INTRODUCTION —
Cryptococcus gattii is a basidiomycetous yeast that is endemic in tropical, subtropical, and temperate climatic regions especially in Australia and parts of the Americas. Taxonomically, C. gattii is a species complex that is genetically and biochemically distinct from the Cryptococcus neoformans species complex [1-4]. Together, these two species complexes account for most cases of cryptococcal infections in humans. In this article, for clinical purposes, we refer to the respective species complexes as "C. gattii" and "C. neoformans." Like C. neoformans, infection with C. gattii manifests most often as meningoencephalitis and/or pneumonia.
The microbiology, epidemiology, risk factors, and pathogenesis of C. gattii infection will be reviewed here. The clinical features, diagnosis, and treatment of C. gattii infection are discussed separately. C. neoformans infection is also reviewed elsewhere. (See "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "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".)
MICROBIOLOGY —
C. gattii is a basidiomycetous fungus that is found naturally in the environment (see 'Environmental exposure' below). In clinical specimens, C. gattii is visualized as single or budding yeasts with round to cylindrical cells enveloped in a thick polysaccharide capsule. It was first proposed as a new taxonomic entity within the genus Cryptococcus, as Cryptococcus neoformans var. gattii, in 1970 [5], in parallel with characterization of the capsular antigens of C. neoformans. Molecular methods have now established that C. neoformans and C. gattii are separate species complexes [2-4].
Of the four major capsular serotypes of Cryptococcus spp (A, B, C, and D), B and C serotypes are exclusive to C. gattii [6,7]. Recognition of rare hybrids of C. gattii and C. neoformans provide evidence of taxonomic proximity, but not identity, between the two species [2,8].
Microbiologic tests used for the diagnosis of C. gattii infection are discussed separately. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Culture and histopathology'.)
Molecular types — Phylogenetic studies using different molecular typing techniques and recently, whole genome sequencing (WGS) [2,3], have identified four main genotypes of C. gattii: VGI and VGII (the most common), VGIII, and VGIV. There are also two additional rare genotypes, VGV (discovered recently in Zambian woodland environments) [9] and the now-designated VGVI [10]. Multilocus sequence typing (MLST), based on sequences of multiple gene fragments, provides discriminatory and reproducible strain differentiation and is of value when tracking strains in an outbreak [11-14]. Based on phylogenetic studies it has been proposed that VGI, VGII, VGIII, VGIV, and VGVI are all separate species within C. gattii [4]. However, the clinical value of this more complex nomenclature remains to be elucidated and for now, the term "C. gattii species complex" is preferred [15].
Data from studies of molecular types of clinical, veterinary, and some environmental strains indicate that genotype distribution and frequency vary in different geographic regions (table 1) [1,16,17]. The reasons for this are unknown but may relate to preferred ecologic niches of different genotypes. (See 'Environmental exposure' below.)
Molecular type VGI has a global distribution but is most prevalent in Australia, Africa, and Europe. Molecular type VGII occurs globally but is mostly reported from the Americas. Molecular type VGIII is concentrated in, but not limited to, the Americas. The relatively rare molecular type VGIV has been reported in southern Africa and, less commonly, in India, the very rare molecular type VGVI has been found in Mexico,southeastern United States, and Argentina [10].
Within countries or regions, the following geographic distribution of genotypes has been observed [1,17]:
●VGI is the most common genotype of isolates from Australia and Papua New Guinea, where C. gattii is endemic. VGII is much less common, and its occurrence appears to be geographically restricted to the "Top End" of the Northern Territory of Australia and to the southwestern region of the state of Western Australia [1,18,19].
●Isolates from British Columbia, Canada, and the United States Pacific Northwest are of the molecular type VGII, represented by three clonal lineages, VGIIa, VGIIb, and VGIIc [20,21]. VGIIa is the most common genotype associated with the initial outbreak and subsequent endemicity, followed by VGIIb. Genotype VGIIc is the least common genotype and has been isolated only from patients in the United States Pacific Northwest [1].
●Other molecular types have been documented to cause disease in other regions of the United States, including VGI, non-outbreak VGII types, and in the southwest, VGIII.
●VGIV is rare outside Africa [22,23].
●In Asia and Mexico, there is a broad distribution of genotypes (table 1).
●Six cases (including one veterinary) due to the very rare genotype VGVI have been reported from the southeastern United States (Arizona), Mexico, and Argentina, strengthening the case that VGVI is genetically distinct [4,10].
Whether the different genotypes affect the site, severity, or outcomes of C. gattii infection remains uncertain. There appear to be differences in fluconazole susceptibility according to molecular type. (See "Cryptococcus gattii infection: Treatment", section on 'Antifungal susceptibilities'.)
EPIDEMIOLOGY —
The epidemiology of C. gattii infection is well described in areas endemic for the organism, such as Australia [24-27], and increasingly in other regions as well. However, some laboratories do not routinely identify cryptococcal isolates to the species level, instead reporting all Cryptococcus spp isolates as C. neoformans. Only after recognition of the North American outbreak (beginning in 1999) and the consequent increased interest in species distinction has the complexity of the epidemiology been appreciated.
Geographic distribution — Mainland Australia and Papua New Guinea have long been known to be sites of C. gattii endemic disease. Although outside of Australia, C. gattii was formerly thought to be geographically restricted to tropical and subtropical regions, an outbreak in British Columbia, Canada, and the Pacific Northwest of the United States changed our understanding of the epidemiology of C. gattii infection [1,17].
Outbreaks of infection due to C. gattii were first detected on Vancouver Island, British Columbia, Canada, in 1999 and later in the United States Pacific Northwest, highlighting the ability of this species to exploit new climatic environments and expanding our knowledge of the epidemiology and clinical manifestations in the outbreak setting [20,28-38]. Between 1999 and 2007, 218 individuals in British Columbia were found to have C. gattii infection [29], and cases continue to occur [39]; the rate of disease in British Columbia has been reported to be 0.3 to 0.5 cases per 100,000 population [39]. As of 2012, over 90 infections had been detected in the United States Pacific Northwest, particularly in Washington and Oregon [1].
Studies have demonstrated that C. gattii causes sporadic disease in multiple regions of North America, including California, Idaho, Hawaii, and multiple states on the East Coast (eg, Georgia, Rhode Island, Florida) [33,40-45]. Sporadic cases have also been detected in temperate regions of Europe [46-48], as well as in Asia, Africa, Mexico, and South America [1,49-51]. Although the epidemiology is not well understood, it is becoming better defined as the relevance of species distinction has been appreciated. As noted above, the distribution of C. gattii genotypes varies by geographic region. (See 'Molecular types' above.)
Environmental exposure — Isolates of C. gattii have been found in the environment most commonly in mainland Australia, in tropical and subtropical areas of Hawaii, Brazil, Southeast Asia, and Central and sub-Saharan Africa [52,53], and in temperate areas including the Pacific Northwest region of Canada and the United States [20,38].
Historically, C. gattii infection has been associated with exposure to certain trees. In particular, an environmental link with two species of Australian eucalypts (or red gum), Eucalyptus camaldulensis and Eucalyptus tereticornis, was first reported in the 1990s [54,55]. The concentration of E. camaldulensis along water courses and the association of rural-dwelling Aborigines with these trees are thought to explain the high prevalence of infection in this population, although host genetic factors in Aborigines and the non-Aboriginal population have not been studied. This environmental link was subsequently confirmed by clinical and molecular epidemiologic studies [26,56] and the association of C. gattii infection with residence or work in a rural or semi-rural domicile has been maintained [57].
C. gattii has also been isolated from eucalypts in countries with small numbers of human cases, including some parts of the United States, Brazil, and Italy [47,55,58]. Cases of C. gattii also occur in regions where eucalypts are not found, such as Malaysia, South America, the Mediterranean basin, and the "Top End" of the northern territory of Australia [1,19,59,60]. In northern Brazil, isolates of C. gattii of the VGII genotype have been isolated from native forests and rivers [61].
In addition to eucalypts, trees native to Vancouver Island in British Columbia, Canada, have been implicated as an environmental niche for C. gattii; such trees include the Douglas fir, coastal western hemlock, alder, Garry oak, grand fir, and cedar [1,20]. In the greater Los Angeles area in the United States, C. gattii has been found in association with trees and soil debris with recovery from the Canary Island pine and American sweetgum, among other species [62]. In other areas of the United States, C. gattii has also been isolated from soil [1]. It has also been associated with foliage of other trees including Acacia, Ficus, and Terminalia trees [63].
In contrast with the cases in Australia, where a large proportion occurred in rural areas, cases from British Columbia, Canada, have occurred predominantly in urban and suburban communities [17]. Many patients in North America have had no apparent exposures other than residing or visiting areas of endemicity.
Hosts — Species-specific differences in the epidemiology of cryptococcosis are well defined and are largely, but not solely, due to differences in host immune status [25,26]. Unlike C. neoformans, which typically causes disease in patients with compromised cell-mediated immunity, most cases of C. gattii have been detected in persons with apparently normal immune systems [24-26,45]. However, it has been hypothesized that some patients with C. gattii infection may have subclinical defects in immunity [64]. In studies of C. gattii in endemic regions, including Australia, 72 to 100 percent of patients were immunocompetent [25,27,57,65,66]. The majority of patients with pulmonary cryptococcosis in the Pacific Northwest outbreak in North America did not have medical conditions or therapies classically associated with immunocompromise [20,35,37]. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Clinical features'.)
However, as C. gattii infection has been studied more intensely, cases of C. gattii meningoencephalitis have been reported in patients with human immunodeficiency virus (HIV) infection, solid organ transplantation, and other causes of immunodeficiency, as illustrated by the following studies:
●Although C. gattii commonly affects people without apparent immunocompromise, up to 50 percent of patients in some studies [33,67], but not others [20,35,37], from the Pacific Northwest of North America have been immunocompromised. During the outbreak in British Columbia, patients with C. gattii infection were more likely than the general population to have HIV [67] and, in the United States Pacific Northwest case clusters, 4 of 59 patients (5 percent) had HIV [33]. It is important to note that only subsets of isolates were identified to the species level in most of these studies; thus, our understanding of the impact of C. gattii in individuals with HIV remains incomplete.
●Although population-based studies in Australia and the Gauteng Province of South Africa have reported that only 2 percent of cases of HIV-associated cryptococcal meningoencephalitis are ascribed to C. gattii [22,26,53], other studies have reported a higher prevalence, ranging from approximately 4 to 17 percent. As an example, the prevalence of C. gattii as a cause of cryptococcal disease was 12.3 percent in a retrospective study of persons with HIV in southern California [68]. In the outbreak in British Columbia, 4.5 percent of all patients had HIV [35]. The highest prevalence of C. gattii, 16.7 percent, was reported in patients with HIV and cryptococcosis in Zimbabwe [23]. The apparent prevalence may continue to change as laboratories are increasingly able to characterize cryptococcal isolates.
In addition to HIV infection, other immunosuppressive conditions that appear to increase the risk for C. gattii disease include organ transplantation, various malignancies, and receipt of glucocorticoids [27,33,42,57,67,69]. Idiopathic CD4+ lymphopenia in the absence of HIV infection, a known risk factor for cryptococcosis due to C. neoformans [70,71], has also been associated with C. gattii infection [57]. Presence of anti-GMCSF antibodies in plasma has also been associated with C. gattii infection [72].
Although rare, donor-derived transmission of C. gattii through infected allografts has been described in kidney transplant recipients [42,73].
Other host factors may also increase the risk for C. gattii infection. A proportion of patients with this infection in North America had a history of chronic lung disease. Changes in lung function associated with smoking may contribute to this risk since, in the British Columbia outbreak, more patients had underlying lung disease and were current smokers than was the case in the general population [67].
PATHOGENESIS —
C. gattii infection is typically acquired by inhalation from the environment, although direct inoculation into the skin has also been reported [74,75]. Both yeast cells and basidiospores probably cause infection since, in nature, C. gattii reproduces both asexually (by budding) and sexually.
Studies of the pathogenesis of C. gattii infection are limited. In animal models, the outcome of infection is determined by a complex set of interacting pathogen and host factors; these include inoculum size, the cryptococcal strain, and the innate susceptibility or resistance (genetic background) of the host [76-78]. As an example, in studies of the VGII molecular type that caused the outbreak in British Columbia, Canada, the predominant strain (strain R265) was more virulent in mice than the less common strain (strain R272) [20,79]. Subsequent research has shown that the increased virulence of the outbreak strain may be mediated through pathogen-derived extracellular vesicles that affect cell-to-cell signaling [80].
Unlike C. neoformans, C. gattii infection typically causes infection in immunocompetent hosts and is more likely than C. neoformans to cause cryptococcomas in the brain and/or lungs (see "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Comparison of C. gattii and C. neoformans infection'). Although the reasons why cryptococcomas are larger and more common in C. gattii infection remain poorly understood, there are increasing data that the immune response to infection among immunocompetent hosts plays a role. In one study, the cytokine profile of peripheral blood mononuclear cells of healthy individuals was evaluated after in vitro stimulation with heat-killed Cryptococcus isolates [81]. Isolates of C. gattii induced higher concentrations of the proinflammatory cytokines, interleukin (IL)-1-beta, tumor necrosis factor-alpha, and IL-6 and the T helper 17/22 cytokines, IL-17 and IL-22, than C. neoformans. Toll-like receptor (TLR)-4 and TLR-9, but not TLR-2, also contributed to the host's cytokine response to C. gattii.
More recently, it was reported that anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies were detected in plasma derived from immunocompetent patients with C. gattii infection but not in the plasma of patients infected with C. neoformans [72].
Virulence determinants — C. gattii has similar virulence characteristics to C. neoformans [2]. These include the polysaccharide capsule (important in evasion and suppression of the host immune response), the ability to grow at 37°C, production of melanin (via laccase activity), which functions as an oxidative stress protectant, the invasins, phospholipase B (Plb1) and urease, and the antioxidant, superoxide dismutase (SODp1) [82]. In animals with C. neoformans infection, Plb1 and laccase are essential for egress of cryptococci from the lung and dissemination to the central nervous system (CNS) [83,84], whereas Plb1 and urease are required for cryptococci to cross the blood-brain barrier [84,85].
Neurologic disease — To cause neurologic disease, cryptococci must traverse the lung, disseminate, and cross the blood-brain barrier. In C. neoformans models, cryptococci are transported in the blood in mononuclear phagocytes and as free cells [84,85]. There is also evidence for transendothelial cell transport of free cryptococci and paracellular transport within the phagolysosome of mononuclear phagocytes (the Trojan horse mechanism) [86]. Cryptococci can be expelled from macrophage phagolysosomes without loss of viability [87,88]. Cryptococci transported within mononuclear phagocytes in blood could therefore be released in cerebral microvessels and cross the blood-brain barrier as free cells. Evidence from murine studies indicates that intraphagocytic cryptococci enter the perivascular space (PVS) at the level of postcapillary venules, along which they may travel to reach the CSF and cause meningitis. Alternatively, cryptococci may be released in the PVS and cross the glia limitans to enter the brain directly, with meningitis resulting from rupture of cerebral lesions into the CSF [89]. Direct transport across cerebral capillaries into the CNS has also been demonstrated in a high cryptococcal inoculum mouse model [85]. In human immunodeficiency virus (HIV)-associated cryptococcal meningoencephalitis, HIV infection of macrophages facilitates their translocation into the CNS [90].
Whether C. gattii differs from C. neoformans in its ability to cause CNS disease is unclear. Among immunocompetent hosts, isolated CNS disease with C. gattii, or CNS plus pulmonary disease, is more common in endemic areas such as Australia, whereas in the outbreak setting in British Columbia, Canada, pulmonary disease is more common [29].
In rats with C. gattii genotype VGII infection, VGIIa and VGIIb strains from the British Columbia, Canada, outbreak caused fatal infection confined to the lung, whereas VGIIa strains from Colombia and Australia caused dissemination to the CNS [91].
SUMMARY
●Epidemiology – Cryptococcus gattii is an important fungal pathogen that is now established within several countries in the tropics, subtropics, and in temperate climates, most commonly in Australia and the Americas. C. gattii is genetically and biochemically distinct from Cryptococcus neoformans. Information about the epidemiology and clinical syndromes caused by C. gattii in nonendemic regions is relatively limited due to the failure of many microbiology laboratories to distinguish between C. neoformans and C. gattii. (See 'Epidemiology' above.)
●Geographic distribution – Mainland (including temperate) Australia and Papua New Guinea have long been known to be sites of C. gattii endemic disease. Although C. gattii was formerly thought to be geographically restricted to tropical and subtropical regions, an outbreak that began in Vancouver Island, Canada, in 1999 and that has spread to the United States Pacific Northwest, and emergence of cases in Europe, has changed our understanding of the epidemiology of C. gattii infection. (See 'Geographic distribution' above.)
●Host factors – The primary difference in host distribution between C. gattii and C. neoformans is that, at least in regions endemic for C. gattii, this species to a large extent causes infection in people with no apparent immunocompromise, although it has been hypothesized that some patients may have subclinical defects in immunity. C. gattii has also been detected in patients with human immunodeficiency virus (HIV) infection, solid organ transplantation, and other causes of immunodeficiency. (See 'Hosts' above.)
●Microbiology – There are at least six molecular types or genotypes of C. gattii, VGI to VGVI, each containing subtypes, but thus far only types VGI, VGII, VGIII, VGIV, and the rare VGVI have been reported to cause human disease. Data from studies of molecular types of clinical and environmental strains indicate that genotype distribution and frequency vary in different geographic regions (table 1). The reasons for this are unknown but may relate to preferred ecologic niches for different genotypes. (See 'Molecular types' above.)
●Pathogenesis – The outcome of infection is determined by a complex set of interacting pathogen and host factors, including inoculum size, the cryptococcal strain, and the innate susceptibility or resistance of the host. (See 'Pathogenesis' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Kieren Marr, MD, who contributed to an earlier version of this topic review.