Chronic Mucocutaneous Candidiasis

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.

The image below depicts CMC of the nails. 

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.

Chronic mucocutaneous candidiasis (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 (IL)–2 and interferon-gamma levels (TH 1 cytokines) and increased IL-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.

A study of peripheral-blood mononuclear cells from 14 patients with autosomal dominant CMC found poor production of interferon-gamma, IL-17, and IL-22. Gene sequencing identified mutations in signal transducer and activator of transcription 1 (STAT1), leading to defective immune responses in type 1 and type 17 helper T cells.[3, 4, 5]

Chronic mucocutaneous candidiasis (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.

Race

No racial predilection is reported for chronic mucocutaneous candidiasis (CMC) , although autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (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.

Chronic mucocutaneous candidiasis (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.

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, the 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.[6] 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.

Patients should be aware of the chronic, recurrent nature of their disease and the current paucity of effective long-lasting therapies.

For patient education resources, visit the Infections Center. Also, see the patient education article Candidiasis (Yeast Infection).

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 chronic mucocutaneous candidiasis (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.

Chronic mucocutaneous candidiasis (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 first image below). Skin lesions more frequently are acral and characterized by erythematous, hyperkeratotic, serpiginous plaques (see second image below). The scalp may be involved with similar hyperkeratotic plaques, which can result in scarring alopecia (see third image below).

A subset of CMC patients has recurrent or severe noncandidal infections,[7] 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. It is estimated that around half the patients with isolated CMC have a signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation leading to impaired IL-17 immunity.[8, 9] Onset is in childhood, and no associated endocrine or autoimmune disorders are observed.

CMC with endocrinopathy

APECED

CMC may occur as part of autoimmune polyendocrinopathy syndrome type 1 (Online Mendelian Inheritance in Man #240300), also known as APECED.[10, 11, 12, 13, 14]

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.[15] Autoantibodies against IL-17A, IL-17F, and/or IL-22 underlie the development of CMC in these patients.[16, 17] A study found that APECED patients have defective receptor-mediated Candida internalization, leading to altered Candida-specific immune responses.[10]

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.[15]

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.

Thyroid disease

CMC may be associated with thyroid disease. An autosomal dominant CMC associated with thyroid disease has been mapped to 2p.[18] Hypothyroidism was also noted in patients with Toll-like receptor 3 defect (L412F mutant), which is involved in the suppression of autoimmune disorders, adaptive immune response, and defense against viral infections.[19]

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. As in APECED patients, autoantibodies to IL-17A, IL-17F, and/or IL-22 are implicated in this subgroup.[16, 20]

CMC with other conditions

CMC may be seen in patients with autosomal dominant hyperimmunoglobulin E syndrome, autosomal dominant signal transducer and activator of transcription 1 (STAT1) gain-of-function, autosomal recessive deficiencies of IL-12 receptor β1 (IL-12Rβ1), autosomal recessive caspase recruitment domain-containing protein 9 (CARD9), or retinoic acid–related orphan receptor γT (RORγT).[21] The shared process among these conditions in the context of CMC is impaired IL-17 immunity.

Patients with autosomal dominant hyperimmunoglobulin E syndrome present with CMC as well as recurrent staphylococcal infections. T lymphocytes producing IL-17 and IL-22 are significantly decreased, which may be explained by impaired STAT3 signaling of IL-6, IL-21, and IL-23.[22, 23, 24]

In addition to CMC, patients with autosomal recessive CARD9 present with invasive fungal infections and deep dermatophytosis due to impaired neutrophil- and IL-17–producing T-lymphocyte cell defenses.[25, 26]

Nontuberculous mycobacterial infections are the most prominent feature in patients with IL-12Rβ1 deficiency, but milder cases of CMC are also observed. T-helper cells involved in the Th1 pathway, as well as macrophages, contain genetic defects that increase susceptibility to intracellular pathogens. Among other immune-signaling pathway defects such as human JNK1-dependent MAPK signaling pathway and autosomal recessive ACT1 deficiency caused by a mutation of TRAF3IP2 variant, patients have shown decreased circulating T cells producing IL-17A and IL-22.[23, 27, 28, 29]

Recurrent oral candidiasis is not uncommon in patients with HIV infection.

Because of compromised immunity, patients often develop secondary infections. Among other bacterial infections, respiratory and skin infections due to Staphylococcus aureus are frequently encountered. Patients often display viral infections with Herpesviridae causing oral or genital sores and, less commonly, invasive fungal infections due to Candida organisms. Nine patients affected by chronic mucocutaneous candidiasis with heterozygous STAT1 mutations were found to have developed bronchiectasis, chronic lung disease, and early severe reflux disease.[30] A 2016 study reported invasive infections, cerebral aneurysms, and cancers as the strongest predictors of poor outcomes.[31]

When a patient presents with cutaneous manifestations of chronic mucocutaneous candidiasis (CMC), the studies described below 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.

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.[32]

In patients with other recurrent infections, immune studies should be considered; immunoglobulin levels should include B- and T-cell levels, as well as IgE to test for underlying autoimmune causes such as hyper-IgE syndrome.

If the clinical suspicion for APECED is high, genetic analysis of the AIRE gene can be confirmatory.[10, 15]

Anti–interferon-1 and anti-interleukin antibodies have been found to be highly specific for APECED and to precede the appearance of chronic mucocutaneous candidiasis (CMC), suggesting a possible diagnostic test.[33]

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, such as iron, vitamin B-6, vitamin B-12, vitamin C, and zinc. 

Routine hematoxylin and eosin–stained sections of superficial candidiasis lesions reveal subcorneal pustules. Granulomatous lesions of chronic mucocutaneous candidiasis (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.

Management can be difficult, and relapse is common following discontinuation of therapy. Topical therapies are not usually effective in patients with chronic mucocutaneous candidiasis (CMC). Treatment of oral involvement in CMC can be aided by therapy with clotrimazole troches or oral nystatin solution. Treatment falls into three 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. It is estimated that 40% of patients receiving long-term antifungal treatment develop drug resistance, although lower frequency is observed with intermittent therapy.[31] Patients with resistance to antifungals usually present with more severe phenotypes such as systemic infections and recurrent pneumonia. First-line antifungals include fluconazole, itraconazole, and posaconazole, while second-line therapy includes voriconazole, echinocandins, terbinafine, and liposomal amphotericin B.

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.[34] 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. Candida-specific cell immunity may be transferred by this approach. It is not effective in all cases. Long-term remissions have occurred when combined with antifungal medications. Patients with CMC associated with autoimmune manifestations due to STAT1 mutations may show improvement with JAK1/2 tyrosine kinase inhibitors such as ruxolitinib.[35, 36] Novel therapies such as JAK1/2 inhibitors have demonstrated sufficient potency to attenuate the increased STAT1 phosphorylation in CD4+ T lymphocytes, while enhancing IL-production, resulting in improvement of both the immunodeficiency and autoimmune disease processes.[37]

Other systemic immunologic treatments include intravenous immunoglobulin G (IgG) or granulocyte macrophage colony-stimulating factor (GM-CSF) infusions and interferon-alfa.

Refer patients to an endocrinologist if screening laboratory test results suggest an associated endocrine abnormality.

If familial chronic mucocutaneous candidiasis (CMC) is suspected, consultation with a geneticist should be obtained.

Patients with recurrent infections or pneumonia should be referred to an immunologist.

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.[6] Owing to chronic mucocutaneous candidiasis (CMC) and resultant chronic mucocutaneous inflammation, patients are at increased risk of skin and ear, nose, and throat cancers.[38] Sequential biopsies of the esophagus to screen for tumors in patients presenting with recurrent esophagitis and associated dysphagia is recommended by some authors.[31]

If the disease flares, patients may need to be seen on an urgent basis, particularly after a course of antifungals has been discontinued.

Related clinical guidelines have been released by the Infectious Diseases Society of America. See Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.[39]

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.

Class Summary

There are many topical and systemic agents commonly used to treat candidiasis. Patients being treated with systemic antifungal agents should be closely monitored for adverse effects.