Cutaneous Candidiasis and Chronic Mucocutaneous Candidiasis

Also known as: Cutaneous Candidiasis, CMC, Chronic Mucocutaneous Candidiasis

General features

Cutaneous candidiasis is infection of the skin, skin folds, perineum and nails by Candida, almost always Candida albicans. It occurs when occlusion, maceration, moisture, heat or disrupted barrier function allows commensal yeast to invade the stratum corneum. Unlike dermatophytosis, it also affects moist, non keratinised skin and mucosal margins, and it does not spare the depths of the fold.

Risk factors: obesity, diabetes mellitus, hyperhidrosis, occlusive dressings and clothing, incontinence, topical and systemic corticosteroids, antibacterials, immunosuppression, bedridden or elderly patients, and wet work.

Clinical forms

Form	Features
Intertrigo	Beefy red, moist, macerated plaques in skin folds (axillae, groin, inframammary, abdominal folds, finger and toe webs), with a scalloped edge and satellite papules and pustules that rupture to leave collarettes of scale
Candidal diaper dermatitis	Confluent, bright red erythema of the perianal, genital and buttock skin, extending into the folds, with satellite pustules; persistent after 3 days of barrier care; often following antibacterial or diarrhoea
Balanitis and balanoposthitis	Erythema, white coating, small pustules or erosions on the glans and prepuce; common in diabetes and uncircumcised men
Perianal and perineal candidiasis	Intense itch, erythema, maceration; with antibacterials, diabetes or diarrhoea
Erosio interdigitalis blastomycetica	Macerated, white erosions between the third and fourth fingers in wet work
Candidal paronychia	Painful, swollen, erythematous proximal nail fold with loss of the cuticle, and sometimes expressible pus; nail plate ridging and discolouration follow; wet work and diabetes
Candidal onychomycosis	Distal or total nail dystrophy, usually in fingernails, with chronic paronychia or chronic mucocutaneous candidiasis
Candidal folliculitis	Follicular papules and pustules in occluded areas, or in injection drug users
Angular cheilitis	Fissured, erythematous corners of the mouth
Congenital cutaneous candidiasis	Widespread erythematous papules and pustules present at birth or within days, from intrauterine infection; risk of systemic disease in preterm infants
Neonatal and generalised cutaneous candidiasis	Extensive erythematous eruption in preterm infants and in immunodeficiency; a marker of possible invasive disease
Candida granuloma	Hyperkeratotic, horny, crusted plaques, usually on the face or scalp, in chronic mucocutaneous candidiasis

Differential diagnosis

Condition	Discriminating features
Tinea cruris, tinea pedis, tinea corporis	Active scaly edge with central clearing; scrotum spared; hyphae without pseudohyphae on KOH
Erythrasma	Well demarcated brown red patch without satellites; coral red Wood lamp fluorescence
Inverse psoriasis	Smooth, glazed, sharply marginated; psoriasis elsewhere
Seborrhoeic dermatitis	Greasy scale, scalp, face, chest
Irritant and allergic contact dermatitis	Distribution follows contact; spares the depths of folds in diaper dermatitis
Hailey Hailey disease	Painful, macerated erosions in folds; familial
Langerhans cell histiocytosis, zinc deficiency, acrodermatitis enteropathica, psoriasiform diaper dermatitis	Atypical or persistent diaper rash; check in infants
Pustular psoriasis, bacterial folliculitis	Culture negative for yeast, or bacteria grow
Chronic paronychia due to irritant dermatitis	Wet work, no organism, response to steroids

Laboratory diagnosis

Potassium hydroxide preparation or calcofluor white: budding yeasts with pseudohyphae in scale, pustule roofs or nail clippings.
Culture: Sabouraud dextrose agar at 25 to 37 degrees Celsius, with growth in 24 to 48 hours, and indicated for recurrent, refractory and nail disease. Species identification guides therapy.
Histopathology: yeasts and pseudohyphae in the stratum corneum, with neutrophils and spongiosis, on periodic acid Schiff or Grocott methenamine silver.
Neonatal and generalised disease: blood and urine cultures, and a lumbar puncture in the preterm, because these patients may have invasive infection.
Associated testing: glycaemia, HIV and other tests for immunodeficiency in extensive, recurrent or refractory disease.

Treatment

General measures are central: keep the area dry and exposed, remove occlusion, treat incontinence, use absorbent cotton clothing, and control diabetes and weight. Barrier preparations such as zinc oxide help in diaper dermatitis.

Agent	Regimen
Nystatin cream, ointment or powder (100 000 units per g)	Two to three times daily for 2 to 4 weeks
Clotrimazole 1 percent cream	Twice daily for 2 to 4 weeks
Miconazole 2 percent cream or powder	Twice daily for 2 to 4 weeks
Econazole 1 percent cream	Twice daily for 2 to 4 weeks
Ketoconazole 2 percent cream	Once daily for 2 to 4 weeks
Ciclopirox 1 percent cream	Twice daily for 2 to 4 weeks
Luliconazole 1 percent cream	Once daily for 2 weeks

Treatment continues for 1 to 2 weeks after clearance. Allylamines are less active against Candida than azoles, and are not first line. Hydrocortisone 1 percent for a few days with an antifungal reduces inflammation in severe intertrigo. Potent steroids and combined steroid antifungal products are avoided.

Systemic therapy is for extensive disease, failure of topical treatment, folliculitis, and immunosuppressed patients:

Agent	Adult dose	Duration
Fluconazole	100 to 200 mg daily, or 150 mg once weekly	7 to 14 days daily, or 2 to 4 weeks weekly
Itraconazole	100 to 200 mg daily	1 to 2 weeks

Children: fluconazole 3 to 6 mg per kg daily for 7 to 14 days. Infants with diaper dermatitis are treated with nystatin or miconazole 2 percent cream with each diaper change, and zinc oxide barrier, while diapers are changed often and left off when possible. Oral nystatin is added when the gut is the reservoir and oral thrush is present.

Candidal paronychia: keep hands dry, avoid wet work and irritants, wear cotton lined gloves, push back no cuticle, and apply a topical azole and a potent topical corticosteroid to the proximal fold twice daily for several weeks. Oral itraconazole 200 mg daily for 6 weeks, or fluconazole 150 to 300 mg weekly, is added for refractory disease or nail plate involvement.

Congenital and neonatal disease: topical therapy for well term infants, and systemic treatment with fluconazole 6 mg per kg or an echinocandin or amphotericin B in preterm infants and in any infant with signs of invasive disease.

Definition and aetiology

Chronic mucocutaneous candidiasis is persistent or recurrent Candida infection of the skin, nails and mucous membranes, which does not respond fully to treatment, and which occurs without bloodstream or deep invasion. It is a marker of a defect in Th17 and interleukin 17 signalling, or of a wider T cell disorder. Onset is usually in infancy or early childhood.

Cause	Mechanism	Associated features
STAT1 gain of function (commonest cause)	Excess interferon signalling suppresses Th17 differentiation	Autoimmunity (thyroid disease, type 1 diabetes, cytopenias), bacterial and viral infection (herpes viruses), dermatophytosis, endemic mycoses, mycobacterial disease, intracranial and other aneurysms, squamous cell carcinoma of the mouth and oesophagus
AIRE loss of function (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, APS 1)	Autoantibodies against interleukin 17A, interleukin 17F and interleukin 22	Hypoparathyroidism, adrenal insufficiency, enamel hypoplasia, alopecia, vitiligo, hepatitis, malabsorption; candidiasis is usually the first manifestation
STAT3 loss of function (autosomal dominant hyper IgE syndrome)	Failure of Th17 development	High IgE, eczema, staphylococcal abscesses, pneumatoceles with Aspergillus, facial and skeletal features, retained primary teeth
IL17RA, IL17RC, IL17F, TRAF3IP2 (ACT1)	Defective interleukin 17 signalling	Isolated candidiasis, with staphylococcal skin disease in IL17RA deficiency
CARD9 deficiency	Failed signalling from C type lectin receptors	Mucocutaneous candidiasis, CNS candidiasis, deep dermatophytosis, phaeohyphomycosis
CLEC7A (Dectin 1) deficiency	Failed beta glucan recognition	Recurrent vulvovaginal candidiasis and onychomycosis
IL12RB1 deficiency	Impaired interferon gamma axis	Mycobacterial and Salmonella infection, mucocutaneous candidiasis in some
RORC deficiency	Absent Th17 and mucosal associated invariant T cells	Mycobacterial disease with candidiasis
Thymoma, myasthenia gravis	Anti interleukin 17 and anti interleukin 22 autoantibodies	Adult onset
Combined immunodeficiency, SCID, DOCK8 deficiency	T cell defect	Severe infections and eczema
Acquired defects	HIV, immunosuppressive therapy, anti interleukin 17 biologics, Janus kinase inhibitors	Mucosal candidiasis without a genetic cause

Clinical features

Recurrent or persistent oral thrush from infancy, then oesophageal and genital disease.
Hyperkeratotic, crusted, thick nail changes (candidal onychomycosis) of all nails, with paronychia.
Erythematous, scaly, crusted skin lesions of the scalp, face, trunk and hands, and candidal granulomas (hyperkeratotic horn like plaques).
Oral and oesophageal disease causes stricture. Chronic oral candidiasis is a risk factor for squamous cell carcinoma of the mouth and oesophagus.
Failure to thrive, recurrent infections by other organisms, and endocrine disease depending on the genetic cause.
Invasive candidiasis is rare, except in CARD9 deficiency.

In APS 1, the sequence is mucocutaneous candidiasis (first, usually by age 5), hypoparathyroidism (usually by age 10) and adrenal insufficiency (usually by age 15). Adrenal and calcium testing must be repeated over years, because an adrenal crisis can be fatal and is preventable.

Laboratory assessment

Culture and species identification, with susceptibility testing, because azole resistance emerges with long term treatment.
HIV test, full blood count, lymphocyte subsets, immunoglobulins including IgE, vaccine responses, neutrophil function tests.
Th17 cell and cytokine assays in specialist laboratories.
Anti interleukin 17 and anti interleukin 22 autoantibodies, and genetic testing (STAT1, AIRE, STAT3, IL17RA, IL17F, CARD9 and a wider panel).
Endocrine screen: calcium, parathyroid hormone, morning cortisol, adrenocorticotropic hormone, thyroid function tests, glucose, and adrenal autoantibodies.
Chest imaging, thyroid and thymus imaging when appropriate (chest CT in adults to exclude thymoma), and endoscopy for dysphagia.

Treatment

Control of infection is prolonged, and cure is rare unless the immune defect is corrected.

Setting	Regimen
Acute oral or oesophageal infection	Fluconazole 100 to 200 mg orally daily for 2 to 4 weeks (oesophageal 200 to 400 mg daily)
Maintenance	Fluconazole 100 to 200 mg daily or 150 to 200 mg weekly, or itraconazole solution, long term or lifelong; the lowest effective dose is used
Fluconazole resistant disease	Itraconazole oral solution 200 mg daily; posaconazole (suspension 400 mg twice daily, or delayed release tablets 300 mg daily after loading); voriconazole 200 mg twice daily
Azole refractory disease	Echinocandin intravenous (micafungin 100 to 150 mg daily, caspofungin 70 mg loading then 50 mg daily, anidulafungin 200 mg loading then 100 mg daily), or amphotericin B, in specialist care
Skin and nail disease	Topical azoles; oral itraconazole 200 mg daily or fluconazole 150 to 300 mg weekly for nails; nail disease may need 6 months or longer
Children	Fluconazole 3 to 6 mg per kg daily, maximum 400 mg; itraconazole solution 5 mg per kg daily

Supportive and disease modifying measures:

STAT1 gain of function: Janus kinase inhibitor therapy (ruxolitinib or baricitinib) reduces infections and autoimmunity in small series, and is used off label in specialist centres. Haematopoietic stem cell transplantation is considered in severe disease, with a high rate of graft failure and complications.
AIRE deficiency: treatment of hypoparathyroidism (calcium and vitamin D analogues) and adrenal insufficiency (hydrocortisone and fludrocortisone), with endocrine surveillance for life.
Autoantibody mediated disease with thymoma: thymectomy and treatment of the thymoma.
HIV: antiretroviral therapy.
Dental and oral care, surveillance for oral and oesophageal squamous cell carcinoma, and dilatation of strictures.
Interferon gamma and other immunomodulators have been used in individual cases, with limited evidence.

Prophylaxis and resistance: long term azoles select resistant Candida albicans and non albicans species, and susceptibility testing is repeated at each relapse. Drug interactions with fluconazole and itraconazole (calcineurin inhibitors, statins, warfarin) are reviewed, and liver tests are performed regularly, because treatment lasts for years.