CAM 269

Diagnosis of Vaginitis including Multi-target PCR Testing

Category:Laboratory   Last Reviewed:April 2021
Department(s):Medical Affairs   Next Review:April 2022
Original Date:February 2000    

Description:
Vaginitis is defined as inflammation of the vagina with symptoms of discharge, itching and discomfort often due to a disruption of the vaginal microflora. The most common infections are bacterial vaginosis, Candida vulvovaginitis, and trichomoniasis (J. D. Sobel, 1999). Other causes include vaginal atrophy in postmenopausal women, cervicitis, foreign body, irritants and allergens (J. Sobel, 2017a).

Bacterial vaginosis (BV) is characterized by a shift in microbial species from the normally dominant hydrogen-peroxide producing Lactobacillus species to Gardnerella vaginalis and anaerobic commensals (Eschenbach et al., 1989; Hill, 1993; Lamont et al., 2011; Ling et al., 2010; J. Sobel, 2017b).

Vulvovaginal candidiasis (VVC) is characterized by Candida species. It is the second most common cause of vaginitis symptoms (after BV) and accounts for approximately one-third of vaginitis cases (J. Sobel, 2017c; Workowski & Bolan, 2015).

Trichomoniasis is caused by the flagellated protozoan Trichomonas vaginalis, which principally infects the squamous epithelium in the urogenital tract: vagina, urethra, and paraurethral glands (Kissinger, 2015; J. Sobel, 2017d).

Background
The squamous epithelium of the vagina in premenopausal women is rich in glycogen, a substrate for lactobacilli, which create an acidic vaginal environment (pH 4.0 to 4.5). This acidity helps maintain the normal vaginal flora and inhibits growth of pathogenic organisms. Disruption of the normal ecosystem by menstrual cycle, sexual activity, contraceptive, pregnancy, foreign bodies, estrogen level, sexually transmitted diseases, and use of hygienic products or antibiotics can lead development of vaginitis. Bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis are the three most common infections responsible for vaginitis. Other causes include: vaginal atrophy in postmenopausal women, cervicitis, foreign body, irritants and allergens (J. Sobel, 2017a).

Laboratory documentation of the etiology of vaginitis is important before initiating therapy, given the nonspecific nature considerable overlap of the symptoms (Anderson, Klink, & Cohrssen, 2004; Ellis, Lerch, & Whitcomb, 2001; Landers, Wiesenfeld, Heine, Krohn, & Hillier, 2004) Diagnostic testing enables targeted treatment, increases therapeutic compliance, and increases the likelihood of partner notification (J. Sobel, 2017a; Workowski & Bolan, 2015).

Measurement of vaginal pH is the primary initial finding that drives the diagnostic. The pH of the normal vaginal secretions in premenopausal women with relatively high estrogen levels is 4.0 to 4.5. The pH of normal vaginal secretions in premenarchal and postmenopausal women in whom estrogen levels are low is ≥4.7. An elevated pH in a premenopausal woman suggests infections such as BV (pH>4.5) or trichomoniasis (pH 5 to 6), and helps to exclude Candida vulvovaginitis (pH 4 to 4.5). Vaginal pH may also be altered by lubricating gels, semen, douches, intravaginal medications and in pregnant women, leakage of amniotic fluid (Anderson et al., 2004; J. Sobel, 2017a).

Microscopic examination of normal vaginal discharge reveals a predominance of squamous epithelial cells, rare polymorphonuclear leukocytes (PMNs), and Lactobacillus species. The primary goal of the examination is to look for candidal buds or hyphae, motile trichomonads, epithelial cells studded with adherent coccobacilli (clue cells), and increased numbers of PMNs (J. Sobel, 2017a).

The microscopic evaluation of BV is usually based on Amsel criteria (Amsel et al., 1983). If clinical criteria are used to define infection, then reported sensitivity ranges from 62 to 100 percent (Spiegel, 1991). Using Gram's stain as the standard for diagnosing BV, the sensitivity of Amsel criteria for diagnosis of BV is over 90 percent and specificity is 77 percent (Landers et al., 2004). Because BV represents complex changes in the vaginal flora, vaginal culture has no role in diagnosis. If microscopy is not available, commercial diagnostic testing methods (e.g., rapid antigen and nucleic acid amplification tests) are used for confirming the clinical suspicion of BV. PCR-based assays to quantify BV associated bacteria (Cartwright et al., 2012; Menard, Fenollar, Henry, Bretelle, & Raoult, 2008) have good sensitivity and specificity compared with standard clinical tests (Dumonceaux et al., 2009; Menard et al., 2010); however, they are expensive and of limited utility (J. Sobel, 2017b).

Trichomoniasis can be diagnosed by the presence of motile trichomonads on wet mount, but they are identified in only 60 to 70 percent of culture-confirmed cases. Culture on Diamond's medium was considered the gold standard method for diagnosing T. vaginalis infection (Workowski & Bolan, 2015) however, nucleic acid amplification tests (Baron et al., 2013) have become the accepted gold standard for the diagnosis of T. vaginalis. One study found the sensitivities for T. vaginalis using wet mount, culture, rapid antigen testing, and transcription-mediated amplification testing were 65, 96, 90, and 98 percent, respectively(Huppert et al., 2007). Coexistence of T. vaginalis and BV pathogens is common, with coinfection rates of 60 to 80 percent (J. Sobel, 2017d; J. D. Sobel, Subramanian, Foxman, Fairfax, & Gygax, 2013).

Microscopy is negative in up to 50 percent of patients with culture confirmed VVC (J. D. Sobel, 1985). There are no reliable point of care tests for Candida available in the United States (Abbott, 1995; Chatwani et al., 2007; Dan, Leshem, & Yeshaya, 2010; Hopwood, Evans, & Carney, 1985; Marot-Leblond et al., 2009; Matsui et al., 2009), a culture must be obtained. Polymerase chain reaction (PCR) methods have high sensitivity and specificity and a shorter turn-around time than culture (Diba, Namaki, Ayatolahi, & Hanifian, 2012; Mahmoudi Rad, Zafarghandi, Amel Zabihi, Tavallaee, & Mirdamadi, 2012; Tabrizi, Pirotta, Rudland, & Garland, 2006; Weissenbacher et al., 2009), but are costly and offer no proven benefit over culture in symptomatic women (J. Sobel, 2017c).

Policy: 

  1. Testing of pH, testing for the presence of amines, saline wet mount, hydrogen peroxide (KOH) wet mount and microscopic examination of vaginal fluids is considered MEDICALLY NECESSARY in patients with symptoms of vaginitis.
  2. Direct Probe DNA-based identification of  Gardnerella, Trichomonas, and Candida is considered MEDICALLY NECESSARY in patients with symptoms of vaginitis.
  3. Vaginal cultures for Candida species are considered MEDICALLY NECESSARY for the diagnosis of vulvovaginal candidiasis in patients with clinical signs and symptoms of vaginitis and negative findings on wet-mount preparations and a normal pH test.
  4. Measurement of sialidase activity in vaginal fluid is considered MEDICALLY NECESSARY for the diagnosis of bacterial vaginosis in women with symptoms of vaginitis.
  5. Nucleic Acid Amplification Test (NAAT) or Polymerase Chain Reaction (PCR)-based identification of Trichomonas is considered MEDICALLY NECESSARY in patients with symptoms of vaginitis.
  6. Polymerase Chain Reaction (PCR) based identification of Candida species is considered INVESTIGATIONAL for any indication.
  7. Screening for Trichomonas is considered MEDICALLY NECESSARY for women with risk factors including: new or multiple partners; history of sexually transmitted diseases (STDs); exchange of sex for payment; or injection drug use.
  8. Screening for trichomoniasis and bacterial vaginosis is considered NOT MEDICALLY NECESSARY in asymptomatic patients, including asymptomatic pregnant patients at average or high risk for premature labor.
  9. Rapid identification of Trichomonas by enzyme immunoassay is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in patients with symptoms of vaginitis.
  10. PCR testing and Multitarget polymerase chain reaction (PCR) testing for diagnosis of bacterial vaginosis is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.
  11. Using molecular-based panel testing, including, but not limited to, testing such as SmartJane™, to test for microorganisms involved in vaginal flora imbalance and/or infertility is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Rationale:
Vaginitis is characterized by several symptoms including odor, itching, abnormal vaginal discharge, burning and irritation; this inflammatory ailment is considered the most common gynecologic diagnosis in primary care as most women experience vaginitis at least once in their lives. A diagnosis of vaginitis can be given based on a combination of symptoms, physical examination, and office or laboratory-based testing methods.

The squamous epithelium of the vagina in premenopausal women is rich in glycogen, a substrate for lactobacilli, which create an acidic vaginal environment (pH 4.0 to 4.5). This acidity helps maintain the normal vaginal flora and inhibits growth of pathogenic organisms. Disruption of the normal ecosystem by menstrual cycle, sexual activity, contraceptive, pregnancy, foreign bodies, estrogen level, sexually transmitted diseases, and use of hygienic products or antibiotics can lead to development of vaginitis. Bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis are the three most common infections responsible for vaginitis. Other causes include: vaginal atrophy in postmenopausal women, cervicitis, foreign body, irritants and allergens.

Bacterial vaginosis is caused by an imbalance of naturally occurring vaginal bacteria, characterized by both a change in the most common type of bacteria present, along with an increase in the total number of bacteria present. Normal vaginal microbiota is dominated by the species Lactobacilli, which are known to produce hydrogen peroxide and lactic acid, which help to keep the acidic vaginal environment below pH 4.5. Though the origin of vaginal bacterial infections is still unclear, it is believed that most of such infections are the result of another bacteria, Gardnerella vaginalis, creating a biofilm which allows opportunistic bacteria to grow within the vagina, causing a decrease in the Lactobacilli and subsequent disruption of the pH of the system. An entire host of etiologic organisms have been identified as possible instigators and exacerbators, including Atopobium vaginae, Megasphaera phylotype 1 and 2, Leptotrichia aminionii, Mobiluncus spp, Prevotella spp, Mycoplasma hominis, Bacteroides spp, Sneathia, and BV-associated bacteria (BVAB)1, 2, and 3, though as aforementioned the causative mechanism and the interaction between these species are still uncertain.

Laboratory documentation of the etiology of vaginitis is important before initiating therapy, given the nonspecific nature and considerable overlap of the symptoms. Diagnostic testing enables targeted treatment, increases therapeutic compliance, and increases the likelihood of partner notification.

Measurement of vaginal pH is the primary initial finding that drives the diagnostic. The pH of the normal vaginal secretions in premenopausal women with relatively high estrogen levels is 4.0 to 4.5. The pH of normal vaginal secretions in premenarchal and postmenopausal women in whom estrogen levels are low is ≥4.7. An elevated pH in a premenopausal woman suggests infections, such as BV (pH>4.5) or trichomoniasis (pH 5 to 6) and helps to exclude Candida vulvovaginitis (pH 4 to 4.5). Vaginal pH may also be altered by lubricating gels, semen, douches, intravaginal medications and in pregnant women, leakage of amniotic fluid.

Analytical Validity
Microscopic examination of normal vaginal discharge reveals a predominance of squamous epithelial cells, rare polymorphonuclear leukocytes (PMNs), and Lactobacillus species. The primary goal of the examination is to look for candidal buds or hyphae, motile trichomonads, epithelial cells studded with adherent coccobacilli (clue cells), and increased numbers of PMNs. The microscopic evaluation of BV is usually based on Amsel criteria. Amsel criteria state that the presence of at least three out of the following four criteria are indicative of a BV diagnosis: increased homogeneous thin vaginal discharge, pH secretion > 4.5, amine odor when potassium hydroxide 10% solution is added to a vaginal secretion sample, and the presence of clue cells in wet preparations. If clinical criteria are used to define infection, then reported sensitivity may range from 62 to 100 percent. Using Gram's stain as the standard for diagnosing BV, the sensitivity of Amsel criteria for diagnosis of BV is over 90 percent and specificity is 77 percent. The Nugent score is also available as a Gram staining scoring system to diagnose BV based on vaginal swab samples. Because BV represents complex changes in the vaginal flora, vaginal culture has no role in diagnosis. If microscopy is not available, commercial diagnostic testing methods (e.g., rapid antigen and nucleic acid amplification tests) are used for confirming the clinical suspicion of BV. Polymerase chain reaction (PCR)-based assays to quantify BV-associated bacteria have good sensitivity and specificity compared with standard clinical tests. However, they are expensive and of limited utility.

Trichomoniasis can be diagnosed by the presence of motile trichomonads on wet mount, but it is identified in only 60 to 70 percent of culture-confirmed cases. Culture on Diamond's medium was considered the gold standard method for diagnosing a T. vaginalis infection; however, nucleic acid amplification tests have become the accepted gold standard for the diagnosis of T. vaginalis. One study found the sensitivities for T. vaginalis using wet mount, culture, rapid antigen testing, and transcription-mediated amplification testing were 65, 96, 90, and 98 percent, respectively. Coexistence of T. vaginalis and BV pathogens is common, with coinfection rates of 60 to 80 percent.

Microscopy is negative in up to 50 percent of patients with culture-confirmed VVC. Since there are no reliable point of care tests for Candida available in the United States, culture must be obtained. PCR methods have high sensitivity and specificity and a shorter turn-around time than culture, but they are costly and offer no proven benefit over culture in symptomatic women.

Lynch et al. (2019) collected vaginal swabs from 93 women in a cross-sectional study; results from microscopy were compared to two molecular approaches (a qPCR assay with a BV interpretive algorithm and a microbiome profiling test of the 16S rRNA gene produced by Illumina). Results show that “Microscopy plus BV Nugent score had 76% overall agreement with the qPCR plus BV interpretive algorithm method”; further, “Microscopic identification of Candida versus that by qPCR had 94% agreement (9 positive, 78 negative).” The qPCR assays gave additional information regarding the types of bacteria present, and the 16S microbiome analysis identified differentiating patterns between BV, aerobic vaginitis (AV), and Lactobacillus type infections.

Cartwright, Pherson, Harris, Clancey, and Nye (2018) have published data regarding the clinical validity of a PCR-based assay for the detection of BV. This multicenter study included 1,579 patients and compared PCR results to samples realized by both the Nugent gram stain and a clinical evaluation using Amsel criteria. Next-generation sequencing was used to confirm differing results. After the resolution of discordant test results using next-generation sequencing, the BV-PCR assay reported a sensitivity of 98.7%, a specificity of 95.9%, a positive predictive value of 92.9% and a negative predictive value of 96.9%. These results show that this PCR-based assay can diagnose BV in symptomatic women efficiently.

Clinical Validity and Utility
As previously stated, microscopy, rather than bacterial culture, is the standard of care for diagnosing BV, and commercially available tests are available in the absence of microscopy but are not widely used. A study of 176 women using the Affirm VP III test (a DNA hybridization probe test that identifies high concentrations of G. vaginalis) reported comparable results to wet mount examination with no false positives and only three false negatives for T. vaginalis, and three false positives and four false negatives for G. vaginalis. This test “takes less than one hour to perform and is the best option when findings on physical examination suggest BV… but microscopy cannot be performed to look for clue cells.”

The OSOM BVBlue chromogenic diagnostic point-of-care test is a CLIA-waived test with a reported 10 minute read time. One study of 173 pregnant women reported a sensitivity and specificity of 94% and 96% respectively, as compared to Gram stain score. These results were comparable to the previously reported values of 91.7% sensitivity and 97.8% specificity in an earlier, smaller study of non-menstruating women (n=57). A larger study (n=288 women) reported a sensitivity of 88% and specificity of 91% as compared to the Amstel criteria. The authors of this report concluded that women who “are not in settings where the conventional diagnostic methods are either practical or possible… would greatly benefit from access to rapid and reliable point-of-care tests to improve the diagnosis and management of BV.”

The FDA approved the use of the BD MAX Vaginal Panel as “an automated qualitative in vitro diagnostic test for the direct detection of DNA targets from bacteria associated with BV (qualitative results reported based on detection and quantitation of targeted organism markers), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis from vaginal swabs in patients who are symptomatic for vaginitis/vaginosis. The test utilizes real-time PCR for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA." A 2017 cross-sectional, multi-site study into the clinical validation of this system (n=1,740 symptomatic women) reported a sensitivity and specificity of 90.9% and 94.1%, respectively for the Candida group and 90.5% sensitivity and 85.8% specificity for BV. For C. glabrata specifically, the assay had only 75.9% sensitivity but 99.7% specificity. For trichomoniasis, the sensitivity and specificity were 93.1% and 99.3%, respectively. These researchers also compared the results of this test to clinician assessment. Again, to qualify for the study, the women must have at least one symptom of BV. Using Amsel’s criteria, the investigational test sensitivity was 92.7% as compared to the 75.6% sensitivity of the clinician assessment. The authors conclude, “The investigational test showed significantly higher sensitivity for detecting vaginitis, involving more than one cause, than did clinician diagnosis. Taken together, these results suggest that a molecular investigational test can facilitate accurate detection of vaginitis.” It should be noted, however, that these studies only included symptomatic women, and, therefore, the possible clinical nonspecificity (i.e. instances where an asymptomatic woman would test positive) is not addressed. Sherrard (2019) compared BV, candidiasis, and trichomoniasis diagnostic results from the BD MAX Vaginal Panel to a current test used in a UK specialist sexual health service center. The authors reported that the BD MAX Vaginal Panel had a sensitivity of 86.4% and specificity of 86.0% for Candida species, and a sensitivity of 94.4% and specificity of 79% for BV; the specificity for BV was lower in this study than what has been previously reported.

SureSwab®(Quest Diagnostics, Inc.) is a multi-target PCR test using RT-PCR to screen for a number of microorganisms involved in vaginal flora imbalances, including B. vaginalis, T. vaginalis, C. albicans, C. glabrata, C. tropicalis, and C. parapsilosis, from a vaginal swab. The swab can be collected either by a physician or the patient. Similarly, Quest Diagnostics also offers the SureSwab® Vaginosis/Vaginitis Plus test, which tests for the presence of Chlamydia trachomatis and Neisseria gonorrhoeae in addition to the microorganisms of the SureSwab® test. The test is based on the unique set of primers synthesized by a CDC research team to identify Candida that purports to diagnose vulvovaginal candidiasis while ruling out other genital infections. The CDC research group, led by Dr. C.J. Morrison, developed the DNA probes to identify medically important Candida species by the internal transcribed spacer 2 region of ribosomal DNA. The specific hybridization was measured by a sample-to-background ratio of 58.7, 53.2, 46.9, 59.9, and 54.7 for C. albicans, C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei, respectively. The negative control sample-to-background ratio was 0.9.

The OSOM Trichomonas vaginalis (TV) Rapid Test by Sekisui Diagnostics is “an antigen-detection test using immunochromatographic capillary flow dipstick technology that can be performed at the point of care.” The diagnostic accuracy of the OSOM TV Rapid assay was tested against the common laboratory-based Anyplex II STI-7 Detection in a South African cross-sectional study; all irregular results were further tested with the Fast Track Diagnostics (FTD) STD9 assay. Vaginal swabs from 247 women were tested for this study. “The sensitivity and specificity of OSOM TV were 75.0% (45.0-100) and 100% (100-100)”, respectively, showing a very high specificity and lower sensitivity.

The AMPLISwab™ by MedLabs is a comprehensive test created to assess the different organisms responsible for a variety of female genital tract infections, including causative pathogens for cervicitis, nongonococcal urethritis, pelvic inflammatory disease and infertility, sexually transmitted infections, and vaginitis (e.g., bacterial vaginosis, candidiasis and trichomoniasis). The test requires one swab to test for 23 total organisms, broken down into four categories (7 yeast, 12 bacteria and 1 reference bacteria, 1 parasite, and 2 types of herpes viruses), employing testing methodologies such as automated DNA/RNA extraction, transcription mediated amplification (TMA), and real-time polymerase chain reaction (RT-PCR) for the quantification of select organisms implicated in bacterial vaginosis.

The multiplex PCR assay SmartJane™ measures a specimen’s vaginal flora (such as Lactobacillus iners or Treponema pallidum). The test proposes that the results can provide a health snapshot of the environment tested based on the levels of microorganisms detected. The procedure for the test requires the user to self-sample by collecting a vaginal swab and sending the sample back to Ubiome where it is analyzed. The labs use Precision Sequencing technology to extract DNA from the microorganisms in the sample and Illumina Next-Generation to sequence the targeted genes. Then, phylogenetic algorithms are used to analyze and organize the DNA from those microorganisms. Finally, a clinical report detailing the levels of the targeted microorganisms is sent to the user and medical provider. The report contains measurements of its targeted microorganisms, informing the patient whether those measurements are within the normal reference ranges for certain conditions, and whether certain high danger pathogens are present. The manufacturers state that on average SmartJane™ has a sensitivity and specificity for the species of microorganism of 99.4% and 100.0%, respectively. SmartJane™ tests for 19 different HPV strains and common pathological agents involved in sexually transmitted infections in addition to more than 20 different microorganisms involved in BV, including G. vaginalis.

Even though studies have shown that PCR methods have a higher specificity and sensitivity than culture and shorter turn-around time in identifying Candida, their use may be adding to clinical nonspecificity. Tabrizi et al. (2006) reported that PCR “detected four additional Candida albicans, three Candida parapsilosis and one Candida tropicalis when compared with culture. All but one case additionally detected by PCR were found in patients with no VVC symptoms.”  These data support the earlier findings by Giraldo et al. (2000) where, unlike culture testing, “Candida was identified by PCR in a similar proportion of patients with previous recurrent vulvovaginal candidiasis (30%) and in controls (28.8%).” Taken together, these studies indicate that, even though PCR is more sensitive than culture, it may be identifying cases of Candida in asymptomatic women that are clinically irrelevant. 

Centers for Disease Control and Prevention (CDC)
The CDC published recommendations for the evaluation of diseases characterized by vaginal discharge in the 2015 Sexually Transmitted Diseases Treatment Guidelines. These guidelines state, “Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge…In the clinician’s office, the cause of vaginal symptoms might be determined by pH, a potassium hydroxide (KOH) test, and microscopic examination of fresh samples of the discharge” and “In settings where pH paper, KOH, and microscopy are not available, alternative commercially available point-of-care tests or clinical laboratory testing can be used to diagnose vaginitis.”

For the evaluation of BV, the CDC recommends that “BV can be diagnosed by the use of clinical criteria (i.e., Amsel’s Diagnostic Criteria) or Gram stain”; further, “Other tests, including Affirm VP III (Becton Dickinson, Sparks, MD), a DNA hybridization probe test for high concentrations of G. vaginalis, and the OSOM BV Blue test (Sekisui Diagnostics, Framingham, MA), which detects vaginal fluid sialidase activity, have acceptable performance characteristics compared with Gram stain. Although a prolineaminopeptidase card test is available for the detection of elevated pH and trimethylamine, it has low sensitivity and specificity and therefore is not recommended. PCR has been used in research settings for the detection of a variety of organisms associated with BV, but evaluation of its clinical utility is still underway. Detection of specific organisms might be predictive of BV by PCR.. Additional validation is needed before these tests can be recommended to diagnose BV. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. Cervical Pap tests have no clinical utility for the diagnosis of BV because of their low sensitivity and specificity.” The guidelines also state that “evidence is insufficient to recommend routine screening for BV in asymptomatic pregnant women at high or low risk for preterm delivery for the prevention of preterm birth”, which is in compliance with the 2008 USPSTF recommendations.

For the evaluation of vulvovaginal candidiasis, the CDC recommends: “Examination of a wet mount with KOH preparation should be performed for all women with symptoms or signs of VVC, and women with a positive result should be treated. For those with negative wet mounts but existing signs or symptoms, vaginal cultures for Candida should be considered…PCR testing for yeast is not FDA-cleared; culture for yeast remains the gold standard for diagnosis.” DNA hybridization probe tests are not addressed.

For the evaluation of Trichomoniasis, the CDC recommends: “Diagnostic testing for T. vaginalis should be performed in women seeking care for vaginal discharge… The use of highly sensitive and specific tests is recommended for detecting T. vaginalis. Among women, NAAT is highly sensitive, often detecting three to five times more T. vaginalis infections than wet-mount microscopy, a method with poor sensitivity (51%–65%).” Regarding point of care testing, it is stated that “Other FDA-cleared tests to detect T. vaginalis in vaginal secretions include the OSOM Trichomonas Rapid Test (Sekisui Diagnostics, Framingham, MA), an antigen-detection test using immunochromatographic capillary flow dipstick technology that can be performed at the point of care, and the Affirm VP III (Becton Dickinson, Sparks, MD), a DNA hybridization probe test that evaluates for T. vaginalisG. vaginalis, and Candida albicans. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, with sensitivity 82%–95% and specificity 97%–100%. Self-testing might become an option, as a study of 209 young women aged 14–22 years found that >99% could correctly perform and interpret her own self-test using the OSOM assay, with a high correlation with clinician interpretation (96% agreement, κ = 0.87). The results of the Affirm VP III are available within 45 minutes. Sensitivity and specificity are 63% and 99.9%, respectively, compared with culture and TMA; sensitivity might be higher among women who are symptomatic.”

American Academy of Family Physicians (AAFP)
The AAFP published an article on the diagnosis of vaginitis which states that: “Physicians traditionally diagnose vaginitis using the combination of symptoms, physical examination, pH of vaginal fluid, microscopy, and the whiff test. When combined, these tests have a sensitivity and specificity of 81 and 70 percent, respectively, for BV; 84 and 85 percent for vulvovaginal candidiasis; and 85 and 100 percent for trichomoniasis when compared with the DNA probe standard…A cost-effectiveness analysis of diagnostic strategies for vaginitis undiagnosed by pelvic examination, wet-mount preparation, and related office tests showed that the least expensive strategy was to perform yeast culture, gonorrhea and chlamydia probes at the initial visit, and Gram stain and Trichomonas culture only when the vaginal pH exceeded 4.9. Other strategies cost more and increased duration of symptoms by up to 1.3 days.”

In 2018, the AAFP has published the following guidelines:   

  • “Symptoms alone cannot differentiate between the causes of vaginitis. Office-based or laboratory testing should be used with the history and physical examination findings to make the diagnosis. (C evidence rating)
  • Do not obtain culture for the diagnosis of bacterial vaginosis because it represents a polymicrobial infection. (C evidence rating)
  • Nucleic acid amplification testing is recommended for the diagnosis of trichomoniasis in symptomatic or high-risk women. (C evidence rating).”

U.S. Preventive Services Task Force Recommendations (USPSTF)
In 2020, the USPSTF published recommendations discouraging the use of screening for BV in pregnancy: “The USPSTF recommends against screening for bacterial vaginosis in pregnant persons not at increased risk for preterm delivery”. On a similar note, the USPSTF maintains its 2008 recommendation stating “that the current evidence is insufficient to assess the balance of benefits and harms of screening for bacterial vaginosis in pregnant persons at increased risk for preterm delivery”.

American College of Obstetrics and Gynecology (ACOG)
ACOG published recommendations for the evaluation of vaginitis in 2006, and reaffirmed in 2017, which state: “Evaluation of women with vaginitis should include a focused history about the entire spectrum of vaginal symptoms, including change in discharge, vaginal malodor, itching, irritation, burning, swelling, dyspareunia, and dysuria.” Further, “During speculum examination, samples should be obtained for vaginal pH, amine (“whiff”) test, and saline (wet mount) and 10% potassium hydroxide (KOH) microscopy. The pH and amine testing can be performed either through direct measurement or by colorimetric testing.” With a Level B recommendation, ACOG states, “Microscopy is the first line for diagnosing vulvovaginal candidiasis and trichomoniasis. In selected patients, culture for yeast and T. vaginalis should be obtained in addition to standard office-based testing.” Additionally, “A vaginal Gram stain for Nugent scoring of the bacterial flora may help to identify patients with BV. Other currently available ancillary tests for diagnosing vaginal infections include rapid tests for enzyme activity from BV-associated organisms, Trichomonas vaginalis antigen, and point-of care testing for DNA of G. vaginalis, T. vaginalis, and Candida species; however, the role of these tests in the proper management of patients with vaginitis is unclear. Depending on risk factors, DNA amplification tests can be obtained for Neisseria gonorrheae and Chlamydia trachomatis.”

The ACOG published in 2020 Practice Bulletin Number 215 on vaginitis in nonpregnant patients. In these guidelines, the ACOG made these recommendations for diagnostic testing based on good and consistent scientific evidence (Level B):  

  • “The use of Amsel clinical criteria or Gram stain with Nugent scoring is recommended for the diagnosis of bacterial vaginosis.”
  • “Nucleic acid amplification testing is recommended for the diagnosis of trichomoniasis.”
  • “In a symptomatic patient, diagnosis of vulvovaginal candidiasis requires one of the following two findings: 1) visualization of spores, pseudohyphae, or hyphae on wet-mount microscopy or 2) vaginal fungal culture or commercial diagnostic test results positive for Candida species.”

The ACOG also published recommendations based on limited or inconsistent scientific evidence (Level B), along with a series of recommendations based on consensus and expert opinion (Level C). Those relating to diagnostic testing are reported below:  

  • “Patients should be retested within 3 months after treatment for T vaginalis because of the high rates of infection recurrence.” (Level B)
  • “Pap tests are not reliable for the diagnosis of vaginitis. Diagnostic confirmation is recommended for incidental findings of vulvovaginal candidiasis, bacterial vaginosis, or trichomoniasis on a Pap test.” (Level B)
  • “A complete medical history, physical examination of the vulva and vagina, and clinical testing of vaginal discharge (ie. pH testing, a potassium hydroxide [KOH] “whiff test”, and microscopy) are recommended for the initial evaluation of patients with vaginitis symptoms.” (Level C)

Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines
IDSA has published an updated clinical guideline for the management of candidiasis in which recommendations include diagnosing vulvovaginal candidiasis before proceeding with empiric antifungal therapy. The usual diagnosis is clinical based on signs and symptoms of vaginitis such as pruritus, irritation, vaginal soreness, vulvar edema, erythema and many others. Clinical signs and symptoms are nonspecific and could be attributed to causes other than vulvovaginal candidiasis. Therefore, authors recommend confirming clinical diagnosis by a wet -mount preparation with saline and 10% KOH to demonstrate the presence of yeast and a normal pH. In cases where signs and symptoms are suggestive of vulvovaginal candidiasis, but microscopic findings and pH are negative, culture testing confirms the diagnosis according to published guidelines. The IDSA also discusses the possible use of PCR in diagnosing invasive candidiasis, even though the guidelines later state that “Cultures of blood or other samples collected under sterile conditions have long been considered diagnostic gold standards for invasive candidiasis…The role of PCR in testing samples other than blood is not established.”

In the 2018 IDSA A guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases, the IDSA states, “For vaginosis (altered vaginal flora) a Gram stain and recently available microbiome-based assays are more specific than culture and probe testing for Gardnerella vaginalis alone… A number of point-of-care tests can be performed from a vaginal discharge specimen while the patient is in the healthcare setting. Although point-of-care tests are popular, the sensitivity and specificity for making a specific diagnosis vary widely and these assays, while rapid, are often diagnostically poor.” The IDSA notes that the FDA has approved the use of the Max Vaginal Panel by Becton Dickinson in symptomatic females. “Preliminary data show greater specificity of this approach compared to methods that identify only G. vaginalis, as well as consistency in both reproducible as well as standardized results.”

Society of Obstetricians and Gynecologists of Canada (SOGC)
The SOGC published guidelines for the screening and management of BV in pregnancy. These guidelines state that the following:  

  • “In symptomatic pregnant women, testing for and treatment of bacterial vaginosis is recommended for symptom resolution. Diagnostic criteria are the same for pregnant and non-pregnant women (I-A).
  • Asymptomatic women and women without identified risk factors for preterm birth should not undergo routine screening for or treatment of bacterial vaginosis (I-B).
  • Women at increased risk for preterm birth may benefit from routine screening for and treatment of bacterial vaginosis (I-B).
  • Testing should be repeated one month after treatment to ensure that cure was achieved (III-L).”

The SOGC also published guidelines regarding the screening and management of trichomoniasis, VVC, and BV. These guidelines state that “Bacterial vaginosis should be diagnosed using either clinical (Amsel’s) or laboratory (Gram stain with objective scoring system) criteria (II-2A).”

References:

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  3. ACOG. (2017). College Publications. Obstet Gynecol, 129(6), 1147-1148. doi:10.1097/aog.0000000000002107
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Coding Section 

Code Number Description
CPT   81513 (effective 01/01/2021) 

Infectious disease, bacterial vaginosis, quantitative real-time amplification of RNA markers for Atopobium vaginae, Gardnerella vaginalis, and Lactobacillus species, utilizing vaginal-fluid specimens, algorithm reported as a positive or negative result for bacterial vaginosis  

  81514 (effective 01/01/2021)  

Infectious disease, bacterial vaginosis and vaginitis, quantitative real-time amplification of DNA markers for Gardnerella vaginalis, Atopobium vaginae, Megasphaera type 1, Bacterial Vaginosis Associated Bacteria-2 (BVAB-2), and Lactobacillus species (L. crispatus and L. jensenii), utilizing vaginal-fluid specimens, algorithm reported as a positive or negative for high likelihood of bacterial vaginosis, includes separate detection of Trichomonas vaginalis and/or Candida species (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis), Candida glabrata, Candida krusei, when reported 

  82120

Amines, vaginal fluid, qualitative

  83986 Ph; body fluid, not otherwise specified
  87070 Culture, bacterial; any other source except urine, blood or stool, aerobic, with isolation and presumptive identification of isolates 
  87149 Culture, typing; identification by nucleic acid (DNA or RNA) probe, direct probe technique, per culture or isolate, each organism probed
  87150 Culture, typing; identification by nucleic acid (DNA or RNA) probe, amplified probe technique, per culture or isolate, each organism probed
  87210  Smear, primary source with interpretation; wet mount for infectious agents (eg, saline, India ink, KOH preps)  
  87480 Infectious agent detection by nucleic acid (dna or rna); candida species, direct probe technique
  87481 Infectious agent detection by nucleic acid (dna or rna); candida species, amplified probe technique 
  87482  Infectious agent detection by nucleic acid (dna or rna); candida species, quantification technique 
  87510  Infectious agent detection by nucleic acid (dna or rna); gardnerella vaginalis, direct probe technique 
  87511 

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

  87512  Infectious agent detection by nucleic acid (DNA or RNA); Gardnerella vaginalis, quantification 
  87660  Infectious agent detection by nucleic acid (dna or rna); trichomonas vaginalis, direct probe technique 
  87661  Infectious agent detection by nucleic acid (dna or rna); trichomonas vaginalis, amplified probe technique 
  87797  Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; direct probe technique, each organism 
  87798  Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; amplified probe technique, each organism 
  87799  Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; quantification, each organism 
  87800  Infectious agent detection by nucleic acid (dna or rna), multiple organisms; direct probe(s) technique 
  87808 Infectious agent antigen detection by immunoassay with direct optical observation; trichomonas vaginalis 
  87905 Infectious agent enzymatic activity other than virus (eg, sialidase activity in vaginal fluid) 
  Q0111  Wet mounts, including preparations of vaginal, cervical or skin specimens 
ICD-10-CM  A56.11

Chlamydial female pelvic inflammatory disease

  A59  Trichomoniasis 
  A59.0 Urogenital trichomoniasis  
  A59.00 Urogenital trichomoniasis, unspecified 
  A59.01  Trichomonal vulvovaginitis
  B37.3  Candidiasis of vulva and vagina 
  B96.89  Other specified bacterial agents as the cause of diseases classified elsewhere [Gardnerella vaginitis]
  F11.10-F11.99  Opioid related disorders [injecting drug users] 
  F13.10-F13.99  Sedative, hypnotic, or anxiolytic related disorders [injecting drug users] 
  F14.10-F14.99  Cocaine related disorders [injecting drug users] 
  F15.10-F15.99  Other stimulant related disorders [injecting drug users] 
  L29.0  Pruritus ani 
  L29.2  Pruritus vulvae 
  L29.8  Other pruritus 
  L29.9  Pruritus, unspecified 
  N72  Inflammatory disease of cervix uteri 
  N73  Other female pelvic inflammatory diseases 
  N73.9  Female pelvic inflammatory disease, unspecified 
  N76  Other inflammation of vagina and vulva 
  N76.0  Acute vaginitis 
  N76.1  Subacute and chronic vaginitis 
  N76.2  Acute vulvitis
  N76.3  Subacute and chronic vulvitis 
  N76.89  Other specified inflammation of vagina and vulva 
  N77.1  Vaginitis, vulvitis and vulvovaginitis in diseases classified elsewhere 
  N89.0  Mild vaginal dysplasia 
  N89.1  Moderate vagina dysplasia 
  N89.8  Other specified noninflammatory disorders of vagina 
  N90.89  Other specified noninflammatory disorders of vulva and perineum 
  N93  Other abnormal uterine and vaginal bleeding 
  N94.11  Superficial (introital) dyspareunia 
  N94.89  Other specified conditions associated with female genital organs and menstrual cycle 
  O09.211  Suprvsn of preg w history of pre-term labor, first trimester 
  O09.212  Suprvsn of preg w history of pre-term labor, second tri 
  O09.213  Suprvsn of preg w history of pre-term labor, third trimester 
  O09.219  Suprvsn of preg w history of pre-term labor, unsp trimester 
  R10.2  Pelvic and perineal pain 
  Z01.411  Encounter for gynecological examination (general) (routine) with abnormal findings 
  Z11.2  Encounter for screening for other bacterial diseases 
  Z11.3  Encounter for screening for infections with a predominantly sexual mode of transmission 
  Z11.8  Encounter for screening for other infectious and parasitic diseases [High risk screening for Trichomonas only] 
  Z13.89  Encounter for screening for genitourinary disorders 
  Z20.2  Contact with and (suspected) exposure to infections with a predominantly sexual mode of transmission 
  Z20.9  Contact with and (suspected) exposure to unspecified communicable disease 
  Z33.1  Pregnant state, incidental 
  Z72.5  High risk sexual behavior 
  Z86.19  Personal history of other infectious and parasitic diseases 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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

History From 2014 Forward     

04/01/2021 

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

12/10/2020 

Updating Coding Section with 2021 codes.

09/23/2020 

Interim review, removing 0068U from coding. 

04/15/2020

Annual review, no change to policy intent. Updating coding. 

07/16/2019 

Updating coding section with N89.8 ICD-10 code. No other changes made. 

04/04/2019 

Annual review, adding one additional policy statement 

04/17/2018 

Interim review with change to month of annual review, no other changes made. 

12/04/2017 

Annual review with a major revision to all aspects of the policy for clarity and expanded testing criteria. 

08/29/2017 

Updating Coding Section with code N89.8. No change to policy intent

06/06/2017 

Corrected typo in Coding section. No other changes. 

04/26/2017 

Updated category to Laboratory. No other changes. 

03/06/2017 

Updated coding to add Z20.2. 

10/11/2016 

Annual review, no change to policy intent. 

05/09/2016 

Interim review adding coding: 87512 and 87999. No change to policy intent. 

10/07/2015 

Annual review,no changes made. 

10/28/2014

Annual review. Updated title, rationale, references. Added verbiage related to multitarget PCR testing.


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