Cryptococcus neoformans and Cryptococcus gattii

Etiology

While more than 30 cryptococcal species have been described, 2 species ( Cryptococcus neoformans and C. gattii ) are responsible for the vast majority of disease. These species can be further classified by serologic and molecular typing techniques. Both C. neoformans and C. gattii are encapsulated, facultative intracellular pathogens. There is significant overlap in the disease caused by these pathogens; however, important differences in epidemiology and clinical presentation exist. Cryptococcal disease may rarely also be caused by other species (e.g., C. laurentii and C. albidus ), especially in immunocompromised individuals (including neonates).

Epidemiology

C. neoformans is distributed in temperate climates predominantly in soil contaminated with droppings from certain avian species, including pigeons, canaries, and cockatoos. It may also be found on rotting wood, fruits, and vegetables and may be carried by cockroaches. Disease secondary to C. neoformans primarily occurs in immunocompromised individuals and especially in those with defects in cellular immunity, though apparently normal individuals can also be affected. A large increase in the incidence of cryptococcosis was noted in association with the AIDS epidemic, with disease generally occurring with severe immunosuppression (CD4 ⁺ T cells < 100/µL). However, since the development of highly active anti-retroviral therapy (HAART), the incidence of AIDS-associated cryptococcosis has decreased dramatically, except in resource-limited areas of the world such as sub-Saharan Africa, where HAART is not readily available.

Other risk factors for cryptococcal infection include immunosuppression associated with organ transplantation, diabetes mellitus, renal failure, cirrhosis, corticosteroids, rheumatologic conditions, chemotherapeutics, and immune modulating monoclonal antibodies (e.g., etanercept, infliximab, and alemtuzumab). In patients who have undergone organ transplantation, cryptococcosis is the third most common fungal infection after candidiasis and aspergillosis. Children with certain primary immunodeficiency diseases may also be at increased risk for cryptococcosis, including those with hyper-IgM syndrome, severe combined immunodeficiency, idiopathic CD4 ⁺ lymphopenia, autoantibodies to granulocyte-macrophage colony-stimulating factor or interferon-γ, CD40 ligand deficiency, and monoMAC syndrome (monocytopenia, B and natural killer cell lymphopenia).

C. gattii was initially recognized for its tendency to cause disease in tropical regions, especially among the native peoples of Australasia, where the organism can be found in association with Eucalyptus trees. In these regions, affected individuals are typically immunocompetent. More recently, C. gattii disease has been observed outside these tropical regions. An outbreak of C. gattii disease involving British Columbia and extending into the Pacific Northwest region of the United States was first recognized in 1999. Affected individuals were typically adults, with disease occurring in both immunocompetent and immunocompromised individuals. Comorbid conditions were often present, with examples including chronic lung and heart disease. A disproportionate fraction of patients (relative to those infected with C. neoformans ) presented with pulmonary disease. An incubation period ranging from 2 to 12 mo is typical. In the appropriate clinical context, cryptococcosis should be considered in the differential diagnosis of residents of the Pacific Northwest as well as returning travelers.

Overall, cryptococcosis is significantly less common in children than in adults. The basis for this discrepancy is poorly understood but could be related to differences in exposure or immune response. Serologic studies suggest that subclinical infection is common among children living in urban areas after age 2 yr. During the early AIDS epidemic, the incidence of cryptococcosis in the United States was reported to be on the order of 10% in adults and 1% in children. The largest series of pediatric cryptococcosis comes from South Africa and describes 361 cases, accounting for 2% of the cryptococcosis cases over a 2-yr period. More recent series of pediatric cases, including those from Asia, the United States, and Colombia, highlight the potential for Cryptococcus (including C. neoformans ) to cause disease in immunosuppressed and non-immunosuppressed children.

Pathogenesis

Like many fungi, C. neoformans and C. gattii survive as saprophytes in the environment. Their virulence characteristics appear to have evolved as an adaptive response to environmental stressors. Several key factors have been identified, including the ability to grow at 37°C, encapsulation, and melanin production. The polysaccharide capsule exhibits a variety of biologic activities that are important in the pathogenesis of disease, including interference with opsonization, inhibition of chemotaxis, and enhancement of non-protective TH2 inflammation. Capsular material is shed by the organism into body tissues and fluids during infection and has been implicated in the development of increased intracranial pressure (ICP), a hallmark of cryptococcal meningoencephalitis. Detection of shed capsular antigen in the serum and CSF are key to the diagnosis of cryptococcal disease. The organism also has the ability to undergo phenotypic variation in response to environmental changes through a variety of mechanisms and can form large giant cells (on the order 20 times its normal size), which are resistant to phagocytosis.

In most cases, infection is acquired by inhalation of desiccated forms of the organism, which upon deposition within the lungs are engulfed by alveolar macrophages. An additional portal of entry can be seen with organ transplantation of infected tissue. Furthermore, direct inoculation can lead to cutaneous or ophthalmic infection. After entry into the respiratory tract, infection can be latent and later progress in the context of immunodeficiency. Alternatively, infection can progress and disseminate to produce symptomatic disease. Cell-mediated immunity that leads to macrophage activation is the most important host defense for producing granulomatous inflammation and containing cryptococcal infection. Entry of the organism into the CNS may occur via several mechanisms, including infected macrophages, through infected endothelial cells, and between the tight junctions of endothelial cells.

Clinical Manifestations

The manifestations of cryptococcal infection reflect the route of inoculation, the infecting strain, and immune status of the host. Sites of infection include lung, CNS, blood, skin, bone, eyes, and lymph nodes.