This policy provides limited coverage for outpatient testing with molecular
syndromic panels for infectious disease pathogen identification testing. This
policy does NOT address coverage for the inpatient setting.

This policy defines a panel as a test that detects > 1 pathogen. This policy
also differentiates (where appropriate) between small, targeted panels (up to
5 pathogens) and larger, expanded panels (6 pathogens). This distinction is
_primarily_ applied to the Respiratory and Gastrointestinal Panels. A
'syndromic panel' is further defined as one that simultaneously detects
multiple different pathogens associated with similar and overlapping clinical
symptomatology.

This is NOT a coverage policy for metagenomic next-generation sequencing, mass
spectrometry, or fluorescence in situ hybridization (FISH).

**_General Criteria For Coverage For A Molecular Syndromic Infectious Disease
Pathogen Identification Panel Test_**

This Medicare Contractor will cover molecular syndromic infectious disease
pathogen identification panel tests when ALL of the following criteria are
met:

  * The patient has a clinical indication for infectious disease _testing_ :
    * For immunocompetent patients, the clinical indication includes a presumption of active infection OR infection-associated complications (which may include exacerbation of underlying disease) _that require the identification of a causative organism for appropriate management._ Atypical clinical presentations of disease are considered appropriate indications for special populations who may not present with classic symptoms of infection (i.e., the elderly).
    * For immunocompromised patients (i.e., those with weakened immune systems including those with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), patients who are taking immunosuppressive medications (i.e., chemotherapy, biologics, transplant-related immunosuppressive drugs, high-dose systemic corticosteroids) and those with inherited diseases that affect the immune system (i.e., congenital immunoglobulin deficiencies), atypical clinical presentations of disease are considered appropriate indications for testing. In this patient population, testing may be performed ONCE as part of a pre-transplant evaluation, regardless of the presence of symptoms.
    * **Note:** For certain panels, such as the Urogenital/Anogenital Panel, epidemiologic indication or potential exposure to pathogens as a result of a high-risk experience is considered a covered clinical indication, even in the absence of clinical symptoms. These are specifically noted below in **LIMITED COVERAGE FOR _EXPANDED_ (>5 Pathogens) PANEL TESTING**.
  * The results of testing will impact clinical management in a manner already demonstrated in the peer-reviewed published literature to improve patient outcomes.
  * Testing is performed according to the intended use of the test in the intended patient population for which the test was developed and validated.
    * This includes performing the test using the intended sample types along with parallel testing that must accompany the test (i.e., the meningoencephalitis and bloodstream pathogen tests include requirements for parallel testing using conventional Gram stain and culture-based detection for correlation of results). 
    * This also includes the provision - by the laboratory to ordering providers - of the major limitations of a given panel test.
  * An evaluation for more than 1 pathogen by molecular testing is necessary for patient management (testing for a single pathogen is NOT reasonable and necessary for the specific infection, patient, or indication). The panel performed includes _at least_ the minimum pathogens required for clinical decision making for its intended use that can be reasonably detected by the test.
    * If additional organisms are not included in a panel, testing for those organisms separately for the same indication may be reasonable and necessary in limited circumstances.
    * More than 1 _panel_ may not be performed on the same date of service for the same clinical indication, except for bloodstream and meningoencephalitis panels; in such circumstances, a second panel may be performed for non-duplicative content.
  * Expanded panel testing is only indicated when targeted panel testing is not appropriate (i.e., will not provide sufficient information for the appropriate clinical management of the patient). See **LIMITED COVERAGE FOR _EXPANDED_ (>5 Pathogens) PANEL TESTING **below.
  * Services that do not have Food and Drug Administration (FDA)-cleared/approved indicated uses, as well as FDA-approved tests performed in ways not consistent with their intended-use labeling directions, will require registration with Molecular Diagnostic Services Program (MolDX) and a Technical Assessment (TA) to demonstrate compliance of the service with this policy. Similarly, tests (and CPT codes) for which there are no accompanying ICD-10 codes in the associated Billing and Coding Article will require registration with MolDX and a TA to demonstrate compliance of the service with this policy.
    * Registered tests must demonstrate equivalent or superior test performance characteristics - analytical validity (AV) and clinical validity (CV) - to established standard-of-care (SOC) methods (i.e., culture, pathogen-specific polymerase chain reaction [PCR]) _for the majority of targets included on the panel_.
    * CV of any new organisms and analytes that are not already established as SOC or that do not have a predicate test that is covered by this contractor, must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population.
  * Documentation of the following is clearly stated in the medical record:
    * Specific clinical indications for testing (i.e., clinical suspicion of a pathogen as the cause of the patient's condition)
    * Specific reasons for performing panel testing 
    * Provider type/specialty and Place of Service 

Testing must be performed according to Clinical Laboratory Improvement
Amendments (CLIA) and/or FDA regulations. For example, CLIA-non-waived tests
may only be performed in certified laboratories and according to CLIA
regulations. CLIA-waived tests may be performed in healthcare settings that
operate under a CLIA Certificate of Waiver or Certificate of
Compliance/Certificate of Accreditation. Panels intended for home use
(including those that have been FDA approved or cleared) do NOT meet the
coverage criteria of this policy.

**_Non-Coverage Criteria_**

_Molecular Syndromic Panel Tests will NOT be covered in the following
circumstances:_

  * If the test is performed as a test of cure.
  * If the patient has been previously tested by molecular diagnostic methods for the same pathogens within 14 days for the same clinical indication. 
    * If a previous panel test was performed with a similar/duplicative intended use, a subsequent test is only reasonable and necessary if the non-duplicative content of the second test is reasonable and necessary.
    * Exception: Repeat panel testing for the same clinical indication will only be covered if first panel yielded a negative result AND there is a high index of suspicion for a pathogen as the cause of symptoms AND the patient's clinical condition is not improving or is deteriorating after a clinically appropriate length of time. In such cases, 1 additional panel test may be covered between 1 and 14 days _after_ the initial panel test, so long as the test fulfills the criteria for coverage as set forth in this policy.

**_LIMITED COVERAGE FOR _EXPANDED_ (>5 Pathogens) PANEL TESTING_**

**_FOR THE SPECIFIC PANEL TYPES LISTED BELOW, ALL OF THE FOLLOWING
_ADDITIONAL_ CRITERIA MUST BE MET:_**

  * **Respiratory (RP) and Pneumonia (PNP) Panels** will _only_ be covered when targeted testing is not appropriate AND according to the following additional criteria: 
    * For immune-competent patients, at least 1 of the following must apply:
      * Testing is ordered by a clinician specialist in Infectious Diseases or Pulmonology for a patient with severe and established underlying respiratory pathology (i.e., severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, radiation therapy to the lung) AND treatment with antibiotics may be indicated according to established guidelines.1,2 Specific examples that do NOT meet coverage criteria according to established guidelines include the following:
        * Asthma exacerbations without the additional presence of either fever and purulent sputum or radiographic evidence of pneumonia2
        * Uncomplicated community acquired pneumonia (CAP)1
      * The patient is _seriously or critically ill or at imminent risk of becoming seriously or critically ill_ (as defined by the American Hospital Association's "General Guide for the Release of Information on the Condition of Patients")3 as a result of a presumed respiratory infection AND the patient is being treated in an appropriate critical care facility.
    * For immune-suppressed patients: Testing is ordered by a clinician specialist in 1 of the following: Infectious Diseases, Pulmonology, Oncology, Transplant OR the patient is being managed in an appropriate critical care facility.
    * For ALL patients: Only 1 of the following panels - RP **OR** PNP- will be covered for a given patient for the same clinical indication. The PNP should be prioritized in the evaluation of pneumonia from lower respiratory tract specimens (i.e., bronchoalveolar lavage samples [BALs]). For the purposes of repeat panel testing for the same clinical indication, RP and PNP will be considered as equivalent tests, such that if criteria for repeat testing are met (as defined above), a clinician may choose to perform the repeat test using the PNP, even if the original test was performed using the RP.
    * For ALL patients, exceptions to the limitation on medical specialists who can order expanded panel tests are provided in the accompanying Billing and Coding Article, such that patient geography and access to care do not preclude the receipt of appropriate diagnostic testing when indicated.
  * **Gastrointestinal (GI)** **Panels** will _only_ be covered when targeted testing is not appropriate AND according to the following additional criteria: 
    * For immune-competent patients, at least 1 of the following must apply:
      * Testing is ordered by a clinician specialist in Infectious Diseases or Gastroenterology for a patient with severe and established underlying GI pathology (i.e., inflammatory bowel disease (IBD), paralytic ileus, radiation therapy to the intestine) AND identification of an infectious cause is necessary to determine next steps in patient management.
      * The patient is _seriously or critically ill or at imminent risk of becoming seriously or critically ill_ (as defined by the American Hospital Association's "General Guide for the Release of Information on the Condition of Patients")3 as a result of a presumed GI infection AND the patient is being treated in an appropriate critical care facility. 
      * The patient's clinical indication for GI panel testing is diarrhea, and ALL of the following apply:
        * The diarrheal illness MUST be acute or persistent with signs or risk factors for severe disease (i.e., fever, bloody diarrhea, dysentery, dehydration, severe abdominal pain) that may warrant hospitalization AND/OR 
        * The diarrheal illness is not resolving after 7 days AND the patient has NOT taken laxatives within 24 hours of the test.
    * For immune-suppressed patients:
      * Testing is ordered by a clinician specialist in 1 of the following: Infectious Diseases, Gastroenterology, Oncology, Transplant OR the patient is being managed in an appropriate critical care facility.
    * For ALL patients, exceptions to the limitation on medical specialists who can order expanded panel tests are provided in the accompanying Billing and Coding Article, such that patient geography and access to care do not preclude the receipt of appropriate diagnostic testing when indicated.
  * **Urogenital/Anogenital (UG/AG) Panels**
    * For the UG/AG panels, epidemiologic indication or potential exposure to sexually transmitted pathogens (i.e., in the case of clinical concern for multiple sexually transmitted infections (STIs) due to a high-risk experience) is considered a covered clinical indication, even in the absence of clinical symptoms. Documentation of the high-risk reason for panel testing is clearly stated in the medical record.
    * In the absence of a high-risk experience, if the primary clinical concern is for a few specific pathogens due to specific signs and symptoms (i.e., lesions suggestive of herpes simplex virus [HSV]), then it is expected that only a small targeted panel (i.e., including HSV-1 and HSV-2) will be performed. In such cases, expanded panels are NOT considered reasonable and necessary and will NOT be covered.
    * For the diagnosis of infectious vaginosis/vaginitis, it is reasonable to perform a (targeted or expanded) panel that includes a combination of at least 2 of the following: _Gardnerella vaginalis,_ other bacterial vaginosis (BV)-associated bacteria (BVAB) (such as _Atopobium vaginae_ and/or _Megasphaera types)_ _, Trichomonas vaginalis,_ and _Candida_ species.
  * **Meningoencephalitis (ME) Panels** will be covered according to the following additional criteria: 
    * For immune-competent patients: the patient has at least 2 of the following indicators of central nervous system (CNS) infection: cerebrospinal fluid (CSF) markers, radiology, clinical signs and symptoms consistent with meningitis or encephalitis, epidemiologic indication or exposure. For immune-compromised patients, at least 1 of these indicators is required.
    * For all patients: Testing is from a sample collected via lumbar puncture, and NOT an indwelling medical device (i.e., CSF shunts). 
  * **Bloodstream Infection (BSI) Panels** will be covered according to the following additional criteria: 
    * There is clinical concern for bacteremia or sepsis AND microbe(s) were seen on a Gram stain from the patient's blood AND the patient is being managed in an appropriate critical care facility (this includes the Emergency Room), AND
    * Personnel (i.e., an antimicrobial stewardship team [ASP]) are equipped for rapid (within 24 hours) tailoring of antimicrobial therapy as a result of rapid testing.
  * **Urinary Tract Infection (UTI) Panels** will be covered according to the following additional criteria:
    * The patient is symptomatic AND at higher risk for UTI complications (i.e., the elderly, patients with recurrent symptomatic UTIs and/or complicated urinary tract anatomy) AND/OR is seen in urogynecology or urology specialty care settings.

Additional information related to specific panels may be found in the related
Billing and Coding article.

_Tests that demonstrate similar indicated uses and equivalent or superior
performance to SOC or other covered tests, as demonstrated in a TA, may
similarly be covered under this policy._

_A dditional syndromic panel types and indications may also be covered
according to the established criteria outlined in this policy._

Molecular panel tests for infectious diseases have changed the landscape of
clinical microbiology. They play an important role in diagnostic testing, as
they simultaneously detect several different pathogens associated with similar
and overlapping clinical symptomatology. For this reason, they are also known
as 'syndromic panel' tests. These panels belong to a category of testing known
as culture-independent diagnostic tests (CIDTs), which are tests that detect
pathogens without the need to grow and isolate them in culture. These tests
have shorter turnaround times, often have good test performance
characteristics, and require limited technical expertise, making them
appealing for use by clinicians as well as clinical laboratories.

Historically, physicians were required to select the specific pathogens most
likely thought to be associated with a patient's disease. They often had to
rely on empiric therapy until results from the laboratory could be used in
identifying definitive or targeted antimicrobial therapy, with results taking
days and sometimes weeks. In recent years, molecular panel tests, including
multiplex PCR, have become increasingly used for the detection of pathogens,
and clinicians are no longer required to name (or separately test for) many of
the bacterial, viral, fungal, and parasitic species sought for a given
clinical 'syndrome'. As the use of multiplex molecular tests have decreased
the need to perform multiple assays to diagnose a given infection, results are
often available to the physician within minutes to hours. Though culture-based
methods of diagnosis are still routinely utilized, and definitive
antimicrobial therapy may still lag pending full culture and susceptibility
information, these tests have revolutionized infectious disease diagnostics
and have made the road from diagnosis to treatment very rapid, in some cases
occurring at the point-of-care (POC).

For some conditions, such as respiratory tract infections, RP panels have
become the SOC. These respiratory panels are exceptionally rapid, providing
results in minutes to hours.4,5 They are unlike the older conventional
respiratory viral testing methods such as viral culture and
immunofluorescence, which could take days to weeks to obtain a result.
Moreover, they display test performance characteristics (sensitivity and
specificity) which are often superior to other rapid diagnostic tests for
respiratory viruses, such as rapid (antigen-based) influenza detection tests
(RIDTs).6-8 For these reasons, many laboratories have stopped offering some of
the other diagnostic modalities described for respiratory viral pathogens
detection. In fact, many of those methods have become obsolete in routine
clinical care.

Finally, some of these multiplex panels are smaller, or 'targeted', detecting
just a few pathogens whereas others are very large, detecting approximately 20
targets. The larger panels are sometimes referred to as 'expanded'. These
distinctions most commonly apply to the RP and GI panels, as panels for BSI
and ME (and in some circumstances UG/AG) are expected to detect >5 pathogens
(though a UG/AG panel is not expected to detect as many as 20 pathogens, due
to the epidemiology of disease in that organ system). Many commercial
platforms for multiplex panel testing have been developed for a variety of
infection types in different organ systems.4,5 Both smaller and larger panels
are being used in clinical laboratories, though their optimal use and
application in various settings, and for various patient populations and
indications remains a challenge.

**Test Performance**

In recent years, molecular syndromic panels have become routinely used for a
number of infection types, including respiratory, gastrointestinal, central
nervous system, bloodstream, and urogenital/anogenital. These panels provide
rapid turnaround times for results, and are often more sensitive than
traditional testing for the various organisms included.4,5,9 However, test
performance characteristics do vary depending on the specific panels and
pathogens. For example, though overall sensitivities and specificities have
ranged from 84-100% for various RP platforms evaluated, the sensitivities for
adenovirus, influenza A H1/2009, and influenza B using the FilmArray RP have
been reported as low as 57%, 73%, and 77%, respectively, while more recent
versions of the platform (the FilmArray RP2) have shown improved detection
(94%-100%) of these pathogens.10,11 Additionally, the FilmArray PNP and RP
panels have targets in common, though the PNP also contains numerous bacterial
targets as well as antimicrobial resistance determinants; the PNP is also
semiquantitative.12,13 The PNP has shown strong agreement with both SOC
methods as well as with the RP in identifying pathogens from lower respiratory
tract specimens.12,13 Because the PNP performs similarly to the RP for viral
pathogens, but can additionally detect bacterial pathogens and antimicrobial
resistance determinants, it should be prioritized in the evaluation of
pneumonia from lower respiratory tract specimens.14 A study comparing the
performance of additional RP assays reported the following sensitivities and
specificities: 98.3% and 99.2% for GenMark Dx eSensor Respiratory Viral
Panel (RVP), 92.7% and 99.8% for Luminex xTAG RVPv1, and 84.4% and 99.9% for
Luminex xTAG RVP Fast.10 In this study, sensitivities also varied by viral
target.10 Smaller targeted panels detecting influenza and respiratory
syncytial virus (RSV) have also shown overall high sensitivity and specificity
in studies evaluating their performance. A prospective and retrospective
evaluation of the Xpert Flu/RSV XC assay reported sensitivity/specificity of
97.8%/100% and 97.9%/100% for influenza and RSV, respectively.15 Another study
using prospective patient samples reported 96.6%-100% agreement between the
ARIES Flu A/B & RSV and Cepheid Xpert Flu/RSV XC assays.16 This is
important, as some of the targeted respiratory panels have been granted CLIA-
waived status and are being used in non-laboratory settings.17,18 In a study
evaluating the Roche cobas Liat Influenza A/B & RSV assay performed by
nonlaboratory staff, reported sensitivities/specificities were 99.6%/97.5%,
99.3%/99.7%, and 96.8%/98.8% for influenza A, B, and RSV, respectively.19 Yet
another study comparing rapid POC nucleic acid amplification tests (NAATs)
found that the sensitivity of AlereTM i was only 71.3% (compared to 100% for
the Liat).20 The poor sensitivity of the AlereTM i in that study was
attributed to the inclusion of many low-positive samples.20

The BioFire FilmArray and Luminex xTAG GI panels demonstrate overall high
sensitivity (>90%) for the majority of their targets.21 However, sensitivities
have been very low for certain targets, specifically _Aeromonas sp_. (23.8%)
on the FilmArray and _Yersinia enterocolitica_ (48.1%) on the xTAG21;
because of its low sensitivity, _Aeromonas_ is not included as a reportable
analyte on the cleared version of the FilmArray test.22 A multicenter study
evaluating the FilmArray GI panel found the sensitivity to be 100% for 12 of
the 22 targets and >94.5% for an additional 7 targets (performance of the
remaining targets was not assessed due to their low prevalence); specificity
was >97.1% for all panel targets.22 In a study comparing the Luminex xTAG to
conventional methods of testing found that the panel had a higher sensitivity
than SOC for detecting _C. difficile, Campylobacter_ species, norovirus, and
rotavirus.23

The ME panel (the BioFire FilmArray ME panel is currently the only
commercially available panel) has overall good sensitivity for most targets,
but does suffer from a lack of sensitivity for certain targets, such as
_Cryptococcus_ species, relative to conventional testing methods for this
pathogen.24-26 In 1 prospective multicenter evaluation, the FilmArray ME
panel showed a percent positive agreement (PPA) with SOC methods of 100% for 9
of 14 analytes, with another 2 analytes showing PPA between 85.7-95.7%; the
percent negative agreement (NPA) with SOC methods was >99% for all analytes
but _S. agalactiae_.24 Importantly, the ME panel detected 43 pathogens that
were not recovered by conventional testing; however, additional testing
confirmed the ME panel to be correct in only 43% of these cases.24 In this and
other studies, false positive results of the ME panel have been reported,
primarily for _S. pneumoniae_ , _S. agalactiae_ , and HSV-1, and false
negatives have been reported primarily for HSV-1 and HSV-2, Enterovirus, and
_Cryptococcus neoformans/gattii_.24-26 A systematic review and meta-analysis
of 13 studies evaluating the ME panel reported a sensitivity and specificity
of 90% and 97%, respectively.26

BSI panel tests also show good overall performance. Studies have found the
FilmArray Blood Culture Identification (BCID) panel and the Verigene (Gram-
positive and Gram-negative blood culture) panels provide correct
identification for 87%-99% of monomicrobial samples, compared to conventional
methods.27,28 One study comparing the 2 panel tests to SOC found that the
FilmArray and the Verigene correctly identified 95% and 99% of isolates,
respectively, in monomicrobial cultures.27 False positives and false negatives
have been reported in these panels, for both organism and resistance gene
identification, particularly in polymicrobial samples; however, the failure to
detect organisms in polymicrobial samples is often the result of organisms not
included on the panels.5,29 Nevertheless, because of limitations inherent in
the tests (including the fact that not all organisms are represented on the
panels and these are high-stakes infections), both the ME and BSI panel tests
must be accompanied by Gram stain and culture.

Molecular panel tests are also increasingly being used for the detection of
urogenital and anogenital infections. The BD MAXTM vaginal panel has reported
sensitivities and specificities of 89.8%/96.5%, 97.4%/96.8%, and 100%/100% for
bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis
(TV), respectively.30 In another study, the BD AffirmTM VPIII Microbial
Identification Test showed a lower specificity of 81.6% for BV and lower
sensitivity of 69.4% for VVC, while it performed equally well as the BD MAXTM
for TV.31 These panels, however, have been shown to perform better than
clinician assessment of vaginitis, for which many diagnoses remain empirical
and for which guideline non-adherence is broad.32-34 Further, high rates of
coinfection with STIs (24.4%-25.7%) have been observed.35-37 Panels detecting
sexually transmitted pathogens have also become routine in clinical
laboratories, as they provide a rapid result for organisms like _Chlamydia_
species, that can be difficult to culture. Moreover, it is well-established
that _N. gonorrhoeae_ and _C. trachomatis_ not only cause similar clinical
syndromes, but also coexist in a significant proportion of patients,
highlighting the need for panel testing.38

For the evaluation of UTI, multiplex PCR panels have shown agreement of 90%
with SOC urine cultures for the identification of organisms from urine, though
there are currently no United States (U.S.) FDA-approved panels for this
indication.39,40 Similarly, there are no currently approved panels for use
with sterile body fluids other than blood and CSF, though studies evaluating
existing panels (such as the BSI panel) with such fluids have shown pathogen
detection in cases where SOC cultures were negative, possibly due to the
effect of prior antimicrobial therapy.41,42 Though testing may require assay
optimization for use with 'other' sterile fluid specimens, 1 study found 100%
detection of organisms from sterile fluids inoculated into blood culture
bottles when tested using BSI panels.43

There are many commercially available multiplex panels for the diagnosis of
infectious diseases, and this review of their performance is not inclusive of
all of them. As noted in this review, the performance of these panel tests
varies, depending on the platform and specimen types used and the targets
included. These panel tests should display performance that is equivalent or
superior to SOC or other established tests, with _ideal_ sensitivity and
specificity or PPA and NPA of 95% for the majority of targets included on
their panels. However, it is important to consider the entire picture. For
example, as some of these panels are not intended to be used as stand-alone
tests, parallel testing by additional methods can be used to support their
application in clinical settings, particularly in cases where the assay has
not achieved the ideal performance metrics for a given target. Finally, the
specific performance limitations of the various panel tests (in some cases due
to enhanced sensitivity for targets that may not be pathogenic) must be
considered. These issues are further discussed in the **Clinical Utility**
section below.

**Clinical Utility - Impact on Patient Management and Interpretation of
Results**

Rapid diagnostics require rapid intervention to be impactful for patient
management. Rapid, user-friendly, multiplexed molecular tests have great
potential in this regard, though their impact on patient outcomes is clearer
for some types of panels, infections, and patients than for others, as studies
are variable in design and quality.4,5,8,44 A systematic review of the impact
of rapid point-of-care testing (POCT) (including molecular assays) for
influenza found that, in patients with acute respiratory infection, a positive
POCT result significantly increased use of antivirals for influenza and
decreased unnecessary antibiotic use.45 Another study of adult patients found
a decreased time to diagnosis (of influenza and non-influenza viruses) using
the FilmArray RP, compared to conventional methods of testing; moreover, a
diagnosis of influenza was associated with lower odds ratio for admission,
length of stay (LOS), duration of antimicrobial use, and number of chest
x-rays.46 Better influenza detection, a reduced LOS, and improved antiviral
use were also found in a study of routine molecular POCT for respiratory
viruses (the ResPOC study), for adults presenting to the hospital with acute
respiratory illness.47 However, studies have shown that other factors, such as
the presence of infiltrates on chest x-ray and uncertainty regarding the
possibility of a bacterial infection, also play a significant role in the
decision to treat with antibiotics, regardless of the result of the RP test.48
A systematic review of the literature concluded that RPs provide accurate
results, and that there is high-quality evidence to support that rapid testing
can result in a decreased LOS and can increase appropriate oseltamivir use.8
Notably, the majority of RP studies have focused on the benefits in influenza-
positive patients. For example, in a study evaluating antimicrobial
prescriptions following RP testing among adult outpatients, antibiotic
prescription rates were significantly different between patients who tested
positive for influenza virus and those who did not; however, antibiotic
prescription rates were not different between the patients who tested positive
for viruses other than influenza and those who tested negative.49 Since
influenza is 1 of the few respiratory infections that can be treated with
antivirals, this suggests that a more targeted testing approach is sufficient
for most immune-competent patients with a presumed acute viral respiratory
infection. Moreover, guidelines on CAP by the Infectious Disease Society of
America (IDSA) recommend NOT obtaining testing (specifically sputum Gram stain
and culture) routinely in adults with CAP managed in the outpatient setting;
rather, they recommend that empiric antibiotic therapy be initiated in adults
with clinically suspected and radiographically confirmed CAP, _even if these
patients test positive for influenza_.1 In other words, RP testing does not
impact initial management with antibiotics in such circumstances. However,
IDSA guidelines do suggest testing for influenza in adult patients with CAP
when influenza is circulating in the community.1 In such cases, a targeted
panel for influenza testing can be performed. Finally, specific diagnosis and
definitive antimicrobial therapy is needed for pneumonia that is complicated
(i.e., by meningitis, endocarditis, or abscess), and testing using expanded
panels is warranted in these circumstances; however, these patients are
expected to be managed in the inpatient setting.

A more expansive testing approach may be appropriate in patients with
underlying pulmonary pathology and in immune-compromised patients, _but only_
_in certain circumstances_. In a study of adult patients with exacerbation of
airway disease, 35% of those testing positive for viruses (using molecular
POCT) had early discontinuation of antibiotics compared to 13% of those who
tested negative and 6% of controls; moreover, of those positive for viruses,
only 20% were positive for influenza and the discontinuation of antibiotics
was not different between the various viruses detected.50 The authors of this
study stress that many of the patients in this study should not have been
treated with antibiotics, on clinical grounds alone, "given that antibiotic
use in patients with asthma exacerbation is strongly discouraged by national
society guidelines."2,50 The Global Strategy for Asthma Management and
Prevention states "evidence does NOT support the role of antibiotics in asthma
exacerbations unless there is strong evidence of lung infection (e.g., fever
and purulent sputum or radiographic evidence of pneumonia)."2 Finally, a study
evaluating respiratory virus infections prior to hematopoietic cell transplant
(HCT) found that patients with viruses detected pre-HCT had fewer days alive
and out of the hospital and lower survival at day 100 than patients with
negative results (even when the only virus present was rhinovirus);
importantly, most patients in this study were asymptomatic when surveillance
samples were collected.51 This finding suggests that pre-transplant evaluation
is 1 limited circumstance in which expanded RP panel testing may be warranted
in asymptomatic patients.

Impact studies of GI panels have been even more mixed, though some have found
that implementation of such panels was associated with a decrease in
endoscopic procedures, abdominal radiology, and/or antibiotic
prescriptions.52,53 A prospective multi-center study evaluating 1887 fecal
specimens from patients with acute diarrhea found that use of a GI panel
enhanced organism detection and improved clinical sensitivity, and enabled
clinicians to provide more timely and targeted antimicrobial therapy;
moreover, positive Shiga-like toxin producing _E. coli_ (STEC) results led to
the appropriate discontinuation of antimicrobials in the majority of cases
when empiric therapy had been initiated.9 However, in outpatients with
uncomplicated diarrhea that is likely to be self-limited, testing is often not
warranted.5 Guidelines from the American College of Gastroenterology regarding
acute diarrheal infections in adults state that diagnostic studies may be used
in cases of "dysentery, moderate-to-severe disease, and symptoms lasting >7
days to clarify the etiology of the patient's illness and enable specific
directed therapy."54 Regarding the use of the GI panel in special populations,
an impact study in patients with IBD found that GI panel testing led to lower
rate of IBD treatment modification.55 In outpatients with relapse of IBD,
testing with a GI panel was associated with significantly lower rates of IBD
therapy escalation and endoscopy, compared to patients who underwent
conventional testing.56 Finally, in a study evaluating gastrointestinal
infections prior to HCT in asymptomatic patients found that 62% of patients
colonized with _C. difficile_ pre-transplantation developed a clinical _C.
difficile_ infection post-transplantation, and 80% of patients colonized with
enteropathogenic _Escherichia coli_ (EPEC) or enteroaggregative _E. coli_
developed clinical infections due to their colonizing pathogen post-
transplantation.57 As noted above with respiratory infections, these findings
suggest that pre-transplant evaluation is 1 limited circumstance in which
expanded GI panel testing may be warranted in asymptomatic patients.

Bloodstream and CNS infections are emergency situations that can progress
rapidly, even in previously healthy individuals.58 As such, rapid panel
testing can prove invaluable in the prompt management of patients with such
infections. The following widely cited statistic is sobering -in sepsis, for
each hour of delay in _effective_ (appropriate for a given pathogen)
antimicrobial administration, there is an average decrease in patient survival
of approximately 8%.59 Because bacterial culture and full antimicrobial
susceptibility results traditionally take 2 or more days, rapid BSI panels
have emerged to rapidly (within hours) identify a causative pathogen such that
the most appropriate and targeted antibiotics can be administered. A
prospective randomized controlled trial found that use of a BSI panel resulted
in a decrease in time between Gram stain to microorganism identification by
approximately 21 hours.60 Moreover, the use of broad-spectrum antibiotics and
the treatment of bloodstream contaminants were reduced; further, antimicrobial
de-escalation occurred with the additional intervention by the ASP.60 Other
studies have similarly shown more rapid organism identification and
antimicrobial de-escalation with the use of BSI panel (plus ASP intervention)
over conventional culture methods, even if the latter also included ASP. 61
However, the effect of BSI panels on other outcome measures such as mortality,
30-day readmission, and LOS has been more variable between studies.5,61 Pre-
post intervention studies62 as well as a meta-analysis63 have shown that rapid
molecular diagnostic testing is associated with significant decreases in LOS
and mortality risk, _particularly when combined with an ASP_. For patients
with multi-drug resistant bacteria, rapid _escalation_ of antimicrobial
therapy is also important. In 1 study, use of a BSI panel decreased the mean
time to appropriate antimicrobial therapy by more than 30 hours in a study of
patients with vancomycin-resistant enterococci (VRE) bacteremia.64 In another,
more rapid implementation of effective therapy was observed in cases of
extended-spectrum beta-lactamase-producing organisms, but not overall; this
same study reported a significantly decreased length of intensive care unit
(ICU) stay, 30-day mortality, and mortality associated with multidrug-
resistant organisms after the implementation of a BSI panel.62 There are fewer
outcome studies evaluating the clinical utility of ME panels, particularly for
patients generalizable to the Medicare population. One study found that use of
the FilmArray ME panel reduced time to diagnosis by approximately 3 days,
allowed an earlier discontinuation of empiric therapy in 32% of patients, and
led to an earlier hospital discharge in 18%, saving 82 hospital days.65
Another study found that use of the panel significantly reduced the turnaround
time for HSV detection, days of therapy for antivirals (acyclovir) and
antimicrobials, and hospital LOS, in adults undergoing a lumbar puncture for a
suspected community-onset CNS infection.66

Results from multiplex molecular panel tests must be interpreted with caution.
First, they detect significantly more pathogens than were detected in the past
using conventional methods of testing.5,9 For example, studies evaluating
multiplex urine panels (UPs) have detected up to 26% additional organisms that
culture methods did not.39 Importantly, multiplex UPs have detected more
organisms in polymicrobial infections than urine cultures in symptomatic
patients,39,67 and a modeling study has shown bacterial combinations that
increase the probability of antibiotic resistance.68 As with all such panel
tests, it is important to determine whether these additional organisms
detected are pathogens or colonizers that simply could not be detected before,
using traditional SOC methods. As these tests detect microbial nucleic acid,
they do not require live and actively replicating organisms. Therefore, not
all positive results indicate current active infection. However, in 1 study of
150 urogynecology patients, standard urine culture missed 50% of uropathogens
in patients with severe urinary symptoms; moreover, approximately 40% percent
of patients with missed uropathogens reported no symptom resolution after
treatment based on standard urine culture results.69 Importantly, all of the
missed uropathogens were detected using the study's comparator method (an
enhanced quantitative culture technique), though additional bacteria of
unknown pathogenicity were also detected.69

Asymptomatic carriage and prolonged shedding (days to weeks) of viral nucleic
acid are common, particularly for respiratory and GI pathogens. In BIG-LoVE, a
study of 108 adults and children who underwent weekly respiratory panel
testing for a year, approximately half of all viral detection episodes were
asymptomatic.70 Further, PCR detection of viruses at 3 weeks was a fairly
frequent finding, occurring in 16% of episodes; prolonged viral detection was
particularly common in children and in individuals living with children.70
Prolonged shedding is also common in immune-compromised patients.71 On the GI
panels, interpretation of a positive _C. difficile_ result in a patient
without risk factors for infection with this organism can be difficult, as
4%-15% of healthy adults, and up to 21% of those admitted to a hospital, are
asymptomatically colonized; moreover, detection by PCR does not indicate
active infection, particularly in patients without classic clinical
symptoms.72,73 The high rate of mixed infections observed when using expanded
RP (in 30%-40% of positive cases)74,75 and GI panels (up to 27% of positive
cases)5,21-23 can be difficult to interpret. The significance of previously
unidentified organisms in stool samples (such as Sapovirus and Astrovirus) can
also be clinically challenging to interpret, as it is unclear whether
detection of these organisms represents colonization or infection. Mixed
infections detected by GI panels most commonly occur with enteropathogenic _E.
coli, Y. enterocolitica_ , Norovirus, and _C. difficile_.9,21,53 Moreover, in
some studies with very high rates of observed _C. difficile_ there are also
high rates of inappropriate GI panel testing. In 1 study evaluating more than
440 GI panels at a community hospital, 61% of the panels ordered were deemed
inappropriate, for reasons including lack of documented diarrhea, laxative
use, and having a duplicate _C. difficile_ PCR test ordered.53 Notably, in
this study, rates of _C. difficile_ were 51%.53

ME and BSI panels also have their own challenges. For example, though co-
infections are less commonly observed with multiplex panel testing from
sterile body sites (such as from CSF or blood), they do occur and can cause
interpretive challenges.24 Additionally, the ME panel cannot differentiate
active from latent infection. It detects certain organisms, such as human
herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), that may be latent and not
the causative agents of disease, particularly if the host is immunocompetent.
Moreover, there are a number of organisms that can cause meningitis and
encephalitis that are not included on the panel, including bacteria (such as
non-K1 _E. coli_ serotypes and non-encapsulated strains of _Neisseria
meningitidis_ ), viruses (including arboviruses), and _Mycobacterium
tuberculosis_. Therefore, there are significant limitations associated with
the use of this panel; however, these are mitigated, in part, by a requirement
for additional testing (i.e., bacterial culture, cryptococcal antigen) to
occur in parallel, as well as by clinician education and laboratory
stewardship. It is important to remember, however, that traditional means of
diagnosing CNS infections also come with diagnostic challenges that can delay
a diagnosis. Such challenges include the low sensitivity of CSF culture
(particularly in patients with antimicrobial exposure prior to lumbar
puncture)76 as well as the historically unrecognized etiology in most cases of
encephalitis.77 The large nature of the panels may cause an ordering clinician
to assume that, because so many organisms are being tested, a negative result
makes infection a less likely cause of the patient's symptoms. Therefore, it
is important for clinicians to realize that, even in expanded syndromic
panels, not all pathogens will be detected. New strains of viruses may also go
undetected, and the panels are limited to only those organisms found on the
'menu'. Though the ME panel cannot fully replace current assays, it can
provide unparalleled rapid results for a syndrome that can be rapidly fatal.
Similarly, BSI panels are limited by the targets available on the panels, both
for identification of microbes as well as identification of genes responsible
for resistance mechanisms. In fact, many Gram-negative organisms harbor
resistance mechanisms not encoded by any genes on these BSI panels, adding
another diagnostic hurdle to overcome. However, they do tend to detect the
most common bloodstream pathogens and can provide rapid results for rapid
targeted antimicrobial therapy.4,5,60

**Additional Challenges and Appropriate Use of Panel Tests**

With few exceptions, the FDA-approved molecular panels for a given platform
are 'fixed', i.e., they consist of a predetermined test menu of pathogens. The
smaller of these tests, sometimes referred to as 'targeted panels', typically
detect about 3-5 pathogens. The commonly used commercially available larger,
or 'expanded', panels detect approximately 20 targets or pathogens, and some
include pathogens that typically cause different clinical presentations, such
that simultaneously testing for these pathogens should not be a common event.
In other words, they deviate from being 'syndromic' in their approach to
diagnosis. For example, the classic infection associated with _Bordetella
pertussis_ is whooping cough. The clinical case definition of a probable case
of pertussis is a cough illness lasting at least 2 weeks, _in the absence of a
more likely alternate diagnosis or epidemiologic linkage_ , and 1 of the
following symptoms: paroxysms of coughing, inspiratory whoop, post-tussive
emesis, or apnea.78 Though some individuals (such as those with a history of
prior infection or vaccine-induced immunity) may not show classic
manifestations or may be altogether asymptomatic,79 diagnosis of this organism
generally should require a high index of suspicion. Although it is a
respiratory infection, in most patients, the clinical presentation of whooping
cough is unlike that of most other viral respiratory syndromes. Yet, it is
included on many respiratory syndromic panels and a patient who is likely
infected with influenza or RSV may still end up being tested for _B.
pertussis_ , simply because it is a target on a fixed panel. Finally, the
targets and organisms on a panel can vary between manufacturers, with some
panels differentiating among numerous subtypes and strains of species, many of
which are not clinically meaningful for the majority of patients.5 For
example, differentiating among the different types and subtypes of
parainfluenza virus may be good for epidemiologic tracking, but is not likely
to result in any meaningful impact to patient care.

Further, large (fixed) panels do not appropriately regard patient risk
factors, or a pre-test probability of a particular pathogen causing infection.
The patient's medical history and exposures are important to assess prior to
testing. For example, infection with _Clostridioides difficile_ (formerly
known as _Clostridium difficile_ ) is typically associated with specific risk
factors including exposure to antimicrobials, healthcare facilities and
hospitals, chemotherapy, and GI procedures.80 Conversely, many of the other
pathogens on the panels are typically associated with foodborne
transmission.81,82 Variables like season and geography are also pertinent to a
specific diagnostic case or patient. In the case of respiratory panels, a
patient can be tested for more than 20 pathogens, when in fact only a couple
of viruses may be the predominant ones circulating in the community during a
given season. For example, though influenza can circulate throughout the year,
it primarily occurs and peaks during the winter months, whereas certain other
viruses are more prevalent during other seasons.83 Fixed panels may also not
be applicable across populations, and immune-competent patients who are not
severely ill may not require testing at all, or may require limited testing.84
Viral infections in immune-competent patients are often self-limiting and
resolve without complication. Further, with few exceptions, there is often no
specific treatment for viral infections, other than supportive care, and
testing may not change patient management. All of this may result in an excess
of unnecessary testing in immune-competent individuals. On the other hand, in
immune-compromised patients, common and rare pathogens can cause severe
illness, and concurrent infection with multiple respiratory viruses (which
occur more commonly than previously thought, thanks to these multi-analyte
panels) have been identified as predictors of in-hospital mortality.85
Moreover, immune-compromised patients often do not present with classic
symptoms of infection. Therefore, casting a wider diagnostic net for this
population may be both reasonable and necessary.

However, even in immune-competent individuals, expanded panels can provide
rapid, highly impactful, and epidemiologically important information.86 They
can lead to the diagnosis of some infections that, in the past, may have been
missed altogether. In 1 study, 75% of _Mycoplasma pneumoniae_ infections were
unintentionally detected by multiplex PCR; in this study, clinicians had only
specifically requested testing for _M._ _pneumoniae_ in 2 (10%) of 20 patients
positive for this pathogen.87 Importantly, this was an actionable finding, as
infection with _M._ _pneumoniae_ is treatable with antibiotics.87 Expanded
panels can also help rapidly diagnose and, in some cases, avert public health
outbreaks. For example, during an outbreak of a 'mystery' respiratory illness
among children in 2014, hospitals were able to rapidly identify the
presumptive cause, which turned out to be enterovirus D68.88 Similarly, use of
rapid multiplex GI panels significantly contributed to the recognition of a
large Cyclospora outbreak in 2018.89

For all these reasons, instituting the appropriate use of these panels can be
challenging. Notably, these tools do not necessarily replace certain
conventional methods of microbial detection, such as bacterial and fungal
culture, in the diagnosis of infection. These many challenges and
opportunities have led to the implementation of measures to promote diagnostic
stewardship. Some of these include limiting expanded syndromic panels to
certain groups of patients, such as the immune-compromised, hospitalized,
critically ill, or patients from specialty clinics (such as pulmonary for
respiratory panels). Others include the implementation of test ordering
algorithms and 'controls', decision support tools, and the prohibition of
repeat testing within a specific timeframe.5,53,90,91

**Summary of Contractor Advisory Committee (CAC) Meeting**

A multi-jurisdictional CAC Meeting to discuss the clinical literature related
to Molecular Diagnostic Testing for Pathogens took place on Monday, January
11, 2021. The general consensus from the CAC panel is that there is accuracy
and reliability in these pathogen panels and that the results from panel
testing may improve patient health outcomes. However, the CAC panel also noted
that outcome studies from use of these panels is limited, depending on the
specific panel (and use) in question. The panel emphasized the importance of
regarding patient population and setting, as indications for testing can vary
among beneficiaries with different medical backgrounds and needs, and
highlighted differences in testing requirements between immune-compromised and
immune-competent patients. Overall, the panel expressed that a key
consideration is whether a result is going to positively impact patient care.
Finally, there was consensus from the CAC participants that the use of this
technology in the diagnosis of onychomycosis (fungal infections) of the nail
was unnecessary.

The goal of diagnostic stewardship is to select the right test for the right
patient at the right time, to optimize patient care.92 The evidence shows that
molecular syndromic panels for infectious disease testing can result in prompt
patient management, including the rapid initiation of appropriate
antimicrobial therapy, the timely de-escalation of therapy, and the decrease
in unnecessary therapy. In some cases, these panels have resulted in
additional improvements in overall care, including a decrease in the use of
unnecessary diagnostic procedures and even a decrease in LOS, morbidity, and
mortality. Moreover, infectious disease testing has traditionally relied on
testing for multiple organisms when a physician was unsure of the pathogen
causative of a presumed infectious disease. Historically, this investigation
was performed _using multiple different tests and/or culture (which also
detects multiple different organisms using agar plates)._ In this regard, __
panel testing can be thought of as the use of new methodology (i.e., multiplex
NAAT) for the detection of many of the same clinically valid pathogens that
were historically detected using combinations of SOC methods (culture, antigen
testing, etc.). Importantly, these SOC methods also suffer from significant
limitations. For all these reasons, such panel tests are considered reasonable
and necessary.

However, the implementation of syndromic panels has also been a challenge, as
these panels detect a fixed number of organisms, not all of which are
appropriate for a given patient or setting, or during a given season. Some of
these pathogens may, in fact, be extremely rare and not be appropriate for a
patient's medical history and clinical symptoms. Further, infections with some
of the organisms included on the panels are self-limited and their detection
may not change management. In such cases, testing is not required.5,18
Finally, despite their many advantages including diagnostic speed, expanded
syndromic panels have shown limited clinical utility for routine use in
general populations. There is not a common circumstance in the outpatient
setting for which it is reasonable and necessary to perform _expanded_ panel
testing. Rather, the clinical utility of expanded panels is most evident for
select indications, populations, and settings such as immune-compromised and
hospitalized patients. On the other hand, smaller targeted panels are more
applicable to broader populations, and have a broader role in the routine
testing of immune-competent beneficiaries.

Additionally, while there is no evidence to suggest that a specific number of
pathogens is required for inclusion in limited and expanded panels, the
selected cutoff of <6 pathogens for limited panels and 6 for expanded panels
is based on the following: 1. CPT codes for such panel tests are listed
according to number of _targets_ , 2. The distinction between limited and
expanded panel testing is a conventional distinction used in the field,
particularly for the RP and GI panels, 3. In clinical medicine, a typical
differential diagnosis usually includes the top 3-5 diagnoses for most
indications for otherwise healthy populations, and is therefore aligned with
such a distinction in testing, and 4. A single pathogen in the clinical sense
(i.e., 'Influenza') may have multiple types that require testing by the
laboratory (i.e., Influenza testing, at a minimum, should include targets for
Influenza A and B), rendering this type of test a 'panel' if used with even 1
additional pathogen, such as RSV. While we would prefer to focus solely on
relevant pathogens in different patient settings and indications, based on the
literature and feedback of the CAC this is currently quite difficult;
additionally, the field has settled on a distinction between smaller targeted
panels and larger 'syndromic' panels. We will subsequently consider this
distinction for the time being in this policy until such time that the
distinction is no longer necessary. For these reasons, we believe in the
general Medicare population that, for most indications, only smaller targeted
tests are reasonable and necessary outside of immune-compromised patients and
other limited special circumstances, as outlined in this policy and in the
related Billing and Coding article. It is important that testing is guided by
the evidence in consideration of which patients will truly benefit. At
present, acceptable thresholds for coverage have been met for a number of
molecular syndromic infectious disease panels. This contractor will continue
to assess the evidence for coverage for additional types and indications,
according to the criteria outlined in this policy.

Finally, the landscape of infectious disease diagnostics is rapidly evolving
such that currently covered tests may become obsolete as new pathogens and
methodologies become important for testing. One example is metagenomic testing
for infectious diseases. Unlike panel tests, which identify fixed organisms on
a panel, this technology may further revolutionize the field with its high-
throughput capacity, rapid results, and the ability to simultaneously identify
all organisms present in a sample.93-97 This contractor will continue to
monitor the evidence, and new developments that may impact this coverage
decision.