Treating Rare Fungal Infections: Cryptococcosis
Cryptococcosis is a deep cutaneous mycotic infection caused by the opportunistic organism Cryptococcus neoformans (Figure 1). This encapsulated budding yeast is isolated from pigeon droppings and contaminated soil worldwide. Inhalation can result in an acute, subacute or chronic pulmonary infection, with systemic dissemination occurring more often in immunocompromised patients. Cutaneous involvement is usually secondary to disseminated disease, but primary disease from direct inoculation can occur. Systemic infection has a poor prognosis, so rapid detection and treatment is critical.
Epidemiology and Pathogenesis
C neoformans has two varieties: variety neoformans, the major variety, and variety gatii. There are four capsular serotypes of C neoformans, with C neoformans var. neoformans possessing types A, D or AD. C neoformans is found worldwide with var. neoformans commonly isolated from pigeon droppings as well as contaminated soil, fruits and vegetables.1,2
The organism enters the body by inhalation. Pulmonary disease is most often transitory. Hematogenous spread can occur, most commonly to the central nervous system as well as skin, bones and other viscera.3 Risk factors for systemic disease include individuals with decreased cell mediated immunity. Immunocompromised individuals with HIV, those on corticosteroid therapy, organ transplant recipients and patients with sarcoidosis, chronic leukemia or lymphoma are at risk; infections with cryptococcosis may be the first sign of an underlying illness.4 Primary inoculation of the skin can occur but is very rare.5,6 Risk factors for primary disease include living in a rural area, a lifestyle that predisposes one to traumatic skin lesions and frequent contact with soil.6
During clinical exam, the presence of cutaneous lesions almost always represents part of a systemic infection, even when clinical evidence or other organ involvement is not readily apparent (Figure 2).3 Skin lesions occur in up to 15% of disseminated disease.4,7 As with other deep cutaneous mycotic infections, a large clinical spectrum exists for the lesions of cryptococcosis. Translucent papules, nodules and ulcers may be present and lesions can also resemble herpes simplex, molluscum contagiosum or neoplasms (Figure 3).1-3 Lesions on the mucosal surface can occasionally be present (Table 1).3
In cutaneous cryptococcosis, there are two general responses that both result in significant changes in the dermis. The same lesion can also show both reactions in different areas. In the mucoid or gelatinous response, there are numerous organisms occupying and replacing the collagen with little tissue reaction (Figure 4).3 In the granulomatous tissue reaction, there are few organisms with little necrosis.2 In this type of reaction, the infiltrate is predominantly composed of giant cells, along with histiocytes, moderate plasma cells and fibrosis. Organisms are seen within the giant cells and free within the tissue (Figure 5, below, top right). Generally, the yeasts do not cause significant stimulation and recruitment of polymorphonuclear leukocytes, as in other deep mycoses.3
Visualization of the organisms is possible by routine gram stain and results in light blue yeast forms with a relatively thick wall.3 Spherical or oval bodies varying from 5 to 10 microns are typically surrounded by a clear halo, or capsule, that can be demonstrated by various special stains (Table 2).3 India ink visualizes the hallmark capsule (Figure 1). Mucicarmine stain is also recommended (Figure 6). The halo or capsule may be inconspicuous or absent in some lesions and are variable in size depending on the genetics of the strain as well as the growth conditions.3,4
Clinically, the lesions of cryptococcosis are non-specific; therefore, the differential diagnosis is broad (Table 3). Umbilicated papules can resemble molluscum contagiosum or herpes simplex virus and a translucent papule can mimic a basal cell carcinoma. Similarly, other deep cutaneous mycotic infections have non-specific presentations and should be considered in the differential.
Histologically, organisms are usually numerous in tissue and not easily confused if a capsule can be visualized.3 However, an individual cell may be very difficult to distinguish from that seen in North American blastomycosis.3 The two are differentiated by size, the number of organisms present, demonstration of a capsule with special stains and degree of tissue reaction (Table 4).
Direct microscopic exam can be used to detect organisms with routine H&E stain.3 If cryptococcosis is suspected, but organisms cannot be visualized, a culture can be taken using routine lab media. Colonies grow within 36 to 72 hours and show white to cream-colored, opaque colonies similar to Candida.2,4 Serology is also used to detect antibodies against the capsule with a latex agglutination test of serum, cerebrospinal fluid or urine.2,4 High titers correlate with a poor prognosis. Molecular DNA-based methods are also available but are less commonly used since other methods are usually sufficient for making an accurate diagnosis.
Secondary cutaneous cryptococcosis has a poor prognosis and is frequently fatal, so adequate and timely treatment is critical. Recently, detailed guidelines on the treatment of systemic disease has been described by the Infectious Diseases Society of America.7 Treatment depends on several factors, including the host’s immune status, severity of disease and the virulence of the causative species.7 Induction therapy with Amphotericin B with flucytosine is the standard for treatment and fluconazole is necessary for maintenance therapy.2,7 Other antifungals such as itraconazole, fluconazole and voriconazole are additional options for treatment (Table 5).2 In primary cutaneous disease of an immunocompetent host with no signs of systemic involvement, fluconazole should be considered for treatment, as it has less toxic effects than amphotericin B.7
• Cryptococcosis is a deep cutaneous mycotic infection caused by the opportunistic organism Cryptococcus neoformans.
• Cryptococcosis has a variable clinical presentation and can appear as single or multiple translucent or umbilicated papules, nodules, ulcerations or abscesses.
• Histology reveals either a gelatinous response with numerous organisms or a granulomatous reaction with fewer organisms and little tissue necrosis.
• Organisms can usually be visualized with H&E stain, but additional special stains like India ink and mucicarmine are frequently used to visualize the capsule.
• Fungal culture, serology and molecular methods are additional tools to aid in diagnosis if visualization by direct microscopic exam cannot confirm the diagnosis.
• Amphotericin B is the standard for treatment of secondary cutaneous cryptococcosis.
• Additional treatment options include other antifungal agents including itraconazole, fluconazole, voriconazole and flucytosine.
Ms. Feneran is a medical student at Wake Forest University School of Medicine in Winston-Salem, NC, and is associated with the Center for Dermatology Research there. Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine, Winston-Salem, NC.
Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Ms. Feneran and Dr. Feldman disclose that they have no real or apparent conflicts of interest or financial interests or arrangements with any companies or products mentioned in this article.