Etiology
Cryptococcosis is an infection caused by species of the fungus Cryptococcus, which is ubiquitous in the environment. Of the 30 species within the Cryptococcus genus, most clinical disease is ascribable to Cryptococcus neoformans var. grubii (serotype A), Cryptococcus neoformans var. neoformans (serotype D), and Cryptococcus var. gattii (serotypes B and C).[16]
Cryptococcus neoformans serotypes A and D are associated with bird droppings, especially those of pigeons.[2] Pigeons may carry the fungus on their beaks, feathers, and legs, thus contributing to the worldwide distribution of these strains. Cryptococcus neoformans has also been isolated from the heartwood of several species of trees.[4] Cryptococcus var. gattii is most commonly isolated from Eucalyptus species in tropical and subtropical climates, although other environmental reservoirs have been documented.[5]
In immunocompromised patients, the majority of infections are caused by Cryptococcus neoformans, whereas Cryptococcus var. gattii is more commonly identified in immunocompetent populations.[1][4][5][6][13]Cryptococcus neoformans can cause infections in a wide range of domestic and wild animals.[17] Non-neoformans cryptococci have historically been regarded as saprophytes and rarely reported as human pathogens, but, in patients with impaired cell-mediated immunity, the incidence of infection has increased, with Cryptococcus laurentii and Cryptococcus albidus together responsible for 80% of cases.[18]
Symptoms of Cryptococcus var. gattii infection begin 2 to 11 months after exposure. The incubation period for Cryptococcus neoformans is not known as it may cause asymptomatic pneumonitis. Severe symptomatic pulmonary cryptococcosis has been seen in immunocompetent patients with Cryptococcus var. gattii infection.[13][16] Patients infected with Cryptococcus var. gattii often have inflammatory masses in the central nervous system and lungs and neurologic signs, and may require surgery or prolonged antifungal therapy.[19]
Although exposure to Cryptococcus species is common, the development of symptomatic disease usually requires immunosuppression. Organ transplantation, the use of corticosteroids or other immunosuppressive agents and monoclonal antibodies (e.g., alemtuzumab and infliximab), idiopathic CD4 lymphocytopenia, systemic lupus erythematosus, diabetes mellitus, and hematologic malignancies can result in immunosuppression and allow reactivation of a cryptococcal infection.[1]
Patients with compromised cell-mediated immunity are at higher risk of acquiring cryptococcosis, particularly those with CD4 cell counts <100 cells/mm³.[20] HIV infection is associated with more than 80% of cryptococcosis cases worldwide.[1][9][11][21][22] The use of antiretroviral treatment (ART) has been associated with a lower incidence of cryptococcosis.[20] However, in countries with uncontrolled HIV infection and limited access to ART, such as in Africa and Asia, the incidence and mortality from cryptococcosis are extremely high.[11]
Pathophysiology
The lungs are the initial site of almost all cryptococcal infections. Dry yeast cells or basidiospores (<5-10 micrometers) are inhaled and deposited in the alveoli.[1][2] The yeasts are processed by alveolar macrophages, which release cytokines and chemokines to recruit other inflammatory cells. A helper T-cell (Th1) response involving cytokines (e.g., tumor necrosis factor-alpha, interferon-gamma, interleukin-2) is related to the development of granulomatous inflammation. Other sources of infection include the gastrointestinal tract, direct inoculation into tissue from trauma, and transplantation of infected tissue. After the fungus enters the body, it can produce acute disease or latent infection depending on the immune status of the host and virulence of the strain. Cryptococcus neoformans and Cryptococcus var. gattii have a predilection for invading the central nervous system (CNS) and can cause life-threatening meningoencephalitis. Capsule formation, melanin pigment production, and the ability to grow well at 98.6°F (37°C) are the principal virulence factors of members of the Cryptococcus species.
A cell-mediated immune response is crucial for host defense and for producing granulomatous inflammation. Latent infection, in which the yeasts remain dormant for years in hilar lymph nodes or pulmonary foci in asymptomatic individuals, can be reactivated to produce disease when cellular immunity is suppressed.
In immunosuppressed patients, hematogenous dissemination can occur in multiple organs including the CNS, skin, prostate, eyes, bone, gastrointestinal tract, urinary tract, and blood.[1] On autopsy, silent disseminated disease throughout the body is often present. Cutaneous infections resulting from direct inoculation or secondary to disseminated disease are the third most common clinical site of cryptococcosis, especially in immunocompromised patients.
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