Cutaneous Candidiasis

Updated: Sep 25, 2024
  • Author: Richard Harold "Hal" Flowers, IV, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Practice Essentials

Cutaneous candidiasis and other forms of candidiasis (eg, mucosal) are infections caused by the yeast Candida albicans or other Candida species. [1] Yeasts are unicellular fungi that typically reproduce by budding, which entails progeny pinching off of the mother cell. C albicans, the principal infectious agent in human infection, is an oval yeast 2-6 µm in diameter.

Superficial infections of skin and mucous membranes are the most common types of cutaneous candidiasis. These include intertrigo, diaper dermatitis, erosio interdigitalis blastomycetica, perianal dermatitis, and candidal balanitis. (See Presentation.) Candidal infections of the skin have become more prevalent, principally because of the increased numbers of immunocompromised patients. Less common manifestations of candidiasis include esophagitis, bloodstream infection (BSI), endocarditis, peritonitis, and urinary tract infection.

Although C albicans is the most common cause of human candidal infection, the genus Candida includes more than 150 species. Candida tropicalis, Candida parapsilosis, Candida guilliermondi, Candida krusei, Candida kefyr, Candida zeylanoides, and Candida glabrata (formerly Torulopsis glabrata) are less common causes of human disease. Candida auris is an emerging pathogen often showing antifungal resistance. [2]

Humans carry yeast, including Candida species, throughout the gastrointestinal (GI) tract as part of the normal commensal flora. The vagina is commonly colonized by yeast, most often by C albicans and C glabrata. The commensal oral isolation of candidal species ranges from 30% to 60% in healthy adults. [3] Candida species are not part of the normal flora of the skin but may colonize fingers or body folds transiently.

Topical antifungal drugs are commonly used to treat cutaneous candidiasis, but concern about rising resistance to these agents has led to consideration of other treatment options (eg, antimicrobial peptides, blue or ultraviolet light, probiotics, and nanoparticle-based therapies [4] ). (See Treatment.) Research is under way into different antifungal agents with different mechanisms of action. [5]

Clinical practice guidelines for the management of candidiasis have been published by the Infectious Diseases Society of America (IDSA). [6] (See Guidelines.)

Pathophysiology

Candida is a versatile fungus that can exist commensally in many locations of the human body. Several different adaptive mechanisms help the organism survive in such diverse anatomic areas. The ability of C albicans to adjust to the different pH environments found in regions such as the bloodstream (neutral pH) and the vagina (more acidic pH) is explained by the differential expression of pH-regulated genes. In acidic environments, C albicans expresses PHR2, whereas in environments with a pH of 5.5 or higher, ir expresses PHR1 to a greater extent. [7]

Another critical virulence factor is the ability of Candida to adhere to the host tissue. The protein Hwp1 is vital for C albicans to form attachments to host tissue, as is CaMnt1p, a mannosyl transferase. [8, 9] The ability of yeast forms to adhere to the underlying epithelium is an important step in the production of hyphae and tissue penetration.

In a broad overview of pathologic mechanisms of C albicans, Mayer et al cited the following [10] :

  • Secretion of hydrolases
  • Molecules that mediate adhesion with concomitant invasion into host cells
  • Yeast-to-hypha transition
  • Biofilm formation
  • Contact sensing and thigmotropism
  • Phenotypic switching
  • Various fitness attributes

Candida species also produce proteases, which contribute to pathogenicity.

In a more focused view, research has elucidated the effect of Candida on keratinocytes. Within the epidermis, C albicans phospholipomannan triggers an inflammatory response through Toll-like receptor (TLR)-2. [11] Additionally, C albicans aborts the expression of interferon (IFN) gamma–inducible protein-10 in human keratinocytes. [12] Once C albicans invades the keratinocytes, the host cells express defense proteins and secrete chemokines and cytokines. [9, 13]

Melanocytes also play a role in the innate immune system; these cells detect C albicans through TLR-4 and begin producing antimicrobial products and melanin, which can sequester and, in some cases, kill, the fungi. Langerhans cells detect C albicans via Dectin-1 and initiate a Th17 response via interleukin (IL)-6. [13] Furthermore, CD103+ dermal Langerhans cells, upon interaction with TLR-2, enhance Th1 production in secondary lymphoid organs. [13]

Observing the effects of deficiency in key regulatory molecules has helped elucidate host defense against Candida. For example, IL-17 is essential to combat C albicans infections. [14, 15, 16] Thus, phenotypes that knock out IL-17 are more susceptible to C albicans, and drugs such as secukinumab (an IL-17 blocker used for psoriasis) can increase the incidence of candidal infections. Relatedly, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)—secondary to mutations in the autoimmune regulator (AIRE) gene—predisposes to mucocutaneous Candida infection. [17] In patients with this disease, autoantibodies to IL-17A can be linked to mucocutaneous candidiasis severity. [18]

Both STAT1 gain-of-function mutations and STAT3 loss-of-function mutations (which cause the autosomal dominant hyper-immunoglobulin E [IgE] syndrome) are associated with mucocutaneous candidiasis. [19, 20] Mucocutaneous Candida infections can be the presenting sign of IL-12 receptor β1 deficiency. [21]  Additionally, Candida is a catalase-positive fungus; therefore, patients with chronic granulomatous disease (CGD), which is due to a mutation in the NADPH oxidase complex involved in respiratory burst, are at increased risk for Candida infection. [22] In those with CGD, Candida is the most common cause of meningitis, fungemia, and lymphadenitis. [23]

Etiology

Host factors that predispose patients to infections include the following:

  • Local factors
  • Endocrine diseases
  • Nutritional deficiencies
  • Systemic immunodeficiency

Local factors (eg, tissue damage resulting from trauma, xerostomia, radiation-induced mucositis, ulcerations, skin maceration, and occlusion) enhance adhesion and predispose patients to increased infection rates. Cutaneous candidiasis has been reported to be more common in women than in men. [24, 25]

Endocrine diseases (eg, diabetes mellitus, Cushing syndrome, hypoparathyroidism, hypothyroidism, and polyendocrinopathy) are also associated with increased susceptibility to infection. The mechanism by which diabetes mellitus is believed to raise infection rates involves increased tissue glucose, altered yeast adhesion, and decreased phagocytosis. [26]  Diabetes is a risk factor for various forms of cutaneous candidiasis. [27] Chronic mucocutaneous candidiasis (CMC; ie, recurrent and chronic Candida infections of the epidermis, nails, and mucosal membranes) is associated with a variety of endocrine disorders and autoimmune conditions. [28]

Nutritional deficiencies may alter host defense mechanisms or epithelial barrier integrity, allowing increased adherence or penetration. Iron deficiency anemia and deficiencies including vitamins B1, B2, B6, C, and folic acid are associated with heightened infection rates. [29, 30]

T cell–mediated immunity plays an important immunologic role against infection through phagocytosis and killing by polymorphonuclear cells (PMNs) and macrophages. Individuals with deficient T-cell function (eg, those with AIDS) appear to be particularly vulnerable to mucosal or cutaneous candidiasis. Patients with primary immune deficiencies (eg, lymphocytic abnormalities, phagocytic dysfunction, IgA deficiency, viral-induced immune paralysis, and severe congenital immunodeficiencies) are often affected by oropharyngeal candidiasis and other fungal mycoses. [31]

Epidemiology

The number of candidal infections continues to rise, mirroring an increase in the number of patients who are immunocompromised. [32] Increased age appears to be associated with increased morbidity and mortality. [33] Older adults are more likely to be exposed to situations that increase the risk of invasive candidiasis, including treatment with broad-spectrum antibiotics, hyperalimentation, and increased contact with invasive monitoring devices in an ICU. [34]

Candida species are a common cause of intertrigo in both elderly and diabetic patients. Candida species are among the leading causes of BSIs in the United States, with occurrence at a disproportionately high rate in persons aged 65 years or older. [35]

Candidal infections are exacerbated by certain medications (eg, antibiotics), poor self-care, and decreased salivary flow (oral candidiasis), all of which often are associated with aging. In addition, treatment with cytotoxic agents (eg, methotrexate, cyclophosphamide) for dermatologic and rheumatic conditions or aggressive chemotherapy for malignancy in elderly patients puts them at higher risk.

The prevalence of neonatal cutaneous and systemic candidiasis have become increasingly prevalent in neonatal intensive care nurseries has been increasing. Postnatal acquisition has been attributed to increased survival rates of low-birth-weight babies in association with increased performance of invasive procedures and widespread use of broad-spectrum antibiotics. In neonates, parenteral nutrition, time in the ICU, and mechanical ventilation are major risk factors for infection. [36]  

Neonatal candidiasis presents 3-7 days after birth with oral thrush and diaper dermatitis. This has been attributed to mucosal contact with the organism during labor and delivery. Neonatal candidiasis is distinct from congenital candidiasis, a more common infection, which occurs after birth as opposed to in utero and often preferentially involves the oral area. [37]

 

Prognosis

Superficial candidal infections cause significant morbidity in older adults but are well treated with topical or oral therapy. Identification and cessation of triggers or aggravating factors is critical for preventing recurrence.

Systemic congenital candidiasis carries a grave prognosis and can lead to respiratory distress, meningitis, sepsis, or death. [38] Although the prognosis for congenital cutaneous candidiasis is generally good, untreated disease may carry a mortality of 8-40%. [37, 39]

CMC is an isolated cutaneous disease with a good prognosis; however, it is incurable and remains a chronic condition. CMC is often found in conjunction with endocrine and autoimmune disorders and, in some instances, may progress to an invasive infection; in both of these cases, morbidity is high. [40] Furthermore, fatal conditions such as oral or esophageal squamous cell carcinoma and cerebral aneurysm, though rare, can be associated with CMC. [28, 41]

In patients with CGD, those with Candida infection of the soft tissue or bone have a good prognosis overall; however, if the infection becomes disseminated, significant morbidity may be observed.

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