Response to Comments: MolDX: Multiplex Nucleic Acid Amplified Tests for Respiratory Viral Panels (DL37764)

The Association of Public Health Laboratories (APHL) appreciates the opportunity to comment on the Palmetto Molecular Diagnostics (MolDx) Draft Local Coverage Determination (“dLCD”) for Multiplex Nucleic Acid Amplified Tests for Respiratory Viral Panels (RVPs) (DL37713). APHL’s membership comprises governmental public health laboratories who are experts in both diagnostic and surveillance testing for respiratory pathogens. While we recognize that Palmetto’s proposed non-coverage decision is strictly a clinical testing reimbursement issue, we would like to take the opportunity to express our concerns about the impact on public health and clinical care. Additionally, we would like to clarify several public health issues that were cited in the decision rationale.

• Clinical and Seasonal Overlap of Respiratory Viruses: To clarify the proposal’s assertion that diagnosis can be made by a clinician on the basis of seasonality and clinical symptoms, as public health practitioners, our individual state laboratory-based surveillance systems for respiratory illnesses provide ample evidence that many of the viruses included in these panels share symptoms and overlap in seasonality. These findings are supported by studies in the U.S. and abroad.1,2,3,4
• Utility in Outbreak Situations for Patient Care: During outbreaks, multiplex panels fill an important role in clinical decisions by ruling in other etiologies and providing reassurance in a rapid manner to clinicians, patients, families and public health officials. As currently written, this proposal oversimplifies the clinical manifestations of these viruses and ignores the value of determining a specific etiology of a disease that cannot be determined from direct testing for influenza and RSV alone. This additional information is crucial in tailoring pathogen specific intervention and prevention efforts.
• Unusual Clinical Presentations: The multiplex panel is also useful when unexpected disease activity occurs. For example, HIV infection in the acute phase often presents as an influenza-like- illness. However, if the initial clinical suspicion is wrong and tests are negative for respiratory viruses, this allows clinicians to have further conversations with their patients to determine if an HIV test is indicated. Without the multiplex panel ruling out other viruses, this delays a healthcare provider’s ability to determine a diagnosis. Respiratory virus panels save time and resources and ultimately lead to a faster public health intervention and prevent transmission to other people.

Another example of the utility of respiratory pathogen multiplex panels occurred during 2014- 2015 when over 300 patients across multiple states presented with parotitis and symptoms similar to mumps in the winter months, though all tested negative for mumps. Molecular testing, including the use of a respiratory virus panel, led to the detection of influenza and several other respiratory viruses in over 70% of these patients and revealed that the circulating influenza A H3 subtype that year could cause rare parotitis symptoms. Respiratory virus panels can be very important for patient management decisions especially when there are other viral pathogens known to cause similar symptoms. By using a broad panel for diagnosis, clinical decisions are made in an effective and efficient manner.

• Traveler Diagnosis: Palmetto should not disregard the utility of these panels in case of traveler illness and novel disease detection. These panels can be conducted in parallel when ruling out pathogens of high consequence. For example, a physician may request a respiratory virus panel on all MERS-CoV rule outs in parallel to MERS-CoV testing because time is critical when ruling in another etiology if the MERS-CoV test is negative. Being able to provide an alternative answer gives more confidence to the physician, public health officials and patient in a negative result for a pathogen of high consequence.
• Assay Performance: While further data would be useful on these panels, particularly for sensitivity for different pathogens, the assays have demonstrated reliable positive predictive values. Furthermore, these assays are far superior to rapid antigen detection assays and timelier than culture, which many laboratories no longer maintain for respiratory pathogens.
• Impact on Public Health Affects Clinical Care and Patient Management: While APHL recognizes that reimbursement should not occur for the sake of public health surveillance testing, the clinical laboratory data collected from these panels serve as the foundation for many state and federal respiratory surveillance reports. The healthcare system relies on these surveillance reports to make informed clinical judgments for patient care. Knowledge of which pathogens are currently circulating helps physicians in their differential diagnosis. The proposal will likely have a negative impact on state and federal public health surveillance systems and will diminish the amount of data available to physicians, ultimately compromising the quality of patient care.

Recognizing that the use of these panels not only benefits individual patients, but also public health, APHL proposes that reimbursement be changed to a per panel basis rather than per pathogen basis. Alternately, Palmetto should consider reimbursing only for a universal core set of pathogens that have clinical and seasonality overlap, including the following:

• Adenovirus
• Coronaviruses
• Human metapneumovirus
• Influenza viruses
• RSV
• Parainfluenza viruses
• Human rhinovirus/enteroviruses

The commenter makes a hypothetical argument pointing out that there potentially exists a clinical application for a respiratory viral panel in some patients so as to lead to a better outcome.

However, the commenter does not provide evidence that any particular panel (where a panel is a specified group of tests which must be ordered together) or any group of panels has clinical utility for a particular population or for beneficiaries with well identified indications. For coverage purposes Palmetto GBA must make coverage decisions regarding specific panels or specific selections of pathogens for specific indications. As such, while we agree that it is conceivable that there exists a patient population who might benefit from a particular group of multiple respiratory viral tests, at this point no evidence has been brought to our attention regarding how a clinician is to identify such a population for any specific available test. Moreover, the only virus group in the core set of pathogens for which treatment is widely (but still not universally) appropriate is influenza.

For those cases in which more than one causative virus could be related to the observed signs or symptoms (either due to overlap of typical symptoms or the presence of atypical symptoms), and diagnosis of a specific causative agent is expected to alter treatment in a way that improves the outcome, the clinician could order individual viral tests for which a result would be expected to lead to clinically actionable information.

If new evidence develops demonstrating that a particular panel or the use of a particular set of respiratory viral tests, which match the components of a panel, leads to enhanced patient outcomes we would be willing to reconsider this coverage determination.

A representative of a test sponsor commented as follows:
I am sure you have received valuable information and data from sources, much more qualified than I am, addressing these Drafts. The purpose of this email is to emphasize our desire and willingness to continue to collaborate and work towards the most appropriate reimbursement model for Multiplex Syndromic testing. One that truly benefits the Medicare beneficiaries while having a positive impact on the quality and cost of care. Please advise if we can provide further information and additional data to assist in this endeavor. We have appreciated this opportunity to have these types of discussions as well as your openness to engage us in them.

Coverage decisions of respiratory viral panels are based on analytical validity, clinical validity, and clinical utility. In the case of respiratory viral panels, we expect that most labs will be able to develop tests with analytical and clinical validity. However, to have clinical utility, it must be evident that obtaining the results of the full panel leads to a better outcome in a patient. The challenge of many panels is that while they contain assay components, each of which individually may be reasonable and necessary in particular circumstances, the panel by its very nature requires that all of the components be tested. As such, there must be evidence that there is clinical utility to the panel as a whole.

Hologic agrees with Palmetto/WPS that the diagnostic approach to multiplex respiratory viral panel testing isn't "one size fits all" and the Proposed/Draft LCD (DL:37713) aims to support target specific testing vs. large multiplex panel testing. However, as currently outlined in the Draft LCD, labs that run, report and bill on small, targeted panels to diagnose specific pathogens that cause common syndromes (i.e., Influenza A, Influenza Band Respiratory Syncytial Virus) would be denied as the below CPT codes are listed as examples of non -covered codes:

• 87631- Infectious agent detection by nucleic acid (DNA or RNA); respiratory virus (e.g., adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 3-5 targets.
• 87632 - Infectious agent detection by nucleic acid (DNA or RNA); respiratory virus (e.g., adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 6-11 targets.

Therefore, we request that Palmetto include the above CPT codes in the final LCD. These two CPT codes are clinically warranted when a clinician is choosing disease-specific testing based on the severity and complexity of the patient's symptoms.

Both the Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA) recommend PCR testing for the diagnosis of Influenza if the result will influence clinical management decisions.¹ Molecular diagnostic tests have become the gold standard for pathogen detection due to their sensitivity and specificity. Clinicians are primarily responsible for determining which methods are used for respiratory testing in both inpatient and outpatient settings. Often, clinicians choose from a list of targets available to test and the lab reports out the CPT code corresponding to the number of targets chosen.

For example, a clinician may want to differentiate between Influenza A and Parainfluenza viruses 1, 2, 3 and 4 on a critically ill adult patient as it' s important to identify the cause of the infection in order to make sound clinical decisions about the patient's treatment, whether that be prescribing oseltamivir phosphate for Influenza or supportive care (i.e., inhalers and/or steroid s) to reduce inflammation from Parainfluenza.

A modular approach to syndromic respiratory testing via the ability for a clinician to order and a laboratory to run one, two, three or multiple assays on the most frequently ordered tests, meets specific patient needs without running unnecessary tests.

CONCLUSION

In light of the concerns discussed above, we support Palmetto in implementing an LCD that meets Medicare's criteria for " reasonable and necessary" services, however, it is important to offer clinicians a choice between targeted and panel testing as it relates to diagnosing respiratory viruses. Our recommendation to include CPT codes 87631 and 87632 allow clinicians to accurately diagnose and appropriately manage patient care.

Presently each test for which a lab bills that is payable under Medicare is mapped to the appropriate CPT code. The present policy does not prohibit a treating physician or a lab from testing for multiple respiratory viruses in specific clinical cases where it would be reasonable and necessary. Rather these would be covered as individual tests mapped to appropriate CPT codes.

However, in recognition of the fact testing for 3-5 pathogens may have a role in limited clinical circumstances, we will cover 87631 under specific conditions as reflected in the LCD text. In summary, 87631 will be covered in settings that may care for critically ill patients or for patients who are immunosuppressed and are being treated by an infectious disease specialist.

A member of the National Academy of Medicine who is retired from the USPHS as an Assistant Surgeon General commented as follows:
I have worked on infectious disease issues for many years, and focused in the past decade on respiratory diseases. The IDSA/ATC guidelines published over a decade ago on community acquired pneumonia have been criticized for the lack of focus on diagnostics. They are currently being updated.

I have reviewed available literature and the available data suggest use of diagnostic testing for patients with pneumonia will decrease mortality and significantly decrease side effects of therapy. I have analyzed raw data and these data do not support empiric treatment in hospitalized patients with pneumonia.

We are in trouble with antimicrobial resistance in large part because our medical institutions have been (without sufficient data to support) focused on empiric therapy. It seems easy: Get a CXR and treat with the "kitchen sink."

I chaired the Public and Scientific Affairs Board for the American Society of Microbiology and was surprised and disappointed to see the long-standing lack of emphasis on diagnostic reimbursement for infectious diseases by CMS.

It is not a cost-saver to deny incentives to know what we are treating, and to target therapy.

We appreciate the comment from an informed voice. Our coverage decisions are made based on publicly available evidence and guidelines. We acknowledge that there may be the ongoing development of research, which in the future will support the use of a non-covered respiratory virus panel, and we encourage providers or the public to submit new scientific studies or society guidelines to us as part of a coverage reconsideration request when they become publicly available.

Because of the international concern over rapidly increasing levels of antibiotic resistance and few clinical options to treat such resistant bacteria, I urge a favorable assessment on the Local Coverage Determination for Multiplex Nucleic Acid Amplified Platforms for Respiratory Tract pathogens (DL37713). Numerous professional organizations have expressed, with eloquence, their sense of urgency for a favorable determination. After 45 years of taking care of patients and leading academic pursuits, I wish to add my voice in support of such a determination.

The overuse of empiric antibiotics for both upper and lower respiratory tract infections is well documented. Such infections are common. For Medicare purposes, it should be emphasized that they are more common, especially pneumonia and bronchitis, in the Medicare population. The incidence, morbidity and mortality all increase with age.

For any medical illness, precision in diagnosis reduces morbidity, mortality, unnecessary drug exposure, adverse drug effects, days of therapy, length of care, and, of course, a concomitant reduction in the expense of care. All of this is true with respect to the use of antibiotics. In addition, the reduction in antibiotic use reduces the propensity for promotion of antibiotic resistance.

Physicians are highly motivated to provide quality care to their patients. At times, they lack the tools to make precise diagnoses. In such periods of uncertainty, they often, as repeatedly demonstrated in academic studies, resort to empiric therapy. When queried, they report difficulties dealing with such uncertainty and patient expectations. In the attached article from The New York Times magazine (Gilbert DN. Fight Fear with Science. New York Times 12/29/2013 (online), I emphasized the fear factor. Physicians are afraid of missing a treatable bacterial infection and/or causing emotional distress on the part of patients.

History shows us that such uncertainty can be rectified. Point-of-care, rapid turn-around time diagnostics empower providers and change patient care paradigms. This can happen in the blink of an eye.

The management of pharyngitis is a relevant, historical example. Virtually all providers now take advantage of the rapid detection of Streptococcus pyogenes antigen or nucleic acid as the basis for prescribing, or not prescribing, an antistreptococcal antibiotic. This logical approach was unheard of prior to the availability of point-of-care immunoassays for streptococcal antigen. Previously, virtually all patients got empiric beta-lactam antibiotics unless they were allergic. Arguably, it is now far below the standard of care to manage pharyngitis without utilizing a rapid detection test for the presence/absence of Streptococcus pyogenes.

An example more relevant to the Medicare population, is the import of establishing a microbial etiology for Medicare patients who suffer from chronic bronchitis and chronic obstructive pulmonary disease. It is common for such patients to ask their providers for help due to increased sputum production, sputum that is increased in purulence, and worsening shortness of breath. As you know, the etiology of an acute exacerbation of chronic bronchitis may be viral, bacterial, a combination of virus and bacteria, a response to allergens or air pollutants, and/or continued use of inhaled tobacco products.

Prior to availability of molecular diagnostics, all patients with acute exacerbations of chronic bronchitis received pulse steroids, bronchodilators and empiric antimicrobial therapy. With molecular diagnostics, we now know that viruses are responsible for 50% or more of such exacerbations, often with associated bacteria. The bacteria may be colonizing or invading. It should be emphasized that the concern of viral infection extends far beyond presence or absence of influenza and/or respiratory syncytial virus. Any of the other respiratory viruses (for example, adenovirus, rhinovirus, coronavirus, human metapneumovirus, parainfluenza) can trigger an exacerbation of chronic bronchitis. Now providers can now do a nasopharyngeal swab and with a turn-around time of a little over one hour, manage such patients with knowledge of whether or not a respiratory virus is present. If present, the patient’s illness can be managed with “precision”. It would seem we are poised for a pharyngitis-like paradigm shift in management.

Providing access to such powerful diagnostic modalities, removes the “fear factor” from provider treatment decisions. Surgical procedures come to mind. We have no hesitation in rapidly utilizing new instruments that lessen patient morbidity for invasive surgical procedures because they are more precise, lead to better outcomes and ultimately reduce overall expense. The rational us, or non-use, of antibiotics are, in my view, similar.

There is emerging literature to document the value of point-of-care molecular diagnostics. One can anticipate a flood of such data as the testing becomes more widely available. We have a substantive amount of data on the positive effects of molecular diagnostics on community-acquired pneumonia of sufficient intensity to require hospitalization. The multiplex nucleic acid platforms in the hospitalized patients are included in DRG reimbursement. The results of application of multiplex PCR platforms is all positive and a publication from our group is attached. Similar data has been generated by colleagues in Rochester, New York for patients with acute exacerbations of chronic bronchitis (see attached).

In short, the world of point-of-care molecular diagnostics is rapidly moving forward to include outpatient point-of-care management. Platforms will become easier to use, more comprehensive, and studies documenting cost effectiveness will surely follow. One can easily foresee guidelines and other standard of care publications including molecular diagnostics as part of the core management of outpatients with respiratory tract infections.

• Providers want to do the right thing. Providers are educable. However, physicians need the best tools available to allow precision management.
• Specific therapy leads to better clinical outcomes and empiric therapy with fewer adverse effects.
• Specific therapy reduces exposure of the microbiome to unnecessary antibiotics which, in turn, reduces selection of antibiotic resistant strains of bacteria.

After due diligence, I am hopeful that your organization will agree that modern point-of-care molecular diagnostic platforms for respiratory tract infections deserve Medicare reimbursement coverage.

We agree that the identification of a specific bacterial agent causing pneumonia may help to focus treatment. This LCD non-covers panel tests of respiratory viruses specifically, however. Tests to rapidly and accurately identify bacteria are not in the scope of this LCD, though there are some assays that test for both types of organisms. For the majority of Medicare beneficiaries, the only respiratory virus included in these panels for which specific identification can broadly be tied to a focused treatment is influenza. Focused testing for influenza is a covered service outside of the scope of this LCD. We acknowledge that in specific cases, testing for the presence of other viruses may be clinically important, and this LCD does not prohibit clinicians from ordering additional specifically selected virus tests based on needs of an individual beneficiary’s case; rather it non-covers panel tests, which do not allow specific selection based on an individual beneficiary’s needs.

Interesting articles coming out in recent times addressing FLU testing and the use of single testing vs panel testing. The article below has very good views and comments on over use of Biofire respiratory panel and the endorsement for single analyte testing specially during FLU season.
Interesting perspective from several medical institutions agreeing that respiratory panels are not the answer….
See the below article. Good data on lowering costs for Flu testing by using immunoassay as a screen and syndromic panels as a back up.

NEW YORK (GenomeWeb) – Using a Quidel Sofia influenza immunoassay as an initial screening tool saved Tufts Medical Center approximately $36,000 during the 2014 winter flu season, researchers at the center have reported.

In a retrospective analysis of a respiratory illness testing algorithm using the Quidel assay prior to syndromic testing with the BioFire FilmArray respiratory panel, clinicians and laboratorians at Tufts said the $36,000 was saved in comparison to a summer period in which the 20-target FilmArray panel test was used alone as the first-line assay.

Brad Gardiner, an infectious diseases clinician and coauthor on a Diagnostic Microbiology and Infectious Disease study describing the algorithm, said Tufts had previously been using viral culture before adopting the FilmArray respiratory panel. The lab had also been running antigen tests while waiting for viral cultures and decided to incorporate these as a screen when introducing the FilmArray panel.

"Then, the crazy flu season of 2014 hit." Gardiner said in an interview., "I was seeing patients … and I could see in real time the advantages of this two-stage approach."

Combining the speed and high specificity of an antigen test with the backup of a highly-sensitive multiplex PCR assay was "basically the best of both worlds," he said, adding that at the same time it saved a bit of money.

"In the peak of flu season, if you get all the positives out as quickly as possible, you can save your [syndromic test] for the negatives," he explained.

Specifically, 1,814 samples were processed with the two-stage method during the winter flu season. The protocol was then compared to 1,162 samples processed by FilmArray alone in the summer months.

The lab was able to diagnose 282 cases of influenza with the Quidel Sofia influenza immunoassay using the two-stage approach. It then tested all nasopharyngeal specimens that were shown to be negative for flu by immunoassay with the FilmArray panel, picking up an additional 163 influenza cases that would otherwise have been missed by immunoassay alone.

The two-stage approach also included a respiratory syncytial virus immunoassay test in children under age 5 and in adults upon physician request, testing 363 patients. Approximately 28 percent of samples were Sofia RSV negative but FilmArray RSV positive, and an additional 71 RSV cases were discovered by FilmArray in patients who did not have the immunoassay.

Beyond influenza diagnosis, 580 of the patient samples who tested negative with the Sofia flu test who then went on to FilmArray RP testing were positive for one of the 20 viruses or bacteria in the multiplex panel. And, combining the winter and summer FilmArray test results, there were a total of 77 cases in which more than one pathogen was detected, particularly the viral targets.

The median time to result using the two-stage protocol was just over one hour, compared to almost three and a half hours with FilmArray alone, even though that test technically runs in about one hour. This was due to the fact that the lab had access to only two FilmArray instruments during the study period, Gardiner noted, so queueing could be a problem at peak times, nullifying the on-demand benefit of the system. Although the lab now has four instruments, it has also expanded its menu and runs the FilmArray blood culture and gastrointestinal panels on these instruments as well, Gardiner said.

Importantly, although the Sofia immunoassay can be a point-of-care test, the Tufts group chose to use it as a lab-based assay to avoid having to train staff throughout the hospital and to better manage quality control. This strategy was enabled by the fact that the Tufts hospital system is located on a single campus, with all facilities closely situated. Additionally, a rapid tube transport system can get specimens to lab in a few minutes, Gardiner said. This allowed the lab to perform the two-stage process on a single specimen, saving time and eliminating the inconvenience of collecting a second nasopharyngeal swab.

Overall, the strategy allowed the lab to process almost twice as many specimens in the busy winter months without delaying results, Gardiner said. It also saved the lab $36,353, based on the cost to the lab of $15.75 for the Quidel Sofia immunoassays and $129 for the BioFire FilmArray RP.

The total costs to the hospital and patients were not evaluated in the study, nor was the clinical significance of the additional panel diagnoses, generally, and clinical impact or outcomes analyses need to be studied further, Gardiner said.

For example, FilmArray detects human metapneumovirus or adenovirus, but it remains to be seen whether these diagnoses ultimately result in earlier discharge or less antibiotic utilization. "If you make a diagnosis that changes the patient's outcome, that's money well spent, but if you are diagnosing people with rhinovirus and it makes no difference, perhaps that money could have been spent better elsewhere," Gardiner said. Reimbursement is also highly variable, and Gardiner pointed out that some patients have been charged large sums by their insurance companies for the panel tests.

On the other hand, rapid flu diagnosis is believed to reduce the time to antivirals, and Gardiner himself had this experience when he contracted the flu during the study period. "I was diagnosed by Sofia and I knew within 20 minutes of my swab being taken that I had the flu—I was able to get antivirals straight away and put a mask on to stop infecting my colleagues, rather than having to wait for three hours."

A panel maker weighs in

As long as labs follow the test's parameters, they can use the FilmArray RP assay in any testing algorithm or approach which is validated and makes health economic sense, Mark Miller, CMO of BioFire parent company BioMérieux said in an interview.

But, Miller added that upfront screening tests for the detection of any infectious disease should be highly sensitive. Such is the case with rule-out tests for Clostridium difficile for example. But Gardiner pointed out that, unfortunately, immunoassays for respiratory viruses tend to have sensitivities in the 50 percent range.

In fact, this low sensitivity of rapid influenza diagnostic tests, or RIDTs, was one of the motives for the US Food and Drug Administration reclassifying them from class I to class II medical devices, requiring manufacturers to have tests reevaluated by the agency.

In the Tufts study — which was done prior to reclassification — the Sofia flu immunoassay picked up 63 percent of the total flu cases diagnosed, while Sofia RSV detected 72 percent of cases. The Sofia flu test was also among the first to meet the FDA's more stringent standards when it was reclassified earlier this year.

However, a negative immunoassay required secondary confirmatory testing due to low sensitivity.

"By using an insensitive upfront test for flu A, B and RSV, like the immunoassay, further delays and workload are produced — not to mention the mistrust of clinicians in a negative result," Miller asserted.

Gardiner, however, explained that real-world time-to-result was similar with the two-stage approach despite processing many more samples, in part due to the lab's queuing issues for its FilmArray system. The Tufts lab also chose not to release a negative Sofia result to clinicians, but, instead, held it as "testing in progress" until final PCR results were available to avoid the potential problems from reporting false negative results.

Miller noted that four patients in the Tufts study who tested negative for flu were subsequently discovered to have Mycoplasma pneumoniae by the FilmArray panel, so testing with the panel first would have resulted in more prompt therapy with a targeted antibiotic in these cases.

The other targets in the FilmArray test can also provide patients and parents with a definitive diagnosis, even if a non-influenza virus is found, as well as provide "important information for infection control, patient reassurance, less unnecessary antibiotic use, and optimal patient management for admissions" Miller said.

Arthur Rabson, a coauthor on the study and director of the Tufts tissue typing and molecular pathology, clinical immunology, and microbiology laboratories, emphasized that it made sense to use the immunoassay system first. "This gave a result in 30 minutes and we were able to diagnose 63 percent of flu cases very rapidly," he said in an email.

Practically speaking, the majority of samples sent for respiratory pathogen testing are sent to eliminate flu, Rabson said. "They are not sent with the primary aim of deciding [whether] the cause of the problem rhino/entero or corona or adenovirus. Patients resent receiving a bill for hundreds of dollars simply to be told that they had a 'cold'."

Cassandra Parker, also a coauthor on the study and a senior medical technologist at Tufts, pointed out that the Tufts antimicrobial therapy and infectious disease teams have found that identification of a virus often does not result in withdrawal of antibiotic treatment, since bacterial co-infection is not uncommon. And, she said, "Patient reassurance, especially with the high price tag that some patients are being asked to cover themselves, is also not a good enough reason to perform the BioFire routinely."

One caveat to this argument may be that a 2015 study — which looked at a pediatric patient population — suggested patient satisfaction, or in this case parent satisfaction, achieved by identifying a pathogen was an important factor when treating children, even if it did not ultimately alter treatment.

Miller stressed that the syndromic approach has taken hold globally and has received broad acceptance. He attributed this in part to clinicians recognizing that they do not know what infectious agent is causing most of the cases of influenza-like illnesses. "A broad panel of pathogens can give accurate results the first time, with no additional testing, and with no guessing," he said.

In the US, FilmArray RP panels are restricted to CLIA labs of at least moderate complexity. That is also the case for BioFire's newer RP2 and RP2plus panels. However, satellite CLIA labs can be located near emergency departments or intensive care units, and FilmArray assays in these locations would bring them physically closer to the patient. Outside of the US, regulations differ, and panels can be run in other hospital areas or even in community settings, Miller said. BioFire also makes the CLIA-waived RP-EZ panel, which can be run outside of CLIA labs and by non-laboratory personnel.

The firm believes that the BioFire FilmArray system has set the global standard for syndromic testing for upper respiratory infections, as well as for gastrointestinal and meningoencephalitis infections. As reported in the firm's 2017 financial results, the installed base continues to expand and now stands at approximately 6,100 units. Sales outside the US almost doubled and represent nearly 14 percent of total FilmArray sales. Overall, BioFire FilmArray sales in 2017 reached €368 million ($452 million), representing growth of over 50 percent from the previous year.

Targeting panel use

Although there is a paucity of published literature on the subject, some other laboratorians seem to be on board with using upfront immunoassays in conjunction with syndromic panel testing.

Rick Nolte, director of clinical laboratories and a professor of pathology at the Medical University of South Carolina, said in a recent interview that his lab uses Becton Dickinson's BD Veritor digital immunoassays for flu testing at the point of care prior to lab-based FilmArray RP. Nolte's lab also prefers this two-stage algorithm over point-of-care molecular testing for now, and he noted that the turnaround time for lab-based testing in the real world is not so much longer than POC testing alone, in many instances.

However, more studies need to be done on these workflows. Matthew Binnicker, coauthor of a recent paper in Clinical Microbiology Reviews on syndromic panels, noted that panels have only been used routinely in clinical microbiology labs for the past five or six years, so data on their overall cost-effectiveness has yet to accumulate.

Binnicker, who is director of clinical virology in the department of laboratory medicine and pathology at the Mayo Clinic, said that although it isn’t entirely clear whether the use of syndromic panels can reduce overall health care costs, there are several published studies that have shown that the routine use of syndromic panels can reduce length of stay in the hospital, impact patient management and infection-control decisions, and reduce the use of antibiotics. Reducing antibiotic use can in turn have immediate benefits of lower costs associated with prescription and side-effects of treatment, and play a role in curbing the development of antibiotic resistance.

Binnicker highlighted that while there are certain situations in which the use of first-line rapid tests prior to more costly testing makes sense, prevalence in a given patient population is a very important consideration.

"Rapid antigen tests perform best in terms of sensitivity and specificity when the disease is highly prevalent in a community, but their performance suffers when the incidence is low," he explained.

There are also certain clinical situations in which targeted molecular tests may be recommended over starting with a syndromic panel.

For example, considering a hospitalized patient who has been on antibiotics and develops diarrhea, a targeted molecular test for C. diff would make sense because that is the most likely pathogen, Binnicker said.

Or, if a patient presents in January with a high fever, headache, and severe body aches, and there is also a high prevalence of influenza in the community, then a targeted test for influenza would be appropriate. "In those situations, starting with a broad, multiplex panel may not be needed," he said.

Along similar lines, a group at Yale Medical Center argued in a 2016 study that, for adult outpatients with uncomplicated upper respiratory infections, targeted influenza virus testing alone may be more cost-effective than syndromic panel testing. That study also found that diagnosing respiratory pathogens other than influenza did not impact therapeutic management and suggested implementation of multiplex testing should also involve provider education and antimicrobial stewardship to discourage the use of antibiotics for otherwise healthy adult outpatients.

Binnicker also pointed out that for all tests, healthcare providers need to ask themselves, "What are we going to do with the result?" If the result isn't going to be used to change patient management, then the test may not need to be performed.

For example, in an otherwise healthy patient with flu-like symptoms in peak flu season, the main question that needs to be asked is, "Does this patient need Tamiflu, or not?" On the other hand, if the patient is a bone-marrow transplant recipient and hospitalized with a respiratory illness, performing a syndromic panel as the first-line test makes a lot of sense, Binnicker said. "In that situation, we need to know what is causing the illness as fast as possible. We may not be able to wait for rounds and rounds of targeted immunoassay or molecular testing," he said.

Furthermore, Binnicker noted that with the increasing use of multiplex panels, it is important for clinical laboratorians to be actively involved in the development of test-utilization strategies, focusing on the use and interpretation of test results.

Diagnostic stewardship, or utilization management, which can involve physicians and laboratory directors meeting to discuss how new and existing lab tests should be used, is "especially important in this era of high-cost molecular and genetic testing, when 'more' is not always better," he said.

Thank you for this comment. In summary, the study discussed by the commenter compared an immunoassay test for influenza versus a PCR. Additional cases of influenza detected by PCR after they were not detected by immunoassay would not be attributable to the use of a panel testing for non-influenza viruses but rather to the use of a different laboratory technique to test for influenza specifically. Influenza testing by PCR is a covered test outside of a panel. Notably, the IDSA guidelines for influenza management (Harper 2009), recommend PCR as the optimal test for influenza detection. While PCR can also be used in the detection of non-influenza viruses, which the panel under study does, it is not clear that the detection of these other viruses has a clinical benefit. In the study discussed, non-influenza viruses were also diagnosed in some patients using the panel, but as the news article points out, it is not clear that the detection of these other viruses lead to clinically actionable information that improved patient outcomes.

Harper, S. A., Bradley, J. S., Englund, J. A., File, T. M., Gravenstein, S., Hayden, F. G., ... & Uyeki, T. M. (2009). Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clinical infectious diseases, 1003-1032.

Coverage Indications, Limitations and/or Medical Necessity

We agree with Palmetto that multiplex respiratory viral panel testing is not clinically indicated in all clinical scenarios. However, a global, non-coverage approach for multiplex PCR testing fails to recognize individual patient needs and can lead to a delay in treatment or ineffective treatment for many patients, particularly in elderly patients or those who are immunocompromised. Therefore, we request that Palmetto allow for coverage of these assays when they are determined to be clinically warranted, and especially in the three clinical scenarios detailed in this letter.

Respiratory viruses are a common cause of community-acquired pneumonia (CAP) and acute respiratory illness (ARI) in adults. There is evidence and/or clinical practice guidelines to support the use of frontline multiplex PCR respiratory virus testing in three clinical ARI scenarios: 1) immunocompromised individuals, 2) adult patients with ARI in outpatient settings, and 3) select patients who are admitted to the intensive care unit (ICU), especially when the results are rapidly available allowing for timely patient management decisions to be made (e.g., antimicrobial treatment, hospital admission).

Nucleic acid amplification tests for the detection of viruses and atypical bacteria have been shown to improve the microbiologic diagnosis of CAP compared to traditional, insensitive assays culture and antigen tests), especially in the elderly who shed lower titers of virus. Furthermore, there are no reliable clinical symptoms that allow for differentiation of the underlying heterogeneous pathogens that can cause CAP or polymicrobial infections, which can be caused by either viruses and/or bacteria.10,16 The consensus clinical and diagnostic utility for these multiplex assays has recently been summarized in a comprehensive review.

The following are several clinical scenarios where multiplex respiratory viral panels are well documented to be clinically-warranted, and should thus be a covered Medicare benefit.

1. Immunocompromised hosts. A broad spectrum of respiratory pathogens can cause significant morbidity and mortality in adult and pediatric patients with a weakened immune system. This is especially true for hematopoietic stem cell or solid organ transplant recipients, as well as for patients receiving high-dose chemotherapy and/or steroids. Early diagnosis is essential for optimal patient management (e.g., to direct antiviral therapy, to initiate or discontinue antibiotic therapy, to guide decisions about chemotherapy or timing of transplant, and (although not a patient-specific Medicare benefit), for informing optimized hospital infection control practices. Current U.S. and international guidelines endorse upfront, simultaneous testing for multiple respiratory viruses (i.e., testing beyond influenza A/B and RSV only) in transplant and cancer patients.
2. Adult patients appearing acutely ill with respiratory conditions in certain settings such as influenza outbreaks who are potential hospital admissions. Two different studies evaluating rapid multiplex respiratory viral testing have shown the positive clinical impact of rapid, comprehensive multiplex panels relative to traditional testing or individual molecular methods. Access to rapid multiplex testing in the clinic or ED, was associated with a decrease in unnecessary antibiotic use in both studies. Additionally, the study by Rappo et al., observed that ED length of stay, need for hospital admission, and number of chest radiographs were statistically reduced for patients with influenza who had a multiplex assay. There is also a trend toward higher rates of discharge from the ED (without hospital admission) for patients that tested positive for non-influenza viruses. These studies are in agreement with a recent pediatric cost- effectiveness model that found rapid multiplex testing to be the most effective approach for evaluating ARIs in the ED.

To date, there is a single prospective randomized trial comparing rapid multiplex testing to routine clinical care for adults presenting to the ED. Pre-specified secondary outcome assessments showed that patients in the group tested by a multiplex respiratory panel were statistically more likely to receive a single-dose or brief course of antibiotics, as well as have a shorter median length of hospital stay than the control group. Furthermore, more patients in the multiplex panel group were diagnosed and treated for influenza. Early detection and appropriate treatment of influenza could have resulted in reduced mortality and complications for hospitalized patients.

3. Critically-ill adult patients, particularly ICU patients. Human metapneumovirus, parainfluenza viruses, rhinoviruses, and coronaviruses have all been associated with severe ARI in adult and elderly patients. Furthermore, viral and bacterial co-infection has been linked to more severe CAP and longer hospitalization than those with a bacterial etiology alone. Currently, the FDA-cleared multiplex panels are the only diagnostic option for many of these non-influenza viruses and atypical bacterial pathogens associated with CAP. Even though there are no proven antiviral therapies for the non-influenza viruses, the ability to make a diagnosis of an ARI in the ICU enhances the ability to reduce unnecessary antibiotic use, which is a major cause of morbidity in hospitalized patients.

Other indirect benefits for diagnosing these non-targetable viral infections include ending the “diagnostic odyssey”, allowing for the de-escalation of broad, empiric therapy, and enhancing hospital infection prevention and prognosis efforts, which may impact the emergence of antimicrobial resistance.

The misuse of antibiotics, as when used inappropriately for viral infections, can lead to severe adverse effects in patients. A recent study by Tamma et al., demonstrated that a large proportion of hospitalized patients experience antibiotic-associated adverse effects. The authors drew several conclusions from this research, including that 20% of patients experienced one or more adverse effects and with each additional 10 days of antibiotics the adverse effects increased by 3%. It was also noted that 4% of patients developed Clostridium difficile infections, 6% of patients developed infections with multidrug-resistant organisms, and 24% of patients had prolonged hospital stays as a result of their adverse effects. In addition, the authors concluded that 19% of antibiotics prescribed in this study were unnecessary. Undoubtedly, some of the unnecessary antibiotic use reported in this study could have been reduced with timely multiplex respiratory virus testing.

ICD-10 Coding

Based on our above recommendations, we request that Palmetto include the following additional ICD-10 coded indications in the final LCD. Many of these requested ICD-10 codes are clinically warranted due to the inability to clinically distinguish (with signs and symptoms) the various viral and/or bacterial causes of respiratory infections before doing the definitive diagnostic test.

ICD-10 Code

Descriptor

B34.1                Enterovirus

B34.8                Parainfluenza virus - rhinovirus

A37.01              Bordetella pertussis

B96.3                Haemophilus influenzae [H. influenzae] as the cause of diseases classified elsewhere

B96.89              Other specified bacterial agents as the cause of diseases classified elsewhere

B97.0                Adenovirus as the cause of diseases classified elsewhere

B97.29              Other coronavirus as the cause of disease classified elsewhere

B97.89              Rhinovirus - as cause of disease classified elsewhere

J06.9                Acute Upper Respiratory Infection, unspecified

J09-J18             Influenza and Pneumonia

J10.00 - J10.89  Influenza due to other identified influenza virus

J11.00 - J11.89  Influenza due to unidentified influenza virus

J12                   Viral pneumonia, not elsewhere classified

J12.0                Adenoviral pneumonia

J12.1                Respiratory syncytial virus pneumonia

J12.2                Parainfluenza virus

J12.3                Human metapneumovirus pneumonia

J13                   Pneumonia due to streptococcus pneumoniae

J14                   Pneumonia due to haemophilus influenzae

J15                   Bacterial pneumonia, not elsewhere classified

J15.0                Pneumonia due to Klebsiella pneumoniae

J15.1                Pneumonia due to pseudomonas

J15.212            Pneumonia due to methicillin resistant staphylococcus aureus

J15.4                Pneumonia due to other streptococci

J15.7                Pneumonia due to Mycoplasma pneumoniae

J16                   Pneumonia due to other infectious organisms, not elsewhere classified

J16.0                Chlamydial pneumonia

J17                   Pneumonia in diseases classified elsewhere

J18                   Pneumonia, unspecified organism

J20.0                Acute bronchitis due to Mycoplasma pneumoniae

J20.1                Acute bronchitis due to Haemophilus influenzae

J20.3                Acute bronchitis due to coxsackievirus

J20.7                Acute bronchitis due to echovirus

J21.0                Acute bronchitis due to respiratory syncytial virus

J39.8                Other specified diseases of upper respiratory tract

Z94.1               Heart transplant status

Z94.2               Lung transplant status

Z94.4               Liver transplant status

Z94.81             Bone marrow transplant status

Z94.82             Intestine transplant status

Z94.83             Pancreas transplant status

Z94.84             Stem cells transplant status

Z94.89             Other transplanted organ and tissue status

Conclusion

We respectfully disagrees with Palmetto’s/WPS’s conclusions that “the use of highly multiplexed NAAT tests as front-line diagnostics cannot be justified at the current time” and that they do not meet Medicare's criteria for "reasonable and necessary" services. Disease severity can be especially high in the immunocompromised and elderly patient populations. Studies show that rapid identification of the causative agent(s) of respiratory tract infections is essential to provide an accurate diagnosis and appropriately manage patient care. It is also a key component in restricting antibiotic use to those circumstances in which antibiotic therapy is clearly indicated. Therefore, we urge Palmetto to consider the evidence that we have presented in this letter and allow for coverage of these assays when documented as clinically necessary. 

The commenter specifically mentions three broad clinical scenarios in which a respiratory virus panel multiplex test may have clinical utility. We address each of the clinical paradigms individually. In recognition of the fact testing for 3-5 pathogens may have a role in limited clinical circumstances, we will cover 87631 under specific conditions as reflected in the modified LCD text. In summary, 87631 will be covered in settings that may care for critically ill patients or for patients who are immunosuppressed and are being treated by an infectious disease specialist.

1. Immunocompromised hosts – We acknowledge that this patient population may be very susceptible to infections. This LCD does not prohibit physicians from testing patients for multiple respiratory viruses based on the viruses of concern and the patient’s unique clinical situation. Additionally, we are modifying the LCD to allow testing for 3-5 pathogens in this population.

Additionally, the commenter points out that use of panel testing may help guide optimal hospital infection control practices. As the commenter also implies, measures taken to enhance hospital infection control are not a payable Medicare benefit for services delivered to a beneficiary. If hospitals require the use of tests that do not change the outcomes for individual patients to optimize their overall quality, they are free to use these tests, but the use of the tests is not reimbursable under the Medicare laboratory benefit.

2. Adult patients appearing acutely ill with respiratory conditions in certain settings such as influenza outbreaks who are potential hospital admissions – As regards the role of viral diagnosis in this population, detection of whether the patient has influenza is particularly important. The commenter cites a study by Rappo suggesting that a multiplex PCR respiratory viral panel testing for influenza and other pathogens with a 1-2 hour turn-around time (FilmArray®) has clinical utility. This study compared the FilmArray® test to other influenza testing strategies including rapid antigen testing, direct fluorescent antibody testing, viral culture, and 2 different PCR tests one of which is run in the lab in batches and the other of which was a send out test for the lab. The results of the study showed that when the hospital used the PCR test with the 1-2 hour turn-around time, patients received influenza treatment sooner than when they were diagnosed with non-PCR methods and PCR tests that took longer than 1-2 hours. While this study does suggest that there was a benefit to the rapid turnaround time of the FilmArray® as compared with other testing methods for influenza, the study does not provide data that suggests a benefit to testing for non-influenza viruses, and the benefit appears entirely due to the rapidly obtainable results of the influenza component of the test in particular.
3. Critically Ill patients, particularly ICU patients – We are modifying the LCD text to allow the use of panels for 3-5 pathogens in this population, a population who would be located in an acute care hospital.

On behalf of the Roche Diagnostics Corporation (“Roche”), I am pleased to submit comments in response to the draft local coverage determination (“LCD”) from Palmetto GBA entitled “MolDX: Multiplex Nucleic Acid Amplified Tests for Respiratory Viral Panels”. Roche Diagnostics is the manufacturer of the cobas® Influenza A/B and RSV nucleic acid test, an FDA-cleared, CLIA-waived test utilized by providers in the MolDx program jurisdiction, and is part of one of the world's leading research-oriented healthcare organizations — the Roche Group. Roche develops innovative products and services that address the prevention, diagnosis and treatment of diseases and medical conditions. As a global leader in the fields of diagnostics and pharmaceuticals, we believe personalized health care will transform lives, improve patient outcomes and reduce costs of care.
The U.S. Food and Drug Administration has cleared or approved a number of commercially available tests to diagnose Influenza A/B with RSV including the Roche cobas Influenza A/B and RSV Nucleic acid test. The cobas® Influenza A/B and RSV Nucleic acid test for use on the cobas® Liat® System is an automated multiplex real-time RT-PCR assay for the rapid in vitro qualitative detection and discrimination of Influenza A virus, Influenza B virus and respiratory syncytial virus (RSV) RNA in nasopharyngeal swab specimens from patients with signs and symptoms of respiratory infection in conjunction with clinical and epidemiological risk factors. The test is intended for use as an aid in the differential diagnosis of Influenza A, Influenza B, and RSV.

This letter outlines our concerns regarding Palmetto’s proposed non-coverage for multiplex PCR respiratory viral panels and, as such, we respectfully request that you revise the draft LCD to allow for smaller panels when medically necessary and supported by documentation by the ordering physician.

Coverage Indications, Limitations, and/or Medical Necessity

In the proposed/draft LCD, Palmetto proposes to deny coverage for three CPT codes under which respiratory viral panels would be reported. Roche does not contend with Palmetto’s assertion that the “use of highly multiplexed [nucleic acid amplification tests] as front-line diagnostics cannot be justified at the current time” in all scenarios. We also concur that “[a] panel that includes pathogens that are very rare, or a panel in which all pathogens do not cause overlapping clinical syndromes, or when some pathogens are found only in specific patient populations (immunocompromised patients) is not reasonable and necessary”. However, we believe that it would be inappropriate to extend non-coverage to panels that target limited number of clinically-indicated targets (such as panels limited to Influenza A, Influenza B and RSV testing) when supported by documentation from the treating provider. Therefore, we request that the Final LCD allow coverage for these limited panels in appropriate clinical scenarios when medically necessary.
Limited respiratory panel laboratory tests furnished at the point of care, such as in a physician’s office, offer many benefits to the health care system. Patients are often able to undergo the test and receive the results during the course of an office visit (while the patient is still at the office), avoiding additional appointments and providing timely information on the patient’s clinical needs thus minimizing unnecessary antimicrobial use and reducing secondary complications for the patient.

In the draft LCD, Palmetto discusses the benefits of and importance of RSV diagnosis including the need to avoid unnecessary antibacterial agents.

Without definitive diagnosis, patients with viral infection are more likely to receive unnecessary antibacterial agents. Although current treatment for respiratory viral infection is limited to influenza A and B, detection of other viral agents is valuable because clinical suspicion of viral respiratory tract infections can be confirmed, additional workup and therapy can be avoided, and clinicians and parents can be reassured.

The speed and accuracy of these tests also allow for improved infection control measures. These types of tests are frequently used to diagnose respiratory infections such as Influenza A/B or RSV. With a non-coverage policy, beneficiaries would be denied access to these important tests.

In summary, we request that Palmetto revise the draft LCD to allow for coverage of the smaller panels, such as limited panels comprising Influenza A, Influenza B, and RSV, billed under code 87631 (i.e., 3 – 5 targets), when medically necessary.

In recognition of the fact testing for 3-5 pathogens may have a role in limited clinical circumstances, we will cover 87631 under specific conditions as reflected in the modified LCD text. In summary, 87631 will be covered in settings that may care for critically ill patients or for patients who are immunosuppressed and are being treated by an infectious disease specialist.

A practicing clinician and expert in infectious diseases and diagnostics who cares for patients with respiratory infection wrote to provide a clinical perspective on the utility of multiplex testing for respiratory illness. The commenter indicating that the comments were written at the request of a manufacturer and. The commenter was compensated for time in putting it together, the opinions expressed were the commenter’s own and not influenced by the company. Comments were as follows:

While multiplex viral pathogen testing is not clinically indicated in all scenarios in which patients present with respiratory infection, there are a number of situations in which the ability to use multiplex panels for the detection and identification of respiratory pathogens affects the care

I can provide to my patients. Particularly for patients with severe infection, immune compromising conditions and those in whom hospital admission is being considered, the results of testing lead to changes in downstream care that I believe lead to better outcomes for patients.

Patients who present with severe respiratory illness are at high risk of death. These patients are often prescribed broad-spectrum antimicrobial therapy due to the possibility of bacterial pneumonia. However, as we continue to learn (often through data obtained by multiplex testing for respiratory pathogens), severe respiratory illness can be caused by a range of viral as well as bacterial pathogens. Limited testing for influenza and/or RSV alone may not provide actionable answers for a hospitalized patient with severe illness, whereas a broader panel can also lead to detection of viruses such as human metapneumovirus or parainfluenza that might explain continued fever and oxygen requirement, and obviate the need to broaden antibacterial coverage or perform further tests. In some cases antibacterial therapy can be discontinued in the setting of a viral detection, decreasing adverse events and promoting stewardship. Negative testing on a broad panel suggests more strongly the contribution of bacterial pathogens to disease, and guides appropriate escalation of therapy if patients are not improving.

Patients with immune compromising conditions, underlying illnesses, very young children and the elderly can have atypical presentations of respiratory disease. These atypical presentations are coupled with an inability to adequately fight off infection and the need for rapid identification of pathogens. Due to their overall compromise (or underdeveloped immune system in the case of young infants) these patients are at risk for a range of infections, and can require extensive work up if a pathogen cannot be identified quickly. Respiratory viral illness is common in these populations, and the ability to use a high-order multiplex test to identify a pathogen quickly can not only lead to rapid therapy for a treatable illness such as influenza, but allow for appropriate support in the case of other viral infection (such as RSV) and decreased use of unnecessary antibiotics. For patients with cancer or those who are undergoing/have undergone organ transplantation, detection of any respiratory virus can have implications for therapy for their underlying disease.

Adults and children presenting to the ED with acute respiratory illness may need admission to the hospital. While in some cases this is required for supportive care, often it is for further work up or antibiotics when bacterial pneumonia is suspected or cannot be ruled out.
The availability of broad multiplex testing for viral respiratory pathogens has been shown to decrease unnecessary antibiotic use, ancillary testing and most importantly can decrease time in the ED, hospital length of stay and in some cases it prevents admission. All of these are primary drivers of healthcare cost.

Finally, in the areas of quality of care, efficiency of care and patient satisfaction, multiplex panels for respiratory pathogens can play a huge role. Upper respiratory tract infections evaluated by a healthcare provider are a major contributor to inappropriate antibiotic use, as documented in a number of studies. Identification of a specific viral cause for the disease can decrease antibiotic use, and increase appropriate antiviral therapy and anticipatory guidance. Patient satisfaction is a huge healthcare driver today, and the ability of a provider to identify a specific cause of a patients respiratory illness, provide targeted guidance for home care, expectations, and discuss scenarios in which a return to health care is appropriate go a long way to improving a patient's satisfaction in the provider as well as the care and the coverage they have received. The ability to send multiplex respiratory testing when clinically indicated for our patients is critical to maintain trust and continuity of care with our patients. Overall, while it is clearly appropriate to offer singleplex or dual detection systems for pathogens such as RSV or influenza that can be used when these are the only clinically actionable infections, there remain a wide range of clinical scenarios in which multiplex respiratory testing provides information that can lead to better patient care, outcomes and patient satisfaction. I hope that this type of testing can remain a covered benefit to the patients I care for.

The commenter points out that broad testing for possible respiratory pathogens may have implications for clinical care in selected patients. As noted in response to other comments, we have modified the LCD to allow for tests covering 3-5 pathogens. We are unaware of high quality evidence demonstrating that a defined patient population of a group of patients with a set of signs and symptoms will benefit from broader multiplex testing.

The commenter also notes that these panels may have the ability to reduce unnecessary antibiotic use. It is presently not clear in which patients a positive test for the presence of a given viral infection would obviate the need for antibiotics. Existing guidelines from the Infectious Disease Society of America do not recommend cessation of antibiotics in community-acquired pneumonia if a viral infection has been genomically detected, and these guidelines only recommend testing for pathogens when the presence of a pathogen would significantly alter empirical management decisions.

Finally the commenter refers to the possibility that the use of these panels may improve patient outcomes in a wide range of clinical scenarios. However, at present no stakeholders have brought evidence supporting this assertion to Palmetto GBA’s attention.

I read the draft non-coverage policy determination online for respiratory viruses. I think this is one of the most important and difficult decisions for diagnostic coverage for Medicare in recent memory and especially important to get right. I’m curious about the references for the following statements ("A negative test result does not necessarily rule out a virus and requires additional testing to confirm its negativity. False negative results can occur as the virus mutates within a local geographical area."). Mutational change for diagnostic accuracy in respiratory viruses is a pretty limited problem. And the first sentence seems to argue that anything other than metagenomics at $2500 a test should not be covered for diagnostics, if there’s no direct treatment.

The commenter is referring to a statement taken from the analysis of the evidence. As with many reviews in peer-reviewed literature, the concluding statements in this LCD, which are a synthesis of the information from the evidence summarized above, reflect our own analysis and synthesis of the evidence. However, the evidence which is has led us to a conclusion is summarized and referenced above. As regards the need to confirm a negative test result, this is from the 501(k) document for a number of the tests on the market, some of which we have quoted in the draft LCD text. The issue of geographic mutation is not discussed in the evidence above. Since this statement does not have bearing on the coverage decision, we will remove it.

The commenter also seems to indicate an understanding of part of the LCD text as stating that a test should not be covered if there is no direct treatment from the results. Indeed, it is generally the case that when there is no direct treatment based on knowledge of the specific infectious virus (e.g. general supportive treatment for a non-specific viral infection), testing to positively identify the specific infectious virus would not be reasonable and necessary under Medicare. However, this is not an absolute statement, and in acknowledgement of the fact that in isolated cases, there may be a clinical value to identifying a specific virus, the LCD does not limit coverage of such testing. Rather it requires a clinician to deliberately choose to order the specific viral tests of importance rather than use a panel test.

It is also important to note that hospital infection control, epidemiologic surveillance, and public health uses for a test, while important, are a distinct matter from whether a test provides value to the care of the specific beneficiary in whom it is being ordered.

We are clarifying some of the text in the evidence review of the LCD and the coverage indications of the LCD to further clarify this.  

An emergency room physician wrote the following comments:

1. In my Emergency Department experience working with a wide variety of complex patients presenting with acute issues, there is value performing Respiratory Multiplex PCR testing in select patients.
2. The ability to obtain and perform timely resulting Respiratory Multiplex panels can aid in determining the disposition of select patients home versus a hospital admit.
3. Immunocompromised patients, oncology patients, and autoimmune patients on immunomodulatory medications can sometimes be discharged home from an Emergency Department instead of being admitting when the clinical situation warrants based on results of multiplex testing.
4. Disposition decisions are made in coordination with the patient’s oncologist or specialists managing their acute or chronic immunocompromised state after Multiplex testing results are known.
5. During typical winter months when the prevalence of high viral loads exist in admitted patients in hospitals, it can be advantageous and safer to keep immunocompromised and immune- modulated patients out of the hospital when possible. When clinicians have a high suspicion an immunocompromised patient in the Emergency Dept. has a virus causing their acute symptoms (often fever, tachycardia, maybe some tachypnea), based on multiplex testing, clinical history, and clinical findings; after discussion with the patients specialists to arrange close outpatient follow- up, we can often discharge patients home instead of admit saving CMS significant cost for the admission. Blood cultures and urine cultures will often be sent and followed outpatient. Rapid identification of bacteria from cultures allows us to call back patients when needed or treat them outpatient if appropriate adjusting medication regimens.
6. Cohorting of patients can be performed when hospitals are crowded with little capacity when we multiplex testing is covered making it available. This allows for more efficient throughput and improved use of limited inpatient bed capacity when appropriate. This reduces morbidity for patients.
7. I have seen oncology, autoimmune, immunocompromised patients discharged early from the hospital once initial/prelim bacteria culture results are known when there is a positive respiratory Multiplex highly likely confirming a viral syndrome as the cause of a patient’s symptoms warranting the admission initially.

Overall, in select patient populations, having Multiplex respiratory viral testing covered and available can improve patient outcomes, prevent increased cross contamination of hospitalized patients, families, and staff during high viral load parts of the season, and reduce admission rates.
I have witnessed use of multiple respiratory viral testing for the past couple of years being used in ways detailed above improving efficiencies and safety of patient care in select patients.

The commenter indicates that clinical experience has shown a use for multiplex testing in making clinical care decisions, particularly in a hospital setting, either in the emergency room or in a hospital unit. As noted in other responses to comments, we are modifying the LCD to allow coverage of panels testing for the presence of 3-5 pathogens, particularly in hospital and emergency care settings.

As regards the use of testing to alter the clinical management of patients, the commenter indicates that the diagnosis from multiplex testing can lead to disposition decisions and possibly decisions not to admit the patient. Present guidelines for the management of community-acquired pneumonia and influenza do not include the use of specific viral diagnosis except for influenza so as to inform the decision to prescribe oseltamivir. However, in special cases in which the identification of a specific non-influenza virus or pathogen by a nucleic-acid amplification technique may be appropriate to alter clinical management, providers may individually order tests for the relevant organisms.

The commenter also indicates that the use of multiplex testing helps hospitals with operational decisions. While this may be important, tests obtained to help with hospital operations are not coverable under the Medicare laboratory benefit. This coverage policy does not have any bearing on the tests hospitals to choose to use for their operational decision making.

Mercy Health Systems includes over 40 hospitals across Missouri and the adjacent states. Our laboratories work in coordination under the guidance of our Pathology Specialty Council (comprised of pathologists with broad expertise) and Subject Matter Expert groups (comprised of experienced clinical lab scientists) to determine which lab tests best meet the needs of our patients. We have chosen to offer the BioFire FilmArray Respiratory Virus Panel in our laboratories because we believe this assay benefits the health of the individual patient, the health of our communities, and the fiscal health of our system.

Time and again, we have seen the benefits of these rapid assays for individual patients. The coverage guidance implies that the symptoms and signs of the infections assayed in respiratory pathogen panels are completely distinct. If this were true, respiratory illnesses could be diagnosed by history and physical exam alone, which is definitely not the case. Particularly in the case of children, who often cannot provide a history, we have found the respiratory pathogen panel to be valuable in establishing a diagnosis. Earlier this year, we diagnosed Bordetella pertussis in an infant without definitive symptoms of the disease. This surprise diagnosis allowed appropriate treatment to be initiated in a timely manner. Additionally, the guidance seems to suggest that because an illness does not have a specific treatment, diagnosis is not warranted. This is flawed logic. Once a diagnosis is established, even if it is a viral illness with no treatment other than supportive care, we can stop looking for another cause of the patient’s illness and move forward with supporting the patient through their illness. We have diagnosed human metapneumonia virus in numerous cases where the diagnosis allowed clinicians to stop searching for a cause and focus on supportive care.

The respiratory pathogen panel benefits the health of all our patients and our communities, not just the patients getting tested. We circulate a weekly report of the pathogens detected in our assays tracking the dynamics of different respiratory diseases in our community, keeping our clinicians aware of which respiratory pathogens predominate in our communities at any given time. This information helps clinicians prioritize their differential diagnosis and shift away from panel testing towards testing for specific diseases at times when those diseases are highly prevalent, i.e. testing for influenza during peak flu season. In addition to highlighting what viruses are in circulation, respiratory pathogen panel testing helps us cohort and triage our patients for both their own health and the health of our other patients and the community. Establishing a diagnosis within an hour or two of testing allows us to rapidly triage patients. Indeed, we have found over the two years for which we have full data (2016 and 2017), patients who were diagnosed using the BioFire FilmArray Respiratory Virus Panel compared to traditional methods had a significantly shorter length of stay; 0.33 days versus 2.38 days (n = 34,417 patients). Many critics of rapid respiratory pathogen panel testing argue that these assays are more expensive than traditional diagnostic methods. Simply comparing the cost of a rapid respiratory pathogen panel to traditional testing, this may be true. However, this is shortsighted. We have found the overall cost of caring for a patient with a respiratory illness is lower when we compare patients who underwent rapid respiratory pathogen panel testing to patients tested with traditional methods. When considering direct variable and fixed costs (including labor, medical supplies, medication, physician costs, and capital) as well as indirect costs (indirect physician cost) for the 34,417 patients who underwent respiratory viral diagnostics in 2016 and 2017 we found that patients who had a BioFire FilmArray Respiratory Virus Panel had an average of $5,881.55 LESS in cost per patient compared to patients tested using traditional methods.

We appreciate your consideration of the Mercy Health system experience with the BioFire FilmArray Respiratory Virus Panel as you make final determinations regarding reimbursement for this assay. Simply put, we believe rapid respiratory pathogen panels save lives and money and we hope you draw the same conclusion.

The commenter begins by pointing out that they believe that the use of a particular viral panel benefits the health of individual patients based on the guidance from their own panel of subject matter experts and discusses some of the internal data that they have collected showing a potential benefit to the use of a panel.

Palmetto GBA’s coverage determinations are based on publicly available data typically published in peer-reviewed literature. Present respiratory illness treatment guidelines from the IDSA do not clearly indicate a role for broad viral pathogen identification in most patients. Additionally, we have been made aware of no high quality published study presenting significant evidence supporting the use of broad panel testing in the Medicare population.

However, coverage determinations are subject to change based on the development of new evidence. As such, internal data currently known only to a group of providers or researchers may be grounds for the basis of a change in coverage in the future once that internal data is made public in a peer-reviewed publication.

GenMark Diagnostics, Inc. (GenMark) appreciates the opportunity to comment on the proposed local coverage determination for multiplex nucleic acid amplified tests for respiratory viral panels (RVP).

We acknowledge Noridian’s perspective on rapid, multiplex RVP testing and agree that “one size fits all” diagnostic approaches are not medically necessary for all patients. We further agree that clinical and laboratory stewardship be employed to ensure appropriate utilization of diagnostic tests in cases where pathogens on multiplex panels do not cause overlapping clinical syndromes or are found only in specific patient populations.

However, we would like to highlight certain aspects of the utility of rapid, multiplex RVP testing to complement statements in the draft LCD. Our comment focuses on three primary considerations:

1. With respect to multiplex panel design, we note that the literature supports the overlapping clinical presentations of the pathogens on the GenMark respiratory products. These targets are selected to cover the most common differential diagnoses for acute respiratory syndromes and community acquired pneumonia.
2. Providing tools that cover the range of a differential diagnosis enables efficient, definitive diagnosis and optimizes antibiotic therapy use. This counteracts the crisis of growing antimicrobial resistance that affects the Medicare patient population and our public health system at large.
3. Providing rapid, accurate diagnosis in support of patient care and antimicrobial stewardship has the most impact in specific care settings, such as the Emergency Department (ED), where patient status remains unclear while need for admission is assessed, in part based on results from tests like rapid, multiplex RVP.

In light of these considerations, we respectfully request that Noridian reconsider its draft coverage determination to allow for continued coverage of rapid, multiplex RVP testing of appropriately selected patients presenting to the ED and urgent care. We also propose working collaboratively with the Medicare Administrative Contractors (MACs) to develop additional data and guidelines for the most efficient use of rapid, multiplex RVP testing in these care settings.

Clinical Presentation and Differential Diagnosis of Acute Respiratory Infections

Influenza-like illness (ILI) is caused by 20+ pathogens that present with overlapping clinical syndromes. The common cold, the most frequent acute illness in the United States, has been associated with over 200 subtypes of viruses. Multiplex respiratory panels, such as GenMark’s RVP, incorporate viral pathogens including rhinovirus (30-50% percent of colds), coronaviruses (10-15% of colds), influenza virus (5-15%), parainfluenza (PIV) (~5% of colds), and respiratory syncytial virus (RSV) (~5% of colds) responsible for the majority of cases. The differential diagnosis also includes adenoviruses, enteroviruses, and B. pertussis.1 Experts comment that “It is not possible to determine the likely viral pathogen on the basis of the observed clinical illness; all of the above viral pathogens may cause similar symptoms.”¹

Other upper respiratory pathogens present a similar challenge of overlapping clinical presentation and a broad differential diagnosis. A systematic review of 16 studies on influenza in adult patients aged 60 years or older concluded that “clinical findings are helpful but do not confirm or exclude the diagnosis of influenza.” While clinical diagnosis can be relied upon with greater reliability during an influenza outbreak, “sporadic cases of influenza cannot be differentiated from infections caused by other respiratory viruses on clinical grounds alone.”²

For RSV in adults, the differential diagnosis includes influenza and PIV. Studies have shown that RSV infection develops annually in 3-7% of healthy older adults and “may be responsible for as much as 25% of excess wintertime mortality, previously attributed solely to influenza.”³ While PIVs usually cause mild upper respiratory infections in adults, they can lead to life threatening infections, particularly in immunocompromised and older adult patients.⁴ The differential diagnosis for PIV includes both viral and bacterial targets such as adenovirus, B. pertussis, C. pneumoniae, enterovirus, influenza, human metapneumovirus (hMPV), M. pneumoniae and RSV.⁵

Accurate and rapid diagnosis of these different pathogens is critical in selecting proper treatment. The draft LCD acknowledges the range of pathogens that can be implicated in acute respiratory infections and in this regard is consistent with the evidence-based best practices summarized here. However, the draft’s generalization that “pathogen targets that compose the panels are determined by the manufacturers that make them, and do not represent specific pathogens that cause a common syndrome” and that the “panels include pathogens that are very rare, or a panel in which all pathogens do not cause overlapping clinical syndromes, or when some pathogens are found only in specific patient populations” does not align with the characteristics of GenMark’s RVP assay and similar products. Rather, these targets are selected to conform to evidence based clinical practice covering the most common pathogens in the differential diagnosis of acute respiratory infections. Rapid, multiplex RVP testing serves as an important complement to clinical diagnostic indicators in syndromes with overlapping patient presentation spanning a wide range of patient populations, including the elderly adult population. The rapid, definitive test results provide by multiplex RVP tests facilitate efficient patient management, leading to improved treatment outcomes and reduced per-patient healthcare expenditures, as discussed in more detail below.

Antibiotic Overuse

The U.S. Centers for Disease Control and Prevention (CDC) estimates that at least two million illnesses and 23,000 deaths annually are caused by antibiotic-resistant bacteria in the United States.⁶ The CDC’s report led to the creation of a National Strategy for Combating Antibiotic Resistant Bacteria which noted that one-third to one-half of all antibiotics used in inpatient and outpatient settings are either unnecessary or incorrectly prescribed.⁷

Pervasive inappropriate use of antibiotic therapy is a major contributor to this public health crisis. A major population study of an estimated 76 million office visits for acute respiratory infections found that 41 million antibiotic prescriptions were written, which is 22.6 million (55%) more than was expected to treat bacterial infections.⁸ A more recent report confirmed this result in a large, population based study of over 185,000 elderly patients who presented with a confirmed nonbacterial acute upper respiratory infection in the outpatient setting. The study showed that 46% of patients received an antibiotic prescription, with 70% of those receiving broad-spectrum therapy.⁹ The literature demonstrates similar results related to misuse and overuse of antibiotics in varying care settings and across diverse patient populations, sometimes resulting in adverse patient outcomes and progressive antimicrobial resistance. ^{10,11,12,13,14,15,16}

Inappropriate use of antimicrobial therapy not only contributes to growing antimicrobial resistance, but also places an unnecessary economic burden on the healthcare system as the CDC estimates that more than $1.1 billion is spent annually in the U.S. on unnecessary antibiotic prescriptions for respiratory infections in adults.¹⁷

Use of rapid diagnostics to address this challenge is aligned with the objectives of the National Strategy for Combating Antibiotic Resistant Bacteria, which include “develop(ing) new diagnostics, including tests that rapidly distinguish between viral and bacterial pathogens and…that can be implemented in a wide range of settings.”⁷ The CDC report continues:

Presently, most diagnostic tests take 24 to 72 hours from specimen collection to results…thus, treatment decisions are typically required and made before laboratory results are available. As a consequence, patients may be initially treated with antibiotics when none are needed, prescribed an inappropriate antibiotic, or treated with multiple antibiotics when a single antibiotic would have been effective….However, the technological landscape is changing at a rapid pace. The current trend is moving towards clinical presentation or point-of-need diagnostic tests suitable for use during a healthcare visit because they require only minutes.⁷

A growing body of literature shows that rapid, multiplex testing for common respiratory pathogens contributes to reduced inappropriate antibiotic use across a wide range of care settings and patient populations.^{18,19,20,21,22} This positive impact is due to both providing a definitive diagnosis through a higher positivity rate^18,21,22 as well as empowering physicians with actionable data in a clinical relevant timeframe.^18,19,20,21 These studies, and others, demonstrate that the use of multiplex RVP testing can inform the definitive diagnosis of patients who present with ILI and that these rapid results contribute to more appropriate use of antibiotic therapy, consistent with CDC guidelines and the public health goals of the federal government.

Patient Testing in the Emergency Department

We agree that unconstrained, frontline testing with rapid, multiplex RVPs in uncomplicated, ambulatory outpatients is not medically necessary in most cases. However, a broad non-coverage determination for use of this testing in all outpatient settings may ultimately limit access for appropriately indicated patients. The ED and urgent care settings provide a practical case study for consideration.

Testing in the ED and urgent care setting is understood to represent a significant portion of the multiplex RVP volume in many centers.^{21,23,24,25,26} A major reason for this is that timely, accurate diagnosis in this setting is critical to informing patient management, and among other considerations, the decision of whether or not to admit the patient to in-patient service. Use of rapid, multiplex RVP testing in the ED setting has been shown to:

• lower hospital admission rates¹⁹
• reduce time in the ED by up to 23%²⁰
• reduce time to appropriate therapy^21,22
• reduce overall LoS for patients subsequently admitted by up to 15%,^{20, 22}

Rapid, multiplex RVP testing is also commonly used in the ED to triage and cohort patients for the purposes of infection control. CDC and Infectious Disease Society of America (IDSA) guidelines indicate infection control practices should include patient isolation, cohorting, barrier protections, and use of vaccine or chemoprophylaxis agents.²⁷ Guidelines indicate that proper implementation of these infection control practices are dependent on “application of rapid diagnostic tests to support clinical decisions involving patient treatment.”^27,28 During respiratory virus season, many emergency departments do not have the space to adequately isolate patients with suspected respiratory infection and rapid, multiplex RVP testing is commonly used to inform cohorting strategies.²¹

These benefits were recently confirmed in a prospective, randomized controlled trial assessing the impact of a rapid, multiplex RVP deployed at the point-of-care in the ED.22 This study showed:

• a positive test result shortened antibiotic duration by enabling clinicians to stop antibiotics earlier, rather than completing a standard 5–7 day course
• 91% of influenza positive patients in the rapid multiplex testing group received appropriate, guideline driven antiviral therapy compared to only 65% in the control group
• for patients that were admitted, the rapid multiplex testing group experienced a 1.1 day shorter overall length-of-stay, contributing an estimated $500 cost savings per patient
• twice as many patients in the rapid multiplex testing group with confirmed respiratory virus infections were isolated compared to the control group

Broad non-coverage of rapid, multiplex RVP testing may limit patient access to this beneficial technology in the ED as providers may be hesitant to order the test while the patient’s in-patient vs. out-patient status remains uncertain. This would limit the ability of patients and providers to realize the clinical, economic and quality benefits that rapid, multiplex RVP testing has been shown to have in the ED setting.

Conclusion

Recognizing the influence that Medicare LCDs have on coverage policies more broadly for a range of patient populations, there is concern that a blanket non-coverage determination will have a ripple effect across patient populations and care settings that have been shown to benefit from appropriate use of rapid, multiplex RVP testing.
We acknowledge that front-line use of rapid, multiplex RVP testing in low risk patients in the ambulatory outpatient population is not an optimal use of healthcare resources. However, we also assert that a more balanced coverage policy would ensure access to this service for appropriate patients in settings such as the ED and urgent care, where rapid, definitive results have significant impact on patient management, but where patient status is often ambiguous until after the test results are available to the physician. We also believe there is a need to develop additional data and evidence-based guidelines for the appropriate use of this service in the ED and urgent care setting, with a specific focus on higher risk populations including the elderly, the immunocompromised and others.

To that end, GenMark has already begun research related to the implementation of our next generation rapid, multiplex RVP test in the ED setting, with preliminary data expected to be reported later this year (unreported results, Stanford University Medical Center, Palo Alto, CA). Further studies are currently being planned (protocol outline available upon request) to support the development of additional data assessing the clinical utility of rapid, multiplex RVP testing in the ED and urgent care setting. In responding to a similar draft LCD on RVP testing recently put forward by Palmetto GBA, we indicated our willingness to engage with Palmetto MolDX in refining these protocols to ensure study design and endpoint selection would provide the data needed to support future coverage assessments of rapid, multiplex RVP testing in this care setting. We also expressed our interest in additional dialogue with Palmetto MolDX regarding how this might be implemented within Coverage with Data Development (CDD) mechanisms. We extend this willingness to engage in a dialog on building additional clinical utility evidence to the relevant Medical Directors at Noridian to ensure a coordinated effort with Palmetto and other MACs.

In light of current clinical evidence and utilization, GenMark respectfully recommends that Noridian reconsider its draft local coverage determination to allow for continued coverage of rapid, multiplex RVP testing of appropriately indicated patients presenting to the ED and urgent care. We would also request the opportunity to engage with Noridian and other Medicare Administrative Contractors to inform our efforts to develop additional data that demonstrate the clinical, economic and quality benefits rapid, multiplex RVP testing can provide in these care settings.

While antibiotic overuse may indeed be a significant problem, the use of multiplex viral tests does not clearly help to overcome that problem. As other comments have pointed out, bacterial and viral co-infection may exist, as such diagnosis of a viral infection on a strictly genomic basis would not necessarily obviate the need for antibiotics. Currently IDSA recommendations for the treatment of pneumonia rely foremost on clinical and radiographic features of a patient, with microbiological data being helpful in antibiotic selection. While it is potentially possible that the genomic data can be used in conjunction with clinical and radiographic data regarding a particular patient to improve the diagnosis, we are unaware of high quality evidence showing that such genomic information does inform existing clinical practice in a way that improves patient outcomes.

However, in recognition of the fact testing for 3-5 pathogens may have a role in limited clinical circumstances, we will cover 87631 under specific conditions as reflected in the LCD text. In summary, 87631 will be covered in settings that may care for critically ill patients or for patients who are immunosuppressed and are being treated by an infectious disease specialist.

The commenter also discusses the utility of rapid turn-around genomic tests for viral pathogens and provides citations to a number of references. In summary, the evidence cited shows a benefit to the rapid diagnosis of viral illness. However, it is not clear that the identification of a wide range of viral pathogens has a significant benefit. The detection of influenza may be important for the decision to initiate influenza treatment, particularly when influenza is not known to be present in the community at the time of a patient presenting with respiratory symptoms. While multiplex tests can be used to detect influenza, it is not clear that there the detection of non-influenza pathogens by these panels will improve patient outcomes for Medicare beneficiaries.

As the clinical science for the diagnosis and treatment of infectious respiratory illnesses evolves, Palmetto GBA would be willing to reconsider this coverage decision.

Luminex Corporation appreciates the opportunity to comment on the above-referenced Noridian Healthcare Solutions ("Noridian") draft LCD related to respiratory viral panel molecular assays identified by multiplex nucleic acid amplification tests (NAATs). Luminex manufacturers five

(5) IVD respiratory viral assays, ARIES® Flu A/B & RSV Assay, NxTAG® Respiratory Pathogen Panel, VERIGENE® Respiratory Pathogens Flex Test, xTAG® Respiratory Viral Panel, and xTAG® RVP FAST v2. These commercial assays have been cleared by the FDA for the detection of respiratory viral pathogens and are relevant to the Noridian draft LCD.

Our interest in the draft LCD pe1iains to the non-coverage of respiratory viral panels. We seek to ensure that the appropriate utility of the test is realized and is consistent with the national specialty society guidelines and coverage decision in the proposed LCD.

1. Proposed/Draft LCD Coverage Decision

The proposed LCD from Noridian provides that multiplex respiratory viral panel molecular testing may not be indicated for common conditions and that, "only after common conditions are ruled out, should uncommon viral conditions be tested." Furthermore, the draft policy states that, "although current treatment for respiratory viral infection is limited to influenza A and B, detection of other viral agents is valuable because clinical suspicion of viral respiratory tract infections can be confirmed, additional workup and therapy can be avoided, and clinicians and parents can be reassured." The draft policy discusses influenza as the predominant cause of community acquired pneumonia (CAP) and that respiratory syncytial virus (RSV), adenovirus, and parainfluenza virus are included as viral etiologies of CAP, and states that, "the need for diagnostic testing to determine the etiology of CAP is justified when test results will change antibiotic management for an individual patient."

Luminex requests that Noridian expand the proposed LCD to cover multiplex respiratory viral panel nucleic acid amplification tests for multiple targets when clinical circumstances are medically necessary and appropriate.

2. Infectious Disease Society of America (IDSA) Guidelines

The IDSA published guidelines for the treatment of persons with influenza virus entitled Seasonal Influenza in Adults and Children- Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines oft he Infectious Diseases Society of America.1 The IDSA recommended testing "if the result will influence clinical management (decisions on initiation of antiviral treatment, impact on other diagnostic testing, antibiotic treatment decisions, and infection control practices), with consideration for the sensitivity and specificity of the test used and information about local influenza virus circulation," and recommends that the following persons should be considered for influenza testing:

During Influenza Season:

1. Outpatient immunocompetent persons of any age at high risk for complications of influenza (e.g., hospitalization or death) (table 3) presenting with acute febrile respiratory symptoms, within 5 days of illness onset, when virus is usually being shed (A-11).
2. Outpatient immunocompromised persons of any age presenting with febrile respirato1y symptoms, irrespective of time from illness onset, because immunocompromised persons can shed influenza viruses for weeks to months (A­ Ii).
3. Hospitalized persons of any age (imrnunocompetent or imrnunocompromised)with fever and respiratory symptoms, including those with a diagnosis of community-acquired pneumonia, irrespective of time from illness onset (A-II).
4. Elderly persons and infants presenting with suspected sepsis or fever of unknown origin, irrespective of time from illness onset (A-III).
5. Children with fever and respiratory symptoms presenting for medical evaluation, irrespective of time from illness onset (A-11).
6. Persons of any age who develop fever and respiratory symptoms after hospital admission, irrespective of time from illness onset (A-II).
7. Immunocompetent persons with acute febrile respiratory symptoms who are not at high risk of developing complications secondary to influenza infection may be tested for purposes of obtaining local surveillance data (A-III).

During Any Time of the Year:

1. Health care personnel, residents, or visitors in an institution experiencing an influenza outbreak who present with febrile respiratory symptoms within 5 days after illness onset (A- II).
2. Persons who are epidemiologically linked to an influenza outbreak (e.g., household and close contacts of persons with suspected influenza, returned travelers from countries where influenza viruses may be circulating, participants in international mass gatherings, and cruise ship passengers) who present within 5 days after illness onset (A-II).

The IDSA defines the strength of recommendation "A" as good evidence to support a recommendation for or against use. The IDSA guidelines provide information regarding the grading system for ranking recommendations in clinical guidelines.

IDSA Recommendations: What Influenza Tests Should Be Used for Persons with Suspected Influenza?

The IDSA guidelines state, "tests that yield results in a timely manner that can influence clinical management (decisions on initiation of antiviral treatment, impact on other diagnostic testing, antibiotic treatment decisions, and infection control practices) are recommended to guide patient care. Results of testing should take into account the a priori likelihood of influenza infection based on the patient's signs and symptoms, the sensitivity and specificity of the test used, and information on circulation of influenza in the community."

ISDA Recommendations: RT-PCR Listed as the Highest Priority for Influenza Tests

The ISDA ranks RT-PCR highest for influenza tests. The guidelines state, "RT-PCR. This is currently the most sensitive and specific of testing modalities for influenza, with results available within 4-6 h after specimen submission. RT-PCR shows greater sensitivity than viral culture, may be used as a confirmatory test, and is useful for quickly differentiating between influenza types and subtypes."

Luminex requests that Noridian expand coverage of respiratory viral assays consistent with the IDSA guidelines when clinical circumstances are medically reasonable and necessary.

3. ARIES® Flu A/B & RSV Assay (Kl 61220)2

The 51O(k) summaiy specifies that, "the ARIES® Flu A/B & RSV Assay is a polymerase chain reaction (PCR) based qualitative in vitro diagnostic test for the direct detection and differentiation of influenza A virus, influenza B virus, and respiratory syncytial virus (RSV) nucleic acid in nasopharyngeal swab (NPS) specimens from patients with signs and symptoms of

respiratory tract infection in conjunction with clinical and laboratory findings. The test is intended for use as an aid in the differential diagnosis oflnfluenza A, Influenza B, and RSV in humans."

Clinical viral targets:

• Influenza A
• Influenza B
• Respiratory Syncytial Virus

The ARIES® Flu A/B & RSV Assay is a rapid, accurate method for the detection and differentiation of influenza A virus, influenza B virus, and RSV from NPS specimens using ARIES® Systems. Influenza A, influenza B, and RSV are contagious human viral pathogens that are transmitted from person to person primarily by aerosolized virus-containing droplets (influenza) or contaminated secretions (RSV) which can result in respiratory disease.

The Noridian draft policy discusses RSV infection and specifically mentions the availability of commercial RT-PCR assays. The proposed policy states, "some high-risk adults, such as those with chronic illness or immunosuppression, may have more severe symptoms consistent with a lower respiratory tract infection, such as pneumonia." The policy fmiher discusses that, "use of highly sensitive RT-PCR assay should be considered when testing adults because they may have low viral loads in their respiratory specimens."

Use of the ARIES® Flu A/B & RSV Assay should be covered for testing Medicare beneficiaries when clinical circumstances are appropriate based on signs and symptoms.

Luminex requests that Noridian revise the draft policy to include coverage of the influenza and RSV targets for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary.

4. Other Luminex Respiratory Assays

The Noridian non-coverage policy discusses limitations of the multiplex PCR respiratory viral panels as, "the multiplex PCR respiratmy viral panels are effectively a "one size fits all" diagnostic approach, and do not meet Medicare's "reasonable and necessary" criteria. Non­ coverage of these multiplex PCR respiratory viral panels does not deny patient access because appropriate clinician directed testing is available."

The Luminex assays where all the primers are "plexed" (combined) together and have the capability of masking targets include: NxTAG® Respiratory Pathogen Panel5, VERIGENE® Respiratmy Pathogens Flex Test6, xTAG® Respiratory Viral Panei7, and xTAG® RVP FAST v28•

These assays allow selection of specific targets that are appropriate for an individual based on signs and symptoms. Luminex requests that Noridian cover these assays for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary.

NxTAG® Respiratory Pathogen Panel (K152386)3

The 51O(k) summary specifies that, "NxTAG® Respiratory Pathogen Panel is a qualitative test intended for use on the Luminex® MAGPIX® Instrument for the simultaneous detection and identification of nucleic acids from multiple respiratory viruses and bacteria extracted from nasopharyngeal swabs collected from individuals with clinical signs and symptoms of a respiratory tract infection" and "the test is indicated as an aid in the detection and identification of viral and bacterial agents causing respiratory tract infections in symptomatic adult and pediatric patients, who are either hospitalized, admitted to emergency departments or who are outpatients with suspected respiratory tract infection."

Clinical viral targets:

• Influenza A
• Influenza A Hl
• Influenza A H3
• Influenza B
• Respiratory Syncytial Virus A
• Respiratory Syncytial Virus B
• Rhinovirus
• Parainfluenza virus 1
• Parainfluenza virus 2
• Parainfluenza virus 3
• Parainfluenza virus 4
• Human Metapneumovirus
• Adenovirus
• Coronavirus HKUI
• Coronavirus NL63
• Coronavirus 229E
• Coronavirus OC43
• Human Bocavirus

The NxTAG® Respiratory Pathogen Panel software allows for the selection of specific targets that are appropriate for an individual based on signs and symptoms.

Luminex requests that Noridian revise the draft policy to include coverage of the influenza and other clinical viral targets in the NxTAG® Respiratory Pathogen Panel for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary. 

VERIGENE® Respiratory Pathogens Flex Test (K143653)4

The 51O(k) summary specifies the assay is "intended for use with the automated Verigene System for the qualitative in vitro detection and identification of multiple respiratory pathogen nucleic acids in nasopharyngeal swabs (NPS) collected in viral transport media and obtained from individuals suspected of respiratory tract infection."

Clinical viral targets:

• Influenza A
• Influenza A HI
• Influenza A H3
• Influenza B
• Respiratory Syncytial Virus A
• Respiratory Syncytial Virus B
• Rhinovirus
• Parainfluenza virus 1
• Parainfluenza virus 2
• Parainfluenza virus 3
• Parainfluenza virus 4
• Hnman Metapneumovirus
• Adenovirus

The VERIGENE® Respiratory Pathogens Flex Test allows for the selection of specific targets that are appropriate for an individual based on signs and symptoms.

Luminex requests that Noridian revise the draft policy to include coverage of the influenza and other clinical viral targets in the VERIGENE® Respiratory Pathogens Flex Test for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary.

xTAG® Respiratory Viral Panel (K091667)5

The 51O(k) summary specifies that the test is "intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections. The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respirat01y infection aids in the diagnosis of respirat01y viral infection if used in conjunction with other clinical and laboratory findings."

Clinical viral targets:

• Influenza A matrix
• Influenza A Hlsubtype
• Influenza A H3 subtype
• Influenza B
• Respiratory Syncytial Virus A
• Respiratory Syncytial Virus B
• Rbinovirus
• Parainfluenza virus 1
• Parainfluenza virus 2
• Parainfluenza virus 3
• Human Metapneumovirus
• Adenovirus

The xTAG® Respiratmy Viral Panel allows for the selection of specific targets that are appropriate for an individual based on signs and symptoms.

Luminex requests that Noridian revise the draft policy to include coverage of the influenza and other clinical viral targets in the xTAG® Respiratory Viral Panel for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary.

xTAG® Respiratory Viral Panel FAST (KI03776) 6

The 51O(k) summary specifies that, "the xTAG® Respiratmy Viral Panel Fast (RVP FAST) is a qualitative nucleic acid multiplex test intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections" and "the detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection if used in conjunction with other clinical and epidemiological information."

Clinical viral targets:

• Influenza A
• Influenza A matrix
• Influenza A Hl subtype
• Influenza A H3 subtype
• Influenza B
• Respiratory Syncytial Virus
• Rhinovirus
• Human Metapneumovirus
• Adenovirus

The xTAG® Respiratory Viral Panel FAST allows for the selection of specific targets that are appropriate for an individual based on signs and symptoms.

Luminex requests that Noridian revise the draft policy to include coverage of the influenza and other clinical viral targets in the xTAG® Respiratory Viral Panel FAST for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessary.

5. CPT Coding7

1. The Luminex ARIES® Flu A/B & RSV Assay tests for influenza and RSV viral targets. Luminex requests that Noridian revise the draft policy to include the following CPT® code to report the influenza and RSV viral targets for testing Medicare beneficiaries when clinical circumstances are medically reasonable and necessmy:

87631 respirato1y virus (e.g., adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 3-5 targets

2. The Luminex NxTAG® Respiratory Pathogen Panel, VERIGENE® Respirato1y Pathogens Flex Test, xTAG® Respiratory Viral Panel, and xTAG® RVP FAST v2 assays allow for the selection of specific targets that are appropriate for an individual based on signs and symptoms. These assays allow for the selection of specific viral targets that are appropriate for an individual based on signs and symptoms. Luminex requests that Noridian revise the draft policy to include the following CPT® codes to report the influenza and other clinical viral targets for testing Medicare beneficim·ies when clinical circumstances are medically reasonable and necessary:

87632 respiratory virus (e.g., adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 6-11 targets)

87633 respiratory virus (e.g., adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 12-25 targets)

6. ICD-10 Codes that Support Medical Necessity

Luminex requests that Noridian cover the ICD-10 codes that support medical necessity consistent with the IDSA guidelines and draft policy to include the following viral codes:

The proposed policy does not cover respiratory viral testing for clinical circumstances recommended in the IDSA guidelines. The IDSA expe1i panel recommends testing individuals if the result will influence clinical management of the immunocompromised patient. Luminex requests that Noridian revise the policy to include the following ICD-10 codes as support of medical necessity consistent with testing the imrnunocompromised patient.

The IDSA expert panel recommends testing individuals if the result will influence clinical management of the immunocompromised patient. Luminex requests that Noridian expand the ICD-10 codes that support medical necessity to include the following transplant recipient status codes in addition to the above codes:

7. Revision Request for the VERIGENE® Respiratory Pathogen Panel

Luminex Corporation manufactures the FDA-cleared VERIGENE® Respiratory Pathogens Flex Test. The Noridian draft LCD lists Nanosphere as the manufacturer. Luminex requests that Noridian revise the policy to reflect Luminex as the manufacturer of this assay.

The commenter discusses the role of influenza diagnostic testing, particular by PCR, in the diagnosis and management of patients with influenza. We agree that testing for influenza is reasonable and necessary, and this remains a service that is not affected by this LCD. However, an assay to test for the presence of other viral pathogens is not necessary to detect influenza.

Additionally, the commenter raises the issue of diagnosing viral pathogens in immunosuppressed patients in particular, citing IDSA recommendations to perform a test when it will change management. While it is quite possible that broad viral pathogen testing is appropriate when it will influence clinical management of immunosuppressed patients, we would not expect such testing to influence management in many cases. In recognition of the fact testing for 3-5 pathogens may have a role in limited clinical circumstances, such as in immunosuppressed patients, we will cover 87631 under specific conditions as reflected in the LCD text. In summary, 87631 will be covered in settings that may care for critically ill patients or for patients who are immunosuppressed and are being treated by an infectious disease specialist. 

Diatherix Eurofins is pleased to submit its comments to Palmetto GSA regarding the decision of a non-coverage policy for multiplex PCR respiratory viral panels.

Respiratory Pathogen Diagnosis (all ages)

The recent movement towards the integration of molecular multiplex polymerase chain reaction has been with the urging of key opinion leaders whose primary focus is on the management and prevention of infectious diseases. The ability to detect multiple pathogens associated with an infectious disease rather than one particular organism has added new insights into the pathogenesis of complex infections.¹ These assays have proven to be more sensitive that culture-based or antigen detection assays that have been the 'gold standard' of diagnostics for nearly a hundred years. Their high diagnostic yield has been particularly helpful when clinical samples are difficult to collect or when specimen volumes are low (e.g. CSF). The use of multiplex technology has a distinct advantage when different pathogens cause an illness that cannot be distinguished by symptoms alone. With this new technology the causative pathogen(s) can be identified and more effective early treatment and infection­ control protocols can be applied.¹

Molecular assays have become the new standard for the diagnosis of polymicrobial infections that involve heavily colonized surfaces such as those of the respiratory and gastrointestinal tracts. ² Current recommendations from the IDSA state that new tests are needed that can identify specific pathogens, or at a minimum, distinguish between bacterial and viral infections, and also provide information on susceptibility to antimicrobial agents. These molecular based infectious disease panels should include most of the common infectious agents (both viruses and bacteria) so that the clinician can identify which organism(s) are causing or contributing to the infection.³ These advanced diagnostics provide actionable data on which to base a treatment regimen. Used in conjunction with the patient's clinical presentation, these test results provide the basis of a more informed diagnosis. Moreover, multiplex diagnostic assays that can establish co-infections are becoming increasingly important because they provide evidence of viral-bacterial synergy where worsening symptoms and infections with a longer duration are often seen.⁴

The concept of a respiratory tract infection has evolved from a single organism link to one of a more complex poly-microbial nature. Koch's original postulates, designed to link one causative microbe to one specific disease, have been subject to reconsideration since they were formatted in 1884. It is increasingly being accepted that a number of diseases that include both respiratory and gastrointestinal tract infections are polymicrobial. Quite simply, they are a direct result of the synergy between pathogens.^5·6

The majority of respiratory tract infections (upper and lower) are the result of these synergistic relationships between viruses and bacteria that promote colonization, invasion, and spread of the infection to adjacent mucosal surfaces.⁷ Viral and bacterial synergies exist between the common viral and bacterial causes of respiratory infections which may account for the significant overlap of symptoms; particularly upper respiratory infections (URls). In addition, it is a challenge for the clinician to discriminate between infectious etiologies and the allergic causes of respiratory symptoms. The risk of not knowing all of the potential etiological agents that may be contributing to an infection promotes the use of antimicrobials that can be inappropriate and ineffective.

It is implied in the language of the Local Coverage Determination (LCD) statement that the current multiplex tests are "one size fits all". Based upon the recommendations of key opinion leaders and medical advisory boards, the panels that have been designed (both FDA approved and LDTs) include the most commonly encountered pathogens that are associated with respiratory tract infection. Seasonality, particularly the influenza season, is not always a reliable determinate of directing diagnostic assays (H1N1 2009 season) and there is a frequent and significant overlap with agents (enteroviruses) that cause the 'summer flu' that typically begins in mid-summer and continues into the usual influenza season. As a result, clinician directed testing cannot be a reliable means of diagnosis particularly with the significant overlap of symptoms.

The LCD cites that the 'identification of viral infections in older adults is of practical importance for a number of reasons'. Not only is the accurate diagnosis important to start the appropriate anti-viral medications, but, also, to properly cohort patients in long term care facilities and limit the spread of highly contagious infections. Multiplex assays that accurately identify both the influenza virus as well as any contributing bacterial agent is essential to administer appropriate therapy. The unreliability of rapid flu testing in recent years only reinforces the need for comprehensive and accurate diagnostics to properly manage the aging population.

In the 'Summary of Coverage Decision' section of the LCD, there are several inaccurate or misleading statements. For example, "A panel that includes pathogens that are very rare, or a panel in which all pathogens do not cause overlapping clinical syndromes, or when some pathogens are found only in specific patient populations (immunocompromised patients) is not reasonable and necessary" is unfounded. The fact that several viruses can cause a similar clinical presentation is precisely why their inclusion in a multiplex panel is necessary. Moreover, treatment is appropriate for some; e.g. influenza and RSV, and is unavailable at the present time for others. In addition, the statement that "false negative results can occur as the virus mutates" is misleading. Changes in viral antigens due to 'antigenic drift' will affect rapid FDA approved tests more often than LDT PCR assays since target specific primers used in LDTs can be re-engineered quickly to make the assay more specific.⁹ The statement that "No clinical utility studies demonstrate that rapid, accurate multiplexed NM T tests decrease the use of empirical antibiotics and allow for a more targeted approach to using antivirals" is misleading.¹⁰

Conclusion

We implore Palmetto GBA to reconsider its decision of a non-coverage policy for multiplex PCR respiratory viral panels. Gaining insight into the synergism and competition between viruses and bacteria in the respiratory tract is essential to understand the progression of both upper and lower airway disease. The pathogens that cause respiratory tract infections are abundant and a multiplex molecular technology that can detect the organisms involved is essential to better understand and manage these infections. The Diatherix proprietary, multiplex PCR assay is unique in that the potential contribution of both viral and bacterial components of respiratory infections can be enumerated.

At this point in time, most of the information that a multiplex respiratory viral test can provide to a clinician is not clinically actionable information. Tests for influenza in particular may be clinically actionable, since this viral respiratory illness has a specific treatment. There may also be special cases where a treating clinician believes that the positive identification of another virus will alter clinical management. In such special cases, the clinician may specifically order a test for that virus.

The multiplex assays of which we are aware do not distinguish between viral and bacterial respiratory infections; rather they can test for the presence of specific pathogens, but they are not able to rule out the possible presence of a pathogen that is not being explicitly tested for.

The commenter also discusses that respiratory infections may be the result of synergistic bacterial and viral infections and that multiplex molecular technology has the potential to let us gain insight into how these pathogens contribute to progression of respiratory infectious illnesses. Regardless of whether the commenter is correct, the commenter is essentially referring to a scientific and experimental pursuit. While this may be important to advance clinical science, the Medicare benefit is not intended to be used as a funding mechanism to advance clinical science but rather to pay for services that will influence the outcome of the specific Medicare beneficiary being tested.