Identification of Microorganisms Using Nucleic Acid Probes
DESCRIPTIONUntil recently, identification of microorganisms depended either on 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 is limited by the inability to distinguish between past exposure and current infection. Response to treatment is typically assessed according to the patient's clinical response or by rising titers of specific antibodies and falling antigen titers.
Recently, the availability of nucleic acid probes has permitted the rapid direct identification of microorganisms' DNA or RNA. Amplification techniques, including but not limited to the polymerase chain reaction (PCR), results in a doubling of copies of the specified target DNA with each round of amplification, eventually resulting in millionfold levels of amplification. The product of amplification (i.e. DNA) is then 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 amount 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), which serves as a prognostic factor.
Until 1998, these nucleic acid probe techniques were coded using nonspecific CPT codes describing the multiple steps in the laboratory process. However, in 1998, the CPT codes were revised to include a series of new codes that describe the direct probe technique, amplified probe technique, and quantification for 22 different microorganisms. These series of CPT codes were introduced as a group; however at present, probe technologies and clinical applications for some microorganisms are either not widely disseminated or are used primarily for research purposes. The 22 different microorganisms are reviewed as follows:
Bartonella henselae or quintana: Bartonella henselae or quintana is thought to be responsible for cat scratch disease, which is characterized by chronic regional lymphadenopathy developing about 2 weeks after contact with a cat. A cat scratch skin antigen test is positive in the majority of patients with cat scratch disease, but this test cannot distinguish between active and remote infection.
Bartonella may also cause an opportunistic infection in HIV-infected patients, where 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.
Borrelia burgdorferi: Borrelia burgdorferi is responsible for Lyme disease. The clinical symptoms and diagnosis of Lyme disease are more thoroughly discussed in Intravenous Antibiotic Therapy for Lyme Disease policy. Antibody assays are typically the first diagnostic laboratory test performed; but these assays may be negative during early disease, and, in the later course of the disease, immunologic assays cannot distinguish between past and present infections, a severe limiting factor in areas of high prevalence. The spirochete is also difficult to culture, in part because the number of organisms in clinical specimens is extremely low. Therefore, in some instances, PCR amplification has been used to confirm the diagnosis of active Lyme disease. The highest sensitivities have been reported from CSF or synovial fluid samples; the sensitivity of the PCR technique in blood or urine samples has been disappointing.
Candida species: A commonly occurring yeast, Candida species can be normally found on diseased skin, throughout the entire GI 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 bacterial vaginosis.
Chlamydia pneumoniae: Chlamydia pneumoniae is an important cause of pneumonia, bronchitis, and sinusitis. Culture and isolation of the microorganism is difficult; a microimmunofluorescence 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. Chlamydia trachomatis is also responsible for lymphogranuloma venereum (LGV). 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 HEDIS 3.0. This microoganism 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. Direct probe techniques can be used on urethral or cervical swabs, while amplification techniques may be used on urine specimens.
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.
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.
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 as a technique for monitoring the response to interferon and/or ribavarin therapy in patients with hepatitis C.
Herpes simplex virus (HSV): 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 areas, 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 HSV in the cerebrospinal fluid has been used to provide a rapid diagnosis of herpes virus encephalitis.
Herpes virus-6: Human herpes virus-6 (HHV-6) is widespread in the general population and is also responsible for roseola, a benign rash and fever occurring in young children. HHV-6 may also cause meningitis, encephalitis, pneumonitis and hepatitis in children and adults. Diagnosis is typically based on rising serologic titers.
HIV-1, 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 with 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 48-72 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. Anti-viral 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 (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, or intracellular) 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.
Neisseria gonorrhoeae: Isolation by culture is the conventional form of diagnosis for this common pathogen. Direct DNA probes have been used on cervical or urethral swabs, while amplification techniques are used on urine specimens. 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 papillomavirus to identify patients at highest risk of progressing to invasive cervical carcinoma.
Streptococcus, group A: Also referred to as S treptococcus 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 S. 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 (GBS): Also referred to as Streptococcus agalactiae, 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 (CDC), the American College of Obstetrics and Gynecology (ACOG), and the American Academy of Pediatricians (AAP) 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' 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 trichimonas 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.
POLICYThe status of nucleic acid identification using direct probe, amplified probe, or quantification for the 22 microorganisms listed in the CPT book are summarized in the following table:
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY10/26/2006: Policy added
1/2/2007: Code reference section updated per the 2007 CPT/HCPCS revisions. Added CPT 87797 and 87798 to covered table. Added CPT 87799 to non-covered table with see policy note.
5/14/2007: Policy reviewed; updated to include enterovirus, staphylococcus aureus, and MRSA. CPT codes 87640-87641 added to covered table. CPT code 87948 added to non-covered table. Added ICD-9 codes 041.01, 041.02, 041.11, and V09.0 to covered table.
9/7/2007: Code reference section updated per annual ICD-9 code updates.
6/25/2008: Vancomycin resistance (eg., enterococcus vanA, vanB) amplified probe added as medically necessary. CPT 87500 added to covered
8/26/2008: Code reference section reviewed. CPT codes 87797, 87798, and 87799 removed
9/10/2008: Annual ICD-9 updates applied
03/11/2010: Code reference section updated. New CPT code 87493 added to non-covered table.
12/13/2011: Policy description updated. Medically necessary indications added for clostridium difficile, influenza virus, and trichomoniasis vaginalis. Moved 87493 from the Non-Covered Codes table to the Covered Codes table. Added CPT codes 87501, 87502, 87503, and 87660 and ICD-9 codes 008.45, 131.00 - 131.09, and 487.0 - 488.19 to the Covered Codes table.
01/09/2013: Added coverage guidelines for respiratory syncytial virus (RSV). Added ICD-9 code 079.6 and CPT codes 87631 , 87632 , and 87632 to the Code Reference section.
01/21/2014: Policy statement revised to change Candida species amplified probe from investigational to medically necessary. Added medically necessary indication for Trichomonas vaginalis amplified probe. Moved CPT code 87481 from non-covered to covered. Added the following new 2014 CPT code(s) to the Code Reference section: 87761.
SOURCE(S)Blue Cross Blue Shield Association Policy # 2.04.10
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.