AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Chronic mucocutaneous candidiasis (CMC) refers to a heterogeneous group of disorders characterized by recurrent or persistent superficial infections of the skin, mucous membranes, and nails with Candida organisms, usually Candida albicans. These disorders are confined to the cutaneous surface, with little propensity for systemic dissemination. CMC does not represent a specific disease, but rather a phenotypic presentation of a spectrum of immunologic, endocrinologic, and autoimmune disorders. The unifying feature of these heterogeneous disorders is impaired cell-mediated immunity against Candida species.

Pathophysiology

C albicans is an opportunistic yeast that is part of the normal flora of the gastrointestinal tract, skin, and mucous membranes. The fungus can exist in the yeast, the mycelial (pseudohyphal), or the chlamydospore phase. Invasive disease is rare; however, when it occurs, it is usually associated with mycelial elements. Several host factors are important in defending against infection by candidal organisms. Healthy, intact skin that continuously desquamates and regenerates is usually an effective initial barrier. An intact immune system is critical for keeping this opportunistic organism at bay.

CMC is associated with a defect in cell-mediated immunity that may either be limited to Candida antigens or be part of a more general immune abnormality. Recent data suggest alterations in cytokine production in response to Candida antigens. These alterations include decreased interleukin 2 and interferon-gamma levels (T_H1 cytokines) and increased interleukin 10 levels in some studies.^{1, 2} Patients who lack T-cell immunity (eg, those with severe combined immune deficiency syndrome or DiGeorge syndrome) or patients with severely impaired T-cell function (eg, patients with AIDS) are susceptible to chronic candidal infections. Defects in humoral immunity are not commonly observed in patients with CMC, and patients with antibody deficiencies are not particularly prone to candidiasis.

Mortality/Morbidity

CMC is not associated with a high degree of mortality because disseminated invasive candidal infections are rare. In isolated CMC, the prognosis is good; however, significant morbidity is related to chronic and persistent skin, nail, and mucous membrane candidal infections. The risk of mycotic aneurysms, while low, remains a real possibility.³ In a subset of patients, malignant thymomas or cancers of the oral cavity and digestive tract may occur. Patients with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) have significant morbidity from endocrinopathies or other autoimmune diseases associated with this condition. Several cases of Pneumocystis carinii pneumonia in patients with CMC are reported in the literature.

Race

No racial predilection is reported for CMC, although APECED is most prevalent in Finnish, Sardinian, and Iranian Jewish populations.

Sex

The male-to-female ratio for CMC is equal.

Age

CMC usually manifests in infancy or early childhood (60-80% of cases), with a mean age of onset of 3 years. Delayed or adult onset of the disease is reported and can be associated with thymoma, myasthenia gravis, and bone marrow abnormalities.

CLINICAL

Section 3 of 11  

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History

Patients present with recurrent or persistent superficial candidal infections of the oral cavity (thrush) or intertriginous or periorificial areas. Infants often present with recalcitrant thrush, candidal diaper dermatitis, or both. More extensive scaling of skin lesions and thickened nails and red, swollen periungual tissues can follow these infections.

Systemic candidiasis and invasive fungal dermatitis, although rare, usually occur in premature infants, particularly those with extremely low birth weight.

Persistent and refractory candidal infections, which characterize CMC, must be distinguished from the more common and treatment-responsive overgrowth of Candida that occurs in the setting of systemic antibiotic therapy, local/systemic corticosteroid treatment, or hyperglycemia in persons with diabetes mellitus.

Physical

CMC is diagnosed based on physical examination findings, potassium chloride (KOH) preparation results, fungal culture, and a history of recurrent and refractory candidiasis infections. Oral examination may reveal the white adherent plaques of thrush or the angular cheilitis of perlèche. Oral involvement may extend to the esophagus, but further extension is extremely uncommon. Nails may be markedly thickened, fragmented, and discolored, with significant edema and erythema of the surrounding periungual tissue, simulating clubbing (see Media File 1). Skin lesions more frequently are acral and characterized by erythematous, hyperkeratotic, serpiginous plaques (see Media File 2). The scalp may be involved with similar hyperkeratotic plaques, which can result in scarring alopecia (see Media File 3).

A subset of CMC patients has recurrent or severe noncandidal infections,⁴ including those from viral, bacterial, and other fungal pathogens. Some patients with CMC have low serum iron levels and decreased iron stores, possibly related to decreased iron absorption. Iron replacement should be initiated in these patients. Several patients reportedly have improved after parenteral iron therapy.

Several classifications exist for CMC. The authors categorize CMC based on its association with other conditions.

• CMC without endocrinopathy
• • This category comprises a spectrum of clinical presentations.
  • Inheritance may be autosomal recessive or dominant, but many cases are sporadic.
  • Onset is in childhood, and no associated endocrine or autoimmune disorders are observed.
• CMC with endocrinopathy
• • CMC may occur as part of autoimmune polyendocrinopathy syndrome type 1 (Online Mendelian Inheritance in Man #240300), also known as APECED.⁵
  • • APECED is characterized by at least 2 of the following: CMC, hypoparathyroidism, and Addison disease. Other autoimmune disorders may be associated, such as, type 1 diabetes, autoimmune thyroiditis, Graves disease, alopecia areata, vitiligo, hypogonadism, biliary cirrhosis, hepatitis, idiopathic thrombocytopenic purpura, and pernicious anemia.
    • APECED is inherited in an autosomal recessive fashion and usually manifests early in childhood. It is caused by mutations in the autoimmune regulator gene (AIRE) on 21q22.3, which encodes a protein that plays an important role in establishing and maintaining tolerance in the thymus.⁶
    • A recent study found that APECED patients have defective receptor-mediated Candida internalization, leading to altered Candida-specific immune responses.⁵
    • Candidiasis is often the first manifestation of APECED, appearing before age 5 years in most cases, followed by manifestations of the other endocrine and nonendocrine conditions, including ectodermal dysplasia. Ectodermal dysplasia manifestations include dental enamel hypoplasia and pitted nail dystrophy. Keratopathy and calcifications of the tympanic membrane also may occur.
    • A 2006 review of 18 APECED patients found candidiasis in all patients as the presenting symptom, and researchers concluded that ectodermal dystrophy usually only occurs as a secondary phenomenon.⁶
    • No correlation exists between the severity of the endocrinopathy and the severity of the candidal infections. Treatment of the underlying endocrinopathy does not usually improve candidal infections.
  • CMC may be associated with thyroid disease. An autosomal dominant CMC associated with thyroid disease has been mapped to 2p.⁷
• CMC with thymoma
• • Patients in this subgroup typically present after the third decade of life.
  • These patients are at increased risk of myasthenia gravis and bone marrow abnormalities.
• CMC with other conditions
• • CMC may be seen in patients with hyperimmunoglobulin E syndrome.
  • Recurrent oral candidiasis is not uncommon in patients with HIV infection.

Causes

CMC occurs in a heterogeneous group of patients with a wide spectrum of immune dysregulation, ranging from Candida-specific decreased immunity to a broader immune defect.

DIFFERENTIALS

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Other Problems to be Considered

Immunodeficiency diseases characterized by decreased T-cell function.
Nezelof syndrome
HIV infection
Nutritional deficiency with superimposed candidal infection
Biotin deficiency

WORKUP

Section 5 of 11  

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Lab Studies

• When a patient presents with cutaneous manifestations of CMC, the following studies should be performed:
• • Scrapings from the infected site are suspended in 10-20% KOH and microscopically examined. The presence of yeast cells and pseudohyphae confirms the diagnosis. Fungal stains, such as chlorazol black E stain or Parker blue-black ink, may be added to highlight the organism.
  • Candidal organisms grow well on several culture media. They grow as yeasts on Sabouraud agar with chloramphenicol and cycloheximide. C albicans also grows on dermatophyte test medium but does not demonstrate the red color change characteristic of dermatophytes.
  • Screening laboratory tests for a CMC-associated endocrine dysfunction include blood glucose or glycosylated hemoglobin testing, thyroid function tests, liver functions tests, serum electrolyte evaluation, corticotropin testing, and serum cortisol values. Consider a complete blood cell count, to screen for leukopenia, and an HIV test. Other endocrine screening tests that may be considered include follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, parathyroid-stimulating hormone, calcium, phosphate, magnesium, and short synacthen test. Perform baseline and yearly follow-up tests to screen for associated endocrinopathy.

Other Tests

• Results from cellular immunity tests, such as the prick-test with Candida antigens, may be negative. In vitro lymphocyte proliferation is usually reduced for C albicans extracts.
• Immunoglobulin G subclass deficiencies have been reported in some patients with CMC, who have a predisposition toward respiratory tract infections. Isolated immunoglobulin A and immunoglobulin M deficiencies have also been reported, in addition to a single case of complete agammaglobulinemia.⁸
• In patients with other recurrent infections, immune studies should be considered.
• If the clinical suspicion for APECED is high, genetic analysis of the AIRE gene can be confirmatory.^{5, 6}
• Recently, anti-interferon-1 antibodies were found to be highly specific for APECED and to precede the appearance of CMC, suggesting an important new diagnostic test.⁹

Procedures

• A skin biopsy is rarely needed to make a diagnosis of Candida infection, but it may be performed to rule out the possibility of superinfection of a primary dermatosis. A periodic acid-Schiff stain can confirm the presence of pseudohyphae. Nutritional deficiencies with cutaneous manifestations should also be considered.

Histologic Findings

Routine hematoxylin and eosin–stained sections of superficial candidiasis lesions reveal subcorneal pustules. Granulomatous lesions of CMC show hyperkeratosis and parakeratosis, with a dense mixed dermal infiltrate containing lymphocytes and plasma cells. Periodic acid-Schiff or silver stains of skin biopsy specimens can help identify organisms in the stratum corneum and dermis.

TREATMENT

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Medical Care

Management can be difficult, and relapse is common following discontinuation of therapy. Topical therapies are not usually effective in patients with CMC. Treatment of oral involvement in CMC can be aided by therapy with clotrimazole troches or oral nystatin solution. Treatment falls into 3 main categories: antifungal agents, immunologic therapies, and combination therapy.

• Systemic antifungal therapy is the mainstay of CMC therapy. It may be used alone or in combination with an immunomodulatory agent. The drawbacks of systemic antifungal therapy include the risk of adverse effects or toxicity, a failure to correct the underlying immune deficiency, relapse following the cessation of therapy, and antifungal resistance to some antifungal agents.
• Several immunologic therapies have been proposed in an effort to correct the underlying immune deficiency in persons with CMC. The most widely studied treatment is the use of transfer factor.¹⁰ Transfer factor is a cell-free protein extracted from the T lymphocytes of Candida-immune donors. Although the precise mechanism is unknown, it has been shown to transfer delayed-type hypersensitivity reactions to patients previously anergic to candidal skin testing.

Consultations

• Refer patients to an endocrinologist if screening laboratory test results suggest an associated endocrine abnormality.
• If familial CMC is suspected, consultation with a geneticist should be obtained.
• Patients with recurrent infections or pneumonia should be referred to an immunologist.

MEDICATION

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Many good antifungal agents are available and usually are effective; however, upon cessation of therapy, most patients relapse. Specific immunotherapies are under investigation and have been used with some success. This area needs further research.

Drug Category: Antifungals

Ketoconazole and amphotericin B are commonly used to treat candidiasis. Patients being treated with systemic antifungal agents should be closely monitored for adverse effects.

Drug Name	Amphotericin B (Fungizone)
Description	Polyene antibiotic that binds to sterol in fungal membranes and alters membrane permeability. Often reserved for severely ill patients with disseminated disease. As an IV medication, it requires drug monitoring during infusion. Newer formulations incorporate active drug into a liposomal delivery system.
Adult Dose	Patient tolerance varies considerably; dosage tailored to individual patient and clinical status Test dose: 1 mg (in 20 mL of 5% dextrose solution) IV over 30 min 0.25-0.5 mg/kg/d IV qd/qod over 2-6 h initially; increase as tolerated by 0.25-0.5 mg/kg/d, not to exceed 1 mg/kg qd or 1.5 mg/kg qod
Pediatric Dose	Children <3 years: Not recommended Children >3 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concurrent administration of corticosteroids and corticotropin, skeletal muscle relaxants, or digitalis may induce hypokalemia; concurrent administration with antineoplastic agents, cyclosporine A, zidovudine, aminoglycosides, or pentamidine may potentiate renal toxicity; concurrent administration with flucytosine may increase flucytosine toxicity; concurrent administration of imidazole antifungals may antagonize antifungal effect of amphotericin B
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Administer under close observation by experienced personnel; monitor for renal toxicity with serial BUN/creatinine and electrolyte levels; monitor liver function, CBC count, and magnesium levels; other adverse effects include chills, nausea, and fever

Drug Category: Immunomodulators

Immune modulators used in CMC attempt to improve or correct cell-mediated immune dysfunction.

FOLLOW-UP

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Further Outpatient Care

• Baseline studies and yearly screening for associated endocrinopathy should be performed. Long-term follow-up is necessary for identifying and addressing accompanying disorders.
• Some authors suggest screening angio-MRI for all patients with diagnosed CMC to rule out aneurysm; but this is not a universal recommendation.³
• If the disease flares, patients may need to be seen on an urgent basis, particularly after a course of antifungals has been discontinued.

Prognosis

• CMC is a chronic disease, and recurrent and relapsing superficial infections with Candida organisms should be expected.
• Life expectancy is generally normal but significant morbidity is associated with the chronic nail and mucocutaneous infections and associated endocrine and/or autoimmune disease.
• In rare cases, premature death occurs secondary to disseminated Candida infection, sepsis, pneumonia, or mycotic aneurysms.

Patient Education

• Patients should be aware of the chronic, recurrent nature of their disease and the current paucity of effective long-lasting therapies.
• For excellent patient education resources, visit eMedicine's Yeast and Fungal Infections Center. Also, see eMedicine's patient education article Candidiasis (Yeast Infection).

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to recognize the condition, which is characterized by chronic, recurrent, and refractory skin infections with Candida organisms: The diagnosis may be delayed because of multiple attempts to eradicate the infection using standard cutaneous candidal drugs and doses.
• Failure to screen for well-recognized associated conditions, including endocrine and autoimmune diseases.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Thickened, fragmented, hyperkeratotic nails and erythematous periungual skin. Courtesy of Walter Reed Army Medical Center.
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Media file 2:  Crusted hyperkeratotic plaques on and around the nose. Courtesy of Walter Reed Army Medical Center.
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Media file 3:  Crusted hyperkeratotic plaques on eyebrow, forehead, and scalp. Courtesy of Walter Reed Army Medical Center.
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REFERENCES

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1. Lilic D. New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis. Apr 2002;15(2):143-7. [Medline].
2. Lilic D, Gravenor I, Robson N, Lammas DA, Drysdale P, Calvert JE, et al. Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis. Infect Immun. Oct 2003;71(10):5690-9. [Medline].
3. Marazzi MG, Bondi E, Giannattasio A, Strozzi M, Savioli C. Intracranial aneurysm associated with chronic mucocutaneous candidiasis. Eur J Pediatr. Apr 19 2007;[Medline].
4. Herrod HG. Chronic mucocutaneous candidiasis in childhood and complications of non-Candida infection: a report of the Pediatric Immunodeficiency Collaborative Study Group. J Pediatr. Mar 1990;116(3):377-82. [Medline].
5. Brännström J, Hässler S, Peltonen L, Herrmann B, Winqvist O. Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens. Clin Immunol. Dec 2006;121(3):265-73. [Medline].
6. Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. Jun 2006;154(6):1088-93. [Medline].
7. Atkinson TP, Schäffer AA, Grimbacher B, Schroeder HW Jr, Woellner C, Zerbe CS, et al. An immune defect causing dominant chronic mucocutaneous candidiasis and thyroid disease maps to chromosome 2p in a single family. Am J Hum Genet. Oct 2001;69(4):791-803. [Medline].
8. Patiroglu T, Tahan F. Chronic mucocutaneous candidiasis with agammaglobulinaemia. J Eur Acad Dermatol Venereol. Jul 2007;21(6):833-4. [Medline].
9. Meager A, Visvalingam K, Peterson P, Möll K, Murumägi A, Krohn K, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. Jul 2006;3(7):e289. [Medline].
10. Masi M, De Vinci C, Baricordi OR. Transfer factor in chronic mucocutaneous candidiasis. Biotherapy. 1996;9(1-3):97-103. [Medline].
11. Abuzakouk M, Feighery C. Primary immunodeficiency disorders in the Republic of Ireland: first report of the national registry in children and adults. J Clin Immunol. Jan 2005;25(1):73-7. [Medline].
12. Chiu SJ, Tsao CH, Chen LC, Kao CC, Lue KH, Huang JL. Chronic mucocutaneous candidiasis in a 6-year-old boy. J Microbiol Immunol Infect. Jun 2004;37(3):196-9. [Medline].
13. Ee HL, Tan HH, Ng SK. Autosomal dominant familial chronic mucocutaneous candidiasis associated with acne rosacea. Ann Acad Med Singapore. Oct 2005;34(9):571-4. [Medline].
14. Guidelines/Outcome Committee, American Academy of Dermatology. Guidelines of care for superficial mycotic infections of the skin: mucocutaneous candidiasis. J Am Acad Dermatol. Jan 1996;34(1):110-5. [Medline].
15. Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J. Feb 2001;20(2):197-206. [Medline].
16. Mangino M, Salpietro DC, Zuccarello D, Gangemi S, Rigoli L, Merlino MV, et al. A gene for familial isolated chronic nail candidiasis maps to chromosome 11p12-q12.1. Eur J Hum Genet. Jun 2003;11(6):433-6. [Medline].
17. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. Aug 2006;91(8):2843-50. [Medline].

Article Last Updated: Jan 15, 2008