Identification of Microorganisms Using Nucleic Acid Probes - CAM 303

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)
    29.  Varicella-Zoster infections
    30. 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
    31. 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

Term

Definition

AMA

American Medical Association

CDC   

Centers of Disease Control and Prevention

CIDT

Culture-independent diagnostic test

CMV

Cytomegalovirus

CPT

Current procedural terminology

DFA

Direct fluorescent antibody testing

DNA

Deoxyribonucleic acid

DNMCC

Does not meet coverage criteria  

EBV

Epstein Barr virus

EVD

Ebola virus disease

FDA

Food and Drug Administration

FRET

Fluorescent resonance energy transfer

H5N1

Hemagglutinin type 5 and neuraminidase type 1 (Avian Influenza A)

HDV

Hepatitis D virus

HEV

Hepatitis E virus

HIV 1

Human immunodeficiency virus type 1

HIV 2

Human immunodeficiency virus type 2

HPV

Human papillomavirus 

HSV

Herpes simplex virus

HTLV-I

Human t lymphotropic virus type 1

HTLV-II

Human t lymphotropic virus type 2

IDSA

Infectious Diseases Society of America

ITS

Internal transcribed region

MCC

Meets coverage criteria

MRSA

Methicillin-Resistant Staphylococcus Aureus

NAATs

Nucleic acid amplification tests

NGU

Nongonococcal urethritis

PCR

Polymerase chain reaction

PID

Pelvic inflammatory disease

qPCR

Quantitative polymerase chain reaction

rDNA

Recombinant deoxyribonucleic acid

RNA

Ribonucleic acid

rRT-PCR

Real-time reverse transcriptase-polymerase chain reaction

RSV

Respiratory syncytial virus infection

RT-PCR

Reverse transcriptase-polymerase chain reaction

SARS

Severe acute respiratory syndrome

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

 Code          

 Number          

Description

CPT 

87471

Infectious agent detection by nucleic acid (DNA or RNA); Bartonella henselae and Bartonella quintana, amplified probe technique

 

87472

Infectious agent detection by nucleic acid (DNA or RNA); Bartonella henselae and Bartonella quintana, quantification

 

87480

Infectious agent detection by nucleic acid (DNA or RNA); Candida species, direct probe technique

 

87481

Infectious agent detection by nucleic acid (DNA or RNA); Candida species, amplified probe technique

 

87482

Infectious agent detection by nucleic acid (DNA or RNA); Candida species, quantification

 

87485

Infectious agent detection by nucleic acid (DNA or RNA); Chlamydia pneumoniae, direct probe technique

 

87486

Infectious agent detection by nucleic acid (DNA or RNA); Chlamydia pneumoniae, amplified probe technique

 

87487

Infectious agent detection by nucleic acid (DNA or RNA); Chlamydia pneumoniae, quantification

 

87493

Infectious agent detection by nucleic acid (DNA or RNA); Clostridium difficile, toxin gene(s), amplified probe technique

 

87495

Infectious agent detection by nucleic acid (DNA or RNA); cytomegalovirus, direct probe technique

 

87496

Infectious agent detection by nucleic acid (DNA or RNA); cytomegalovirus, amplified probe technique

 

87497

Infectious agent detection by nucleic acid (DNA or RNA); cytomegalovirus, quantification

 

87498

Infectious agent detection by nucleic acid (DNA or RNA); enterovirus, amplified probe technique, includes reverse transcription when performed

 

87500

Infectious agent detection by nucleic acid (DNA or RNA); vancomycin resistance (e.g., enterococcus species van A, van B), amplified probe technique

 

87516

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis B virus, amplified probe technique

 

87517

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis B virus, quantification

 

87525

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis G, direct probe technique

 

87526

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis G, amplified probe technique

 

87527

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis G, quantification

 

87531

Infectious agent detection by nucleic acid (DNA or RNA); Herpes virus-6, direct probe technique

 

87532

Infectious agent detection by nucleic acid (DNA or RNA); Herpes virus-6, amplified probe technique

 

87533

Infectious agent detection by nucleic acid (DNA or RNA); Herpes virus-6, quantification

 

87540

Infectious agent detection by nucleic acid (DNA or RNA); Legionella pneumophila, direct probe technique

 

87541

Infectious agent detection by nucleic acid (DNA or RNA); Legionella pneumophila, amplified probe technique

 

87542

Infectious agent detection by nucleic acid (DNA or RNA); Legionella pneumophila, quantification

 

87563 

Infectious agent detection by nucleic acid (DNA or RNA); Mycoplasma genitalium, amplified probe technique 

 

87580

Infectious agent detection by nucleic acid (DNA or RNA); Mycoplasma pneumoniae, direct probe technique

 

87581

Infectious agent detection by nucleic acid (DNA or RNA); Mycoplasma pneumoniae, amplified probe technique

 

87582

Infectious agent detection by nucleic acid (DNA or RNA); Mycoplasma pneumoniae, quantification

 

87634

Infectious agent detection by nucleic acid (DNA or RNA); respiratory syncytial virus, amplified probe technique

 

87640

Infectious agent detection by nucleic acid (DNA or RNA); Staphylococcus aureus, amplified probe technique

 

87641

Infectious agent detection by nucleic acid (DNA or RNA); Staphylococcus aureus, methicillin resistant, amplified probe technique 

 

87797

Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; direct probe technique, each organism

 

87798

Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; amplified probe technique, each organism

 

87799

Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; quantification, each organism

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.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/21/2022 Annual review, policy rewritten for clarity, no change to policy intent. Updating description, rationale and references. 

10/01/2021 

Interim review updating coverage criteria for 87481 and 87482 related to vaginitis per CDC guidlelines. No other changes made. 

07/26/2021 

Annual review, no change to policy intent. Updating rationale and references. 

10/15/2020 

Interim Review. Correcting policy verbiage on code 87487. No other changes made. 

09/24/2020 

Updating annual review date to 07/2021. No other changes. 

07/01/2020 

Interim review, updating Chlamydia pneumoniae to medically necessary. Also reformatting the policy for clarity. 

04/08/2020 

Interim review to add coverage criteria and coding related to COVID-19. 

10/29/2019 

Annual review, no change to policy intent. Reformatting for clarity. Updating coding.

09/25/2019 

Corrected formatting. No other changes made. 

05/29/2019 

Corrected typo. No change to policy intent. 

11/27/2018 

Major rewrite of this policy related to adoption of diagnostic testing of most common sexually transmitted infections, B-Hemolytic Streptococcus Testing, and testing for mosquito- or tick-related infections. All four policies will be implemented on 02/01/2019. 

12/7/2017 

Updating policy with 2018 coding. No other changes. 

11/28/2017 

Annual review. Updating background, description, regulatory status, policy, guidelines, references and coding.

04/25/2017 

Updated category to Laboratory. No other changes. 

01/10/2017 

Annual Review. No significant changes.

11/30/2016 

Updated coding section with 2017 codes. 

05/09/2016 

Interim review, updating Human herpes virus 6 testing to indicate that direct probe and quantification can be considered medically necessary, but, that amplified probe (87532) is considered investigational. No other changes. 

01/21/2015 

Returning Borrelia burgdorferi as medically necessary with reference to: See policy 50108. 

01/05/2016 

Interim review with the following policy intent changes: Medically necessary statement added for non-quantified nucleic acid-based testing for enterovirus, Legionella pneumophila, Mycoplasma pneumoniae, and Bartonella spp, and for quantified testing for human herpesvirus 6. Borrelia, major revision in the visual look of the policy, but, only the content listed has been altered in intent. Updating background, description, guidelines, verbiage, rationale, references, and coding. 

11/24/2015 

Annual review, no changes made. 

3/16/2015 

Removed the word "archived" in table 1 on Candida species, Gardnerella vaginalis and  Human Papillomavirus lines. No other changes.

10/27/2014

Annual review. Added description and coding. Updated background, policy, rationale and references. New CPT codes (8751xx 1-3 and 876xx 3-5 added.

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