Transcript CD4 T-Cell Th1 Response

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
Severe Yeast
Satellite lesions
Summers PR. Topical therapy for mucosal yeast
infections in: Topical Applications and the Mucosa
(Current Problems in Dermatology volume 40), Surber
C, Elsner P, Farage MA eds. Karger New York 2011
World War II
50 to 80 million deaths world wide
USA cost $4 trillion (current value)
World War II Advances in Technology
Jet engine
Guided
rockets
Nuclear
Radar
Synthetic
rubber
Sonar
(ultrasound)
* Colposcope
*
History of Colposcopy
Developed by Dr. Hans Hinselmann in Hamburg
Germany (first described in1925)
Dr. Helmut Wirts was Hinselman’s partner in
Hamburg
Dr Eduard Wirts (Helmut’s brother) was the chief
doctor for the notorious Jewish “medical block 10”
of Auschwitz Concentration camp
In 1943 Eduard published his unethical colposcopy
prisoner experimentation, “Carcinom: die Geissel
der Frauen der Welt is Heilbar”
HIV
Thrush
Currently 2.6 million children, 37 million total living with HIV worldwide
1.7 million deaths in 2013
30 years of Advances in HIV Research
Dynamics of an
Epidemic
Antiretrovirals
Better
understanding
of the
Immune System
*Better
*
understanding
of the
pathophysiology
of infection
Vaginal Immune Defenses
Skin
Barrier
Cell
mediated
immunity
Innate
immunity
Key Immune Elements
*Langerhans cells
*CD4 T-helper cells
Macrophages
vaginal and oral mucosa
are similar
vaginal innate response
Is stronger
Cytokines
*Innate elements
mannose binding lectin (MBL)
human beta defensin 2 and 3 (HBD 2 or 3)
secretory leukocyte protease inhibitor (SLPI)
40 others
Vulvovaginal Skin Physiology
human beta defensins (HBD-2, 3)
Stratum Corneum or
human cathelicidin (LL-37)
Surface glycoproteins (mucus)
superficial
Mannose binding lectin
intermediate
parabasal
basal
lipids and free fatty acids fill the
intercellular space
Langerhans cells
Skin is the Body’s Primary Immune Organ!
The immune system of the skin:
 Langerhans cells (2-5% of cells in the skin)
recognize and process antigens
 The highest concentration of Langerhans cells is
in the cervical transformation zone (Pudney. Biol
Reprod. 2005;73:1253)
 The most likely site of entry of HIV is the
transformation zone
Langerhans Cells
 Bone marrow-derived cells residing in the skin
 Consume foreign antigens that appear in the skin
 Activate an important defense against bacteria, viruses,
yeast, and cancer cells
 Microbes are killed and processed for antigens that are
transported to the immune system
 Cancer cells that randomly appear in the skin have
abnormal surface proteins and are recognized by the
Langerhans cells
CD4 T-Cell Th1 Response
 T-helper cell type 1 response (Th1) eliminates
infection and individual malignant cells
 Auto-immune skin disease is an excessive Th1
response
 Rejection of a transplanted organ is a Th1
response
CD4 T-Cell Th2 Response
Mediates allergy
 Does not effectively eliminate bacteria, yeast,
viruses or cancer cells in the skin
 A Th2 response down-regulates the ability to
have a good Th1 response
 A persisting Th2 response increases the risk
for viral and yeast infection, as well as skin
cancer
*
Infection is worse if there is no good Th1 Response
Diagram:
Abbas and Lichtman. Basic Immunology 2nd Edition Saunders 2006:116
Good
Bad (vulvovaginal allergy or estrogen)
Skin Microbicides
 The intermediate layer of the skin produces over
800 chemicals important for growth, healing,
etc.
 Human beta defensins and cathelecidin are the
most important but over 40 have been identified
(Ichiro J Immunol 2003;171:3262)
 The MIC 90 of HBD3 against Saccharomyces
cerevisiae is 13.2 micrograms / ml (Jose-Ramon. Cell and
Tissue Research. Online publication, Springer-Verlag 11 Sept 2001)
Mannose Binding Lectin
The lectin Pathway
Mannose binding lectin is produced by
vaginal epithelial cells and the liver
MBL binds microbes that have Mannose on
their surface
This activates microbe killing by the lectin
complement pathway
Bulla R, et al. Mannose-binding lectin is produced by vaginal epithelial cells and
its level in the vaginal fluid is influenced by progesterone. Mol Immunol
2010:48(1-3);281-6
Vaginal Immune Deficiency
Loss of skin barrier (flaking skin)
Inhibition or loss of Th1 response
Decrease in HBD3 in allergy
Deactivation or congenital
deficiency in MBL
Who is at high risk for yeast infection?
AIDS
Eczema
Pregnancy
SGLT2 inhibitors
(Invokana, etc)
Diabetes
Antibiotics
(topical) estrogen
HIV
Basic Immunology of AIDS
Compromised genital skin barrier
Langerhans cells phagocytize HIV
Langerhans cells activate and infect T-helper
cells (CD4 cells)
HIV destroys CD4 population of T-helper cells
Resulting opportunistic infections and
malignancies
Kawamura et al. The role of Langerhans cells in the sexual
transmission of HIV. J Dematol Sci 2005:40;147-55
Infection is worse if there is No CD4 Th1 Response
Good
X HIV
Bad
Herpetic Whitlow
Herpetic Whitlow in AIDS with
minimal Th1 response
Severe herpes in AIDS with
minimal Th1 response
What to do for HIV with Recurrent Yeast
Antiviral therapy to improve
CD4 count
Oral or topical antifungal
Eczema
Relative Sensitivity of Vulvar Skin
 Transepidermal water loss is higher on the vulva
than elsewhere Elsner, Maibach. Acta Derm Venereol 1990;70:141-4
 Vulvar friction coefficient is greater, making the
vulva more susceptible to mechanical damage
Elsner, Maibach. Dermatologica 1990;181:88-91
 Hydration, occlusion, and tissue permeability
heighten vulvar susceptibility to topical irritants
Ferage. Arch Gynecol Obstet 2005;272:167-72
Universally high risk for irritant and allergic dermatitis
Numerous Articles link Allergy to Yeast
Moraes PS et al. Recurrent vaginal candidiasis
and allergic rhinitis: a common association. Ann
Allergy Asthma Immunol 1998:81;165-69
Neves NA et al. Association between atopy and
recurrent vaginal candidiasis. Clin Exp Immunol
2005:142;167-71
White DJ et al. Zafirlukast for severe recurrent
vulvovaginal candidiasis: an open label pilot study
Sex Transm Infect 2004:80;219-22
Combination steroid / antifungal creams are commercially available
but typically contain irritating propylene glycol
Eczema and Yeast Infection
Eczema favors staph, strep
and yeast infection
(impetigo and intertrigo)
Obstetric and Gynecologic Dermatology Black M
and McKay M, eds Mosby 2002:75, 201-203
Women with recurrent yeast
generally have a vaginal
baseline TH2 environment
Witkin SS et al. Localized vaginal allergic response in
women with recurrent vaginitis J Allergy Clin Immunol
1988:81;412-16
The Consequences of Allergic Dermatitis
 Deficient cathelicidin (LL-37) and beta defensin
(hbd-2, 3) allows microbe colonization of the skin
Nomura et al. Cytokine milieu of atopic dermatitis…prevents induction of innate
immune response genes J Immunol 2003:171;3262-69
 Flaking of the stratum corneum facilitates microbe
entry into the skin
 Deficient cell-mediated Th-1 response allows
microbe proliferation in the skin and increases
cancer risk
Skin flake probably due to
interferon gamma
compromises the skin barrier
Vulvovaginal irritant and allergic response
causes the skin to flake, as is seen frequently
in the saline wet prep (spongiotic response)
Contact dermatitis (spongiotic dermatitis)
Hyperkeratosis and Spongiosis
Severe Allergic Dermatitis
Scratching here
History of asthma, hay
fever, eczema, sinusitis
Deficient HBD2 and 3
Lichen Simplex Chronicus with
Recurrent Yeast Infection
Deficient HBD 2, 3
Therapy for Vulvar Atopic Dermatitis
 Avoid allergens (and irritants)
 Topical non irritating (compounded) corticosteroid
ointment
 Moisturize daily with vaseline, Crisco, or coconut oil
 Antihistamine
 Consider the long-term risk of squamous cancer
 (Oral) yeast therapy for superimposed infection
Lichen Sclerosus
Complications of Lichen Sclerosus
 Poor skin barrier function (topical creams burn)
 Vulvar contact dermatitis (mixed vulvar
dystrophy)
 Down-regulation of Th1, enhanced Th2 CD4 Tcell response
 Recurrent yeast infection and Squamous
cancer
Lichen Sclerosus Therapy
 Avoid irritants and allergens
 Not topical testosterone
 Treat any associated infection (oral fluconazole
or topical clotrimazole)
 Apply non-irritating topical corticosteroid
ointment
 Biopsy any suspicious areas (risk of cancer)
Chronic Dermatitis leads
to Nerve Proliferation
Figure from Misery, Staender. Pruritus Springer 2010 p. 4
Nerve Proliferation in “Vulvar
Vestibulitis”
 Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Increased
intraepithelial innervation in Women with vulvar
vestibulitis syndrome. Gynecol Obstet Invest 1998;46:25660
 Westrom LV, Willen R. Vestibular nerve fiber proliferation in
vulvar vestibulitis syndrome. Obstet gynecol 1998;91:572-6
 Bohm-Starke N, Hilliges M, Falconer C, Rylander E.
Neurochemical characterization of the vestibular nerves in
women with vulvar vestibulitis syndrome. Gynecol Obstet
Invest 1999;48:270-5
Pregnancy
Pregnancy and Eczema
Eczema is more severe
during menses and
pregnancy
Kemmett D, et al. The influence of the
menstrual cycle and pregnancy on
atopic dermatitis. Br J Dermatol
1991:125;59-61
Basic Immunology of Pregnancy
Compromised genital skin barrier
Estrogen down regulates Th1 response
Any tendency for a Th2 response is enhanced
Th2 response lowers human beta defensin 3
Yeast produce acid proteases that enhance the
Th2 response
Glucosuria deactivates mannose binding lectin
What to do for Pregnancy and Recurrent Yeast
Oral glucose challenge test
Clotrimazole cream
Possibly topical steroid
Moisturize with vaseline, Crisco,
coconut oil
May prefer to avoid oral diflucan
(fluconazole)
Risk of Fluconazole in Pregnancy
Increase in miscarriage (7 to 22
weeks gestation)
Hazard ratio 1.48
Also increased rate of stillbirth but
not statistically significant
No increased risk with topical azoles
*
Moigaard-Nielsen et al. Association between use of oral
fluconazole during pregnancy and risk of spontaneous
abortion and stillbirth. JAMA 2016:315;58-67
SGLT2 inhibitors
(prevent glucose reabsorption in the
renal distal tubule for diabetic
glucose control)
Invokana, etc
Mannose Binding Lectin
Mannose binding lectin
plays a crucial role in innate immunity
against yeast by enhanced
complement activation and enhanced
uptake of polymorphonuclear cells. BMC
Van Asbeck EC et al.
Microbiol 2008:8;229
Why does Glucosuria cause yeast?
The lectin Pathway
Mannose binding lectin is produced by
vaginal epithelial cells and the liver
Progesterone enhances MBL production
during the secretory phase of menses and
pregnancy
This can compensate for the downregulation of the CD4 T cell Th1 response
Bulla R, et al. Mannose-binding lectin is produced by vaginal epithelial cells and
its level in the vaginal fluid is influenced by progesterone. Mol Immunol
2010:48(1-3);281-6
Why does Glucosuria cause yeast?
The lectin Pathway
(Fucose is a plant sugar)
MBL binds mannose, fucose, glucose, and
all sugars with 3 or 4 hydroxyl groups in an
“equatorial plane” Weiss WI et al. Structure of a c-type
mannose binding protein complexed with an oligosaccharide. Nature
1992:360(6400);127-34
Mannose is found on the surface of
Salmonella, Neisseria, yeast, and other
mucosal pathogens
Why does Glucosuria cause yeast?
The lectin Pathway
MBL binds pathogens that have mannose
on the surface
MBL activates pathogen killing by the lectin
complement pathway
Urine contacts the vulva and refluxes into
the vagina
A significant amount of glucosuria binds and
deactivates MBL
Do Yeast Thrive on Sugar?
Ingredients in Sabourauds Agar
1% Tryptone
(numerous peptides resulting from
the digestion of casein by the
protease trypsin)
4% Dextrose
1.5% Agar (inert galactose polymer)
NO
What to do for Glucosuria and Yeast
Diflucan or clotrimazole once
weekly
Diflucan or clotrimazole with
menses
Avoid irritants
Topical steroid or daily moisturizer if
vulvar atopic changes
Diabetes
Immunology of Diabetes
Active tuberculosis is 10X more common in
juvenile and long duration diabetes
Root HF The association of diabetes and pulmonary tuberculosis N Engl J Med 1943:210;127-47, 192-200
Administered insulin has an antiinflammatory
action that shifts toward a Th2 response in insulin
resistance
Viardot A, Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T
helper 2 phenotype
Glucosuria neutralizes Mannose Binding Lectin
Diabetic Recurrent Yeast treatment
Maintain hemoglobin A1c less than 7
Moisturize with vaseline, Crisco, or
coconut oil for any dermatitis
May use oral fluconazole if not taking
an oral hypoglycemic
Antibiotics and Yeast
Antibiotics and Yeast
Vulvar dermatitis from mascerated genital
skin
Impetigo, intertrigo, infection under pannus
Staph, Strep (GBS), yeast colonization
Antibiotics eliminate staph and strep so yeast
can move in
Yeast replicate more slowly than bacteria
What to do for Antibiotics and Yeast
Use antifungal concurrently with
antibiotic
Treat any vulvar atopic tendency
Estrogen Replacement
Decreased Allergy after Menopause
 Asthma may become less severe after
menopause Belzano. Asthma and sex hormones.
Allergy
2001;56(1):13-20
 Lower estrogen decreases risk for yeast infection after menopause
 Hormone replacement therapy after menopause
may make asthma worse Kos-Kudla. Effects of
hormone replacement therapy on endocrine and spirometric
parameters in asthmatic postmenopausal women. Gynecol
Endocrinol 2001;15(4):304-11
 Yeast infection risk is restored
Yeast Infection with Estrogen
Replacement
Adverse Event
(Preferred Term)
Vagifem®
(n=91)
Placebo
(n=47)
%
%
Headache
9
6
Abdominal Pain
7
4
Upper Respiratory
Tract Infection
5
4
Moniliasis Genital
5 Statistically significant 2
Back Pain
7
source: Vagifem® [prescribing information].
Princeton, NJ: Novo Nordisk Inc.; 2006.
6
Resistant Yeast
Candida albicans
Resistant Non-albicans Yeast
Blastospores, no hyphae
May respond to butoconazole, terconazole,
itraconazole (or oral combined with topical)
Treatment for Resistant Yeast
Topical 600 mg boric acid in a
capsule BID Sobel JD et al. Treatment of vaginitis
caused by Candida Glabrata: use of topical boric acid and
flucytosine. Am J Obstet Gynecol 2003:189;1297-1300
Highly poisonous if boric acid is
ingested orally Baker MD et al. Ingestion of boric
acid by infants. Am J Emerg Med 1986:4;358-61
Flucytosine is expensive, impractical
Horowitz BJ. Topical flucytosine therapy for chronic recurrent
Candida Tropicalis infections J Reproduct Med 1986:31;821-24
Lactobacillus Probiotic Therapy
Normal flora, lactobacilli
Lactobacillus Therapy
 Lactobacillus therapy does not prevent post
antibiotic yeast vaginitis (BMJ 2004;329:548)
 Lactobacillus therapy shortens pediatric
diarrhea by .7 days with 1.6 fewer stools by day
2 (pediatrics 2002;109:678)

Rafael CR, et al. Improved cure of bacterial vaginosis with single dose of
tinidazole (2 g), lactobacillus rhamnosus GR-1, and lactobacillus reuteri
RC-14: a randomized, double-blind, placebo-controlled trial. Can J
Microbiol 55:2009;133-38
Vaginal pH and lactobacilli
 Normal vaginal pH is regulated by estrogen
 Vaginal pH of newborn is around 5 at birth
 Skin metabolizes glucose to lactate
 “acid mantle” of the skin is 4.5
 Linhares IM, Summers PR, Larsen B, Giraldo PC, Witkin SS.
Contemporary perspectives on vaginal pH and lactobacilli. Am J
Obstet Gynecol 2011:204;120.e1-5
False but Popular Concept
yeast
Yeast
True concept for some bacteria and trichomonas, but not yeast