Cryptococcal meningitis

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By Joseph R Berger MD

Prevention is only relevant in the AIDS population. Two forms of prevention are possible. As the risk of cryptococcal meningitis is considerable in HIV-infected persons with CD4 T lymphocyte counts below 100 cells/cu mm, primary prophylaxis is considered in this population. Relapse is common in the patient with AIDS who has already suffered from cryptococcal meningitis. Prevention in that population is regarded as secondary prophylaxis.

Primary prophylaxis. The safety and efficacy of triazole antibiotics has raised the possibility of primary prevention in susceptible immunosuppressed HIV-infected individuals. An open label trial showed a reduced rate of cryptococcal meningitis in patients with CD4 levels less than 68/mm3 given 100 mg/day fluconazole compared to controls from the previous 2 years seen in the same site (Nightingale et al 1992). One review suggested that primary prophylaxis be considered for patients with CD4 counts less than 50/mm3, but noted that the impact of such therapy on survival or on the susceptibility of various fungi to current agents is uncertain (Pinner et al 1995). A Cochrane Database review supported either fluconazole or itraconazole to reduce the incidence of cryptococcal disease in adults with advanced HIV infection (Chang 2005).

Prevention of relapse. Early series of AIDS patients with cryptococcal meningitis treated only with acute therapy were associated with relapse rates of 50% to 60% (Kovacs et al 1985; Zuger et al 1986; Clark et al 1990). Open label trials of fluconazole (Sugar and Saunders 1988) and itraconazole (de Gans et al 1988; Denning et al 1991) and a retrospective series in which some patients were given amphotericin B or ketoconazole (Chuck and Sande 1989) suggested survival benefit for maintenance therapy. A large placebo-controlled trial documented a 19% persistence of positive CSF cultures following 6 weeks of primary therapy with amphotericin alone or in combination with flucytosine and a significant benefit for fluconazole 100 to 200 mg/day in preventing relapse in patients with sterile CSF (Bozzette et al 1991). Subsequently, a study comparing fluconazole 200 mg/day to amphotericin B 1.0 mg/kg per week found the former agent to be more effective with less toxicity (Powderly et al 1992).

Despite maintenance therapy, recurrent cryptococcal meningitis occurs in 2% to 16% of AIDS patients (Chuck and Sande 1989; Clark et al 1990; Bozzette et al 1991; Powderly et al 1992). Serum cryptococcal antigen is not a reliable marker for CNS infection (Eng et al 1986; Bozzette et al 1991). CSF cryptococcal antigen titers decline with successful therapy, but subsequent rises with recurrence are apparently acute and not predicted by routine monitoring of CSF (Bozzette et al 1991). Persistence of cryptococcus in the prostate despite sterilization of CSF has been shown (Larsen et al 1989). Molecular genetic studies have revealed clonal identity of serial isolates obtained from 3 AIDS patients with recurrent meningitis (Spitzer et al 1993). Although prospective studies have yet to be done on the natural history of persistently positive cultures in patients with suppression of clinical disease, it seems likely that recurrence results from sequestered organisms in CSF or elsewhere.

Failures of primary or secondary prophylactic therapy might potentially be due to resistant fungi. A case in which resistance to fluconazole appeared to evolve during therapy has been reported (Paugam et al 1994), and another in which resistance of a Cryptococcus neoformans var gattii species to fluconazole was noted (Peetermans et al 1993). In one small series, no change in sensitivity of serial isolates to either fluconazole or amphotericin was detected, but there was a wide variation in the dose sensitivity to fluconazole among different isolates (Casadevall et al 1993). Higher doses of fluconazole to 800 mg/day have been reported to be effective salvage therapy in patients failing conventional therapy with either fluconazole or amphotericin (Berry et al 1992), and response may be observed in those resistant to amphotericin B (Powderly et al 1992).

In the era of highly active antiretroviral therapy with which a significant return to normal immune function may be observed, the necessity of secondary prophylaxis remains an open question. One prospective study addressing that issue found no recurrence of cryptococcal meningitis during a median 48 month follow up in a group of patients with CD4 cell counts greater than 100 cell/cu mm and an undetectable HIV RNA level that had been sustained over 3 months (Vibhagool et al 2003).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited