Vulvovaginitis
Irene E. Aga
Jenny J. Duret
Silvia T. Linares
The Centers for Disease Control and Prevention (CDC) defines vaginitis as a disorder commonly presenting with vaginal discharge and/or vulvar itching and irritation, with or without the presence of vaginal odor. These symptoms may be caused by infections of the urogenital tract, contact dermatitis, hormonal changes, systemic diseases with dermatologic manifestations, and neuropathies of different origins. Women commonly assume the cause of their symptoms to be yeast infections or contact allergies, which prompt them to self-treat or seek medical advice. Bacterial vaginosis, trichomoniasis, and candidiasis are the most common causes of vaginal discharge. In bacterial vaginosis, the normal vaginal flora is replaced by an excess of anaerobic microorganisms, mycoplasmas, and Gardnerella vaginalis. Vaginal discharge may also be caused by cervicitis.1 This chapter covers the most common causes of vulvovaginitis.
NORMAL VAGINAL FLORA
Identification techniques for independent bacteria in the means of culture have revolutionized the study of microorganisms in the vaginal ecosystem. The use of amplification, cloning techniques and subsequent analysis of sequences of bacterial genes (genes that codify for bacterial rRNA 16 S) in samples of vaginal fluid have allowed the identification of the majority of common species of lactobacilli and other microorganisms. Thus, these techniques have demonstrated that Lactobacillus spp. do not always correspond to the dominant species in the vagina of healthy women.2,3
A variety of hydrogen peroxide—H2O2 and non-H2O2—producing Lactobacillus spp. and other organisms such as Streptococcus spp. can maintain proper vaginal pH between 3.8 and 4.5 and microbial equilibrium in healthy women.4 Acid pH prevents the excessive proliferation of potentially pathogenic microorganisms. There are racial differences in the normal composition of the vaginal flora, as well as the concentration and behavior of particular vaginal microbes, suggesting a role for human and bacterial genetic variations.5
The composition of the vaginal flora is not constant; there are variations in response to exogenous and endogenous factors. These factors include the menstrual cycle, pregnancy, hormonal contraception, frequency of sexual intercourse, use of douching or deodorant products, and use of antibiotics and/or other medications with immunosuppressive properties.
BACTERIAL VAGINOSIS
Bacterial vaginosis (BV) is defined as a clinical syndrome resulting from an alteration of the microbial ecosystem of the vagina. It is classified as a vaginosis, instead of a vaginitis, because it is limited to the epithelium, without tissue infection. It is often considered to be the most common cause of abnormal vaginal discharge in the United States, with some studies suggesting a prevalence of almost 30%, and it has emerged as a global problem contributing to the HIV epidemic.6,7 Unfortunately, even after proper treatment, the risk of recurrence is high, with 30 to 50% of patients relapsing within 2 to 3 months.
Risk Factors
Risk factors for BV include new or multiple sexual partners if condoms or other barrier methods are not used, increasing douching frequency, spermicide use, intravaginal foreign bodies or products, history of a female sexual partner, other sexually transmitted diseases, low income, low educational attainment, increasing body mass index, and decreasing general health status.6,8, 9, 10 Cigarette smoking increases the risk for BV by suppressing the growth of hydrogen peroxide-producing lactobacilli.11 Women who have never been sexually active can also be affected. The risk of BV may be lower among women who use oral contraceptive pills.12 It is more common in African American women than in other ethnic groups, but the prevalence among Latinas is significantly higher than among Whites.13
The epidemiologic profile of BV corresponds to a sexually transmitted disease. BV is associated with several sexual behaviors; it is less common among women who consistently use condoms during intercourse and is also less frequent among those whose male partner are circumcised. However, significant debate exists about its sexual transmission because it has been found in women who have never had sex; it is difficult to isolate BV-associated organisms from the male genital tract, and partner treatment does not appear to prevent recurrences.14
Etiology
In BV, a marked decrease in lactobacilli that produce hydrogen peroxide (H2O2) is associated with a massive overgrowth of G. vaginalis and other anaerobic bacteria such as Atopobium vaginae, Prevotella spp., Mobiluncus spp., and Mycoplasma hominis.1 A. vaginae, in particular, appears to be dependent on G. vaginalis for the colonization of the vaginal epithelium, and their concurrent presence is highly specific for BV and seems associated with treatment failure and BV recurrence.15,16 Mobiluncus spp. also seems highly specific for BV, found merely when BV is present, although only in 50% of the cases.17
Using fluorescent rDNA-targeted probes, researchers have identified a complete or partial biofilm adherent to epithelial cells in vaginal biopsies of women with BV. In women without BV, the vaginal mucosa is mostly covered with Lactobacillus spp. growing unorganized, but in women with BV almost consistently appears a dense biofilm composed of 60 to 95% G. vaginalis and 1 to 40% A. vaginae. The characteristic “clue cells”—squamous vaginal epithelial cells covered with G. vaginalis—are actually small fragments of the biofilm following desquamation.15
Interestingly, certain strains of G. vaginalis may be unable or unlikely to cause disease, whereas others are better suited to elicit disease. Strains that fail to elicit BV may not be able to adhere to, or form a biofilm on, the vaginal epithelium as avidly as strains that cause BV. Also, BV- and non-BV-associated strains of G. vaginalis have significant genetic differences.18 On the other hand, studies of the biofilm-forming potential and cytotoxic activity of G. vaginalis have shown that of several BV associated anaerobes, only G. vaginalis possesses both properties.19 If indeed G. vaginalis is more virulent than other BV-associated anaerobes and those having relatively low virulence, other BV-associated anaerobes may be opportunists that colonize the vagina after a biofilm-forming strain of G. vaginalis has invaded the vaginal epithelium.
Although many consider BV as a polymicrobial infection, and BV is a condition characterized by remarkable bacterial diversity, recent evidence suggests that the presence of G. vaginalis could be the essential element. It is also likely that A. vaginae and G. vaginalis are the decisive pathologic basis of BV.15
BV appears strongly related to host immunity and microbial virulence. For example, some women produce G. vaginalis-specific IgA that gives them immune defense against BV, whereas in others, vaginal bacteria may produce sialidase and enzymes that attenuate this protective factor.20
Genetic predisposition could play an important factor in the etiology of BV. Recognition of microorganisms by the innate immune system is the trigger for a successful antimicrobial defense. Heat shock protein 70 (hsp70) and mannose-binding lectin (MBL) are two transmembrane proteins of the innate immunity system. In patients with BV, a decrease in hsp70 production or release and/or inadequate MBL function may inhibit the innate immune response, facilitating the anaerobic overgrowth. Several genes codify the production of these proteins. Carriage of some polymorphisms of those genes is associated with instability and/or malfunction of the aforementioned innate immune system, thus rendering basis for a hypothesis of a genetically determined immunity that is altered in women with BV.21
Complications of Bacterial Vaginosis
BV has been linked to gynecologic opportunistic infections with BV-associated bacteria and infections due to sexually transmitted agents (Table 4.1). Opportunistic ascending genital tract infections include postabortion and postpartum endometritis, pelvic inflammatory disease (PID), and vaginal cuff infection after hysterectomy.
Pregnancy complications including first-trimester miscarriage, late fetal loss, premature rupture of membranes, preterm labor, and preterm births, especially in women with history of preterm deliveries.1,22, 23, 24
The alteration of the local flora characteristic of BV diminishes colonization resistance, increasing the risk of acquiring Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, HSV-2, and HIV-1. In addition, BV increases viral replication and vaginal shedding of the HIV-1 and HSV-2 viruses, accelerating the spread of these infections.25 BV also appears to be associated with uterine cervical human papilloma virus (HPV) infection26 and with subfertility.27 Because of its possible association with vaginal cuff infection after hysterectomy and with postabortion endometritis, screening and treatment before these procedures may be beneficial.28
Diagnosis of Bacterial Vaginosis
The most common presenting symptoms of BV are foul-smelling, homogenous, clear, white or gray discharge, often more apparent and odorous when vaginal alkalinity increases after intercourse exposure to semen or
during the menses, in the absence of signs of inflammation. Nevertheless, more than half of the women with BV could be asymptomatic.29 Given the unspecific or absent symptoms, clinical suspicion of BV or vaginitis warrants a laboratory study to reach a definitive diagnosis.
during the menses, in the absence of signs of inflammation. Nevertheless, more than half of the women with BV could be asymptomatic.29 Given the unspecific or absent symptoms, clinical suspicion of BV or vaginitis warrants a laboratory study to reach a definitive diagnosis.
TABLE 4.1 Complications of Bacterial Vaginosis | |||||||||||||
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TABLE 4.2 Diagnostic Features of Vulvovaginitis | |||||||||||||||||||||||||||||||||||||||||||||
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Clinical Diagnosis (see Table 4.2)
The clinical diagnosis of BV is made if three or more of the following Amsel criteria are present:
Thin, adherent, and homogenous grayish-white vaginal discharge
Vaginal pH higher than 4.5
The presence of more than 20% or more clue cells of the total of epithelial cells on saline wet mount. Clue cells are vaginal epithelial cells with borders obscured by a heavy coating of adherent coccobacilli (G. vaginalis and other anaerobic bacteria).
A fishy amine odor before or after adding potassium hydroxide at 10% to a wet mount slide (“whiff” test)
Although the appearance and odor of the discharge are subjective criteria, a pH greater than 4.5 is the most sensitive indicator, whereas the presence of clue cells is considered the single most specific indicator of BV.30,31 Despite the development of more sensitive and specific laboratory test, cost and practicality make the Amsel criteria the best in-office way to diagnose BV. Cultures are not used in its diagnosis because they include bacteria normally present in the vagina.1 The Pap test can be used to detect clue cells and BV flora, but its sensitivity is lowered by observer bias.20
Gram Stain-Based Diagnosis
The Nugent Gram stain score is a diagnostic alternative with higher sensitivity than the Amsel criteria. Vaginal fluid or discharge is collected on a glass slide, stained in the laboratory, and examined under oil immersion for the presence of lactobacilli, Gardnerella, and Mobiluncus morphotypes. A Nugent Gram score of 7 or higher indicates flora corresponding to BV.31 A score of 4 to 6 is indicative of intermediate vaginal microflora, and a score of 0 to 3 is considered normal. Although an intermediate score does not constitute BV, it seems to be linked to a range of complications. Despite concerns about different collection techniques, the way the specimen is spread on the glass slide, and the use of different fixation methods and time, the Nugent Gram is highly reliable and accurate and is commonly considered the current gold standard.
The alternative Ison Score of Gram-stained vaginal fluid uses grade I (normal flora), Lactobacillus morphotype only; grade II (intermediate flora), reduced Lactobacillus morphotype with mixed bacterial morphotypes; grade III (BV), mixed bacterial morphotypes with few or absent Lactobacillus morphotypes. Two grades have been added: grade 0, epithelial cells with no bacteria seen and grade IV, epithelial cells covered with Gram-positive cocci only.32 Some clinicians find useful for its more complete characterization of the vaginal flora, and because the test is easier and faster, although it has shown low interobserver reliability.
Point-of-Care Commercial Tests
A series of tests has been developed and are commercially available to assist in the diagnosis of BV in an office setting.
A rapid chromogenic test to detect sialidase enzyme-producing flora (BV Blue) is a useful point-of-care diagnostic tool to provide a presumptive diagnosis of BV, especially in situations where microscopic capabilities are unavailable. BV Blue has shown good sensitivity, specificity, and positive and negative predictive value, compared to Amsel criteria and Nugent Gram stain.33, 34, 35
FemExam is a point-of-care test card that determines pH and triethylamine levels in vaginal fluid, but it does not seem to have significant benefits over the Amsel criteria and the Nugent Gram slide.36,37 The CDC does not recommend its use because of its low sensitivity and specificity.1
The so called electronic nose (Electronic Sensor Array) is used to detect volatile organic amino acids in vaginal fluid is also sued at point-of care. It has shown a sensitivity and specificity of about 80% compared to the Amsel criteria and Gram-stain diagnosis.38, 39, 40
Pip Activity Testcard is a test to detect proline iminopeptidase activity of anaerobic flora in vaginal discharge, especially G. vaginalis. It was developed in the 1990s, and it appears to have high diagnostic accuracy.1,41
DNA probes of G. vaginalis, T. vaginalis, and Candida spp. are available as office procedures that can detect concentrations higher than 2 × 105 bacterial cells per mL of vaginal fluid.30 The Affirm VP III (Becton Dickenson, San Jose, California) is commercially available and can be performed in less than 45 minutes, although it is usually better done in the laboratory.
Office dipstick tests to measure pH show good correlation of increased pH with BV (88% sensitivity), but they lack specificity (58%) because other vaginal pathologies can also increase the pH. A self-test pH globe containing acidity indicator paper is commercially available. Women can monitor their vaginal pH by inserting in their vagina one finger cover with the globe. Because pH is a sensitive indicator of BV, the test has been widely used in screening programs to prevent preterm births in Europe. Pregnant women are instructed to seek medical care if the globe indicates a pH greater than 4.7.30,31,37
Molecular Diagnosis of Bacterial Vaginosis
Molecular diagnosis of BV is an important diagnostic alternative to make the study of BV more precise and overcome the reliability problems of Gram stain diagnosis. Polymerase chain reaction (PCR) methods have shed light on the bacterial microflora of the vagina, showing that bacteria from the Clostridials order (BVAB 1-3) as well as Atopobium, Snethea/Leptotrichia, Megasphaera 1 and 2, and a TM7 bacterium, are highly specific for BV, and therefore can be used to assist in its diagnosis and treatment follow-up. Several conventional PCR assays were available for sensitive study of the vaginal flora, but despite their high sensitivity, these tests did not gain widespread use. Recent studies of vaginal bacteria using qualitative real-time polymerase chain reaction (QRT-PCR) in individuals with different presentations of BV and different responses to treatment, suggest that distinct BV profiles—different combinations of vaginal bacteria— might predispose to different health outcomes.42, 43, 44 Once large cohort studies validate the use of QRT-PCR, newly available methods will allow a more precise diagnosis of BV, and more importantly, the detection of women at risk by determining bacterial profiles that predispose them to develop BV.
Treatment of Bacterial Vaginosis
The primary objective of treating BV is to resolve or alleviate the presenting symptoms. Although BV may resolve spontaneously, treating it, even in asymptomatic patients, helps prevent common associated complications such as C. trachomatis or N. gonorrhoeae, HIV, and other sexually transmitted diseases (STDs). In addition, BV tends to be a recurring problem, thus treatment should also aim at reducing recurrences. Treatment modalities include antibiotics, antiseptics and disinfectants, acidifying agents, and probiotics.
Bacterial Vaginosis Treatment With Antibiotics
Topical or oral metronidazole and clindamycin are currently the drugs of choice (Table 4.3). Both medications seem to be equally effective either orally or topical.1,44,45 The most appropriate treatment depends on the patient preference and lifestyle, possible side effects, drug interactions, and other associated infections and comorbidities. The recommended regimens are as follows:
Metronidazole 500 mg orally, twice a day for 7 days, or
Metronidazole gel (0.75%), one full applicator (5 g) intravaginally, or
Clindamycin cream (2%), one full applicator (5 g) intravaginally at bedtime for 7 days Other effective regimens include the following:
TABLE 4.3 Treatment
Antibiotic
Dose
Time
Oral metronidazole
500 mg twice a day
7 days
Topical metronidazole gel 0.75%
Full applicator 5 g intravaginally
7 days
Topical clindamycin cream 2%
Full applicator 5 g intravaginally
7 days
Alternative regimes
Oral tinidazole
2 g once a day
2 days
Oral tinidazole
1 g once a day
5 days
Oral clindamycin
500 mg twice a day
7 days
Topical clindamycin ovules
1 g ovule once a day intravaginally
3 days
Antiseptics
Chlorhexidine
No data
Hydrogen peroxide
Povidone iodine
Benzydamine
Dequalinium chloride
Polyhexamethylene biguanide
Probiotics
Lactobacilli
Promising data
Oral tinidazole either 2 g once a day for 2 days, or 1 g a day for 5 days, or
Clindamycin 500 mg orally twice a day for 7 days, or 100 mg ovules intravaginally once a day at bedtime for 3 days
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