Identification of Microorganisms Using Nucleic Acid Probes

POLICY NUMBER

A.2.04.10

DESCRIPTION

Nucleic acid probes are available for the identification of a wide variety of microorganisms. Nucleic acid probes can also be used to quantitate the number of microorganisms present. This technology offers advantages over standard techniques when rapid identification is clinically important, microbial identification using standard culture is difficult or impossible, and/or treatment decisions are based on quantitative results.

Nucleic Acid Probes

A nucleic acid probe is used to detect and identify species or subspecies of organisms by identifying nucleic acid sequences in a sample. Nucleic acid probes detect genetic materials, such as RNA or DNA, unlike other tests, which use antigens or antibodies to diagnose organisms.

The availability of nucleic acid probes has permitted the rapid direct identification of microorganism DNA or RNA. Amplification techniques result in exponential increases in copy numbers of a targeted strand of microorganism-specific DNA. The most used amplification technique is polymerase chain reaction (PCR) or reverse transcriptase PCR. In addition to PCR, other nucleic acid amplification techniques have been developed, such as transcription-mediated amplification, loop-mediated isothermal DNA amplification, strand displacement amplification, nucleic acid sequence-based amplification, and branched-chain DNA signal amplification. After amplification, target DNA can be readily detected using a variety of techniques. The amplified product can also be quantified to assess how many microorganisms are present. Quantification of the number of nucleic acids permits serial assessments of response to treatment; the most common clinical application of quantification is the serial measurement of human immunodeficiency virus RNA (called viral load).

The direct probe technique, amplified probe technique, and probe with quantification methods vary based on the degree to which the nucleic acid is amplified and the method for measurement of the signal. The direct probe technique refers to detection methods in which nucleic acids are detected without an initial amplification step. The amplified probe technique refers to detection methods in which either target, probe, or signal amplification is used to improve the sensitivity of the assay over direct probe techniques, without quantification of nucleic acid amounts.

• Target amplification methods include PCR (including PCR using specific probes, nested or multiplex PCR), nucleic acid-based sequence amplification, transcription-mediated amplification, and strand displacement amplification. Nucleic acid-based sequence amplification and transcription-mediated amplification involve amplification of an RNA (rather than a DNA) target.

• Probe amplification methods include ligase chain reaction.

• Signal amplification methods include branched DNA (bDNA) probes and hybrid capture methods using an anti-DNA/RNA hybrid antibody.

The probe with quantification techniques refers to quantitative PCR or real-time PCR methods that use a reporter at each stage of the PCR to generate absolute or relative amounts of a known nucleic acid sequence in the original sample. These methods may use DNA-specific dyes (ethidium bromide or SYBR green), hybridization probes (cleavage-based [TaqMan] or displaceable), or primer incorporated probes.

Direct assays will generally have lower sensitivity than amplified probes. In practice, most commercially available probes are amplified, with a few exceptions. For this policy, indications for direct and/or amplified probes without quantification are considered together, while indications for a probe with quantification are considered separately.

Classically, identification of microorganisms relies either on the culture of body fluids or tissues or identification of antigens, using a variety of techniques including direct fluorescent antibody technique and qualitative or quantitative immunoassays. These techniques are problematic when the microorganism exists in very small numbers or is technically difficult to culture. Indirect identification of microorganisms by immunoassays for specific antibodies reactive with the microorganism is limited by difficulties in distinguishing between past exposure and current infection.

Potential reasons for a nucleic acid probe to be associated with improved clinical outcomes compared with standard detection techniques include the following (note: In all cases, for there to be clinical utility, making a diagnosis should be associated with changes in clinical management, which could include initiation of effective treatment, discontinuation of other therapies, or avoidance of invasive testing.):

• Significantly improved speed and/or efficiency in making a diagnosis.

• Improved likelihood of obtaining any diagnosis in cases where standard culture is difficult. Potential reasons for difficulty in obtaining standard culture include low numbers of the organisms (eg, HIV), fastidious or lengthy culture requirements (eg, Mycobacteria, Chlamydia, Neisseria species), or difficulty in collecting an appropriate sample (eg, herpes simplex encephalitis).

• There is no way to definitively make a diagnosis without nucleic acid testing.

• The use of nucleic acid probe testing provides qualitatively different information than that available from standard cultures, such as information regarding disease prognosis or response to treatment. These include cases where quantification of viral load provides prognostic information or is used to measure response to therapy.

The risks of nucleic acid testing include false-positive and false-negative results; inaccurate identification of pathogens by the device, inaccurate interpretation of test results, or incorrect operation of the instrument.

• False-positive results can lead to unnecessary treatment, with its associated toxicities and side effects, including allergic reaction. In addition, true diagnosis and treatment could be delayed or missed altogether.

• False-negative results could delay diagnosis and initiation of proper treatment.

• It is possible that these risks can be mitigated by the use of a panel of selected pathogens indicated by the clinical differential diagnosis while definitive culture results are pending.

The U.S. Food and Drug Administration maintains a list of nucleic acid amplification tests (NAATs) that have been cleared by the Center for Devices and Radiological Health. These NAATs have been cleared for many of the microorganisms discussed in this policy and may be reviewed on this site.

The table below summarizes the NAATs cleared for central nervous system panels when diagnosing meningitis and/or encephalitis, for panels when diagnosing gastroenteritis, and for respiratory panels.

FDA Cleared NAATs for CNS, GI, and Respiratory Panels

CNS: central nervous system; DEN: de novo; FDA: Food and Drug Administration; NAAT: nucleic acid amplification tests.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing.

Related Medical Policy -

• Multitarget Polymerase Chain Reaction Testing for Diagnosis of Bacterial Vaginosis

• Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease

• Pathogen Panel Testing

POLICY

Respiratory virus panel testing should not be performed on individuals with signs and symptoms compatible with COVID-19. Refer to the following COVID-19 testing policies:

• Coronavirus Disease 2019 (COVID-19) Reverse Transcription-Polymerase Chain Reaction (RT-PCR) Testing

• Antigen Testing for Rapid Detection of Coronavirus Disease 2019 (COVID-19)

Theuse of nucleic acid testing usinga director amplified probe technique (without quantificationof viral load) may be considered medically necessary for the following microorganisms (See Policy Guidelines):

• Bartonella henselae or quintana

• Bordetella pertussis

• Candida species

• Chlamydia pneumoniae

• Chlamydia trachomatis

• Clostridium difficile

• Enterococcus, vancomycin-resistant (eg, enterococcus vanA, vanB)

• Enterovirus

• Herpes simplex virus

• Human papillomavirus

• Influenza virus

• Legionella pneumophila

• Mumps

• Mycobacterium species

• Mycobacterium tuberculosis

• Mycobacterium avium-intracellulare

• Mycoplasma genitalium (MG)

• Mycoplasma pneumoniae

• Neisseria gonorrhoeae

• Rubeola (measles)

• Staphylococcus aureus

• Staphylococcus aureus, methicillin-resistant

• Streptococcus, group A

• Streptococcus, group B

• Trichomonas vaginalis

• Zika virus.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) may be considered medically necessary for the following microorganisms:

• Cytomegalovirus

• Hepatitis B virus

• Hepatitis C virus

• HIV-1

• HIV-2

• Human herpesvirus 6.

The use of nucleic acid testing with quantification of viral load is considered investigational for microorganisms that are not included in the list of microorganisms for which probes with or without quantification are considered medically necessary.

The use of nucleic acid testing using a direct or amplified probe technique is considered investigational for the following microorganisms:

• Gardnerella vaginalis

• Hepatitis G.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The use of molecular diagnostics for the diagnosis and management of Borrelia burgdorferi infection (Lyme disease) is addressed in the Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease medical policy.

The term “panel” refers to all respiratory pathogens tested in the outpatient setting on a single date of service from a single biologic specimen, not ordered as a reflex test. A respiratory pathogen panel test is a single service with a single unit of service. A respiratory pathogen panel test must not be unbundled and billed as individual components regardless of the fact that the panel reports multiple individual pathogens and/or targets.

The use of pathogen panel testing is addressed in the Pathogen Panel Testing medical policy.

Vaccine-preventable diseases surveillance for outbreaks and diagnosis of isolated cases: the Centers for Disease Control and Prevention (CDC) Pertussis and Diphtheria Laboratory has developed its own PCR and serological assays to diagnose pertussis, mumps, and rubeola (measles) and has recommendations for their appropriate use.

For bacterial vaginosis, this policy addresses the use of single organism direct or amplified nucleic acid probes with or without quantification. The Multitarget Polymerase Chain Reaction Testing for Diagnosis of Bacterial Vaginosis medical policy addresses the use of multitarget PCR tests for bacterial vaginosis.

For Candida species, culture for yeast remains the criterion standard for identifying and differentiating these organisms. Although sensitivity and specificity are higher for nucleic acid amplification tests (NAATs) than for standard testing methods, the CDC and other association guidelines do not recommend NAATs as first-line testing for Candida species. The CDC classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent; or mild to moderate; or in nonimmunocompromised individuals, as likely to be caused by C. albicans. A presumptive diagnosis can be made in the clinical care setting. However, for complicated infections, the CDC states that NAATs may be necessary to test for multiple Candida subspecies. Complicated vulvovaginal candidiasis is classified as being recurrent or severe; or in individuals with uncontrolled diabetes, debilitation, or immunosuppression as less likely to be caused by C. albicans species.

Antibiotic sensitivity of streptococcus A culture is generally not performed for throat cultures. However, if an antibiotic sensitivity is considered, then the most efficient method of diagnosis would be a combined culture and antibiotic sensitivity.

In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared with traditional culture techniques is the rapidity of results. This advantage suggests that the most appropriate use of the DNA probe technique is in the setting of impending labor, for which prompt results could permit the initiation of intrapartum antibiotic therapy.

It should be noted that the technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both quantification with either amplification or direct probes is not warranted.

Many probes have been combined into panels of tests. For the purposes of this policy, other than the gastrointestinal pathogen panel, central nervous system panel, and the respiratory pathogen panel, only individual probes are reviewed.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

10/26/2006: Policy added 

1/2/2007: Code reference section updated per the 2007 CPT/HCPCS revisions. Added CPT 87797 and 87798 to covered table. Added CPT 87799 to non-covered table with see policy note.

5/14/2007: Policy reviewed; updated to include enterovirus, staphylococcus aureus, and MRSA. CPT codes 87640-87641 added to covered table. CPT code 87948 added to non-covered table. Added ICD-9 codes 041.01, 041.02, 041.11, and V09.0 to covered table.

9/7/2007: Code reference section updated per annual ICD-9 code updates.

6/25/2008: Vancomycin resistance (eg., enterococcus vanA, vanB) amplified probe added as medically necessary. CPT 87500 added to covered

8/26/2008: Code reference section reviewed. CPT codes 87797, 87798, and 87799 removed

9/10/2008: Annual ICD-9 updates applied

03/11/2010: Code reference section updated. New CPT code 87493 added to non-covered table.

12/13/2011: Policy description updated. Medically necessary indications added for clostridium difficile, influenza virus, and trichomoniasis vaginalis.  Moved 87493 from the Non-Covered Codes table to the Covered Codes table. Added CPT codes 87501, 87502,  87503, and 87660 and ICD-9 codes 008.45, 131.00 - 131.09, and 487.0 - 488.19 to the Covered Codes table.

01/09/2013: Added coverage guidelines for respiratory syncytial virus (RSV). Added ICD-9 code 079.6 and CPT codes 87631, 87632, and 87632 to the Code Reference section.

01/21/2014: Policy statement revised to change Candida species amplified probe from investigational to medically necessary. Added medically necessary indication for Trichomonas vaginalis amplified probe. Moved CPT code 87481 from non-covered to covered. Added the following new 2014 CPT code(s) to the Code Reference section: 87761.

12/31/2014: Policy description updated to add information regarding amplification techniques. Enterovirus, and Mycoplasma pneumoniae. Policy statement updated to add investigational indications for Gastrointestinal Pathogen Panel amplified probe, Mycobacterium tuberculosis quantification, and Mycoplasma pneumoniae direct probe, amplified probe, and quantification. Added medically necessary indications for Mycobacterium tuberculosis direct probe and amplified probe. Policy guidelines updated regarding quantification and probe techniques. Made the following correction in the Code Reference section: changed "87761" to "87661." Code Reference section updated to revise the description of the following CPT codes: 87504, 87502, 87503, 87631, 87632, and 87633. Added the following new 2015 CPT codes: 87623, 87624, 87625, 87806, 87505, 87506, and 87507.

08/31/2015: Medical policy revised to add ICD-10 codes.

12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to revise code descriptions for the following CPT codes: 87502 and 87503.

02/15/2016: Policy description updated regarding probe methods and microorganisms. Removed information regarding Borrelia burgdorferi from policy. Policy section revised to remove probe techniques table and group direct and amplified probe techniques (without quantification) into medically necessary policy statements. Enterovirus, Legionella pneumophila, Mycoplasma pneumoniae, and Bartonella added as medically necessary for nonquantified nucleic acid-based testing. Human herpesvirus 6 added as medically necessary for quantified testing. Policy guidelines updated regarding antibiotic sensitivity of streptococcus A cultures and testing for infections. The following CPT codes moved from the Investigational Codes table to the Covered Codes table: 87470, 87471, 87498, 87511, 87531, 87532, 87533, 87540, 87541, 87551, 87561, and 87651. Added CPT codes 87580 and 87581 to the Covered Codes table and CPT code 87582 to the Investigational Codes table. Removed deleted CPT codes 87620, 87621, and 87622 from the Code Reference section.

06/06/2016: Policy number A.2.04.10 added.

08/12/2016: Medically necessary policy statement regarding probes without quantification of viral load updated to add Clostridium difficile. Added investigational statement for probes with quantification of viral load that do not meet criteria for quantification.

12/31/2016: Code Reference section updated to add new 2017 CPT code 87483. Removed CPT codes 87475, 87476, and 87477.

09/29/2017: Code Reference section updated to add new ICD-10 diagnosis codes A04.71 and A04.72, effective 10/01/2017.

12/21/2017: Code Reference section updated to add new 2018 CPT code 0500T.

01/15/2018: Policy description revised and updated regarding diagnostic tests. Policy statement regarding the use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load was updated to add "central nervous system pathogen panel" as investigational. Policy Guidelines updated.

01/14/2019: Policy description updated. Policy statements unchanged. Code Reference section updated to remove deleted CPT codes 87470 and 87515 and ICD-10 diagnosis codes A04.7 and Z36.

07/01/2019: Code Reference section updated to add new CPT code 0096U.

03/24/2020: Policy statement updated to add that respiratory virus panel testing should not be performed on individuals with signs and symptoms compatible with COVID-19. Added link to the Coronavirus Disease 2019 (COVID-19) Testing Medical Policy.

10/13/2020: Code Reference section updated to revise the code description for CPT code 87806, effective 10/06/2020.

12/16/2020: Code Reference section updated to add new CPT codes 81513 and 81514, effective 01/01/2021.

12/17/2021: Code Reference section updated to add new CPT codes 0301U and 0302U, effective 01/01/2022.

03/18/2022: Policy description extensively revised. First medically necessary statement regarding nucleic acid testing without quantification of viral load updated to add the following: bordetella pertussis, chlamydia pneumoniae, influenza virus, mumps, rubeola (measles), and zika virus. Medically necessary policy statement regarding nucleic acid testing with or without quantification of viral load updated to remove influenza virus from the list of microorganisms. Gardnerella vaginalis changed from medically necessary to investigational. Chlamydia pneumonia changed from investigational to medically necessary. Added separate medically necessary statement for respiratory virus panel testing. Policy Guidelines updated regarding respiratory pathogen panel tests, vaccine preventable diseases, and candida species. Moved 81513, 81514, 87510, 87511, 87632, and 87633 from the Medically Necessary Codes table to the Investigational Codes table. Moved 87485 and 87486 from the Investigational Codes table to the Medically Necessary Codes table. Added 87662 as medically necessary and 0115U, 0202U, 0223U, and 0025U as investigational codes. Added the following ICD-10 diagnosis codes: A37.00 - A37.01, A92.5, B26.0 - B26.9, B05.0 - B05.9, and J16.0.

07/13/2022: Revised investigational policy statement to remove "using a direct or amplified probe technique" and state: "The use of the following nucleic acid testing panels (with or without quantification of viral load for viral panel elements) is considered investigational." Policy Guidelines updated regarding policies for Lyme disease and bacterial vaginosis.

10/10/2022: Policy reviewed; no changes.

03/30/2023: Code Reference section updated to add new CPT codes 0369U, 0370U, 0371U, 0372U, 0373U, and 0374U as investigational, effective 04/01/2023.

07/31/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "respiratory virus panel" to "respiratory pathogen panel."

09/27/2023: Code Reference section updated to add new CPT codes 0402U and 0416U, effective 10/01/2023.

12/21/2023: Code Reference section updated to add new 2024 CPT code 0429U, effective 01/01/2024.

02/15/2024: Policy description updated to add link to the Pathogen Panel Testing medical policy. Policy section updated to remove statements regarding the use of respiratory pathogen panel nucleic acid testing, multiplex PCR respiratory panels, and nucleic acid testing panels (with or without quantification of viral load for viral panel elements). Policy Guidelines updated to state that the use of pathogen panel testing is addressed in the Pathogen Panel Testing medical policy. Code Reference section updated to remove CPT codes 87631, 0115U, 0202U, 0223U, 0225U, 0369U, 0370U, 0371U, 0372U, 0373U, 0374U, 87483, 87505, 87506, 87507, 87632, and 87633 as they are addressed in the Pathogen Panel Testing medical policy.

03/28/2024: Code Reference section updated to make note of deleted HCPCS code 0416U.

08/28/2024: Policy description updated regarding FDA cleared nucleic acid amplification tests for gastroenteritis pathogen panels and respiratory viral panels. Policy statement regarding nucleic acid testing without quantification of viral load updated to add mycoplasma genitalium as a medically necessary indication. Code Reference section updated to add CPT code 87563 to the Covered Codes table.

12/19/2024: Code Reference section updated to add new CPT codes 87564 and 87626. Revised code description for CPT code 87624. Effective 01/01/2025.

03/27/2025: Policy reviewed; no changes.

04/01/2025: Code Reference section updated to add new HCPCS code G0567, effective 04/01/2025. Removed deleted CPT code 0416U.

08/20/2025: Policy description updated regarding nucleic acid amplification tests. Policy statements unchanged.

01/01/2026: Code Reference section updated to add new CPT code 87494.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 2.04.10 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes 

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.