Version May 2024
INTRODUCTION — Cryptococcosis is an invasive fungal infection due to Cryptococcus neoformans or Cryptococcus gattii that has become increasingly prevalent in immunocompromised patients. C. neoformans is the principal pathogenic member of the genus and has a worldwide distribution.
The microbiology and epidemiology of Cryptococcus neoformans will be reviewed here. Topic reviews that discuss the microbiology and epidemiology of C. gattii, as well as the clinical manifestations, diagnosis, and treatment of C. neoformans infection, are found elsewhere.
●(See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis".)
●(See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
●(See "Cryptococcus neoformans infection outside the central nervous system".)
MICROBIOLOGY
Taxonomy — Pathogenic cryptococci are basidiomycetous, encapsulated yeasts that can be subclassified into four serotypes and two species. Cryptococcus neoformans is further subdivided into two varieties. The serotypes are based upon capsular agglutination reactions and are designated A, B, C, or D.
The cryptococcal taxonomic nomenclature continues to rapidly evolve with more strains sequenced. It is presently reasonable from a clinical perspective to divide Cryptococcus into two species complexes: Cryptococcus neoformans (Serotype A,D) and Cryptococcus gattii (Serotype B,C) [1]. However, Serotype A strains are considered C. neoformans var. grubii and divided into four molecular types: VNI, VNII, VNBI, and VNBII. Serotype D is classified as C. neoformans var neoformans or C. deneoformans. The C. gattii species complex (serotype B,C) has now been divided into five to six subspecies or lineages [1-3] without apparent clinical relevance yet for these subspecies/lineages.
A detailed discussion of C. gattii is found elsewhere. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis", section on 'Molecular types'.)
Life cycle — The life cycle of C. neoformans involves asexual and sexual forms. The asexual form exists as yeast and reproduces by budding. These haploid, unicellular yeasts are the only forms of C. neoformans that have been recovered from human infections.
The sexual state (also known in mycology as the "perfect state") of C. neoformans has been observed only in the laboratory. Sexual structures have not been found in nature, but apparent sexual recombination events have been detected [4]. The yeast forms can exist in one of two mating types designated "a" and alpha. Coculture of yeast of each mating type on certain agars can result in conjugation that produces the sexual state. Conjugation between the alpha and "a" types results in the formation of the teleomorph, which consists of dikaryotic hyphae that contain clamp connections.
Some of the hyphae develop into specialized structures called basidia. Meiosis occurs at the terminal portion of the basidia resulting in formation of uninucleate basidiospores. These spores are initially unencapsulated but can quickly develop capsules when released from the basidia. Budding may begin after encapsulation, thereby completing the life cycle.
Growth and identification — C. neoformans produce white mucoid colonies on a variety of agars that usually become visible to the naked eye within 48 hours (picture 1). The identification of C. neoformans in the clinical laboratory begins with isolation of a urease-positive, encapsulated yeast. C. neoformans can be distinguished from C. gattii by growth features on canavanine-glycine-bromothymol blue (CGB) agar or by molecular tests. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Culture and histopathology' and "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Molecular tests'.)
Further confirmation can be achieved with biochemical tests contained in commercial kits and by detection of the enzyme phenol oxidase, which is solely produced by C. neoformans and C. gattii. However, most clinical microbiology laboratories do not stock the expensive agars required for detecting this enzyme. Most laboratories use a variety of sugar fermentations contained in commercial kits to identify the organism. In some clinical laboratories, these species can be rapidly and efficiently identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) [5-7].
Histologic identification — The yeast form of Cryptococcus can be identified in histopathologic specimens using methenamine silver stain. Mucicarmine stain highlights both the yeast form and the capsule and is specific for Cryptococcus (picture 2). The Fontana-Masson stain reveals melanin contained in the yeast.
Capsule — The polysaccharide capsule surrounding C. neoformans can be visualized in a suspension of India ink when examined under the microscope. The capsule appears as a clear area amidst the ink particles (picture 3). The thickness of the capsule can vary but can comprise more than 50 percent of the diameter of the yeast cell in some isolates.
The capsule has antiphagocytic properties and is an important virulence determinant [8]. Mutant cryptococci that are either hypocapsular or acapsular are less virulent in animal models than encapsulated strains and undergo increased phagocytosis by white blood cells in vitro [9,10].
C. neoformans strains can undergo phenotypic switching with prolonged in vitro passage (prolonged growth on standard fungal media), and one group has demonstrated this phenomenon in vivo in mice, resulting in increased virulence and death [11]. In this model, phenotypic switching led to changes in the polysaccharide capsule, which further reduced alveolar macrophage phagocytosis and promoted a more vigorous inflammatory reaction that was destructive to lung tissue.
The capsule is composed of a polysaccharide scaffold onto which are attached proteins and enzymes. The vast majority of the polysaccharide is glucuronoxylomannan (GXM), and this is shed by the organism during the course of infection and can be detected in fluid and tissue. The current serologic assays for cryptococcal antigen that are used for diagnosis detect the capsular polysaccharides. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Cryptococcal antigen (CrAg)' and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV", section on 'Cryptococcal antigen'.)
Melanin production — The presence of the enzyme phenol oxidase in C. neoformans and C. gattii is unique among members of the genus. This enzyme catalyzes one step in the conversion of phenolic compounds to melanin. A wide variety of phenolic substrates can be utilized by the cryptococcal phenol oxidase, including catecholamines, such as dopamine and epinephrine.
The phenol oxidase enzyme may be an important virulence factor for cryptococcal infection. Cryptococcal mutants lacking phenol oxidase activity are avirulent in animal models and are more susceptible to antibody-mediated phagocytosis [12].
Phenol oxidase may promote virulence via one of several possible mechanisms:
●High level of dopamine in the central nervous system may serve as a substrate for melanin production by the organism [13]. In addition, the ability to degrade catecholamines may protect the yeast from toxic effects of catecholamines in the central nervous system [14].
●Melanin is an antioxidant that is produced and accumulates in the cell wall where it may protect against attack by immune effector cells and oxidative products [15].
EPIDEMIOLOGY — C. neoformans is the principal pathogenic member of the genus and has a worldwide distribution. The majority of patients with cryptococcosis are immunocompromised due to one of the following conditions (listed in order of decreasing frequency):
●AIDS
●Prolonged treatment with glucocorticoids
●Organ transplantation
●Malignancy
●Liver disease [16]
●Sarcoidosis [17]
The serotypes or genotypes of C. neoformans in cases of cryptococcosis vary according to geographic location and whether the patient has HIV infection as a predisposing condition [18-21]. An extensive review of 725 clinical isolates of C. neoformans obtained from around the world prior to the AIDS epidemic found that C. neoformans var grubii and C. neoformans var neoformans accounted for 80 percent of isolates [18]. The majority of cryptococcal isolates from patients with AIDS have been C. neoformans var grubii but, in certain locales, C. gattii infections have also been observed in patients with HIV. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis", section on 'Hosts'.)
C. neoformans var grubii and var neoformans have been found in soil samples from around the world in areas frequented by birds, especially pigeons and chickens [22]. This fungus has also been isolated from roosting sites of pigeons and in association with rotting vegetation [23].
The basis for the association of pigeons with C. neoformans var neoformans is uncertain. Pigeons do not become infected with C. neoformans in nature. The organism is probably inhibited within pigeons by their elevated body temperature (over 40°C). Pigeons can, however, harbor the yeast as saprophytes in their gastrointestinal tract.
The role of pigeon guano in the transmission and pathogenesis of human infections is obscure. A history of intense pigeon exposure is only rarely elicited from patients with cryptococcosis. In addition, outbreaks of the disease have never been traced to pigeon roosting areas. It is possible that pigeons come into contact with C. neoformans var grubii and var neoformans by eating contaminated vegetation. Human infection may result from a similar exposure to contaminated vegetation. One case has been documented of transmission of C. neoformans from a pet cockatoo to a renal transplant recipient who developed cryptococcal meningitis [24].
Spread of infection from person to person has not been documented except with transplanted tissue [25]. Interestingly, cryptococcosis is very uncommon in children, even those with AIDS. The reason for the reduced incidence in children is not known.
Additional discussions of the epidemiology of C. neoformans in patient with and without HIV infection are found is separate topic reviews. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)
SUMMARY
●Introduction – Cryptococcosis is an invasive fungal infection due to Cryptococcus neoformans or Cryptococcus gattii. C. neoformans is the principal pathogenic member of the genus and has a worldwide distribution. (See 'Introduction' above.)
●Taxonomy – C. neoformans is a basidiomycetous, encapsulated yeast that can be subclassified in two varieties, var grubii and var neoformans. These organisms are found in soil samples from around the world, in areas frequented by birds, especially pigeons and chickens. (See 'Taxonomy' above and 'Epidemiology' above.)
●Life cycle – The life cycle of C. neoformans involves asexual and sexual forms. The asexual forms exist as yeasts and reproduce by budding. These haploid, unicellular yeasts are the only forms of C. neoformans that have been recovered from human infections. (See 'Life cycle' above.)
●Epidemiology – The vast majority of patients with cryptococcosis are immunocompromised. The serotypes or genotypes of C. neoformans in cases of cryptococcosis vary according to geographic location. (See 'Epidemiology' above.)
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