| Coverage Policy Manual | |
| Policy #: | 2016004 |
| Category: | Laboratory |
| Initiated: | February 2016 |
| Last Review: | November 2023 |
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| Lab Test: Identification of Microorganisms Using Nucleic Acid Probes | |
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| Description: |
Nucleic acid probes are available for the identification of a wide variety of microorganisms. Nucleic acid probes can also be used to quantitate the number of microorganisms present. This technology offers advantages over standard techniques when rapid identification is clinically important, microbial identification using standard culture is difficult or impossible, and/or treatment decisions are based on quantitative results.
Nucleic Acid Probes
A nucleic acid probe is used to detect and identify species or subspecies of organisms by identifying nucleic acid sequences in a sample. Nucleic acid probes detect genetic materials, such as RNA or DNA, unlike other tests, which use antigens or antibodies to diagnose organisms.
The availability of nucleic acid probes has permitted the rapid direct identification of microorganisms’ DNA or RNA. Amplification techniques result in exponential increases in copy numbers of a targeted strand of microorganism-specific DNA. The most commonly used amplification technique is polymerase chain reaction (PCR) or reverse transcriptase (RT)-PCR. In addition to PCR, other nucleic acid amplification techniques have been developed such as transcription-mediated amplification, loop-mediated isothermal DNA amplification (LAMP), 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 give an assessment of 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 in terms of 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.
The “probe with quantification” techniques refer 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 the purposes of 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):
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.
Microorganisms and Clinical Disease
Various bacteria, viruses, and fungi that can cause clinical disease and can be detected with various nucleic acid probe techniques are briefly outlined below.
BK Polyomavirus
BK virus (BKV) is a double-stranded DNA, human polyomaviruses (Quest Diagnostics, 2005). More than 70 % of the adult population has antibodies to BKV and JCV, with primary infections typically occurring in childhood. Polymerase chain reaction testing detects the presence of the virus, not antibodies to the virus; thus, the detection of viral DNA may be indicative of an active infection (Randhawa et al, 2005). BK viruria increases in prevalence and magnitude (i.e., viral load) in immunocompromised patients. After kidney transplantation, high-level viruria, or shedding of urothelial or tubular epithelial cells with cytopathologic changes is seen in 30 to 60 percent of patients. However, only one-third of patients with BK viruria develop BK viremia and nephropathy (Hirsch et al, 2010; Sood et al, 2012).
Bartonella henselae or quintana
Bartonella henselae is responsible for cat-scratch disease. In most patients (90%-95%), the infection is a localized skin and lymph node disorder that occurs close to the site of inoculation and is characterized by chronic regional lymphadenopathy that develops about 2 weeks after contact with a cat. Less commonly, Bartonella henselae infection may lead to disseminated infection, which can manifest as visceral organ involvement, often with fever and hepatosplenomegaly, a variety of ocular manifestations, and neurological manifestations (most commonly, encephalopathy).
Bartonella may also cause an opportunistic infection in HIV-infected patients, in whom it is characterized by an acute febrile bacteremic illness, evolving to an asymptomatic bacteremia and finally indolent vascular skin lesions. The organism is typically detected using culture techniques, although an incubation period of 5 to more than 30 days is required. DNA probe technology has been investigated as a diagnostic technique.
Bartonella quintana has classically been associated with “trench fever,” which is characterized by systemic symptoms (bone pain, malaise, headache), along with recurring fevers of varying durations. Among HIV-infected patients, B. quintana has been associated with bacillary angiomatosis. Bartonella are fastidious organisms, making culture difficult. Histology of lesions affected by bacillary angiomatosis may be characteristic. Histology of affected lymph nodes or other tissue with B. henselae may demonstrate findings that are suggestive of cat-scratch disease, but which may be seen in other conditions. Two antigenic methods are available, one using indirect fluorescence assay (IFA) and one using enzyme immunosorbent assay (EIA), for both B. henselae and B. quintana infections. A positive serologic test is generally considered supportive, but not definitive, for Bartonella infection. Serologic methods may have limited yield in immunosuppressed patients.
Candida Species
A commonly occurring yeast, Candida species normally can be found on diseased skin, throughout the entire gastrointestinal tract, expectorated sputum, the female genitalia, and in urine of patients with indwelling Foley catheters. Clinically significant Candida infections are typically diagnosed by clinical observation or by identification of the yeast forms on biopsy specimens. Candida species are a common cause of vaginitis.
Chikungunya Virus
Chikungunya virus is transmitted by mosquitoes. Symptoms include, most commonly, fever and joint pain but may also include headache, muscle pain, joint swelling or rash. Symptoms can be severe, but infected individuals usually feel better within a week. In some people, joint pain may persist for months. Newborns infected around the time of birth, older adults (65 years and older) and people with medical conditions such as high blood pressure, diabetes, or heart disease are at risk for more severe disease. Once a person has been infected, he or she is likely to be protected from future infections.
Chlamydophila pneumoniae
Chlamydophila pneumoniae is an important cause of pneumonia, bronchitis, and sinusitis. Culture and isolation of the microorganism is difficult; a micro-immunofluorescence serum test may be used. The use of PCR amplification now offers a rapid diagnosis.
Chlamydia trachomatis
Chlamydia trachomatis is a significant intracellular pathogen causing, most prominently, urogenital disease (including pelvic inflammatory disease) and perinatal infections. C. trachomatis is also responsible for lymphogranuloma venereum. Due to its prevalence and association with pelvic inflammatory disease and perinatal disease, widespread testing of chlamydia is recommended; routine chlamydia testing has been adopted as a quality measure by Healthcare Effectiveness Data and Information Set. This microorganism can be diagnosed by: (1) identifying the typical intracytoplasmic inclusions in cytology specimens; (2) isolation in tissue culture; (3) demonstration of chlamydial antigen by enzyme-linked immunosorbent assay or by immunofluorescent staining; or (4) demonstration of DNA using a direct probe or amplification technique.
Cytomegalovirus
Cytomegalovirus (CMV) is a common virus that infects many, but rarely causes clinical disease in healthy individuals. However, this virus can cause protean disease syndromes, most prominently in immunosuppressed patients, including transplant recipients or those infected with the HIV virus. CMV can also remain latent in tissues after recovery of the host from an acute infection. Diagnosis depends on demonstration of the virus or viral components or demonstration of a serologic rise. DNA probe techniques, including amplification, have also been used to identify patients at risk for developing CMV disease as a technique to triage antiviral therapy.
Clostridium difficile
Clostridium difficile is an anaerobic, toxin-producing bacteria present in the intestinal tract. It causes clinical colitis when the normal intestinal flora is altered and overgrowth of C. difficile occurs. The common precipitant that disrupts the normal intestinal flora is previous treatment with antibiotics. The disorder has varying severity but can be severe and in extreme cases, life-threatening. C. difficile is easily spread from person-to-person contact and is a common cause of hospital-acquired outbreaks. Hospital infection control measures, such as wearing gloves and handwashing with soap and water, are effective methods of reducing the spread of C. difficile. The standard diagnosis is made by an assay for the C. difficile cytotoxin or by routine culture methods.
Enterovirus
Enteroviruses are single-stranded RNA viruses. This group of viruses includes the polioviruses, coxsackieviruses, echoviruses, and other enteroviruses. In addition to 3 polioviruses, there are more than 60 types of non-polio enteroviruses that can cause disease in humans. Most people who are infected with a non-polio enterovirus have no disease symptoms at all. Infected persons who develop illness usually develop either mild upper respiratory symptoms, flu-like symptoms with fever and muscle aches, or an illness with rash. Less commonly, enteroviruses can cause “aseptic” or viral meningitis, encephalitis, acute paralysis, and/or myocarditis. Enteroviral infections can cause life-threatening systemic infections in neonates, which are often associated with myocarditis or fulminant hepatitis. The use of amplified probe DNA test(s) can be used to detect enteroviruses.
Gardnerella vaginalis
A common microorganism, Gardnerella vaginalis is typically found in the human vagina and is usually asymptomatic. However, G. vaginalis is found in virtually all women with bacterial vaginosis and is characterized by inflammation and perivaginal irritation. The microorganism is typically identified by culture. The role of G. vaginalis in premature rupture of membranes and preterm labor is also under investigation.
Hepatitis B, C, and G
Hepatitis is typically diagnosed by a pattern of antigen and antibody positivity. However, the use of probe technology permits the direct identification of hepatitis DNA or RNA, which may also provide prognostic information. Quantification techniques are used to monitor the response to direct-acting antiviral, interferon, and/or ribavirin therapy in patients with hepatitis C.
Herpes Simplex Virus
Herpes simplex infection of the skin and mucous membranes is characterized by a thin-walled vesicle on an inflammatory base typically in the perioral, ocular, or genital area, although any skin site may be involved. The diagnosis may depend on pathologic examination of cells scraped from a vesicle base or by tissue culture techniques. Herpes simplex encephalitis is one of the most common and serious sporadic encephalitides in immunocompetent adults. The PCR technique to detect herpes simplex virus in the cerebrospinal fluid has been used to provide a rapid diagnosis of herpes virus encephalitis.
Human Herpesvirus 6
Human herpesvirus 6 (HHV-6) is the common collective name for HHV-6A and HHV-6B. These closely related viruses are 2 of the 9 herpesviruses known to have humans as their primary host. HHV-6 is widespread in the general population. In immunocompetent hosts, HHV-6 primary infection typically causes a mild, self-limited illness in childhood, often roseola. HHV-6 may also cause meningitis and encephalitis in children and adults. Diagnosis is typically based on rising serologic titers. In immunosuppressed patients, HHV-6 reactivation may cause meningitis, encephalitis, pneumonitis,
and/or bone marrow suppression (Yoshikawa, 2004).
HIV-1 and HIV-2
DNA probe technology for HIV-1 is widely disseminated, and HIV-1 quantification has become a standard laboratory test in HIV-1 infected patients. HIV-2 can result in severe immunosuppression and the development of serious opportunistic diseases. Although HIV-2 has been reported in the United States, it is most commonly found in Western Africa. Blood donations are routinely tested for HIV-2, but due to its rarity in this country, clinical testing for HIV-2 is typically limited to those in contact with persons in a country where HIV-2 is endemic or when the clinical picture suggests HIV infection but testing for HIV-1 is negative.
Influenza Virus
Influenza virus is a very common pathogen that accounts for a high burden of morbidity and mortality, especially in elderly and immunocompromised patients. The most common means of identifying influenza is by viral culture, which takes 48 to 72 hours to complete. Influenza is highly contagious and has been the etiology of numerous epidemics and pandemics. Identification of outbreaks is important so that isolation measures may be undertaken to control the spread of disease. Antiviral treatment can be effective if instituted early in the course of disease. Therefore, rapid identification of influenza virus is important in making treatment decisions for high-risk patients and in instituting infection control practices.
Legionella pneumophila
Legionella pneumophila is among the most common microbial etiologies of community-acquired pneumonia. Laboratory diagnosis depends on culture, direct fluorescent antibody tests, urinary antigens, or DNA probe. DNA probe techniques have also been used in epidemiologic investigations to identify the source of a Legionella outbreak.
Mycobacteria Species
Although mycobacterium can be directly identified in sputum samples (i.e., acid fast bacilli), these organisms may take 9 to 16 days to culture. DNA probes have also been used to identify specific mycobacterial groups (i.e., mycobacterial tuberculosis, avian complex, intracellulare) after culture. In addition, amplification techniques for Mycobacterium tuberculosis may be used in patients who have a positive smear. The rapid identification of M. tuberculosis permits prompt isolation of the patient and identification of the patient’s contacts for further testing.
Mycoplasma pneumoniae
Mycoplasma pneumoniae is an atypical bacterium that is a common cause of pneumonia. It is most prevalent in younger patients below age 40 years and in individuals who live or work in crowded areas such as schools or medical facilities. The infection is generally responsive to antibiotics of the macrolide or quinolone class. Most patients with M. pneumonia recover completely, although the course is sometimes prolonged for up to 4 weeks or more. Extrapulmonary complications of M. pneumonia occur uncommonly, including hemolytic anemia and the rash of erythema multiforme.
Neisseria gonorrhoeae
Isolation by culture is the conventional form of diagnosis for this common pathogen, but culture requires specific sampling and plating techniques. Direct DNA probes and amplification techniques have also been used. Neisseria is often tested for at the same time as chlamydia.
Papillomavirus
Papillomavirus species are common pathogens that produce epithelial tumors of the skin and mucous membranes, most prominently the genital tract. Physical examination is the first diagnostic technique. Direct probe and amplification procedures have been actively investigated in the setting of cervical lesions. The ViraPap test is an example of a commercially available direct probe technique for identifying papillomavirus. There has also been interest in evaluating the use of viral load tests of HPV to identify patients at highest risk of progressing to invasive cervical carcinoma.
SARS-CoV-2
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of COVID-19 and is of the genus Betacoronavirus. The virus primarily spreads between people through close contact and via respiratory droplets produced from coughs or sneezes.
Streptococcus, Group A
Also referred to as Streptococcus pyogenes, this pathogen is the most frequent cause of acute bacterial pharyngitis. It can also give rise to a variety of cutaneous and systemic conditions, including rheumatic fever and post-streptococcal glomerulonephritis. Throat culture is the preferred method for diagnosing streptococcal pharyngitis. In addition, a variety of commercial kits are now available that use antibodies for the rapid detection of group A carbohydrate antigen directly from throat swabs. While very specific, these kits are less sensitive than throat cultures, so a negative test may require confirmation from a subsequent throat culture. DNA probes have also been used for direct identification of streptococcus and can be used as an alternative to a throat culture as a back-up test to a rapid, office-based strep test.
Streptococcus, Group B
Also referred to as Streptococcus agalactiae, group B streptococcus (GBS), is the most common cause of sepsis, meningitis, or death among newborns. Early-onset disease, within 7 days of birth, is related to exposure to GBS colonizing the mother’s anogenital tract during birth. The Centers for Disease Control and Prevention, the American College of Obstetrics and Gynecology, and the American Academy of Pediatricians recommend either maternal risk assessment or screening for GBS in the perinatal period. Screening consists of obtaining vaginal and anal specimens for culture at 35 to 37 weeks of gestation. The conventional culture and identification process requires 48 hours. Therefore, there has been great interest in developing rapid assays using DNA probes to shorten the screening process, so that screening could be performed in the intrapartum period with institution of antibiotics during labor.
Trichomonas vaginalis
Trichomonas is a single-cell protozoan that is a common cause of vaginitis. The organism is sexually transmitted and can infect the urethra or vagina. The most common way of diagnosing Trichomonas is by clinical signs and by directly visualizing the organism by microscopy in a wet prep vaginal smear. Culture of Trichomonas is limited by poor sensitivity. Treatment with metronidazole results in a high rate of eradication. The disease is usually self-limited without sequelae, although infection has been associated with premature birth and higher rates of HIV transmission, cervical cancer, and prostate cancer.
West Nile Virus
West Nile virus (WNV), an infectious disease carried by mosquitoes, first appeared in the United States in 1999. Persons who get WNV usually have no symptoms or mild symptoms which include, headache, fever, skin rash, body aches and swollen lymph glands. Symptoms may last a few days to several weeks but usually go away on their own.
West Nile virus can cause encephalitis or meningitis and can be life-threatening.
Older people and those with weakened immune systems are most at risk. There are no specific vaccines or treatments for human WNV disease.
Regulatory Status
The U.S. Food and Drug Administration maintains a list of nucleic acid amplification tests (NAATs) that have been cleared by the Center for Devices and Radiological Health.
A list of current U.S. Food and Drug Administration (FDA)‒approved or cleared nucleic acid-based microbial tests is available at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm330711.htm
The Association of Molecular Pathology website also provides a list of current FDA approved tests for diagnosis of infectious diseases (available online at: http://www.amp.org/FDATable/FDATable.pdf).
The following tests are FDA-approved/cleared but do not have specific CPT codes:
Bacillus anthracis (Real-time PCR), Coxiella burnetii (Q fever) (Real-time PCR), Enterococcus faecalis (PNA FISH), Escherichia coli and Pseudomonas aeruginosa (PNA FISH), Escherichia coli and/or Klebsiella pneumoniae and Pseudomonas aeruginosa (PNA FISH), Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (PNA FISH), Francisella tularensis (Real-time PCR), Leishmania (Real-time PCR), Yersinia pestis (Real-time PCR) Adenovirus Multiplex (real-time RT-PCR), Avian flu (Real-time RT-PCR), Human metapneumovirus Multiplex (real-time RT-PCR), Influenza virus A/H5 (Real-time RT-PCR), Influenza virus H1N1 (Real-time RT-PCR), Dengue virus (Real-time RT-PCR), Gram-positive/gram-negative bacteria panel.
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Policy/ Coverage: |
Infectious disease testing ordered or performed as a panel, except as specifically listed in this policy as covered, does not meet primary coverage criteria or is considered not medically necessary. (See statement of non-coverage below.)
Effective January 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
Note: The technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both quantification with either amplification or direct probes, is not warranted.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Infectious disease testing ordered or performed as a panel except as specifically listed in this policy as covered (above), does not meet member benefit certificate primary coverage criteria of effectiveness in improving health outcomes and are noncovered services. For members with contracts without primary coverage criteria, use of infectious disease testing ordered or performed as a panel, except as specifically listed in this policy as covered (above), is considered not medically necessary. Not medically necessary services are considered contract exclusions in most member benefit certificates of coverage.
Any other use of nucleic acid testing with quantification of viral load (other than specifically listed above) does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of nucleic acid testing with quantification of viral load (other than specifically listed above) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load does not meet member benefit certificate primary coverage criteria, or for those members without primary coverage criteria, is considered investigational for the following microorganisms:
Effective August 2023 through December 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
Note: The technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both quantification with either amplification or direct probes, is not warranted.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Infectious disease testing ordered or performed as a panel except as specifically listed in this policy as covered (above), does not meet member benefit certificate primary coverage criteria of effectiveness in improving health outcomes and are noncovered services. For members with contracts without primary coverage criteria, use of infectious disease testing ordered or performed as a panel, except as specifically listed in this policy as covered (above), is considered not medically necessary. Not medically necessary services are considered contract exclusions in most member benefit certificates of coverage.
Any other use of nucleic acid testing with quantification of viral load (other than specifically listed above) does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of nucleic acid testing with quantification of viral load (other than specifically listed above) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load does not meet member benefit certificate primary coverage criteria, or for those members without primary coverage criteria, is considered investigational for the following microorganisms:
Effective January 2023 through July 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
Note: The technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both quantification with either amplification or direct probes, is not warranted.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Infectious disease testing ordered or performed as a panel except as specifically listed in this policy as covered (above), does not meet member benefit certificate primary coverage criteria of effectiveness in improving health outcomes and are noncovered services. For members with contracts without primary coverage criteria, use of infectious disease testing ordered or performed as a panel, except as specifically listed in this policy as covered (above), is considered not medically necessary. Not medically necessary services are considered contract exclusions in most member benefit certificates of coverage.
Any other use of nucleic acid testing with quantification of viral load (other than specifically listed above) does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of nucleic acid testing with quantification of viral load (other than specifically listed above) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load does not meet member benefit certificate primary coverage criteria, or for those members without primary coverage criteria, is considered investigational for the following microorganisms:
Effective October 2022 through December 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) meets member benefit certificate primary coverage criteria for the following microorganisms:
Note: The technique for quantification includes both amplification and direct probes; therefore, simultaneous coding for both quantification with either amplification or direct probes, is not warranted.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Infectious disease testing ordered or performed as a panel except as specifically listed in this policy as covered (above), does not meet member benefit certificate primary coverage criteria of effectiveness in improving health outcomes and are noncovered services. For members with contracts without primary coverage criteria, use of infectious disease testing ordered or performed as a panel, except as specifically listed in this policy as covered (above), is considered not medically necessary. Not medically necessary services are considered contract exclusions in most member benefit certificates of coverage.
Any other use of nucleic acid testing with quantification of viral load (other than specifically listed above) does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of nucleic acid testing with quantification of viral load (other than specifically listed above) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load does not meet member benefit certificate primary coverage criteria, or for those members without primary coverage criteria, is considered investigational for the following microorganisms:
Due to the length of the policy, criteria for dates of service prior to October 1, 2022, is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
Bartonella henselae or quintana
Microbiologic detection of Bartonella henselae or quintana is difficult. A monoclonal antibody (mAb) to B.henselae has
become commercially available, along with several types of PCR testing. A single-step PCR-based assay which amplifies a fragment of the 16S-23S ribosomal RNA (rRNA) intergenic region conserved in Bartonella species had 80% and 100% sensitivity in feline samples with 10 to 30 CFU/mL bacteria and greater than 50 CFU/mL bacteria, respectively (Jensen, 2000). An earlier study demonstrated high sensitivity of a PCR-based assay for the Bartonella riboflavin synthase gene in bacterial samples and samples from feline samples and human lymph node samples (Johnson, 2003). Another study reported high sensitivity of a PCR-based enzyme immunoassay in human lymph node samples (Sander, 1999).
In 2005, Hansmann et al reported on the diagnostic value of a PCR test for the B. henselae htrA gene in lymph node biopsy specimens or cytopunctures from 70 patients with suspected cat-scratch disease (Hansmann, 2005).Twenty-nine patients were considered to have definite cat-scratch disease based on clinical criteria; 16 were considered to have possible cat-scratch disease; and 26 subjects had an alternative diagnosis and served as controls. PCR analysis had specificity of 100%. In patients with definite cat-scratch disease, PCR testing was positive for 76% (95% confidence interval [CI], 56.5% to 89.7%); in those with possible cat-scratch disease, PCR testing was positive in 20% (95% CI, 4.3% to 48.1%).
A 2009 study by Caponetti et al (Capontetti, 2009) compared immunohistochemical analysis (IHC) for diagnosing B.henselae on surgical specimens with PCR detection and serologic testing. The study included 24 formalin-fixed, paraffin-embedded (FFPE) cases of lymphadenitis with histologic and/or clinical suspicion of B. henselae. Control cases included 14 cases of lymphadenopathy. FFPE tissue sections were evaluated with a mAb to B. henselae, Steiner silver stain (SSS), and PCR that targeted B. henselae and B. quintana. Positive cases were as follows: SSS, 11 (46%); PCR, 9 (38%); and IHC, 6 (25%). Only 2 cases (8%) were positive for all 3 techniques. All control cases were negative for IHC and PCR. The diagnostic sensitivity of these 3 tests is low for bartonellae. SSS seems to be the most sensitive test but is the least specific. PCR is more sensitive than IHC and may, therefore, serve as a helpful second-line test on all IHC negative cases.
B. henselae infections can cause a wide range of symptoms, from self-limited regional lymphadenopathy to disseminated infection involving visceral organs, the central nervous system, or the heart. B. henselae may also present with fever of unknown origin. Antibiotic therapy is not always needed for uncomplicated infections, but it is required for severe or systemic infections. In cases where B. Henselae is suspected and treatment will change as a result of a positive test, the use of Bartonella PCR testing has potential for clinical utility.
Candida Species
Candida infections are most commonly caused by Candida albicans but other species may be responsible. In complicated or severe cases, eg, candidemia and invasive focal infections, or in compromised patients, it may be necessary to identify the infecting Candida species for appropriate treatment planning. DNA probes are available to aid in the diagnosis of possible Candida species infections. Amplified peptide nucleic acid tests have demonstrated high sensitivity and specificity levels of up to 100% (Flahaut, 1998; Xia, 2012). Some tests have been able to detect up to 6 Candida species.9 A real-time qPCR assay, developed for the detection of the most common pathogenic Candida species using a single-reaction PCR assay targets a selected region of the 28S subunit of the fungal rDNA gene. In a 2012 study, the sensitivity and specificity of an assay based on quantitative real-time assay using duplex mutation primers were 100% and 97.4%, respectively (Xia, 2012). The data suggest that this assay may be appropriate for use in clinical laboratories as a simple, low-cost, and rapid screening test for the most frequently encountered Candida species.
Vulvovaginal candidiasis can typically be diagnosed by microscopy, and most cases are caused by C.albicans. Other species, such as Candida glabrata, may be responsible but are less common and may be difficult to detect by microscopy. Therefore, identification of Candida subspecies is not usually necessary and should be limited to use in complicated, recurrent or persistent cases that are resistant to azole/antifungal treatment. Additionally, symptomatic patients with negative microscopy may warrant subspecies testing (CDC, 2010).
Central Nervous System Bacterial and Viral Panel
The standard approach to the diagnosis of meningitis and encephalitis is culture and pathogen-specific PCR testing of cerebrospinal fluid (CSF) based on clinical characteristics. These techniques have a slow turnaround time, which can delay administration of effective therapies and lead to unnecessary empirical administration of broad-spectrum antimicrobials.
The FilmArray Meningitis/Encephalitis Panel (BioFire Diagnostics, Salt Lake City, UT) is a nucleic acid-based test that simultaneously detects multiple bacterial, viral, and yeast nucleic acids from CSF specimens obtained via lumbar puncture from patients with signs and/or symptoms of meningitis and/or encephalitis. The test has been cleared for marketing through the U.S. Food and Drug Administration 510(k) process. The test identifies 14 common organisms responsible for community-acquired meningitis or encephalitis:
Bacteria: Escherichia coli K1; Haemophilus influenzae; Listeria monocytogenes; Neisseria meningitides; Streptococcus agalactiae; Streptococcus pneumoniae; Viruses: Cytomegalovirus; Enterovirus; Herpes simplex virus 1; Herpes simplex virus 2; Human herpesvirus 6; Human parechovirus; Varicella zoster virus; Yeast: Cryptococcus neoformans/gattii.
Run-time is approximately 1 hour per specimen.
The clinical validity of the test has been analyzed using 1560 CSF specimens collected at 11 U.S. sites and several smaller studies. The following study selection criteria were used to assess whether the central nervous system panel is clinically valid: (1) eligibility and selection are described, and the study population represents the population of interest; (2) the test is compared with a credible reference standard; (3) studies report sensitivity, specificity, and preferably predictive values; studies that completely report true- and false-positive results are ideal. Several studies failed to meet selection criteria (Wootton, 2016; Launes, 2017; Messacar, 2016; Rhein, 2016; Arora, 2017; Lee, 2017).
In the largest study (Leber et al, 2016), 1560 samples were tested (Leber, 2016). The samples were from children and adults with available CSF but not limited to those with high pretest probability for an infectious cause for meningitis or encephalitis. Even the most prevalent organisms were present only a small number of times in the samples. The specificities ranged from 98% to 100% and, given the high number of true negatives, the specificities were estimated with tight precision. However, given the small number of true positives, the sensitivities to detect any given organism could not be estimated with precision. A total of 141 pathogens were detected in 136 samples with the FilmArray and 104 pathogens detected using comparator methods; 43 FilmArray results were “false-positive” compared with the comparator method and six were “false-negative.” For 21 of the 43 “false-positives,” repeat testing of the FilmArray, comparator, or additional molecular testing supported the FilmArray results. The remaining 22 “false-positives” (16% of all positives) were unresolved. Codetections were observed in 3.7% (5/136) positive specimens. All five included a bacterial and viral positive result, and all 5 specimens were found to have a false-positive result demonstrated by comparator testing. The investigators suggested that the discrepancies could have been due to specimen contamination or another problem with the assay configuration or testing process.
The smaller studies were consistent with Leber (2016) in estimating the specificities for all included pathogens to be greater than 98%. However, there were also a very low number of true positives for most pathogens in these studies and thus the estimates of sensitivities were imprecise.
In summary, the FilmArray ME Panel provides fast diagnoses compared with standard culture and pathogen-specific PCR and, because it combines multiple individual nucleic acid tests, clinicians can test for several potential pathogens simultaneously. The test uses only a small amount of CSF, leaving remaining fluid for additional testing if needed. The test is highly specific for the included organisms. However, due to the low prevalence of these pathogens overall, the sensitivity for each pathogen is not well-characterized. More than 15% of positives in the largest study were reported to be false-positives, which could cause harm if used to make clinical decisions. Also, a negative panel result does not exclude infection due to pathogens not included in the panel.
Chlamydophila pneumoniae or Chlamydia trachomatis
Probes are commercially available for the detection of Chlamydophila pneumoniae or Chlamydia trachomatis. A study by Stanek et al (Stanek, 2012) demonstrated a Chlamydia-specific real-time PCR which targeted the conserved 16S rRNA gene. The test can detect at least 5 DNA copies and shows very high specificity without cross-amplification from other bacterial DNA. The PCR was validated with 128 clinical samples positive or negative for C. trachomatis or C. pneumoniae. Of 65 positive samples, 61 (93.8%) were found to be positive with the new PCR. Another study (Marangoni, 2012) demonstrated the VERSANT® CT/GC DNA 1.0 Assay performed with 99.2% specificity for C. trachomatis detection and sensitivity of 100%.
C. trachomatis, microbial culture is technically difficult, and nucleic acid amplification tests for C.trachomatis are generally preferred over other diagnostic methods, including direct fluorescent antibody tests, enzyme immunoassays, and nucleic acid hybridization tests (CDC, 2014). Diagnosis of C. trachomatis has clinical utility in a variety of settings. Treatment of individuals with C. trachomatis genital infection prevents sexual transmission and complications, including pelvic inflammatory disease. Treatment of pregnant women will prevent the transmission of infection to infants during delivery. Antibiotic treatment is indicated in neonatal conjunctivitis caused by C. trachomatis.
PCR-based tests specific for C. pneumoniae have been described in the investigational setting (Tondella, 2002; Gaydos, 1994).
Gaydos et al compared tissue culture, PCR/EIA, direct fluorescent antibody (DFA) stain, and serology for the diagnosis of C. pneumoniae in 56 patients with respiratory symptoms and 80 asymptomatic individuals (Gaydos, 1994). Determining test characteristics is limited by the lack of a true gold standard, given the difficulty in culturing C. pneumoniae. However, when culture- and/or DFA-positive results were used as a reference, PCR had a sensitivity and specificity of 76.5% and 99.0%, respectively. However, the use of PCR-based tests for C. pneumoniae in clinical practice has not been well defined.
Clostridium difficile
DNA probes for Clostridium difficile using PCR have been commercially available since 2009 (Barbut, 2011; Eastwood, 2009; Huang, 2009; Knetsch, 201).
Eastwood et al (Eastwood, 2009) compared the performance characteristics of numerous DNA probes with cytotoxic assays and cultures. The results demonstrated a mean sensitivity of 82.8% (range, 66.7%-91.7%) and a mean specificity of 95.4% (range, 90.9%-98.8%). Rapid identification of C. difficile allows for early treatment of the disease and timely institution of isolation measures to reduce transmission. Because of the advantages of early identification of C. difficile, the use of PCR-based testing for C. difficile has potential to improve health outcomes.
Cytomegalovirus
Diagnosis of CMV can be made by culture and/or serologies. However, CMV culture for establishing a diagnosis is limited by the slow growth of CMV and low sensitivity. Serologies provide indirect evidence of current and/or historical infection. A variety of tests to detect CMV DNA have been developed, including but not limited to Hybrid Capture (Digene Corp.), Amplicor CMV Monitor Tests (Roche Molecular Diagnostics), and TaqMan. The specific techniques used may vary by local availability, but studies have suggested that all provide complementary information (Boivin, 2000; Humar, 1999; Li, 2003; Razonable, 2003 Weinberg, 2000).
Clinically, molecular assays for CMV are primarily used to quantify CMV viral load, particularly to identify asymptomatic immunosuppressed patients (ie, transplant recipients) who would be candidates for preemptive antiviral therapy. For example, among transplant recipients, CMV infections account for about two-thirds of deaths in the immediate posttransplant period (ie, up to 50 days posttransplant), and thus, a variety of preventive therapies have been investigated. One strategy proposes that all at-risk patients (ie, seropositive patients, or seronegative patients receiving a seropositive organ) be treated prophylactically with antiviral therapy during the first 100 days after transplantation. While this strategy has been shown to be effective in reducing the risk of CMV disease, it results in a large number of patients being treated unnecessarily. Therefore, preemptive therapy has become an accepted option, in which antiviral therapy is initiated when a laboratory technique identifies an increasing viral load. Late CMV disease, defined as occurring after 100 days, is also a concern, and viral loads can also be monitored to prompt antiviral therapy.
Enterovirus
Amplified DNA probes are available for detecting this group of viruses including the polioviruses, coxsackieviruses, echoviruses, and other enteroviruses. In addition to 3 polioviruses, there are more than 60 types of non‒polio enteroviruses that can cause disease in humans. Several FDA-approved test kits are available including the GeneXpert Enterovirus Assay (GXEA), with a sensitivity, specificity, PPV, and NPV of 82.1%, 100%, 100%, and 96.2%, respectively. In this study, molecular assays were superior to viral culture for detecting enterovirus RNA in cerebrospinal fluid. GXEA showed a high specificity but a lower sensitivity for the detection of enterovirus RNA compared with the RT-qPCR assay.25 In at least clinical situations, the yield of virus identification with PCR has been shown to be higher than with viral culture (eg, suspected pediatric enteroviral encephalomyelitis) (Tsai, 2014).
Enteroviruses are associated with a wide spectrum of clinical symptoms, including exanthematous/enanthematous syndromes (eg, hand-foot-and-mouth disease, herpangina), viral meningitis and encephalitis, acute paralysis, and myocarditis. In neonates, enteroviruses can cause life-threatening systemic infections. In general, management is supportive and addresses symptoms. No antiviral medications are currently approved for the treatment of enterovirus infections. However, there are some situations in which PCR-based testing for enteroviruses allows for discontinuation of therapy for alternative diagnoses (eg, bacterial meningitis). For example, the use of enterovirus PCR testing has been associated with shorter hospital length of stay among febrile infants evaluated for serious bacterial infection with lumbar puncture (Dewan, 2010). Similarly, an observational study reported that the use of enterovirus PCR testing is associated with reduced hospital stay and reduced antibiotic duration in adults with aseptic Meningitis (Giulieri, 2015).
Vancomycin-Resistant Enterococcus
Probes are available for detecting vancomycin resistance of organisms (eg, for Enterococcus). These probes are able to detect vancomycin resistance in a rapid and accurate manner so that appropriate antibiotic selection can be made and infectious precautions, such as isolation, can be instituted (Appleman, 2004; Patel, 1997).
Gardnerella vaginalis
A 2006 study (Gazi, 2006) evaluated vaginal specimens from 321 symptomatic women that were analyzed for bacterial vaginosis, by both Gram stain using Nugent criteria and a DNA hybridization test (Affirm VPIII hybridization test). Of the 321 patients, 115 (35.8%) were Gram-positive for bacterial vaginosis and 126 (39.2%) were negative. A total of 80 patients (25.0%) demonstrated intermediate Gram staining that was also considered negative. The DNA hybridization test detected Gardnerella vaginalis in 107 (93.0%) of 115 vaginal specimens positive for bacterial vaginosis diagnosed by Gram stain. Compared with the Gram stain, the DNA hybridization test had a sensitivity of 87.7% and a specificity of 96.0%. PPVs and NPVs of the DNA hybridization test were 93.0% and 92.7%, respectively. The study concluded the Affirm VPIII hybridization test correlated well with Gram stain and may be used as a rapid diagnostic tool to exclude bacterial vaginosis in women with genital complaints.
Gastrointestinal Pathogen Panel
Infectious gastroenteritis may be caused by a broad spectrum of pathogens resulting in the primary symptom of diarrhea. Panels for gastrointestinal pathogens uses multiplex amplified probe techniques and multiplex reverse transcription for the simultaneous detection of many gastrointestinal pathogens such as C. difficile, Escherichia coli, Salmonella, Shigella, norovirus, rotavirus, and Giardia. Several studies of gastrointestinal pathogen panels demonstrate overall high sensitivities and specificities and indicate the panels may be useful for detecting causative agents for gastrointestinal infections (Claas, 2013; Khare, 2014; Onori, 2014).
Studies suggest that panels limited to bacterial pathogens have similarly high sensitivities and specificities compared with bacterial culture (Biswas, 2014). Beckmann et al reported findings on the use of a commercially available gastrointestinal pathogen panel (Luminex Molecular Diagnostics, Toronto, ON) in a group of 120 pediatric patients with suspected viral gastroenteritis and in a group of 151 adult and 25 pediatric patients (n=176) returning from the tropics with gastrointestinal symptoms (Beckmann, 2014). Positive results were detected in 21 samples from adults (11% of 185 samples) and in 66 pediatric samples (52% of samples).
Other studies have evaluated panels for bacteria associated with hemorrhagic diarrhea (Salmonella species, Shigella species, enterohemorrhagic E. coli, and Campylobacter species) and have reported high sensitivities and specificities (Al-Talib, 2014). Other panels are comprised of only viral infectious gastroenteritis pathogens (Jiang, 2014). The yield of testing is likely to vary based on panel composition (Khare, 2014). Access to a rapid method for etiologic diagnosis of gastrointestinal infections may lead to more effective early treatment and infection-control measures. However, in most instances, when there is suspicion for a specific pathogen, individual tests could be ordered. There may be a subset of patients with an unusual presentation who would warrant testing for a panel of pathogens at once, but that subset has not been well defined.
Hepatitis B
Hepatitis B genotyping has been used to predict response to various antiviral agents. In addition, viral load is used to determine which patients with hepatitis B are candidates for antiviral therapy. Guidelines from the National Institutes of Health (2009) (Sorrell, 2009) and the American Association for the Study of Liver Diseases (Lok, 2009) include quantitative hepatitis B DNA levels in the diagnostic criteria for chronic and resolved hepatitis B and inactive hepatitis B carrier states.
Hepatitis C
Diagnostic tests for hepatitis C can be divided into 2 general categories: (1) serological assays that detect antibody to hepatitis C virus (anti-HCV); and (2) molecular assays that detect, quantify, and/or characterize HCV RNA genomes within an infected patient. Detection of HCV RNA in patient specimens by PCR provides evidence of active HCV infection and is used to confirm the diagnosis and monitor the response to antiviral therapy. The use of direct-acting antiviral agents (with or without interferon) has the potential to treat and cure chronic hepatitis C. Therapy-induced sustained virologic remission has been shown to reduce liver-related death, liver failure, and to a lesser extent, hepatocellular carcinoma.
Hepatitis G
It is possible that hepatitis C is part of a group of GB viruses, rather than just a single virus. It is unclear if hepatitis G causes a type of acute or chronic illness. When diagnosed, acute hepatitis G infection has usually been mild and brief and there is no evidence of serious complications, but it is possible that, like other hepatitis viruses, it can cause severe liver damage resulting in liver failure. The only method of detecting hepatitis G is by real-time PCR and direct sequencing for 4 randomly selected samples followed by phylogenetic analysis.
Herpes Simplex Virus
Typing of HSV isolates is required to identify the virus isolated in culture. The methods available for this include antigen detection by immunofluorescence (IF) assays and PCR. A 2009 cross-sectional study (Abraham, 2009) utilized 4 reference strains and 42 HSV isolates obtained from patients between September 1998 and September 2004. These were subjected to testing using a MAb-based IF test and a PCR that detects the polymerase (pol) gene of HSV isolates. The observed agreement of the MAb IF assay with the pol PCR was 95.7%. A total of 54.8% (23/42) of isolates tested by IF typing were found to be HSV-1, 40.5% (17/42) were HSV-2, and 2 (4.8%) were untypable using the MAb IF assay. The 2 untypable isolates were found to be HSV-2 using the pol PCR. According to the American Academy of Family Physicians, antiviral medications have expanded treatment options for the 2 most common cutaneous manifestations, HSV-1 and HSV-2. Acyclovir therapy remains an effective option; however, famciclovir and valacyclovir offer improved oral bioavailability and convenient oral dosing schedules but at a higher cost. Patients who have 6 or more recurrences of genital herpes per year can be treated with daily regimens which are effective in suppressing 70% to 80% of symptomatic recurrences.
Human Herpesvirus 6
Human herpesvirus 6 (HHV-6) can be detected with a number of immunoassays. The high rate of seropositivity in the general population makes interpreting positive results difficult. Historically, paired samples with a rise in antibody titer have been needed to diagnose an active infection. Qualitative and quantitative PCR tests are available for HHV-6 in blood and other samples. At least 1 evaluation of rt-PCR detecting viral mRNA transcripts in hematopoietic stem cell transplant (HSCT) subjects showed good analytic validity (Bressollette-Bodin, 2014).
Most often, in healthy patients, HHV-6 causes no symptoms or a mild-self-limited illness. In these cases, a definitive diagnosis of HHV-6 has little utility. However, primary HHV-6 infection can cause severe disease including thrombocytopenia, hepatitis, myocarditis, and meningoencephalitis. In immunosuppressed patients, particularly HSCT recipients, HHV-6 reactivation may cause a range of severe symptoms. A number of antiviral agents are active against HHV-6 (eg, ganciclovir, foscarnet). A variety of treatment strategies are used for immunosuppressed patients, which can be classified as prophylactic (all at-risk patients treated), preemptive (patients treated when viral replication is detected), and curative (patients treated when disease is confirmed) (Agut, 2015). The use of a quantitative HHV-6 assay may be used in treatment-related decisions.
Human Immunodeficiency Virus 1
Validated DNA probes are widely available for diagnosis and HIV-1 quantification. Quantification is standard of care to determine viral load in infected patients to monitor response to antiretroviral therapies.
Human Immunodeficiency Virus 2
DNA probes are available for diagnosis and quantification of HIV-2. HIV-2 is most commonly found in Western Africa, although it has been reported in the United States. Blood donations are routinely tested for HIV-2, but clinical testing for HIV-2 is typically limited to those in contact with persons in a country where HIV-2 is endemic or when clinical evaluation suggests HIV infection, but testing for HIV-1 is negative. HIV-2 quantification is regularly done to determine viral load in infected patients to monitor response to antiretroviral therapies.
Human Papillomavirus
There has also been research interest in exploring the relationship of human papilloma viral load and progression of low-grade cervical lesions to cervical cancer. While studies have reported that high-grade lesions are associated with higher viral loads,(Abba, 2003; Lorincz, 2002) clinical utility is based on whether or not the presence of increasing viral loads associated with low-grade lesions is associated with disease progression. For example, current management of cervical smears with “atypical cells of uncertain significance” suggests testing with HPV, and then, if positive, followed by colposcopy. It is hypothesized that colposcopy might be deferred if a low viral load were associated with a minimal risk. However, how treatment decisions may be tied to measurements of viral load is unclear (Josefsson, 2000; Schlecht, 2003; Ylitalo, 2000). Persistent infection with various HPV genotypes has also been linked with cervical lesions and may influence treatment decisions. HPV genotypes 16 and 18 have been most associated with carcinogenesis. Patients with high-risk HPV genotypes may warrant direct referral to colposcopy (Saslow, 2012; Wheeler, 2014).
Influenza Virus
Numerous different strains of influenza virus can be identified by DNA probes. Published studies indicate improved sensitivity of PCR for identifying influenza and distinguishing influenza from related viruses. Lassauniere et al (Lassauniere, 2010) used a multiplex RT-PCR probe to identify 13 respiratory viruses, including influenza A and B. Screening of 270 samples that were negative on immunofluorescence assays revealed the presence of a respiratory virus in 44.1%. Probes have also been developed to identify specific strains of influenza associated with epidemics, such as the H1N1 influenza virus (Wenzel, 2009). Because of the importance of early identification of outbreaks for infection-control purposes and of initiating antiviral therapy early in the course of illness (if indicated), there is clinical utility for the use of these tests.
Legionella pneumophila
Typically, methods to detect Legionella pneumophila, which is associated with 90% of culture-confirmed Legionella species infections, have included culture, serology, and/or urine antigen testing, which are limited by relatively low sensitivities and long turnaround times.
DNA probes for Legionella pneumophila have been developed. A 2010 study (Maurin, 2010) compared the usefulness of 2 quantitative RT-PCR assays (qrt-PCRmip targeting L. pneumophila, and qrt-PCR16S targeting all Legionella species) performed on lower respiratory tract (LRT) samples for diagnostic and prognostic purposes in 311 patients hospitalized for community-acquired pneumonia (CAP). The Now Legionella urinary antigen test from Binax (Portland, ME) was used as a reference test. One subset of 255 CAP patients admitted to Chambery hospital in 2005 and 2006 was evaluated and the sensitivities, specificities, PPVs and NPVs for both qrt-PCR tests were 63.6%, 98.7%, 77.7%, and 97.4%, respectively.
Diederen et al evaluated the use of an rt-PCR assay for Legionella species in 151 subjects with respiratory infections, 37 (25%) of whom fulfilled the European Working Group for Legionella Infections criteria for Legionella pneumonia and were considered to have Legionella pneumonia (Diederen, 2008). For a 16S rRNA-based PCR, the estimated sensitivity and specificity were 86% (95% CI, 72% to 95%) and 95% (95% CI, 90% to 98%), respectively. For a mip gene-based PCR, the estimated sensitivity and specificity were 92% (95% CI, 78% to 98%) and 98% (95% CI, 93% to 100%), respectively. Another study reported a significantly higher sensitivity for PCR versus culture in detecting L. pneumophila in samples taken within 2 days or less of hospitalization (94.7% vs 79.6%, respectively) or 3 to 14 days of hospitalization (79.3% and 47.8%, respectively) (Mentasti, 2012).
Delay in initiating appropriate antimicrobial therapy for Legionnaire’s disease is associated with increased mortality, which makes a strong indirect argument for improved early detection with nucleic acid probes.
Mycobacteria Species
DNA probes are available to distinguish between Mycobacterium species. In a recent study, (Choi, 2012) the extracted DNA specimens from Mycobacterium species and non-mycobacterial species were tested using peptide nucleic acid (PNA) probe-based RT-PCR assay to evaluate potential cross-reactivity. A total of 531 respiratory specimens (482 sputum specimens, 49 bronchoalveolar washing fluid specimens) were collected from 230 patients in July and August, 2011. All specimens were analyzed for the detection of Mycobacteria by direct smear examination, mycobacterial culture, and PNA probe-based RT-PCR assay. In cross-reactivity tests, no false-positive or false-negative results were evident. When the culture method was used as the criterion standard test for comparison, PNA probe-based RT-PCR assay for detection of Mycobacterium tuberculosis complex (MTBC) had a sensitivity and specificity of 96.7% (58/60) and 99.6% (469/471), respectively. Assuming the combination of culture and clinical diagnosis as the standard, the sensitivity and specificity of the RT-PCR assay for detection of MTBC were 90.6% (58/64) and 99.6% (465/467), respectively. The new RT-PCR for the detection of nontuberculous mycobacteria had a sensitivity and specificity of 69.0% (29/42) and 100% (489/489), respectively.
Mycobacterium tuberculosis
DNA probes are available to diagnose M. tuberculosis infection. In a recent study, (Seagar, 2012) an in-house IS6110 RT-PCR (IH IS6110), MTB Q-PCR Alert (Q-PCR) and GenoType® MTBDRplus (MTBDR) were compared for the direct detection of (MTBC in 87 specimens. This included 82 first smear-positive specimens and 3 smear-negative specimens. The sensitivities of IH IS6110, Q-PCR, MTBDR, and IH ITS for MTBC detection were 100%, 92%, 87%, and 87% respectively, compared with culture. Both IS6110-based RT-PCRs (in-house and Q-PCR) were similar in performance with 91.2% concordant results for MTBC detection. However, none of the RT-PCR assays tested provide drug resistance data. Detection and drug resistance profiling are necessary for successful treatment of infection.
Mycobacterium avium and Mycobacterium intracellulare
DNA probes are available to diagnose Mycobacterium avium and Mycobacterium intracellulare infection. One study (Bicmen, 2011) evaluated the performance of the GenoType Mycobacteria Direct (GTMD) test for rapid molecular detection and identification of the MTBC and 4 clinically important nontuberculous mycobacteria (M. avium, M. intracellulare, M. kansasii, M. malmoense) in smear-negative samples. A total of 1570 samples (1103 bronchial aspiration, 127 sputum, 340 extrapulmonary samples) were analyzed. When evaluated, the performance criteria in combination with a positive culture result and/or the clinical outcome of the patients, the overall sensitivity, specificity, and PPVs and NPVs were found to be 62.4%, 99.5%, 95.9%, and 93.9%, respectively, whereas they were 63.2%, 99.4%, 95.7%, and 92.8%, respectively, for pulmonary samples and 52.9%, 100%, 100%, and 97.6%, respectively, for
extrapulmonary samples. Among the culture-positive samples which had Mycobacterium species detectable by the GTMD test, 3 samples were identified to be M. intracellulare and 1 sample was identified to be M. avium. However, 5 M. intracellulare samples and an M. kansasii sample could not be identified by the molecular test and were found to be negative. The GTMD test is a reliable, practical, and easy tool for rapid diagnosis of smear-negative pulmonary and extrapulmonary tuberculosis so that effective precautions may be taken and appropriate treatment may be initiated.
Mycoplasma pneumoniae
Probes for Mycoplasma pneumoniae have been developed (Chalker, 2011; Peuchangt, 2009). In 1 study using probes, a very high sensitivity and specificity for M. pneumoniae infection was reported (99.1% and 100%, respectively) (Ishiguro, 2015). Chalker et al (Chalker, 2011) tested 3987 nose and throat swabs from patients presenting with symptoms of a respiratory tract infection. Mycoplasma DNA was present in 1.7% of patients overall and was more common in children aged 5 to 14 years, in whom 6.0% of samples were positive. Probes have also been developed to test for mycoplasma strains with macrolide resistance. Peuchant et al (Peuchant, 2009) found that 9.8% (5/51) of mycoplasma strains were macrolide resistant.
In many cases, management of M. pneumoniae infection does not require definitive diagnosis (eg, community-acquired pneumonia). However, there are some cases where M. Pneumoniae is associated with severe illnesses that can have a variety of causes, in which definitive diagnosis may make a difference in treatment. M. pneumoniae PCR can be used to detect M. pneumoniae in patients with Stevens-Johnson syndrome (Olson, 2015) and refractory/severe pneumonia (Miyashita, 2015). At least 1 study suggests that inappropriate antibiotic use may worsen fulminant mycoplasma infection, and patients benefit from early administration of appropriate antimycoplasmal drugs with steroids (Izumikawa, 2014).
Neisseria gonorrhoeae
Probes for Neisseria gonorrhoeae have been developed for commercial use. These probes are often a combination test with C. trachomatis. A 2012 study (Hopkins, 2012) demonstrated the PPV of the screening PCR (Cobas 4800 CT/NG PCR screening assay) in urine specimens remained high (98.75%) even though the prevalence of gonorrhoeae was low. Another study12 demonstrated the VERSANT® CT/GC DNA 1.0 assay performed with 99.4% and 99.2% of specificity for N. gonorrhoeae and C. trachomatis detection, respectively, whereas sensitivity was 100% both for C. trachomatis and N. gonorrhoeae. As a comparator, culture methods were 100% specific, but far less sensitive. As a clinical consideration, patients accept antibiotic treatment before their infection status has been confirmed.
Respiratory Viral Panel
A broad spectrum of pathogens is causative for respiratory tract infections, but symptoms are mostly similar. The identification of the causative viruses is only feasible using multiplex PCR or several monoplex PCR tests in parallel. Several studies of various respiratory viral panels,(Mansuy, 2012; Dabisch-Ruthe, 2012); Pierce, 2012) demonstrate the multiplex assay detected clinically important viral infections in a single genomic test and thus, may be useful for detecting causative agents for respiratory tract disorders. A 2011 study by Brittain-Long (Brittain-Long, 2011) on a randomized population of 406 patients with access to a rapid, multiplex-PCR assay used to detect 13 viruses had lower antibiotic prescription rates (4.5% vs 12.3%, respectively) versus delayed identification with no significant difference in outcome at follow-up (p=0.359). Access to a rapid method for etiologic diagnosis of respiratory tract infections may reduce antibiotic prescription rates at the initial visit in an outpatient setting.
Staphylococcus aureus and Methicillin-Resistant Staphylococcus aureus
Probes are available for the detection of Staphylococcus aureus (Kaplan, 2005; Zhang, 2004). These probes are able to not only distinguish between coagulase-negative Staphylococcus and S. aureus, they can also detect methicillin-resistant species (MRSA) with high accuracy (Patel, 1997; Claas, 2013). Given the importance of establishing an early and accurate diagnosis in clinical situations in which an S. aureus infection is likely and there is substantial likelihood of MRSA, there is clinical utility for testing in these situations.
Streptococcus, Group A
While group A Streptococcus pyogenes (group A Streptococcus [GAS]) can cause a variety of clinical symptoms including impetigo, pharyngitis, and more invasive infections (eg, necrotizing fasciitis, pneumonia), most of the focus of rapid detection methods is on the diagnosis of GAS pharyngitis. Patients with confirmed acute GAS pharyngitis are typically treated with antibiotics, which shorten the duration of symptoms modestly and help prevent acute rheumatic fever. The diagnosis of GAS pharyngitis can be made by culture, which has a sensitivity of 90% to 95%, but is limited by a slow turnaround time (1-2 days), which may hamper decisions about initiating antibiotic therapy. Point-of-care rapid antigen detection tests (RADTs) are widely used to diagnose GAS pharyngitis. RADTs are characterized by high specificity (approximately 95%) but poor sensitivity (70%-90%) compared with culture (Shulman, 2012).
Several nucleic acid probes that detect either unamplified or amplified nucleotides have been developed. Typically, these tests have a shorter turnaround time than culture, and some are intended to be used as point-of-care tests.
In most studies of the amplified PCR assays, the sensitivity and specificity of the probes are very high. Upton et al reported lower sensitivity and lower PPV for the Illumigene assay than previous studies using this assay (Upton, 2015). The authors hypothesize that the lower PPV may be related to the fact that the study was conducted in a population of children attending school, lowering the pretest probability of actual GAS infection. Alternatively, the PCR assay may be detecting isolates of other Streptococcus species that carry the GAS pyrogenic exotoxin B gene, which is detected by the assay.
The high NPV of nucleic acid-based assays for GAS suggests that as point-of-care tests, they offer improved accuracy over the current standard, RADTs. The high sensitivity, approaching that of standard culture, suggests that it may be reasonable to use them as an alternative to culture.
Streptococcus, Group B
Several different rapid PCR-based tests for group B Streptococcus (GBS) have been developed, with reported sensitivities and specificities similar to that of conventional culture. DNA probes have also been developed to identify GBS from cultured specimens (Bergeron, 2001; Bergeron, 2000). The use of intrapartum antibiotic therapy for GBS is recommended in patients who are known to be carriers for GBS. The postpartum management of newborn infants to prevent early-onset GBS infection is affected by whether the maternal GBS status is positive, negative, or unknown, and whether antibiotic prophylaxis is administered. The availability of rapid testing in peripartum women allows initiation or discontinuation of peripartum antibiotic prophylaxis to prevent vertical transmission of GBS.
Trichomonas vaginalis
Nye et al87 compared the performance characteristics of PCR testing for Trichomonas with wet prep microscopy and culture in 296 female and 298 male subjects. In both women and men, DNA probe testing of vaginal swabs was more sensitive than culture. However, in men, wet prep testing was more sensitive than DNA probe testing. Munson et al (Munson, 2010) compared DNA probe testing and culture in 255 vaginal saline preparations. The DNA probe identified Trichomonas in 9.4% (24/255) of specimens that were negative on culture. This probe offers the ability to better distinguish between causes of vaginitis, which can be difficult clinically and using standard culture methods. Nucleic acid amplification tests have demonstrated higher clinical sensitivity than culture and wet mount microscopy,(Nye, 2009) as well as single-probe nonamplified testing in general. A 2011 prospective multicenter study of 1025 asymptomatic and symptomatic women found nucleic acid amplification testing had clinical sensitivity of 100% for both vaginal and endocervical swabs while urine specimen sensitivity was 95.2% (Schwebke, 2011). Specificity levels ranged from 98.9% to 99.6%. Other studies have also reported similar results (Andrea, 2011). PCR amplification tests have higher clinical sensitivity and are considered the standard of care for diagnosing Trichomonas vaginalis when culturing is not an option.
Summary of Evidence
The evidence for the use of nucleic acid probes for Chlamydophila pneumoniae or hepatitis G virus in individuals with suspected C. pneumoniae or with hepatitis, respectively, includes prospective and retrospective evaluations of the tests’ sensitivity and specificity. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, and change in disease status. The body of evidence is limited for both types of organisms. For C. pneumoniae, one study was identified that reported relatively high sensitivity and specificity for a polymerase chain reaction‒based test. However, the total number of patients in this study was small (N=56), and most other studies were conducted in the investigational setting. In addition to the limitations in the evidence based on test characteristics, the clinical implications of these tests are unclear. The evidence is insufficient to determine the effects of the technology on health outcomes.
The evidence for the use of a nucleic acid-based gastrointestinal pathogen panel in individuals who have signs and/or symptoms of gastroenteritis 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. However, in most instances, when a specific pathogen is suspected, individual tests could be ordered. There may be a subset of patients with an unusual presentation who would warrant testing for a panel of pathogens at once, but that subset has not been well defined. The evidence is insufficient to determine the effects of the technology on health outcomes.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2020, the Infectious Diseases Society of America (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 (IDSA, 2020). The current recommendations (published May 6, 2020) support SARS-CoV-2 nucleic acid testing for the following groups:
The IDSA panel further recommends the following:
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).
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Kosai et al evaluated the Verigene Pathogens Nucleic Acid Test (Luminex Corporation), testing 268 clinical stool samples for bacteria and toxins and 167 samples for viruses (Kosai, 2021). Of these samples, 256 and 160 samples, respectively, (95.5% and 95.8%) had fully concordant results between the Verigene EP test and the reference methods (which were culture for bacteria and toxins and xTAG GPP for viral detection). Overall sensitivity and specificity were 97.0% and 99.3%, respectively. Sensitivity for individual pathogens ranged from 87.5% to 100%, and specificity ranged from 98.7% to 100%. A total of 13 false-positive and 6 false-negative results were reported.
American Society for Microbiology
7.1 In 2020, the American Society for Microbiology updated the 2010 guidelines on detecting and identifying GBS that were originally published by the CDC (Filkins, 2020). The guidelines state that "intrapartum NAAT without enrichment has an unacceptably high false negative rate...As such we do not recommend the use of intrapartum NAAT without enrichment to rule out the need for prophylaxis." All GBS screening specimens should be incubated in selective enrichment broth prior to agar media plating or NAAT. " Nucleic acid amplification-based identification of GBS from enrichment broth is acceptable" for GBS screening, "but not sufficient for all patients" due to high false-negative rates.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The CDC published updated guidelines on Zika virus testing (Zika Virus: Testing Guidance, 2019). Routine testing for Zika virus in asymptomatic pregnant patients is not recommended, but NAAT testing may still be considered for asymptomatic pregnant women with recent travel to an area with risk of Zika outside the U.S. and its territories. Symptomatic pregnant patients should receive NAAT testing if they have recently traveled to areas with a risk of Zika virus or if they have had sex with someone who lives in or recently traveled to areas with risk of Zika virus. If a pregnant woman (with risk of Zika virus exposure) has a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection, Zika virus NAAT and IgM testing should be performed on maternal serum and NAAT on maternal urine. If amniocentesis is being performed as part of clinical care, Zika virus NAAT testing of amniocentesis specimens should also be performed.
2.1 The National Institute of Health (NIH), CDC, and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) published guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV (NIH Guidelines, 2022). The most recent update took place in 2022. In these guidelines, NAATs are discussed in the following situations:
2.1.1 Bartonella species
For patients with suspected bacillary angiomatosis, serologic tests are the standard of care and the most accessible test for diagnosing Bartonella infection. There are PCR methods that have been developed for identification and speciation of Bartonella and are becoming increasingly available through private laboratories, as well as the CDC and may aid in diagnosis of Bartonella in freshly biopsied tissue samples or whole blood.
2.1.2 Clostridioides (Clostridium) difficile
Detection of either the C. difficile toxin B gene, using NAAT, or the C. difficile toxin B protein, using an enzyme immunoassay, is required for diagnosis. PCR assays have high sensitivity and can detect asymptomatic carriers.
2.1.3 Cytomegalovirus
For patients with suspected CMV disease, diagnosis is based on clinical symptoms and the presence of CMV in cerebral spinal fluid (CSF) or brain tissue, most often evaluated with PCR. “Viremia can be detected by PCR” however, "a negative serum or plasma PCR assay does not rule out CMV end-organ disease."
2.1.4 Hepatitis B
The CDC, the United States Preventive Services Task Force, and the American Association for the Study of Liver Disease (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.
2.1.5 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.
2.1.6 Herpes Simplex Virus
“HSV DNA PCR and viral culture are preferred methods for diagnosis of mucocutaneous lesions potentially caused by HSV.”
2.1.7 Mycobacterium tuberculosis infection and disease
“NAA tests provide rapid diagnosis of TB, and some assays also provide rapid detection of drug resistance.”
"NAA assays, if positive, are highly predictive of TB disease when performed on Acid-Fast Bacillus (AFB) smear-positive specimens. However, because nontuberculous mycobacterial infections (NTM) may occur in people with HIV with advanced immunodeficiency, negative NAA results in the setting of smear-positive specimens may indicate NTM infection and can be used to direct therapy and make decisions about the need for respiratory isolation."
"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. NAA tests also can be used on extrapulmonary specimens with the caveat that the sensitivity is often lower than with sputum specimens."
The thirty-second edition of the American Academy of Pediatrics (AAP) Red Book describes the diagnostic and treatment options for many infectious diseases in the pediatric population (Kimberlin, 2021). Their diagnostic test recommendations for the pediatric population is listed below.
Red Book Diagnostic Test Recommendations for the Pediatric Population:
Bartonella henselae
Candida species
Chlamydia pneumoniae
Chlamydia trachomatis
Clostridioides (Clostridium) difficile
Coronaviruses (including SARS-CoV-2 and MERS-CoV)
Cytomegalovirus
Enterovirus
Gardnerella vaginalis
Hepatitis B
Hepatitis C
Herpes simplex virus
Human herpesvirus 6
HIV 1
Human papillomavirus
Influenza virus
Legionella pneumophila
Meningitis
Mycobacteria species
Mycoplasma pneumoniae
Neisseria gonorrhoeae
Staphylococcus aureus
Streptococcus, group A
Streptococcus, group B
Trichomonas vaginalis
Vancomycin-resistant Enterococcus
Zika virus
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Meltzer et al conducted a single-center RCT investigating antibiotic use in patients with moderate to severe suspected infectious diarrhea presenting to the emergency department (Meltzer, 2022). Patients were randomized to receive multiplex PCR testing with the BioFire FilmArray GI panel (n=38) or standard care (usual testing or no testing; n=36). In the PCR arm, subjects received antibiotics in 87% of bacterial or protozoal diarrheal infections (13/15) compared to 46% (6/13) in the control arm (p=.042). No significant differences were found between groups in follow-up symptoms as assessed on days 2, 7, and 30, or emergency department length of stay. The study was terminated early due to the COVID-19 pandemic and thus was underpowered. Additional limitations include potential antibiotic prescribing at subsequent healthcare visits that was not captured and lack of a standardized reference test for the control arm.
The RCT conducted by Darie et al was excluded as the Unyvero Hospitalized Pneumonia panel is not currently commercially available in the United States (Darie, 2022).
Clark et al conducted a systematic review and meta-analysis of the impact of multiplex PCR testing among individuals with a suspected acute respiratory tract infection in the hospital setting (Clark, 2023). Twenty-seven studies representing 17,321 patients were identified for analysis. Multiplex testing was associated with a reduction in both time to results (-24.22 h; 95% CI, -28.70 to -19.74 h) and hospital length of stay (-0.82 days; 95% CI, -1.52 to -0.11). Antivirals were more likely to be prescribed among influenza positive individuals (RR, 1.25; 95% CI, 1.06 to 1.48) as was use of an appropriate infection control facility (RR, 1.55; 95% CI, 1.16 to 2.07).
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