Cryptococcosis

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Cryptococcosis

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

image

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.

First-line therapies

image Amphotericin B B
image Amphotericin B plus flucytosine B
image Fluconazole B

Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial.

Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, Harrison TS. Lancet 2004; 363: 1764–7.

This controlled trial assessed the fungicidal activity of combinations of AmB, flucytosine, and fluconazole for the treatment of cryptococcal meningitis. Sixty-four patients with a first episode of HIV-associated cryptococcal meningitis were randomized to initial treatment with: AmB (0.7 mg/kg daily); AmB plus flucytosine (100 mg/kg daily); AmB plus fluconazole (400 mg daily); or triple therapy with AmB, flucytosine, and fluconazole. Results demonstrated that clearance of cryptococci from the CSF was exponential and significantly faster with AmB and flucytosine dual therapy than with any other drug combination.

High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial.

Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, et al. Clin Infect Dis 2008; 47: 123–30.

In this study from South Africa, 64 HIV-seropositive, antiretroviral therapy-naive patients with a first episode of cryptococcal meningitis were randomized to receive either: AmB 0.7 mg/kg/day plus flucytosine 25 mg/kg four times daily (n = 30); or AmB 1 mg/kg daily plus flucytosine, 25 mg/kg four times daily (n = 34). Both regimens were given for 2 weeks followed by oral fluconazole. The primary outcome measure was early fungicidal activity determined by CSF cryptococcal cultures. Early fungicidal activity was significantly greater for the first regimen. The 10-week mortality rate was 24%, with no difference between groups.

Second-line therapies

image Itraconazole B
image Flucytosine plus fluconazole C
image Voriconazole B

Third-line therapies

Recombinant interferon-gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis.

Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, et al. J Infect Dis 2004; 189: 2185–91.

This was a phase II, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)-gamma 1b in patients with AIDS and acute cryptococcal meningitis. Patients received 100 or 200 µg of rIFN-gamma 1b or placebo, thrice weekly for 10 weeks, plus standard therapy with AmB, with or without flucytosine, followed by fluconazole. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN-gamma 1b (100 µg) recipients, and 32% of rIFN-gamma 1b (200 µg) recipients. There was improved combined mycological and clinical success in rIFN-gamma 1b recipients (26% vs 8%; p = 0.078), and therapy was well tolerated.

This study suggests a role for adjuvant therapies.

Guidelines

Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America.

Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clin Infect Dis 2010; 50: 291–322.

These updated guidelines emphasize that control of host immunity, the site of infection, antifungal drug toxicity, and underlying disease are still the most critical factors for the successful management of cryptococcosis. The management strategy for cryptococcal disease is organized under four major headings with additional subdivisions: treatment of meningoencephalitis (in HIV-infected individuals, transplant recipients, and others); treatment of non-meningeal cryptococcosis (pulmonary and extrapulmonary sites); complications during treatment (including IRIS and relapse); and cryptococcosis in special clinical situations (pregnancy, children, resource-limited regions, and C. gatti infections).

The recommended treatment for immunosuppressed and immunocompetent patients with mild to moderate non-meningeal cryptococcosis is fluconazole 400 mg daily for 6 to 12 months. The treatment of choice for patients with HIV infection and cryptococcal meningitis is induction therapy with parenteral AmB 0.7–1.0 mg/kg daily plus oral flucytosine 100 mg/kg daily for 2 weeks, followed by fluconazole 400 mg daily for a minimum period of 8 weeks. Amphotericin B in lipid formulations can be used for patients with renal impairment. It is recommended that all HIV-infected individuals receive prophylaxis against cryptococcosis and that this is continued for life. Fluconazole 200 mg daily is given or itraconazole 200 mg twice daily in those unable to tolerate fluconazole.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Cryptococcosis

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

image

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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