Chronic Yeast Infection: Why and What to do about it

Paul Summers, M.D.Department of Obstetrics and Gynecology

University of Utah School of Medicine

VulvovaginalYeast Infection is not a random event

Yeast infection is always the result of immune and / or dermatologic compromise

No Medication will totally eliminate yeast

Medications and various treatments can control but not eliminate immune and dermatologic disorders

Treatment modalities:

1. Dermatitis control with non irritating steroids and moisturizers(Kenalog ointment, vaseline Crisco or coconut oil, with irritant avoidance)

2. Glucose control

3. Yeast suppression as needed (oral fluconazole, topical clotrimazole)

Severe Yeast

Satellite lesions

Candida albicans

Topical 1% clotrimazole 7 is the least irritating agent (no propylene glycol)

Non-albicans Yeast

Blastospores, no hyphae

30% of C glabrata strains are resistant to fluconazole

600 mg boric acid vaginally BID for 7 days has a 60% success rateCompounded Flucyosine cream costs around $3000

May consider combined oral fluconazole and topical clotrimazole

Levels of Defense against Yeast1. Lactobacillus

2. Mucus

3. Innate Immunity

4. Skin Barrier

5. Cell Mediated Immunity

Lactobacillus and Yeast

(not very effective)

pH was a major scientific topic in the 1920’s

The concept of pH was introduced in 1909by a Danish Chemist, Soren Sorensen and refined for general scientific use in 1924

Lactobacillus acidophilus was initially described in 1920 (subsequently proposed that pH controlled by Lactobacillus regulates vaginal microbes)

An initial interest in pH outside of chemistry was in the food Industry (pH in food could be measured and was proposed to control microbe contamination in dairy and other products)

A Role for Lactobacillus ??

• Research even in the 1930�s showed Lactobacillus not to be essential for a normal vaginal pH (AJOG 32;211:1936 37;698:1937)

• Vaginal skin is an important source of lactate

• Peroxide is not produced by lactobacilli in an anaerobic environment, and vaginal RBCs and WBCs release peroxidase

• Yeast infection is not reliably prevented by lactobacilli or normal pH (Pirotta M et al BMJ 2004;329:548-51)

Lactobacilli• “graze” on the surface of cervicovaginal mucus (Jiri

and Mestecky eds. Mucosal Immunology 4th edition. Elsevir 2005;67)

• Lactobacilli fill potential pathogen binding sites on the surface of the mucus

• Lactobacilli generally do not contact the vaginal epithelium

• Lactobacilli disappear if the cervicovaginal mucus disappears

Probiotics to Prevent Yeast

• The vagina will not populate with lactobacilli or probiotics if mucus is absent (persistent BV or trichomonas)

• Probiotics can cause disease if mucus is absent or the mucosa is disrupted

• There is a strong interest in probiotic therapy but limited success (mainly colon at this time)

Vaginal Mucus and Yeast

(Important element of protection)

The Dominant Role of Mucus• Mucus prevents biofilm formation (Caldara M et al.

Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state. Curr Biol 2012 Dec 18:22(24):2325-30)

• Mucus contains important innate antimicrobial substances (Linden SK et al. Mucins in the mucosal barrier to invasion pgs 1-15

• Mucus has structure (25% protein, 75% carbohydrate)

Biofilm• Pathogenic microbes must pass through the mucus

to attach, then invade the epithelium

• Mucus disruption is achieved with pathogen-produced mucinase, sialidase, and proteinases

• Clue cells present with BV and trichomonas are evidence of biofilm formation due to mucinase production

• Absent mucus increases the risk for infection ascending above the cervix

Clue Cells

Lactobacilli disappear if the mucus is disrupted

No MucusNo Lactobacilli

Normal flora, lactobacilli

No biofilm

Bacterial Vaginosis

Bacterial Vaginosis is not a failure of the Lactobacilli

• BV is characterized by mucinase production

• The growth and proliferation site for lactobacillus is lost

• Lactobacillus ”grazing” on the mucus ends

• With resolution of BV, mucus is restored and lactobacilli (likely from the small bowel) repopulate the vagina

Trichomonas is also Trichomonas is also associated with associated with mucinaseassociated with associated with mucinasemucinase production mucinasemucinase production production and the formation of and the formation of biofilm

Many Mucosal Pathogens can produce Mucinase

Gardnerella vaginalis

Mycoplasma

Bacteroides

Helicobacter pylori

Cervicovaginal Mucus and Yeast

Yeast do not release mucinase

Proteinases produced by yeast allow penetration into mucus and the epithelial surface (Body GP. Candidiasis. Raven Press 1993;15)

Vaginal yeast may spread from a primary vulvar site of established infection

Innate Immunity and Yeast

Numerous innate chemicals with antimicrobial action are released by epithelial cells and WBCs into the cervicovaginal mucus

(Important)

Innate Antimicrobials in MucusHuman beta defensin 2 inhibits bacteria and yeast (Schroder JM, Hunter J. Human beta-defensin2. Int J Biochem Cell Biology 1999 June;31(6):645-51)

Human cathelicidins inhibit bacteria yeast and enveloped viruses (Koscluczuk EM et al. Cathelicidins: Family of antimicrobial peptides. A review Mol Biol Rep 2012;39(12):10957-70)

Secretory leukocyte protease inhibitor (SLPI) inhibits microbial proteinases

Mannose binding lectin

Mannose Binding Lectin• Mainly produced in the liver

• Also produced by vaginal epithelium

• Binds mannose on yeast surface and activates lectin pathway to destroy yeast

• May be neutralized by glucosuria

Diabetes and Yeast

• Diabetes is a relative immunocompromise condition generally

• Glucosuria neutralizes vaginal mannose binding lectin

• Yeast do not grow on sugar: a protein source is needed as well as carbohydrates

Invocana

• Urine refluxes into the vagina

• Glucose, mannose and fucose can adhere to vaginal MBL

• Glucosuria deactivates MBL and contributes to vulvovaginal yeast risk

Skin Barrier and Yeast

(Skin surface compromise is important)

Skin Barrier• Healthy skin only allows entry of chemicals

with a molecular weight less than 500

• Microbes, skin irritants and allergens have a molecular weight greater than 500

• Dermatitis and skin trauma significantly compromise this barrier function

• Yeast bind to fibronectin that is exposed by flaking skin (dermatitis)

FFlaking skin exposes g pfibronectin, allowing ,yeast adherence

Vulvovaginal contact dermatitis causes the skin to gflake, as is seen frequently in the saline wet prep

Cell Mediated Immunity and Yeast

(The final Defense against yeast)

Vulvovaginal Physiology• Mucus protects the vagina, endocervix,

endometrium, fallopian tubes and bladder

• Innate immunity is the next layer of mucosal defense

• Cell mediated immunity can then be activated to defend the vulva and vaginal tissues

• Not the Lactobacillus

Skin: A Major Outpost of the Immune System

• Langerhans Cells (antigen presenting cells): 2 to 5% of the cells in the skin

• Keratinocytes: >90% of the cells in the skin

• Melanocytes: 3 to 7% of the cells in the skin (even present in the eye and middle ear)

Genital Skin Immunology800 melanocytes per mm2 in normal skin

• Face has 1200 to 1800 melanocytes per mm2

• Genital and perirectal area has 1800 melanocytes per mm2

• Genital Skin is more immunoreactive than skin elsewhere

Th1 Immune Response

• Stimulated by foreign antigen exposure in the skin

• The appropriate response to help eliminate infection and individual malignant cells

• Auto-immune skin disease is an excessive Th1 response

• Rejection of a transplanted organ is a Th1 response

Th2 Immune Response

Mediates allergy

Down-regulates a Th1 response and key innate defenses

Does not effectively clear yeast, bacteria, viruses or malignant cells

History of asthma hay fever, eczema, sensitivity to cheap jewelry (nickel sensitivity)

Primary herpes, in atopic skin with a poor Th1 response

Cell Mediated Immune Risk Factors for Recurrent Yeast

• Vulvar contact dermatitis (Th2 response) History of asthma, hay fever, eczema, sinusitis, nickel sensitivity

• Diabetes if HbA1c is >7

• lichen sclerosus

• HIV

HIV (with deficient T cell response)

• Increased risk for yeast infection (oral more than vaginal, likely due to a more robust innate protection in the vagina)

• Other atypical skin disorders and cancer

Severe herpes in AIDS with Severe herpes in AIDS with minimal Th1 response

Herpetic Whitlow

Herpetic Whitlow in AIDS with Herpetic Whitlow in AIDS with minimal Th1 response

Contact Dermatitis• Itching, burning or pain, depending on

severity

• Typically, there is no visual change

• Flakes of skin in the wet prep

• Spongiotic change in the biopsy read by a dermatopathologist

(blue squares)

Allergic Vulvar Dermatitis (Th2)• Lichen simplex, spongiotic change

• May have history of asthma, hay fever, eczema, nickel sensitivity (11% of women)

• Beta defensins and other important antimicrobial peptides are inhibited (Nomura I et al Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes J Immunol 2003Sept 15;171(6);3262-9)

• Allergy worsens with menstrual luteal phase and pregnancy

Severe Allergic Dermatitis (Deficient innate immunity, flaking skin)

Scratching here

History of asthma, hay fever, eczema, sinusitis

Therapy for Vulvar Atopic Dermatitis• Avoid allergens (and irritants)

• Non irritating topical corticosteroid ointment

• Moisturize with Vaseline, Crisco, or coconut oil

• Consider the long-term risk of squamous cancer

• Oral or non irritating topical yeast therapy for superimposed infection

Lichen Sclerosus• Often hour glass-shaped rash

• Skin barrier compromise increases susceptibility to irritants and allergens

• Often superimposed contact dermatitis

• Secondary yeast infection is common

• Squamous cancer risk

Lichen Sclerosus

Lichen Sclerosus Therapy

• Avoid irritants and allergens

• Non irritating topical corticosteroid ointment

• Check for yeast and biopsy any suspicious areas (risk of cancer)

Antibiotic-Induced Vaginal Yeast Infection

• Most directly related to Staph aureus colonization of vulvovaginal contact dermatitis

Staph aureus Colonization of Skin

• Normal skin has 10 bacteria per square cm

• Atopic skin is populated by up to 10 per square cm

4

7

Staphylococcus aureus

• 40% colonization of nasopharynx

• 60% colonization of the vulva

• Potentially universal cofactor for contact dermatitis

• Staph toxins promote a Th2 response

Consequence of Antibiotics• Staph aureus cell wall is disrupted, releasing toxin

• More pronounced Th2 response in the skin

• Free up fibronectin binding sites

• Yeast organisms move in and bind fibronectin

• Cell wall antibiotics have a stronger effect than metabolic inhibitors

Antibiotic Induced Staphylococcus Toxin Release (contributes to the vulvovaginal Th2 Response)

Cell Wall

Metabolic

Nau R, Eiffert H. Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials… Clin Microbiol Rev 2002 Jan; 15(1):95-110

Summary• Yeast are not reliably regulated by lactobacilli

• Contact dermatitis lowers key innate defenses in the mucus and exposes surface fibronectin

• The associated Th2 response does not effectively control yeast

• Non irritating topical steroid ointments and moisturizers control contact dermatitis and lower the yeast risk