Pathogen Panel Testing AHS - G2149

Clinical Utility and Validity

Several studies demonstrated the overall high sensitivity and specificity of the gastroenterology pathogen panels (Buss et al., 2015; Claas et al., 2013; Onori et al., 2014). Several studies have also indicated that gastrointestinal pathogen panels are more sensitive than culture, microscopy, or antigen detection, thus illustrating the potential of panels as a diagnostic tool for gastrointestinal infections (Buss et al., 2015; Couturier et al., 2011; Humphrey et al., 2016; Liu et al., 2014; Operario & Houpt, 2011). Zhang and colleagues concluded that using multiplex PCR assays in the work-up of infectious gastroenteritis has the potential to improve the diagnosis (Zhang et al., 2015).

Numerous studies have examined the clinical utility of the BioFire FilmArray GI Panel. Stockmann et al. (2015) focused on comparing the accuracy in detecting etiologic agents, particularly Clostridioides difficile, in stool specimen of pediatric patients with diarrhea between the FilmArray GI Panel with various standard laboratory methods performed at the discretion of the physician. They found that “a potential aetiologic agent was identified in 46% of stool specimens by standard laboratory methods and in 65% of specimens tested using the FilmArray GI Panel (P<0.001).” This FilmArray GI Panel was also able to detect concurrent infections by diarrheal pathogens other than C.difficile, including norovirus in 12% of supposed C.difficile-only testing cases. The FilmArray GI Panel also detected a pathogen in 63% of cases without additional C.difficile testing performed, and even detected C.difficile in 8% of those cases. These results proved the FilmArray GI Panel to be critical in detecting other diarrheal pathogens, and co-infections with other infectious diarrheagenic agents (Stockmann et al., 2015).

Similar results for the FilmArray GI Panel were found in another study for acute diarrhea. In conducting a prospective study, Cybulski et al. (2018) found that FilmArray detected pathogens at a higher rate than culture and at a faster time (35.3% in 18 hours versus 6.0% in 47 hours). This rapidity and accuracy also allowed patients to receive targeted therapy and facilitated quicker discontinuation of empirical antimicrobial therapy, demonstrating an improved clinical sensitivity with the FilmArray GI Panel when compared to culture (Cybulski et al., 2018). Beal et al. (2018) investigated the impact of submitting patient stool specimen for testing by the FilmArray GI panel (“cases”) and compared overall findings with control patients from the year prior. The researchers concluded that this panel contributed to reducing the number of days on antibiotics (1.73 days among cases versus 2.12 days among controls), reducing “average length of time from stool culture collection to discharge” (3.4 days among cases vs 3.9 days among controls), and reducing overall health care cost by $293.61. They also found results like the previous studies on the FilmArray GI panel, with increased comprehensiveness of detectable pathogens, and eliminating unnecessary testing and antibiotic use (Beal et al., 2018).

Axelrad et al. (2019) performed a retrospective comparative analysis of patients who underwent testing with the FilmArray GI panel from 2015-2017 and those who solely underwent conventional stool testing from 2012-2015. The FilmArray GI panel detected more pathogens (29.2% positive cases vs 4.1%) and reduced the need for additional endoscopic procedures and abdominal radiology imaging within 30 days following stool testing, as well as reduced chances of antibiotic prescription within 14 days following stool testing. The amassed literature communicates the great clinical utility and extended benefits from a multiplex PCR panel like the FilmArray GI Panel.

Zhan et al. (2020) performed a comparison of the BioFire FilmArray gastrointestinal panel and the Luminex xTAG Gastrointestinal Pathogen Panel for detecting diarrheal pathogens in China in a total of 243 diarrhea specimens. These two panels were highly consistent in detecting norovirus, rotavirus, and Campylobacter, but had low consistency in detecting Cryptosporidium, Salmonella, Shiga-toxin producing Escherichia coli (STEC) and enterotoxigenic Escherichia coli (ETEC). The BioFire FilmArray panel was found to be more sensitive, but the Luminex xTAG Gastrointesinal Pathogen Panel was more specific. There appeared to be additional concern for how the Luminex xTAG Gastrointesinal Pathogen Panel yielded more false negatives when detecting ETEC as well (Zhan et al., 2020).

Jo et al. (2021) evaluated the use of the BioFire FilmArray gastrointestinal panel for pediatric patients with diarrhea. The authors compared the FilmArray GI panel results to conventional PCR for E. Coli and Allplex GI-Bacteria Assay results. 184 stool samples were tested, and it was found that “The BioFire GI Panel demonstrated a sensitivity of 100% for 12 targets and a specificity of >95% for 16 targets.” The authors conclude that the FilmArray GI panel is useful for rapid identification of enteropathogenesis in pediatric patients (Jo et al., 2021).

Truong et al. (2021) investigated pediatric healthcare management before and after BioFire FilmArray gastrointestinal panel results were received. The study included 172 children, 120 of which had positive results. Based on the FilmArray GI panel results, the healthcare management plan changed for 23% of patients, including changes to antibiotic treatments, hospitalizations, room isolations, prescription changes, and test cancelations. The authors conclude that the FilmArray GI panel results impacted healthcare management, especially related to antibiotic treatment (Truong et al., 2021). Yoo at al. (2021) also studied the healthcare management of children with acute diarrhea using the BioFire FilmArray gastrointestinal panel. 182 patients were included in the study. “A significant reduction in antibiotic use was observed in the prospective cohort compared to historical cohort, 35.3% vs. 71.8%; p < 0.001), respectively.” The authors conclude that, likely due to the high positive rate and rapid reporting, the FilmArray GI panel was clinically beneficial for children, especially in reducing antibiotic use and enabling early precaution and isolation (Yoo et al., 2021).

Nijhuis et al. (2017) compared the GenMark Diagnostics ePlex Respiratory Pathogen panel with laboratory-developed real-time PCR assays for detecting respiratory pathogens. The study included 343 clinical specimens. The RP panel found an agreement of 97.4% with the real-time PCR assay regarding 464 pathogens found. The RP panel detected 17 more pathogens than the real-time PCR, showing that this panel could improve the efficiency of diagnostic “sample-to-answer testing” and cost-effectiveness, despite potentially costing more (Nijhuis et al., 2017).

van Asten et al. (2021) evaluated the performance of the GenMark Diagnostics ePlex Respiratory Pathogen panel and the QIAGEN Sciences QIAstat-Dx Respiratory Pathogen panel. The authors specifically studied the detection of three bacterial targets: Legionella pneumophila, Mycoplasma pneumoniae and Bordetella pertussis. The study included 56 specimens taken form the lower respiratory tract, five of which were negative and the other 51 had previously tested positive on real-time PCR assays for the targets. “The QIAstat-Dx Respiratory Panel V2 (RP) assay detected all of the L. pneumophila and B. pertussis positive samples but only 11/15 (73.3 %) of the M. pneumoniae targets. The ePlex Respiratory Pathogen Panel (RPP) assay detected 10/14 (71.4 %) of the L. pneumophila targets, 8/12 (66.7 %) of the B. pertussis positive samples and 13/15 (86.7 %) of the M. pneumoniae targets.” The authors concluded that the clinical performance of both panels depend on the bacterial lode and sample type (van Asten et al., 2021).

Mormeneo Bayo et al. (2022) compared real-time PCR with microscopy in detecting intestinal protozoa in children. The study used the Seegene Allplex Gastrointestinal panel for the real-time PCR. Five hundred stool samples were analyzed from children, 15 years of age and under, and grouped into two classifications based on if the children had or had not had clinical parasitosis. Based on microscopy, 6.2% of samples were positive. Based on real-time PCR, 51.2% of samples were positive. The authors concluded that “real-time PCR increases the detection of intestinal protozoa, being underdiagnosed by microscopy, especially D. fragilis, in which PCR is considered the most appropriate method for its detection” (Mormeneo Bayo et al., 2022).

Trujillo-Gómez et al. (2022) the diagnostic test accuracy of the FilmArray Meningitis/Encephalitis panel. The authors perfmored a systematic review of 19 studies containing a total of 11,251 participants, and performed a random-effects bivariate meta-analysis of diagnostic test accuracy. Using CSF/blood samples, the sensitivity was estimated to be 89.5% and the specificity was estimated to be 97.4%. Using the “final diagnosis adjudication based on clinical/laboratory criteria” the sensitivity was estimated to be 92.1% and the specificity was estimated to be 99.2%. The authors note that the certainty of evidence was low. The authors conclude that the FilmArray Meningitis/Encephalitis panel “may have acceptable-to-high sensitivities and high specificities for identifying bacteria, especially for S.pneumoniae, and viruses, especially for HSV-2, and enteroviruses” but suboptimal sensitivities for L.monocytogenes, H.influenzae, E.coli, and HSV-1 (Trujillo-Gómez et al., 2022).

Yoo et al. (2019) compared the Seegene Allplex Gastrointestinal, Luminex xTAG Gastrointestinal Pathogen Panel, and BD MAX Enteric Assays to determine which was the most efficient in detecting gastrointestinal pathogens from clinical stool samples. A total of 858 stool samples were used in this study. “The overall positive percentage agreements of Seegene, Luminex, and BD MAX were 94% (258 of 275), 92% (254 of 275), and 78% (46 of 59), respectfully. For Salmonella, Luminex showed low negative percentage agreement because of frequent false positives (n = 31) showing low median fluorescent intensity. For viruses, positive/negative percentage agreements of Seegene and Luminex were 99%/96% and 93%/99%, respectively” (Yoo et al., 2019). Overall, the authors suggest that these assays are promising in the detection of gastrointestinal pathogens simultaneously. Mahony et al. (2009) concluded that multiplex PCR-based testing was the most cost-effective strategy for the diagnosis of respiratory virus infections in children and resulted in better patient outcomes (shorter hospital stays) at lower costs (Mahony et al., 2009). Ginocchio et al. (2009) compared the sensitivities, specificities, positive predictive values, and negative predictive values of four different Influenza A diagnostic tests, including rapid antigen, direct immunofluorescence, viral culture, and PCR panel. The authors inferred that the PCR panel test provided the best diagnostic option with the highest sensitivity for the detection of all influenza strains and identified a significant number of additional respiratory pathogens (Ginocchio et al., 2009). Subramony et al. (2016) reported the use of multiplex PCR-based assays for respiratory viruses in hospitalized patients resulted in decreased healthcare resource utilization, including decreased use of antibiotics and chest radiographs (Subramony et al., 2016). Babady et al. (2018) evaluated a new panel of 19 viruses and two bacteria (ePlex Respiratory Panel) with 2908 samples by comparing it to BioFire FilmArray. Overall agreement was >95% for all targets, and positive agreement ranged from 85.1% to 95.1%. Negative agreement ranged from 99.5% to 99.8% (Babady et al., 2018).

The Infectious Diseases Society of America (IDSA) stated that CSF RT-PCR can be one of the methods used for the diagnosis of rabies virus and enteroviral encephalitis (Tunkel et al., 2008). Several studies have evaluated the clinical impact of RT-PCR for the detection of enterovirus in the CSF of patients with aseptic meningitis (Ramers et al., 2000; Robinson et al., 2002; Stellrecht et al., 2002). These studies showed a reduction in unnecessary diagnostic and therapeutic intervention (for example, antibiotic use, ancillary tests, etc.), length of hospital stay, and hospital costs. Tzanakaki et al. (2005) evaluated a multiplex PCR assay for detection of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b, and concluded that the test had high sensitivity (between 88% and 93.9%), an overall specificity and positive predictive value of 100%, and a negative predictive value >99% (Tzanakaki et al., 2005). Leber et al. (2016) evaluated the performance of a commercially available multiplex PCR-based panel for meningitis and encephalitis, and concluded that the test is a sensitive and specific aid in diagnosis of CNS infections and leads to improved patient outcomes (Leber et al., 2016). Another study compared the FilmArray meningitis/encephalitis (ME) panel by BioFire Diagnostics, which uses 0.2 mL of CSF to test for 14 pathogens in one hour (BioFire, 2023c), to traditional culture and PCR assay methods. The FilmArray ME panel “demonstrated an overall percent positive agreement (PPA) of 97.5% (78/80) for bacterial pathogens, 90.1% (145/161) for viruses, and 52% (26/50) for Cryptococcusneoformans/C. gattii. Despite the low overall agreement (52%) between the ME panel and antigen testing for detection of C. neoformans/C. gattii, the percent positive agreement of the FilmArray assay for C. neoformans/C. gattii was 92.3%” (Liesenfeld et al., 2014; Liesman et al., 2018). The ME panel has also been proven to aid in “decreas[ing] the utilization of antibiotic therapy among pediatric patients admitted for concerns related to meningitis or encephalitis” (McDonald et al., 2020). Their research demonstrated that introducing the ME panel helped to reduce the days of therapy (DoT) from 5 days to 3 days and the number of inpatient days. Using the ME panel also decreased the empiric use of intravenous third generation cephalosporins and ampicillin for treatment independent of a respiratory viral pathogen diagnosis. Identifying the specific etiology guided more appropriate antibiotic therapy (McDonald et al., 2020).

The use of multiplex PCR assays to identify pathogens following positive blood culture can be faster than standard techniques involving phenotypic identification and antimicrobial susceptibility testing that is required up to 72 hours after the blood culture became positive (Liesenfeld et al., 2014). A prospective randomized controlled trial evaluating outcomes associated with multiplex PCR detection of bacteria, fungi, and resistance genes directly from positive blood culture bottles concluded that the testing led to more judicious antibiotic use (Banerjee et al., 2015). A study by Ward and colleagues compared the accuracy and speed of organism and resistance gene identification of two commercially available multiplex-PCR sepsis panels to conventional culture-based methods for 173 positive blood cultures. The researchers discovered that both the assays accurately identified organisms and significantly reduced the time to definitive results (on average, between 27.95 and 29.17 hours earlier than conventional method) (Ward et al., 2015). Another study assessed the diagnostic accuracy of a commercially available multiplex PCR-based assay for detecting infections among patients suspected of sepsis. They concluded that the test had high specificity with a modest sensitivity and had higher rule-in value than the rule-out value. If the patient had a positive result, a clinician can confidently diagnose sepsis and begin appropriate antimicrobial therapy while avoiding unwanted additional testing (Chang et al., 2013).

There are a few limitations with this type of testing. First, the level—detection or non-detection—of a microorganism does not necessarily imply a diagnosis. The tests can only describe the levels of microorganisms found in the environment, but additional information is required to make a diagnosis. Second, the scope of the 16S rRNA sequencing used in testing may be limited. Differences in regions more specific than rRNA (such as surface antigens or individual toxin genes) cannot be resolved with this test. For example, the test cannot distinguish between a pathogenic C. difficile strain and a nonpathogenic one. Moreover, the tests report some of their targets at a genus level only, which means that these targets cannot be differentiated at the species level (Almonacid et al., 2017; Watts et al., 2017). Finally, the PCR technique can introduce errors during the amplification leading to incorrect detection. PCR enzymes may accidentally create “artefacts” or otherwise incorrect sequences causing the detection or measurement of the microorganisms to be inaccurate (V. Wintzingerode et al., 1997).

UroSwab is a urine-based proprietary test from Medical Diagnostics LLC. UroSwab is a real-time PCR test intended to detect numerous pathogens potentially involved in sexually transmitted and urological infections. This test uses a patient’s urine, and the turnaround time is estimated at 24-72 hours. The results include whether a pathogen’s presence was normal or abnormal and includes comments on what the pathogen’s presence means (Diagnostics, 2015a, 2015b).

McCarty et al. (2023) tested the performance and clinical utility of the GenMark ePlex Blood Culture Identification Gram-Negative Panel. The authors used “matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry on bacterial isolates” as a reference to compare results. In total, 98.1% (106/108) of the bacteria identified by MALDI were on the GenMark panel, and “valid tests (107/108, 99.1%) yielded results on average 26.7 h earlier” (McCarty et al., 2023).

Guidelines and Recommendations

American College of Gastroenterology (ACG) 

American College of Gastroenterology (ACG) stated that “diarrheal disease by definition has a broad range of potential pathogens particularly well suited for multiplex molecular testing. Several well-designed studies show that molecular testing now surpasses all other approaches for the routine diagnosis of diarrhea. Molecular diagnostic tests can provide a more comprehensive assessment of disease etiology by increasing the diagnostic yield compared with conventional diagnostic tests” (Riddle et al., 2016). Furthermore, the ACG recommended that “traditional methods of diagnosis (bacterial culture, microscopy with and without special stains and immunofluorescence, and antigen testing) fail to reveal the etiology of the majority of cases of acute diarrheal infection. If available, the use of Food and Drug Administration-approved culture independent methods of diagnosis can be recommended at least as an adjunct to traditional methods. (Strong recommendation, low level of evidence)” (Riddle et al., 2016).

The ACG also notes:

• “Diagnostic evaluation using stool culture and culture-independent methods if available should be used in situations where the individual patient is at high risk of spreading disease to others, and during known or suspected outbreaks.” 
• “Stool diagnostic studies may be used if available in cases of dysentery, moderate–severe disease, and symptoms lasting >7 days to clarify the etiology of the patient’s illness and enable specific directed therapy” (Riddle et al., 2016). 

In 2013, the ACG made the following recommendations on diagnostic tests used for Clostridium difficile infections (Surawicz et al., 2013):

• “Only stools from patients with diarrhea should be tested for Clostridium difficile. (Strong recommendation, high-quality evidence)”
• “Nucleic acid amplification tests (NAAT) for C. difficile toxin genes such as PCR are superior to toxins A + B EIA testing as a standard diagnostic test for CDI. (Strong recommendation, moderate-quality evidence)”
• “Glutamate dehydrogenase (GDH) screening tests for C difficile can be used in two- or three-step screening algorithms with subsequent toxin A and B EIA testing, but the sensitivity of such strategies is lower than NAATs. (Strong recommendation, moderatequality evidence)” 
• “Repeat testing should be discouraged. (Strong recommendation, moderate-quality evidence)” 
• “Testing for cure should not be done. (Strong recommendation, moderate-quality evidence)” (Surawicz et al., 2013).

Infectious Diseases Society of America (IDSA)

In 2013, the IDSA stated that “molecular diagnostics that detect microbial DNA directly in blood have achieved a modest level of success, but several limitations still exist. Based on available data, well-designed multiplex PCRs appear to have value as sepsis diagnostics when used in conjunction with conventional culture and routine antibiotic susceptibility testing” (Caliendo et al., 2013).

The IDSA published guidelines for the diagnosis and management of infectious diarrhea which state:

Stool testing should be performed for Salmonella, Shigella, Campylobacter, Yersinia, C. difficile, and STEC in people with diarrhea accompanied by fever, bloody or mucoid stools, severe abdominal cramping or tenderness, or signs of sepsis. However, other bacterial, viral, and parasitic agents should be considered regardless of symptoms. Any specimen testing positive for bacterial pathogens by culture independent diagnostics (such as an antigen based molecular assay) should be cultured in a clinical or public health laboratory if isolation was requested or required. Finally, clinical consideration should occur with interpretation of results of multi-pathogen NAATs as these tests only detect DNA and not necessarily pathogens (Shane et al., 2017).

The IDSA acknowledges the availability of an FDA-approved multiplex PCR targeting 14 organisms for diagnosing encephalitis and meningitis, but the society states it “should not be considered a replacement for culture.” The IDSA also notes that for gram-negative or gram-positive bacteria, bacterial culture is noted as the main diagnostic procedure (albeit at low sensitivity and optional). Regarding UTI, the IDSA only recommends nucleic acid testing for adenovirus and BK polyoma virus (Miller et al., 2018).

Regarding “wounds” (termed skin and soft tissue infections in the IDSA guideline), the IDSA typically recommends culture for most pathogens. Only a few strains of bacteria and viruses (such as Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus spp, MRSA, and streptococci) were recommended for nucleic acid testing with the majority of bacterial and fungal pathogens recommended for culture instead (Miller et al., 2018).

The IDSA recommends RT-PCR or other molecular tests over other influenza tests in hospitalized patients. RT-PCR tests targeting a panel of respiratory pathogens are recommended in hospitalized, immunocompromised patients (Uyeki et al., 2018).

Global Wound Biofilm Expert Panel Consensus Guidelines

A Global Wound Biofilm Expert Panel have strongly agreed that “there are currently no routine diagnostic tests available to confirm biofilm presence” and that “the most important measure for future diagnostic tests to consider is indication of where the biofilm is located within the wound” (Schultz et al., 2017). 

Society of Critical Care Medicine and the European Society of Intensive Care Medicine (SCCM)

A collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine issued international guidelines for management of sepsis and septic shock. It states “in the near future, molecular diagnostic methods may offer the potential to diagnose infections more quickly and more accurately than current techniques. However, varying technologies have been described, clinical experience remains limited, and additional validation is needed before recommending these methods as an adjunct to or replacement for standard blood culture techniques” (Rhodes et al., 2017).

A 2020 update regarding “Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children” was published by the Society of Critical Care Medicine (SCCM), European Society of Intensive Care Medicine (ESICM), and the International Sepsis Forum. In it, they acknowledge the presence of new molecular technologies, but remark that they are “currently relatively expensive, are not sufficient for all pathogens and antibiotic sensitivities, and are not universally available” (Weiss et al., 2020).

National Institute for Health and Care Excellence

The NICE states there is “insufficient evidence to recommend the routine adoption in the NHS of the integrated multiplex polymerase chain reaction tests, xTAG Gastrointestinal Pathogen Panel, FilmArray GI Panel and Faecal Pathogens B assay, for identifying gastrointestinal pathogens in people with suspected gastroenteritis.” NICE acknowledges that the tests show promise but need further data on their clinical utility (NICE, 2017) 

American Society for Microbiology/Association for Molecular Pathology/Association of Public Health Laboratories/College of American Pathologists/Infectious Diseases Society of America/Pan American Society for Clinical Virology

These societies made a joint statement regarding respiratory viral panels and noted three populations in which multiplex panels would be beneficial. Those populations were “immunocompromised hosts, adult patients appearing acutely ill who are potential hospital admissions, and critically-ill adult patients, particularly ICU patients” (American Society for Microbiology, 2017).

American College of Chest Physicians (CHEST)

The CHEST has recommended that outpatient adults with an acute cough and suspected pneumonia should not undergo routine microbiological testing because there is no need for such testing. However, testing may be considered if the results would change the therapeutic approach. Microbiological tests may include culture, serologic, and PCR testing (Hill et al., 2019).

Centers for Disease Control and Prevention

Regarding molecular tests that are commonly used for a C. difficile diagnosis, the CDC states that “FDA-approved PCR assays, which test for the gene encoding toxin, are same-day tests that are highly sensitive and specific for the presence of a toxin-producing C. diff organism. Molecular assays can be positive for C. diff in individuals who are asymptomatic. When using multi-pathogen (multiplex) molecular methods, the results should be read with caution as the pre-test probability of C. diff infection might be less” (CDC, 2022a).

Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

The IDSA and SHEA have stated that the best-performing method for detecting patients with a greater risk of a C. difficile infection from a stool sample is to “Use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by nucleic acid amplification test [NAAT]; or NAAT plus toxin) rather than a NAAT alone for all specimens received in the clinical laboratory when there are no preagreed institutional criteria for patient stool submission (Figure 2) (weak recommendation, low quality of evidence)” (McDonald et al., 2018). These guidelines also state that repeat testing (within 7 days) should not be performed. Panel testing is not specifically mentioned in these guidelines (McDonald et al., 2018).

The European Association of Urology (EAU)

The EAU published urological infections guidelines. For uncomplicated UTIs (recurrent UTIs, cystitis, pyelonephritis), the EAU does not mention molecular testing at any point of the treatment algorithm; instead, they recommend bacterial culture or dipstick testing for diagnosis and recommending against extensive workup. The EAU notes that antimicrobial susceptibility testing should be performed in all cases of pyelonephritis, but their guidelines do not suggest any methods over another. In complicated UTIs, the EAU recommends urine culture to identify cases of clinically significant bacteriuria (Bonkat et al., 2023).

American Society of Transplantation Infectious Diseases Community of Practice

These guidelines focus on identifying infections in transplant patients. Their recommendations are as follows:

“For the diagnosis of SOT [solid organ transplant] recipients with suspected gastrointestinal infections”, gastrointestinal multiplex molecular assays are recommended to identify Cryptosporidium, Cyclospora, and Giardia (La Hoz & Morris, 2019).

American Society for Clinical Pathology (ASCP, through ChoosingWisely)

The ASCP states “Do not routinely order broad respiratory pathogen panels unless the result will affect patient management.” They further state that patient management may include “provid [ing] immediate diagnosis and potentially expedite management decisions” and list “rapid molecular or point of care tests for RSV, Influenza A/B, or Group A pharyngitis” as examples (ASCP, 2019).

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

All the below descriptions are taken from the FDA website.

Respiratory Pathogen Panels

On January 10, 2011, the FDA approved the Verigene® Respiratory Virus Plus Nucleic Acid Test (RV+) on the Verigene® System as a qualitative nucleic acid multiplex test intended to simultaneously detect and identify multiple respiratory virus nucleic acids in nasopharyngeal (NP) swab specimens from individuals with signs and symptoms of respiratory tract infection.

On February 17, 2012, the FDA approved the xTAG® Respiratory Viral Panel (RVP) as a qualitative nucleic acid multiplex test intended for the simultaneous detection and identification of multiple respiratory virus nucleic acids in nasopharyngeal swabs from individuals suspected of respiratory tract infections.

On September 10, 2012, the eSensor Respiratory Viral Panel (RVP) was approved as a qualitative nucleic acid multiplex in vitro diagnostic test intended for use on the eSensor XT-8 system for the simultaneous detection and identification of multiple respiratory viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals exhibiting signs and symptoms of respiratory infection.

On December 17, 2015, the FDA approved NxTAG® Respiratory Pathogen Panel as a qualitative test intended for use on the Luminex® MAGPIX® Instrument for the simultaneous detection and identification of nucleic acids from multiple respiratory viruses and bacteria extracted from nasopharyngeal swabs collected from individuals with clinical signs and symptoms of a respiratory tract infection.

On May 30, 2017, the FDA approved the FilmArray® Respiratory Panel 2 (RP2), a multiplexed nucleic acid test intended for use with FilmArray® 2.0 or FilmArray® Torch systems for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals suspected of respiratory tract infections.

On June 9, 2017, the FDA approved the EPlex Respiratory Pathogen Panel as a multiplexed nucleic acid in vitro diagnostic test intended for use on the ePlex® Instrument for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals exhibiting signs and symptoms of respiratory tract infection.

On August 30, 2017, the FDA approved the Idylla Respiratory (IFV-RSV) Panel, which is an in vitro assay intended for the qualitative detection of nucleic acids for Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza A subtype 2009 H1, H275Y mutation of Influenza A subtype 2009 H1, Influenza B and Respiratory Syncytial Virus (A and B) from nasopharyngeal swabs in viral transport media of adult and pediatric patients. The test uses the Idylla system to aid in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings.

On March 30, 2020, under emergency use authorization, the FDA approved the QIAstat-Dx Respiratory SARS-CoV-2 Panel as a multiplexed nucleic acid real-time PCR test intended for the qualitative detection and differentiation of nucleic acid from multiple respiratory viral and bacterial organisms, including the SARS-CoV-2 virus, in nasopharyngeal swabs (NPS) eluted in universal transport media collected from patients suspected of COVID-19 by their healthcare provider.

On October 8, 2020, under emergency use authorization, the FDA approved the EPlex Respiratory Pathogen Panel 2 as a multiplexed nucleic acid in vitro diagnostic test t intended for use on the ePlex Instrument for the simultaneous qualitative detection and differentiation of nucleic acids from multiple respiratory viral and bacterial organisms, including nucleic acid from Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), in nasopharyngeal swabs (NPS) eluted in viral transport media obtained from individuals suspected of respiratory viral infection consistent with COVID-19 by their healthcare provider.

On March 17, 2021, under emergency use authorization, approved the FilmArray® Respiratory Panel 2.1 (RP2.1), which is a multiplexed nucleic acid test intended for the simultaneous qualitative detection and differentiation of nucleic acids from multiple viral and bacterial respiratory organisms, including nucleic acid from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in nasopharyngeal swabs (NPS) obtained from individuals suspected of COVID-19 by their healthcare provider.

Blood Culture Pathogen Panels

On January 30, 2015, the FDA approved FilmArray Blood Culture Identification (BCID) Panel for use with the FilmArray 2.0.

On March 25, 2016, the FDA approved the Great Basin Staph ID/R Blood Culture Panel is a qualitative, multiplex, nucleic acid-based in vitro diagnostic assay intended for the simultaneous identification of nucleic acid from Staphylococcus aureus, Staphylococcus lugdunensis and various Staphylococcus species to the genus level and the detection of the mecA gene for methicillin resistance directly from patient positive blood culture specimens.

On June 22, 2017, the FDA approved FilmArray NGDS Warrior Panel.

Meningitis Pathogen Panels

On October 8, 2015, the FDA approved the FilmArray Meningitis/Encephalitis (ME) Panel as a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with FilmArray and FilmArray 2.0 systems. The FilmArray ME Panel is capable of simultaneous detection and identification of multiple bacterial, viral, and yeast nucleic acids directly from cerebrospinal fluid (CSF) specimens obtained via lumbar puncture from individuals with signs and/or symptoms of meningitis and/or encephalitis.

Gastrointestinal Pathogen Panels 

On January 16, 2013, the FDA approved the Prodesse® ProGastro SSCS Assay as a multiplex real time PCR in vitro diagnostic test for the qualitative detection and differentiation of Salmonella, Shigella, and Campylobacter (C. jejuni and C. coli only, undifferentiated) nucleic acids and Shiga Toxin 1 (stx1) and Shiga Toxin 2 (stx2) genes. Shiga toxin producing E. coli (STEC) typically harbor one or both genes that encode for Shiga Toxins 1 and 2. Nucleic acids are isolated and purified from preserved stool specimens obtained from symptomatic patients exhibiting signs and symptoms of gastroenteritis.

On March 21, 2013, the FDA approved the xTAG® Gastrointestinal Pathogen Panel (GPP) as a multiplexed nucleic acid test intended for the simultaneous qualitative detection and identification of multiple viral, parasitic, and bacterial nucleic acids in human stool specimens from individuals with signs and symptoms of infectious colitis or gastroenteritis.

On May 2, 2014, the FDA approved the FilmArray Gastrointestinal (GI) Panel as a qualitative multiplexed nucleic acid-based in vitro diagnostic test intended for use with the FilmArray Instrument. The FilmArray GI Panel is capable of the simultaneous detection and identification of nucleic acids from multiple bacteria, viruses, and parasites directly from stool samples in Cary Blair transport media obtained from individuals with signs and/or symptoms of gastrointestinal infection.

On June 20, 2014, the FDA approved the Verigene Enteric Pathogens Nucleic Acid Test (EP) as a multiplexed, qualitative test for simultaneous detection and identification of common pathogenic enteric bacteria and genetic virulence markers from liquid or soft stool preserved in Cary-Blair media, collected from individuals with signs and symptoms of gastrointestinal infection.

On September 16, 2014, the FDA approved the e xTAG® Gastrointestinal Pathogen Panel (GPP) as a multiplexed nucleic acid test intended for the simultaneous qualitative detection and identification of multiple viral, bacterial, and parasitic nucleic acids in human stool specimens or human stool in Cary Blair media from individuals with signs and symptoms of infectious colitis or gastroenteritis.

On May 2, 2017, the FDA approved the BD MAX Extended Enteric Bacterial Panel performed on the BD MAX System, as an automated in vitro diagnostic test for the direct qualitative detection and differentiation of enteric bacterial pathogens.

On July 12, 2017, the FDA approved the Great Basin Stool Bacterial Pathogens Panel is a multiplexed, qualitative test for the detection and identification of DNA targets of enteric bacterial pathogens. The Stool Bacterial Pathogens Panel is performed directly from Cary Blair or C&S Medium preserved stool specimens from symptomatic patients with suspected acute gastroenteritis, enteritis, or colitis and is performed on the Portrait™ Analyzer.

On November 29, 2018, the FDA approved the BD Max Enteric Viral Panel for use as an in vitro diagnostic test to detect and differentiate enteric viral pathogens, including Norovirus, Rotavirus, Adenovirus, Sapovirus, and human Astrovirus.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 87154, 87483, 87505, 87506, 87507, 87631, 87632, 87633, 87636, 87637, 0068U, 0086U, 0109U, 0112U, 0115U, 0140U, 0141U, 0142U, 0152U, 0240U, 0241U, 0321U, 0323U, 0369U, 0370U, 0371U, 0373U, 0374U, 0416U, 0441U, 0442U.

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.  

Scientific Background and Reference Sources

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Specialty Matched Consultant Advisory Panel review 3/2020

Medical Director review 3/2020

Specialty Matched Consultant Advisory Panel review 3/2021

Medical Director review 3/2021

Medical Director review 7/2022 

Medical Director review 7/2023

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for Multiplex PCR-based panel testing when it is considered to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019.

4/16/2019 Removed item B that concerns “travel-related diarrhea” from the When Covered section and added second paragraph stating that genetic panel sequencing testing methods such as SmartGut™ and SmartJane™, to identify microbes is investigational to the When Not Covered sectiUpdated policy guidelines and references. Medical Director review 4/2019. (jd)

10/1/2019 Reviewed by Avalon 2nd Quarter 2019 CAB. Related Policies added to Description section. Revised the indications under the When Not Covered section to include the nature of the sample as well as UroSwab®. The following codes were added to the Billing/Coding section: 0068U, 0086U, 0097U, 0098U, 0099U, 0100U, and code table removed. References updated. Medical Director review 8/2019. (jd)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (gm)

2/11/20 Annual review by Avalon 4th Quarter 2019 CAB. Added items 2 and 3 to the When Not Covered section. Billing/Coding section: added the following codes 0107U, 0112U, 0140U, 0141U, 0142U, 0151U, 0152U. Medical Director review 12/2019. (jd)

3/31/20 Specialty Matched Consultant Advisory Panel review 3/2020. Medical Director review 3/2020. (jd)

5/12/20 Reviewed by Avalon 1st Quarter 2020 CAB. Related Policies section updated, added Diagnosis Of Vaginitis Including Multi-Target PCR Testing AHS – M2057 and Onychomycosis Testing AHS – M2172. Revised the When Covered section as follows: item #1: revised reimbursement statement and added “(GIP) up to 5 pathogens”, along with “*(See Note 1)”; item #2: added “In the outpatient setting before the reimbursement statement, along with “gastrointestinal”, “up to 11 pathogens”, “immunosuppressed or HIV positive patients AND any of the following situations *(See Note 1)” along with corresponding criteria noted in items a. and b. Revised item #3 to allow for “up to 5” respiratory pathogens”, added “Note 1”. Revised the When Not Covered section as follows: added items 1-4. Policy guidelines and references updated. Removed codes 87150, 87486, 87496, 87498, 87529, 87532, 87581, 87634, 87653, 87798 and 0107U. Added CPT codes 87631 and 87632. Medical Director reviewed 4/2020. (jd)

7/28/20 Reviewed by Avalon 2nd Quarter 2020 CAB. Note added to the policy statement as follows: “The coverage criteria outlined in this policy are not applicable to diagnostic COVID-19 testing.” Policy guidelines and references updated. The following codes were added to the Billing/Coding section: 87631, 87632. Medical Director review 7/2020. (jd)

3/31/21 Specialty Matched Consultant Advisory Panel review 3/2021. Medical Director review 3/2021. (jd)

5/4/21 Off-cycle review by Avalon 1st Quarter 2021 CAB. The following codes were deleted from the Billing/Coding section: 0098U, 0099U, 0100U. Medical Director review 4/2021. (jd) 

8/24/21 Reviewed by Avalon 2nd Quarter 2021 CAB. Background, policy guidelines and references updated. Medical Director review 7/2021. (jd)

12/30/21 The following codes were added to the Billing/Coding section: 87154, 87636, 87637 effective 1/1/22. (jd)

5/17/22 Off-cycle code review by Avalon 1st Quarter 2022 CAB. The following codes were deleted from the Billing/Coding section: 0097U and 0151U and code 0321U was added to this section. (jd)

7/1/22 The following PLA codes were added to the Billing/Coding section: 0323U, 0330U. (jd)

9/13/22 Reviewed by Avalon 2nd Quarter 2022 CAB. Background, policy guidelines and references updated. Updated Billing/Coding section. No changes to policy statement. Medical Director review 7/2022. (tm)

3/31/23 Updated Billing/Coding section to add codes 0369U, 0370U, 0371U, 0373U, and 0374U effective 4/1/2023. (tm)

8/15/23 Reviewed by Avalon 2nd Quarter 2023 CAB. Background, Policy Guidelines and References updated. When Covered and Not Covered sections edited for clarity, no changes to policy statement. Removed previous Note 1. Removed PLA code 0330U from Billing/Coding section. Medical Director review 7/2023. (tm)

9/29/23 Updated Billing/Coding section to add code 0416U, effective 10/1/2023. (tm)

4/17/24 Codes 0441U and 0442U added to Billing/Coding section, effective 4/1/24. (tm)