Sandbox: Reddy

Candida Vulvovaginitis

Historical Perspective

• In 1839, B. Lagenbeck from Germany described a yeast-like fungus for the first time in the human oral infection "thrush." and its ability to cause it.
• In 1923 the Candida albicans was described by Christine Marie Berkhout. Over the years the classification of the genera and species has evolved. Obsolete names for this genus include Mycotorula and Torulopsis. The species has also been known in the past as Monilia albicans and Oidium albicans. The current classification is nomen conservandum, which means the name is authorized for use by the International Botanical Congress (IBC).
• The full current taxonomic classification is available at Candida albicans.
• The genus Candida includes about 150 different species. However, only a few of those are known to cause human infections. C. albicans is the most significant pathogenic (=disease-causing) species. Other Candida species causing diseases in humans include C. tropicalis, C. glabrata, C. krusei, C. parapsilosis, C. dubliniensis, and C. lusitaniae.

Classification

Candida vulvovaginitis can be classified based on the duration, as well as the strain of Candida causing the infection.

Duration

Candida vulvovaginitis can be divided based on the duration and number of episodes of the infection into:

• Acute, uncomplicated: these are usually sporadic cases of Candida vulvovaginitis, which respond to topical anti-fungal therapy and have a high cure rate.
• Acute, complicated: symptoms are more severe than uncomplicated infections and typically require a combination of oral and topical anti-fungal treatment.
• Recurrent: defined as 4 or more episodes of Candida vulvovaginitis per year, usually caused by the same strain of Candida. Treatment also requires a combination of oral and topical anti-fungal agents.

Microbiology

Candida vulvovaginitis can also be divided based on the strain of Candida causing the infection:

• C. albicans: comprises the majority of cases of Candida vulvovaginitis
• C. glabrata: it is the second most common causative pathogen
• C. tropicalis
• C. krusei
• C. parapsilosis

Pathophysiology

Vaginal Defensive mechanisms aganist Candida

Innate Mechanisms

	Defense	Mechanism of protection	Evidence of protection
1	Vaginal epithelial cells	In Vitro inhibition of Candida growth	Protective role in vivo unknown Patients with recurrent candida infections have a decreased anti Candida activity
2	Mannose-binding lectin	Epithelial-cell associated protein which binds to candida surface mannan. Inhibits Candida growth by activating complement Activity is genetically determined	Decreased expression can increase the susceptibility for vaginal colonization of candida and leading to vaginitis.
3	Activated lactoferrin	Fungistatic and fungicidal activity	Role in protection aganist infection is not clear
4	Vaginal bacterial flora	Lactobacillus species compete for nutrients. Bacteriocins and hydrogen peroxide inhibits yeast growth/germination	Role in protection aganist vaginitis still unclear
5	Phagocytic systems/polymononuclear leucocytes, mononuclear cells, complement	Mainly found in lamina propria in experimental vaginitis, help in reducing the yeast load and its invasion by phagocytosis and intracellular killing Nitric oxide has anti-candida activity	Role in protection still unclear

Adaptive Mechanisms

	Defense	Mechanism	Role in Protection
1	Immunoglobulin mediated immunity	Systemic IgM, IgG and local IgA antibodies are produced in response to the infection	Protective role not proven. Elevated titres of vaginal anti-candida IgG, IgA are detected in women with recurrent vaginitis Persistent symptoms could be attributed to Anti-candida IgE
2	Cell Mediated Immunity	Interleukin 4 (Th2) inhibits anti-candida activity of nitric oxide and protective pro-inflammatory Th1 cytokines.	Role in protection from vulvovaginitis is still not clear It is still a hypothesis Patients with recurrent infection have undetectable Th2 cytokines.

Candida Virulence Factors

• C.albicans in forms vitro blastospores, germ tubes, pseudomycelia, rue mycelia and also chlamydospores on special culture media. C. glabrata exists exclusively in blastospores.
• All strains of Candida species possess a yeast surface mannoprotein which helps in adhering to epithelial cells of the vagina.
• Germination of the spores helps in colonizing the vagina.
• Proteolytic enzymes, toxins and phospholipase destroy the proteins that normally impair fungal invasion, enhancing the ability of Candida to colonize the vagina.
• Phenotypic switching of Candida is described in patients with recurrent vaginitis.
• C.albicans can form bio-films on the intra uterine devices or sponges causing disease recurrence.

Pathogenesis

• Candida vulvovaginitis is a microbial disease and not all patients with detectable pathogen are symptomatic. Multiple risk factors and the imbalance in the protective vaginal defenses predispose patients to develop active disease.
• Candida vaginal infections are more common in the reproductive age group because of the high concentration of estrogen. It increases the amount of glycogen in the vagina providing a carbon source for candida organisms to colonize and also increases the adherence of candida to the vaginal epithelial cells.
• The most common source of the infection is from the peri-anal area. Other less common source is sexual transmission and persistance of organisms in the vagina after treatment, responsible for recurrence.
• The course of the infection begins with colonization, symptoms appear with the invasion of the blastospores or pseudohyphae of the vaginal wall.
• The understanding of the transition from asymptomatic vaginal colonization with Candida to symptomatic vulvovaginitis is not clear.

Genetics

• Few genetic factors are thought to be involved in patients with recurrent Candida vulvovaginitis.
• Supporting evidence is that many cases were found to be more common in African-American women, run in families, as well as being associated with ABO-Lewis non-secretor phenotype, a rare blood group.
• In addition, women with Candida vulvovaginitis were found to have decreased concentrations of mannose binding lectin (MBL), hence, the variant (MBL) gene is thought to be a contributing factor in the development of Candida vulvovaginitis.

Gross Pathology

On speculum examination typical curdy white discharge is present.

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  This photograph is a speculum examination of the vagina with Candida infection and the typical thick, curdy vaginal discharge.

Microscopic Pathology

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  This is a a microscopic image of Candida albicans, grown on cornmeal agar medium.

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  This is a low-power photomicrograph of lymph node with three prominent areas of Candida colonies (arrows). Even at this low magnification, the purple-staining yeast and pseudohyphae can be easily seen. This section was stained with Periodic Acid-Schiff Hematoxylin (PASH), which stains the cell wall of fungi to make them more easily visible.

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  This is a low-power photomicrograph of one of the Candida colonies from this lymph node. The chains of yeast which are termed "pseudohyphae" are apparent at this magnification.

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  This higher-power photomicrograph shows the yeasts and pseudohyphae in this focus of Candida organisms.

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  This high-power photomicrograph shows the yeasts (1) and pseudohyphae (2).

Associated Conditions

• Candida vulvovaginitis may be associated with other pathogens that cause vulvovaginitis which include Trichomonas vaginalis and Gardnerella vaginalis. The presence of these diseases in combination is common therefore they must be excluded before initiation of treatment.

Causes

Candida vulvovaginitis is caused by many different species of Candida. They are divided into Candida albicans and Candida non-albicans species based on the causative pathogen:

Common Causes

• Candida albicans: These strains are isolated in 85 to 95% patients with yeast infection.
• Candida non albicans: Candida glabrata is the most common isolated pathogen in this group affecting 10 to 20% of women and is associated with recurrent Candida vulvovaginitis.

Less Common Causes

These are less commonly isolated in patients but is important to identify the species as they are less sensitive to standard azole therapy causing recurrent infection.

• Candida parapsilosis
• Candida tropicalis
• Candida krusei

Differentiating Candida Vulvovaginitis from other Diseases

Candida Vulvovaginitis must be differentiated from the following diseases which have a similar presentation:

Disease	Findings
Trichomoniasis	Presents with purulent, malodorous, thin discharge associated with burning, pruritus, and dysuria, with the sign of vaginal inflammation and elevated vaginal pH (>4.5) Motile trichomonads on wet mount Positive culture (Gold standard) Positive nucleic acid amplification test (NAAT)
Atrophic vaginitis	Progressive symptoms Presents with yellow and malodorous vaginal discharge, vaginal dryness, postcoital bleeding, and dyspareunia with the sign of vaginal inflammation and elevated vaginal pH (>5) Diagnosis is critical and laboratory tests can confirm hypoestrogenic state
Desquamative inflammatory vaginitis	Chronic clinical syndrome with unknown etiology Presents with dyspareunia, dyspareunia, yellow, grey, or green profuse vaginal discharge with the sign of vaginal inflammation and elevated vaginal pH (>4.5) Microscopy shows large number of parabasal (immature squamous epithelial cells) and inflammatory cells
Bacterial Vaginosis	Presents with dysuria Fishy odor (negative whiff test) Normal vaginal PH (<4.5) On speculum examination signs of vaginal inflammation are demonstrated.

Epidemiology and Demographics

• Epidemiological studies on Candida vulvovaginitis are hard to perform, because of several factors:
  • Candida vulvovaginitis is not a reportable disease.
  • The diagnosis of Candida vulvovaginitis is based on clinical presentation and positive laboratory findings. Relying on a positive culture alone would likely overestimate the prevalence of Candida vulvovaginitis.
  • The use of over-the-counter (OTC) topical anti-fungals makes it difficult to conduct epidemiological studies.
• Candida is the second most common cause of vaginal infection in young women following Bacterial Vaginosis.

Age

• Incidence of Candida vulvovaginitis is higher in pregnant women.
• Women in reproductive age group are prone for Candida vulvovaginits and at least one episode is reported in 70 to 75% in this population group.
• 40 to 50% of patients with a prior yeast infection have multiple episodes of yeast infection.
• Among the adult population 5 to 8% women have more than four episodes of infection.
• In 20% asymptomatic healthy adolescent women, candida species is isolated from the vagina.

Race

Candida vulvovaginitis is more prevalent among African American women than white American women.

Risk Factors

The following risk factors have been implicated in predisposing patients to Candida vulvovaginitis:

• Previous infection with Candida vulvovaginitis
• Previous infection with Neisseria gonorrhea
• Nulliparity
• Luteal phase of the menstrual cycle
• Recent antibiotic use
• Pregnancy
• Diabetes Mellitus
• Obesity
• Immunosuppression, such as HIV or glucocorticoid use
• Condom use

Risk Factors for Recurrent Candida Vulvovaginitis

Microbial Factors	Genetic Factors	Host Behavioural Factors	Other Risk Factors
Non-albicans Candida species	Lewis blood group non-secretor status African American race Familial history of recurrent Candida vulvovaginitis	Oral contraceptive Sponge/intrauterine device use Intercourse frequency/ periodicity Orogenital sexual activity	Antibacterial use Uncontrolled diabetes HIV Corticosteroids Hormone replacement therapy

Table adopted from Vulvovaginal candidiasis Lancet 2007; 369: 1961–71

Diagnosis

Diagnosis of Candida vulvovaginitis requires a correlation of clinical features, microscopic examination, and vaginal culture.

History and Symptoms

Symptoms of vulvovaginitis caused by Candida species are indistinguishable and include the following:

• Pruritus is the most significant symptom
• Change in the amount and the color of vaginal discharge: It is characterized by a thick, white "cottage cheese-like" vaginal discharge
• Pain on urination (dysuria)
• Pain on sexual intercourse (dyspareunia)
• Vulvovaginal soreness
• Symptoms aggravate a week before the menses

Physical Examination

Candida vulvovaginitis requires a careful examination of the external genitalia, the vaginal sidewalls, as well as the cervix. Signs include:

• Edema and erythema of the vulva and labia
• Fissures and excoriations of the external genitalia
• Thick adherent whitish vaginal discharge
• Cervix is not affected and is normal

Laboratory Findings

The laboratory findings consistent with the diagnosis of Candida vulvovaginitis include:

• Vaginal pH: In Candida vulvovaginitis the vaginal pH is normal (ranges from 4.0-4.5)
• Wet mount or Saline preparation: It will help in detection of hyphae, clue cells and motile trichomonas differentiating different causes of vaginitis.
• 10% Potassium hydroxide preparation: It is more sensitive than wet mount to show budding blastospores or pseudohyphae.
• Culture: Culture for diagnosing Candida vulvovaginitis not recommended in patients with positive microscopy. However, it should be done in a symptomatic woman with a negative microscopy and a normal vaginal pH. Culture using Sabouraud agar, Nickerson’s medium, or Microstix-candida medium identify Candida species with equal sensitivity.

Treatment

Medical Therapy

Medical therapy for Candida vulvovaginitis includes:

• Uncomplicated candida Vulvovaginits:
  • 1st line :Any topical antifungal agents can be used and all of them have equal efficacy
  • Alternative : Single 150mg dose of oral fluconazole is recommended.
• Severe acute Candida vulvovaginitis:
  • 1st line: Oral fluconazole 150mg, given every 72 hours for a total of 2 or 3doses
• Candida glabrata: When unresponsive to oral azoles
  • 1st line: Topical intravaginal boric acid administered in a gelatin capsule, 600mg daily for 14days
  • 2nd line: Nystatin intravaginal suppositories, 100,000 units daily for 14days
  • 3rd line: Topical 17% flucytosine cream alone or in combination with amphotericin B cream daily for 14days
• Recurring vulvovaginal candidiasis:
  • 1st line: 10 to 14days of induction therapy with a topical agent or oral fluconazole, followed by fluconazole, 150mg weekly for 6months

Prevention

• Prophylactic maintainence of fluconazole is helpful in patients with idiopathic recurrent candida vulvovaginitis and in secondary recurrent vulvovaginitis associated with lichen sclerosus or topical estrogen application.