20/10/2019 Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis - UpToDate

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Cryptococcus gattii infection: Microbiology, epidemiology,

and pathogenesis
Authors: Sharon Chen, PhD, MBBS, FRACP, FRCPA, Kieren A Marr, MD, Tania C Sorrell, MD
Section Editor: Carol A Kauffman, MD
Deputy Editor: Jennifer Mitty, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2019. | This topic last updated: May 14, 2019.

INTRODUCTION

Cryptococcus gattii is a fungal pathogen that is endemic in the tropics and subtropics and
temperate climatic regions of Australia. In the last three decades, it has become established in
British Columbia, Canada, and the United States Pacific Northwest. C. gattii is genetically and
biochemically distinct from Cryptococcus neoformans [1-3]. Together, these two species
complexes, C. gattii and C. neoformans, account for most cases of cryptococcal infections in
humans, although C. neoformans is more common. 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 HIV-infected
patients" and "Clinical manifestations and diagnosis of Cryptococcus neoformans
meningoencephalitis in HIV-seronegative patients".)

MICROBIOLOGY

C. gattii is a basidiomycetous fungus, which can be found 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, Cryptococcus neoformans var gattii, in 1970 [4], in parallel with the
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characterization of the capsular antigens of C. neoformans. It is now characterized as a separate

species, C. gattii.

Of the four major capsular serotypes of Cryptococcus spp (A, B, C, and D), B and C serotypes are
exclusive to what has become known as C. gattii, a species distinct from C. neoformans [5,6].
Recognition of rare hybrids of C. gattii and C. neoformans provide evidence of taxonomic
proximity, but not identity, between the two species [7,8].

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 — There are at least four molecular types or genotypes of C. gattii, VGI to VGIV,
each containing subtypes, as determined by several genotyping techniques [8,9]. Multilocus
sequence typing (MLST), based on sequences of multiple gene fragments, provides particularly
reproducible and discriminatory strain differentiation and is helpful for tracking of strains in an
outbreak [10-12]. Based on these molecular types and MLST and other genotyping studies, five
species within C. gattii have been proposed [13]; however, the clinical relevance of these with
respect to pathogenicity and epidemiology remains to be elucidated and hence we use the
terminology "C. neoformans species complex" and "C. gattii species complex" for practical
purposes, rather than creating more species [14].

Data from studies of molecular types of clinical (and some environmental) strains indicate that
genotype distribution and frequency vary in different geographic regions (table 1) [3,15,16]. The
reasons for this are unknown but may relate to preferred ecologic niches of different genotypes.
(See 'Environmental exposure' below.)

The following geographic distribution of genotypes has been observed [3,16]:

● 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 [3,17,18].

● Isolates from the outbreak in British Columbia, Canada, and the United States Pacific
Northwest are of the molecular type VGII, represented by three clonal lineages, VGIIa, VGIIb,
and VGIIc [19,20]. VGIIa has been the most common genotype associated with this outbreak,
followed by VGIIb; genotype VGIIc has been the least common genotype and has been
isolated only from patients in the United States Pacific Northwest but not from patients in
Canada [3].

● Other molecular types have been documented to cause disease in other regions of the United
States, including VGI, non-outbreak VGII types, and VGIII.

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● VGIV is rare outside Africa [21,22].

● In Asia and Mexico, there is a broad distribution of genotypes (table 1).

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 [1,23-25], and increasingly in other regions as well. However, many medical centers
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 — 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 in the Pacific Northwest of North
America has changed our understanding of the epidemiology of C. gattii infection [3,16].

The emergence of clusters of cryptococcosis due to C. gattii in British Columbia, Canada, in 1999,
with subsequent clusters documented in the United States Pacific Northwest, has highlighted the
ability of this species to exploit new climatic environments and has expanded our knowledge of the
epidemiology and clinical manifestations in the outbreak setting [26-33]. This outbreak was first
detected on Vancouver Island in British Columbia, Canada, in 1999 [19,34-36]. Between 1999 and
2007, 218 individuals in British Columbia were found to have C. gattii infection [27], and cases
continue to occur [37]. The rate of disease in British Columbia is 0.3 to 0.5 cases per 100,000
population [37]. Since 2004, over 90 infections have been detected in the United States Pacific
Northwest, particularly in Washington and Oregon [3].

Studies have demonstrated that C. gattii causes sporadic disease in multiple regions of North
America, including not only the Pacific Northwest but also California, Idaho, Hawaii, and multiple
states on the East Coast (eg, Georgia, Rhode Island, Florida) [31,38,39]. Sporadic cases have
also been detected in temperate regions of Europe [40-42], as well as in Asia, Africa, Mexico, and
South America [3,43,44]. 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 tropical and subtropical areas, such as Australia, Hawaii, Brazil, Southeast Asia, and

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Central and sub-Saharan Africa [45,46], and in temperate areas such as the Pacific Northwest
region of Canada and the United States [19,36].

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 [47,48]. 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 link was subsequently confirmed by clinical and molecular epidemiologic
studies [25,49] and the association of C. gattii infection with residence or work in a rural or semi-
rural domicile has been maintained [50].

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 [41,48,51]. 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 [3,18,52,53]. In northern Brazil,
isolates of C. gattii of the VGII genotype have been isolated from native forests and rivers [54].

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 [3,19]. 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 [55]. In other areas of
the United States, C. gattii has also been isolated from soil [3].

In contrast with the cases in Australia, of which a large proportion occurred in rural areas, cases
from British Columbia, Canada, have occurred predominantly in urban and suburban communities
[16]. 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 [24,25]. 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 [23-25].
However, it has been hypothesized that some patients with C. gattii infection may have subclinical
defects in immunity [56]. In case series of C. gattii in endemic regions, including Australia, 72 to
100 percent of patients have been immunocompetent [24,50,57,58]. The majority of patients
affected by the Pacific Northwest outbreak in North America have not had medical conditions or
therapies classically associated with immunocompromise and have had pulmonary involvement
[19,33,35]. (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Clinical
features'.)

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However, as C. gattii infection has been studied more intensely, a change in the understanding of
the epidemiology has become apparent, with cases of C. gattii meningoencephalitis 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 [31,59] but not others [19,33,35], from the Pacific
Northwest of North America have been immunocompromised. During the outbreak in British
Columbia, C. gattii patients were more likely than the general population to be infected with
HIV [59] and, in the United States Pacific Northwest case clusters, 4 of 59 patients (5 percent)
were HIV positive [31]. 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
HIV-infected individuals 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 [21,25,46], 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 HIV-
infected patients in southern California [60]. In the outbreak in British Columbia, 4.5 percent of
all patients had underlying HIV infection [33]. The highest prevalence of C. gattii, 16.7
percent, was reported in HIV-infected patients with cryptococcosis in Zimbabwe [22]. The
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 [31,50,59,61]. Idiopathic CD4+ lymphopenia in the absence of HIV infection, a
known risk factor for cryptococcosis due to C. neoformans [62,63], has also been associated with
C. gattii infection [50].

Other, more subtle 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 [59].

PATHOGENESIS

C. gattii infection is typically acquired by inhalation from the environment, although direct
inoculation into the skin has also been reported [1,64]. Both yeast cells and basidiospores

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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 [65-67]. 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) [19,68]. 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 [69].

Unlike C. neoformans, C. gattii infection typically causes infection in immunocompetent hosts and
is more likely than C. neoformans to cause cryptococcomas of 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 with 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 [70]. 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, compared with 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 [71].

Virulence determinants — C. gattii has similar virulence characteristics as C. neoformans [8].

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) [72]. 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) [73,74], whereas Plb1 and urease are required for cryptococci to cross the
blood-brain barrier [74,75].

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 [74,75]. There is also
evidence for transendothelial cell transport of free cryptococci and paracellular transport within the

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phagolysosome of mononuclear phagocytes (the Trojan horse mechanism) [76]. Cryptococci can
be expelled from macrophage phagolysosomes without loss of viability [77,78]. Cryptococci
transported within mononuclear phagocytes in blood could therefore be released in cerebral
microvessels and cross the blood-brain barrier as free cells. In HIV-associated cryptococcal
meningoencephalitis, HIV infection of macrophages facilitates their translocation into the CNS
[79].

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 [27].

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 [80].

SUMMARY

● Cryptococcus gattii is an important fungal pathogen that is endemic in the tropics and
subtropics, but is moved outside of these regions; it has caused an outbreak that is ongoing in
British Columbia, Canada, and the United States Pacific Northwest. C. gattii is genetically and
biochemically distinct from Cryptococcus neoformans. (See 'Introduction' above.)

● 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.)

● There are at least four molecular types or genotypes of C. gattii, VGI to VGIV, each containing
subtypes. 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.)

● 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.)

● 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

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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.)

● 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.)

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Topic 16624 Version 12.0

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GRAPHICS

Cryptococcus gattii genotypes by geographic location

Location Genotypes

Australia VGI>>VGII

Papua New Guinea VGI

British Columbia, Canada VGIIa>VGIIb

Pacific Northwest, United States VGIIa>VGIIc>VGIIb

Southern California, United States VGIII, VGI, VGII

Asia VGI, VGII, VGIII, VGIV

Africa VGIV

South America VGII, VGI, VGIII, VGIV

Mexico VGI, VGII, VGIII, VGIV

Data from:
1. Harris J, Lockhart S, Chiller T. Cryptococcus gattii: Where do we go from here? Med Mycol 2012; 50:113.
2. Cogliati M. Global molecular epidemiology of Cryptococcus neoformans and Cryptococcus gattii: An atlas of the
molecular types. Scientifica 2013. http://www.hindawi.com/journals/scientifica/2013/675213/ (Accessed on
September 4, 2013).
3. Byrnes EJ, Li W, Lewit Y, et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the
northwest United States. PLoS Pathog 2010; 6:e1000850.

Graphic 90024 Version 4.0

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Contributor Disclosures
Sharon Chen, PhD, MBBS, FRACP, FRCPA Grant/Research/Clinical Trial Support: MSD [Fungal infections
- epidemiology (Posaconazole)]; Gilead Sciences [Fungal infections - genomics (Liposomal AMB)]. Kieren A
Marr, MD Grant/Research/Clinical Trial Support: Merck [Antifungals, fungal infections (Caspofungin,
posaconazole)]. Consultant/Advisory Boards: Amplyx (Antifungals); Chimerix Therapeutics [Viral infections
(Brincidofivir)]; Cidara Therapeutics [Antifungals, fungal infections]; Merck [Antifungals, viral infections
(Caspofungin, posaconazole)]; Scynexis (Antifungals); Vical (Antifungals). Patent Holder: MycoMed
Technologies [Diagnostics, antifungals (Fungal diagnostics)]. Equity Ownership/Stock Options: MycoMed
Technologies [Fungal diagnostics]. Tania C Sorrell, MD Nothing to disclose Carol A Kauffman,
MD Consultant/Advisory Boards: Cidara Therapeutics [Treatment of candidiasis (Rezafungin)]. Jennifer
Mitty, MD, MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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to UpToDate standards of evidence.

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