Description 
Nucleic acid hybridization technologies utilize complementary properties of the DNA double-helix structures to anneal together DNA fragments from different sources. These techniques are utilized in polymerase chain reaction (PCR) and fluorescent resonance energy transfer (FRET) techniques to identify microorganisms (Khan, 2014).    

Regulatory Status 
As of May 11, 2020, a list of current U.S. Food and Drug Administration (FDA, 2020) approved or cleared nucleic acid-based microbial tests is available at: https://www.fda.gov/medical-devices/vitro-diagnostics/nucleic-acid-based-tests..

Policy 

1. The status of nucleic acid identification using direct probe, amplified probe, or quantification for the microorganism’s procedure codes is summarized in Table 1 below. "MCC" in the table below indicates that the test is considered MEDICALLY NECESSARY; while “DNMCC” tests indicates that the test is considered NOT MEDICALLY NECESSARY.  

2. The technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both amplification or direct probes is considered NOT MEDICALLY NECESSARY.
3. PCR testing for the following microorganisms that do not have specific CPT codes is considered MEDICALLY NECESSARY (not an all-inclusive list):
   1. Actinomyces, for identification of actinomyces species in tissue specimens
   2. Adenovirus, to diagnose adenovirus myocarditis, and to diagnose adenovirus infection in immunocompromised hosts, including transplant recipients
   3. Bacillus Anthracis
   4. BK polyomavirus in transplant recipients receiving immunosuppressive therapies and persons with immunosuppressive diseases
   5. Bordetella pertussis and B. parapertussis, for diagnosis of whooping cough in individuals with coughing
   6. Brucella spp., for members with signs and symptoms of Brucellosis, and history of direct contact with infected animals and their carcasses or secretions or by ingesting unpasteurized milk or milk products
   7. Burkholderia infections (including B. cepacia, B. gladioli), diagnosis
   8. Chancroid (Haemophilus ducreyi), for diagnosis of persons with genital ulcer disease
   9. Coxiella burnetii, for confirmation of acute Q fever
   10. EBOLA
   11. Epidemic typhus (Rickettsia prowazekii), diagnosis 
   12. Epstein Barr Virus (EBV): for detection of EBV in post-transplant lymphoproliferative disorder; or for testing for EBV in persons with lymphoma; or for those who are immunocompromised for other reasons.
   13. Francisella tularensis, for presumptive diagnosis of tularemia
   14. Hantavirus, diagnosis
   15. Hemorrhagic fevers and related syndromes caused by viruses of the family Bunyaviridae (Rift Valley fever, Crimean-Congo hemorrhagic fever, hemorrhagic fever with renal syndromes), for diagnosis in acute phase in persons with clinical presentation suggestive of these conditions
   16. Hepatitis D virus, for confirmation of active infection in persons with anti-HDV antibodies
   17. Hepatitis E virus, for definitive diagnosis in persons with anti-HEV antibodies
   18. Human T Lymphotropic Virus type 1 and type 2 (HTLV-I and HTLV-II), to confirm the presence of HTLV-I and HTLV-II in the cerebrospinal fluid of persons with signs or symptoms of HTLV-I/HTLV-II
   19. Human metapneumovirus
   20. JC polyomavirus, in transplant recipients receiving immunosuppressive therapies, in persons with immunosuppressive diseases, and for diagnosing progressive multifocal leukoencephalopathy in persons with multiple sclerosis or Crohn's disease receiving natalizumab (Tysabri)
   21. Leishmaniasis, diagnosis
   22. Measles virus (Morbilliviruses), for diagnosis of measles
   23. Mumps
   24. Neisseria meningitidis, to establish diagnosis where antibiotics have been started before cultures have been obtained
   25. Parvovirus, for detecting chronic infection in immunocompromised persons
   26. Psittacosis, for diagnosis of Chlamydophila (Chlamydia) psittaci infection
   27. Rubella, diagnosis
   28. Toxoplasma gondii, for detection of T. gondii infection in immunocompromised persons with signs and symptoms of toxoplasmosis, and for detection of congenital Toxoplasma gondii infection (including testing of amniotic fluid for toxoplasma infection)
   55.  Varicella-Zoster infections
   56. Whipple's disease (T. whippeli), biopsy tissue from small bowel, abdominal or peripheral lymph nodes, or other organs of persons with signs and symptoms, to establish the diagnosis
   57. Yersinia Pestis

Policy Guidelines
A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy. Many probes have been combined into panels of tests. For the purposes of this policy, other than the respiratory virus panel, only individual probes are reviewed.

Table of Terminology

Rationale
Nucleic acid hybridization technologies, including polymerase chain reaction (PCR), ligase- or helicase-dependent amplification, and transcription-mediated amplification, are beneficial tools for pathogen detection in blood culture and other clinical specimens due to high specificity and sensitivity (Khan, 2014). The use of nucleic acid-based methods to detect bacterial pathogens in a clinical laboratory setting offers “increased sensitivity and specificity over traditional microbiological techniques” due to its specificity, sensitivity, reduction in time, and high-throughput capability; however, “contamination potential, lack of standardization or validation for some assays, complex interpretation of results, and increased cost are possible limitations of these tests” (Mothershed & Whitney, 2006).

2018 Infectious Diseases Society of America (IDSA)
Specific guidelines for testing of many organisms listed within the policy coverage criteria is found in the updated 2018 Infectious Diseases Society of America (IDSA) guidelines and recommendations titled, “A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology” (Miller et al., 2018). “This document is organized by body system, although many organisms are capable of causing disease in > 1 body system. There may be a redundant mention of some organisms because of their propensity to infect multiple sites. One of the unique features of this document is its ability to assist clinicians who have specific suspicions regarding possible etiologic agents causing a specific type of disease. When the term “clinician” is used throughout the document, it also includes other licensed, advanced practice providers. Another unique feature is that in most chapters, there are targeted recommendations and precautions regarding selecting and collecting specimens for analysis for a disease process. It is very easy to access critical information about a specific body site just by consulting the table of contents. Within each chapter, there is a table describing the specimen needs regarding a variety of etiologic agents that one may suspect as causing the illness. The test methods in the tables are listed in priority order according to the recommendations of the authors and reviewers” (Miller et al., 2018).

Centers of Disease Control and Prevention (CDC) 
MRSA
The CDC remarks that nucleic acid amplification tests (NAATs, such as PCR) “can be used for direct detection of mecA, the most common gene mediating oxacillin resistance in staphylococci,” but will not detect novel resistance mechanisms or uncommon phenotypes (CDC, 2019b).

Candida Auris (C. auris)
The CDC writes that “Molecular methods based on sequencing the D1-D2 region of the 28s rDNA or the Internal Transcribed Region (ITS) of rDNA also can identify C. auris.” The CDC further notes that various PCR methods have been developed for identifying C. auris (CDC, 2020a).

Chlamydia Pneumoniae (C. pneumoniae)
The CDC writes that RT-PCR is the “preferred” method of detecting an acute C. pneumoniae infection. The CDC further notes that a positive culture should be confirmed by a second test, such as PCR (CDC, 2021a).

Ebola
The CDC states that for diagnosis of Ebola, “There must be a combination of symptoms suggestive of EVD AND a possible exposure to EVD within 21 days before the onset of symptoms.” The CDC notes that PCR is one of the most common diagnostic methods (CDC, 2019a).

Salmonella
The CDC writes that diagnosis requires detection of the Salmonella bacteria, be it through culture or a “culture-independent diagnostic test (CIDT)” (CDC, 2019c).

Giardia 
The CDC states that microscopy with direct fluorescent antibody testing (DFA) is considered the test of choice for diagnosing giardiasis, but rapid immunochromatographic cartridge assays, enzyme immunoassay kits, microscopy with trichrome staining, and molecular assays may be alternatively used as well. To obtain more accurate test results, the CDC recommends collecting three stool specimens from patients over the course of a few days. But, only molecular testing (e.g., DNA sequencing) can identify Giardia strains (CDC, 2021c).

Non-Polio Enterovirus
The CDC remarks that their laboratories “routinely” perform qualitative testing for enteroviruses, parechoviruses, and uncommon picornaviruses (CDC, 2018).

Respiratory Syncytial Virus (RSV)
The CDC writes that real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) and antigen detection tests are the most commonly used diagnostic tests, and are effective in infants and young children. However, the highly sensitive rRT-PCR is recommended to be used when testing older children and adults with RSV (CDC, 2020c).

Mycoplasma Genitalium
The CDC writes that “Men with recurrent NGU [nongonococcal urethritis] should be tested for M. genitalium using an FDA-cleared NAAT. If resistance testing is available, it should be performed and the results used to guide therapy. Women with recurrent cervicitis should be tested for M. genitalium, and testing should be considered among women with PID [pelvic inflammatory disease]. Testing should be accompanied with resistance testing, if available. Screening of asymptomatic M. genitalium infection among women and men or extragenital testing for M. genitalium is not recommended. In clinical practice, if testing is unavailable, M. genitalium should be suspected in cases of persistent or recurrent urethritis or cervicitis and considered for PID” (CDC, 2021d).

Miscellaneous
The CDC does not mention the need to quantify [through PCR] Bartonella, Legionella pneumophila, or Mycoplasma pneumoniae. However, PCR can be performed for both Legionella pneumophila and Mycoplasma pneumoniae specimen (CDC, 2020b, 2021b, 2022). No guidance was found on Hepatitis G.

Committee on Infectious Diseases, American Academy of Pediatrics, 31st Edition (2018-2021, Red Book)
The Committee on Infectious Diseases released joint guidelines with the American Academy of Pediatrics. In it, they note that “the presumptive diagnosis of mucocutaneous candidiasis or thrush usually can be made clinically.” They also state that FISH probes may rapidly detect Candida species from positive blood culture samples, although PCR assays have also been developed for this purpose (Pediatrics, 2018).
 

References:

1. CDC. (2018, November 14). Non-Polio Enterovirus, CDC Laboratory Testing & Procedures. Retrieved from https://www.cdc.gov/non-polio-enterovirus/lab-testing/testing-procedures.html
2. CDC. (2019a, November 5). Ebola (Ebola Virus Disease), Diagnosis. Retrieved from https://www.cdc.gov/vhf/ebola/diagnosis/index.html
3. CDC. (2019b, February 6). Methicillin-resistant Staphylococcus aureus (MRSA), Laboratory Testing. Retrieved from https://www.cdc.gov/mrsa/lab/index.html#anchor_1548439781
4. CDC. (2019c, December 5). Salmonella, Diagnostic and Public Health Testing. Retrieved from https://www.cdc.gov/salmonella/general/diagnosis-treatment.html
5. CDC. (2020a, May 29). Identification of Candida auris. Retrieved from https://www.cdc.gov/fungal/candida-auris/identification.html
6. CDC. (2020b, June 5). Mycoplasma pneumoniae Infections - Diagnostic methods Retrieved from https://www.cdc.gov/pneumonia/atypical/mycoplasma/hcp/diagnostic-methods.html
7. CDC. (2020c, December 18). Respiratory Syncytial Virus Infection (RSV), For Healthcare Professionals. Retrieved from https://www.cdc.gov/rsv/clinical/index.html#lab
8. CDC. (2021a, November 15). Chlamydia pneumoniae Infection, Diagnostic Methods. Retrieved from https://www.cdc.gov/pneumonia/atypical/cpneumoniae/hcp/diagnostic.html
9. CDC. (2021b, March 25). Legionella (Legionnaires' Disease and Pontiac Fever) - Diagnosis, Treatment, and Prevention. Retrieved from https://www.cdc.gov/legionella/clinicians/diagnostic-testing.html
10. CDC. (2021c, March 1). Parasites - Giardia for Medical Professionals. Retrieved from https://www.cdc.gov/parasites/giardia/medical-professionals.html
11. CDC. (2021d, July 22). Sexually Transmitted Infections Treatment Guidelines, 2021. Retrieved from https://www.cdc.gov/std/treatment-guidelines/mycoplasmagenitalium.htm
12. CDC. (2022, January 10). Bartonella Infection. Retrieved from https://www.cdc.gov/bartonella/bartonella-henselae/index.html
13. FDA. (2022, April 19). Nucleic Acid Based Tests. Retrieved from https://www.fda.gov/medical-devices/vitro-diagnostics/nucleic-acid-based-tests
14. Khan, A. (2014). Rapid Advances in Nucleic Acid Technologies for Detection and Diagnostics of Pathogens. J Microbiol Exp, 1(2). doi:10.15406/jmen.2014.01.00009
15. Miller, J. M., Binnicker, M. J., Campbell, S., Carroll, K. C., Chapin, K. C., Gilligan, P. H., . . . Yao, J. D. (2018). A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology. Clinical Infectious Diseases, ciy381-ciy381. doi:10.1093/cid/ciy381
16. Mothershed, E. A., & Whitney, A. M. (2006). Nucleic acid-based methods for the detection of bacterial pathogens: present and future considerations for the clinical laboratory. Clin Chim Acta, 363(1-2), 206-220. doi:10.1016/j.cccn.2005.05.050
17. Pediatrics, C. o. I. D. A. A. o. (2018). Red Book® 2018.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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