Cryptococcus neoformans, a yeast-like fungus, is the etiologic agent of cryptococcosis. Cryptococcal strains are antigenically and genetically diverse. Both C. neoformans and C. gattii are pathogenic for humans and can cause cryptococcosis. C. neoformans consists of serotypes A and D, and C. gattii consists of serotypes B and C. Currently, most authorities further subdivide C. neoformans into two varieties: grubii (serotype A) and neoformans (serotype D). Most clinical microbiology laboratories do not routinely distinguish among cryptococcal species and varieties but rather identify all isolates simply as C. neoformans.  


Cryptococcosis was first described in the 1890s but remained relatively rare until the mid-twentieth century, when advances in diagnosis and increases in the number of immunosuppressed individuals markedly raised its reported prevalence. The spectrum of disease caused by C. neoformans consists predominantly of meningoencephalitis and pneumonia, but skin and soft tissue infections also occur. Serologic studies have shown that, although cryptococcal infection is common among immunocompetent individuals, cryptococcal disease (cryptococcosis) is relatively rare in the absence of impaired immunity. Individuals at high risk for cryptococcosis include patients with hematologic malignancies, recipients of solid organ transplants who require ongoing immunosuppressive therapy, persons whose medical conditions necessitate glucocorticoid therapy, and patients with advanced HIV infection and CD4+ T-lymphocyte counts of <200/ìL.

Since the onset of the HIV pandemic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS (Chap. 90).To understand the impact of HIV infection on the epidemiology of cryptococcosis, it is instructive to note that in the early 1990s there were >1000 cases of cryptococcal meningitis each year in New York City—a figure far exceeding that for all cases of bacterial meningitis.With the advent of effective antiretroviral therapy, the incidence of AIDS-related cryptococcosis has been sharply reduced among treated individuals; however, the disease remains distressingly common in regions where antiretroviral therapy is not readily available, such as Africa and Asia, where up to one-third of patients with AIDS have cryptococcosis. Cryptococcal infection is acquired from the environment. C. neoformans and C. gattii inhabit different ecologic niches.

C. neoformans is frequently found in soils contaminated with avian excreta and can easily be recovered from shaded and humid soils contaminated with pigeon droppings. In contrast, C. gattii is not found in bird feces. Instead, it inhabits a variety of arboreal species, including several types of eucalyptus tree. C. neoformans strains are found throughout the world; however, var. grubii (serotype A) strains are far more common than var. neoformans (serotype D) strains among both clinical and environmental isolates. The geographic distribution of C. gattii was thought to be largely limited to tropical regions until an outbreak of cryptococcosis caused by a new serotype B strain began in Vancouver in 1999. In addition to the different geographic distributions of the two cryptococcal species, individual susceptibility to these species affects epidemiology. Cryptococcosis caused by the C. neoformans varieties occurs mostly in individuals with AIDS (Chap. 90) and other forms of impaired immunity. In contrast, C. gattii–related disease is not associated with specific immune deficits and often occurs in immunocompetent individuals.


Cryptococcal infection is acquired by inhalation of aerosolized infectious particles.The exact nature of these particles is not known; the two leading candidate forms are small desiccated yeast cells and basidiospores. Little is known about the pathogenesis of initial infection. Serologic studies have shown that cryptococcal infection is acquired in childhood, but it is not known whether the initial infection is symptomatic. Given serologic documentation that cryptococcal infection is common yet cryptococcal disease is rare, the consensus is that pulmonary defense mechanisms in immunologically intact individuals are highly effective at containing C. neoformans. It is not clear whether initial infection leads to a state of immunity or whether most individuals are subject throughout life to frequent and recurrent infections that resolve without clinical disease. However, evidence indicates that some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for prolonged periods, possibly in granulomas. Thus the inhalation of C. neoformans can be followed by clearance of the organism or establishment of the latent state.

The consequences of prolonged harboring of C. neoformans in the lung are not known, but evidence from animal studies indicates that the organism’s prolonged presence could alter the immunologic milieu in the lung and predispose to allergic airway disease. Cryptococcosis usually presents clinically as chronic meningoencephalitis.The mechanisms by which C. neoformans undergoes extrapulmonary dissemination and enters the central nervous system (CNS) remain poorly understood. There is evidence that yeast cells can migrate directly across the endothelium by a mechanism that may be associated with changes in polysaccharide structure. C. neoformans has well-defined virulence factors that include the polysaccharide capsule, the ability to make melanin, and the elaboration of enzymes (e.g., phospholipase and urease) that enhance the survival of fungal cells in tissue. Among these virulence factors, the capsule and melanin production have been most extensively studied. The C. neoformans capsule is antiphagocytic, and the capsular polysaccharide has been associated with numerous deleterious effects on host immune function. Cryptococcal infections elicit little or no tissue inflammatory response.The immune dysfunction seen in cryptococcosis has been attributed to the release of copious amounts of capsular polysaccharide into tissues, where it probably interferes with local immune responses (Fig. 106-1). In clinical practice, the cryptococcal polysaccharide is the antigen that is measured as a diagnostic marker of C. neoformans infection. 

Approach to the Patient: CRYPTOCOCCOSIS

Cryptococcosis should be included in the differential diagnosis when any patient presents with findings suggestive of chronic meningitis. Concern about cryptococcosis is heightened by a history of headache and neurologic symptoms in a patient with an underlying immunosuppressive disorder or state that is associated with an increased incidence of cryptococcosis, such as advanced HIV infection or solid organ transplantation.  


The clinical manifestations of cryptococcosis reflect the site of fungal infection. C. neoformans infection can affect any tissue or organ, but the majority of cases that come to clinical attention involve the CNS and/or the lungs. CNS involvement usually presents as signs and symptoms of chronic meningitis, such as headache, fever, lethargy, sensorium deficits, memory deficits, cranial nerve paresis, vision deficits, and meningismus. Cryptococcal meningitis differs from bacterial meningitis in that many Cryptococcus-infected patients present with symptoms of several weeks’ duration. In addition, classic characteristics of meningeal irritation, such as meningismus, may be absent in cryptococcal meningitis. Indolent cases can present as subacute dementia. Meningeal cryptococcosis can lead to sudden catastrophic vision loss. Pulmonary cryptococcosis usually presents as cough, increased sputum production, and chest pain. Patients infected with C. gattii can present with granulomatous pulmonary masses known as cryptococcomas. Fever develops in a minority of cases. Like CNS disease, pulmonary cryptococcosis can follow an indolent course, and the majority of cases probably do not come to clinical attention. In fact, many cases are discovered incidentally during the workup of an abnormal chest radiograph obtained for other diagnostic purposes. Pulmonary cryptococcosis is often associated with antecedent diseases such as malignancy, diabetes, and tuberculosis. Skin lesions are common in patients with disseminated cryptococcosis and can be highly variable, including papules, plaques, purpura, vesicles, tumor-like lesions, and rashes.

The spectrum of cryptococcosis in HIV-infected patients is so varied and has changed so much since the advent of antiretroviral therapy that a distinction between HIV-related and HIV-unrelated cryptococcosis is no longer pertinent. In patients with AIDS and solid organ transplant recipients, the lesions of cutaneous cryptococcosis often resemble those of molluscum contagiosum (Fig. 106-2; Chaps. 84 and 90).


A diagnosis of cryptococcosis requires the demonstration of C. neoformans in normally sterile tissues.Visualization of the capsule of fungal cells in cerebrospinal fluid (CSF) mixed with India ink is a useful rapid diagnostic technique. C. neoformans cells in India ink have a distinctive appearance because their capsules exclude ink particles. However, the CSF India ink examination may yield negative results in patients with a low fungal burden. This examination should be performed by a trained individual, since leukocytes and fat globules can sometimes be mistaken for fungal cells. Cultures of CSF and blood that are positive for C. neoformans are diagnostic for cryptococcosis. In cryptococcal meningitis, CSF examination usually reveals evidence of chronic meningitis with mononuclear cell pleocytosis and increased protein levels. A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood. The assay is based on serologic detection of cryptococcal polysaccharide and is both sensitive and specific. A positive cryptococcal antigen test provides strong presumptive evidence for cryptococcosis; however, because the result is often negative in pulmonary cryptococcosis, the test is less useful in the diagnosis of pulmonary disease. 


Both the site of infection and the immune status of the host must be considered in the selection of therapy for cryptococcosis. The disease has two general patterns of manifestation: (1) pulmonary cryptococcosis, with no evidence of extrapulmonary dissemination; and (2) extrapulmonary (systemic) cryptococcosis, with or without meningoencephalitis. Pulmonary cryptococcosis in an immunocompetent host sometimes resolves without therapy. However, given the propensity of C. neoformans to disseminate from the lung, the inability to gauge the host’s immune status precisely, and the availability of low-toxicity therapy in the form of fluconazole, the current recommendation is for pulmonary cryptococcosis in an immunocompetent individual to be treated with fluconazole (200–400 mg/d for 3–6 months). Extrapulmonary cryptococcosis without CNS involvement in an immunocompetent host can be treated with the same regimen, although amphotericin B (AmB; 0.5–1.0 mg/kg daily for 4–6 weeks) may be required for more severe cases. In general, extrapulmonary cryptococcosis without CNS involvement requires less intensive therapy— with the caveat that morbidity and death in cryptococcosis are associated with meningeal involvement.

Thus the decision to categorize cryptococcosis as “extrapulmonary without CNS involvement” should be made only after careful evaluation of the CSF reveals no evidence of C. neoformans infection. For CNS involvement in a host without AIDS or obvious immune impairment, most authorities recommend initial therapy with AmB (0.5–1.0 mg/kg daily) during an induction phase, which is followed by prolonged therapy with fluconazole (400 mg/d) during a consolidation phase. For cryptococcal meningoencephalitis without a concomitant immunosuppressive condition, the recommended regimen is AmB (0.5–1.0 mg/kg) plus flucytosine (100 mg/kg) daily for 6–10 weeks. Alternatively, patients can be treated with AmB (0.5–1.0 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks and then with fluconazole (400 mg/d) for at least 10 weeks. Patients with immunosuppression are treated with the same initial regimens except that consolidation therapy with fluconazole is given for a prolonged period to prevent relapse. Cryptococcosis in patients with HIV infection always requires aggressive therapy and is considered incurable unless immune function improves. Consequently, therapy for cryptococcosis in the setting of AIDS has two phases: induction therapy (intended to reduce the fungal burden and alleviate symptoms) and lifelong maintenance therapy (to prevent a symptomatic clinical relapse).

Pulmonary and extrapulmonary cryptococcosis without evidence of CNS involvement can be treated with fluconazole (200–400 mg/d). In patients who have more extensive disease, flucytosine (100 mg/d) may be added to the fluconazole regimen for 10 weeks, with lifelong fluconazole maintenance therapy thereafter. For HIV-infected patients with evidence of CNS involvement, most authorities recommend induction therapy with AmB. An acceptable regimen is AmB (0.7–1.0 mg/kg) plus flucytosine (100 mg) daily for 2 weeks followed by fluconazole (400 mg/d) for at least 10 weeks and then by lifelong maintenance therapy with fluconazole (200 mg/d). Fluconazole (400–800 mg/d) plus flucytosine (150–100 mg/d) for 6–10 weeks followed by fluconazole (200 mg/d) as maintenance therapy can be used as an alternative.

Lipid formulations of AmB can be substituted for AmB deoxycholate in patients with renal impairment. Neither caspofungin nor mycofungin is effective against C. neoformans, and neither drug has a role in the treatment of cryptococcosis. Cryptococcal meningoencephalitis is often associated with increased intracranial pressure, which is believed to be responsible for damage to the brain and cranial nerves. Appropriate management of CNS cryptococcosis requires careful attention to the management of intracranial pressure, including the reduction of pressure by repeated therapeutic lumbar puncture and the placement of shunts. In HIV-infected patients with previously treated cryptococcosis who are receiving fluconazole maintenance therapy, it may be possible to discontinue antifungal drug treatment if antiretroviral therapy results in immunologic improvement.However, certain recipients of maintenance therapy who have a history of successfully treated cryptococcosis can develop a troublesome immune reconstitution syndrome when antiretroviral therapy produces a rebound in immunologic function.  


Even with antifungal therapy, cryptococcosis is associated with high rates of morbidity and death. For the majority of patients with cryptococcosis, the most important prognostic factor is the extent and the duration of the underlying immunologic deficits that predisposed them to develop the disease. Therefore, cryptococcosis is often curable with antifungal therapy in individuals with no apparent immunologic dysfunction, but, in patients with severe immunosuppression (e.g., those with AIDS), the best that can be hoped for is that antifungal therapy will induce remission, which can then be maintained with lifelong suppressive therapy. Before the advent of antiretroviral therapy, the median overall survival period for AIDS patients with cryptococcosis was <1 year. Cryptococcosis in patients with underlying neoplastic disease has a particularly poor prognosis. For CNS cryptococcosis, poor prognostic markers are a positive CSF assay for yeast cells by initial India ink examination (evidence of a heavy fungal burden), high CSF pressure, low CSF glucose levels, low CSF pleocytosis (<2/ìL), recovery of yeast cells from extraneural sites, the absence of antibody to C. neoformans, a CSF or serum cryptococcal antigen level of ≥1:32, and concomitant glucocorticoid therapy or hematologic malignancy. A response to treatment does not guarantee cure since relapse of cryptococcosis is common even among patients with relatively intact immune systems. Complications of CNS cryptococcosis include cranial nerve deficits, vision loss, and cognitive impairment.


No vaccine is available for cryptococcosis. In patients at high risk (e.g., those with advanced HIV infection and CD4+ T lymphocyte counts of <200/ìL), primary prophylaxis with fluconazole (200 mg/d) is effective in reducing the prevalence of disease. Since antiretroviral therapy raises the CD4+ T lymphocyte count, it constitutes an immunologic form of prophylaxis. However, cryptococcosis in the setting of immune reconstitution has been reported in patients with HIV infection and recipients of solid organ transplants.