the spectrum of candida related disorders: an allergist’s 33 yr perspective george f kroker md...

The Spectrum of Candida The Spectrum of Candida Related Disorders:Related Disorders:

An Allergist’s 33 yr PerspectiveAn Allergist’s 33 yr Perspective

George F Kroker MDGeorge F Kroker MD

Allergy Associates of La CrosseAllergy Associates of La Crosse

Case History

C.G., a 39 y/o R.N. from Duluth MN , is referred from her gynecologist for allergy assessmentChronic headaches, daily for 1 yearExhaustion, fatigue on awakening in AMEpisodic migraine headaches, – Require frequent ER treatment– Variety of meds tried: lortabs, imitrex, etc.

Chronic rhinitis & sinus headaches--worse in fallc/o chronic recurrent yeast vaginitis– Increasing frequency for 1 year PTA

Premenstrual syndrome: bloating, fatigue, CNS

Case History (cont)Case History (cont)

Recurrent antibiotic use thru childhood for Recurrent antibiotic use thru childhood for chronic pharyngitischronic pharyngitis

Antibiotics twice this year for respiratory Antibiotics twice this year for respiratory infections during fall seasoninfections during fall season

Premenstrually c/o fatigue, cravings for Premenstrually c/o fatigue, cravings for chocolatechocolate

Case History: Patient GoalsCase History: Patient Goals

““Help my energy” “I want to feel normal”Help my energy” “I want to feel normal”

““Help my headaches”Help my headaches”

““I don’t want to keep having yeast I don’t want to keep having yeast infections”infections”

““I don’t want to be sick every fall”I don’t want to be sick every fall”

““What’s going on with me?” What’s going on with me?”

What’s wrong with this patient?How do I approach her allergyevaluation and treatment?

Candida-related DisordersCandida-related Disorders

InfectiousInfectious– CutaneousCutaneous

intertriginous candidiasisintertriginous candidiasisonychia/paronychiaonychia/paronychiacandida granulomacandida granuloma

– MucocutaneousMucocutaneousoral: thrush, glossitis, cheilitis, stomatitisoral: thrush, glossitis, cheilitis, stomatitisgenital: vaginitis, balanitisgenital: vaginitis, balanitisalimentary: esophagitis, enteric, perianalalimentary: esophagitis, enteric, perianal

– SystemicSystemicurinary, cardiovascular, central nervous system, blood, etc. urinary, cardiovascular, central nervous system, blood, etc.

Candida-related disordersCandida-related disorders

Is this the complete list of pathogenic Is this the complete list of pathogenic Candida disorders?? Candida disorders??

The Tomato Effect: The Tomato Effect: Rejection of Highly Efficacious Therapies Because They Rejection of Highly Efficacious Therapies Because They

“don’t make sense and we know they can’t be true” “don’t make sense and we know they can’t be true”

Goodwin, JS & Goodwin JM, JAMA 251: 2387-2390, 1984

Candida AlbicansCandida Albicans

Candida is a heterogeneous genus Candida is a heterogeneous genus grouped with Fungi Imperfectigrouped with Fungi Imperfecti

80 species; 6 species pathogenic80 species; 6 species pathogenic

Candida albicans Candida albicans polyantigenicpolyantigenic– two cell wall antigens: mannan & glucantwo cell wall antigens: mannan & glucan– 77 cytoplasmic antigens; 1 mycelial antigen77 cytoplasmic antigens; 1 mycelial antigen– each strain of Candida has 30-35 of these each strain of Candida has 30-35 of these

antigensantigens

Candida AlbicansCandida Albicans

Characterization of IgE-binding epitopes on Candida Characterization of IgE-binding epitopes on Candida albicans enolasealbicans enolase– Ito K, Ishiguro A, Kanbe T, Tanaka, T, Torri SIto K, Ishiguro A, Kanbe T, Tanaka, T, Torri S– Clin Exp Allergy 25:529-35, 1995Clin Exp Allergy 25:529-35, 1995

Detection of IgE antibody against Candida albicans Detection of IgE antibody against Candida albicans enolase and its crossreactivity to Saccharomyces enolase and its crossreactivity to Saccharomyces cerevisiae enolasecerevisiae enolase– Ito K, Ishiguro A, Kanbe T, Tanaka K, Torri SIto K, Ishiguro A, Kanbe T, Tanaka K, Torri S– Clin Exp Allergy 25:522-8, 1995Clin Exp Allergy 25:522-8, 1995

Candida-related DisordersCandida-related Disorders

InfectiousInfectious– CutaneousCutaneous

intertriginous candidiasisintertriginous candidiasisonychia/paronychiaonychia/paronychiacandida granulomacandida granuloma

– MucocutaneousMucocutaneousoral: thrush, glossitis, cheilitis, stomatitisoral: thrush, glossitis, cheilitis, stomatitisgenital: vaginitis, balanitisgenital: vaginitis, balanitisalimentary: esophagitis, enteric, perianalalimentary: esophagitis, enteric, perianal

– SystemicSystemicurinary, cardiovascular, central nervous system, blood, etc. urinary, cardiovascular, central nervous system, blood, etc.

Candida-related Disorders: A Candida-related Disorders: A more complete listmore complete list

InfectiousInfectiousInfectious/immunologicInfectious/immunologic– Chronic mucocutaneous candidiasisChronic mucocutaneous candidiasis– Allergic Fungal SinusitisAllergic Fungal SinusitisSensitivity DisordersSensitivity Disorders– Localized SensitvityLocalized Sensitvity

UrticariaUrticariaIrritable bowel SyndromeIrritable bowel SyndromeAllergic vaginitisAllergic vaginitis

– Generalized SensitivityGeneralized SensitivityCandida Sensitivity Syndrome Candida Sensitivity Syndrome

Candida Sensitivity DisordersCandida Sensitivity Disorders

Localized SensitivityLocalized Sensitivity– urticariaurticaria

Candida & Chronic UrticariaCandida & Chronic Urticaria

An assessment of the role of Candida An assessment of the role of Candida albicans and food yeasts in chronic albicans and food yeasts in chronic urticaria. James, J & Warin RP BR J urticaria. James, J & Warin RP BR J Dermatology 84:227-237, 1971. Dermatology 84:227-237, 1971. – 100 pts with chronic urticaria100 pts with chronic urticaria– 36% (36 pts) positive prick Candida36% (36 pts) positive prick Candida– 3/36 responded to medication (nystatin)3/36 responded to medication (nystatin)– 23/36 responded to med & yeast-free diet23/36 responded to med & yeast-free diet

Candida and Chronic UrticariaCandida and Chronic Urticaria

Holti, G: Candida allergy. In: Winner HI, Holti, G: Candida allergy. In: Winner HI, Hurley R, eds. Symposium on Candida Hurley R, eds. Symposium on Candida infections. Edinburgh and London: E& S infections. Edinburgh and London: E& S Livingstone 1966; 74-81.Livingstone 1966; 74-81.– 255 patients with chronic urticaria255 patients with chronic urticaria– 49 (19%) had positive prick to Candida49 (19%) had positive prick to Candida– 27 (11%) had positive prick to food yeast27 (11%) had positive prick to food yeast– Rx nystatin x3 weeks cured 27/49 patientsRx nystatin x3 weeks cured 27/49 patients– 18 pts required med plus yeast-free diet18 pts required med plus yeast-free diet

Candida and Chronic Urticaria: Candida and Chronic Urticaria: Clinical CorrelatesClinical Correlates

Patient on multiple antibiotics who gradually Patient on multiple antibiotics who gradually develops longstanding urticariadevelops longstanding urticaria

Patient with chronic urticaria who has other Patient with chronic urticaria who has other signs of overt Candida overgrowth—i.e., signs of overt Candida overgrowth—i.e., recurrent yeast vaginitisrecurrent yeast vaginitis

Patient with chronic urticaria known to be Patient with chronic urticaria known to be sensitive to yeast-containing foods or moldsensitive to yeast-containing foods or mold


Localized SensitivityLocalized Sensitivity– UrticariaUrticaria– Irritable bowel syndromeIrritable bowel syndrome

Candida & Irritable Bowel Syndr Candida & Irritable Bowel Syndr

Santelmann, H & Howard, JM: Yeast metabolic products, yeast antigens, and Yeasts as possible triggers for irritable bowel syndrome. Eur J Gastgroenterol Hepatol 17: 21-26, 2005

Candida & Irritable Bowel SyndrCandida & Irritable Bowel Syndr

““At least 3 different Candida species are At least 3 different Candida species are able to produce proteases which can able to produce proteases which can degrade IgA1, IgA2, and SIgA. This degrade IgA1, IgA2, and SIgA. This protease activity can induce polyclonal B-protease activity can induce polyclonal B-cell response and inflammation. An cell response and inflammation. An infection of the intestinal mucosa with infection of the intestinal mucosa with Candia might lead to an inactivating of Candia might lead to an inactivating of SIgA and inflammation within subgroups of SIgA and inflammation within subgroups of patients with IBS symptoms.”patients with IBS symptoms.”


““It was shown recently that there is a It was shown recently that there is a potential cross reactivity with gluten potential cross reactivity with gluten because of several amino acid sequences because of several amino acid sequences (in the Candia cell wall) that are highly (in the Candia cell wall) that are highly homologous to alpha-gliadin and gamma homologous to alpha-gliadin and gamma gliadin. Such a mechanism might lead to gliadin. Such a mechanism might lead to wheat intolerance with its accompanying wheat intolerance with its accompanying symptoms and even trigger celiac disease symptoms and even trigger celiac disease in genetically susceptible people.” in genetically susceptible people.”


““Candida can be cultured from faeces in Candida can be cultured from faeces in up to 80% of healthy adults ”up to 80% of healthy adults ”

““Unfortunately, there is no accepted “gold Unfortunately, there is no accepted “gold standard” for distinguishing between a standard” for distinguishing between a yeast sensitivity condition and a yeast yeast sensitivity condition and a yeast overgrowth in the gut…overgrowth in the gut…


““Candida can produce alcohols and contains Candida can produce alcohols and contains glycoproteins which have the potential to glycoproteins which have the potential to stimulate mast cells to release histamine and stimulate mast cells to release histamine and apparently PGE2 inflammatory substances apparently PGE2 inflammatory substances which could cause IBS Ssx”which could cause IBS Ssx”

“…“…there is increasing evidence for yeasts being there is increasing evidence for yeasts being able to cause IBS symptoms in sensitized able to cause IBS symptoms in sensitized patients via Candida products, antigens, and patients via Candida products, antigens, and cross-antigenscross-antigens

Candida & Irritable Bowel: Candida & Irritable Bowel: Clinical CorrelatesClinical Correlates

The celiac patient who still has symptoms The celiac patient who still has symptoms or persistently high TTG levels may have or persistently high TTG levels may have Candida issuesCandida issues

The patient with known IBS who markedly The patient with known IBS who markedly worsens following antibiotic use may have worsens following antibiotic use may have Candida issuesCandida issues

The patient with IBS, and known wheat or The patient with IBS, and known wheat or yeast intolerance may have Candida yeast intolerance may have Candida issuesissues


Localized SensitivityLocalized Sensitivity– UrticariaUrticaria– Irritable bowel syndromeIrritable bowel syndrome– Allergic VaginitisAllergic Vaginitis

Candida and Allergic VaginitisCandida and Allergic Vaginitis

There is a strong association between There is a strong association between atopy and recurrent vaginal candidiasisatopy and recurrent vaginal candidiasis

A history of atopy (68%) and positive skin A history of atopy (68%) and positive skin testing to aeroallergens (42%) was higher testing to aeroallergens (42%) was higher in recurrent vaginal candidiasis than in in recurrent vaginal candidiasis than in patients with sporadic vaginal candidiasis patients with sporadic vaginal candidiasis (p<.05)(p<.05)– Neves, NA, De Oliveira, MA et al. J Exp Neves, NA, De Oliveira, MA et al. J Exp

Immunol 142: 167-171, 2005Immunol 142: 167-171, 2005. .


A significant number of women with A significant number of women with recalcitrant yeast vaginitis are found to recalcitrant yeast vaginitis are found to have IgE antibodies in their vaginal fluid have IgE antibodies in their vaginal fluid but not in their serabut not in their sera

Vaginal IgE sometimes directed against C. Vaginal IgE sometimes directed against C. albicans, perennial ryegrass, spermicidesalbicans, perennial ryegrass, spermicides– Witkin, S. Jeremias, AB, Ledger J. A localized Witkin, S. Jeremias, AB, Ledger J. A localized

vaginal allergic response in women with vaginal allergic response in women with recurrent vaginitis. JACI 81: 412-416, 1988recurrent vaginitis. JACI 81: 412-416, 1988


Allergic VulvovaginitisAllergic Vulvovaginitis

Moraes, Paula & Taketomi, Ernesto TMoraes, Paula & Taketomi, Ernesto T

Annals of Allergy 85: 253-265, 2000. Annals of Allergy 85: 253-265, 2000.


“ “Exposure to allergen in the vaginal lumen is followed Exposure to allergen in the vaginal lumen is followed by the transport of this allergen through the by the transport of this allergen through the interepithelial channels and its interaction with mast cell-interepithelial channels and its interaction with mast cell-bound specific IgE”bound specific IgE”

““Mast cell degranulation and the release of histamine Mast cell degranulation and the release of histamine and other inflammatory mediators causing symptoms of and other inflammatory mediators causing symptoms of allergic vaginitis”allergic vaginitis”

““Histamine is a potent inducer of PGE2 from Histamine is a potent inducer of PGE2 from macrophages which suppresses cell-mediated immune macrophages which suppresses cell-mediated immune response…the resulting symptomatic candidal vaginitis response…the resulting symptomatic candidal vaginitis would be a would be a secondarysecondary consequence to a consequence to a primaryprimary allergic vaginitis” allergic vaginitis”

Candida and Allergic VaginitisCandida and Allergic VaginitisAllergen exposure

IgE mediated vaginal rxn

Histamine

Macrophage production of PgE2

Inhibition of IL-2 production

Impaired lymphocyte proliferation Against Candida

Candida Vaginitis

Stress

Beta Endorphin

Candida Allergy


““Women with immediate hypersensitivity reactions Women with immediate hypersensitivity reactions to medications, environmental allergens, or to medications, environmental allergens, or microorganisms would be at increased risk for microorganisms would be at increased risk for candidal vaginitis as a consequence of the induction candidal vaginitis as a consequence of the induction of PGE2 production. Because of the existence of a of PGE2 production. Because of the existence of a countercurrent vascular system supplying the countercurrent vascular system supplying the genital organs, potential allergens may accumulate genital organs, potential allergens may accumulate preferentially in the vagina”preferentially in the vagina”– Witkin, S. Immunologic Factors Influencing Susceptibility Witkin, S. Immunologic Factors Influencing Susceptibility

to Recurrent Candidal Vaginitis Clinical Obstetrics & to Recurrent Candidal Vaginitis Clinical Obstetrics & Gynecology 34: 662-668, 1991Gynecology 34: 662-668, 1991. .


““These data suggest that there are These data suggest that there are twotwo kinds of kinds of allergic recurrent Candida vaginitis:allergic recurrent Candida vaginitis:– (1) primarily due to Candida hypersensitivity(1) primarily due to Candida hypersensitivity– (2) secondary to other types of vaginal allergy, such (2) secondary to other types of vaginal allergy, such

as pollen, semen, and latexas pollen, semen, and latexMoraes, P. Allergic Vulvovaginitis, Annals of Allergy 2000. Moraes, P. Allergic Vulvovaginitis, Annals of Allergy 2000.

Candida and Allergic VaginitisCandida and Allergic VaginitisClinical CasesClinical Cases

Woman with recurrent yeast vaginitis, who has Woman with recurrent yeast vaginitis, who has chronic symptoms helped with zyrtec and singulair; chronic symptoms helped with zyrtec and singulair; major flare-up in June. Found to be grass allergic. major flare-up in June. Found to be grass allergic.

Woman (biology teacher) mushroom picking with Woman (biology teacher) mushroom picking with class, and comes back from activity and has prompt, class, and comes back from activity and has prompt, severe vaginal itching and clear dischargesevere vaginal itching and clear discharge

Woman with recurrent Christmas-time yeast vaginitis, Woman with recurrent Christmas-time yeast vaginitis, tracked down to clementine oranges. Eating for 1 tracked down to clementine oranges. Eating for 1 day: vaginal itchingday: vaginal itching

Eating for 2 days: vaginal itching & clear dischargeEating for 2 days: vaginal itching & clear discharge

Eating for 3 days: yeast vaginitisEating for 3 days: yeast vaginitis

Candida and Allergic VaginitisCandida and Allergic VaginitisImmunotherapy Immunotherapy

For allergic vulvovaginitis due to pollens or house For allergic vulvovaginitis due to pollens or house dust mites, a series of case reports shows important dust mites, a series of case reports shows important Improvement of symptoms after immunotherapy for Improvement of symptoms after immunotherapy for vaginitis due to pollens or house dust mites vaginitis due to pollens or house dust mites

For allergic vaginitis due to primary Candida sensitivity, For allergic vaginitis due to primary Candida sensitivity, there are five case reports and five open studies, there are five case reports and five open studies, including 177 patients with recurrent vaginal candidiasis including 177 patients with recurrent vaginal candidiasis who had been prescribed Candida albicans allergen who had been prescribed Candida albicans allergen immunotherapy. Improvement rates from 65% to 80%. immunotherapy. Improvement rates from 65% to 80%.

Candida and Allergic VaginitisCandida and Allergic VaginitisImportant PointsImportant Points

Many patients with recurrent yeast vaginitis have Many patients with recurrent yeast vaginitis have chronic, low grade vaginal itching and clear discharge chronic, low grade vaginal itching and clear discharge between episodes of infectionsbetween episodes of infections

Patients with allergic vaginitis may note a predilection in Patients with allergic vaginitis may note a predilection in infections or vaginal symptoms during allergy seasonsinfections or vaginal symptoms during allergy seasons

Every allergy patient deserves a gynecological history, Every allergy patient deserves a gynecological history, with attention towards recurrent vaginal infections or with attention towards recurrent vaginal infections or symptomssymptoms

Every woman with chronic vaginitis deserves to be Every woman with chronic vaginitis deserves to be screened for allergic diseasescreened for allergic disease

What about Candida What about Candida Sensitization Sensitization outside of outside of

localized organs? localized organs?

An Illness in Search of a NameAn Illness in Search of a NameCandidiasisCandidiasis

Systemic CandidiasisSystemic Candidiasis

Candida sensitivity/hypersensitivityCandida sensitivity/hypersensitivity

““The Yeast Connection” (Crook)The Yeast Connection” (Crook)

Superficial Candidiasis Syndrome (Truss)Superficial Candidiasis Syndrome (Truss)

Chronic Candidiasis sensitivity syndrome Chronic Candidiasis sensitivity syndrome (Kroker)(Kroker)

Fungal-type Dysbiosis (Eaton)Fungal-type Dysbiosis (Eaton)

Systemic Candida-Related SensitizationSystemic Candida-Related Sensitization

Systemic Candida SensitizationSystemic Candida Sensitization

First described by C. First described by C. Orian Truss, MD in Orian Truss, MD in J Ortho Psych 7:17-J Ortho Psych 7:17-37,197837,1978

Later wrote “The Later wrote “The Missing Diagnosis” Missing Diagnosis”


Concept broadened by Concept broadened by Crook, who wrote “The Crook, who wrote “The Yeast Connection”Yeast Connection”


DefinitionDefinition::– The occurrence of a polysymptomatic The occurrence of a polysymptomatic

complex typically involving (among others) complex typically involving (among others) fatigue, cognitive impairment, gastrointestinal fatigue, cognitive impairment, gastrointestinal distress and sugar cravings coinciding with distress and sugar cravings coinciding with signs and symptoms of significant Candida signs and symptoms of significant Candida colonization and often accompanied by a colonization and often accompanied by a sensitivity to molds and yeast related sensitivity to molds and yeast related products. products.

Systemic Candida Sensitization—Systemic Candida Sensitization—Clinical PresentationClinical Presentation

Signs of excessive Candida colonizationSigns of excessive Candida colonization::– recurrent yeast vaginitisrecurrent yeast vaginitis– thrushthrush– bloating, gas, intestinal upsetbloating, gas, intestinal upset

Signs of systemic illness:Signs of systemic illness:– chronic fatigue, cognitive dysfunctionchronic fatigue, cognitive dysfunction– aching, malaiseaching, malaise– intense cravings for refined carbs, sugarsintense cravings for refined carbs, sugars– gastrointestinal complaints (irritable bowel syndrome)gastrointestinal complaints (irritable bowel syndrome)– increased sensitivity to molds and chemicals increased sensitivity to molds and chemicals – reduced tolerance to alcoholic beveragesreduced tolerance to alcoholic beverages

Systemic Candida SensitizationSystemic Candida SensitizationChronic Candidiasis and AllergyIn Food Allergy and Intolerance, Brostoff, Ed, 1st Edition


Keith Eaton, MdDefinitive review of Candida related illness2nd Edition: Food Allergy & Intolerance, Brostoff, ed 2002

Systemic Candida SensitizationSystemic Candida SensitizationMedical Literature: 3 studiesMedical Literature: 3 studies

Dismukes, WE et al: A randomized, double blind trial of Dismukes, WE et al: A randomized, double blind trial of nystatin therapy for the candidiasis hypersensitivity nystatin therapy for the candidiasis hypersensitivity syndrome. N Engl J Med 323: 1717-1723, 1990. syndrome. N Engl J Med 323: 1717-1723, 1990.

Santelmann, H et al: Effectiveness of nystatin in Santelmann, H et al: Effectiveness of nystatin in polysymptomatic patients. A randomized, double-blind polysymptomatic patients. A randomized, double-blind trial with nystatin versus placebo in general practice. trial with nystatin versus placebo in general practice. Fam Prac 18: 258-265, 2001.Fam Prac 18: 258-265, 2001.

Truss, CO et al: Generalized symptoms in women with Truss, CO et al: Generalized symptoms in women with chronic yeast vaginitis: treatment with nystatin, diet, and chronic yeast vaginitis: treatment with nystatin, diet, and immunotherapy versus nystatin alone. J Advancement immunotherapy versus nystatin alone. J Advancement Med 5: 139-175, 1992. Med 5: 139-175, 1992.

Systemic Candida SensitizationSystemic Candida SensitizationGood Medical Literature ReviewGood Medical Literature Review

Crandall M. Allergic Predisposition in Crandall M. Allergic Predisposition in Recurrent Vulvovaginal Candidiasis. J. Recurrent Vulvovaginal Candidiasis. J. Adv. Med. 4:21-38, 1991Adv. Med. 4:21-38, 1991

Crandall M. The Pathogenic Significance Crandall M. The Pathogenic Significance of Intestinal Candida Colonization. Intl. J. of Intestinal Candida Colonization. Intl. J. Hygiene Environ Health 207: 79-81 (letter Hygiene Environ Health 207: 79-81 (letter to editor)to editor)


Criteria for developing illnessCriteria for developing illness– Clinical conditions to permit excessive yeast Clinical conditions to permit excessive yeast

colonizationcolonization::Recurrent antibioticsRecurrent antibiotics

Recurrent high-dose steroidsRecurrent high-dose steroids

Diet high in refined sugarsDiet high in refined sugars

– Immune system predisposed to dysregulation Immune system predisposed to dysregulation (i.e., over activity to chronic antigen (i.e., over activity to chronic antigen presentation)presentation)

Past history of classical allergic diseasePast history of classical allergic disease

Systemic Candida SensitizationSystemic Candida SensitizationPatterns of DevelopmentPatterns of Development

undiagnosed “simple” allergy(i.e., dust, milk)

recurrent infections

frequent antibiotic use

increased Candida colonization

increased sugar ingestion

Candida Sensitization

Target Organ

Target Organ

Target Organ

Systemic Candida SensitizationSystemic Candida SensitizationCommon Presentation for ENT’sCommon Presentation for ENT’s

History of significant Mold allergy

recurrent infections

frequent antibiotic use

increased Candida colonization

increased sugar ingestion

Candida Sensitization

Target Organ

Target Organ

Target Organ

Systemic Candida SensitizationSystemic Candida SensitizationDiagnosisDiagnosis

HistoryHistory of paramount importance of paramount importance

Crook QuestionnaireCrook Questionnaire

Developed by William Crook MDDeveloped by William Crook MD

Extensive, 70 question assessmentExtensive, 70 question assessment

Very sensitive, but not specificVery sensitive, but not specific

False positives often from food False positives often from food sensitivities, or other allergiessensitivities, or other allergies

False positives from other chronic False positives from other chronic illnessesillnesses

Fungus Related Disease Fungus Related Disease Questionnaire (FRDQ-7)Questionnaire (FRDQ-7)

In an open study of 380 undiagnosed In an open study of 380 undiagnosed polysymptomatic subjects, Santelmann polysymptomatic subjects, Santelmann compared the effect of diet and antifungal compared the effect of diet and antifungal treatment with the responses to the Crook treatment with the responses to the Crook QuestionnaireQuestionnaire

He used discrimination analysis to identify He used discrimination analysis to identify seven questions that were the most seven questions that were the most strongly predictive of treatment responsestrongly predictive of treatment response

Fungus Related Disease Fungus Related Disease Questionnaire (FRDQ-7)Questionnaire (FRDQ-7)

Fungal Related Disease Questionnaire (FRDQ-7)Fungal Related Disease Questionnaire (FRDQ-7)

Candida History—3 Key pointsCandida History—3 Key points

SignsSigns of excessive Candida colonization of excessive Candida colonization::– recurrent yeast vaginitis, thrush, bloating & gasrecurrent yeast vaginitis, thrush, bloating & gas

ReasonsReasons in for excessive Candida colonization in for excessive Candida colonization--antibiotics, steroids, sugar--antibiotics, steroids, sugar

Manifestations of Manifestations of systemic illnesssystemic illness::– chronic fatigue, aching, CNS, PMS, sugar cravingschronic fatigue, aching, CNS, PMS, sugar cravings– Increased sensitivity to molds & chemicalsIncreased sensitivity to molds & chemicals– intense cravings for refined carbs, sugarsintense cravings for refined carbs, sugars– Sensitivity/intolerance to alcoholic beveragesSensitivity/intolerance to alcoholic beverages


History of paramount importanceHistory of paramount importance

Abnormal reactivity (immediate/delayed) to Abnormal reactivity (immediate/delayed) to intradermal intradermal Candida skin testCandida skin test– Inappropriate immediate reactivityInappropriate immediate reactivity– Inappropriate delayed reactivityInappropriate delayed reactivity

Candida Skin Test at 48 hoursCandida Skin Test at 48 hoursPatient with Systemic Candida SensitizationPatient with Systemic Candida Sensitization


History of paramount importanceHistory of paramount importance

Abnormal reactivity (immediate/delayed) to Abnormal reactivity (immediate/delayed) to intradermal Candida skin testintradermal Candida skin test– Inappropriate immediate reactivityInappropriate immediate reactivity– Inappropriate delayed reactivityInappropriate delayed reactivity

Elevation in Serum IgG CandidaElevation in Serum IgG Candida

Elevation of Candida IgG Antibodies in Patients with Elevation of Candida IgG Antibodies in Patients with Medically Unexplained SymptomsMedically Unexplained Symptoms

Lewith, G. et al Lewith, G. et al J of Alternative & Complementary MedicineJ of Alternative & Complementary Medicine

Vol 13:1129-1133, 2007Vol 13:1129-1133, 2007

Compared IgG antibody measurements Compared IgG antibody measurements between population with high FRDQ-7 between population with high FRDQ-7 scores and symptom-free controlsscores and symptom-free controls


““Gold Standard”: Gold Standard”: Clinical response to a 2-Clinical response to a 2-4 week trial of sugar/yeast free diet and 4 week trial of sugar/yeast free diet and antifungal medicationantifungal medication

Systemic Candida SensitizationSystemic Candida SensitizationComorbid conditions often foundComorbid conditions often found

Mold allergy, food yeast allergyMold allergy, food yeast allergy

ThyroiditisThyroiditis

Multiple food sensitivities secondary to Multiple food sensitivities secondary to increased intestinal permeabilityincreased intestinal permeability

Nutritional deficienciesNutritional deficiencies– magnesiummagnesium– fatty acidsfatty acids

Systemic Candida SensitizationSystemic Candida SensitizationThe “Candida-Mold-Yeast Triad” The “Candida-Mold-Yeast Triad”

Candida Sensitivity

Food Yeast SensitivityMold Sensitivity

Candida Sensitization and Mold Candida Sensitization and Mold Allergy: The ConnectionAllergy: The Connection

An intimate connection between Candida An intimate connection between Candida sensitivity and mold sensitivitysensitivity and mold sensitivity

““Everything Candida can do (symptomatically), Everything Candida can do (symptomatically), mold can do, and visa-versa” mold can do, and visa-versa”

Heavy mold exposure can trigger Candida Heavy mold exposure can trigger Candida sensitization; heavy Candida colonization can sensitization; heavy Candida colonization can trigger mold sensitization trigger mold sensitization

Candida Sensitization & Mold Candida Sensitization & Mold Allergy: The ConnectionAllergy: The Connection

Heavy Mold Colonization & sensitization Candida Sensitization

Example: 24 yr old woman working in basement television studiothat flooded. Heavy mold exposure. Became sick, exhausted, headachy. She and coworkers left jobsite and moved to anotherbuilding. All coworkers became well except for her

Heavy Candida Colonization & Sensitization

Mold Sensitization

Example: 31 yr old woman moves into musty home with overt mold contamination. Has had pre-existing yeast vaginitis, gastrointestinal bloating, and thrush. She rapidly becomes ill in the home with increasing sinus congestion & headaches; no other family members affected

Role of Antibiotics & Fungal Microbiota Role of Antibiotics & Fungal Microbiota in Driving Pulmonary Allergic Responsesin Driving Pulmonary Allergic Responses

Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003

Mouse model of antibiotic-induced GI microbial Mouse model of antibiotic-induced GI microbial disruption with C. albicans excess; followed by disruption with C. albicans excess; followed by nasal challenge to moldnasal challenge to mold

Mice easily developed T cell mediated allergic Mice easily developed T cell mediated allergic airway response in lungs to subsequent nasal airway response in lungs to subsequent nasal mold exposure mold exposure without previous systemic without previous systemic antigen primingantigen priming

Effect is Effect is absentabsent in mice challenged with mold in mice challenged with mold notnot receiving chronic antibiotic administration receiving chronic antibiotic administration

Role of Antibiotics & Fungal Microbiota in Role of Antibiotics & Fungal Microbiota in Driving Pulmonary Allergic Responses Driving Pulmonary Allergic Responses

Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003

““These studies indicate that increased numbers of These studies indicate that increased numbers of yeast cells in the microbiota can be a contributing yeast cells in the microbiota can be a contributing factor in up-regulating Th2 responses to antigen factor in up-regulating Th2 responses to antigen exposure in the lungs. In these studies, Candida exposure in the lungs. In these studies, Candida was never isolated from the lungs…these studies was never isolated from the lungs…these studies highlight the concept that events in distal mucosal highlight the concept that events in distal mucosal sites such as the GI tract can play an important sites such as the GI tract can play an important role in regulating immune responses in the lungs”role in regulating immune responses in the lungs”““We have presented a model of a clinically We have presented a model of a clinically feasible, common scenario that occurs for a feasible, common scenario that occurs for a number of humans: antibiotic treatment followed number of humans: antibiotic treatment followed by a non life-threatening low grade increase in by a non life-threatening low grade increase in fungal microbiota…”fungal microbiota…”

Systemic Candida Sensitization and Systemic Candida Sensitization and increased intestinal permeabilityincreased intestinal permeability

a fertile ground for food allergy developmenta fertile ground for food allergy development

Systemic Candida colonization promotes Systemic Candida colonization promotes sensitization against food antigens by affecting sensitization against food antigens by affecting the mucosal barrier in micethe mucosal barrier in mice– Yamaguchi N, et al. Gut 55: 954-60, 2006.Yamaguchi N, et al. Gut 55: 954-60, 2006.

Gut permeability measured by polyethylene Gut permeability measured by polyethylene glycol absorption in abnormal gut fermentation glycol absorption in abnormal gut fermentation as compared with food intoleranceas compared with food intolerance– Eaton, K. et al J Roy Soc Med 68: 63-66, Eaton, K. et al J Roy Soc Med 68: 63-66,

19951995

Candida Sensitization and Candida Sensitization and increased intestinal permeabilityincreased intestinal permeability

Candida sensitization (and food allergy) produced identical increases in intestinal permeability

Candida Colonization

Antibiotics Increased RefinedSugar Ingestion

AntigenicProducts

AllergicPredisposition

immunereactionstypes I, III, IV

autoimmunereactions

thyroiditis

metabolic toxins

oxylipinmolecules

Pg E2

Th2/Th1

nutrient deficienciesB6, ZN, Mg

intestinaldamage

egress offood antigens & bacterial LPS into circulation

Target Organ Symptoms

food sensitivities

acetaldehydeethanol, CO2

Candida Sensitization—Candida Sensitization—Endocrine disruptor? Endocrine disruptor?

Majority of female patients have a Majority of female patients have a “premenstrual variant”“premenstrual variant”

Treatment may resolve premenstrual Treatment may resolve premenstrual symptoms, early peri-menopausal symptoms, early peri-menopausal symptoms, and amenorrheasymptoms, and amenorrhea

Progesterone binding protein in cytosol Progesterone binding protein in cytosol

Could Candida bind to hormones, altering Could Candida bind to hormones, altering their shape to make them unable to fit their their shape to make them unable to fit their target receptor? target receptor?

Candida Sensitization--Candida Sensitization--TreatmentTreatment

Two-pronged strategy:Two-pronged strategy:– 1. Down-regulate Candida sensitivity1. Down-regulate Candida sensitivity– 2. Reduce Candida colonization2. Reduce Candida colonization

Treat co-morbid conditions:Treat co-morbid conditions:– Intestinal permeabilityIntestinal permeability– Mold/inhalant sensitivitiesMold/inhalant sensitivities– Secondary food sensitivities, Secondary food sensitivities,

Candida Sensitization Treatment: Candida Sensitization Treatment: Down regulation of sensitivityDown regulation of sensitivity

Apply intradermal skin test to CandidaApply intradermal skin test to Candida– read immediate reaction at 10 minread immediate reaction at 10 min– read delayed reaction at 24, 48 hoursread delayed reaction at 24, 48 hours

Look for abnormal immediate Look for abnormal immediate oror delayed delayed reactivityreactivity

Rx sublingual immunotherapy (SLIT) Rx sublingual immunotherapy (SLIT) based upon immediate based upon immediate andand delayed delayed reactionreaction

Candida Sensitization Treatment:Candida Sensitization Treatment:Lowering Candida ColonizationLowering Candida Colonization

Antifungal medicationAntifungal medication– Azole medications preferred: Azole medications preferred:

fluconazole, ketoconazole, itraconazole fluconazole, ketoconazole, itraconazole – 14 day course, followed by 2/wk suppression14 day course, followed by 2/wk suppression– ““die off” effects can occurdie off” effects can occur– If drug interactions, liver toxicity a concern, use If drug interactions, liver toxicity a concern, use

nystatin tabletsnystatin tablets

Probiotic administrationProbiotic administration– 10-25 billion units/day minimum10-25 billion units/day minimum

Low refined carbohydrate, low yeast dietLow refined carbohydrate, low yeast diet

Candida Sensitization Treatment:Candida Sensitization Treatment:“Die Off”“Die Off”

““Die off” (Herxheimer) reactionDie off” (Herxheimer) reaction– Typically occurs in first several days of RxTypically occurs in first several days of Rx– Usually is exaggeration of preexisting ssxUsually is exaggeration of preexisting ssx– New symptoms (i.e., severe rash) suggest a New symptoms (i.e., severe rash) suggest a

drug reaction and not “die off”drug reaction and not “die off”– Depending on severity, reduce dose & continueDepending on severity, reduce dose & continue– Seems worse on nystatin than azole RxSeems worse on nystatin than azole Rx

Sugar cravings subside in 3-5 daysSugar cravings subside in 3-5 days

Treating Elevated Intestinal PermeabilityTreating Elevated Intestinal Permeability

Eliminate usage of NSAIDs, AlcoholEliminate usage of NSAIDs, Alcohol

Eliminate primary food allergensEliminate primary food allergens

Eliminate Candida colonizationEliminate Candida colonization

Utilization of probioticsUtilization of probiotics

Utilization of L-glutamine, 3-4 gm bidUtilization of L-glutamine, 3-4 gm bid

Note: a sign of improvement is Note: a sign of improvement is improvement in food allergiesimprovement in food allergies

What about the Candida patient who What about the Candida patient who doesn’tdoesn’t improve on antifungal Rx and diet?improve on antifungal Rx and diet?

Some Common Causes Some Common Causes

Major indoor mold exposure at home/workMajor indoor mold exposure at home/work

Allergic to another food in yeast/sugar free Allergic to another food in yeast/sugar free dietdiet

Other comorbid medical illness (lyme’s Other comorbid medical illness (lyme’s disease, thyroiditis, heavy metal toxicity)disease, thyroiditis, heavy metal toxicity)

Intercurrent illness requiring antibioticsIntercurrent illness requiring antibiotics

Poor dietary compliancePoor dietary compliance

Back to the case !Back to the case !

Case History

C.G., a 39 y/o R.N. from Duluth MN , is referred from her gynecologist for allergy assessmentChronic headaches, daily for 1 yearExhaustion, fatigue in AM on awakeningEpisodic migraine headaches, – Require frequent ER treatment– Variety of meds tried: lortabs, imitrex, etc.

Chronic rhinitis; headaches worse in fallChronic recurrent yeast vaginitis – Increasing frequency for 1 year PTA

Premenstrual syndrome: bloating, fatigue, CNS

moldCandida

Case History (cont)Case History (cont)

Recurrent antibiotic use thru childhood for Recurrent antibiotic use thru childhood for chronic pharyngitis chronic pharyngitis

Antibiotics twice this year for respiratory Antibiotics twice this year for respiratory infections during fall seasoninfections during fall season

Premenstrually c/o fatigue, cravings for Premenstrually c/o fatigue, cravings for chocolatechocolate

Preexisting allergies

Candida

Mold

Case History (cont.)—Diet history

craves sugars, esp chocolate

Favorite foods: bagels, bread/rolls, chocolate

Milk gives stomach upset

At risk for milk and wheat allergy dueTo probable leaky gut from Candida

Case History--Environmental

Dusting causes sneezing

Headaches worse in Fall

3 cats at home

Musty odor in basement

Check out dust, cat, mold allergy

Working HypothesisChronic childhood allergies

Occult allergens (?milk, cat, dust)

Recurrent resp infections/childhood

Increased Candida Carriage

Intestinal permeability

Food sensitivities(? Dairy, wheat)

Yeast infections

Candida sensitization Mold allergy

Target organs

antibiotics

Recurrent ENT Infections

Case History—Intradermal TestingCase History—Intradermal Testing

Antigen Tested Immediate Rxn Delayed Rxn

Dust mite + ++

Alternaria + +++

Cladosporium + +++

Aspergillus + +++

Spring Pollens - -

Fall Pollens - -

Cat ++ -

Case History—Food TestingCase History—Food Testing

Antigen Result

Milk challenge Fatigue, aching

Wheat challenge Nausea, cognition impaired

Yeast challenge Fatigue, cognition impaired

Corn challenge No reaction

Case History—Candida TestingCase History—Candida Testing

Test Result

Intradermal Candida--immed Negative

Intradermal Candida--delayed ++++

Serum IgG to Candida 60% elevated above neg control

Case HistoryCase History

Allergy Reaction = Sensitivity x Load

Case History--TreatmentCase History--Treatment

Reduce allergic Reduce allergic sensitivitysensitivity– SLIT: dust, mold, catSLIT: dust, mold, cat– SLIT: wheat, yeast, milkSLIT: wheat, yeast, milk

Reduce allergic Reduce allergic loadload– Hypoallergenic diet—elim dairy, wheat, yeast, Hypoallergenic diet—elim dairy, wheat, yeast,

refined sugarrefined sugar– Diflucan 100 mg daily x 14 daysDiflucan 100 mg daily x 14 days– probioticsprobiotics


Patient returned to clinic 3 weeks laterPatient returned to clinic 3 weeks later

Dramatic improvement in healthDramatic improvement in health– No headachesNo headaches– No PMSNo PMS– Daily rhinitis, congestion better (but not gone)Daily rhinitis, congestion better (but not gone)– Less fatigueLess fatigue


Treated for 4 years with SLIT, then Treated for 4 years with SLIT, then discontinued after remission obtained discontinued after remission obtained

In remission and did well for next 7 yearsIn remission and did well for next 7 years

Returned to clinic Oct 2007 for Returned to clinic Oct 2007 for reassessmentreassessment

Candida sensitivity relapse following heavy Candida sensitivity relapse following heavy antibiotic usage for chronic dental antibiotic usage for chronic dental problems, stress, increasing carbohydrate problems, stress, increasing carbohydrate intakeintake

Clinical Pearls Clinical Pearls

Every woman with mold allergy, and chronic antibiotic Every woman with mold allergy, and chronic antibiotic use (sinusitis, UTI, etc.) who has chronic symptoms is use (sinusitis, UTI, etc.) who has chronic symptoms is Candida sensitive until proven otherwiseCandida sensitive until proven otherwise

In every patient with mold allergy, think about Candida In every patient with mold allergy, think about Candida and food yeast sensitivity (“the yeast triad”)and food yeast sensitivity (“the yeast triad”)

In a patient with loss of food intolerance shortly after In a patient with loss of food intolerance shortly after antibiotic use, think about Candida antibiotic use, think about Candida

The Mystery of Candida Sensitivity: The Mystery of Candida Sensitivity: Unanswered Questions Unanswered Questions

What is the exact pathogenesis behind What is the exact pathogenesis behind locallocal mucosal mucosal Candida colonization causing ssx in Candida colonization causing ssx in distantdistant organs? organs?

Can we develop a test with high specificity and Can we develop a test with high specificity and sensitivity that can accurately sensitivity that can accurately diagnosediagnose the condition? the condition?

Can we develop Can we develop prognostic indicators prognostic indicators for long-term for long-term improvement? I.E. is there a test we can follow with Rx?improvement? I.E. is there a test we can follow with Rx?

Can we arrive at a consensus on the best Can we arrive at a consensus on the best dietdiet for a for a Candida patient? Candida patient?

"The most beautiful thing we can experience is the mysterious. It is the source of all true art and all science”

--Albert Einstein

The fairest thing we can experience is the mysterious. It is the fundamental emotion which stands at the cradle of true science

--Hans Selye

the spectrum of candida related disorders: an allergist’s 33 yr perspective george f kroker md...

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