Practical path for an onerous condition

Table 1

Figure 1: Yeast vaginitis discharge

Figure 2: Yeast vulvitis

Figure 3: Copious green-yellow discharge of DIV

Figure 4: Microscopy of DIV: parabasal cells and leukorrhea

Vulvovaginitis may be infectious or non-infectious in etiology, and it is often underdiagnosed or misdiagnosed. Chronic or recurrent vulvovaginitis is frustrating to patients and a burden to the health care system. The three types of infectious vulvovaginitis most commonly seen in reproductive-age women are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and trichomoniasis. Other differential diagnoses to consider include herpes simplex infection, allergic reaction to irritants and non-infectious vaginitis such as lichen planus, genitourinary syndrome of menopause (GSM), and desquamative inflammatory vaginitis (DIV). Infection and/or inflammation of the vulva and vagina are associated with itching, burning, irritation, dyspareunia, and abnormal and/or malodorous vaginal discharge.^1-4 This article focuses on the diagnosis and treatment of recurrent and chronic cases.

Initial evaluation
All patients who present with complaints suggestive of vulvovaginitis should have a complete history; physical examination of the vulva, vagina and perianal area; saline microscopy (including pH, 10% potassium hydroxide (KOH) whiff test) if available; point-of-care testing if available; and culture and molecular diagnosis testing as needed.⁵ History should include relationship of symptoms to sexual intercourse, menstrual cycle, use of feminine products and practices, over-the-counter medications, and medical and medication history. 

On examination, patients with BV may have a malodorous grey, creamy or thin homogeneous discharge whereas patients with VVC may present with evidence of inflammation such as erythema, edema, fissures, or excoriations in moderate to severe cases, while patients with trichomoniasis may exhibit signs of inflammation like erythema.⁴ Patients with GSM may show signs of vulvovaginal atrophy while patients with DIV may show signs of inflammation (Figures 1 to 4). Vaginal samples should be obtained from the posterior fornix in BV and lateral vaginal wall in VVC and microscopy performed. (Table 1).

Clinical testing
Office based testing of the vaginal discharge using pH test, 10% KOH and saline microscopy is preferred if available. This approach may provide immediate diagnosis, and treatment can be initiated. The United States Food and Drug Administration (FDA)-approved commercially available tests (point-of-care test or molecular diagnostics) can be used as alternatives.⁵

Recurrent infectious vulvovaginitis

Bacterial vaginosis
BV, the most common cause of abnormal vaginal discharge in reproductive-age women is characterized by abnormal vaginal flora, decreased or absent lactobacilli, and an increased number of anaerobes and facultative anaerobes. It is a dysbiosis, and some of the associated  bacteria include Gardnerella vaginalis, Prevotella species, Atopobium vaginae, Megasphaera type 1, and Sneathia sanguinegens.^4,6 BV is associated with increased risk of pelvic inflammatory disease; increased risk of acquisition and transmission of sexually transmitted infections (STIs); adverse obstetric and gynecologic outcomes such as preterm labor, preterm birth, and chorioamnionitis; and vaginal cuff cellulitis post-hysterectomy. Patients may describe the malodorous discharge as “rotten egg or fishy” and worse after sexual intercourse or a menstrual period. The diagnosis is usually clinical (Table 1). 

Presence of three of four Amsel criteria is needed to make the diagnosis⁷: 

• Homogenous discharge 

• Clue cells

• pH > 4.5

• Positive  whiff test

Gram stain with Nugent score is the gold/reference standard used in research settings, while Amsel criteria are used in clinical setting. Although microscopy is preferred and cost effective, it may not be available in all clinical settings and data evaluating US Food and Drug Administration (FDA)-approved commercially available tests have acceptable performance against the reference standards.^5,8-11 FDA-approved commercially available tests can be used to diagnose BV but should be interpreted alongside patient history and examination.

Recurrent BV
Recurrent bacterial vaginosis (RBV) is defined as three or more episodes in 12 months.^6,12 Recurrence rate is high, and often involves frequent telephone calls and visits to the clinic; multiple treatments are prescribed in the absence of curative therapy.  Bradshaw et al. reported recurrence rates of 58% over a 12-month period in women treated with oral metronidazole for 7 days. In their study, recurrence was associated with prior history of BV, lack of hormonal contraceptive use, having the same sex partner throughout the study duration, and having female sex partners.⁶ Other factors that have been associated with recurrence include douching, frequent sexual intercourse without condoms, and failure to reestablish a lactobacillus-predominant vaginal flora. It has also been suggested that formation of a vaginal biofilm in BV could be one of the factors in RBV.^13,14

Women with RBV should be appropriately treated based on the Centers for Disease Control and Prevention (CDC) recommended conventional therapy of nitroimidazole or clindamycin administered orally or vaginal and offered additional suppressive therapy with 0.75% metronidazole intravaginal gel twice weekly for 4 months.^5,13,15,16 In a multicenter study, Sobel et al randomized patients with RBV to twice- weekly intravaginal metronidazole gel or placebo for 16 weeks after initial treatment. He documented that during 28-week follow-up, recurrence was less in the suppressive therapy group. Recurrence occurred in 51% of treated women compared with 75% of women receiving placebo.¹⁶ Patients should be educated about the risk of possible yeast infection during the suppressive therapy phase.

Another option for RBV is a combination of oral nitroimidazole with intravaginal boric acid as the induction phase, followed by suppression therapy. Reichman et al treated women who met criteria with either tinidazole or metronidazole 500 mg orally twice daily for 7 days followed by intravaginal boric acid 600 mg at bedtime for 21 days as the induction phase.¹³ Asymptomatic patients then proceeded to the maintenance phase of intravaginal metronidazole gel twice weekly. In this study, the cure rate was 92% at 7 weeks, 88% at 12 weeks, and 50% at 36 weeks. We have modified the suppression therapy in our clinical practice, and documented success with 0.75% metronidazole intravaginal gel once a week for 4 months.

Vulvovaginal candidiasis
VVC is the second most common cause of vulvovaginitis. Although Candida albicans is the most common cause of VVC (85%-90%), other non- albicans candida (NAC) (C. glabrata, C. krusei, C. parapsilosis) could be colonizers or pathogenic.^12,17

Diagnosis should not be based on clinical findings alone due to lack of specificity; symptoms of external dysuria, itching, and burning are not always sufficient to make a diagnosis.^4,18 Clinical features may include curd-like vaginal discharge (Figure 1). On examination, patients may have erythema, edema, fissures, or excoriations (Figure 2). Microscopy with or without addition of 10% KOH may reveal fungal elements. Fungal culture is helpful in patients with clinical features suggestive of VVC but who have a negative saline microscopy. It is also helpful in patients who have failed therapy or those with suspected resistance to commonly used anti-fungals.¹⁸ FDA-approved molecular testing is commercially available for providers who do not have access to microscopy. Some molecular testing has rapid turnover, but may not give speciation and sensitivities. Although fungal culture results may take a week to be returned, they may be needed to plan treatment.

Recurrent vulvovaginal candidiasis
RVVC is  defined as at least three symptomatic episodes in 12 months.¹⁹ Risk of recurrence is increased in patients who frequently take antibiotics, are chronic users of corticosteroids, on prolonged immunosuppressant (e.g. transplant patients) or immunosuppressed patients (uncontrolled HIV/AIDS), have uncontrolled or poorly controlled diabetes, or have azole-resistant or non- C. albicans VVC. 

Patients with RVVC would benefit from maintenance therapy after the induction treatment phase has been successfully completed.²⁰ Those with azole-resistant C. albicans should have sensitivity testing performed and be treated based on the results. Sobel et al and Marchaim et al have documented success with compounded medications in patients with azole resistance and those who have failed multiple doses of first-line medications.^21,22 In patients with azole-resistant VVC, treatment options include intravaginal boric acid 600 mg daily for 14-21 days, intravaginal 15.5% flucytosine vaginal cream (5 g) daily for 14 days, and intravaginal amphotericin B 50-mg vaginal suppository daily for 14 days. It is important to consider other differential diagnosis of vulvovaginal itch. All that itches is not yeast and patients with persistent itching despite treatment should be referred to a specialist. 

Examples of vaginal specialist-recommended regimens for RVVC include:¹⁹

• Fluconazole 150 mg orally every 72 hours x 3 doses; followed by fluconazole orally 150 mg weekly x 6 months or miconazole 1200 mg vaginally weekly x 6 months (for patients who prefer vaginal route for maintenance therapy).

• Itraconazole 200 mg orally twice daily x 3 days followed by itraconazole orally, 100-200 mg daily for 6 months.

Recurrent trichomoniasis
Trichomoniasis is the most common non-viral STI in women worldwide.⁵ It is associated with reproductive morbidity and increased risk of HIV acquisition and transmission. Patients may be asymptomatic or present with abnormal yellow –green vaginal discharge, inflammatory symptoms such as itching, burning, and dyspareunia. On examination, there may be erythema of the vulva, vagina and “strawberry cervix.” Microscopy, if available, may reveal motile trichomonads; other diagnostic modalities include point-of-care testing or FDA-approved commercially available molecular testing. Nucleic acid amplification testing (NAAT) is recommended for diagnosis of trichomoniasis.⁵

Treatment of the patient and her sex partner(s) is recommended.^5,23 Nitroimidazole is the drug of choice. Treatment is usually a single 2-g dose of metronidazole or tinidazole.⁵ Kissinger et al, in a randomized trial of single-dose 2-g metronidazole versus 7 days of metronidazole, showed that the 7-day oral-dose metronidazole is the preferred treatment for trichomoniasis treatment in non-HIV-infected women.²⁴ Reinfection is more common than treatment failure, but patients suspected to have failed treatment or who have nitroimidazole resistance  should be referred to an infectious disease specialist. Patients with nitroimidazole allergy should be referred for desensitization. CDC offers resistance testing by request. Health providers can access the CDC website and contact the office in charge for this service. 

In women who fail 2 g metronidazole without evidence of reinfection, metronidazole 500 mg orally twice daily x 7 days is recommended. If treatment fails, tinidazole or metronidazole 2 g orally for 5 days is then recommended. 

If persistent infection is documented despite the previous therapy without evidence of reinfection, there are case series and reports documenting success using high-dose tinidazole and compounded paromomycin in management of refractory trichomoniasis, as follows:^25,26

• Tinidazole 500 mg orally 4 times daily for 1 week OR

• Tinidazole 500 mg orally 4 times daily PLUS Tinidazole 500 mg vaginally twice daily x 14 days OR 

• Tinidazole 1 g orally 3 times daily plus 5 g of compounded 5% intravaginal paromomycin nightly X 14 days. 

We have had success in our clinical practice with use of 5 g of 5% compounded paromomycin alone x 14 days in three patients who were allergic to nitroimidazole. (Unpublished data). Of significance, the compounded creams could be irritants to the skin and should be inserted inside the upper and mid third of the vagina at bedtime. Patients should apply an emollient as barrier to the vulva, and refrain from all sexual intercourse while using compounded vaginal medications. Compounded medications are also expensive.

Non-infectious vulvovaginitis
A review of chronic/recurrent vulvovaginitis would not be comprehensive without a discussion of the two commonly encountered non-infectious causes: GSM and DIV.

DIV, a diagnosis of exclusion, is a chronic vulvovaginitis that is poorly understood.² It occurs mostly in perimenopausal and postmenopausal women, and may be associated with low estrogen levels. Diagnosis is usually clinical with patients complaining of copious yellow–green discharge. They may describe the discharge as thick, “sticky,” mucoid staining of their underwear. Patients sometimes wear panty liners or sanitary pads due to the volume or discoloration of their undergarments. They may complain of itching, pain, burning, and sometimes dyspareunia. On examination, the vulva maybe erythematous, friable and may bleed on contact. The vagina may be erythematous and purulent yellow-green discharge noted (Figure 3). Microscopy shows sheets of white blood cells and parabasal cells maybe present if the patient is hypoestrogenic (Figure 4).

Diagnosis is based on specific criteria:

• At least one symptom (vaginal discharge, dyspareunia, pruritus, pain, irritation or burning)

• Evidence of vulvovaginal inflammation

• Vaginal pH > 6

• Leukorrhea +/- parabasal cells on microscopy

Management involves counseling and education about this poorly understood condition. Initial treatment is 2% intravaginal clindamycin for 4 to 6 weeks. Patient who fail to respond to vaginal clindamycin may repeat treatment with 10% intravaginal compounded hydrocortisone for the same duration. Patient education should include the possibility of failed therapy and relapse. Presence of parabasal cells indicates a hypoestrogenic state and vaginal estrogen twice a week should be included in the regimen. Patients who relapse should be referred to a vaginal specialist.

GSM is often seen in postmenopausal patients or hypoestrogenic women such as those who are breastfeeding or who have undergone menopause due to surgery or exposure to chemotherapy or radiation. Patients may present with vaginal dryness, pain, itching, thin watery discharge, and dyspareunia.^27,28 On examination, the vagina may be pale, with loss of elasticity. Vaginal pH is elevated in symptomatic patients. Microscopy may show some parabasal cells, paucity of normal vaginal epithelial cells, and lack of lactobacilli. 

Management should include evaluation for secondary bacterial and fungal infections and treatment. 

1. First-line management is with vaginal lubricants and moisturizers. 

2. Patients who remain symptomatic and have no contraindications to use of hormones may benefit from systemic or vaginal hormones. In our practice, we usually start with vaginal estrogen in various formulations or vaginal dehydroepiandrosterone  before considering systemic formulations.^1,27,28