MolDX: Molecular Syndromic Panels for Testing to Identify Infectious Disease Pathogens (L38988) (2023)

the document information

coverage guide

Indications of coverage, limitations and/or medical necessity

This policy provides limited coverage for outpatient molecular syndrome panel testing to identify infectious disease agents. This policy does NOT apply to hospitalization coverage.

This policy defines a panel as a test that detects > 1 pathogen. This policy also distinguishes (where applicable) between small, specific panels (up to 5 pathogens) and larger, expanded panels (≥6 pathogens). This distinction ismainlyapplied to the Respiratory and Gastrointestinal Panels. A "syndrome panel" is further defined as one that simultaneously detects several different pathogens associated with similar and overlapping clinical symptoms.

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

General criteria for coverage of a panel test to identify infectious disease-causing agents of the molecular syndrome

Panel testing to identify molecular syndromic infectious disease-causing agents is covered by this Medicare contractor when ALL of the following criteria are met:

• The patient has a clinical indication for an infectious disease.proof:
  • In immunocompetent patients, the clinical indication includes the assumption of active infection OR complications associated with the infection (which may include exacerbation of the underlying disease).that require identification of a causative organism for appropriate treatment.Atypical clinical conditions are considered appropriate indications for special groups of patients who may not have classic symptoms of infection (eg, the elderly).
  • For immunocompromised patients (i.e., those with a compromised immune system, including those with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), patients taking immunosuppressive drugs (i.e., chemotherapy, biologics, transplant-related immunosuppressants, high-dose systemic drugs) immunosuppressive corticosteroids) and patients with inherited disorders that compromise the immune system (i.e., congenital immunoglobulin deficiency), atypical clinical conditions provide an appropriate testing indication. In this patient population, the test may be performed ONCE as part of a pre-transplant evaluation, regardless of the presence of symptoms.
  • Observation:For certain panels, such as the urogenital/anogenital panel, the epidemiological indication or potential exposure to pathogens resulting from a high-risk experience is considered a covered clinical indication, even in the absence of clinical symptoms. These are specifically listed belowLIMITED COVERAGE FORADVANCED(>5 pathogens) PANEL TESTS.
• The test results will inform clinical management in ways already shown in the peer-reviewed published literature to improve patient outcomes.
• Tests are performed in accordance with 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 tests that must accompany the test (i.e., tests for meningoencephalitis and bloodstream pathogens include requirements for parallel tests using conventional Gram stain and culture-based evidence). for correlated results).
  • This includes providing, by the laboratory to ordering suppliers, the key limitations of a specific panel test.
• Evaluation of more than one pathogen using molecular testing is necessary for patient management (testing for a single pathogen is NOT useful or necessary for the specific infection, patient, or indication). led panel includesat leastthe minimum pathogens necessary for clinical decision making for the intended use that the test can reasonably detect.
  • If no additional organisms are included in a panel, it may be useful and necessary in certain circumstances to test these organisms separately for the same indication.
  • more than 1low hillthey should not be performed on the same day of care for the same clinical indication, with the exception of blood panels and meningoencephalitis; In such circumstances, a second panel may be made for non-duplicate content.
• Extended panel testing is indicated only when directed panel testing is inadequate (ie, does not provide sufficient information for proper clinical management of the patient). To seeLIMITED COVERAGE FORADVANCED(>5 pathogens) PANEL TESTSsob.
• Services that do not have Food and Drug Administration (FDA) authorized/approved uses and FDA-approved tests that are performed inconsistently with the intended instructions for use should be submitted to the Molecular Diagnostic Services (MoDX) Program^®) and a technical assessment (AT) to demonstrate compliance of the service with this policy. Similarly, tests (and CPT codes) that do not have ICD-10 codes attached in the related Billing and Coding article require MolDX registration.^®and a TA to demonstrate the Service's compliance with this Policy.
  • Registered tests must demonstrate equivalent or superior test performance characteristics (analytical validity (AV) and clinical validity (CV)) to established standard methods of care (SOC) (i.e., culture, drug-specific polymerase chain reaction). pathogens [PCR]).for most targets included in the dash.
  • The curriculum for all new organisms and analytes not yet established as a SOC or for which there is no predicate test covered by this contractor must be generated through a study published in the peer-reviewed literature for the intended use of the test. test for the intended population. .
• Documentation of the following items is clearly indicated in the medical record:
  • Specific clinical testing indications (for example, clinical suspicion of a pathogen as the cause of the patient's condition)
  • Specific Reasons for Panel Testing
  • Type/specialty of provider and location of service

Testing must be performed in accordance with the Clinical Laboratory Improvement Amendments (CLIA) and/or FDA regulations. For example, CLIA non-waiver testing can only be performed at certified laboratories and in accordance with CLIA regulations. CLIA-waived testing can be performed at healthcare facilities operating under a CLIA waiver or certificate of compliance/accreditation. Panels intended for home use (including those approved or cleared by the FDA) DO NOT meet the coverage criteria of this policy.

Non-Coverage Criteria

Molecular syndromic panel testing is NOT covered in the following circumstances:

• Whether the check is made as a healing check.
• If the patient has been molecularly tested for the same pathogens within 14 days for the same clinical indication.
  • If a previous panel exam was taken for a similar/duplicate purpose, a new exam is only useful and necessary if the unduplicated content of the second exam is reasonable and necessary.
  • Exception: Repeat panel tests for the same clinical indication will only be accepted if the first panel is negative AND there is a high suspicion that a pathogen is the cause of the symptoms AND the patient's clinical condition does not improve or worsens after one test. clinical evaluation of adequate duration. In these cases, 1 additional panel test may be covered between 1 and 14 daysafterthe initial panel test, provided the test meets the coverage criteria set forth in this Policy.

LIMITED COVERAGE FORADVANCED(>5 pathogens) PANEL TESTS

FOR THE SPECIFIC PANEL TYPES LISTED BELOW, ALL OF THE FOLLOWINGADDITIONALLYCRITERIA MUST BE MET:

• Respiratory Panels (RP) and Pneumonia (PNP)willingfaircovered when targeted testing is not appropriate AND according to the following additional criteria:
  • In immunocompetent patients, at least 1 of the following should be applied:
    • The tests are ordered by a clinical specialist in infectious diseases or pulmonology for a patient with established severe underlying respiratory disease (ie, severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, radiation therapy to the lungs) AND antibiotic treatment can be established, guidelines can be indicated.^1,2Specific examples that do NOT meet coverage criteria under established guidelines include:
      • Asthma exacerbations without coexistent fever and purulent sputum or radiographic evidence of pneumonia²
      • Uncomplicated community-acquired pneumonia (CAP)¹
    • the patient isseriously or critically ill or in imminent danger of becoming seriously or critically ill(such as the "General Guide for the Disclosure of Information about the Condition of Patients" established by the American Hospital Association)³as a result of a suspected respiratory infection AND the patient is being treated in an appropriate intensive care unit.
  • For immunocompromised patients: the test is ordered by a clinical specialist in one of the following areas: Infectious Diseases, Pulmonology, Oncology, Transplant OR the patient is being treated in an appropriate intensive care unit.
  • For ALL patients: Only 1 of the following panels - RPOPNP- is covered for a specific patient for the same clinical indication. PNP should be given priority when evaluating for pneumonia from lower respiratory tract specimens (ie, bronchoalveolar lavage [BAL] specimens). For the purposes of repeat panel testing for the same clinical indication, PR and PNP are considered equivalent tests, so if the criteria for repeat testing (as defined above) are met, a physician you may choose to perform retesting using the PNP. , even if the original test was done with the RP.
  • For ALL patients, exceptions to the limitation for Specialist Physicians who may request Expanded Panel Testing are provided in the attached Coding and Billing Article so that patient geographic location and access to care do not preclude receipt of appropriate diagnostic tests when indicated.
• Gastrointestinal (GI) disheswillingfaircovered when targeted testing is not appropriate AND according to the following additional criteria:
  • In immunocompetent patients, at least 1 of the following should be applied:
    • Testing is ordered by a clinical specialist in infectious disease or gastroenterology for a patient with established severe underlying GI disease (ie, inflammatory bowel disease [IBD], paralytic ileus, radiation therapy to the intestine) AND identification of an infectious cause is required for defined the next steps in patient management.
    • the patient isseriously or critically ill or in imminent danger of becoming seriously or critically ill(such as the "General Guide for the Disclosure of Information about the Condition of Patients" established by the American Hospital Association)³as a result of a suspected gastrointestinal infection AND the patient is being treated in an appropriate intensive care unit.
    • The patient's clinical indication for GI panel testing is diarrhea and ALL of the following are true:
      • Diarrheal illness MUST be acute or persistent with signs or risk factors for severe illness (i.e., fever, bloody diarrhea, dysentery, dehydration, severe abdominal pain) that may warrant hospitalization AND/OR
      • Diarrhea does not subside after 7 days And thisThe patient has NOT taken any laxatives in the 24 hours prior to the test.
  • For immunocompromised patients:
    • The test is ordered by a clinical specialist in one of the following areas: Infectious Diseases, Gastroenterology, Oncology, Transplantation OR the patient is being treated in an appropriate intensive care unit.
  • For ALL patients, exceptions to the limitation for Specialist Physicians who may request Expanded Panel Testing are provided in the attached Coding and Billing Article so that patient geographic location and access to care do not preclude receipt of appropriate diagnostic tests when indicated.
• Urogenital/anogenital panels (UG/AG)
  • For UG/AG panels, epidemiological indication or possible exposure to sexually transmitted pathogens(i.e. when there is clinical suspicion of multiple sexually transmitted infections (STIs) due to a high-risk experience)it is considered a covered clinical indication even in the absence of clinical symptoms.Documentation of the high-risk reason for panel testing is clearly indicated in the medical record..
  • If, due to specific signs and symptoms (i.e., lesions suggestive of herpes simplex virus [HSV]), the primary clinical concern in the absence of a high-risk experience is directed toward some specific pathogens, it is expected that only a small Affected fraction panel (ie including HSV-1 and HSV-2) performed. In these cases, extended panels will NOT be considered appropriate and necessary and will NOT be covered.
  • For the diagnosis of vaginosis/infectious vaginitis, it makes sense to perform a panel (targeted or extended) that includes a combination of at least 2 of the following:Gardnerella vaginalis,other bacteria associated with bacterial vaginosis (BV) (BVAB) (such ascases of atopobiaIMegasphaera-Typen), Trichomonas vaginalis,micandidSpecies.
• Meningoencephalitis (ME) panelsare covered according to the following additional criteria:
  • For immunocompetent patients: Patient has at least 2 of the following signs of central nervous system (CNS) infection: cerebrospinal fluid (CSF) markers, radiology, clinical signs and symptoms consistent with meningitis or encephalitis, epidemiologic indication, or exposure. At least one of these indicators is required in immunocompromised patients.
  • For all patients: Testing is performed using a lumbar puncture specimen and NOT around an internal medical device (eg, CSF shunts).
• Bloodstream infection (BSI) panels.are covered according to the following additional criteria:
  • There is clinical concern for bacteremia or sepsis AND microbes were seen on a Gram stain of the patient's blood AND the patient is being treated in an appropriate intensive care unit (this includes the emergency department) AND
  • Staff (ie, an Antimicrobial Stewardship Team [ASP]) are equipped to rapidly (within 24 hours) adjust antimicrobial therapy as a result of the rapid test.
• Urinary tract infection (UTI) panels.are covered according to the following additional criteria:
  • Patient is symptomatic AND is at increased risk of UTI complications (ie, elderly patients, patients with recurrent symptomatic UTI, and/or complicated urinary tract anatomy) AND/OR seen in urogynecology or specialist urology facilities.

For more information on specific dashboards, see the appropriate Billing and Coding article.

Tests that demonstrate similar indicated uses and performance equal to or greater than the SOC or other covered tests, as demonstrated by a TA, may also be covered by this policy.

AOther types and indications of syndromic panels may be covered according to the established criteria detailed in this guide.

evidence summary

Molecular panel tests for infectious diseases have changed the landscape of clinical microbiology. They play an important role in diagnostic tests, as they simultaneously detect many different pathogens associated with similar and overlapping clinical symptoms. For this reason, they are also called "syndrome panel" tests. These panels belong to a category of tests known as culture-independent diagnostic tests (CIDTs). These are tests that detect pathogens without the need to culture and isolate them. These tests have shorter turnaround times, generally show good performance characteristics, and require limited technical knowledge, making them attractive to both clinicians and clinical laboratories.

In the past, physicians had to select the specific pathogens considered most likely to be associated with a patient's disease. They often had to rely on empiric therapy until laboratory results could be used to identify definitive or targeted antimicrobial therapy, with results taking days and sometimes weeks. In recent years, molecular panel tests, including multiplex PCR, have been increasingly used to detect pathogens, and clinicians no longer need to name (or test separately for) many bacterial, viral, fungal, and parasitic species. what they are looking for a specific clinical “syndrome”. Because the use of multiplex molecular tests has reduced the need to run multiple assays to diagnose a given infection, results are often available to the physician within minutes to hours. Although culture-based diagnostic methods are still routinely used and definitive antimicrobial therapy can still await comprehensive information on culture and susceptibility, these tests have revolutionized the diagnosis of infectious diseases and have made the path from diagnosis to treatment to be very fast, in some cases even to the end. the point of care (POC).

For some diseases such as B. respiratory infections, RP panels were converted to SOC. These breathing panels are exceptionally fast, providing results in minutes or hours.^4,5They differ from older conventional respiratory virus test methods, such as viral culture and immunofluorescence, which can take days or weeks to obtain a result. In addition, they have superior test performance characteristics (sensitivity and specificity) than other rapid tests for diagnosing respiratory viruses, such as B. Influenza Detection Tests (RIDTs) (based on antigens), are many times superior.^6-8For these reasons, many laboratories have stopped offering some of the other diagnostic modalities described for the detection of respiratory viral pathogens. In fact, many of these methods have become obsolete in clinical routine.

Finally, some of these multiplex panels are smaller or "targeted" and only detect a few pathogens, while others are very large, detecting around 20 targets. The larger panels are sometimes referred to as "extended". These distinctions are most common for RP and GI panels, as BSI and ME (and potentially UG/AG) panels must detect more than 5 pathogens (although a UG/AG panel is unlikely to detect even 20 pathogens due to the epidemiological disease in that organ). Many commercial platforms have been developed for multiplex panel tests for a variety of infection types in different organ systems.^4,5Increasingly smaller panels are used in clinical laboratories, although their optimal use and application in different settings and for different patient populations and indications remains a challenge.

proof

In recent years, syndromic molecular panels have been used routinely for a variety of infection types, including respiratory, gastrointestinal, central nervous system, bloodstream, and urogenital/anogenital infections. These panels provide rapid results and are generally more sensitive than traditional tests for the different organisms contained.^4,5,9However, test performance characteristics vary between panels and specific pathogens. For example, while overall sensitivities and specificities for various PR platforms tested ranged from 84-100%, sensitivities for adenovirus, influenza A H1/2009, and influenza B using FilmArray were^®PR was reported in only 57%, 73% and 77% respectively, while the latest versions of the platform (FilmArray^®RP2) showed better detection (94% - 100%) of these pathogens.^10,11Furthermore, the FilmArray^®The PNP and RP panels share common targets, although the PNP also contains several bacterial targets as well as antimicrobial resistance determinants; the PNP is also semiquantitative.^12,13PNP showed strong agreement with the SOC and RP methods in identifying pathogens from lower respiratory tract samples.^12,13Since PNP works similarly to PR for viral pathogens, but can also detect bacterial pathogens and antimicrobial resistance determinants, it should be prioritized when evaluating for pneumonia from lower respiratory tract specimens.¹⁴A study comparing the performance of additional PR assays revealed the following sensitivities and specificities: 98.3% and 99.2% for GenMark Dx^®electronic sensor^®Respiratory Viral Panel (RVP), 92.7% and 99.8% for Luminex^®xTAG^®RVPv1 and 84.4% and 99.9% for Luminex^®xTAG^®fast RVP.¹⁰In this study, sensitivities also varied depending on the viral target.¹⁰Smaller dedicated panels for the detection of influenza and respiratory syncytial virus (RSV) have also shown high sensitivity and specificity in studies evaluating their performance. TOprospective and retrospective evaluation of Xpert^®The Flu/RSV XC assay reported a sensitivity/specificity of 97.8%/100% and 97.9%/100% for influenza and RSV, respectively.¹⁵Another study using prospective patient samples found a 96.6% to 100% concordance between theARIES^®Influenza A/B and RSV and Cepheid^®specialist^®Grippe/RSV XC tests.^sixteenThis is important as some of the specific respiratory panels have received CLIA waived status and are used in non-laboratory settings.^17,18In a study evaluating Roche cobas^®Look for^®The Influenza A/B and RSV assay, performed by non-laboratory personnel, reported sensitivities/specificities of 99.6%/97.5%, 99.3%/99.7%, and 96.8%/98.8% for influenza A, B and RSV, respectively.¹⁹Another study comparing POC rapid nucleic acid amplification assays (NAATs) found the sensitivity of Alere™ i to be only 71.3% (compared to 100% for Liat^®).²⁰The low sensitivity of Alere™ i in this study was attributed to the inclusion of too many weakly positive samples.²⁰

O BioFeuer^®movie matrix^®y Luminex^®xTAG^®GI panels show high overall sensitivity (>90%) for most of their targets.²¹However, the sensitivities were very low, especially for certain targets.Aeromonas sp. (23.8%) no FilmArray^®miYersinia enterocolitica(48.1%) no xTAG^®21; Due to its low sensitivity,Aeromonasit is not included as a reportable analyte in the released version of FilmArray^®proof.²²A multicenter study evaluating FilmArray^®The GI Panel noted that the sensitivity was 100% for 12 of the 22 targets and >94.5% for an additional 7 targets (the remaining targets were not evaluated due to their low prevalence); Specificity was >97.1% for all panel endpoints.²²In a study comparing Luminex^®xTAG^®compared to traditional test methods, found that panel had higher sensitivity than SOC for detectionC. difficile, Campylobacterspecies, norovirus and rotavirus.²³

Das ME-Panel (das BioFire^®movie matrix^®The ME panel is currently the only commercially available panel) has good overall sensitivity for most lenses, but suffers from a lack of sensitivity for certain lenses such ascriptococosspecies compared to conventional test methods for this pathogen.^24-26In 1 multicenter prospective evaluation, the FilmArray^®The ME panel showed a percent positive agreement (PPA) with the SOC methods of 100% for 9 of 14 analytes, with an additional 2 analytes showing a PPA between 85.7 and 95.7%; however, the Negative Percent Agreement (NPA) with the SOC methods was >99% for all analytesS. agalactiae.²⁴It is important to highlight that the ME panel detected 43 pathogens not detected by conventional tests; however, additional testing confirmed that the ME panel was correct in only 43% of these cases.²⁴False positive results from the MS panel have been reported in this and other studies, mainly forS. pneumoniae,S. agalactiaeand HSV-1, and false negative results have been reported primarily for HSV-1 and HSV-2 and enteroviruses.Cryptococcus neoformans/gats.^24-26A systematic review and meta-analysis of 13 studies evaluating the MS panel found a sensitivity and specificity of 90% and 97%, respectively.²⁶

BSI panel tests also show good overall performance. Studies have found that FilmArray^®Blood Culture Identification Panel (BCID) and Verigene^®The panels (gram-positive and gram-negative blood cultures) allow the correct identification of 87% to 99% of monomicrobial samples compared to conventional methods.^27,28A study comparing the 2-panel test with SOC found that FilmArray^®and the verigen^®It correctly identified 95% and 99% of the isolates in monomicrobial cultures, respectively.²⁷False positive and false negative results have been reported in these panels for the identification of resistance organisms and genes, particularly in polymicrobial samples; However, failure to detect organisms in polymicrobial samples is often the result of organisms not present in the panels.^5,29Due to the inherent limitations of the tests (including not all organisms represented in the panels and these are high-risk infections), the ME and BSI panel tests require Gram stain and culture.

Molecular panel tests are also increasingly used to detect urogenital and anogenital infections. The BD MAX™ Vaginal Panel has 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).³⁰In another study, theThe BD Affirm™ VPIII Microbial Identification Test showed 81.6% lower specificity for BV and 69.4% lower sensitivity for CVV, while performing as well as CVV.BD MAX™ for televisions.³¹However, these panels have been shown to exceed clinical evaluation of vaginitis, for which many diagnoses remain empirical and for which non-compliance with guidelines is common.^32-34In addition, high rates of co-infection with STIs (24.4%–25.7%) were observed.^35-37Panels for the detection of sexually transmitted pathogens have also become routine in clinical laboratories, as they provide a rapid result for organisms such asclamidiaSpecies that can be difficult to grow. Also, this is common knowledge.N. gonorrhoeaemiC. trachomatisnot only do they cause similar clinical syndromes, but they also coexist in a significant proportion of patients, underscoring the need for panel testing.³⁸

For UTI evaluation, multiplex PCR panels have demonstrated ≥90% agreement with SOC urine cultures for identification of organisms in urine, although there are currently no US FDA-approved panels for this indication. .^39,40Also, there are currently no panels approved for use with sterile body fluids other than blood and CSF, although studies evaluating existing panels (such as the BSI panel) with these fluids have shown that in cases where SOC cultures were negative, possibly due to the effect of prior antimicrobial therapy.^41,42Although the test may require optimization of the assay for use with "other" sterile fluid samples, one study found 100% detection of organisms from sterile fluids seeded in blood culture bottles when tested with BSI panels.⁴³

There are many commercially available multiplex panels for the diagnosis of infectious diseases and this overview of their performance is not all-inclusive. As mentioned in this overview, the performance of these panel tests will vary depending on the platform used, the sample types used, and the objectives included. These panel tests must demonstrate performance equal to or better than the SOC or other established tests.IdealSensitivity and specificity or PPA and NPA of ≥95% for most of the targets included in your panels. However, it is important to look at the big picture. For example, since some of these panels are not intended to be used as stand-alone trials, parallel trials with additional methods may be used to support their application in clinical settings, especially in cases where the trial has not met clinical benchmarks. performance metrics for a predetermined period. goal. Finally, the specific performance limitations of different panel tests (in some cases due to increased sensitivity to potentially non-pathogenic targets) must be considered. These issues are discussed later in theClinical benefitsection below.

Clinical utility: implications for patient management and interpretation of results

Rapid diagnosis requires prompt intervention to be effective in patient management. Rapid, easy-to-use, multiplexed molecular tests have great potential in this regard, although their impact on patient outcomes is more apparent for some types of panels, infections, and patients than for others, because studies vary in design and quality.^4,5,8,44A systematic review of the impact of Rapid Point-Von-Nursing care testing (POCT) (including molecular assays) for influenza found that, in patients with acute respiratory infection, a positive POCT result significantly increased influenza antiviral use and reduced unnecessary antibiotic use.⁴⁵Another study in adult patients found reduced time to diagnosis (both influenza and other viruses) using FilmArray.^®PR, compared to traditional test methods; In addition, an influenza diagnosis was associated with a lower odds ratio for admission, length of stay (LOS), duration of antimicrobial use, and number of chest X-rays.⁴⁶Better flu detection, aIn a routine molecular POCT study for respiratory viruses (RePOC study) in hospitalized adults with acute respiratory illness, shorter length of stay and better use of antivirals was also observed.⁴⁷ HHowever, studies have shown that other factors, such as the presence of infiltrates on chest radiographs and uncertainty about the possibility of bacterial infection, also play an important role in the decision to treat with antibiotics, regardless of the RP result. .⁴⁸A systematic review of the literature concluded that RPs provide accurate results and that there is good-quality evidence that rapid tests can reduce length of stay and increase appropriate use of oseltamivir.⁸In particular, most public relations studies have focused on the benefits in influenza-positive patients. In a study evaluating antimicrobial prescribing after PR testing in adult outpatients, antibiotic prescribing rates were significantly different between patients who tested positive for influenza virus and those who did not; However, antibiotic prescription rates did not differ between patients who tested positive for viruses other than influenza and those who tested negative.⁴⁹Since influenza is one of the few respiratory infections that can be treated with antivirals, this suggests that a more specific testing approach is sufficient for the majority of immunocompetent patients with suspected acute viral respiratory infection. In addition, the Infectious Diseases Society of America (IDSA) guidelines on CAP recommend NOT routine testing (particularly sputum and Gram cultures) in adults with CAP receiving outpatient treatment; instead, they recommend starting empirical antibiotic therapy in adults with clinically suspected and radiologically confirmed CAP,even if these patients test positive for influenza.¹In other words, the PR test is not related to the initial antibiotic treatment in these circumstances. However, IDSA guidelines suggest testing for influenza in adult patients with CAP if influenza is circulating in the community.¹In these cases, a specific panel for influenza testing may be performed. Finally, a specific diagnosis and definitive antimicrobial therapy is required for complicated pneumonia (ie, due to meningitis, endocarditis, or abscess), and expanded panel testing is required in these circumstances; However, these patients are expected to be treated as inpatients.

A more comprehensive testing approach may be appropriate in patients with underlying lung pathology and in immunocompromised patients,yes only in certain circumstances. In a study of adult patients with exacerbation of respiratory disease, 35% of those who tested positive for the virus (by molecular POCT) stopped antibiotics early, compared with 13% of those who tested negative and 6 % of control group; Furthermore, only 20% of the positive viruses tested positive for influenza, and antibiotic discontinuation did not differ between the different viruses detected.⁵⁰The authors of this study emphasize that many of the patients in this study should not have been treated with antibiotics for clinical reasons alone, "given that the national society guidelines strongly discourage the use of antibiotics in patients with asthma exacerbation."^2,50The Global Strategy for the Control and Prevention of Asthma establishes"The evidence does NOT support a role for antibiotics in asthma exacerbations unless there is strong evidence of pulmonary infection (eg, fever and purulent sputum or radiographic evidence of pneumonia)."²Finally, a study evaluating respiratory viral infections prior to hematopoietic cell transplantation (HCT) found that patients with virus detected prior to HCT were alive and out of hospital for fewer days and had shorter 100-day survival than patients. patients with negative results (even though the only virus present was rhinovirus); It is important to note that most of the patients in this study were asymptomatic when the monitor samples were collected.⁵¹This result suggests that pre-transplant screening is a limited circumstance in which expanded RP panel testing in asymptomatic patients may be warranted.

Studies on the effect of GI panels have been even more mixed, although some have found that the implementation of such panels was associated with a decrease in endoscopic procedures, abdominal radiology, and/or antibiotic prescriptions.^52,53A prospective multicenter study evaluating 1887 stool samples from patients with acute diarrhea found that the use of a GI panel improved organism detection and clinical sensitivity and allowed clinicians to administer more timely and targeted antimicrobial therapy; also produces positive Shiga-like toxinE. coli(STEC) led to adequate discontinuation of antibiotics in most cases once empiric therapy was started.⁹However, testing is often not warranted in outpatients with uncomplicated diarrhea that is likely to be self-limiting.⁵The American College of Gastroenterology guidelines on acute diarrheal infections in adults state that in cases of "dysentery, moderate to severe illness, and symptoms lasting longer than 7 days, diagnostic studies may be used to clarify the etiology of the patient's illness." and provide specific information to enable targeted therapy.”⁵⁴ Regarding the use of the GI panel in special populations, an impact study in IBD patients found that testing the GI panel resulted in a lower rate of IBD treatment modifications.⁵⁵In outpatients with recurrent IBD, testing with a GI panel was associated with significantly lower rates of escalation of IBD therapy and endoscopy compared with patients who underwent conventional testing.⁵⁶Finally, in a study that evaluated gastrointestinal infections prior to HCT in asymptomatic patients, it was found that 62% of patients colonized byIt's hardbefore the transplant he developed a clinical pictureIt's hardInfection after transplantation and 80% of patients with colonizationenteropathogenicEscherichia coli(EPEC)the enteroaggregativeE. colideveloped clinical infections due to their colonizing pathogen after transplantation.⁵⁷As noted above for respiratory infections, these results suggest that pretransplant evaluation is a limited circumstance in which expanded GI panel testing in asymptomatic patients may be warranted.

Bloodstream and CNS infections are emergencies that can progress rapidly, even in previously healthy people.⁵⁸Therefore, rapid panel tests may be invaluable for the rapid treatment of patients with such infections.The following oft-cited statistic is troubling: in the case of sepsis, for every hour of delayEffective(appropriate for a given pathogen) of antimicrobials, there is a median decrease in patient survival of approximately 8%.⁵⁹Because bacterial culture and full antimicrobial susceptibility results traditionally take 2 or more days, rapid BSI panels have been developed to quickly (within hours) identify a causative pathogen so that the most appropriate antibiotics can be administered. and specific.A prospective randomized controlled trial found that the use of a BSI panel resulted in a reduction in the time between Gram stain and identification of the organism by approximately 21 hours.⁶⁰In addition, the use of broad-spectrum antibiotics and the treatment of contaminants in the bloodstream were reduced; in addition, antimicrobial de-escalation occurred with an additional PSA intervention.⁶⁰Other studies similarly demonstrated faster organism identification and antimicrobial de-escalation using the BSI panel (plus ASF intervention) compared to conventional culture methods, even when the latter also included ASF.⁶¹However, the effect of BSI panels on other outcomes, such as mortality, readmission within 30 days, and length of stay, was more variable between studies.^5,61Pre-post-intervention studies⁶²and a meta-analysis⁶³showed that rapid molecular diagnostic tests are associated with a significant reduction in the risk of mortality and LOS,especially in combination with an ASP. For patients with multi-resistant bacteria, quicklyline upAntimicrobial therapy is also important. In a study of patients with vancomycin-resistant enterococci (VRE) bacteremia, use of a BSI panel reduced the median time to adequate antimicrobial therapy by more than 30 hours.⁶⁴In another case, faster implementation of effective therapy was observed in extended-spectrum beta-lactamase-producing organisms, but not overall; The same study reported a significant reduction in intensive care unit (ICU) length of stay, 30-day mortality, and mortality associated with multidrug-resistant organisms after implementation of a BSI panel.⁶² There are fewer outcome studies evaluating the clinical utility of MI panels, particularly for patients, that can be generalized to the Medicare population. One study found that using FilmArray^®The EM panel reduced time to diagnosis by approximately 3 days, allowed 32% of patients to discontinue empiric therapy earlier, and resulted in early hospital discharge in 18%, saving 82 days of hospitalization.^Sixty-fiveAnother study found that use of the panel significantly reduced response time for HSV detection, days of antiviral (acyclovir) and antimicrobial therapy, and hospital stay in adults undergoing lumbar puncture for suspected CNS infection in community.⁶⁶

The results of the molecular multiplex panel test should be interpreted with care. First, they detect significantly more pathogens than was previously possible with conventional testing methods.^5,9For example, studies evaluating multiplexed urine panels (UPs) detected up to 26% additional organisms when culture methods did not.³⁹Importantly, multiplex UP detected more organisms in polymicrobial infections than urine cultures in symptomatic patients.^39,67and a model study showed combinations of bacteria that increase the likelihood of antibiotic resistance.⁶⁸As with all of these panel tests, it is important to determine if these additional organisms detected are pathogens or colonizers that previously simply could not be detected with traditional SOC methods. Because these tests detect microbial nucleic acid, they do not require living organisms or active replicators. Therefore, not all positive results indicate a current active infection. However, in a study of 150 urogynecologic patients, standard urine culture missed 50% of uropathogens in patients with severe urinary symptoms; In addition, approximately 40% of patients who missed uropathogens reported that symptoms did not improve after treatment based on standard urine culture results.⁶⁹Importantly, all missed uropathogens were detected using the read-across method of the study (an improved quantitative culture technique), although additional bacteria of unknown pathogenicity were also detected.⁶⁹

Asymptomatic transmission and prolonged (days to weeks) release of viral nucleic acid are common, particularly in respiratory and gastrointestinal pathogens. In BIG-LoVE, a study of 108 adults and children who underwent weekly breath tests for one year, approximately half of all viral detection episodes were asymptomatic.⁷⁰In addition, virus detection by PCR at ≥3 weeks was a fairly common finding, occurring in 16% of episodes; prolonged detection of the virus was particularly common in children and those living with children.⁷⁰Prolonged hair loss is also common in immunocompromised patients.⁷¹When interpreting GI panels of a positive resultIt's hardThe outcome in a patient without risk factors for infection by this organism can be difficult, since 4-15% of healthy adults and up to 21% of those hospitalized are asymptomatically colonized; Furthermore, PCR detection does not indicate active infection, especially in patients without classic clinical symptoms.^72,73The high rate of mixed infections seen when using expanded PR (in 30% - 40% of positive cases)^74,75and gastrointestinal panels (up to 27% of positive cases)^5,21-23can be difficult to interpret. The significance of previously unidentified organisms in stool samples (such as sapoviruses and astroviruses) may also be difficult to interpret clinically, as it is unclear whether detection of these organisms represents colonization or infection. Mixed infections detected by gastrointestinal panels are more common among enteropathogenic infectionsE. coli, Y. enterocolitica, norovirus yIt's hard.^9,21,53In addition, very high rates are observed in some studies.It's hardThere are also high rates of inappropriate GI panel testing. In a study evaluating more than 440 gastrointestinal panels at a community hospital, 61% of the indicated panels were deemed inadequate for reasons such as lack of documented diarrhea, laxative use, and presence of duplicates.It's hardPCR test requested.⁵³In particular, in this study, the rates ofIt's hardthey were 51%.⁵³

ME and BSI panels also have their own challenges. For example, although coinfections are seen less frequently in multiplex panel tests of sterile body sites (eg, CSF or blood), they do occur and can cause interpretation problems.²⁴Also, the ME panel cannot differentiate between active and latent infection. It recognizes certain organisms, such as human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), which may be dormant and not the causative agent of disease, especially when the host is immunocompetent. In addition, there are a number of organisms that can cause meningitis and encephalitis that are not included in the panel, including bacteria (such as non-K1 bacteriaE. coliNon-encapsulated serotypes and strains ofmeningococcus), viruses (including arboviruses), andmycobacterial tuberculosis. Therefore, there are significant limitations associated with the use of this dashboard; however, these are partially mitigated by the requirement for additional parallel testing (ie, bacterial culture, cryptococcal antigen) and training of clinical staff and laboratory management. However, it is important to remember that there are also traditional means of diagnosing CNS infections.diagnostic challenges that can delay a diagnosis. These challenges include the low sensitivity of CSF culture (particularly in patients with prior antimicrobial exposure to lumbar puncture)⁷⁶and the historically unrecognized etiology in most cases of encephalitis.⁷⁷ The size of the panels may lead a referring physician to believe that a negative result makes infection a less likely cause of the patient's symptoms because many organisms are being tested. Therefore, it is important that clinicians are aware that not all pathogens are detected even in expanded syndromic panels. New virus strains can also go unnoticed, and panels are limited to organisms found on the "menu." While the ME panel cannot completely replace current trials, it can provide unprecedented rapid results for a syndrome that can quickly become fatal. Also, BSI panels are limited by the targets available in the panels, both to identify microbes and to identify genes responsible for resistance mechanisms. In fact, many gram-negative organisms harbor resistance mechanisms that are not encoded by genes in these BSI panels, adding another diagnostic hurdle to overcome. However, they generally detect the most common pathogens in the bloodstream and can provide rapid results for rapid targeted antimicrobial therapy.^4,5,60

Additional challenges and appropriate use of panel tests

With few exceptions, FDA-approved molecular panels are "locked" to a specific platform. H. consist of a predetermined pathogen test menu. The smallest of these tests, sometimes called "targeted panels," typically detect between 3 and 5 pathogens. The largest or "extended" panels in common use and commercially available recognize approximately 20 targets or pathogens, and some include pathogens that generally cause different clinical presentations, so testing for these pathogens at the same time should not be a common occurrence. In other words, they deviate from being "syndromic" in their approach to diagnosis. For example, the classic infection associatedBordetella pertussisIt's whooping cough. The clinical case definition of a probable case of pertussis is a cough disorder lasting at least 2 weeks,in the absence of a more likely alternative diagnosis or epidemiological link, and 1 of the following: coughing fits, pertussis, posttussive vomiting, or apnea.⁷⁸Although some individuals (for example, individuals with a history of prior infection or vaccine-induced immunity) may not have classic manifestations or may be generally asymptomatic,⁷⁹Diagnosis of this organism usually requires a high index of suspicion. Although it is a respiratory infection, the clinical presentation of pertussis in most patients differs from most other viral respiratory syndromes. However, it is included in many respiratory syndrome panels, and a patient likely to be infected with influenza or RSV may still end up being tested.B. whooping cough, simply because it is a target on a fixed panel. Finally, the targets and organisms in a panel can vary between manufacturers, with some panels distinguishing between various subtypes and strains, many of which are not clinically relevant to most patients.⁵For example, distinguishing between different types and subtypes of the parainfluenza virus may be good for epidemiological detection, but is unlikely to have a significant impact on patient care.

In addition, large (fixed) panels do not adequately represent patient risk factors or the pretest probability that a given pathogen will cause an infection. It is important to assess the patient's medical history and exposures prior to testing. For example, an infectionClostridioides difficile(previously known asClostridium difficile) is generally associated with specific risk factors, including antimicrobial exposure, health care facilities and hospitals, chemotherapy, and gastrointestinal procedures.⁸⁰On the other hand, many of the other pathogens in the panels are often associated with foodborne transmission.^81,82Variables such as time of year and geography are also relevant to a given patient or diagnosis case. In the case of respiratory panels, a patient may be tested for more than 20 pathogens, although in fact only a few viruses may be predominant circulating in the community during any given season. For example, although the flu can circulate throughout the year, it mainly occurs and peaks in the winter months, while other viruses are more common at other times of the year.⁸³Additionally, fixed panels may not be applicable in all populations, and immunocompetent patients who are not critically ill may need limited or no testing.⁸⁴Viral infections in immunocompetent patients are usually self-limiting and resolve without complications. Also, with few exceptions, there is usually no specific treatment for viral infections other than supportive care, and testing may not change patient management. All of this can lead to unnecessary overtesting in immunocompetent individuals. On the other hand, in immunocompromised patients, both common and rare pathogens can cause severe illness, and co-infections with multiple respiratory viruses (which are more common than previously thought thanks to these multi-analyte panels) have been identified as predictors of hospital complications. . mortality.⁸⁵In addition, immunocompromised patients usually do not present the classic symptoms of infection. Therefore, it may be useful and necessary to carry out a broader diagnostic network for this population.

However, extended panels can also provide rapid, highly effective, and epidemiologically important information for immunocompetent individuals.⁸⁶They can lead to the diagnosis of some infections that may have gone completely unnoticed in the past. In 1 study, 75% ofmicoplasma pneumoniaeInfections were incidentally detected by multiplex PCR; In this study, doctors ordered only specific testsMETRO. lung infectionin 2 (10%) of 20 patients positive for this pathogen.⁸⁷Importantly, this was an actionable finding as infection withMETRO. lung infectionIt is treatable with antibiotics.⁸⁷Advanced dashboards can also help quickly diagnose and, in some cases, prevent public health outbreaks. For example, during an outbreak of a "mysterious" childhood respiratory illness in 2014, hospitals quickly identified the suspected cause, which turned out to be enterovirus D68.⁸⁸Likewise, the use of fast multiplex GI panels contributed significantly to the detection of a large Cyclospora outbreak in 2018.⁸⁹

For all these reasons, it can be difficult to establish the proper use of these panels. In particular, these tools do not necessarily replace certain conventional methods of microbial detection, such as B. bacterial and fungal cultures, in the diagnosis of infections. These multiple challenges and opportunities have led to the implementation of measures to promote diagnostic management. Some of these include restricting extended syndromic panels to specific groups of patients, such as immunocompromised, hospitalized, critically ill, or specialist clinic patients (eg, pulmonary airway panels). Others include the implementation of test request algorithms and "checks," decision support tools, and a ban on repeat testing within a specified period of time.^5,53,90,91

Summary of the Contractors Advisory Council (CAC) meeting.

A multi-jurisdictional CAC meeting was held on Monday, January 11, 2021 to discuss the clinical literature related to molecular diagnostic tests for pathogens. The general consensus of the CAC Panel is that these pathogen panels are accurate and reliable and that panel test results can improve patient health outcomes. However, the CAC panel also noted that outcome studies on the use of these panels are limited, depending on the specific panel (and specific use). The panel emphasized the importance of considering the patient population and setting, as indications for testing may vary among recipients with different medical history and needs, and highlighted differences in testing requirements between immunocompromised and immunocompetent patients. In general, the panel expressed that an important consideration is whether an outcome has a positive impact on patient care. Ultimately, CAC participants agreed that the use of this technology to diagnose onychomycosis (fungal infections) of the nail was unnecessary.

Analysis of evidence (reason for discovery)

The goal of Diagnostic Stewardship is to select the right test for the right patient at the right time to optimize patient care.⁹²Evidence shows that syndromic molecular panels for infectious disease testing can lead to prompt patient care, including prompt initiation of appropriate antimicrobial therapy, timely reduction of therapy, and reduction of unnecessary therapy. In some cases, these panels have resulted in further improvements in overall care, including reductions in the use of unnecessary diagnostic procedures and even reductions in length of stay, morbidity, and mortality. In addition, infectious disease testing has traditionally relied on testing for multiple organisms when a physician is uncertain as to which pathogen is causing a suspected infectious disease. Historically, this research was carried outusing several different tests and/or cultures (which also detect several different organisms using agar plates).In this regard Panel testing can be considered to use a new methodology (ie, NAAT multiplex) to detect many of the same clinically valid pathogens that have been detected in the past using combinations of SOC methods (culture, antigen test, etc.). Importantly, these SOC methods also suffer from significant limitations. For all these reasons, such panel tests are considered useful and necessary.

However, implementation of syndromic panels has also been challenging because these panels detect a fixed number of organisms, not all of which are appropriate for a given patient, setting, or time of year. In fact, some of these pathogens may be extremely rare and inappropriate for a patient's medical history and clinical symptoms. In addition, infections with some of the organisms included in the panels are self-limiting and their detection may not change treatment. In these cases, the test is not necessary.^5,18Finally, despite their many advantages, including speed of diagnosis, extended syndrome panels have shown limited clinical utility for routine use in the general population. There is no ordinary circumstance in the outpatient setting that makes it sensible and necessary to provide a serviceexpandedpanel testing In contrast, the clinical utility of expanded panels is more apparent for selected indications, populations, and settings, such as B. immunocompromised and hospitalized patients. On the other hand, smaller specific panels are more applicable to broader populations and play a larger role in routine testing of immunocompetent recipients.

While there is no evidence that a specific number of pathogens are required for inclusion in limited and expanded panels, the selected threshold of < 6 pathogens for limited panels and ≥ 6 for expanded panels is based on the following: 1. CPT^®The codes for such panel tests are listed by number.Goals, 2. The distinction between limited and extended panel testing is a conventional distinction used in the professional community, particularly for PR and GI panels, 3. In clinical medicine, a typical differential diagnosis generally includes the top 3-5 diagnoses for the most indications in healthy populations and is therefore designed to make such a distinction in testing, and 4. a single pathogen in the clinical sense (i.e., "influenza") may have multiple types that require laboratory testing (ie, it must contain at least targets for influenza A and B), making this type of test a "panel" when testing for a single additional pathogen, such as B. RSV. While we would prefer to focus exclusively on relevant pathogens in different patient settings and indications, based on the literature and CAC feedback, this is currently quite difficult; Furthermore, the discipline has been committed to distinguishing between specific smaller panels and larger "syndromic" panels. We will honor that distinction in this policy for now, until the distinction is no longer needed. For these reasons, we, the general Medicare population, believe that, for most indications, only small-scale, targeted testing outside of immunocompromised patients and other limited special circumstances is meaningful and necessary, as described in this policy. and the Codification article. billing. It is important that trials are evidence based to consider which patients will actually benefit. Currently, acceptable coverage thresholds have been reached for several molecular syndromic infectious disease panels. This contractor will continue to evaluate evidence of species coverage and additional indications in accordance with the criteria established in this policy.

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