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William G. Powderly



Treatment of cryptococcal meningitis in patients with AIDS—recommendation for initial use of the combination of amphotericin B and flucytosine, and that all patients should receive antiretroviral therapy, but this should be delayed for at least 6–8 weeks.

Updated on 28 Nov 2013. The previous version of this content can be found here.
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Cryptococcus neoformans, which is found worldwide as a soil organism and thought to be transmitted by inhalation, most often causes disease in patients with abnormal cell-mediated immunity, notably patients with HIV infection and solid-organ transplant recipients, but the infection also occurs rarely in apparently immunocompetent people in restricted geographical areas, especially involving C. neoformans var. gattii.

The most common presentation is with subacute meningoencephalitis, but other manifestations, e.g. isolated pulmonary disease, are well described. Diagnosis is by culture or serology. Untreated cryptococcal meningitis is fatal: aside from supportive care (including monitoring for raised intracranial pressure), the therapy of choice is an initial period (at least two weeks) of amphotericin B, followed by at least 3 months of fluconazole. Most immunocompromised patients subsequently require maintenance suppressive therapy, usually with fluconazole.

Aetiology and epidemiology

Infection with the fungus Cryptococcus neoformans occurs mainly in patients with impaired cell-mediated immunity. It is the most common systemic fungal infection in patients infected with HIV and is also seen as a complication of solid-organ transplantation, lymphoma, and corticosteroid therapy. C. neoformans is found worldwide as a soil organism; it is an encapsulated yeast measuring from 4 to 6 μ‎m with a surrounding polysaccharide capsule ranging in size from 1 to over 30 μ‎m. Two varieties exist, distinguishable by serology: C. neoformans var. neoformans (serotypes A and D) and C. neoformans var. gattii (serotypes B and C). Virtually all HIV-associated infection is caused by C. neoformans var. neoformans. About 5% of HIV-infected patients in the Western world develop disseminated cryptococcosis; the disease is more prevalent in sub-Saharan Africa and South-East Asia. C. neoformans var. gattii infection is more common in tropical and subtropical areas (Australia, New Guinea, and the Philippines) in apparently immunocompetent people. Recent outbreaks of C. neoformans var. gattii infection have occurred in the Pacific Northwest of North America. It has only rarely been reported in HIV-immunosuppressed patients.

The exact mechanism of infection is unknown. It is assumed that transmission occurs via inhalation of the organism leading to colonization of the airways and subsequent respiratory infection. Throughout the world, the excreta of birds such as pigeons are the richest environmental source of C. neoformans var. neoformans. The ecological association of C. neoformans var. gattii is with river red and forest river gum trees (Eucalyptus camaldulensis and E. tereticornis) and with mammals such as koalas. It has been suggested that infective basidiospores are released at flowering.

In the case of C. neoformans var. neoformans, the absence of an intact cell-mediated response results in ineffective clearance with subsequent dissemination. The polysaccharide capsule, composed mainly of glucuronoxylomannan, is thought to be its primary virulence factor. It is not clear whether cryptococcal infection in immunocompromised patients represents acute primary infection or reactivation of previously dormant disease.

Clinical features

The most common presentation of cryptococcosis is a subacute meningitis or meningoencephalitis with fever, malaise, headache, and altered behaviour and level of consciousness. Symptoms are usually present for 2 to 4 weeks before diagnosis. Classic meningeal symptoms and signs (such as neck stiffness or photophobia) (Fig. occur in only about a quarter to a third of patients. Papilloedema and cranial nerve palsies (especially VI and VII) are common (Fig. Patients may present with encephalopathic symptoms such as lethargy, altered mentation, personality changes, and memory loss. Analysis of the cerebrospinal fluid usually shows a mildly elevated serum protein, normal or slightly low glucose, and a lymphocytic pleocytosis. India ink staining of the cerebrospinal fluid will usually reveal the yeast. Cryptococcal antigen is almost invariably detectable in the cerebrospinal fluid. The opening pressure in the cerebrospinal fluid is elevated in a majority of patients.

Fig. Neck stiffness in a Papua New Guinean patient with Cryptococcus neoformans var. gattii meningitis.

Neck stiffness in a Papua New Guinean patient with Cryptococcus neoformans var. gattii meningitis.

(Copyright D A Warrell.)

Fig. Right cranial VI (abducens) nerve paralysis in an African HIV-seropositive patient with Cryptococcus neoformans var. neoformans meningitis.

Right cranial VI (abducens) nerve paralysis in an African HIV-seropositive patient with Cryptococcus neoformans var. neoformans meningitis.

(Copyright D A Warrell.)

Infection with C. neoformans can involve sites other than the meninges. Isolated pulmonary disease has been well described and usually presents as a solitary nodule in the absence of other symptoms. Cryptococcal pneumonia also occurs. In immunocompromised patients, especially those with AIDS, subsequent dissemination is common but presentations such as cough or dyspnoea, and abnormal chest radiographs may be the initial finding. Many patients have positive blood cultures. Skin involvement is common; several types of skin lesion have been described (Fig. but the most common form is that resembling molluscum contagiosum. Osteolytic bone lesions and prostatic involvement have also been described.

Fig. Cryptococcal cutaneous ulcer.

Cryptococcal cutaneous ulcer.

(Courtesy of Professor R Hay.)

In New Guinea, C. neoformans var. gattii is the commonest cause of chronic meningitis (Fig. Immunocompetent people are affected. Compared to C. neoformans var. neoformans meningitis in AIDS patients, patients with C. neoformans var. gattii have more aggressive retinal involvement with papilloedema and haemorrhagic papillitis in more than a half of patients, leading to blindness in one-third of survivors.

Emergence of Cryptococcus gattii in British Columbia, Canada and the Pacific Northwest

Cases of Cryptococcus gattii were described on Vancouver Island, British Columbia, Canada, in 1999. The Pacific Northwest of North America (British Columbia in Canada, and Washington and Oregon in the United States) now has one of the highest incidences of this infection worldwide. Although not as clearly associated with classic immunosuppressed states such as HIV/AIDS or transplantation, infection with C. gattii in this region of the world is more likely to occur in older patients with other comorbid conditions. Infection with C. gattii appears to cause cryptococcomas in the lung and brain (often large, multifocal lesions) more commonly than C. neoformans.


The latex agglutination test for cryptococcal polysaccharide antigen in the serum is highly sensitive and specific in the diagnosis of infection with C. neoformans and a positive serum cryptococcal antigen titre of greater than 1:8 is presumptive evidence of cryptococcal infection. Such patients should be evaluated for possible meningeal involvement. Culture of C. neoformans from any site should also be regarded as significant and is an indication for further evaluation and initiation of therapy.


Management of patients with cryptococcal infection depends on the extent of the disease and the immune status of the patient. The finding of a solitary pulmonary nodule in a normal host may not need treatment, provided patients have careful follow up. Fluconazole (200–400 mg/day) can be given for 3 to 6 months in most patients with localized pulmonary disease. Extrapulmonary disease is generally managed in the same way as meningitis. In patients who are not known to be immunosuppressed, a search for underlying problems should be initiated. An HIV antibody test should be performed, as cryptococcal meningitis may be the initial AIDS-defining event. Additionally, a CD4+ lymphocyte count should be considered, as cryptococcal infection has been described as one of the manifestations of so-called ‘isolated CD4 T lymphocytopenia’.

CryptococcosisUntreated, cryptococcal meningitis is fatal. In patients with AIDS, the combination of amphotericin B (0.7—1.0 mg/kg intravenously) and flucytosine (100 mg/kg per day in three or four divided doses) given for 2 weeks followed by fluconazole (400 mg orally) for a further 8 weeks is associated with the best outcome to date in prospective trials, with a mortality of 10-15% and a mycological response of approximately 70%. This regimen is also reasonable for treatment of meningitis in other circumstances. In other hosts, more prolonged use (4–6 weeks) of amphotericin B and flucytosine may be curative but is also toxic. In this circumstance (e.g. solid-organ transplant patients requiring immunosuppressive therapy), lipid or liposomal formulations of amphotericin B may be less toxic options.

Clinical deterioration in patients with meningitis may be due to cerebral oedema, which may be diagnosed by a raised opening pressure of the cerebrospinal fluid. All patients with cryptococcal meningitis should have the opening pressure measured when a lumbar puncture is performed; if the opening pressure is high (>25 cmH2O), pressure should be reduced by repeated lumbar punctures, a lumbar drain, or a shunt.

Cryptococcosis in the immunocompetent patient

Provided HIV infection and isolated CD4 lymphopenia have been excluded, immunocompetent patients with cryptococcal meningitis can be generally managed with a shorter (3–4 months) course of treatment. An approach similar to that recommended for immunosuppressed patients is still recommended; i.e. an initial (2–4 weeks) of amphotericin B-based induction therapy followed by 8 to 10 weeks of fluconazole.

Cryptococcal meningitis in AIDS requires lifelong suppressive therapy unless the immunosuppression is reversed with effective treatment of HIV infection. In that circumstance, treatment can be discontinued if the CD4+ lymphocyte count increases to over 200 cells/mm3. In other immunocompromised patients, suppressive treatment for 6 to 12 months may be given. Effective antiretroviral therapy may also sufficiently improve the immune system such that there is an immunological response to the fungal infection. This may be associated with clinical deterioration and apparent relapse of symptoms; this immune reconstitution syndrome (IRIS) should not prompt change in antifungal therapy and patients should receive anti-inflammatory therapy, as needed. It has also been described in transplant patients whose immunosuppressive therapy is decreased during management of the cryptococcal infection.

CryptococcosisAll patients should receive antiretroviral therapy. However, recent randomized clinical trials suggest that early (within two weeks of diagnosis) initiation of anti-retroviral therapy is associated with an increased mortality in patients with cryptococcal meningitis, possibly because of the development of IRIS. Consequently initiation of antiretroviral therapy should be delayed for at least 6–8 weeks.

Fluconazole, 200 mg daily, is the suppressive treatment of choice. Fluconazole, in dosages ranging from 400 mg weekly to 200 mg daily, and itraconazole, 100 mg twice daily, are very effective in preventing invasive cryptococcal infections, especially in HIV-positive patients with CD4 counts less than 50 to 100 cells/mm3. However, because of the relative infrequency of invasive fungal infections, antifungal prophylaxis does not prolong life and is not routinely recommended where antiretroviral therapy is readily available.

Further reading

Bicanic T, Harrison TS (2005). Cryptococcal meningitis. Br Med Bull, 72, 99–118.Find this resource:

    Boulware D, et al. (2013). ART initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia. Abstract 144.Find this resource:

      Datta K, et al. (2009). Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerg Infect Dis, 15, 1185–91.Find this resource:

        Day JN, et al. (2013). Combination antifungal therapy for HIV-associated cryptococcal meningitis. N Engl J Med, 368, 1291–1302.Find this resource:

          Ellis DH, Pfeiffer TJ (1990). Ecology, lifecycle, and infections propagule of Cryptococcus neoformans. Lancet, 36, 923–5.Find this resource:

            Graybill JR, et al. (2000). Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis, 30, 47–54.Find this resource:

              Makadzange AT, et al. (2010). Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa. Clin Infect Dis, 50, 1532–8.Find this resource:

                Perfect JR, et al. (2010). Clinical Practice guidelines for the management of cryptococcal disease: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis, 50, 291–322.Find this resource:

                  Shelbourne S, et al. (2005). The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis, 40, 1049–52.Find this resource:

                    Sorrel TC (2001). Cryptococcus neoformans variety gattii. Med Mycol, 39, 155–68.Find this resource:

                      Speed B, Dunt D (1995). Clinical and host differences between infection of the two varieties of Cryptococcus neoformans. Clin Infect Dis, 21, 28–34.Find this resource: