Dermatology

Chronic Mucocutaneous Candidiasis (candidiasis of unspecified site), unspecified disorder of immune mechanism)

Chronic mucocutaneous candidiasis, ICD-9 112.9 (candidiasis of unspecified site), 279.9 (unspecified disorder of immune mechanism)

Are You Confident of the Diagnosis?

Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of disorders in which persistent or recurrent fungal infections of nail beds, skin, and mucosal surfaces occur in primary or secondary immunodeficiencies. It presents as recurring infections of the skin and mucous membranes with yeasts, mostly Candida albicans. The different CMC disorders differ in their clinical manifestations, immunologic findings, and genetic features.

Often children with CMC present with persistent thrush and diaper dermatitis with spread to involve the nails, scalp, and extremities. Over time, nails can become thickened and fragmented with a surrounding paronychia. Skin lesions are characterized by thickened hyperkeratotic plaques, often located on the head and extremities. When involving the scalp a scarring alopecia can occur.

Diagnosis of CMC can be made by first confirming the presence of Candida infection by examining scrapings from the suspected site in 1-20% potassium hydroxide using a microscope. The presence of pseudohyphae and yeast confirms the diagnosis. In persistent Candida infections a search for underlying immunodeficiency and/or endocrinopathy should be undertaken.

Protection from Candida infection is thought to be T cell mediated, particularly by Th17 cells which produce IL-17 and IL-22 at epithelial surfaces. Th17 cells are proinflammatory linkers between myeloid and lymphoid host defense that (1) help B cells, (2) have poor regulative susceptibility to T regulatory cells, and (3) show low cytotoxicity.

It is thought that IL-17 producing T cells promote candidicidal effects in clearing infection by inducing IL-8 in keratinocytes and recruiting neutrophils. IL-17 and IL-22 also synergistically induce beta defensins in keratinocytes that kill C albicans. Thus, the decrease in number of IL-17 producing T cells and the resulting decreased stimulation of epithelial cells could explain why candidiasis is limited to the skin and mucosal membranes in CMC patients, while sparing systemic involvement.

Because patients with CMC rarely develop Candida sepsis or internal candidiasis, the immunodeficiency is unique to the skin, nails, and mucosal surfaces.

CMC with impaired Th17 production is prominent in hyper-IgE syndrome caused by STAT3 mutations. This is also seen in patients with defective CARD9 or dectin-1. Patients with isolated CMC also show reduced levels of Th17-associated cytokines.

CMC is often the earliest and most common sign of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). This is an autosomal recessive disorder in which defects in the autoimmune regulator (AIRE) gene occur. This gene normally prevents autoimmunity by regulating expression of peripheral tissue-specific antigens that induce self-tolerance in developing T cells. AIRE gene mutation is specific for APECED and is not found in other autoimmune endocrine disorders. Autoimmunity in APECED syndrome targets not only the acquired immune system, leading to impaired mucosal protection against C albicans, but also endocrine tissues.

APECED is characterized by hypoparathyroidism, adrenal or gonadal failure, type 1 diabetes mellitus, or hypothyroidism. Sixty percent of patients have two or more endocrinopathies. In about a third of patients malabsorption, gastric cell atrophy, or autoimmune hepatitis can occur. Alopecia, dental enamel dysplasia, keratopathy, or vitiligo may also be present. When suspecting APECED, laboratory evaluation should include blood glucose, hemoglobin A1C, thyroid function tests, liver function tests, cortisol level, and serum electrolytes.

Development of endocrinopathy in APECED does not always occur in childhood or adolescence. In fact, hypoadrenalism and hypothyroidism have been reported as late as the fourth or fifth decade.

Chronic localized candidiasis is characterized by thick, tightly adherent crusts on the scalp and face, often with hyperkeratosis. It has been termed “Candida granuloma” because of this appearance. Most patients also have oral candidiasis. The disorder usually presents in early childhood before the age of 5 years.

Chronic mucocutaneous candidiasis with thymoma is seen in adults who develop thymus tumors (benign or malignant). It is characterized by mucous membrane and cutaneous candidiasis. These patients do not develop endocrinopathies but may develop aplastic anemia, myasthenia gravis, or hypogammaglobulinenia. Removal of the thymus does not result in resolution of the candidiasis.

Table I provides a list of clinical syndromes of CMC.

Table I.

Table I. Clinical syndromes of chronic mucocutaneous candidiasis
Chronic oral candidiasis (HIV, inhaled steroids, etc)
Familial CMC
APECED
Chronic localized candidiasis
CMC with thymoma
Candidiasis with chronic keratitis
Candidiasis with hyper-IgE syndrome

Who is at Risk for Developing this Disease?

CMC usually presents in childhood and may have an autosomal recessive, dominant, or sporadic mode of inheritance. A family history is helpful in dominant cases but may not be available in sporadic and recessive cases.

What is the Cause of the Disease?

The cause of CMC is selective cutaneous immunodeficiency against C albicans. Affected patients have decreased IL-17 and IL-22. CMC can occur as an isolated finding, or with other immunodeficiencies such as HIV or Hyper-IgE, or as part of APECED. Patients have involvement of the skin, nails, and mucosal surfaces. When involving the oral cavity, infection may extend to the esophagus. Systemic infection does not occur in CMC.

Systemic Implications and Complications

Other disorders that may accompany CMC include: infections (dermatophytes, viruses, and bacteria), vitiligo, alopecia, enamel dysplasia, gastrointestinal malabsorption, iron deficiency, hepatitis, hematologic disorders (aplastic anemia, hemolytic anemia, thrombocytopenia, neutropenia), myopathy, and cancer. In APECED it is important to evaluate for underlying endocrinopathies and provide appropriate treatment. This can best be done in conjunction with an endocrinologist.

Treatment Options

The treatment of CMC mainly consists of the liberal use of antifungals. These can be given therapeutically or prophylactically. Fluconazole is considered first line. A loading dose of 200mg/day or 4mg/kg/day in children is recommended. This is followed by a daily suppressive dose of 100mg/day or 2mg/kg/day in children. The dose can be increased back to the loading dose amount during worsening disease. Most patients do much better on a daily prophylactic dose.

In fluconazole resistant cases, other antifungal agents may be used. It is important to obtain culture and sensitivities as the candida may be resistant to other azoles as well, such as ketoconazole and voriconazole. In these cases caspofungin or amphotericin may be used.

Another option includes immune reconstitution. One example of immune reconstitution is using transfer factor. Transfer factors are small proteins that transfer cell-mediated immunity from immune to non-immune individuals. These are obtained from healthy individuals with normal candida immunity. Tranfer factors are not commercially available and have only been used in research settings.

Optimal Therapeutic Approach for this Disease

Once a diagnosis is established, it is important to determine the type of CMC. If endocrinopathy is present then it will need to be treated. A geneticist may also be helpful in providing counseling. An infectious disease specialist should be consulted regarding chronic use of antifungals and/or using immunotherapy. Many oral antifungals are available, including ketoconazole and fluconazole. Amphotericin B may be given intravenously in severe cases.

Patient Management

Patients with CMC should undergo annual evaluation of endocrine function.

Hypoadrenalism and hypothyroidism have been reported as late as the fourth or fifth decade. Antifungals may be given therapeutically or prophylactically, depending on the patient. Liver enzymes should be monitored regularly with long-term use.

Unusual Clinical Scenarios to Consider in Patient Management

Rarely APECD may present for the first time in adulthood.

Candidiasis patients can also have dermatophyte infections of the skin or nails. It is important to be aware of this association in order to avoid labeling the patient as having “antifungal-resistant candidiasis.”

What is the Evidence?

Kisand, K, Bøe Wolff, AS, Podkrajsek, KT, Tserel, L, Link, M, Kisand, KV. "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines". J Exp Med. vol. 207. 2010 Feb 15. pp. 299-308.

(This article focuses on APECED with reports of severely reduced IL-17F and IL-22 responses to Candida albicans. This reduction was strongly associated with neutralizing antibodies to IL-17F and IL-22. These findings support the conclusion that IL-22 and IL-17F are natural defenders against Candida albicans and that their reduction in CMC has an autoimmune basis.)

Lilic, D. "New perspectives on the immunology of chronic mucocutaneous candidiasis". Curr Opin Infect Dis. vol. 15. 2002 Apr. pp. 143-7.

(This article provides a nice, brief review of CMC.)

Kirkpatrick, CH. "Chronic mucocutaneous candidiasis". Pediatr Infect Dis J. vol. 20. 2001 Feb. pp. 197-206.

(This is another review article that goes into greater depth regarding the different CMC disorders.)

Kirkpatrick, CH. "Chronic mucocutaneous candidiasis". J Am Acad Dermatol. vol. 31. 1994 Sep. pp. S14-7.

(This article discusses the various types of CMC as well as available treatment.)

Eyerich, K, Foerster, S, Rombold, S, Seidl, HP, Behrendt, H, Hofmann, H. "Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22". J Invest Dermatol. vol. 128. 2008 Nov. pp. 2640-5.

(This is a nice article in which the authors perform studies showing that patients with CMC produce lower levels of IL-17 and Il-22 compared with healthy unaffected individuals.)

Jayasinghe, M, Schmidt, S, Walker, B, Röcken, M, Schaller, M. "Successful treatment of azole-resistant chronic mucocutaneous candidosis with caspofungin". Acta Derm Venereol. . vol. 86. 2006. pp. 563-4.

(This article provides a nice case report of caspofungin working to treat CMC in a case of azole-resistant infection.)
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