Nothing less than high-quality, rapid, and globally useful tools will do

Interview by Steve Halasey

Walter E. Phillips, Jr, PhD, TriStar Health System

Walter E. Phillips, Jr, PhD, TriStar Health System

It has been more than a year since the US Centers for Disease Control and Prevention (CDC) released its evaluation of 11 commercially available rapid influenza detection tests (RIDTs), demonstrating significant and worrisome variation in the sensitivity of such tests available for clinical use. Since then, FDA has proposed to up-classify RIDTs as Class II devices subject to special controls and performance standards, and CDC has issued new guidelines for clinicians using such tests. To catch up with progress in the field, CLP spoke with Walter E. Phillips, Jr, PhD, director of microbiology for the TriStar Health System, Nashville, Tenn, and a frequent collaborator in research leading to the development of infectious disease diagnostics.


CLP: In recent years, public health authorities throughout the world have expressed concern over the potential for another influenza pandemic similar to the H1N1 outbreak of 2009. Many US officials have said that this winter’s flu season is an especially bad one. What makes for a “bad flu season”?

Walter E. Phillips, Jr: In our area, one thing that has made this flu season bad is that it arrived a little bit earlier than normal, starting in November and peaking in December. And the number of positive cases that we have identified through testing has been extremely high compared to the last two or three seasons.

Another thing that’s made this flu season bad is the fact that about 95% of the positive influenza assays in our area have been for the H1N1:2009 strain of the flu—the same strain that caused the pandemic of 2009. The 2009 strain that’s circulating now is apparently more virulent than other strains, in that it can lead to more-severe disease, including pneumonia and acute respiratory distress syndrome (ARDS). Not only that, but it is affecting patients of middle age more than those of old age, which is uncommon.

So for those two reasons, I think, this is a bad flu season compared to the past 2 or 3 years.

CLP: Is there potential for the emergence of more-virulent strains of flu virus—or even therapy-resistant strains—as a result of the virus’s antigenic shift or antigenic drift from year to year?

Phillips: Yes, there is definitely that potential. Antigenic drift of the influenza virus is rapid, and the types of cases we’re seeing this year may be a direct result of this. This year, we’ve seen a lot of patients who have come down with cases of H1N1:2009 disease, in spite of the fact that they’ve been inoculated with this year’s vaccine—which, of course, includes the H1N1:2009 virus.

We don’t really know the cause of this trend, and there could be two or three reasons behind it. One explanation could very well be that the virus now circulating is H1N1:2009, but that it has gone through an antigenic drift to the point that the virus in the vaccine is no longer as protective as it was against the original version of the virus.

Another explanation relates to the possibility that we can, without question, develop resistant strains over time. Because these viruses are susceptible to it, we are using a lot of Tamiflu. But, as with most organisms, these micro-organisms are very adaptive. Once you start treating them with antivirals, they tend to change and become resistant.

CLP: How much warning would health authorities have if another pandemic were to begin taking shape?

Phillips: Our facility is a sentinel laboratory in CDC’s laboratory response network, so we would expect the Tennessee Department of Health and its division of laboratory services to keep us advised on a weekly basis, or even a daily basis, if there were any notices from CDC or other evidence of a pandemic developing. So our facility would have fairly quick warning of an impending pandemic.

I’m not sure how quickly community hospitals that are not part of the laboratory response network would get that information. But as a consolidated lab performing microbiology testing for about 2,000 hospital beds in Nashville, we would communicate that information to our sister hospitals very quickly.

CLP: Do US authorities also have good information about strains that have begun to circulate abroad?

Phillips: Internationally, if an outbreak were to begin abroad—like some of the avian influenza cases that have been diagnosed first in Europe or Asia—we would get that information through the national networks, coming through CDC, then the Tennessee Department of Health, and then on to us. So even for a pandemic beginning in a foreign country, we would still have pretty quick knowledge through CDC and the state.


CLP: Diagnostics play a critical role in gathering information about the circulation of seasonal flu virus. But many have expressed concern about the performance abilities of RIDTs, which are among the most commonly used because of their very quick time to result. What are the major drawbacks of the RIDTs currently in use?

Phillips: The major drawback of RIDTs is the one that everyone has known about for years: the relative lack of sensitivity. In different studies, sensitivity can range anywhere from a low of 25% to a maximum of 75%. In clinical tests for influenza, such a lack of sensitivity results in many false negatives. By far, this is the most serious problem with using RIDTs.

Without question, our own RIDTs and others continue to have false negatives when compared to PCR assays.

CLP: Within the past year, FDA has proposed to up-classify RIDTs from Class I to Class II, with special controls, and CDC has issued new guidance for the clinical use of those tests. How important are those moves as potential solutions for the problem?

Phillips: They are very important. Without question, FDA and CDC should move to ensure that there is a minimum sensitivity standard for rapid diagnostic testing, including both influenza and respiratory syncytial virus (RSV). The sensitivity requirements for these tests must be higher—especially if they are to be used at the point of care in emergency departments or physicians’ offices. Right now, the negative predictive value of these tests is not very good, as indicated by the fact that we encounter many false negatives among patients who have clinical influenza.

CLP: You mentioned physicians’ offices as out-of-hospital settings where the speed and convenience of RIDTs makes them especially useful. One can imagine many other such settings—urgent care clinics, long-term care facilities, and even patients’ homes—where it would make sense to use RIDTs. But what are the effects on clinical care in those settings if the results of such tests aren’t reliable?

Phillips: During flu season we frequently see people with influenza going to their physician’s office with symptoms suggesting bronchitis or bronchiolitis, or potentially pneumonia. Since it’s flu and pneumonia season, the physician runs an RIDT, and perhaps gets a negative result. But even knowing that the negative predictive value of RIDTs is very low, a lot of times the physician will conclude that the patient doesn’t have the flu, but may have something else.

As a result, the physician will put the patient on an antibiotic—which, of course, will have no effect on a viral infection—leading to poor antimicrobial stewardship. Such indiscriminate use of antibiotics is one of the reasons that treatment-resistant organisms are developing in a lot of areas.

RIDT tests are really not reliable for identifying other viruses or bacterial micro-organisms that might be the cause of pneumonia, bronchitis, or other upper respiratory infections.

CLP: Is the issue of poor sensitivity unique to influenza because the virus undergoes so many antigenic changes, or do these same kinds of drawbacks also affect other infectious disease diagnostics?

Phillips: No, the problem is not unique to influenza tests. We’ve also seen it with rapid tests for RSV. This year, we’ve seen cases that have come through an emergency department where the rapid tests that were run have come back negative. But later, the patient returns with continuing and worsening symptoms. As a result of their clinical condition, the patient is then admitted to the hospital, where a PCR assay reveals that the patient has an RSV infection.

So even though the BD Veritor test that we use is more sensitive than previous rapid tests, there can still be issues related to the insensitivity of influenza and RSV tests. When compared to PCR-based tests for upper respiratory viruses and bacteria, RIDTs still present issues of insensitivity.


CLP: Clearly, the laboratory community at large—and especially, the IVD manufacturing community—is looking for breakthroughs in this area. What characteristics are needed to improve the current generation of flu diagnostics and make them more acceptable?

Phillips: These tests will have to migrate toward the use of amplified DNA technologies, and particularly PCR-based technologies. Without a doubt, PCR-based assays are much more sensitive than the old lateral-flow rapid assays, so the smart move has to be in the direction of PCR-based testing.

Another change that has to take place is for testing to move in the direction of multiplexing. Right now, when a patient comes in with flu-like symptoms, physicians typically run two tests: an influenza test and an RSV test. But these are not necessarily the only viruses that could be causing the patient’s clinical symptoms. Doctors should also be checking for pertussis, and for other bacteria that can cause atypical pneumonias, such as Legionella, Chlamydophila, and Mycoplasma pneumonias. Tests need to be moved in the direction of multiplexing to look for multiple viruses using a single sample swab.

CLP: RIDTs have been widely adopted in part because they give doctors point-of-care access to test results in almost any setting—and they are very fast. Is it challenging for the new PCR assays to match up in this regard?

Phillips: Yes, I think it is. PCR assays take anywhere from an hour to an hour and a half—compared to 5 to 15 minutes for rapid lateral-flow tests—so that is a challenge.

When we began using PCR-based assays, we issued clear instructions to our emergency department that these tests were not to be used for in-and-out patients that were not going to be admitted. In those cases, the emergency department still has to use RIDTs because we cannot turn around PCR test results in time to be useful for an in-and-out patient. Our turnaround time for PCR-based tests is actually very good—a couple of hours—but that’s not on the same scale as the 30-minute time frame for the rapid-response stat tests that we run for influenza and RSV.


CLP: You mentioned PCR-based testing as a key shift in the technologies that are being brought to bear on influenza diagnostics. Are there other advances that are beginning to take hold?

Phillips: Without question, the use of multiplexed PCR assays for upper respiratory pathogens has been a dramatic change in technology over the past couple of years. As I described, the advantage is that only a single nasopharyngeal swab is needed, and in a matter of 2 hours the assay can provide results for 16 viruses and three bacteria. That’s a paradigm shift from RIDTs, which obviously are providing results for just one target.

One of the disadvantages of such multiplexed tests is their cost; they are much more expensive than single-target RIDTs. But these costs, I think, are far outweighed by the value of the outcomes they produce.

In our pediatric population, for instance, we see a wide variety of respiratory viruses that would never be picked up by the two tests that physicians typically run, including coronavirus, human metapneumovirus, rhino/enterovirus, and so on. If an infection isn’t influenza or RSV, there is a lot of value in knowing what virus is involved. Without knowing that a viral infection is involved, doctors often unnecessarily administer antibiotics.

But once doctors know the result of multiplexed testing, sometimes they can get the patient out of the hospital more quickly—or even dismiss the patient before they are admitted. Knowing that a virus is involved permits doctors to treat the symptoms and get the patient out of the hospital quicker.

For our pediatric population, we have a clinical triage unit called Kids’ Express, which is devoted to quickly figuring out what course of treatment the child requires. Our lab runs the pediatrician’s orders, which may include x-rays, lab tests, and so on. When infectious disease is suspected, our multiplexed PCR assay can determine within a few hours whether antibiotics are required, and whether the patient can go home or needs to be admitted. So this test really helps better triage patients and can shorten length of stay and prevent antimicrobial therapy. In the end, those are also cost savings.

CLP: The BD Veritor system is the first CLIA-waived digital readout assay for detecting influenza. What is important about having a digital readout?

Phillips: The Veritor system is a qualitative assay for Influenza A and Influenza B that uses a readout instrument to provide an objective measure of the pink-colored line indicating positivity. The operator places the cartridge into the readout instrument, which then determines whether the sample is positive or negative. Using an instrumented system helps to eliminate the inevitable variability of reading by a literal visual method, just eyeballing it.

CLP: As a lab director, how important is it to you that this test is CLIA-waived?

Phillips: Our lab is a high-complexity facility approved by the College of American Pathologists, so having a test that is CLIA-waived isn’t especially important. In our lab, we don’t run CLIA-waived tests because of the way specimens are extracted and submitted to us. But being CLIA waived certainly would be important in point-of-care settings, including physicians’ offices.

CLP: Are rank-and-file laboratorians and clinicians able to keep up with the changes in this field? Do they understand the different assay technologies and the resulting sensitivity of the tests? Are they moving to use the latest generation of materials at hand?

Phillips: At the rank-and-file level, probably not. When we went into the respiratory panel assay PCR arena, we expected to be educating practitioners about the new technology we were offering and how to order it. But we were surprised to receive questions like, “What is PCR?” “What are the viruses that PCR is detecting, and what types of disease do they cause?” “What age people do they cause disease in?” and “What is the season in which they cause disease?”

To address these questions, we developed and sent a handout to our own hospital’s physicians—including hospitalists, internists, and intensivists—as well as to physicians at our sister hospitals.

At this point, there still needs to be some continuing education. Both laboratorians and clinicians need to be informed about the new tests and technologies, how they represent a new paradigm shift in diagnostics, and what the advantages are of ordering the new test over older ones. We have had a lot of calls and questions from laboratorians and clinicians about these changes in the field.

CLP: Is the payor community supportive of reimbursement for advanced tests? Do payors understand the clinical significance and different outcomes associated with tests using newer technologies?

Phillips: For the most part, the payor community is accepting and providing CPT codes for PCR-based assays, so there can be reimbursement. But keep in mind that the majority of these tests are performed on inpatients—with the notable exception of those performed in emergency departments in anticipation that the patient will be admitted. So regardless of CPT coding, a lot of these tests will be paid under the diagnosis-related group (DRG) codes for inpatient services. Hospitals will be paid a certain amount of money, depending on the clinical diagnosis of the patient, and it will be up to the laboratories to control their related costs.

Payors may be a little behind the technology curve, and they don’t want to pay for everything. But for the most part, they do try to stay abreast of new technologies. Once the technology comes out and the payor community can see it’s being used effectively, it’s pretty certain they will assign a CPT code to allow for reimbursement for performing the test.