Cryptococcosis

Essentials of Diagnosis

• Predisposing factors

  • Chemotherapy for hematologic malignancies

  • Hodgkin disease

  • Corticosteroid therapy

  • Structural lung diseases

  • AIDS

  • Transplant recipients

  • TNF-alpha inhibitor therapy

• Most common cause of fungal meningitis

• Symptoms of headache, abnormal mental status; meningismus seen occasionally, though rarely in patients with AIDS

• Demonstration of capsular polysaccharide antigen in cerebrospinal fluid (CSF) diagnostic

General Considerations

• Infection is due to

  • Cryptococcus neoformans, an encapsulated budding yeast that is found worldwide in soil and in dried bird droppings

  • Cryptococcus gattii is a closely related species that also causes disease in humans, although it may affect more ostensibly immunocompetent persons

• C neoformans accounts for majority of disease worldwide and is especially problematic in immunocompromised patients

• C neoformans variety gattii causes localized infections (cryptococcomas) in tropical climates and has close association with eucalyptus plants

• C neoformans has a special predilection for the CNS and is the most common fungal cause of meningitis

• The polysaccharide capsule is a major virulence factor and provides the basis for antigen testing that is widely available and quite useful in establishing the diagnosis

• Infection is acquired through inhalation of the organisms into the lungs where infection may remain localized, heal, or disseminate

• Progressive pulmonary disease can occur in either HIV-infected or noninfected patients in the absence of dissemination

• Disseminated disease in immunocompetent patients can be especially recalcitrant to therapy

Demographics

• Symptomatic cryptococcal pneumonia rarely develops in immunocompetent patients but can occur

• Progressive lung disease and dissemination usually occur in

  • Cellular immunodeficiency, including underlying hematologic malignancies under treatment

  • Hodgkin disease

  • Long-term corticosteroid therapy

  • Solid-organ transplant

  • HIV infection

Symptoms and Signs

• Disseminated cryptococcosis

  • Most commonly manifests as meningitis, which usually begins with headache, then confusion

  • Cranial nerve abnormalities, nausea, and vomiting may occur

• Nuchal rigidity and meningeal signs in about 50%, but uncommon in patients with AIDS

• C gattii infection frequently presents with respiratory symptoms along with neurologic signs caused by space-occupying lesions in the CNS

• Primary C neoformans infection of the skin may mimic bacterial cellulitis, especially in persons receiving immunosuppressive therapy such as corticosteroids

• The immune reconstitution inflammatory syndrome (IRIS), which is paradoxical clinical worsening associated with improved immunologic status, has been reported in HIV-positive and transplant patients with cryptococcosis as well as non-AIDS patients being treated for C gattii infection

Differential Diagnosis

• Histoplasmosis

• Coccidioidomycosis

• Tuberculous meningitis

• Neurosyphilis

• Acanthamoeba (amebic encephalitis)

• Toxoplasmosis

• Lyme meningitis

Laboratory Tests

• In HIV-infected patients with cryptococcosis, serum cryptococcal antigen positive in 95%

• In patients with cryptococcal meningitis, CSF shows

  • Increased opening pressure

  • Variable pleocytosis

  • Increased protein

  • Decreased glucose

  • Budding encapsulated fungi

• Up to 50% of AIDS patients have no CSF pleocytosis

• CSF positive for cryptococcal capsular antigen in > 90%

• Blood cultures also have good yield, especially in HIV-infected patients

• Antigen testing by a lateral flow assay

  • Has improved sensitivity and specificity over the conventional latex agglutination test

  • Can provide more rapid diagnostic results

Imaging Studies

• MRI is more sensitive than CT in finding CNS abnormalities, such as cryptococcomas

Diagnostic Procedures

• Given the high propensity of the organism for the CSF, lumbar puncture is mandatory for any patient with disseminated disease

• Examination of CSF via fungal stain, culture, and antigen tests usually sufficient to establish diagnosis

Medications

Acute therapy

• Because of decreased efficacy initial therapy with an azole alone is not recommended for treatment of acute cryptococcal meningitis

• Induction therapy

  • Liposomal amphotericin B, 3–4 mg/kg/day intravenously for 14 days followed by fluconazole, 400 mg/day orally for an additional 8 weeks is preferred

  • This regimen has been quite effective, achieving clinical responses and CSF sterilization in about 70% of patients

• Switch from amphotericin B to fluconazole after clinical improvement and conversion of CSF culture to negative

• Early addition of flucytosine, 100 mg/kg/day orally divided into four equal doses given every 6 hours, improves survival, but toxicity is common

• Non–AIDS-related cryptococcal meningitis

  • Similar treatment, although mortality is higher

  • Continue therapy until CSF culture is negative

Maintenance therapy

• AIDS-related cryptococcal meningitis: fluconazole, 200 mg orally once daily long-term, after immediate therapy to prevent > 50% relapse rate

• Secondary prophylaxis can be discontinued after patients have had satisfactory response to antiretroviral therapy (eg, CD4 cell count > 100–200 cells/mcL for at least 6 months)

• Published guidelines suggest that 6–12 months of fluconazole can be used as maintenance therapy in patients without AIDS following successful treatment of the acute illness

Therapeutic Procedures

• Repeated lumbar punctures or ventricular shunting should be done to relieve high CSF pressures or hydrocephalus

Complications

• Communicating hydrocephalus

Prognosis

• Poor prognosis indicated by

  • Activity of predisposing conditions

  • Older age

  • Organ failure

  • Lack of CSF pleocytosis

  • High initial antigen titer in serum or CSF

  • Decreased mental status

  • Increased intracranial pressure

  • Disease outside CNS

• Fluconazole maintenance therapy after HIV-related meningitis in patients whose CSF has been sterilized by induction therapy

  • Decreases relapse rate tenfold compared with placebo

  • Decreases relapse rate threefold compared with weekly amphotericin B