The Spectrum of Candida Related Disorders: An Allergist’s 33 yr Perspective George F Kroker MD Allergy Associates of La Crosse Case History C.G., a 39 y/o R.N. from Duluth MN , is referred from her gynecologist for allergy assessment Chronic headaches, daily for 1 year Exhaustion, fatigue on awakening in AM Episodic migraine headaches, – Require frequent ER treatment – Variety of meds tried: lortabs, imitrex, etc. Chronic rhinitis & sinus headaches--worse in fall c/o chronic recurrent yeast vaginitis – Increasing frequency for 1 year PTA Premenstrual syndrome: bloating, fatigue, CNS Case History (cont) Recurrent antibiotic use thru childhood for chronic pharyngitis Antibiotics twice this year for respiratory infections during fall season Premenstrually c/o fatigue, cravings for chocolate Case History: Patient Goals “Help my energy” “I want to feel normal” “Help my headaches” “I don’t want to keep having yeast infections” “I don’t want to be sick every fall” “What’s going on with me?” What’s wrong with this patient? How do I approach her allergy evaluation and treatment? Candida-related Disorders Infectious – Cutaneous intertriginous candidiasis onychia/paronychia candida granuloma – Mucocutaneous oral: thrush, glossitis, cheilitis, stomatitis genital: vaginitis, balanitis alimentary: esophagitis, enteric, perianal – Systemic urinary, cardiovascular, central nervous system, blood, etc. Candida-related disorders Is this the complete list of pathogenic Candida disorders?? The Tomato Effect: Rejection of Highly Efficacious Therapies Because They “don’t make sense and we know they can’t be true” Goodwin, JS & Goodwin JM, JAMA 251: 2387-2390, 1984 Candida Albicans Candida is a heterogeneous genus grouped with Fungi Imperfecti 80 species; 6 species pathogenic Candida albicans polyantigenic – two cell wall antigens: mannan & glucan – 77 cytoplasmic antigens; 1 mycelial antigen – each strain of Candida has 30-35 of these antigens Candida Albicans Characterization of IgE-binding epitopes on Candida albicans enolase – Ito K, Ishiguro A, Kanbe T, Tanaka, T, Torri S – Clin Exp Allergy 25:529-35, 1995 Detection of IgE antibody against Candida albicans enolase and its crossreactivity to Saccharomyces cerevisiae enolase – Ito K, Ishiguro A, Kanbe T, Tanaka K, Torri S – Clin Exp Allergy 25:522-8, 1995 Candida-related Disorders Infectious – Cutaneous intertriginous candidiasis onychia/paronychia candida granuloma – Mucocutaneous oral: thrush, glossitis, cheilitis, stomatitis genital: vaginitis, balanitis alimentary: esophagitis, enteric, perianal – Systemic urinary, cardiovascular, central nervous system, blood, etc. Candida-related Disorders: A more complete list Infectious Infectious/immunologic – Chronic mucocutaneous candidiasis – Allergic Fungal Sinusitis Sensitivity Disorders – Localized Sensitvity Urticaria Irritable bowel Syndrome Allergic vaginitis – Generalized Sensitivity Candida Sensitivity Syndrome Candida Sensitivity Disorders Localized Sensitivity – urticaria Candida & Chronic Urticaria An assessment of the role of Candida albicans and food yeasts in chronic urticaria. James, J & Warin RP BR J Dermatology 84:227-237, 1971. – 100 pts with chronic urticaria – 36% (36 pts) positive prick Candida – 3/36 responded to medication (nystatin) – 23/36 responded to med & yeast-free diet Candida and Chronic Urticaria Holti, G: Candida allergy. In: Winner HI, Hurley R, eds. Symposium on Candida infections. Edinburgh and London: E& S Livingstone 1966; 74-81. – 255 patients with chronic urticaria – 49 (19%) had positive prick to Candida – 27 (11%) had positive prick to food yeast – Rx nystatin x3 weeks cured 27/49 patients – 18 pts required med plus yeast-free diet Candida and Chronic Urticaria: Clinical Correlates Patient on multiple antibiotics who gradually develops longstanding urticaria Patient with chronic urticaria who has other signs of overt Candida overgrowth— i.e., recurrent yeast vaginitis Patient with chronic urticaria known to be sensitive to yeast-containing foods or mold Candida Sensitivity Disorders Localized Sensitivity – Urticaria – Irritable bowel syndrome 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 Syndr “At least 3 different Candida species are able to produce proteases which can degrade IgA1, IgA2, and SIgA. This protease activity can induce polyclonal Bcell response and inflammation. An infection of the intestinal mucosa with Candia might lead to an inactivating of SIgA and inflammation within subgroups of patients with IBS symptoms.” Candida & Irritable Bowel Syndr “It was shown recently that there is a potential cross reactivity with gluten because of several amino acid sequences (in the Candia cell wall) that are highly homologous to alpha-gliadin and gamma gliadin. Such a mechanism might lead to wheat intolerance with its accompanying symptoms and even trigger celiac disease in genetically susceptible people.” Candida & Irritable Bowel Syndr “Candida can be cultured from faeces in up to 80% of healthy adults ” “Unfortunately, there is no accepted “gold standard” for distinguishing between a yeast sensitivity condition and a yeast overgrowth in the gut… Candida & Irritable Bowel Syndr “Candida can produce alcohols and contains glycoproteins which have the potential to stimulate mast cells to release histamine and apparently PGE2 inflammatory substances which could cause IBS Ssx” “…there is increasing evidence for yeasts being able to cause IBS symptoms in sensitized patients via Candida products, antigens, and cross-antigens Candida & Irritable Bowel: Clinical Correlates The celiac patient who still has symptoms or persistently high TTG levels may have Candida issues The patient with known IBS who markedly worsens following antibiotic use may have Candida issues The patient with IBS, and known wheat or yeast intolerance may have Candida issues Candida Sensitivity Disorders Localized Sensitivity – Urticaria – Irritable bowel syndrome – Allergic Vaginitis Candida and Allergic Vaginitis There is a strong association between atopy and recurrent vaginal candidiasis A history of atopy (68%) and positive skin testing to aeroallergens (42%) was higher in recurrent vaginal candidiasis than in patients with sporadic vaginal candidiasis (p<.05) – Neves, NA, De Oliveira, MA et al. J Exp Immunol 142: 167-171, 2005. Candida and Allergic Vaginitis A significant number of women with recalcitrant yeast vaginitis are found to have IgE antibodies in their vaginal fluid but not in their sera Vaginal IgE sometimes directed against C. albicans, perennial ryegrass, spermicides – Witkin, S. Jeremias, AB, Ledger J. A localized vaginal allergic response in women with recurrent vaginitis. JACI 81: 412-416, 1988 Candida and Allergic Vaginitis Allergic Vulvovaginitis Moraes, Paula & Taketomi, Ernesto T Annals of Allergy 85: 253-265, 2000. Candida and Allergic Vaginitis “Exposure to allergen in the vaginal lumen is followed by the transport of this allergen through the interepithelial channels and its interaction with mast cell-bound specific IgE” “Mast cell degranulation and the release of histamine and other inflammatory mediators causing symptoms of allergic vaginitis” “Histamine is a potent inducer of PGE2 from macrophages which suppresses cell-mediated immune response…the resulting symptomatic candidal vaginitis would be a secondary consequence to a primary allergic vaginitis” Candida and Allergic Vaginitis Stress Beta Endorphin Allergen exposure IgE mediated vaginal rxn Histamine Macrophage production of PgE2 Inhibition of IL-2 production Impaired lymphocyte proliferation Against Candida Candida Vaginitis Candida Allergy Candida and Allergic Vaginitis “Women with immediate hypersensitivity reactions to medications, environmental allergens, or microorganisms would be at increased risk for candidal vaginitis as a consequence of the induction of PGE2 production. Because of the existence of a countercurrent vascular system supplying the genital organs, potential allergens may accumulate preferentially in the vagina” – Witkin, S. Immunologic Factors Influencing Susceptibility to Recurrent Candidal Vaginitis Clinical Obstetrics & Gynecology 34: 662-668, 1991. Candida and Allergic Vaginitis “These data suggest that there are two kinds of allergic recurrent Candida vaginitis: – (1) primarily due to Candida hypersensitivity – (2) secondary to other types of vaginal allergy, such as pollen, semen, and latex Moraes, P. Allergic Vulvovaginitis, Annals of Allergy 2000. Candida and Allergic Vaginitis Clinical Cases Woman with recurrent yeast vaginitis, who has chronic symptoms helped with zyrtec and singulair; major flare-up in June. Found to be grass allergic. Woman (biology teacher) mushroom picking with class, and comes back from activity and has prompt, severe vaginal itching and clear discharge Woman with recurrent Christmas-time yeast vaginitis, tracked down to clementine oranges. Eating for 1 day: vaginal itching Eating for 2 days: vaginal itching & clear discharge Eating for 3 days: yeast vaginitis Candida and Allergic Vaginitis Immunotherapy For allergic vulvovaginitis due to pollens or house dust mites, a series of case reports shows important Improvement of symptoms after immunotherapy for vaginitis due to pollens or house dust mites For allergic vaginitis due to primary Candida sensitivity, there are five case reports and five open studies, including 177 patients with recurrent vaginal candidiasis who had been prescribed Candida albicans allergen immunotherapy. Improvement rates from 65% to 80%. Candida and Allergic Vaginitis Important Points Many patients with recurrent yeast vaginitis have chronic, low grade vaginal itching and clear discharge between episodes of infections Patients with allergic vaginitis may note a predilection in infections or vaginal symptoms during allergy seasons Every allergy patient deserves a gynecological history, with attention towards recurrent vaginal infections or symptoms Every woman with chronic vaginitis deserves to be screened for allergic disease What about Candida Sensitization outside of localized organs? An Illness in Search of a Name Candidiasis Systemic Candidiasis Candida sensitivity/hypersensitivity “The Yeast Connection” (Crook) Superficial Candidiasis Syndrome (Truss) Chronic Candidiasis sensitivity syndrome (Kroker) Fungal-type Dysbiosis (Eaton) Systemic Candida-Related Sensitization Systemic Candida Sensitization First described by C. Orian Truss, MD in J Ortho Psych 7:1737,1978 Later wrote “The Missing Diagnosis” Systemic Candida Sensitization Concept broadened by Crook, who wrote “The Yeast Connection” Systemic Candida Sensitization Definition: – The occurrence of a polysymptomatic complex typically involving (among others) fatigue, cognitive impairment, gastrointestinal distress and sugar cravings coinciding with signs and symptoms of significant Candida colonization and often accompanied by a sensitivity to molds and yeast related products. Systemic Candida Sensitization— Clinical Presentation Signs of excessive Candida colonization: – recurrent yeast vaginitis – thrush – bloating, gas, intestinal upset Signs of systemic illness: – – – – – – chronic fatigue, cognitive dysfunction aching, malaise intense cravings for refined carbs, sugars gastrointestinal complaints (irritable bowel syndrome) increased sensitivity to molds and chemicals reduced tolerance to alcoholic beverages Systemic Candida Sensitization Chronic Candidiasis and Allergy In Food Allergy and Intolerance, Brostoff, Ed, 1st Edition Systemic Candida Sensitization Keith Eaton, Md Definitive review of Candida related illness 2nd Edition: Food Allergy & Intolerance, Brostoff, ed 2002 Systemic Candida Sensitization Medical Literature: 3 studies Dismukes, WE et al: A randomized, double blind trial of nystatin therapy for the candidiasis hypersensitivity syndrome. N Engl J Med 323: 1717-1723, 1990. Santelmann, H et al: Effectiveness of nystatin in polysymptomatic patients. A randomized, double-blind trial with nystatin versus placebo in general practice. Fam Prac 18: 258-265, 2001. Truss, CO et al: Generalized symptoms in women with chronic yeast vaginitis: treatment with nystatin, diet, and immunotherapy versus nystatin alone. J Advancement Med 5: 139-175, 1992. Systemic Candida Sensitization Good Medical Literature Review Crandall M. Allergic Predisposition in Recurrent Vulvovaginal Candidiasis. J. Adv. Med. 4:21-38, 1991 Crandall M. The Pathogenic Significance of Intestinal Candida Colonization. Intl. J. Hygiene Environ Health 207: 79-81 (letter to editor) Systemic Candida Sensitization Criteria for developing illness – Clinical conditions to permit excessive yeast colonization: Recurrent antibiotics Recurrent high-dose steroids Diet high in refined sugars – Immune system predisposed to dysregulation (i.e., over activity to chronic antigen presentation) Past history of classical allergic disease Systemic Candida Sensitization Patterns 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 Sensitization Common 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 Sensitization Diagnosis History of paramount importance Crook Questionnaire Developed by William Crook MD Extensive, 70 question assessment Very sensitive, but not specific False positives often from food sensitivities, or other allergies False positives from other chronic illnesses Fungus Related Disease Questionnaire (FRDQ-7) In an open study of 380 undiagnosed polysymptomatic subjects, Santelmann compared the effect of diet and antifungal treatment with the responses to the Crook Questionnaire He used discrimination analysis to identify seven questions that were the most strongly predictive of treatment response Fungus Related Disease Questionnaire (FRDQ-7) Fungus Related Disease Questionnaire (FRDQ-7) Fungal Related Disease Questionnaire (FRDQ-7) Candida History—3 Key points Signs of excessive Candida colonization: – recurrent yeast vaginitis, thrush, bloating & gas Reasons in for excessive Candida colonization --antibiotics, steroids, sugar Manifestations of systemic illness: – – – – chronic fatigue, aching, CNS, PMS, sugar cravings Increased sensitivity to molds & chemicals intense cravings for refined carbs, sugars Sensitivity/intolerance to alcoholic beverages Systemic Candida Sensitization Diagnosis History of paramount importance Abnormal reactivity (immediate/delayed) to intradermal Candida skin test – Inappropriate immediate reactivity – Inappropriate delayed reactivity Candida Skin Test at 48 hours Patient with Systemic Candida Sensitization Systemic Candida Sensitization Diagnosis History of paramount importance Abnormal reactivity (immediate/delayed) to intradermal Candida skin test – Inappropriate immediate reactivity – Inappropriate delayed reactivity Elevation in Serum IgG Candida Elevation of Candida IgG Antibodies in Patients with Medically Unexplained Symptoms Lewith, G. et al J of Alternative & Complementary Medicine Vol 13:1129-1133, 2007 Compared IgG antibody measurements between population with high FRDQ-7 scores and symptom-free controls Systemic Candida Sensitization Diagnosis “Gold Standard”: Clinical response to a 24 week trial of sugar/yeast free diet and antifungal medication Systemic Candida Sensitization Comorbid conditions often found Mold allergy, food yeast allergy Thyroiditis Multiple food sensitivities secondary to increased intestinal permeability Nutritional deficiencies – magnesium – fatty acids Systemic Candida Sensitization The “Candida-Mold-Yeast Triad” Candida Sensitivity Mold Sensitivity Food Yeast Sensitivity Candida Sensitization and Mold Allergy: The Connection An intimate connection between Candida sensitivity and mold sensitivity “Everything Candida can do (symptomatically), mold can do, and visa-versa” Heavy mold exposure can trigger Candida sensitization; heavy Candida colonization can trigger mold sensitization Candida Sensitization & Mold Allergy: The Connection 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 Heavy Mold Colonization & sensitization Candida Sensitization Example: 24 yr old woman working in basement television studio that flooded. Heavy mold exposure. Became sick, exhausted, headachy. She and coworkers left jobsite and moved to another building. All coworkers became well except for her Role of Antibiotics & Fungal Microbiota in Driving Pulmonary Allergic Responses Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003 Mouse model of antibiotic-induced GI microbial disruption with C. albicans excess; followed by nasal challenge to mold Mice easily developed T cell mediated allergic airway response in lungs to subsequent nasal mold exposure without previous systemic antigen priming Effect is absent in mice challenged with mold not receiving chronic antibiotic administration Role of Antibiotics & Fungal Microbiota in Driving Pulmonary Allergic Responses Noverr Et al. Infec & Immunity Sept 2004 pp 4996-5003 “These studies indicate that increased numbers of yeast cells in the microbiota can be a contributing factor in up-regulating Th2 responses to antigen exposure in the lungs. In these studies, Candida was never isolated from the lungs…these studies highlight the concept that events in distal mucosal sites such as the GI tract can play an important role in regulating immune responses in the lungs” “We have presented a model of a clinically feasible, common scenario that occurs for a number of humans: antibiotic treatment followed by a non life-threatening low grade increase in fungal microbiota…” Systemic Candida Sensitization and increased intestinal permeability a fertile ground for food allergy development Systemic Candida colonization promotes sensitization against food antigens by affecting the mucosal barrier in mice – Yamaguchi N, et al. Gut 55: 954-60, 2006. Gut permeability measured by polyethylene glycol absorption in abnormal gut fermentation as compared with food intolerance – Eaton, K. et al J Roy Soc Med 68: 63-66, 1995 Candida Sensitization and increased intestinal permeability Candida sensitization (and food allergy) produced identical increases in intestinal permeability Increased Refined Sugar Ingestion Antibiotics Allergic Predisposition Candida Colonization Antigenic Products immune reactions types I, III, IV oxylipin metabolic molecules toxins autoimmune reactions Pg E2 thyroiditis Th2/Th1 intestinal damage acetaldehyde ethanol, CO2 egress of food antigens & bacterial LPS nutrient deficiencies into circulation B6, ZN, Mg food sensitivities Target Organ Symptoms Candida Sensitization— Endocrine disruptor? Majority of female patients have a “premenstrual variant” Treatment may resolve premenstrual symptoms, early peri-menopausal symptoms, and amenorrhea Progesterone binding protein in cytosol Could Candida bind to hormones, altering their shape to make them unable to fit their target receptor? Candida Sensitization-Treatment Two-pronged strategy: – 1. Down-regulate Candida sensitivity – 2. Reduce Candida colonization Treat co-morbid conditions: – Intestinal permeability – Mold/inhalant sensitivities – Secondary food sensitivities, Candida Sensitization Treatment: Down regulation of sensitivity Apply intradermal skin test to Candida – read immediate reaction at 10 min – read delayed reaction at 24, 48 hours Look for abnormal immediate or delayed reactivity Rx sublingual immunotherapy (SLIT) based upon immediate and delayed reaction Candida Sensitization Treatment: Lowering Candida Colonization Antifungal medication – Azole medications preferred: fluconazole, ketoconazole, itraconazole – 14 day course, followed by 2/wk suppression – “die off” effects can occur – If drug interactions, liver toxicity a concern, use nystatin tablets Probiotic administration – 10-25 billion units/day minimum Low refined carbohydrate, low yeast diet Candida Sensitization Treatment: “Die Off” “Die off” (Herxheimer) reaction – Typically occurs in first several days of Rx – Usually is exaggeration of preexisting ssx – New symptoms (i.e., severe rash) suggest a drug reaction and not “die off” – Depending on severity, reduce dose & continue – Seems worse on nystatin than azole Rx Sugar cravings subside in 3-5 days Treating Elevated Intestinal Permeability Eliminate usage of NSAIDs, Alcohol Eliminate primary food allergens Eliminate Candida colonization Utilization of probiotics Utilization of L-glutamine, 3-4 gm bid Note: a sign of improvement is improvement in food allergies What about the Candida patient who doesn’t improve on antifungal Rx and diet? Some Common Causes Major indoor mold exposure at home/work Allergic to another food in yeast/sugar free diet Other comorbid medical illness (lyme’s disease, thyroiditis, heavy metal toxicity) Intercurrent illness requiring antibiotics Poor dietary compliance Back to the case ! Case History C.G., a 39 y/o R.N. from Duluth MN , is referred from her gynecologist for allergy assessment Chronic headaches, daily for 1 year Exhaustion, fatigue in AM on awakening Episodic migraine headaches, – Require frequent ER treatment – Variety of meds tried: lortabs, imitrex, etc. Chronic rhinitis; headaches worse in fall mold Chronic recurrent yeast vaginitis Candida – Increasing frequency for 1 year PTA Premenstrual syndrome: bloating, fatigue, CNS Case History (cont) Recurrent antibiotic use thru childhood for chronic pharyngitis Preexisting allergies Antibiotics twice this year for respiratory infections during fall season Mold Premenstrually c/o fatigue, cravings for chocolate Candida 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 due To 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 Hypothesis Chronic childhood allergies Occult allergens (?milk, cat, dust) Recurrent resp infections/childhood antibiotics Increased Candida Carriage Candida sensitization Yeast infections Mold allergy Intestinal permeability Food sensitivities (? Dairy, wheat) Recurrent ENT Infections Target organs Case History—Intradermal Testing Antigen Tested Immediate Rxn Delayed Rxn Dust mite + ++ Alternaria + +++ Cladosporium + +++ Aspergillus + +++ Spring Pollens - - Fall Pollens - - Cat ++ - Case 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 Testing Test Result Intradermal Candida--immed Negative Intradermal Candida--delayed ++++ Serum IgG to Candida 60% elevated above neg control Case History Allergy Reaction = Sensitivity x Load Case History--Treatment Reduce allergic sensitivity – SLIT: dust, mold, cat – SLIT: wheat, yeast, milk Reduce allergic load – Hypoallergenic diet—elim dairy, wheat, yeast, refined sugar – Diflucan 100 mg daily x 14 days – probiotics Case History Patient returned to clinic 3 weeks later Dramatic improvement in health – No headaches – No PMS – Daily rhinitis, congestion better (but not gone) – Less fatigue Case History Treated for 4 years with SLIT, then discontinued after remission obtained In remission and did well for next 7 years Returned to clinic Oct 2007 for reassessment Candida sensitivity relapse following heavy antibiotic usage for chronic dental problems, stress, increasing carbohydrate intake Clinical Pearls Every woman with mold allergy, and chronic antibiotic use (sinusitis, UTI, etc.) who has chronic symptoms is Candida sensitive until proven otherwise In every patient with mold allergy, think about Candida and food yeast sensitivity (“the yeast triad”) In a patient with loss of food intolerance shortly after antibiotic use, think about Candida The Mystery of Candida Sensitivity: Unanswered Questions What is the exact pathogenesis behind local mucosal Candida colonization causing ssx in distant organs? Can we develop a test with high specificity and sensitivity that can accurately diagnose the condition? Can we develop prognostic indicators for long-term improvement? I.E. is there a test we can follow with Rx? Can we arrive at a consensus on the best diet for a 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