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Identification of Microorganisms Using Nucleic Acid Probes

Policy Number: MP-548

Latest Review Date: July 2020

Category: Laboratory

Policy Grade: B

POLICY:

Effective for dates of service on or after April 1, 2020:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see Table 1 at the end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Herpes simplex virus
  • Human papillomavirus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Respiratory virus panel
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • 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 herpes virus-6
  • Influenza 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 gastrointestinal pathogen panels (GIPP) for the following:

  • Individuals with acute diarrhea with moderate-to-severe symptoms (such as fever, dysentery, severe dehydration); OR
  • Individuals with community-acquired diarrhea that persists for more than seven days, or individuals with travel-associated diarrhea of uncertain etiology; OR
  • Immunocompromised individuals with acute diarrhea

*Gastrointestinal Pathogen Panel testing is limited to the minimum number of targets needed for therapeutic decision making.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered not medically necessary for gastrointestinal pathogen panels (GIPP) for the following:

  • Immunocompetent individuals with mild diarrhea, particularly of less than or equal to seven (7) days’ duration; OR
  • Individuals in whom the clinical presentation of acute diarrhea suggests a specific infectious etiology, unless first-line laboratory testing should fail to detect the suspected organism, and there is still a high clinical suspicion of infectious etiology; OR
  • Individuals with chronic diarrhea

*Diarrhea defined:

  • Acute diarrhea: 0-2 weeks duration
  • Persistent diarrhea: 2-4 weeks
  • Chronic diarrhea: > 4 weeks

The use of nucleic acid testing with quantification of viral load for microorganisms that are not included in the list of microorganisms are considered investigational and not medically necessary.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered investigational and not medically necessary for the following microorganisms including but not limited to:

  • Hepatitis G virus
  • Human papillomavirus (low risk panel)

CPT CODES:

Table 1. Provides a list of CPT codes for various nucleic acid probes.

Table 1. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

0068U (eff 10/01/18) (Med Nec)

87482 (Inv)

Central Nervous System Pathogen Panel

 

87483 (eff 01/01/17) (Med Nec)

 

Chlamydia pneumoniae

87485 (Med Nec)

87486 (Med Nec)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Enterococcus, Vancomycin resistant (e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Med Nec)

0097U (eff 07/01/19) (Med Nec)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623(Inv)

87624-87625 (Med Nec)

 

Infectious Agent detection and identification

   

0112U (eff 10/01/19) (Inv)

Infectious disease

 

0140U-0142U (eff 01/01/20) (Inv)

 

Influenza virus

87501 (Med Nec)

87502 (Med Nec)

87503 (Med Nec)

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551(Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (eff 07/01/19) (Med Nec)

0115U (eff 10/1/19) (Med Nec)

0202U (eff 5/20/20) (Med Nec)

0151U (eff 1/1/2020) (Med Nec)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

87635 (eff 3/13/20) (Med Nec)

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ac

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Bd

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

 

Unlisted (infectious agent detection by nucleic acid (DNA or RNA, not otherwise specified)e

87797 (Inv)

87798 (Inv)

87799 (Inv)

Zika Virus

 

87662 (Med Nec)

 

a Refer to medical policy #359, Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

b For uncomplicated infections, testing for only one candida species, C albicans, may be considered medically necessary. For complicated infections, testing for multiple candida subspecies may be considered medically necessary. The Centers for Disease Control and Prevention classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent or mild to moderate or likely to be C. albicans or in non-immunocompromised women. Complicated vulvovaginal candidiasis is classified as being recurrent or severe or not a C. albicans species or in women with uncontrolled diabetes, debilitation or immunosuppression.

c Antibiotic sensitivity of streptococcus A cultures is frequently 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.

d In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to 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.

e Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy.

fUse of NAAT for SARS-CoV-2 is for confirming Coronavirus Disease 2019 (COVID-19) diagnoses. This medical policy does not address antibody testing (serological IgG assays).

Table 1 Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

Eff—effective

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


Effective for dates of service on or after January 15, 2020 through March 31, 2020:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see Table 1 at the end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Herpes simplex virus
  • Human papillomavirus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Respiratory virus panel
  • Staphylococcus aureus
  • Staphylococcus aureus, methicillin resistant
  • Streptococcus, group A
  • Streptococcus, group B
  • Trichomonas vaginalis

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 herpes virus 6
  • Influenza 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 gastrointestinal pathogen panels for the following:

  • Individuals with acute diarrhea with moderate-to-severe symptoms (such as fever, dysentery, severe dehydration); OR
  • Individuals with community-acquired diarrhea that persists for more than seven days, or individuals with travel-associated diarrhea of uncertain etiology; OR
  • Immunocompromised individuals with acute diarrhea

*Gastrointestinal Pathogen Panel testing is limited to the minimum number of targets needed for therapeutic decision making.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered not medically necessary for gastrointestinal pathogen panels for the following:

  • Immunocompetent individuals with mild diarrhea, particularly of less than or equal to seven (7) days’ duration; OR
  • Individuals in whom the clinical presentation of acute diarrhea suggests a specific infectious etiology, unless first-line laboratory testing should fail to detect the suspected organism, and there is still a high clinical suspicion of infectious etiology.

The use of nucleic acid testing with quantification of viral load for microorganisms that are not included in the list of microorganisms are considered investigational and not medically necessary.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered investigational and not medically necessary for the following microorganisms including but not limited to:

  • Chlamydophila pneumoniae
  • Hepatitis G virus

Human papillomavirus (low risk panel)

CPT codes 87797, 87798, and 87799 describe the use of direct probe, amplified probe, and quantification, respectively, for infectious agents not otherwise specified. Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy. Table 1 provides a list of CPT codes for various nucleic acid probes.

A new PLA code is effective 10/01/18 that represents the MYCODART Dual Amplification Real Time PCR Panel: 0068U Candida species panel (C. albicans, C. glabrata, C. parapsilosis, C. kruseii, C tropicalis, and C. auris), amplified probe technique with qualitative report of the presence or absence of each species.

A new PLA code is effective 10/01/19 that represents MicroGenDX: 0112U - Infectious agent detection and identification, targeted sequence analysis (16S and 18S rRNA genes) with drug resistance gene. (Inv)

Table 1. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

87482 (Inv)

Chlamydia pneumoniae

87485 (Inv)

87486 (Inv)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Enterococcus, Vancomycin resistant (e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Med Nec)

0097U (eff 07/01/19) (Med Nec)

 

Central Nervous System Pathogen Panel

 

87483 (eff 01/01/17) (Med Nec)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623(Inv)

87624-87625 (Med Nec)

 

Influenza virus

87501 (Med Nec)

87502 (Med Nec)

87503 (Med Nec)

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551(Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (eff 07/01/19) (Med Nec)

0115U (eff 10/1/19) (Med Nec)

0151U (eff 1/1/2020) (Med Nec)

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ac

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Bd

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

 

a Refer to medical policy #359, Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

b For uncomplicated infections, testing for only one candida species, C albicans, may be considered medically necessary. For complicated infections, testing for multiple candida subspecies may be considered medically necessary. The Centers for Disease Control and Prevention classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent or mild to moderate or likely to be C. albicans or in non-immunocompromised women. Complicated vulvovaginal candidiasis is classified as being recurrent or severe or not a C. albicans species or in women with uncontrolled diabetes, debilitation or immunosuppression.

c Antibiotic sensitivity of streptococcus A cultures is frequently 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.

d In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to 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.

Table 1 Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

Eff—effective

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


Effective for dates of service December 1, 2016 through January 14, 2020:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see Table 1 at end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Herpes simplex virus
  • Human papillomavirus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Respiratory virus panel
  • Staphylococcus aureus
  • Staphylococcus aureus, methicillin resistant
  • Streptococcus, group A
  • Streptococcus, group B
  • Trichomonas vaginalis
  • 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 herpes virus 6
  • Influenza virus

The use of nucleic acid testing with quantification of viral load for microorganisms that are not included in the list of microorganisms are considered investigational and not medically necessary.

The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load is considered investigational and not medically necessary for the following microorganisms including but not limited to:

  • Chlamydophila pneumoniae
  • Hepatitis G virus
  • Human papillomavirus (low risk panel)
  • Gastrointestinal pathogen panel

CPT codes 87797, 87798, and 87799 describe the use of direct probe, amplified probe, and quantification, respectively, for infectious agents not otherwise specified. Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy. Table 1 provides a list of CPT codes for various nucleic acid probes.

A new PLA code will be effective 10/01/18 that represents the MYCODART Dual Amplification Real Time PCR Panel: 0068U Candida species panel (C. albicans, C. glabrata, C. parapsilosis, C. kruseii, C tropicalis, and C. auris), amplified probe technique with qualitative report of the presence or absence of each species.

A new PLA code will be effective 10/01/19 that represents MicroGenDX: 0112U - Infectious agent detection and identification, targeted sequence analysis (16S and 18S rRNA genes) with drug resistance gene. (Inv)

Table 1. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

87482 (Inv)

Chlamydia pneumoniae

87485 (Inv)

87486 (Inv)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Enterococcus, Vancomycin resistant

(e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Inv)

0097U (eff 07/01/19) (Inv)

 

Central nervous system pathogen panel

 

87483 (eff 01/01/17) (Med Nec)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623(Inv)

87624-87625 (Med Nec)

 

Influenza virus

87501 (Med Nec)

87502 (Med Nec)

87503 (Med Nec)

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551(Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (eff 07/01/19) (Med Nec)

0115U (eff 10/1/19) (Med Nec)

0151U (eff 1/1/2020) (Med Nec)

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ac

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Bd

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

 

a Refer to medical policy #359, Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

b For uncomplicated infections, testing for only one candida species, C albicans, may be considered medically necessary. For complicated infections, testing for multiple candida subspecies may be considered medically necessary. The Centers for Disease Control and Prevention classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent or mild to moderate or likely to be C. albicans or in non-immunocompromised women. Complicated vulvovaginal candidiasis is classified as being recurrent or severe or not a C. albicans species or in women with uncontrolled diabetes, debilitation or immunosuppression.

c Antibiotic sensitivity of streptococcus A cultures is frequently 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.

d In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to 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.

Table 1 Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

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


DESCRIPTION OF PROCEDURE OR SERVICE:

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 HIV 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 (qPCR) or real-time PCR (rt-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 evidence review, 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 (e.g., HIV), fastidious or lengthy culture requirements (e.g., Mycobacteria, Chlamydia, Neisseria species), or difficulty in collecting an appropriate sample (e.g., 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.

KEY POINTS:

The most recent literature review was conducted for the period through May 27, 2020.

Summary of Evidence

For individuals who have signs and/or symptoms of gastroenteritis who receive nucleic acid-based gastrointestinal pathogen panel testing, the evidence includes prospective and retrospective evaluations of the tests’ sensitivity and specificity. Relevant outcomes include test accuracy and validity, other test performance measures, symptoms, and change in disease status. The evidence suggests that gastrointestinal pathogen panels are likely to identify both bacterial and viral pathogens with high sensitivity, compared with standard methods. Access to a rapid method for etiologic diagnosis of gastrointestinal infections may lead to more effective early treatment and infection-control measures. The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals who have signs and/or symptoms of respiratory infection who receive a nucleic acid-based respiratory pathogen panel, the evidence includes a systematic review and two RCTs. Relevant outcomes include test accuracy and validity, other test performance measures, medication use, symptoms, and change in disease status. The systematic review reported that all three reviewed multiplex PCR systems were highly accurate. One RCT and one quasi-RCT evaluated utility of a respiratory panel and found benefits in time-to-treat and length of hospital stay; in addition, one sub analysis found fewer antibiotics being prescribed for patients diagnosed with the panel. However, the panel did not significantly affect duration of antibiotic use, readmission, or mortality rates. The evidence is sufficient to determine the effects of the technology on health outcomes.

For other nucleic acid probes discussed in this review, the tests’ clinical utility was evaluated based on whether there is demonstrated clinical validity, along with either direct evidence of improved outcomes or a chain of evidence indicating that changes in management leading to improved outcomes are likely to occur with testing. In many cases, clinical input has indicated that nucleic acid-based testing is considered the standard of care.

Practice Guidelines and Position Statements

Numerous guidelines have been identified concerning the use of NAATs for the diagnosis of the pathogens discussed in this review.

Centers for Disease Control and Prevention

The CDC has published ten recommendations and statements regarding the use of NAATs to diagnose the viruses and infections discussed in this evidence review since 2009.

  • In 2019, the CDC published guidance for laboratory testing for Cytomegalovirus (CMV), the guideline stated that the standard laboratory test for congenital CMV is PCR on saliva, with confirmation via urine test to avoid false-positive results from ingesting breast milk from CMV seropositive mothers. Serologic tests were recommended for person >12 months of age.
  • In 2018, the CDC published diagnostic methods for mycoplasma pneumoniae. They cited NAAT as a method of diagnosis, along with culture or serology.
  • In 2017, the CDC published updated interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection. It recommended:
    • Asymptomatic pregnant women with ongoing possible Zika virus exposure (residing in or frequently traveling to an area with risk for Zika virus transmission) should be offered a Zika virus nucleic acid test (NAT) as part of routine obstetric care; and
    • For infants with possible Zika virus infection, “if cerebrospinal fluid (CSF) is obtained for other purposes, NAT and IgM antibody testing should be performed on CSF because CSF was the only sample that tested positive in some infants with congenital Zika virus syndrome.”
  • In 2017, the CDC updated its guidelines on norovirus gastroenteritis outbreak management and disease prevention. Real-time reverse transcription-PCR assays, specifically, TaqMan-based real-time assays, which can contain multiple probes, is considered the effective laboratory diagnostic protocol for testing suspected cases of viral gastroenteritis.
  • In 2015, the following recommendations were made for the use of NAATs in diagnosing sexually transmitted diseases:
    • For Candida Species: "PCR testing for yeast is not FDA-cleared; culture for yeast remains the gold standard for diagnosis."
    • For Chlamydia and Gonorrhea:
      • "NAATs for chlamydia and gonorrhea are recommended because of their high sensitivity and specificity; a specific diagnosis can potentially reduce complications, re-infection, and transmission."
      • "Pregnant women found to have chlamydial infection should have a test-of-cure to document chlamydial eradication (preferably by nucleic acid amplification testing [NAAT]) three to four weeks after treatment and then retested within three months. Screening during the first trimester might prevent the adverse effects of chlamydia during pregnancy, but evidence for such screening is lacking."
      • "NAAT performed on rectal specimens is the preferred approach to testing."
      • For follow-up, "the use of chlamydial NAATs at <3 weeks after completion of therapy is not recommended because the continued presence of nonviable organisms can lead to false-positive results."
    • For Chlamydia pneumoniae: NAAT is recommended as an alternative to tissue culture, which “is the definitive standard diagnostic test for chlamydial pneumonia…NAATs are not FDA-cleared for the detection of chlamydia from nasopharyngeal specimens, and clinical laboratories must verify the procedure according to CLIA regulations.”
    • For Gardnerella vaginalis: Although PCR has been researched “for the detection of various organisms associated with BV [bacterial vaginosis],” its clinical utility has not yet been established.
    • For Hepatitis C infection:
      • NAATs are recommended for screening pregnant women with known risk factors; NAAT “is necessary to confirm the diagnosis of current HCV infection.”
      • In addition, “testing for HCV infection should include use of an FDA-cleared test for antibody to HCV…followed by NAAT to detect HCV RNA for those with a positive antibody result.”
    • For Herpes Simplex Virus:
      • “Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions;” and
      • “PCR is the test of choice for diagnosing HSV infections affecting the central nervous system and systemic infections.”
    • For HIV-1: The use of NAAT is not mentioned; serologic tests are recommended for detecting antibodies against HIV-1 and by virologic tests that detect HIV antigens or RNA.
    • For Human Papillomavirus:
      • There are several FDA-cleared HPV tests that detect viral nucleic acid or messenger RNA; however, there are currently no algorithms for HPV 16/18/45 testing in the clinical guidelines;
      • The “use of non-oncogenic tests is not recommended;” and
      • “HPV assays should be FDA-cleared and used only for the appropriate indications” and should not be performed if the patient is “deciding whether to vaccinate against HPV;” while “conducting STD screening in women or men at risk for STDs;” when “providing care to persons with genital warts or their partners;” when “conducting screening for cervical cancer as a stand-alone test;” when “testing women aged <30 years as part of routine cervical cancer screening;” or when “testing oral or anal specimens.”
    • For Trichomonas vaginalis:
      • NAAT is recommended for detecting vaginalis in women due to its high sensitivity and specificity. The APTIMA T. vaginalis assay (Hologic Gen-Probe, San Diego, CA) is FDA-cleared to detect T. vaginalis from vaginal, endocervical, or urine specimens for women.
      • In one study, “[f]or vaginalis diagnosis in men, the sensitivity of self-collected penile-meatal swabs was higher than that of urine.” However, there is currently no FDA-cleared test for men.
  • In 2014, the CDC published recommendations regarding the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections. It stated:
    • NAATs are superior other available diagnostic tests in “overall sensitivity, specificity, and ease of specimen transport;”
    • The use of “NAAT to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls” is supported by evidence; and
    • Only NAATs that have been cleared by the FDA for detection of C. trachomatis and N. gonorrhoeae “as screening or diagnostic tests because they have been evaluated in patients with and without symptoms” should be used.
  • In 2010, the CDC published guidelines on perinatal group B streptococcus (GBS) disease. It stated:
    • The use of NAATs with the addition of an enrichment broth to the sample increases NAAT sensitivity for GBS to 92.5%-100.0%;
    • However, “data on the currently available assays do not support their use in replacement of antenatal culture or risk-based assessment of women with unknown GBS status on admission for labor;” and
    • Because of the additional time needed to enrich samples, NAAT with enrichment is “not feasible for intrapartum testing, and the sensitivity of assays in the absence of enrichment is not adequate in comparison to culture.”
  • In 2009, the CDC published updated guidelines for the use of NAATs in the diagnosing Mycobacterium tuberculosis bacteria. The CDC recommended that “NAA testing be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities.” Although it noted that “culture remains the gold standard for laboratory confirmation of TB and is required for isolating bacteria for drug-susceptibility testing and genotyping,” the guideline stated that “NAA testing should become standard practice for patients suspected to have TB, and all clinicians and public health TB programs should have access to NAA testing for TB to shorten the time needed to diagnose TB from one to two weeks to one to two days.”

National Institute of Health et al

The NIH, CDC, and HIV Medicine Association of the IDSA (2019) published guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. NAATs are discussed in the following situations:

  • Bartonella species: For patients with suspected bacillary angiomatosis, serologic tests are the standard of care of diagnosing Bartonella infection. There are PCR “methods that have been developed for identification and speciation of Bartonella but are not widely available.”
  • Clostridium difficile: Routine testing with PCR is necessary for patients with diarrhea who have “recently received or are currently receiving antibiotics or cancer chemotherapy, those who have been hospitalized in the past four to six week, those who reside in a long-term care facility, those with CD4 counts <200 cells/mm3, those taking acid-suppressive medication, and those with moderate-to-severe community-acquired diarrhea.”
  • Cytomegalovirus: For patients with suspected cytomegalovirus disease, “viremia can be deterred by PCR” and “a positive result is highly suggestive that CMV is the cause of end-organ disease. However, PCR assays are not standardized; therefore, sensitivity, specificity, and interassay comparability are not clearly delineated.”
  • Hepatitis B: The CDC, the United States Preventive Services Task Force, and the AASLD recommend that patients with HIV infection should be tested for hepatitis B; however, NAATs are not recommended for initial testing in patients with HIV.
  • Hepatitis C: Patients with HIV are recommended to undergo routine hepatitis C screening, initially “performed using the most sensitive immunoassays licensed for detection of antibody to HCV in blood.” The use of NAATs are not mentioned for initial testing in patients with HIV.
  • Herpes Simplex Virus: “HSV DNA PCR… is the preferred method for diagnosis of mucocutaneous HSV lesions caused by HSV.”
  • Mycobacterium tuberculosis Infection and Disease: “It is recommended that for all patients with suspected pulmonary TB, a NAA test be performed on at least one specimen.”; “Rapid diagnosis is essential in patients with HIV given the risk of rapid clinical progression of TB among patients with advanced immunodeficiency. NAA tests provide rapid diagnosis of TB.”; “NAA tests have at least two uses among patients with suspected HIV-related TB. First, NAA assays, if positive, are highly predictive of TB disease when performed on AFB smear-positive specimens…. Second, NAA tests are more sensitive than AFB smear, being positive in 50% to 80% of smear-negative, culture- positive specimens and up to 90% when three NAA tests are performed. Therefore, it is recommended that for all patients with suspected pulmonary TB, a NAA test be performed on at least one specimen.”

Infectious Disease Society of America et al

The IDSA has partnered with various societies to publish nine recommendations regarding the use of NAATs to diagnose the viruses and infections discussed.

In 2018, the IDSA and the American Society for Microbiology published a guide on the diagnosis of infectious diseases. NAATs were recommended diagnostic procedures for Enterovirus, Hepatitis C, Hepatitis B, Cytomegalovirus, Herpes Simplex Virus, Human Herpesvirus 6, HIV, Influenza Virus, and Zika Virus. NAATs were not recommended diagnostic procedures for Bacterial vaginosis. In addition to providing guidance on diagnosing these diseases, the guidelines also provided recommendations on testing for other conditions by testing for common etiologic agents.

NAATs for diagnosing Candida species, Gardnerella vaginalis, Streptococcus Group B, and Vancomycin-resistant enterococcus as etiologic agents were not recommended.

In 2017, the IDSA published clinical practice guidelines for the management of healthcare-associated ventriculitis and meningitis. When making diagnostic recommendations, the IDSA notes cultures as the standard of care in diagnosing healthcare-associated ventriculitis and meningitis, but that “nucleic acid amplification tests, such as PCR, on CSF may both increase the ability to identify a pathogen and decrease the time to making a specific diagnosis (weak, low).” (Strength of recommendation and quality of evidence established using the GRADE [Grading of Recommendations Assessment, Development and Evaluation] methodology.)

In 2008, the IDSA published clinical practice guidelines for the management of encephalitis. The following recommendations were made:

  • “Biopsy of specific tissues for culture, antigen detection, nucleic acid amplification tests (such as PCR), and histopathologic examination should be performed in an attempt to establish an etiologic diagnosis of encephalitis (A-III).” (Strength of recommendation level “A indicates good evidence to support recommendation for use.” Quality of evidence level III indicates “evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.”)
  • “Nucleic acid amplification tests (such as PCR) of body fluids outside of the CNS may be helpful in establishing the etiology in some patients with encephalitis (B-III).” (Strength of recommendation level B indicates “moderate evidence to support recommendation.” Quality of evidence level III indicates “evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.”)
  • “Nucleic acid amplification tests (such as PCR) should be performed on CSF specimens to identify certain etiologic agents in patients with encephalitis (A-III). Although a positive test result is helpful in diagnosing infection caused by a specific pathogen, a negative result cannot be used as definitive evidence against the diagnosis.”
  • The use of NAATs was recommended for diagnosing CMV, HSV-1 and -2, Human herpesvirus 6, Bartonella henselae, Mycoplasma pneumoniae, and Mycobacterium tuberculosis.

In 2018, the IDSA and the Society for Healthcare Epidemiology of America (SHEA) published weak recommendations with low quality evidence for the use of NAATs to diagnose Clostridium difficile.

  • “The best-performing method (i.e., in use positive and negative predictive value) for detecting patients at increased risk for clinically significant C. difficile [CDI] infection” is use of a “stool toxin test as part of a multistep algorithm…rather than NAAT along for all specimens received in the clinical laboratory when there are no preagreed institutional criteria for patient stool submission.”
  • “The most sensitive method of diagnosis of CDI in stool specimens from patients likely to have CDI based on clinical symptoms” is use of “a NAAT alone or a multistep algorithm for testing…rather than a toxin test alone when there are preagreed institutional criteria for patient stool submission.”

In 2017, the IDSA published clinical practice guidelines for the diagnosis and management of infectious diarrhea. The following recommendations were made:

  • In situations where enteric fever or bacteremia is suspected, “culture-independent, including panel-based multiplex molecular diagnostics from stool and blood specimens, and when indicated, culture-dependent diagnostic testing should be performed” (GRADE: strong, moderate).
  • In testing for Clostridium difficile in patients >2 years of age, “a single diarrheal stool specimen is recommended for detection of toxin or toxigenic C. difficile strain (e.g., nucleic acid amplification testing)” (GRADE: strong, low).
  • NAATs are not recommended for diagnosing Cytomegalovirus.
  • It was also noted that “clinical consideration should be included in the interpretation of results of multiple-pathogen nucleic acid amplification tests because these assays detect DNA and not necessarily viable organisms” (GRADE: strong, low).

In 2017, the IDSA published clinical practice guidelines for the management of healthcare-associated ventriculitis and meningitis. When making diagnostic recommendations, the IDSA notes cultures as the standard of care in diagnosing healthcare-associated ventriculitis and meningitis, but that “nucleic acid amplification tests, such as PCR, on CSF may both increase the ability to identify a pathogen and decrease the time to making a specific diagnosis (weak, low).”

In 2016, the IDSA published updated clinical practice guidelines for managing candidiasis. The guideline noted many limitations of PCR testing. No formal recommendation was made, but the guidelines did state that “the role of PCR in testing samples other than blood is not established.”

In 2020, the IDSA established a panel composed of 8 members including frontline clinicians, infectious diseases specialists and clinical microbiologists who were members of the IDSA, American Society for Microbiology (ASM), Society for Healthcare Epidemiology of America (SHEA), and the Pediatric Infectious Diseases Society (PIDS). Panel members represented the disciplines of adult and pediatric infectious diseases, medical microbiology, as well as nephrology and gastroenterology. The panel created a COVID-19 Diagnosis guideline using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for evidence assessment; and, given the need for rapid response to an urgent public health crisis, the methodological approach was modified according to the GIN/McMaster checklist for development of rapid recommendations. The panel published recommendations for COVID-19 Diagnosis in an online format, as when substantive new information becomes available the recommendations will require frequent updating. The current recommendations (published May 6, 2020) support SARS-CoV-2 nucleic acid testing for the following groups:

  • all symptomatic individuals suspected of having COVID-19;
  • asymptomatic individuals with known or suspected contact with a COVID-19 case;
  • asymptomatic individuals without known exposure when the results will impact isolation/quarantine/personal protective
  • equipment (PPE) usage decisions, dictate eligibility for surgery, or inform administration of immunosuppressive therapy.

The IDSA panel further recommends the following:

  • collecting nasopharyngeal, or mid-turbinate or nasal swabs rather than oropharyngeal swabs or saliva alone for SARS-CoV-2 RNA testing in symptomatic individuals with upper respiratory tract infection (URTI) or influenza like illness (ILI) suspected of having COVID-19 (conditional recommendation, very low certainty of evidence).
  • nasal and mid-turbinate (MT) swab specimens may be collected for SARS-CoV-2 RNA testing by either patients or healthcare providers, in symptomatic individuals with upper respiratory tract infection (URTI) or influenza like illness (ILI) suspected of having COVID-19 (conditional recommendation, low certainty of evidence).
  • a strategy of initially obtaining an upper respiratory tract sample (e.g., nasopharyngeal swab) rather than a lower respiratory sample for SARS-CoV-2 RNA testing in hospitalized patients with suspected COVID-19 lower respiratory tract infection. If the initial upper respiratory sample result is negative, and the suspicion for disease remains high, the IDSA panel suggests collecting a lower respiratory tract sample (e.g., sputum, bronchoalveolar lavage fluid, tracheal aspirate) rather than collecting another upper respiratory sample (conditional recommendations, very low certainty of evidence) performing a single viral RNA test and not repeating testing in symptomatic individuals with a low clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence).
  • repeating viral RNA testing when the initial test is negative (versus performing a single test) in symptomatic individuals with an intermediate or high clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence).

The IDSA panel makes no recommendations for or against using rapid (i.e., test time ≤ 1hour) versus standard RNA testing in symptomatic individuals suspected of having COVID-19 (knowledge gap).

American Society of Transplantation

The AST Infectious Diseases Community of Practice (2019) published guidelines which addressed vancomycin-resistant enterococci infections in solid organ transplant patients. The guidelines noted the cost-effectiveness and accuracy of “emerging molecular diagnostics for VRE colonization, including multiplexed PCR performed after culture on selective media,” compared with culture alone.

American Academy of Pediatrics

The current edition of the AAP Red Book describes the diagnostic and treatment options of many infectious diseases in the pediatric population.

American College of Gastroenterology

The ACG (2016) published clinical guidelines on the diagnosis, treatment, and prevention of acute diarrheal infections in adults. It recommended that, given 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,… the use of FDA-approved culture-independent methods of diagnosis can be recommended at least as an adjunct to traditional methods. (Strong recommendation, low level of evidence).” These are described in the rationale as multiplex molecular testing.

APPROVED BY GOVERNING BODIES:

The United State Food and Drug Administration (FDA) maintains a list of NAATs that have been cleared by the Center for Devices and Radiological Health. NAATs have been cleared for many of the microorganisms discussed in this review and may be reviewed on this site.

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 Act. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Act for high-complexity testing.

KEY WORDS:

Bartonella henselae or quintana, Borrelia burgdorferi, Candida species, Chlamydia pneumonia or trachomatis, Clostridium difficile, Cytomegalovirus (CMV), Enterovirus, Vancomycin-resistant Enterococcus, Gardnerella vaginalis, Hepatitis B, Hepatitis C, Hepatitis G, Herpes simplex virus, Herpes virus-6, Human immunodeficiency virus 1 (HIV-1), Human immunodeficiency virus (HIV-2), Human papillomavirus (HPV), Influenza virus, Legionella pneumophila, Mycobacterium species, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycoplasma pneumonia, Neisseria gonorrhoeae, Respiratory Viral Panel, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, Streptococcus, Group A, Streptococcus, Group B, Trichomonas vaginalis, Human Herpes virus-6, MicroGenDX, MYCODART, BioFire, FilmArray GI Panel, FilmArray Respiratory Panel, GI panel, Respiratory Panel, ePlex, GIPP, BV, Bacterial Vaginosis, Aptima BV Assay, BD Max, Zika Virus, COVID-19, Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will review for medical necessity.

CURRENT CODING: CPT Codes: See Policy Section

PREVIOUS CODING:

CPT codes:

87470

Infectious agent detection by nucleic acid (DNA or RNA); Bartonella henselae and Bartonella quintana, direct probe technique (deleted effective 1/1/18)

87477

Infectious agent detection by nucleic acid (DNA or RNA); Borrelia burgdorferi, quantification (deleted effective 1/1/18)

87515

Infectious agent detection by nucleic acid (DNA or RNA); hepatitis B virus, direct probe technique (deleted effective 1/1/18)

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POLICY HISTORY:

Medical Policy Panel, September 2013

Medical Policy Group, November 2013 (2): New Policy

Medical Policy Administration Committee, November 2013

Available for comment November 20, 2013 through January 4, 2014

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (1): Updated Description, Policy statement, Key Points, Coding and References related to adding gastrointestinal pathogen panel (new CPT codes 87505-87507) as investigational, and adding new HPV probe CPT codes 87623-87625, which are considered medically necessary, all new codes effective 1/1/15. For Annual coding, placed deleted codes under Previous coding section.

Medical Policy Administration Committee, October 2014

Medical Policy Panel, February 2016

Medical Policy Group, May 2017 (3): Updates to Description, Key Points, Key Words, Approved Governing Bodies, & References; multiple coverage changes added to Policy statements

Medical Policy Administration Committee, June 2017

Available for comment May 23 through July 6, 2017

Medical Policy Group, July 2017 (3): Updated CPT code 87476 as medically necessary on coverage table under Policy Section

Medical Policy Panel, December 2017

Medical Policy Group, January 2018 (3): Updates to Description, Key Points & References; removed Previous Coding section for codes deleted 12/31/14; added central nervous system pathogen panel, ENT/pulmonary panel & nail panel to list of tests considered investigational; no change in intent of policy statements.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2019 Updates to Description, Key Points & References. Added previous coding section for codes: 87470, 87477, 87515-deleted 1/1/18 and removed them from Table 1, added PLA code 0068u-new code effective 10/1/18. Added key word: MYCODART. Removed the following from investigational policy statement: Central nervous system pathogen panel, ENT/pulmonary panel, Nail panel. Added to Table 2 (CPT Codes for Nucleic Acid Probes): Central nervous system pathogen panel, CPT code 87483 to amplified probe column.

Medical Policy Group, June 2019: July 2019 quarterly coding update. Added new CPT codes 0097U and 0098U – 0100U to Table 1 under Policy section. Added Key Words BioFire, FilmArray GI Panel, FilmArray Respiratory Panel, GI panel, Respiratory Panel.

Medical Policy Group, July 2019 (9): Added CPT code 87634 to Table 1 under Policy section for Respiratory Virus Panel.

Medical Policy Group, September 2019: October 2019 quarterly coding update.  Added new CPT codes 0112U and 0115U to the Policy section. Added Key Word ePlex.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Added new CPT code 0151U code to the Policy section.

Medical Policy Group, December 2019 (9): Updated policy section dated January 15, 2020 and after to include criteria for gastrointestinal pathogen panels. Removed policy section dated January 1, 2014 through November 30, 2016. Removed 2015 coding information statement from policy section. Added key word: GIPP

Medical Policy Administration Committee, January 2020

Available for comment: December 13, 2019 through January 26, 2020.

Medical Policy Panel, December 2019

Medical Policy Group, January 2020 (9): 2019 Updates to information contained within policy regarding BV. Description, Key Points, Regulatory Status updated with BV information. Key words added: BV, Bacterial Vaginosis, Aptima BV Assay, BD Max. No change to policy statement.

Medical Policy Panel, February 2020

Medical Policy Group, March 2020 (9): 2020 Updates to Description, Key Point, References. Key Words added: Zika Virus. Policy statement updated: Zika virus direct or amplified probe without quantification medically necessary indication added to table 1 (this is not a change in stance); Chlamydia pneumoniae direct or amplified probe without quantification medically necessary (this is a change in stance from previous investigational stance) added to table 1; Infectious agent detection and identification AND infectious disease probe investigational statement added to table 1. Added CPT codes 0112U, 0140U, 0141U, 0142U, 87662

Medical Administration Policy Committee, April 2020.

Available for comment, March 24, 2020 through May 8, 2020.

Medical Policy Group, May 2020 (9): Added CPT code 0202U due to Ad Hoc Coding Update related to Coronavirus.

Medical Policy Group, June 2020 (9): For clarification, added the following bullet point to policy statement: individuals with chronic diarrhea do not meet medical necessity for GIPP testing. For clarification, added definition of acute, persistent, and chronic diarrhea. No change to intent of policy statement.

Medical Policy Panel, June 2020

Medical Policy Group, July 2020 (9): Updates to Key Points, References. Added CPT code 87635. Added key words: COVID-19, Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2. Policy statement updated to support diagnostic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using NAAT.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.