36-06: Cryptococcosis

General Considerations

Cryptococcosis is mainly caused by Cryptococcus neoformans, an encapsulated budding yeast that has been found worldwide in soil and on dried pigeon dung. Cryptococcus gattii is a closely related species that also causes disease in humans, although C gattii may affect more ostensibly immunocompetent persons. It is a major cause of cryptococcosis in the Pacific northwestern region of the United States and may result in more severe disease than C neoformans.

Infections are acquired by inhalation. In the lung, the infection may remain localized, heal, or disseminate. Clinically apparent cryptococcal pneumonia rarely develops in immunocompetent persons. Progressive lung disease and dissemination most often occur in the setting of cellular immunodeficiency, including underlying hematologic malignancies under treatment, Hodgkin lymphoma, long-term corticosteroid therapy, solid-organ transplant, TNF-alpha inhibitor therapy, or HIV infection.

Clinical Findings

A. Symptoms and Signs

Pulmonary disease ranges from simple nodules to widespread infiltrates leading to respiratory failure. Disseminated disease may involve any organ, but CNS disease predominates. Headache is usually the first symptom of meningitis. Confusion and other mental status changes as well as cranial nerve abnormalities, nausea, and vomiting may be seen as the disease progresses. Nuchal rigidity and meningeal signs occur about 50% of the time but are uncommon in patients with AIDS. Communicating hydrocephalus may complicate the course. 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 patient being treated for C gattii infection.

B. Laboratory Findings

Respiratory tract disease is diagnosed by culture of respiratory secretions or pleural fluid. For suspected meningeal disease, lumbar puncture is the preferred diagnostic procedure. Spinal fluid findings include increased opening pressure, variable pleocytosis, increased protein, and decreased glucose, though as many as 50% of AIDS patients have no pleocytosis. Gram stain of the CSF usually reveals budding, encapsulated fungi. Cryptococcal capsular antigen in CSF and culture together establish the diagnosis over 90% of the time. Patients with AIDS often have the antigen in both CSF and serum, and extrameningeal disease (lungs, blood, urinary tract) is common. In patients with AIDS, the serum cryptococcal antigen is also a sensitive screening test for meningitis, being positive in over 95% of cases. MRI is more sensitive than CT in finding CNS abnormalities such as cryptococcomas. Antigen testing by lateral flow assay has improved sensitivity and specificity over the conventional latex agglutination test and can provide more rapid diagnostic results.

Treatment

Because of decreased efficacy, initial therapy with an azole alone is not recommended for treatment of acute cryptococcal meningitis. Liposomal amphotericin B, 3–4 mg/kg/day intravenously for 14 days, is the preferred agent for induction therapy, followed by an additional 8 weeks of fluconazole, 400 mg/day orally for consolidation (Table 36–1). This regimen is quite effective, achieving clinical responses and CSF sterilization in about 70% of patients. The addition of flucytosine has been associated with improved survival, but toxicity is common. Flucytosine is administered orally at a dose of 100 mg/kg/day divided into four equal doses and given every 6 hours. Hematologic parameters should be closely monitored during flucytosine therapy, and it is important to adjust the dose for any decreases in kidney function. The cost of flucytosine has made it prohibitively expensive in areas with limited resources. Fluconazole (800–1200 mg orally daily) may be given with amphotericin B when flucytosine is not available or patients cannot tolerate it. Frequent, repeated lumbar punctures or ventricular shunting should be performed to relieve high CSF pressures or if hydrocephalus is a complication. Corticosteroids should not be used. Failure to adequately relieve raised intracranial pressure is a major cause of morbidity and mortality. The end points for amphotericin B therapy and for switching to maintenance with oral fluconazole are a favorable clinical response (decrease in temperature; improvement in headache, nausea, vomiting, and Mini-Mental State Examination scores), improvement in CSF biochemical parameters and, most importantly, conversion of CSF culture to negative. Serial determinations of cryptococcal antigen titers have been demonstrated to be of limited value in following response to therapy.

A similar approach is reasonable for patients with cryptococcal meningitis in the absence of AIDS, though the mortality rate is higher. Therapy is generally continued until CSF cultures become negative. Maintenance antifungal therapy is important after treatment of an acute episode in AIDS-related cases, since otherwise the rate of relapse is greater than 50%. Fluconazole, 200 mg/day orally, is the maintenance therapy of choice, decreasing the relapse rate approximately tenfold compared with placebo and threefold compared with weekly amphotericin B in patients whose CSF has been sterilized by the induction therapy. After successful therapy of cryptococcal meningitis, it is possible to discontinue secondary prophylaxis with fluconazole in individuals with AIDS who have had a satisfactory response to antiretroviral therapy (eg, CD4 cell count greater than 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.

Prognosis

Factors that indicate a poor prognosis include the activity of the predisposing conditions, older age, organ failure, lack of spinal fluid pleocytosis, high initial antigen titer in either serum or CSF, decreased mental status, increased intracranial pressure, and the presence of disease outside the nervous system.