonia.

We've interviewed clinicians who feel strongly that syndromic panels have the potential to deliver the best patient care compared to cases where physicians order whatever test they suspect might be appropriate. What kinds of cases would you recommend panels be used on?

I'm an adult physician. I think a lot of the studies on panels, particularly the respiratory viral panels, apply mainly to pediatric populations. On the adult side, I don't buy it as much. Clinical appropriateness really depends on who you ask and what patient population they take care of.

Clinicians also have many different approaches to ordering lab tests, and what may be appropriate to one doc might be interpreted as being excessive to another. To me, any test that influences how a clinician manages a patient is an appropriately ordered test.

Regarding multiplex panels, these are so new, I'm trying to determine the role that these play, and I think a large part of it stems from the degree of certainty or uncertainty around a patient's illness. In the pediatric population, there are so many overlaps in clinical symptoms between different pathogens that it's really difficult to tease apart. And the consequences [of missed diagnosis] could be a greater in the pediatric population. A parainfluenza virus, for example, will behave completely differently in the pediatric versus the adult population, so the needs and the outcomes are a bit different.

If, after an encounter, there is a fair degree of certainty around the cause of an illness, a clinician may or may not test the patient at all, or targeted testing may be appropriate if a targeted test is available. On the other hand, sometimes there is no targeted test for the suspected pathogen, and a broader panel [which includes that target] is the only way to go.

So, does that mean your lab has to stock every kind of test available?

We try to have different options. Before the low-complexity panels were around, we offered a broad respiratory panel, but we also offered targeted influenza testing and RSV antigens. Some docs will call and say, 'I only want to know influenza A or B, I don't care about RSV, don't report that because I don't want it.' But others will want to know everything, and it all hinges on what is in front of them clinically.

We try to accommodate the different approaches by offering both bigger panels and targeted testing.

How does your lab deal with reporting results of panels to physicians if they include targets that are hard to interpret or that may add complexity without necessarily benefiting the patient?

When we use big panels, we report whatever comes off. We do try to customize it, because there are some things for which there is not enough data to support them, particularly in the GI panels. They're also so new, it is hard to know how to interpret some of the results and it has contributed to a lot of confusion.

What about targets such as Clostridium difficle or carbapenemase-resistant enterobactericea — how can you differentiate carriers?

For C. diff, there are two commonly used detection methods, and a third gold-standard one which has a slower turnaround time. The most important thing [to ask] is: What is the clinical suspicion and what is the clinical syndrome?

We've had confusion where a patient comes in with what sounds like classical norovirus infection. A broad panel gets ordered and it will be positive for norovirus, but also for C. diff. I don't know how other labs are addressing this, but what we are trying to do is, if the C. diff is positive in the panel, we attempt to adjudicate it with alternative methods before reporting it to the clinician.

The lab test is there to find the pathogen that is consistent with the clinical finding. The problem is, with every pathogen there are mild presentations and severe presentations, and they all overlap. That's what makes these panels so challenging, but also so helpful.

Also, with C. diff for example, there is no grey zone in reporting to [the Centers for Medicare and Medicaid Services] and it counts against the hospitals, so we have to think carefully about the implications of things included in a panel. 

What do you do if the adjudicating tests don't agree?

We're currently evaluating to see if this is the best way to go, but we will tell the clinician, for example, that the PCR is positive, the [glutamate dehydrogenase antigen test] was positive, and the toxin test was negative. If the GDH is there, that tells us the bacteria is there, so perhaps the toxin degraded or it was below the limit of detection. In that situation, the PCR has a bit more meaning. The situation that is just completely confusing is if both GDH and toxin are negative but the PCR is positive. In that case, we tell them the results and [suggest they look for] clinical correlation.

What is your relationship with different diagnostics manufacturers?

We were a clinical trial site for a Phase II study for Nanosphere, and I also performed an outcome study which was partly supported by them. I also serve as a medical consultant to Nanosphere and I have presented a webinar on their behalf. I've received research support from BioFire and presented an ID Week symposium supported by BioMérieux. I also currently receive research support from OpGen, and I am PI for a clinical study evaluating a novel gene expression test made by Immunexpress to distinguish sepsis from non-infectious causes of systemic inflammation

What advice might you give to firms developing new multiplex diagnostics panels?

I would say: think carefully about what you include in your panels. You can't test for everything; there are just so many different pathogens out there. ... And whatever you choose to detect, make sure to detect it very well. Maybe two thirds of the time a pathogen will be consistent with the clinical presentation, so I think we ultimately need an alternative strategy like pairing molecular testing with something that gives a better degree of confidence ... such as host gene expression, or a biomarker like pro-calcitonin. That's my way of saying, "You're almost there, there's just something else that is needed."