Latest Review Date: February 2024

Category:  Laboratory

DRAFT

POLICY:

Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational.

The use of nucleic acid testing expanded panels using a direct or amplified probe technique with or without quantification of viral load is considered investigational for the Bacterial Vaginosis (BV) microorganism.

DESCRIPTION OF PROCEDURE OR SERVICE:

Bacterial vaginosis (BV) is a common medical condition resulting from an imbalance in the normal vaginal flora. Although the identification of Gardnerella vaginalis has traditionally been associated with BV, there is no single etiologic agent. Most cases are asymptomatic, and most symptomatic cases can be diagnosed using clinical and microscopic evaluation. Multitarget polymerase chain reaction (PCR) testing is proposed as an alternative to currently available laboratory tests to diagnose BV. This test may improve outcomes if it is a more accurate and reliable method to diagnose BV.

Bacterial Vaginosis

BV is a condition caused by an imbalance in the normal bacteria vaginal flora. It is common, especially in women of reproductive age. While there is no single known etiologic agent, there is a shift in vaginal flora that involves depletion of hydrogen peroxide-producing Lactobacillus species with a rise in vaginal pH and overgrowth of other bacteria, including Gardnerella vaginalis, Mycoplasma hominis, Peptostreptococcus, Mobiluncus species, and other anaerobic gram-negative rods.

Vaginal culture is not an appropriate diagnostic method to identify BV because BV is not caused by the presence of a particular bacterial species.

Various commercial tests provide rapid and accurate pH evaluation and amine detection. For example, automated devices that measure the volatile gases produced from vaginal samples and a colorimetric pH test are commercially available.

Nucleic acid probes of DNA fragments are available to detect and quantify specific bacteria in vaginal fluid samples. Polymerase chain reaction (PCR) methods extract and amplify the DNA fragments using either universal or specific primers. The result can be qualitative (to assess whether a specific microorganism is present) or quantitative (to assess how many microorganisms are present). The technology can be used to measure multiple organisms (eg, those known to be associated with BV) at the same time and is commercially available as multitarget PCR testing.

Multitarget PCR Tests

Five quantitative multiplex PCR assays are available: BD Max (Becton Dickinson), Aptima BV (Hologic), NuSwab VG (LabCorp), OneSwab BV Panel PCR with Lactobacillus Profiling by qPCR (Medical Diagnostic Laboratories), and SureSwab BV (Quest Diagnostics).

The SureSwab Total test involves obtaining vaginal swab specimens, extracting total DNA, and quantitating the 4 types of bacteria using PCR. Results are reported as log cells per milliliter for each organism and concentrations of all Lactobacilli species are reported together then classified into 1 of the following 3 categories: not supportive, equivocal, and supportive.

A classification of not supportive of BV diagnosis is based on:

• The presence of Lactobacillus species, G. vaginalis levels <6.0 log cells/mL, and absence of Atopobium vaginae and Megasphaera species; or
• The absence of Lactobacillus species, G. vaginalis levels <6.0 log cells/mL, and absence of A. vaginae and Megasphaera species; or
• The absence of all targeted organisms.

A classification of equivocal is based on:

• The presence of Lactobacillus species, plus G. vaginalis at least 6.0 log cells/mL, and/or presence of A. vaginae and/or Megasphaera species.

A classification of supportive of BV diagnosis is based on the absence of Lactobacillus species, and presence of G. vaginalis levels of at least 6.0 log cells/mL, and presence of A. vaginae and/or Megasphaera species.

The BD Max (Becton, Dickinson), tests for markers of BV and vaginitis. The test uses a similar process to that described for SureSwab. Vaginal swab specimens are collected, DNA is extracted, and real-time PCR is used to quantitate targeted organisms. Results of BV marker tests are not reported for individual organisms. Instead, qualitative BV results are reported as positive or negative for BV based on the relative quantity of the various organisms.

The Aptima BV Assay was cleared by the U.S. Food and Drug Administration with the BD Max as the predicate device. The Aptima assay is a nucleic acid amplification test (NAAT) for detection and quantitation of ribosomal RNA.

Medical Diagnostics Laboratory offers a Bacterial Vaginosis Panel. Markers are assessed using real-time PCR and Lactobacillus is profiled using quantitative PCR. GenPath Diagnostics also offers a bacterial vaginosis test.

The NuSwab Select BV test (Laboratory Corporation of America) uses semiquantitative PCR analysis of 3 predictive marker organisms of vaginal dysbiosis to generate a total score that is associated with the presence or absence of BV. In this test system, samples with a total score of 0 to 1 are considered negative for BV, samples with a score of 3 to 6 are positive for BV, and samples with a score of 2 are indeterminate for BV.

KEY POINTS:

The most recent literature review was updated through November 6, 2023.

Summary of Evidence

In individuals who have signs or symptoms of BV who receive multitarget PCR testing, the evidence includes several prospective studies on technical performance and diagnostic accuracy. Relevant outcomes are test validity, symptoms, and change in disease status. Several studies have evaluated the diagnostic accuracy of multitarget PCR tests for BV, including 5 studies evaluating commercially available tests. The studies found sensitivities between 84% and 95% and specificities between 85% and 97% compared with standard methods of diagnosis. Most studies used a combination of the Amsel criteria and Nugent scoring as the reference standard. There is a lack of direct evidence on the clinical utility of PCR testing for BV (ie, studies showing that testing leads to better patient management decisions and/or better health outcomes than current approaches). Moreover, a chain of evidence does not currently support multitarget testing because most symptomatic individuals can be diagnosed with a standard workup. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Practice Guidelines and Position Statements

American College of Obstetricians and Gynecologists

Published in 2012 and reaffirmed in 2018, the American College of Obstetricians and Gynecologists (ACOG) has produced a Practice Bulletin on the prediction of preterm birth. The Bulletin stated that BV testing is not recommended as a screening strategy in asymptomatic pregnant women at increased risk of preterm birth.

Published in 2020, the ACOG has issued a Practice Bulletin on vaginitis in nonpregnant patients. The Bulletin made the following recommendations on the initial evaluation of patients with symptoms of vaginitis, citing CDC guidelines:

"A complete medical history, physical examination of the vulva and vagina, and clinical testing of vaginal discharge (ie, pH testing, a potassium hydroxide "whiff test," and microscopy) are recommended for the initial evaluation of patients with vaginitis symptoms."

The Bulletin noted that single-swab multiplex PCR testing "may be a promising alternative to microscopy," but that its clinical utility is still under evaluation.

Centers for Disease Control and Prevention

In 2021, the Centers for Disease Control and Prevention updated its guidelines on sexually transmitted infections. Regarding the diagnosis of bacterial vaginosis (BV), the guidelines stated:

“BV can be diagnosed by.... clinical criteria (i.e., Amsel’s Diagnostic Criteria) or by determining the Nugent score from a vaginal Gram stain. Vaginal Gram stain, considered the reference standard laboratory method for diagnosing BV, is used to determine the relative concentration of lactobacilli …"

The guidelines state that multiplex PCR assays are available, but noted that traditional methods of BV diagnosis, including the Amsel criteria, Nugent score, and the Affirm VP III assay, remain useful for diagnosing symptomatic BV because of their lower cost and ability to provide a rapid diagnosis. The guidelines also stated that BV nucleic acid amplification tests should be used among symptomatic women only (e.g., women with vaginal discharge, odor, or itch) because their accuracy is not well defined for asymptomatic women.

U.S. Preventive Services Task Force Recommendations

The USPSTF (2020) recommendations on screening for BV in pregnancy have stated that:

“The USPSTF recommends against screening for bacterial vaginosis in pregnant persons who are not at increased risk for preterm delivery.” (Grade D recommendation)

“The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for bacterial vaginosis in pregnant persons who are at increased risk for preterm delivery.” (I statement)

KEY WORDS:

BV, Bacterial Vaginosis, BD Max, Aptima BV Assay

APPROVED BY GOVERNING BODIES:

Two assays are FDA cleared (BD Max and Aptima BV), and 3 (NuSwab VG, OneSwab BV Panel PCR with Lactobacillus Profiling by qPCR, and SureSwab BV) are laboratory-developed tests.

Several of the manufacturers of the BV tests also have extensions that include other causes of vaginitis such as Trichomonas vaginalis and Candidiasis species. For example, the BD Vaginal Panel was cleared in March 2023 with the BD Max as the predicate device. It is intended to aid in the diagnosis of vaginal infections in individuals with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing.

BENEFIT APPLICATION:

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

ITS: Home Policy provisions apply.

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

There is no single CPT code for BV testing.

REFERENCES:

1. Aguirre-Quiñonero A, Castillo-Sedano IS, Calvo-Muro F, et al. Accuracy of the BD MAX™ vaginal panel in the diagnosis of infectious vaginitis. Eur J Clin Microbiol Infect Dis. May 2019; 38(5): 877-882.
2. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med. Jan 1983; 74(1): 14-22.
3. Broache M, Cammarata CL, Stonebraker E, et al. Performance of a Vaginal Panel Assay Compared With the Clinical Diagnosis of Vaginitis. Obstet Gynecol. Dec 01 2021; 138(6): 853-859. PMID 34736269
4. Cartwright CP, Lembke BD, Ramachandran K, et al. Development and validation of a semiquantitative, multitarget PCR assay for diagnosis of bacterial vaginosis. J Clin Microbiol. Jul 2012; 50(7): 2321-9.
5. Cartwright CP, Pherson AJ, Harris AB, et al. Multicenter study establishing the clinical validity of a nucleic-acid amplification-based assay for the diagnosis of bacterial vaginosis. Diagn Microbiol Infect Dis. Nov 2018; 92(3): 173-178.
6. Centers for Disease Control and Prevention (CDC). Bacterial Vaginosis (BV) Statistics. www.cdc.gov/std/bv/stats.htm.
7. Committee on Practice Bulletins—Obstetrics, The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. Oct 2012; 120(4): 964-73.
8. Food and Drug Administration. Evaluation of Automatic Class III Designation For BD MaxVaginalPanel:DecisionSummary.2016;www.accessdata.fda.gov/cdrh_docs/reviews/DEN160001.pdf.
9. FoodandDrugAdministration.BDVaginalPanel.510(k)K223653. www.accessdata.fda.gov/cdrh_docs/pdf22/K223653.pdf.
10. Gaydos CA, Beqaj S, Schwebke JR, et al. Clinical Validation of a Test for the Diagnosis of Vaginitis. Obstet Gynecol. Jul 2017; 130(1): 181-189. PMID 28594779
11. Hemalatha R, Ramalaxmi BA, Swetha E, et al. Evaluation of vaginal pH for detection of bacterial vaginosis. Indian J Med Res. 2013;138(3):354-359.
12. Hilbert DW, Smith WL, Chadwick SG, et al. Development and Validation of a Highly Accurate Quantitative Real-Time PCR Assay for Diagnosis of Bacterial Vaginosis. J Clin Microbiol. Apr 2016; 54(4): 1017-24.
13. Ison CA, Hay PE. Validation of a simplified grading of Gram stained vaginal smears for use in genitourinary medicine clinics. Sex Transm Infect. Dec 2002; 78(6): 413-5.
14. Kusters JG, Reuland EA, Bouter S, et al. A multiplex real-time PCR assay for routine diagnosis of bacterial vaginosis. Eur J Clin Microbiol Infect Dis. Sep 2015; 34(9): 1779-85.
15. Landers DV, Wiesenfeld HC, Heine RP, et al. Predictive value of the clinical diagnosis of lower genital tract infection in women. Am J Obstet Gynecol. Apr 2004; 190(4): 1004-10.
16. Muzny, CA, Balkus, JE, et al. Diagnosis and Management of Bacterial Vaginosis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines. Clinical Infectious Dis. 2022; 74(Supplement 2): S144-S151.
17. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. Feb 1991; 29(2): 297-301.
18. Richter SS, Otiso J, Goje OJ, et al. Prospective Evaluation of Molecular Assays for Diagnosis of Vaginitis. J Clin Microbiol. Dec 23 2019; 58(1).
19. Rumyantseva T, Shipitsyna E, Guschin A, et al. Evaluation and subsequent optimizations of the quantitative AmpliSens Florocenosis/Bacterial vaginosis-FRT multiplex real-time PCR assay for diagnosis of bacterial vaginosis. APMIS. Dec 2016; 124(12): 1099-1108.
20. Rumyantseva TA, Bellen G, Romanuk TN, et al. Utility of microscopic techniques and quantitative real-time polymerase chain reaction for the diagnosis of vaginal microflora alterations. J Low Genit Tract Dis. Apr 2015; 19(2): 124-8.
21. Schwebke JR, Gaydos CA, Nyirjesy P, et al. Diagnostic Performance of a Molecular Test versus Clinician Assessment of Vaginitis. J Clin Microbiol. Jun 2018; 56(6).
22. Schwebke JR, Taylor SN, Ackerman R, et al. Clinical Validation of the Aptima Bacterial Vaginosis and Aptima Candida/Trichomonas Vaginitis Assays: Results from a Prospective Multicenter Clinical Study. J Clin Microbiol. Jan 28 2020; 58(2).
23. Thompson A, Timm K, Borders N, et al. Diagnostic performance of two molecular assays for the detection of vaginitis in symptomatic women. Eur J Clin Microbiol Infect Dis. Jan 2020; 39(1): 39-44.
24. U.S. Preventive Services Task Force. Bacterial Vaginosis in Pregnancy to Prevent Preterm Delivery: Screening. 2020;www.uspreventiveservicestaskforce.org/uspstf/recommendation/bacterial-vaginosis-in-pregnancy-to-prevent-preterm-delivery-screening.
25. Vaginitis in Nonpregnant Patients: ACOG Practice Bulletin, Number 215. Obstet Gynecol. Jan 2020; 135(1): e1-e17.
26. van den Munckhof EHA, van Sitter RL, Boers KE, et al. Comparison of Amsel criteria, Nugent score, culture and two CE-IVD marked quantitative real-time PCRs with microbiota analysis for the diagnosis of bacterial vaginosis. Eur J Clin Microbiol Infect Dis. May 2019; 38(5): 959-966.
27. van der Veer C, van Houdt R, van Dam A, et al. Accuracy of a commercial multiplex PCR for the diagnosis of bacterial vaginosis. J Med Microbiol. Sep 2018; 67(9): 1265-1270.
28. van der Veer C, van Houdt R, van Dam A, et al. Accuracy of a commercial multiplex PCR for the diagnosis of bacterial vaginosis. J Med Microbiol. Sep 2018; 67(9): 1265-1270.
29. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. Jul 23 2021; 70(4): 1-187.

POLICY HISTORY:

Medical Policy Group, February 2024 (5): Created separate MP for Multitarget Polymerase Chain Reaction Testing for Diagnosis of Bacterial Vaginosis- MP 758. All information pertaining to Bacterial Vaginosis (BV) pulled from MP 548 and transferred to this policy.

Medical Policy Administration Committee, April 2024.

Available for comment April 1, 2024 through May 15, 2025.

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

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

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

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

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

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

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

3. The technology must improve the net health outcome;

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

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

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

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

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

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

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