Vaginosis/Vaginitis: Diagnostic Updates to Improve Cure Rates and Patient Outcomes
Most women will have one or more vaginal infections during their lifetime, typically characterized by discharge, itching, or odor. Nearly 90% of all cases of vaginitis are attributable to 3 causes (1):
Trichomonas vaginalis (trichomoniasis)
Caused by trichomonads, a flagellated protozoan
Vaginal candidiasis (also termed vulvovaginal candidiasis or VVC)
85% due to yeast infection with Candida albicans; 5 to 10% caused by Candida glabrata or Candida parapsilosis, with other Candida species to a lesser extent
Bacterial vaginosis (BV; non-inflammatory)
Typically overgrowth by Gardnerella vaginalis, Mobiluncus species, Mycoplama hominis, and Peptostreptococcus species
Vaginal symptoms/vaginitis account for millions of women’s healthcare visits annually (1, 2). Despite technological advances, standard diagnostic testing often consists of history and physical examination, pH determinations, whiff test, and wet prep microscopy. Application of culture gold-standards in Diamond’s media, Gram stain with Nugent’s criteria, and agar culture were reported generally to be not available in many office settings. The result—nearly 30% of symptomatic women remain undiagnosed after clinical evaluation, and worse, nearly 25% are put on a pharmacologic therapy not based on validated diagnostic testing. This clinical failure puts these women at risk for acquiring additional STIs as well as being at increased risk for adverse pregnancy outcomes (1, 3-9). New testing platforms have made diagnosis more accurate and rapid, so timely treatment can be offered without guesswork. Of course, that happens only if the new testing platforms are widely accepted into daily clinical practice.
This CME Journal article focuses primarily on trichomoniasis caused by Trichomonas vaginalis, but also briefly describes diagnosis of vulvovaginal candidiasis and bacterial vaginosis.
Trichomonas Vaginalis (Trichomoniasis)
Trichomoniasis is caused by Trichomonas vaginalis with an estimated 5 million women infected annually in the U.S. (3). This STI is diagnosed in 4% to 35% of women with symptoms of vaginosis/vaginitis (4). Trichomoniasis is associated with increased risk of co-infection with human immunodeficiency virus (HIV), adverse pregnancy outcomes including premature rupture of the membranes, preterm labor and delivery, and low birth weight (5-9). In men, Trichomonas vaginalis infection may cause urethritis that is commonly asymptomatic.
New developments in diagnostic testing have greatly improved the ability to detect this infection. This section of the article will address these new diagnostic tests, the integration of current STI screening and treatment guidelines for Trichomonas vaginalis into one’s practice, and the integration of knowledge of the epidemiology of trichomoniasis to assist when counseling and managing patients.
A recent assessment of the incidence of trichomoniasis the U.S. estimated an annual incidence of 7.4 million new cases (10). The World Health Organization has estimated that Trichomonas vaginalis infection accounts for almost half of all curable infections worldwide (11). A survey of adolescent women in the U.S. estimated the overall prevalence to be 3.1%, with a much higher prevalence of 13.3% among African-American women (12). Infection with Trichomonas vaginalis is also common in older women in the U.S., with one study demonstrating a prevalence of 11.3% and 13.0% among women ages 40-49 and ≤50 years of age, respectively (13).
Reported prevalence of urethral infection with Trichomonas vaginalis in males has varied depending on the population studied and the diagnostic techniques used. Among men attending an STD clinic in Birmingham, AL, Trichomonas vaginalis was detected by PCR in 17% of men attending the clinic for a new-problem visit or screening. There was no significant difference in the detection of the organism between men with and without urethral symptoms (20 and 14.5%, respectively). Among men with nongonococcal urethritis, nearly as many had Trichomonas vaginalis detected as had chlamydia (19.9 and 25.2%, respectively) (14). In a multi-center study of a new diagnostic test for Trichomonas vaginalis conducted at a wide range of clinical settings, the overall prevalence in men was 2.7% (unpublished data, Schwebke)
The incubation period of trichomoniasis is unknown; however, in vitro studies suggest an incubation period of 4 to 28 days in women (15). Symptoms in women include vaginal discharge, pruritus, and irritation. Signs of infection include vaginal discharge (42%), odor (50%), and edema or erythema (22% to 37%). The discharge is classically described as frothy, but it is actually frothy in only about 10% of patients. The color of the discharge may vary. Colpitis macularis (strawberry cervix) is a specific clinical sign for this infection but is detected with reliability only by colposcopy and rarely during routine examination (16). Other complaints may include dysuria and lower abdominal pain; the etiology of the latter is unclear. The urethra is also infected in the majority of women (17). Nearly half of all women with Trichomonas vaginalis infectionsare asymptomatic (18). Therefore, if these women are not screened, the diagnosis will be missed. In men, recent data suggests that Trichomonas vaginalis infection is a more common cause of non-gonococcal urethritis (NGU) than previously recognized (14,19), and should be considered a diagnostic possibility in men who fail initial therapy for NGU. Trichomonas vaginalis infection in men may also rarely cause epididymitis, prostatitis, and superficial penile ulcerations (20).
Diagnosis and Screening
Diagnosis of trichomoniasis in the female can be accomplished at the time of care via direct microscopic examination of the vaginal fluid. However, even for skilled diagnosticians the sensitivity of this test is only 60% overall and may be less in asymptomatic women (21). Presence of motile trichomonads is diagnostic. The pH of the vaginal fluid will be greater than 4.5 in the majority, but can be normal (≤4.5). In these cases the trichomonads are often more sparse as they prefer a more alkaline pH. Neutrophils as well as altered vaginal bacterial flora are often seen. Interestingly, Wiesenfeld and colleagues found that even these simple bedside tests were not utilized to determine a diagnosis of vaginitis in a women’s health referral center, resulting in over half of the women receiving inappropriate therapy (22). Reliance upon signs and symptoms alone for the diagnosis of vaginitis has been shown to be unreliable (23). Until recently, culture media was the gold standard for diagnosis but was not widely available to clinicians (24). Other commercially available tests include an RNA probe semi-automated system, which also detects candidiasis and bacterial vaginosis, and a dipstick ELISA. Both of these tests are currently licensed only for vaginal specimens, can be used as point-of-care tests, and have sensitivities of about 80% (25,26). They may be a good choice if microscopy is not available.
The current gold standard for diagnosing trichomoniasis in both men and women is use of a nucleic acid amplification test (NAAT). Sensitivities and specificities for these tests are each in the 98-99% range. For women, various specimen types may be used including vaginal, endocervical, ThinPrep PAP (Hologic; San Diego, CA), and urine (27,28). For men, only one NAAT has been FDA approved for use with male urine (Schwebke et al, manuscript in press); however, the other commercially available tests may be run by laboratories in an analyte specific reagent (ASR) format once internally validated by the laboratory.
In the CDC 2015 guidelines (1), the Aptima Trichomonas vaginalis assay (Hologic; San Diego, CA), a NAAT, was identified as a test cleared by the Food and Drug Administration (FDA) for the detection of Trichomonas vaginalis; the assay detected 3- to 5-fold more Trichomonas vaginalis infections than did wet mount microscopy. Other tests mentioned included the BD ProbeTec Trichomonas vaginalis Qx Amplified DNA Assay (Becton Dickinson; Franklin Lakes, NJ), the OSOM Trichomonas Rapid Test (Sekisui Diagnostics; Framingham, MA), and the BD Affirm VPIII Microbial Identification Test (Becton Dickinson; Franklin Lakes, NJ), a DNA hybridization probe test.
CDC 2015 guidelines (1) also stated that “although data are lacking on whether screening and treatment for asymptomatic trichomoniasis in high prevalence settings or persons at high risk can reduce any adverse health events and health disparities or reduce community burden of infection...decisions about screening [asymptomatic women] might be informed by local epidemiology of Trichomonas vaginalis infection.” Also suggested was if highly sensitive testing, such as NAAT, is not feasible, a testing algorithm should be employed using wet mount first, followed by NAAT if wet mount is negative (1,29,20).
Current CDC STD Treatment Guidelines recommend screening for trichomonas in all HIV-infected women at entry to care and then annually due to high rates of infection in this population (1,31). The Guidelines also state that screening may be considered for other at-risk populations such as STD clinic attendees and incarcerated individuals (1,29). Routine screening with NAATS in both men and women has been shown to greatly enhance identification of infected individuals at STD clinics (33). Re-screening for all infected women is recommended at 3 months due to high rates of reinfection (34).
The recommended therapy for trichomoniasis is a single 2 gram oral dose of metronidazole or tinidazole. Sexual partners should be routinely treated (34). Tinidazole has superior pharmacokinetics against Trichomonas vaginalis but is more expensive than metronidazole (35). Metronidazole intravaginal gel has limited efficacy and should not be used (35). Failure to treat the male sexual partners is likely the most common cause of recurrent disease in women (35,36). Women with asymptomatic infection should be treated. Although there continues to be some controversy about the safety of metronidazole in pregnancy, there has never been a documented case of fetal malformation attributed to its use, even when it is used in the first trimester (37). There is no data on the safety of tinidazole in pregnancy (37).
Resistance to metronidazole has been reported and tinidazole with its more favorable pharmacokinetics may be the drug of choice when resistance is encountered. Paromomycin cream has also been used in combination with high dose oral tinidazole with some success (38).
As mentioned, Trichomonas vaginalis has been implicated as a cause of preterm delivery (7,39). Trichomoniasis has also been associated with vaginal cuff cellulitis following abdominal hysterectomy (38). Acquisition and transmission of HIV has been associated with trichomoniasis. The associations between HIV and trichomoniasis may relate to increased shedding of HIV as a result of the local inflammation produced by the STI and/or increased susceptibility to HIV as a result of the macro- or microscopic breaks in mucosal barriers caused by inflammation (40).
Given the higher prevalence and incidence of trichomoniasis than most other treatable STDs in most studies to date, the attributable fraction of HIV acquisitions due to trichomoniasis may eclipse the relative contribution of other STIs (41). Transmission of HIV is also enhanced by infection with Trichomonas vaginalis. HIV viral loads in the seminal fluid of men with urethritis was significantly higher in men with trichomoniasis than in those with symptomatic urethritis due to an unidentified cause (42). Treatment of trichomonal urethritis reduced the levels of HIV so that they were similar to those seen in uninfected controls (43).
Vulvovaginal Candidiasis (VVC)
VVC is present in 17% to 39% of women with symptoms (4). Nearly three-quarters of women develop VVC during their lifetime; about 45% suffer a second occurrence, and approximately 5% will have [frequently] intractable recurrent candidiasis (5). Although Candida albicans accounts for 80% to 90% of such infections, VVC has also been associated with Candida glabrata, Candida parapsilosis, and Candida tropicalis; and, rarely, with Candida kefir, Candida krusei, Candida pseudotropicalis, Candida lusitaniae, and/or Candida rugose (44). Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge, none of which is specific for VVC (1,44).
While laboratory diagnosis of VVC/yeast infection had classically been to perform by wet preparation of vaginal discharge to assess for budding yeast, hyphae, or pseudohyphea, or a culture assessment (1,2), these approaches are often time-consuming and not readily available in most offices.
DNA probes have been developed to detect the presence of numerous organisms associated with vaginitis (1,2). The Affirm VP III Microbial Identification System (Becton Dickinson) is a commercially available office-based DNA probe test kit that simultaneously detects the presence of Gardnerella vaginalis, Trichomonas vaginalis, and Candida species. The approximate sensitivity of DNA probes for Candida species is substantially higher (80%) when compared to wet mount (35% to 45%) or culture (67%) techniques. NAATS are being developed and recently a diagnostic panel for trichomonas, yeast, and bacterial vaginosis was FDA approved (BD Diagnostics) which has excellent sensitivity and specificity for Candida. However, as Candida may colonize the vagina, it will be important to distinguish colonization from true infection based on compatible symptoms when using these newer highly sensitive diagnostic tests.
VVC can be classified as either uncomplicated or complicated (1):
Uncomplicated VVC disease:
Sporadic and infrequent, and
Mild to moderate, and
Likely Candida albicans, and
A non-immunocompromised woman
Complicated VVC disease:
Nonalbicans candidiasis, or
Women with diabetes, immunocompromising condition, debilitation, or on immunosuppressive therapy
Approximately 10% to 20% of women will have complicated VVC, requiring special diagnostic and therapeutic considerations. A short-course of topical formulations for 1 to 3 days or single dose oral fluconazole (150 mg) are usually effective in treating uncomplicated VVC, with azole drugs being more effective than nystatin. Azole treatment results in relief of symptoms and negative cultures in 80% to 90% of patients completing therapy. Recurrent VVC and complicated VVC require more complex therapeutic regimens; the reader is directed to current CDC treatment recommendations for a more exhaustive listing (1).
Bacterial Vaginosis (BV)
BV is the most common finding in women with vaginal symptoms, affecting between one-quarter and one-half of symptomatic women (4). BV is characterized by replacement of normal Lactobacillus flora with large concentrations of predominantly Gardnerella vaginalis, Mobiluncus species, Mycoplasma hominis, and other BV-associated anaerobic bacteria. Treatment of BV may reduce the risk of acquiring other STIs (5), including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, HIV, and herpes simplex type 2 (1,45-47).
Symptoms are absent in approximately 50 % of women with BV infection. While BV is not typically associated with soreness, itching or irritation, there may be a classical "fishy" odor and vaginal discharge. A diagnosis of BV can be made if 3 out of 4 of "Amsel's criteria" are met (1):
A strong fishy odor on adding alkali to vaginal fluid (positive amine test)
Clue cells (vaginal epithelial cells heavily coated with bacilli) on microscopy
Thin, white, homogenous discharge
Vaginal pH greater than 4.5.
Based on CDC recommendations (1), other tests, including Affirm VP III (Becton Dickinson, Sparks, MD), a DNA hybridization probe test for high concentrations of Gardnerella vaginalis, and the OSOM BV Blue test (Sekisui Diagnostics, Framingham, MA), which detects vaginal fluid sialidase activity may be used. Recently NAATS based on detection of a combination of BV-associated bacteria has been developed with high sensitivity and specificity compared with Gram stain.
Currently the CDC recommends treatment only for symptomatic women with BV (1).
Recommended treatment regimens include:
Metronidazole 500 mg orally twice a day for 7 days
Metronidazole gel 0.75%, one full applicator (5 g) intravaginally, once a day for 5 days
Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days
Alternative regimens include:
Tinidazole 2 g orally once daily for 2 days
Tinidazole 1 g orally once daily for 5 days
Clindamycin 300 mg orally twice daily for 7 days
Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days
Follow-up is unnecessary if symptoms resolve but recurrence is common.
Trichomoniasis is the most common curable STD worldwide. Treatment is usually achieved with metronidazole. In the CDC 2015 guidelines, the Aptima Trichomonas vaginalis assay (Hologic; San Diego, CA), a NAAT, was identified as a test cleared by the Food and Drug Administration (FDA) for the detection of Trichomonas vaginalis; the assay detected 3- to 5-fold more Trichomonas vaginalis infections than did wet mount microscopy. Other tests mentioned included the BD ProbeTec Trichomonas vaginalis Qx Amplified DNA Assay (Becton Dickinson; Franklin Lakes, NJ), the OSOM Trichomonas Rapid Test (Sekisui Diagnostics; Framingham, MA), and the BD Affirm VPIII Microbial Identification Test (Becton Dickinson; Franklin Lakes, NJ), a DNA hybridization probe test. CDC 2015 guidelines also suggested that if highly sensitive testing, such as NAAT, is not feasible, a testing algorithm should be employed using wet mount first, followed by NAAT if wet mount is negative.
VVC is present in 17% to 39% of women with symptoms. Nearly three-quarters of women develop VVC during their lifetime; about 45% suffer a second occurrence, and approximately 5% will have [frequently] intractable recurrent candidiasis. Laboratory diagnosis is often time-consuming and not readily available in most offices. DNA probes and more recently NAATS have been developed to detect the presence of numerous organisms associated with vaginitis. A short-course of topical formulations for 1 to 3 days or single dose oral fluconazole are usually effective in treating uncomplicated VVC, with azole drugs being more effective than nystatin.
BV is the most common finding in women with vaginal symptoms, affecting between one-quarter and one-half of symptomatic women. Treating women may reduce the risk of acquiring other STIs, including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, HIV, and herpes simplex type 2. There are a number of established treatment regimens for BV using metronidazole, clindamycin, and tinidazole.
Clinicians need to be more aware of these STIs and be knowledgeable of their signs and symptoms…and the means to diagnose and treat them effectively.
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