Bacterial vaginosis

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Overview

Historical Perspective

Pathophysiology

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Differentiating Bacterial vaginosis from other Diseases

Epidemiology and Demographics

Risk Factors

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Natural History, Complications and Prognosis

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Amsel Criteria

History and Symptoms

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Alara Ece Dagsali, M.D.[2]

Synonyms and keywords: Anaerobic vaginosis; Nonspecific vaginitis

## Overview

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Bacterial vaginosis (BV) is a clinical condition characterized by a shift in vaginal microbiota away from Lactobacillus species toward more diverse bacterial species, including facultative anaerobes. The altered microbiome causes a rise in vaginal pH and symptoms that range from none to very bothersome (eg, abnormal vaginal discharge and odor). Future health implications of BV include, but are not limited to, increased susceptibility to other sexually transmitted infections (STIs), including HIV, and preterm birth.

BV is characterized by three alterations in the vaginal environment:

* A shift in vaginal microbiota from Lactobacillus species to one of high bacterial diversity, including facultative anaerobes.
* Production of volatile amines by the new bacterial microbiota and reduced lactic acid production.
* Resultant rise in vaginal pH to >4.5 (normal vaginal pH of estrogenized females typically ranges from 4.0 to 4.5).

## Historical Perspective

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BV is the most common cause of abnormal vaginal discharge in females of childbearing age, accounting for 40 to 50 percent of vaginitis cases. In the United States, the National Health and Nutrition Examination Survey (NHANES), which included results from self-collected vaginal swabs from over 3700 women, estimated the prevalence of BV was 29 percent in the general population of women aged 14 to 49 years and 50 percent in African American women. This included both symptomatic and asymptomatic infection. Worldwide, a meta-analysis of studies from seven regions of the world found that the prevalence of Nugent-diagnosed BV was 23 to 29 percent among women of reproductive age, with small variations according to the population studied.

## Pathophysiology

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Processes that contribute to clinical BV include a shift in vaginal microbiota from hydrogen peroxide-producing lactobacilli to anaerobic bacteria, release of amines, and production of a protective biofilm.

Altered vaginal microbiota and dysbiosis – BV represents a complex change in the vaginal microbiota characterized by a reduction in concentration of the normally dominant lactobacilli, which produce hydrogen peroxide and lactic acid, and an increase in concentration of other organisms, especially anaerobic Gram-negative rods [9-13]. Age also appears to impact the vaginal microbial community [14]. The absence of clinical signs of inflammation is the basis for the term "vaginosis" rather than "vaginitis." Some authors use the term "dysbiosis" to reflect the microbial imbalance in the vaginal microbiota that can ultimately impact vaginal function and lead to negative health consequences Processes that contribute to clinical BV include a shift in vaginal microbiota from hydrogen peroxide-producing lactobacilli to anaerobic bacteria, release of amines, and production of a protective biofilm.

* Commonly associated bacteria – The major bacteria detected in females with BV are Gardnerella vaginalis, Prevotella species, Porphyromonas species, Bacteroides species, Peptostreptococcus species, Mycoplasma hominis, and Ureaplasma urealyticum, as well as Mobiluncus, Megasphaera, Sneathia, and Clostridiales species. Fusobacterium species and Atopobium vaginae (now renamed Fannyhessea vaginae) [19] are also common.

* Bacteria identified with ribosomal DNA probes – The difference in vaginal microbiota between those with and without BV was illustrated in a study that used broad range ribosomal DNA probes to determine the vaginal microbiota of 27 women with BV and 46 controls [1]. Overall, 35 bacterial phylotypes were identified in women with BV, including 16 that were newly recognized. Women with BV had a mean of 12.6 phylotypes (range 9 to 17) per sample compared with 3.3 phylotypes (range 1 to 6) per sample in women without BV. The organisms newly identified by polymerase chain reaction included fastidious bacteria termed "BV-associated bacteria (BVAB) 1, 2, and 3" in the Clostridiales order, which appear to be specific indicators of BV [20]. Subsequent studies suggest BVAB1, now known as Candidatus lachnonocura vaginae, has likely been mistaken for Mobiluncus on microscopy and Nugent scoring [21-23]. Additional studies have also further characterized BVAB3, which is now known as Mageebacillus indolicus, and identified other bacterial species in the human vagina, including the novel strains Peptoniphilaceae DNF01163 and Prevotellaceae DNF00733, and [24-27].

* Production of amines Hydrogen peroxide-producing lactobacilli appear to be important in preventing overgrowth of the anaerobes normally present in the vaginal microbiota. With the loss of lactobacilli, pH rises and massive overgrowth of vaginal anaerobes occurs. These anaerobes produce large amounts of proteolytic carboxylase enzymes, which break down vaginal peptides into a variety of amines that are volatile, malodorous, and associated with increased vaginal transudation and squamous epithelial cell exfoliation, resulting in the typical clinical features observed in patients with BV. The rise in pH also facilitates adherence of G. vaginalis to the exfoliating epithelial cells.

* Role of biofilm Increasing evidence suggests that G. vaginalis is a key player in the pathogenesis of BV and the development of a biofilm may be an essential component of this process, in addition to the gradual overgrowth of resident anaerobic vaginal microbiota [28-34]. In this model, a cohesive form of G. vaginalis adheres to the vaginal epithelium and then becomes the scaffolding to which other species adhere [35].

* Biopsy data The biofilm hypothesis is supported by a study of microbiota on the epithelial surfaces of vaginal biopsy specimens from individuals with BV that showed a biofilm adhered to part or all of the epithelium, and G. vaginalis comprised 90 percent of bacteria in the biofilm, while Atopobium vaginae accounted for most of the remainder [28]. Subsequent desquamation of these epithelial cells would result in the classic clue cells diagnostic of the disorder (see 'Diagnostic evaluation' below). By contrast, most healthy controls had unstructured accumulations of bacteria within secretions loosely attached to epithelial surfaces.

* Role of extracellular DNA (eDNA) Extracellular DNA (eDNA) is a factor in the structural stability of biofilms in a variety of bacterial species and appears to play an important role in the establishment and maintenance of the G. vaginalis biofilm in BV [36]. The presence of a biofilm may make it difficult to eradicate BV and increase the rate of recurrence, but discovery of the role of eDNA has led to the hypothesis that a DNase might be able to destroy the eDNA that helps to maintain the BV biofilm.

* Impact of gender-affirming therapy The impact of hormonal and surgical gender-affirming treatment on the microbiota of the vagina and neovagina are not yet well understood. Whether a non-Lactobacillus dominant microbiome in trans people is BV requiring antibiotic treatment is an area needing further study.

* Estrogen-dominant neovagina Transfeminine individuals may elect gender-affirming surgery with creation of a neovagina. Scrotal and penile skin is typically used and may require an extension with colon or skin graft. Individuals with neovaginas who use estrogen therapy have reported symptoms of vaginal discharge and malodor [37]. In one study comparing the microbiome of 5 individuals with neovaginas with 32 individuals with vaginas, the most common taxa in the neovaginas were Porphyromonas (30.2 percent), Peptostreptococcus (9.2 percent), Prevotella (9.0 percent), Mobiluncus (8.0 percent), and Jonquetella (7.2 percent) compared with Lactobacillus and Gardnerella in the vaginas [38]. Of the patients with neovaginas, four had penile inversion/scrotal graft with sigmoid colon graft and one had penile inversion/scrotal graft only.

## Risk Factors

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* Sexual activity While the majority of epidemiologic data support the hypothesis that BV is a sexually transmitted infection (STI), it is not yet classified as such because of lack of a single causative agent and absence of a clear disease counterpart in males [17,40-44]. Data indicating sexual transmission include that BV is associated with having multiple sex partners (male and/or female), having a new sex partner, and abstaining from condom use [40,45,46].

Early studies reported mixed results on the impact of treatment of the male sexual partner [47-52]. However, a subsequent review of early negative or inconclusive studies reported that these studies lacked sufficient power to detect reasonable effect sizes, had deficient or inadequately reported randomization methods, and lacked information on adherence to therapy [53].

Additionally, in contrast to trichomoniasis, chlamydial, or gonococcal infections, there is also a high rate of symptomatic recurrence of BV in the absence of new sexual activity or reinfection.

* Impact of first sexual encounter An observational study including 400 Kenyan females age 16 to 21 years reported BV prevalence (Nugent score ≥7) increased from 2.8 percent to 13.7 percent in the time period from before first sex to after first sex [56]. First sex was associated with more than two-fold increased risk of BV in both adjusted analysis (adjusted hazard ratio [aHR] 2.44, 95% CI 1.25-4.76) and a generalized estimating equations model (aHR 1.92, 95% 1.12-3.31).

* Impact of male partner treatment A trial evaluating male partner treatment with seven days of oral metronidazole was stopped early after interim analysis reported similar BV recurrence rates in both treatment (81 percent) and placebo (80 percent). However, in a subset analysis, women who stated that their partners had higher adherence to the course of metronidazole had a lower risk for BV recurrence [58].

* Impact of sexual contact  In a systematic review and meta-analysis of 43 observational studies, sexual contact with new and multiple male and female partners was associated with an increased risk of BV, while condom use was associated with a decreased risk

* Male penile microbiome Many BV-associated species have been isolated from the male penile skin, semen, urethra, and urine specimens, and the penile microbiome has been reported to correlate with incident BV infections

* Studies of same-sex female partnerships BV is highly prevalent (25 to 50 percent) in females who have sex with females and is associated with increasing numbers of female sexual partners, a female partner with symptomatic BV, and various sexual practices, suggesting sexual transmission is an important factor [63-68]. However, in one study, sexually active monogamous female same-sex partnerships over six months tended to have concordant, stable, vaginal microbiota, which was most concordant for normal microbiota [65]. This suggests that longer duration, sexually active partnerships led to stability and alignment of a favorable vaginal microbiota in the couples. Accordingly, the majority of investigators believe that BV, as an original or first infection or occurrence, is sexually transmitted.

* Infection with sexually transmitted infections The presence of other STIs appears to be associated with an increased prevalence of BV. In a systematic review and meta-analysis of studies evaluating the association between BV infection and herpes simplex virus (HSV) type 2 infection, women infected with HSV-2 had a 55 percent higher risk of BV infection compared with women who were HSV-2 uninfected [69]. Similarly, a five-year prospective cohort study reported that BV was both more prevalent and more persistent among HIV-infected women compared with those without HIV [70]. Conversely, BV may also be a risk factor for HIV and other STI acquisition

* Race and ethnicity While higher rates of BV have been reported in some populations, it is not clear if this finding reflects genetic, socioeconomic, behavioral, or other differences [6,14,77,78]. In the United States National Health and Nutrition Examination Survey (NHANES) 2001 to 2004 study, the rates of BV based on self-collected swabs were 51 percent for African American women, 32 percent for Mexican-American women, and 23 percent for White women [6]. By contrast, in a small study comparing the vaginal microbiota of White women and Black women by both cultivation-dependent and cultivation-independent methods, there were no differences in colonization and density of bacterial species by race once women with BV by Nugent criteria were removed

* Diet One questionnaire study reported an association between high fat diets and BV as well as an inverse relationship for BV with the intakes of folate, vitamin E, and calcium [86]. A diet high in fiber has been associated with higher likelihood of a Lactobacillus-dominant vaginal microbial community [87]. While these dietary factors were associated with differences in the vaginal microbiota, further studies are needed to determine causality.

* Body Mass Index One study that evaluated Nugent scores for nearly 6000 women reported that overweight (body mass index [BMI] 25.0 to 29.9 kg/m2) and obese (BMI ≥30 kg/m2) women had higher Nugent scores and rates of BV compared with women of normal BMI (BMI 18.5 to 24.9 kg/m2) [78]. The prevalence rates of BV were 21, 30, and 35 percent for lean, overweight, and obese BMIs, respectively.

## Differentiating Bacterial vaginosis from other Diseases

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BV is usually suspected because of high vaginal pH (>4.5). Other causes of increased pH include trichomoniasis, atrophic vaginitis, and desquamative inflammatory vaginitis. These four entities are easily distinguishable by clinical and microscopic features

* Dyspareunia and/or vaginal inflammation Individuals with BV generally do not have dyspareunia or signs of vaginal inflammation; by contrast, those with atrophic vaginitis, desquamative inflammatory vaginitis, and trichomoniasis usually have these signs and symptoms.

Additional microscopy findings

* Parabasal cells Both atrophic vaginitis and desquamative inflammatory vaginitis are associated with an increased number of parabasal cells on microscopy, which is not observed in individuals with BV.

* White blood cells Large numbers of white blood cells, specifically polymorphonuclear leukocytes (PMNs), on microscopy are characteristic of desquamative inflammatory vaginitis, trichomoniasis, and atrophic vaginitis with infection, but not BV.

* Trichomonads Visualization of trichomonads readily makes the diagnosis of trichomoniasis in the setting of an elevated pH; in the absence of visible trichomonads or if microscopy is not available, we suggest using more sensitive and specific diagnostic tests to diagnose or exclude trichomoniasis.

* Mixed infections Mixed infections with BV and a second pathogen, either T. vaginalis or Candida species, are not infrequent, with clinical and laboratory findings reflecting features of both entities.

## Epidemiology and Demographics

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BV is the most common cause of abnormal vaginal discharge in females of childbearing age, accounting for 40 to 50 percent of vaginitis cases [3-5]. In the United States, the National Health and Nutrition Examination Survey (NHANES), which included results from self-collected vaginal swabs from over 3700 women, estimated the prevalence of BV was 29 percent in the general population of women aged 14 to 49 years and 50 percent in African American women [6]. This included both symptomatic and asymptomatic infection. Worldwide, a meta-analysis of studies from seven regions of the world found that the prevalence of Nugent-diagnosed BV was 23 to 29 percent among women of reproductive age, with small variations according to the population studied [7,8]. The health consequences of BV infection are presented below.

## Screening

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All patients undergo testing of abnormal vaginal discharge. Clinician training and test availability drive test selection. Options include laboratory tests, which typically use nucleic acid amplification test (NAAT) technology, clinical evaluation of vaginal discharge with pH testing and microscopy, or gram stain with Nugent criteria (typically in research settings). NAAT-based laboratory tests are increasingly used because their high sensitivity and specificity (ie, >90 percent), although they require time for processing that delays diagnosis and treatment. Cervicitis caused by gonorrhea or chlamydia should also be excluded. The relative advantages, disadvantages, and efficacy of each test approach are briefly presented here and discussed in detail in related content.

* Clinical laboratory tests Clinical laboratory tests are increasingly used for diagnosing BV because they have improved diagnostic accuracy compared with pH testing and microscopy (ie, greater sensitivity and specificity), are able to identify fastidious bacteria, are easy to use, and can test for multiple infections from the same swab (eg, candidiasis and trichomoniasis) Limitations include the need for clinician education to interpret the tests, time delay for diagnosis, and potential identification of non-pathogenic organisms

* Nucleic acid amplification tests (NAATs) NAATs are laboratory-based tests that exponentially multiply specific nucleic acid sequences through polymerase chain reactions (PCRs) to identify evidence of various vaginal pathogens, including those specific to the diagnosis of bacterial vaginosis, vaginal candidiasis, and trichomoniasis. The vaginal swab can be collected by a clinician or patient [127,129]. As noted above, we advise a complete physical examination to guide the differential diagnosis and evaluate for alternative diagnoses. Some of the tests are FDA approved (BD Max vaginal panel, Aptima BV) while other are laboratory-developed tests (NuSwab VG, SureSwab BV, and OneSwab BV panel) that require internal validation prior to use. all have high sensitivity and specificity (ie, >90 percent) . BV cannot be diagnosed by NAATs that are not specific to BV organisms.

* Point of care tests

These tests can be done in the office at the time of the physical examination and are to be used in conjunction with physical examination, vaginal pH, and whiff-amine test. All have become less commonly used since the development of NAATs.

* pH and microscopy using Amsel criteria

When pH testing and microscopy are available, the diagnosis of BV in premenopausal females is usually based upon the presence of at least three Amsel criteria (characteristic vaginal discharge, elevated pH, clue cells seen on microscopy, fishy odor). Compared with Gram stain for diagnosing BV, reported sensitivity of Amsel criteria for diagnosis of BV is over 90 percent and specificity is 77 percent when used by expert clinicians. However, this approach is limited by availability of microscopy equipment and trained providers; lower sensitivities and specificities have been reported when Amsel criteria are used by general clinicians. Advantages, disadvantages, diagnostic accuracy, and how to perform the vaginal pH and microscopy is reviewed in detail in related content.

Amsel criteria for diagnosis of BV (at least three criteria must be present):

* Homogeneous, thin, grayish-white discharge that smoothly coats the vaginal walls.

* Vaginal pH >4.5.

* Positive whiff-amine test, defined as the presence of a fishy odor when a drop of 10 percent potassium hydroxide (KOH) is added to a sample of vaginal discharg

* Clue cells on saline wet mount. Clue cells are vaginal epithelial cells studded with adherent coccobacilli that are best appreciated at the edge of the cell. For a positive result, at least 20 percent of the epithelial cells on wet mount should be clue cells. The presence of clue cells diagnosed by an experienced microscopist is the single most reliable predictor of BV.

However, these criteria are not exclusive to BV; the first three findings are sometimes also present in patients with trichomoniasis Mobiluncus species may be noted on microscopy as well

* Gram stain with Nugent criteria Gram stain of vaginal discharge is the gold standard for diagnosis of BV. But is mostly performed in research studies because it requires more time, resources, and expertise than Amsel criteria. The Gram-stained smear is evaluated using Nugent criteria or Hay/Ison criteria . When clinical criteria are used to define infection, the reported sensitivity of Gram stain scoring ranges from 62 to 100 percent

## Natural History, Complications and Prognosis

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Presence of BV increases the risk of poor obstetric and gynecologic outcomes as well as risk of acquisition of HIV and other sexually transmitted infections (STIs).

* Obstetric outcomes

Preterm delivery, postpartum fever

* Gynecologic complications

Endometrial bacterial colonization and plasma-cell endometritis, Posthysterectomy vaginal cuff cellulitis, Postabortal infection

* Other infections

HIV, Sexually Transmited Infections (STI), PID (Pelvic Inflamatory Disease), HPV and subsequent cervical pathology

## Diagnosis

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Amsel Criteria | History and Symptoms | Physical Examination | Laboratory Findings | Other Imaging Findings | Other Diagnostic Studies

## Treatment

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Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

## Case Studies

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Case #1

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## References

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