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Wanda Sonia Robles and Mahreen Ameen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports


Cryptococcosis is a systemic mycosis acquired by the respiratory route with the primary focus of infection in the lungs. It is caused by yeasts associated with avian feces of which there are two species, Cryptococcus neoformans and Cryptococcus gattii. C. neoformans occurs worldwide and C. gattii is restricted mainly to subtropical regions and usually affects immunocompetent hosts. Pulmonary infection is often asymptomatic and self-limiting. Hematogenous dissemination typically involves the central nervous system (CNS) causing meningitis. Dissemination to the skin occurs in 10–15% of cases, and produces a variety of lesions including flesh-colored or erythematous papules and nodules. In the immunocompromised individual, molluscum contagiosum-like and acneiform lesions occur, particularly affecting the face. Cryptococcal cellulitis with necrotizing vasculitis can mimic bacterial cellulitis, and occurs more commonly in the immunocompromised patient.

With the global emergence of AIDS, the incidence of cryptococcosis is increasing and it represents the most common invasive mycosis in advanced HIV infection. With HIV co-infection, the disease is characteristically widespread affecting the lungs, meninges, skin, bone marrow, and genitourinary tract including the prostate. In the era of antiretroviral therapy (ART) the overall survival after cryptococcosis has dramatically improved: immune restoration and low serum cryptococcal antigen titers are associated with lower cryptococcosis relapse rates. However, a subset of HIV-infected individuals commenced on ART are at risk of immune reconstitution inflammatory syndrome (IRIS)-associated cryptococcosis that can be very severe. Other immunosuppressed patients also at risk of cryptococcosis include solid organ transplant recipients, those with hematologic malignancies, and those on long-term immunosuppressive therapy including corticosteroids and anti-tumor necrosis factor-α therapies.

Management strategy

Cryptococcal infection if left untreated is fatal. Treatment depends on disease extent and predisposing factors, particularly AIDS or any other immunosuppressive state. The recommended treatment in the immunocompetent with symptomatic non-meningeal infection is fluconazole 200–400 mg daily for 3 to 6 months. An alternative is itraconazole 200–400 mg daily for 6 to 12 months. More severe non-meningeal infection is treated with amphotericin B (AmB) 0.5–1.0 mg/kg daily for 6 to 10 weeks. Meningeal infection in the immunocompetent or non-HIV immunocompromised is treated with AmB 0.7–1.0 mg/kg daily plus 5-flucytosine 100 mg/kg daily for 2 weeks followed by fluconazole 400 mg daily for a minimum of 10 weeks (up to six to 12 months depending on the clinical status of the patient).

Cryptococcal disease with HIV always requires treatment. For non-disseminated infection, fluconazole (200–400 mg daily) is given or itraconazole (200–400 mg daily) as an alternative. More severe infection is treated with a combination of fluconazole (400 mg daily) and flucytosine (100–150 mg daily) for 10 weeks followed by fluconazole maintenance therapy (200 mg daily). Cryptococcal meningitis with HIV is treated with AmB (0.7–1.0 mg/kg daily) and flucytosine (100 mg/kg daily) for a two- to 10-week induction period followed by fluconazole maintenance therapy, or alternatively with fluconazole (400–800 mg daily) and flucytosine (100–150 mg/kg daily) for 6 weeks. The lipid formulation of AmB can be used instead in those with impaired renal function. There is now trial data suggesting that it is safe to discontinue maintenance therapy in patients treated for cryptococcal meningitis receiving highly active antiretroviral therapy (HAART) provided the CD4 count increases to an excess of 100 cells/µL.

The extended spectrum azoles (posaconazole and voriconazole) may have a role in salvage situations. The echinocandins have no in vivo activity against Cryptococcus species.

Specific investigations

India ink examination of cerebrospinal fluid (CSF), pus, skin scrapings and other fluids may demonstrate the yeast. Culture of skin, CSF, blood, sputum, urine or bone marrow enables confirmation. The cryptococcal antigen test (on CSF, blood, and urine) is sensitive and specific, and it can be used for following therapy response. In tissue specimens, C. neoformans is difficult to visualize with routine hematoxylin and eosin stains, requiring the use of special stains.

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