Are You Confident of the Diagnosis?
What you should be alert for in the history
Candida albicans and other Candida species are fungal infections commonly involved in human disease. Clinical disease may be as varied as mucocutaneous infections, chronic mucocutaneous candidiasis, candidemia and sepsis, and invasive infections of internal organs. The mortality rate for invasive candidal disease is high, estimated to range from 20-40% in children, particularly preterm infants. Mortality is also high among the elderly, especially when other comorbid conditions are present.
The increasing incidence of diabetes, malignancy and chemotherapy, and human immunodeficiency virus and the widespread use of immunosuppressives and broad-spectrum antibiotics have all contributed to the rise of Candida infections.
There are over 200 species of the genus Candida; however, only 12 are associated with significant disease. The most common strain of Candida involved in cutaneous infection is C. albicans. Other less common strains include C. tropicalis, C. glabrata, C. parapsilosis, C. stellatoidea, C. krusei, C. kefyr, and C. dubliniensis.
Candida is a dimorphic fungus (yeast) that colonizes approximately 30% of healthy individuals. Colonization begins shortly after birth and persists throughout life. It can be found in the respiratory, gastrointestinal, and genitourinary tracts and the skin and mucous membranes. Candida exists in both yeast (blastospore) phase and hyphal (mycelial) phase, depending on surrounding conditions. Immunocompetent individuals provide effective immune surveillance against Candida but any immune defect can lead to infection and visible disease. Transformation of Candida from the yeast phase to the filamentous form may result in increased virulence due to increased adhesion to epithelial and endothelial cells.
Characteristic findings on physical examination
Superficial candidiasis can be classified as (1) cutaneous, (2) mucosal (vulvovaginal, balanopreputial, or oral), (3) paronychial or onychial, or (4) chronic mucocutaneous candidiasis.
Common sites of involvement include the skin folds (under the breasts (Figure 1), within the gluteal and inguinal folds, diaper area (Figure 2), under pannus, and the armpits. Predisposing factors include heat, humidity, and maceration and patients often complain of burning and itching. On exam there may be erythema with satellite papules and overlying white plaques. This presentation is called “intertrigo.”
This presentation is referred to as “thrush.” It can affect people of all ages but most often occurs in infants and the elderly. Antibiotics, corticosteroids (oral or inhaled), dental prostheses, chemotherapy, radiation treatment, and HIV are the most common predisposing factors.
Pseudomembranous candidiasis presents as whitish plaques on the oral mucosa. The superficial white component can be wiped off to reveal an underlying erythematous surface that can bleed easily. This characteristic differentiates it from leukoplakia, which presents as a white plaque with irregular borders that is difficult to remove from the tongue’s surface. Chronic cases of oral thrush can spread to involve the esophagus.
Diaper dermatitis is the most common dermatologic skin finding in infants and toddlers. These rashes are episodic in nature and appear on the protruding surfaces of the buttocks, upper thighs, and lower abdomen.
Atrophic thrush is shiny, atrophic, and can ulcerate. It does not have overlying white plaques. It is commonly associated with dental prostheses.
Angular cheilitis affects the labial commissures and appears clinically as erythematous, fissured lesions affecting the corners of the mouth. It can occur in patients with dentures due to increased saliva drainage along the corners of the mouth. Skin folds and wrinkling along the labial commissures can also contribute to this condition due to chronic pooling of saliva. In acne patients taking isotretinoin, angular cheilitis is common due to cracking at the corners of the mouth with saliva accumulation.
Median rhomboid glossitis is characterized by an elliptical or rhomboid-like area on the posterior dorsal tongue, anterior to the circumvallate papillae.
Mastitis can occur in nearly 20% of breastfeeding women and is associated with acute erythema and pain on the nipple surface. Risk factors include a compromised skin surface on the nipple to allow pathogen entry. Oversupply of breast milk and use of nipple shields can bring this presentation on.
This presentation can occur at any age but is mainly seen in pregnant women, those with intrauterine devices, and in women taking oral contraceptives. Other associations include diabetes, obesity, and corticosteroid use. It is characterized by erythema of the vulvar and vaginal mucosa, leucorrhea, and itching.
This occurs in uncircumcised or obese men in which the foreskin or extra skin folds lead to occlusion of the coronal sulcus. It is characterized by burning, pain, and white sores and secretions along the glans and foreskin.
Paronychial and onychial
This occurs more commonly on the fingernails, most likely in individuals who have chronically wet hands such as dishwashers or laundry workers. Frequent manicures are also a risk factor. Affected individuals have erythema and tenderness along the proximal and lateral nail folds. The nail may have a greenish-yellow, ochre, or whitish discoloration with distal subungual onycholysis.
Chronic mucocutaneous candidiasis
Chronic mucocutaneous candidiasis (CMC) represents a heterogeneous group of disorders characterized by chronic Candida infection of the skin, nails, and mucosa. Some of these conditions may be associated with endocrinopathies as well as decreased cutaneous immune function, most often due to deficiency of the autoimmune regulator (AIRE) gene. Unique to CMC is that affected individuals do not develop invasive candidiasis.
Patients with invasive candidiasis appear sick, are febrile, and may be hypotensive, whereas those affected with cutaneous candidiasis alone might be uncomfortable but do not appear sick. It is possible for cutaneous candidiasis to progress to invasive candidiasis in pre-term infants, transplant patients, and others with compromised immune systems
A superficial scraping can be obtained from the mucosa or skin and placed on a microscope slide. A drop of saline is added and pseudohyphae and yeast can be seen under the microscope. A drop of potassium hydroxide should be added to nail or skin specimens to help dissolve the keratin; this will help to visualize the yeast.
Some have found calcolfluor white to be helpful in providing a rapid diagnosis. It needs to be used with a fluorescent microscope. A specimen can also be obtained for culture and sensitivities. Skin biopsy with periodic acid-Schiff (PAS) staining may be helpful in cases of CMC, but rarely is required in the diagnosis of other Candida infections.
A specimen can also be obtained for culture and sensitivities. This is imperative in the cases of suspected invasive candidiasis; however, these cultures take many days to have a final result so empiric antifungal treatment should be started in the meantime. In elusive cases, such as intra-abdominal infections, adding a beta-D-glucan assay may aid in the diagnosis. Additionally, in advanced infections, punch biopsies will show microabscesses.
Who is at Risk for Developing this Disease?
Use of broad-spectrum antibiotics can alter commensal mucosal microflora, leading to unimpeded candidal overgrowth. Inhalation, topical, and systemic corticosteroids can lead to candidal overgrowth due to immunosuppressive effects. Certain drugs, such as anticholinergics and psychotropics, can cause dry mouth. The decrease in antifungal salivary properties (lactoferrin, lysozyme, histatins, immunoglobulins) can lead to increased Candida levels.
Malnutrition can lead to angular stomatitis due to vitamin B12 or iron deficiency. Malignancy and chemotherapy can cause impaired immune response to prevent candidal overgrowth.
Uncontrolled diabetes mellitus can lead to oral Candida infections, most likely due to reduced salivary flow, reduced salivary pH, and increased salivary glucose levels. Reduced or defective immune function can lead to increased infection. Both humoral and cell-mediated immunity take part in preventing and eliminating Candida infection; notably, 60% of HIV patients and 80% of AIDS patients have significant candidiasis.
The mortality rate for invasive candidal disease is high, estimated to range from 20-40% in children, particularly preterm infants. Mortality is also high among the elderly, especially when other comorbid conditions are present. Risk factors for invasive candidal disease include neonatal colonization, prolonged stay in intensive care units, use of central venous catheters, broad-spectrum antibiotics, parenteral nutrition, and mechanical ventilation.
Candida species account for the most common fungi causing invasive infection in very low birth weight infants (<1500 g).
What is the Cause of the Disease?
Healthy individuals should be able to mount an effective immune response against Candida. This happens by recognition of the fungus on phagocyte receptors (granulocytes, monocytes/macrophages) and dendritic cells. Stimulation of the receptors triggers cytokine release, neutrophil and macrophage activation, and initiation of adaptive immunity which occurs through Th1 or Th17 response.
Systemic Implications and Complications
Three components are involved in the pathogenesis of invasive candidiasis:
Breakdown of normal mucosal, skin, or epithelial barrier.
Loss of immune mechanisms responsible for preventing candidemia and invasion to deeper tissues.
These risk factors are associated with invasive candidiasis:
Use of corticosteroids
Treatment in ICU with invasive procedures
-Central venous lines
-Peritoneal dialysis catheters
-Intubation and mechanical ventilation
-Enhanced colonization of cutaneous and mucosal surfaces
—Use of broad-spectrum antibiotics
—Use of H2 receptor antagonists (e.g., ranitidine, famotidine, cimetidine)
—–Total parenteral nutrition with lipids
—–Previous fungal infection
Careful handling of intravenous catheters, careful use of antimicrobial agents, and prompt removal of infected devices should be performed when possible. Fluconazole prophylaxis has been used with good results in preventing invasive disease in extremely low birth weight infants.
In cutaneous or mucosal candidiasis, topical antifungal agents are usually adequate. A topical imidazole (e.g., ketoconazole gel or cream, oxiconazole cream, ketoconazole cream) applied twice daily is generally effective in treating intertrigo. Ketoconazole should be avoided in the diaper area due to concerns of systemic absorption.
Nystatin oral suspension (100,000 U/ml – 1 ml swish and spit 4 times a day) or 100,000-unit pastille for 7-14 days is effective for oral candidal infections. Amphotericin lozenges (10mg) or suspension (100mg/ml) 4 times a day for 14-21 days is effective as well. Miconazole gel 2% 2.5 ml applied topically 4 times a day for 14-21 days is also a treatment option.
Esophageal candidiasis has more complicated treatment, as the extension of oral candida into the esophagus is typically in the context of immune deficiency. Systemic therapy is required with oral fluconazole, 200-400 mg daily for 14-21 days. These patients may not be able to tolerate oral treatment, in which case intravenous therapy with fluconazole or an echinocandin is the next best step; if possible, de-escalate therapy back to oral medication.
Topical imidazoles can also be used twice daily to treat vulvovaginal and balanopreputial candidiasis until resolved. Recent studies showed two doses of clotrimazole vaginal tablet 500 mg were equivalent in treating severe vulvovaginal candidiasis to two doses of oral fluconazole 150 mg and had the added benefit of adverse effects localized to the vaginal canal only.
In cutaneous or mucosal candidiasis, systemic antifungals are indicated when topicals are ineffective. Some examples include: ketoconazole 200 mg daily for 7 days, fluconazole 100 mg daily for 1-2 weeks, itraconazole 100 mg daily for 2-4 weeks. Voriconazole intravenously (4 mg/kg every 12 hours) or orally (200 mg every 12 hours) has also been reported to be effective. Caspofungin 70 mg on day 1, followed by 50 mg daily for 30 days is another option.
For paronychia and onychia, systemic treatment should be used. Effective regimens include: itraconazole 200 mg daily for 3 months or 200 mg BID for 1 week each month for 3 months and fluconazole 150-300 mg weekly in adults or 1-2 mg/kg weekly in children for 4-6 weeks. Topical treatments with topical azoles, such as efinaconazole and tavaborole, can be attempted in children and adults who cannot take systemic antifungals.
Chronic systemic antifungals are used in the prevention and treatment of CMC. Antifungal sensitivity studies are helpful in directing therapy. Adjunct therapy with calcium channel blockers can overcome resistance to antifungals through a synergistic effect.
Empiric therapy should be considered for patients known to be neutropenic to reduce risk of invasive candidiasis. For patients with candidemia, echinocandins (caspofungin loading dose 70 mg, then 50 mg daily; anidulafungin loading dose 200 mg, then 100 mg daily; micafungin 100 mg daily) may be more effective than fluconazole or amphotericin B.
Lipid formulation amphotericin B (3-5 mg/kg daily) is an alternative if there is resistance to a more desired medication or lack of availability of other therapies. Transition to fluconazole should be done promptly within 5-7 days if the strain is susceptible or repeat cultures are negative, as there is significant toxicity with using amphotericin B.
Probiotics have been shown to suppress candidal growth in oral, vaginal, and enteric cavities, as well as biofilm development. As such, they can be included in the treatment regimen against chronic colonization.
Optimal Therapeutic Approach for this Disease
For mucocutaneous disease, it is reasonable to start out with a topical agent. Nystatin is probably the most commonly prescribed first-line drug in treating superficial candidiasis. It has both a fungistatic and fungicidal activity, depending on the concentration. It is not absorbed through the skin or mucous membranes; it cannot be given systemically due to toxic side effects. Should symptoms persist longer than 2 weeks with nystatin therapy, search for a source of re-exposure, such as a pacifier or bottle. Treatment with an oral antifungal is indicated in such instances. Failure to improve at this point warrants a culture or evaluation for immunodeficiency.
Topical azoles are also effective topical agents. They are fungistatic. Clotrimazole cream is a popular choice for treating angular cheilitis because it has some anti-staphylococcal properties as well.
Oral antifungals are also popular for treating mucocutaneous disease, especially when compliance may be an issue or disease is widespread. Oral agents are also helpful in immunocompromised states. Fluconazole is often first-line because of its safety profile, relative to some of the other oral antifungals. However, liver enzymes should be monitored with prolonged use.
A reasonable approach for apprehensive patients worried about liver damage is to reassure that liver damage is rare for short courses (less than 1 month) of drug therapy. Baseline labs at the beginning and end of therapy can be drawn if patients continue to be worried.
Any non-infant child or adult without predisposing factors (corticosteroid use, recent antibiotics, HIV, etc.,) who presents with oral candidiasis should be evaluated for underlying disease. Specifically, HIV should be checked in an adult or adolescent. Congenital immunodeficiency should be considered in a child. Screening labs might include quantitative immunoglobulins and CD4 count.
Predisposing factors should be eliminated when possible. These may include use of corticosteroids, broad-spectrum antibiotics, prolonged washing of dishes without gloves, manicures/pedicures, picking at cuticles, etc.). It is important to evaluate for systemic disease, such as HIV or leukemia/lymphoma, when patients without risk factors present with oral candidiasis.
Prolonged use of systemic antifungals requires monitoring of the liver (azoles) and kidneys (amphotericin). It is important to check for drug interaction when prescribing an oral antifungal.
Unusual Clinical Scenarios to Consider in Patient Management
Despite many effective medications, treatment failure is not uncommon. The effect of saliva in diluting the antifungals can reduce the medication availability below the effective therapeutic concentration. Candida biofilms can form on mucosal and inert surfaces (e.g., catheters) and contribute to therapeutic failure. It is also important to remember that poor compliance can lead to treatment failure.
Oropharyngeal candidiasis can be used to predict the progress of HIV infection as 50% of HIV-infected individuals that present with oral candidiasis develop AIDS within 3 years. The infection may be harder to clear in these patients, as there is a higher rate of antifungal resistance among their pathogens.
For any patient with persistent fever and hypotension despite treatment with broad-spectrum antibiotics, candidemia or invasive candidiasis should be suspected. Empiric antifungal treatment may be warranted in these cases. An infrequent but dire complication of invasive candida is endophthalmitis, or inflammation of the inner parts of the eyelids; it can present as painless loss of vision, making diagnosis unclear. As such, all nonneutropenic patients with candidemia should have a dilated ophthalmological examination promptly after diagnosis.
What is the Evidence?
Netea, MG, Maródi, L. “Innate immune mechanisms for recognition and uptake of Candida species”. Trends Immunol. vol. 31. 2010 Sep. pp. 346-53. (This is a concise article that reviews the cutaneous immune system and genetic defects that can lead to Candida infections.)
Maródi, L, Johnston, RB. “Invasive Candida species disease in infants and children: occurrence, risk factors, management, and innate host defense mechanisms”. Curr Opin Pediatr. vol. 19. 2007 Dec. pp. 693-7. (This article focuses on very low birth weight infants with a discussion of risk factors and management of invasive candidal disease.)
Healy, CM, Baker, CJ. “Fluconazole prophylaxis in the neonatal intensive care unit”. Pediatr Infect Dis J. vol. 28. 2009 Jan. pp. 49-52. (The authors discuss their experience in using fluconazole prophylaxis in preventing invasive candidal infections in extremely low birth weight infants.)
Farah, CS, Lynch, N, McCullough, MJ. “Oral fungal infections: an update for the general practitioner”. Aust Dent J. vol. 55. 2010 Jun. pp. 48-54. (This article provides a nice review of oral fungal infections with a detailed discussion of different presentations of Candida infection.)
López-Martínez, R. “Candidosis, a new challenge”. Clin Dermatol 2010 Mar. vol. 28. 4. pp. 178-84. (This article offers a review of different types of Candida infections with a discussion of treatment.)
Singhi, S, Deep, A. “Invasive candidiasis in pediatric intensive care units”. Indian J Pediatr. vol. 76. 2009 Oct. pp. 1033-44. (The authors discuss invasive candidiasis and risk factors in pediatric intensive care units.)
Samaranayake, LP, Keung Leung, W, Jin, L. “Oral mucosal fungal infections”. Periodontol 2000. vol. 49. 2009 Feb. pp. 39-59. (The authors provide a nice review of oral mucosal infections with a focus on treatment.)
Cullinane, M, Amir, L, Donath, S, Garland, S. “Determinants of Mastitis in Women in the CASTLE Study: A Cohort Study. BMC Family Practice”. BioMed Central. 16 Dec. 2015. (This article discusses development, risk factors, and prevention of candida mastitis.)
Horii, K, Prossick, T. “Diaper Dermatitis”. 27 Aug. 2015. (This article provides an overview of a very common dermatologic finding in newborns.)
Wang, Q. “Chronic mucocutaneous candidiasis presenting as endophthalmitis”. Canadian Journal of Ophthalmology. vol. Volume 51. pp. e55-e58. (This article discusses an unusual complication of invasive candidiasis in the eye.)
Zhou, XC, Li, T, Fan, SS, Zhu, Y. “The Efficacy and Safety of Clotrimazole Vaginal Tablet vs. Oral Fluconazole in Treating Severe Vulvovaginal Candidiasis”. Mycoses. 2016. (This article discusses options in treating vulvovaginal candidiasis, specifically a vaginal tablet vs. oral therapy.)
Liu, S, Yue, L, Gu, W, Li, X. “Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida Albicans”. PLoS One. vol. 11. (2016): Mar 17. pp. e0150859(The authors detail the synergism they found in combining CCBs and antifungals.)
Matsubara, VH, Bandara, HM, Mayer, MP, Samaranayake, LP. “Probiotics as Antifungals in Mucosal Candidiasis. Clin Infect Dis”. Clinical Infectious Diseases 62.9. 2016. pp. 1143-153. (This article discusses the adjunct role probiotics have in fighting candida colonization.)
Shulman, ST, Bisno, AL, Clegg, HW, Gerber, MA. “Executive Summary: Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America”. Clinical Infectious Diseases 55.10. 2012. pp. 1279-282. (This article is a comprehensive review of treatment options for a variety of presentations of candida infections and for a variety of patient types.)
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