Hindawi Publishing Corporation

Interdisciplinary Perspectives on Infectious Diseases

Volume 2009, Article ID 840452, 13 pages
doi:10.1155/2009/840452

Review Article
Cryptococcus gattii : An Emerging Cause of Fungal Disease
in North America

Ashwin Dixit,1, 2 Scott F. Carroll,1, 3 and Salman T. Qureshi1, 4

1 Centrefor the Study of Host Resistance, McGill University, Montreal, QC, Canada H3G 1A4
2 Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada H3A 2B4
3 Department of Human Genetics, McGill University, Montreal, QC, Canada H3A 1B1
4 Department of Medicine, McGill University, Montreal, QC, Canada H3G 1A4

Correspondence should be addressed to Salman T. Qureshi, salman.qureshi@mcgill.ca

Received 11 November 2008; Accepted 18 January 2009

Recommended by Bettina Fries

During the latter half of the twentieth century, fungal pathogens such as Cryptococcus neoformans were increasingly recognized as
a significant threat to the health of immune compromised populations throughout the world. Until recently, the closely related
species C. gattii was considered to be a low-level endemic pathogen that was confined to tropical regions such as Australia. Since
1999, C. gattii has emerged in the Pacific Northwest region of North America and has been responsible for a large disease epidemic
among generally healthy individuals. The changing epidemiology of C. gattii infection is likely to be a consequence of alterations in
fungal ecology and biology and illustrates its potential to cause serious human disease. This review summarizes selected biological
and clinical aspects of C. gattii that are particularly relevant to the recent North American outbreak and compares these to the
Australian and South American experience.

Copyright © 2009 Ashwin Dixit et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction subtropical climates, is now gaining prominence as a cause

of human and veterinary disease in North America. While
Although less than 500 of the estimated 1.5 million species most clinical cases have occurred among generally healthy
of fungi pose a threat to humans and animals [1, 2], individuals that reside in the Pacific Northwest, a few tourists
the prevalence of fungal infections has risen over the last or visitors to the region have also been affected. The purpose
century due to a progressive increase in the number of of this review is to summarize important biological and
debilitated individuals. Impaired immunity against fungi clinical characteristics of C. gattii that are relevant to the
may result from one or more factors including malignancy, understanding of human disease caused by this emerging
advanced or severe comorbid disease, or the use of cytotoxic fungal pathogen.
drugs and broad-spectrum antibiotics. Species of Candida
remain the most common cause of invasive yeast infection; 2. Identification
however, opportunistic filamentous fungi such as Aspergillus
spp, Fusarium spp, Scedosporium spp, Penicillium spp, and C. neoformans was first isolated in 1894 from fermented
the zygomycota are becoming more prevalent in oncology peach juice by the Italian Francesco Sanfelice [7]. Since
and transplant centers [3, 4]. Human disease resulting that time, this organism has been recovered from numerous
from environmental exposure to the basidiomycetous yeast locations throughout the world where its main ecological
Cryptococcus neoformans increased significantly since the niche is soil, particularly in association with pigeon excreta
onset of the HIV epidemic and continues to be common [8–10]. Cryptococci grow as unicellular, encapsulated cells
among individuals that do not have access to effective in the asexual state or as basidiomycetous filaments in the
antiretroviral therapy [5, 6]. C. gattii, a closely related sexual state [1, 11]. Infection due to this opportunistic
species that was traditionally associated with tropical and fungus is believed to occur by inhalation and primarily
2 Interdisciplinary Perspectives on Infectious Diseases

targets the lung with frequent dissemination to the central in their biochemistry, ecology, epidemiology, and clinical
nervous system as well as a variety of other organs [12, 13]. manifestations (see review [15]) as a result of the divergence
C. gattii was first isolated from a leukemic patient in 1970 of serotypes A and D from serotypes B and C that occurred
and described as a variant of C. neoformans [14]. C. gattii approximately 37 million years ago [15, 39]. Following a
is closely related to C. neoformans, although its distribution series of revisions to the classification of the C. neoformans
is not global. C. gattii is typically restricted to tropical and species complex [11, 14, 17, 38, 40, 41], cryptococci are now
subtropical geographical regions such as Australia, Brazil, divided into two major species, C. neoformans (serotypes A,
and southern California [15, 16]. In the laboratory, these D, and AD) and C. gattii (serotypes B and C). The sexual state
two cryptococcal species can be distinguished on the basis of of C. gattii is known as Filobasidiella bacillispora [38, 41].
their capsular serotype: C. gattii belongs to serotypes B and The most recent classification of cryptococci was estab-
C, while C. neoformans belongs to serotypes A and D [17]. lished by genetic typing using PCR fingerprinting, random
Like C. neoformans, C. gattii typically causes pneumonia and amplification of polymorphic DNA (RAPD), amplified frag-
meningitis [15]. However, C. gattii appears to have a greater ment length polymorphism (AFLP) analysis and multilocus
propensity to infect immune competent humans [18, 19]. sequence typing (MLST) [17, 23, 35, 37, 42–45]. Based
For reasons that are not yet fully understood, C. gattii has on genetic diversity, cryptococci were divided into eight
acquired the ability to colonize new biogeoclimatic regions molecular types associated with distinct AFLP profiles. C.
and is responsible for a recent outbreak of infection among neoformans may be classified into VNI/VNII genotypes
humans and animals in the temperate climate of Vancouver corresponding to AFLP1/1A/1B (serotype A), VNIII/AFLP3
Island, British Columbia (BC), Canada [20]. Between 1999 (serotype AD), and VNIV/AFLP2 (serotype D), while C.
and 2006, 171 human cases of C. gattii infection were gattii may be distinguished as VGI/AFLP4 (serotype B),
identified, including 8 fatalities [21]. Between 2002 and 2005, VGII/AFLP6 (serotype B), VGIII/AFLP5 (serotype B or C),
the incidence of C. gattii infection on Vancouver Island and VGIV/AFLP7 (serotype B or C). Interspecific hybrid
peaked at 36 cases/million people/year, a number that was serotypes BD and AB correspond to AFLP8 and AFLP9,
significantly higher than the 0.94 cases/million people/year respectively [35, 37]. The VNI and VGI genotypes are the
observed in endemic regions of Australia [22, 23]. The most prevalent isolates of each species. The Vancouver C.
most common clinical manifestation of C. gattii infection gattii isolates have a VGII genotype that is further subtyped
on Vancouver Island was pneumonia [21]. Although the into VGIIa (major) and VGIIb (minor) [23]. A recent study
majority of human infections have been found on the east employing MLST of one hundred and seventeen isolates
coast of Vancouver Island [23], clinical cases have also been confirmed previous observations that four monophyletic
reported on the BC mainland, Alberta, and the states of lineages exist within C. gattii. Based on these findings,
Oregon and Washington [22, 24, 25]. Given the ongoing it was suggested that these lineages should be considered
spread of C. gattii infection on the Pacific coast of North as separate taxa, similar to the two monophyletic lineages
America, it will be important for clinicians and laboratory within C. neoformans that correspond to varieties grubii
scientists to remain vigilant for diseases that may be caused and neoformans [45]. Another MLST study has indicated
by this fungal pathogen. that although the Vancouver Island C. gattii strains have
colonized a novel environment, they are not phylogenetically
unique [46].
3. Taxonomy
Cryptococcus is a largely polyphyletic genus that consists of 4. Ecology and Epidemiology of C. gattii
at least 37 different species and belongs to the kingdom
Fungi, phylum Basidiomycota, class Tremellomycetes, and C. gattii is endemic in tropical and subtropical regions such
order Tremellales [26–28]. The subclassification of this genus as Australia where it is most commonly associated with
has been the subject of much debate and modification, eucalyptus trees, particularly Eucalyptus camaldulensis and
particularly in response to the development of newer Eucalyptus tereticornis [15, 47–49]. The fungus has also been
molecular typing methods [26, 27, 29]. The C. neoformans found to grow on other tree species such as almond (Prunus
species complex was first classified according to structural dulcis), golden shower (Cassia fistula), and Douglas fir
variations of the extracellular polysaccharide capsule that are (Pseudotsuga menziesii) in Colombia, Brazil, and Vancouver
distinguished by agglutination assays with antigen-specific Island, respectively [17, 47]. C. gattii has also been isolated
antibodies [30, 31]. Using this approach, C. neoformans was from insect frass in Australia and a wasp nest in Uruguay
classified into four serotypes, A through D, in the 1950s and [50, 51]. Other species in the Filobasidiella lineage, such as
1960s [30, 32]. The hybrid serotype AD is often considered to Cryptococcus amylolentus, Tsuchiyaea wingfieldii, and Bullera
be a fifth serotype of the C. neoformans species complex, and dendrophila, have also been isolated from insect frass [52–
rare hybrid serotypes between C. neoformans and C. gattii 54]. In this context, the recent discovery of C. gattii in the
such as BD and AB have also been observed [33–37]. Pacific Northwest is intriguing, since this temperate climate
C. gattii was initially classified as a variety of C. is characterized by mild and wet winters and warm and
neoformans, bearing the name C. neoformans var. gattii dry summers. On Vancouver Island, C. gattii has mainly
or var. bacillispora [15, 38]. Subsequently, C. gattii and been found on trees in the coastal Douglas fir (CDF)
C. neoformans were shown to have substantial differences biogeoclimatic zone such as fir, cedar, and maple [23, 47].
Interdisciplinary Perspectives on Infectious Diseases 3

The fungus has also been isolated from the air, freshwater, clinical and environmental isolates from South America have
seawater, and upper layer of the soil of the BC mainland, the shown that VGII predominates over the other molecular
Gulf Islands, and Washington state [22, 23, 47]. types in both Colombia and Brazil as observed on Vancouver
Ecological and geographical differences exist among the Island [47, 64, 65]. Meyer et al. have hypothesized that
different molecular types of C. gattii. A survey conducted the Vancouver Island outbreak isolates originated in South
in 16 countries revealed that the molecular types most America based on the finding of α mating-type cells within
commonly found in the clinic and environment were VGI the Brazilian C. gattii VGII population and the fact that all
and VGII [55]. Genotype VGIII has been found in the United Vancouver Island C. gattii isolates found to date have also
States, Mexico, South America, Europe, India, Australia, and been of the α mating type [63, 65, 66]. In addition, the VGII
New Zealand, while VGIV has been isolated in Mexico, genotype has been present in Brazil longer than it has been
Colombia, Europe, South Africa, and India [44, 55–58]. A on Vancouver Island [65]. In contrast, C. gattii VGII isolates
recent epidemiological survey across Europe showed that C. (serotype B) in Colombia are mainly of the opposite a mating
gattii clinical infection is rare in this continent, represented type, although large numbers are present in regions that
by only six of 535 serotyped Cryptococcus isolates [59]. In have a temperate climate that is similar to Vancouver Island
this study, the genotypes of the six European C. gattii isolates [64].
identified were not determined. In Australia, the C. gattii
VGI genotype is the most common clinical or environmental
isolate, while the VGII genotype is an infrequent cause of 5. Virulence Factors
human or animal infection [15, 50]. A notable exception
to this overall pattern is the Northern Territory of Australia C. gattii and C. neoformans share many attributes that
that does not contain eucalyptus trees yet has the highest increase their ability to invade and survive in a host
incidence of clinical C. gattii infection. Interestingly, most organism [92]. The main virulence factors identified in
human cases in this region are due to VGII, suggesting that C. C. gattii to date include an outer polysaccharide capsule,
gattii has colonized a new environmental niche [60, 61]. This melanin, mannitol, extracellular proteinase, products of
possibility is also supported by the fact that eucalyptus trees the laccase pathway, superoxide dismutase, phospholipases,
in the rest of Australia have only yielded the VGI genotype urease, and the STE12α transcription factor (a homologue
[62]. of Saccharomyces cerevisiae STE12) that is present only in
While the majority of C. gattii isolates in Australia’s the α mating type (Table 1) [93]. Other properties of C.
Northern Territory and on Vancouver Island are of the VGII gattii contribute to its infectivity such as its ability to grow
genotype, a notable difference between the two regions is at physiological temperature [15], its tolerance of low pH
the remarkably limited diversity of the latter. Specifically, and elevated salt levels [47], and its ability to switch capsular
ninety five percent of the environmental and clinical samples phenotype [91].
on Vancouver Island are of the VGII genotype, and within A carbohydrate-rich outer capsule that is composed
this group 90% are of the major genotype VGIIa [47]. primarily of glucuronoxylomannan (GXM) with smaller
MLST studies have shown that the Vancouver Island VGIIa proportions of galactoxylomannan (GalXM) and manno-
genotype is identical to two known C. gattii strains: the 1975 proteins is the major virulence factor for both C. gattii and
Seattle human isolate NIH 444 (also known as CBS 6956 C. neoformans [94]. The capsule may change in composition
and ATCC 32609) and the 1992 San Francisco environmental and size through a process called phenotypic switching
isolate CBS 7750 isolated from E. camaldulensis [63]. These (described further in the Notable Attributes section) and
studies have also demonstrated that the VGIIa isolates from induces suppression of the host immune response by various
Vancouver Island, the BC mainland, the Gulf Islands and mechanisms including the downregulation of cytokine and
northern Washington State are genetically identical [22]. chemokine expression in dendritic cells (Table 1) [91, 95].
These findings indicate that the major genotype VGIIa has Kinetic studies have shown that complement component
existed in the Pacific Northwest for more than 30 years and C3 binds less efficiently to C. gattii compared to C. neo-
it is hypothesized that VGIIa originated from sexual mating formans, suggesting that C. gattii enhances virulence by
between VGIIb and another unknown parental strain [63]. preferential evasion of immune recognition [96]. Species-
Notably, VGI and VGII clinical isolates from Oregon differed specific variation in the expression of other virulence factors
from the Vancouver Island VGI and VGII samples at one may also play a role in their pattern of infectivity and
or more of the loci that were analyzed [22]. The reason for organ dissemination. For instance, it was observed that
this is not clear but may be explained by divergent evolution extracellular proteinase production is lower in certain strains
from a common genotype or the presence of distinct genetic of C. gattii compared to a number of C. neoformans isolates,
isolates residing in the Pacific Northwest. The VGIIb minor suggesting that C. gattii may less efficiently degrade proteins
genotype on Vancouver Island is identical to the unusually involved in tissue integrity and host immunity such as
fertile Australian VGIIb clinical isolate NT-13, suggesting collagen, fibrin, complement, and immunoglobulin [79–
that the Vancouver Island isolate originated in Australia [63]. 82]. This finding may explain why C. gattii lesions are
The VGI genotype is rarely found on Vancouver Island and often more circumscribed compared to C. neoformans, a
it remains unclear whether it has actually colonized the characteristic that could also reduce local and systemic
environment, and the molecular types VGIII and VGIV have dissemination [82, 97]. Similarly, in vitro experiments with
not yet been reported [23, 46]. Recent studies on C. gattii a variety of C. neoformans and C. gattii isolates from
4 Interdisciplinary Perspectives on Infectious Diseases

Table 1: C. gattii virulence factors and their functions.

Factor Function
Evasion of phagocytosis [67]
Reduction of antigen presentation [68]
Capsule and its associated polysaccharides Reduction of cytokine production [69]
Induction of suppressor T-cells which inhibit cell-mediated
immunity [70]
Inhibition of T-cell responses by GXM [31]
Inhibition of leukocyte migration into inflammatory sites by GXM
[31, 71]
Protection against UV radiation [72]
Melanin Protection against oxygen and nitrogen free radicals [73, 74]
May contribute to central nervous system tropism [6]
Contributes to negative cellular charge [75]
Suggested increase in intracranial pressure [76]
Mannitol Protection against stress [77]
Protection against oxygen free radicals [78]
Proteolytic activity [79]
Extracellular protease
May contribute to degradation of proteins involved in tissue
integrity and host immunity [79–82]
Diphenol oxidation [83]
Products of laccase pathway Synthesis of melanin [84]
Degradation of wood lignin [15]
Protection against oxidative stress [85]
Superoxide dismutase
Protection against oxidative burst produced by immune effector
cells [85]
Tissue invasion via degradation of mammalian membrane lipids
Phospholipases
and lung surfactant [15, 86]
Exact function is unknown [87]
Urease
May aid in transfer of Cryptococcus to central nervous system [88]
Upregulation leads to synthesis of diphenol oxidase (which is a
STE1α transcription factor (in cells of α mating type)
laccase) [89, 90]
Growth at physiological temperature (37◦ C) Survival and persistence in the host [15]
Tolerance of low pH Survival and persistence in the environment [47]
Tolerance of elevated salt Survival and persistence in the environment [47]
Change in capsule size—mucoid variant more virulent, smooth
Phenotypic switching
variant suggested to be able to cross blood-brain barrier [91]

South America have shown that C. neoformans has increased C. gattii most commonly infects immune competent indi-
urease production relative to C. gattii [98]. Intratracheal viduals while C. neoformans primarily infects the immune
administration of the highly virulent C. neoformans H99 compromised host. One explanation for this observation is
(serotype A) to mice suggests that urease may aid in that immune compromised individuals simply have more
the dissemination of the fungus from the lung to the environmental exposure to C. neoformans compared to C.
central nervous system, although the exact mechanism is gattii [5]. Furthermore, the contribution of host genetic
unknown [88]. It is also interesting to note that virulence background to resistance against cryptococcal infection is
factors are involved not only in pathogenesis but also in even less well understood. Interestingly, certain groups of
commensalism. For instance, C. gattii was observed to share individuals such as the Australian aboriginal population may
an endophytic relationship with decaying wood of both be predisposed to C. gattii disease [62]. Modern molecular
eucalypt and noneucalypt trees, where the laccase enzyme dissection of a microorganism’s virulence factors may allow
system appears to play a role in digestion of lignin [15, researchers to better understand the genetic mechanisms
50]. underlying virulence. A recent example of this approach
Given that C. neoformans and C. gattii appear to share used systematic targeted gene deletion in C. neoformans with
many of the same virulence factors, it is intriguing that comprehensive profiling of individual mutants in an animal
Interdisciplinary Perspectives on Infectious Diseases 5

model [99]. A similar large-scale strategy may be required to was similar in virulence to VGIIa [63]. These findings are
clearly delineate the pathogenesis of C. gattii and may in turn consistent with recent clinical experience that has shown
stimulate the development of novel therapeutic strategies. VGIIa to be the most common isolate from patients [21, 22,
24, 103].
Further insights into disease pathogenesis have been
6. Notable Attributes of C. gattii derived through animal studies using C. gattii isolates
that were not obtained from Vancouver Island. One study
Phenotypic switching and same-sex mating are two inter-
compared mouse and human pulmonary inflammatory
esting attributes that contribute to the virulence of C.
responses to intratracheal infection with 10 different Aus-
gattii. The term phenotypic switching refers to an adaptive
tralian isolates of C. gattii [104]. In BALB/c mice, 6 isolates
mechanism characterized by structural modifications of the
did not elicit any inflammatory response, 3 provoked a
extracellular capsule and cell wall [91]. This phenomenon
minimal response, and 1 resulted in a strong host inflam-
occurs infrequently in vitro or during chronic infection
matory response that took several weeks to develop. The
and a switch to a more mucoid form is associated with
peak inflammatory response was observed 5 weeks after
greater virulence in C. neoformans [91, 100]. Reversible
infection and was characterized by foamy macrophages,
phenotypic switching between a smooth and mucoid variant
lymphocytes, poorly defined granulomas containing some
of C. gattii strain NP1 has also been identified [100].
giant cells as well as C. gattii yeast, and destruction of lung
Shortly after infection, the mucoid form of NP1 is most
tissue. In humans, variable pulmonary pathology has been
commonly observed; however, a subsequent switch to the
detected including poorly formed granulomas containing
smooth form characterized by reduced capsular polysaccha-
intracellular C. gattii, lymphocytic interstitial pneumonitis,
ride allows for easier penetration of the blood-brain barrier
tissue necrosis, and fibrosis. In both species the local
and dissemination to the brain [91]. Evaluation of survival
lymphocyte pool consisted largely of T-cells with a 2:1 ratio
and fungal burden in BALB/c mice following intravenous or
of CD4 to CD8 cells in humans [104].
intratracheal infection with either C. gattii NP1 phenotypic
A second study examined the pathology seen in BALB/c
variant demonstrated increased virulence of the mucoid
mice following systemic infection with the clinical isolate
form. In this study, both mucoid and smooth variants were
C. gattii 9714 (CBS 6996, serotype B, VGIII/AFLP5) under
found in the lung homogenates while only the smooth
different experimental conditions [105, 106]. It was observed
variant was found in the brain homogenates. In terms of
that both immune competent and hydrocortisone-treated
the immune response, infection with the smooth variant
mice developed C. gattii disease, contrasting with the
elicited a greater inflammatory response as characterized
apparent predilection of immune competent humans to this
by lymphocyte and monocyte infiltration and gave rise to
infection. At high doses of C. gattii, immune suppressed
smaller cryptococcomas than the mucoid variant [91].
mice were more likely to develop severe disease compared
In contrast to most Australian C. gattii isolates, it was
to immune competent mice. SCID mice that lack T- and B-
demonstrated that all Vancouver Island isolates belong to
lymphocytes were more susceptible to infection relative to
the α mating-type and are unusually fertile [63, 66]. The
wild-type BALB/c, suggesting a protective role for these cell
mechanism by which cryptococcal cells of an identical
types [105]. Comparative studies showed that C. neoformans
mating type replicate is not known. However, it has been
9759 (a serotype A clinical isolate) has increased virulence
suggested that C. gattii undergoes same-sex mating, a process
compared to C. gattii 9714 after systemic infection of
that has been studied in C. neoformans [63]. Upon nutrient
BALB/c mice, regardless of the immune state of the animal.
limitation, α haploid cells can undergo sexual recombination
Specifically, C. neoformans 9759 infected the brain and lungs
via fruiting, a process by which haploid cells fuse, chromo-
of BALB/c mice, while C. gattii 9714 affected the lungs and
somal reassortment and recombination occur, followed by
skin. Ulcerative lesions on the tail due to intravenous C.
meiosis and sporulation [66, 101]. Same-sex mating between
gattii infection were more common in immune competent
two α cells (rather than an α and an a cell) may confer
mice, while rectal prolapse was more common in immune
a survival advantage and could explain why all Vancouver
suppressed mice. This study also demonstrated that infection
isolates are of the α mating type [101]. Both traditional and
by either C. neoformans 9759 or C. gattii 9714 may cause
same-sex mating in C. neoformans have been observed in the
gastrointestinal pathology, although its incidence was rare
laboratory but not in nature [63, 66, 101, 102].
[105].
A third study examined the pathogenesis of five Cryp-
7. Animal Models of C. gattii Infection tococcus isolates administered to BALB/c mice via the
intraperitoneal route [107]. The isolates included C. gattii
A limited number of animal model studies of C. gattii GR52 and GR56 (both serotype B), from immune competent
infection have been reported in literature. One group goats that died of pneumonia in Spain; C. gattii B4506
has investigated the survival of A/J inbred mice following (serotype B), an Australian environmental isolate known to
intranasal infection with different Vancouver Island C. gattii be highly pathogenic in mice; C. gattii I-682 (serotype C),
molecular types. In this report, the major genotype VGIIa from a Colombian native almond tree; and C. neoformans
appeared most virulent (20% survival at 15 days post- GR297 (serotype D), from an AIDS patient in Spain with
infection), the minor genotype VGIIb was avirulent (100% meningitis. Two of five mice infected with C. neoformans
survival at 55 days post-infection), and the VGI genotype GR297 developed liver and peritoneal abscesses and one
6 Interdisciplinary Perspectives on Infectious Diseases

mouse died after four weeks. Fungal cultures of spleen, respiratory system (52%), central nervous system (42%), and
liver, kidney, testes, lung, and brain were done for each the skin or gastrointestinal tract (6%), while in felines 56%
group and were positive in at least one organ for GR52, were respiratory, 26% involved the central nervous system,
GR297, GR56, B4506, and I-682 in 80%, 77%, 70%, 70%, and 19% were dermal with no cases of gastrointestinal
and 33% of the cases, respectively [107]. Based on the involvement [28].
frequency of cryptococcal growth in the organ cultures, all Another study was carried out on Vancouver Island to
fungal isolates with the exception of the serotype C sample determine whether wild animals were infected with C. gattii.
I-682 displayed similar virulence in BALB/c mice. Among Of the 91 animals that underwent swabbing of the nasal
the organs tested, the spleen was most often positive for cavity, two eastern grey squirrels were found to be positive for
Cryptococcus (91%), followed by the liver (75%), kidney C. gattii. This number is similar to the incidence of infection
(75%), testes (71%), lung (62%), and brain (29%). C. gattii in asymptomatic companion animals; specifically 1.1% of
GR52, the cause of a pneumonia outbreak in goats, was dogs, 4.3% of cats and 1.5% of horses were positive for C.
also isolated from the lungs of all BALB/c mice studied, gattii [109]. Subclinical C. gattii infection in dogs and cats
suggesting that it has a particular tropism for lung tissue. does not necessarily progress to clinical disease. In some
Pathologic findings associated with infection of the brain cases it may be cleared while in other cases it may persist
included areas of spongiosis in the white matter with an or develop into more severe disease [115]. It has also been
abundance of encapsulated yeasts in the basal ganglia while suggested that infected wild animals may be an important
infected lungs showed encapsulated yeasts within alveoli, vector for the spread of C. gattii from Vancouver Island to
peribronchial vessels, and interalveolar spaces. Interestingly, geographic regions that do not harbor the organism and that
inflammation was not observed in either organ among veterinary cases may also be a reliable sentinel of human
infected mice [107]. disease [109]. The latter assertion is based on the observation
These studies show that the route of experimental that C. gattii infection was identified in animals prior to the
cryptococcal infection is a major determinant of the site of human outbreak that began on Vancouver Island in 1999 and
disease. In general, intravenous infection directly induces that nearly twice as many animals appeared to be infected
systemic disease, whereas inhalation of the fungus via the with C. gattii compared to humans between 1999 and 2003
airway mimics the natural route of infection and leads to [116]. These observations also highlight a potential role
primary disease in the lung [108]. For example, in the second for animals in transmission of infection to humans. While
study both the cutaneous and gastrointestinal pathologies zoonotic transmission of C. gattii has not been reported
may have been a direct result of C. gattii administration to date, transmission of C. neoformans from pet birds to
through the tail vein, and significant involvement of the humans has been documented, and possible human-to-
visceral organs and peritoneum in the third animal study human transmission has also been described [117–119]. In
may have resulted from intraperitoneal inoculation of the addition to the veterinary cases in the Pacific Northwest,
fungus. Nonetheless, the tissue tropism observed in humans outbreaks of C. gattii involving goats in Spain [120] and
is similar to that seen in these mouse models [13, 15, 21]. In psittacine birds in Brazil [112] have also been observed.
addition to the route of infection, these studies also confirm
that other variables such as the C. gattii isolate, infectious
dose, and immune status of the host also play a role in the 9. Human C. gattii Infection
virulence of the fungus and the severity of infection [15].
C. gattii may cause mild to severe clinical disease in the
apparently healthy as well as immune compromised host.
8. Veterinary Cases Like other cryptococcal species, C. gattii enters the human
host through the inhalation of airborne propagules and
C. gattii has the potential to infect a wide range of animals targets the lung as a primary site of infection [22, 108]. In
throughout the world, including wild, farm, domestic, and some cases dissemination via the bloodstream may occur,
aquatic animals, along with a variety of birds. This broad most commonly to the central nervous system (CNS) with
host range was observed during the recent outbreak in British occasional spread to other organs such as skin, eye, and
Columbia [23, 109, 110]. In order to study the epidemiology prostate [13, 15, 82]. The predominant manifestations of C.
of veterinary cases, diagnostic methods to test for infection gattii infection involve the lungs in the tropical climate of
in animals generally consist of serum and/or tissue sampling Australia (66% pulmonary) as well as the temperate climate
and nasal swabbing [28, 109, 111–113]. A recent study of Vancouver Island and its surroundings (75% pulmonary)
examined the characteristics of C. gattii infection in domestic [21, 60].
animals in southwestern BC, involving 78 feline and 51 A study performed by the British Columbia (BC) Crypto-
canine cases [28]. It was observed that cats were 4.4 times coccal Working Group at the University of British Columbia
more likely than dogs to be positive for C. gattii infection, reviewed the clinical aspects of 171 individual human cases
and that all cases in dogs and 50% of cases in cats were of C. gattii infection on Vancouver Island from 1999 to 2006
due to C. gattii serotype B [111]. In cats, the median age at [21]. It was determined that the mean age at diagnosis was
diagnosis was 7.3 years, whereas in dogs it was 2.3 years [28]. 59 years, with a range of 2 to 92 years. Males (56%) appeared
The tissue tropism of C. gattii disease differs slightly in cats to be slightly more susceptible to infection than females
and dogs. Among canines, the affected organs included the (44%) [21]. The clinical patterns of C. gattii infection were
Interdisciplinary Perspectives on Infectious Diseases 7

pulmonary (75%), neurological (8%), combined (9%), and rest were unspecified. Apart from place of residence or travel,
unknown (8%). Of those patients with combined disease, the the main risk factors associated with the development of C.
main sites involved the lung and CNS, and less commonly the gattii disease were smoking (50%), oral steroid use (30%),
skin and lung, or skin and CNS. Death was a rare outcome of invasive cancer (24%), and chronic lung disease (13%). HIV
C. gattii infection on Vancouver Island with 8 fatalities from infection (4%) and receipt of an organ transplant (3%) were
1999 to 2006, or approximately one death per year. Of the considered less common risk factors for the development of
deceased patients, five presented with both pulmonary and C. gattii disease in this study population [21]. Examination of
CNS pathology, three had other underlying comorbidities, the case reports shows a similar pattern; 4 of the 12 cases had
and one had an adverse reaction to therapy. The mean age of a current or past history of smoking, and 7 of the 12 patients
the deceased patients was 61 years (range from 26 to 87) [21]. suffered from chronic disease and/or cancer, had undergone
A summary of the most recent case reports associated recent surgery, or had been exposed to corticosteroids.
with the Pacific west coast is presented in Table 2. Among the Thus far, the median incubation time of C. gattii on
first 8 patients, three patients resided in British Columbia, Vancouver Island has been estimated to be 6-7 months with
two patients resided in Oregon State, one resided in Wash- a range from 2 to 11 months [123]. One exception is the
ington state, one resided in Alberta, and one patient was relatively short incubation period of six weeks that was
a tourist from Denmark visiting Vancouver Island [22, 24, observed in the Danish tourist visiting Vancouver Island
25, 103]. The place of residence of patients 9 to 12 was [103]. The potentially long time frame from exposure to
not specified, although they represented patients discharged symptoms may impede the diagnosis of C. gattii infection.
from Vancouver Island hospitals [114]. Six of the cases were It is likely that the clinical incubation period depends on
either not directly exposed to C. gattii on Vancouver Island or several variables such as differences in host immunity and
were exposed many years earlier. This suggests that another the intensity of C. gattii exposure.
source of C. gattii may exist outside of Vancouver Island, or
that the fungus may have been transiently present in other
geographic regions due to dispersal mechanisms [22, 121]. 10. Microbiology
Also, the fact that in two cases infected individuals had
traveled to Vancouver Island 4 and 14 years before developing Laboratory testing is essential to diagnose C. gattii infection
symptoms raises the possibility that C. gattii may remain and generally requires analysis of tissue or fluids from
latent in the body and reactivate at a later time [5]. infected sites such as cerebrospinal fluid, bronchial washings,
In the BC Cryptococcal Working Group study, the blood, and urine [12]. Light microscopy is an efficient
pulmonary symptoms most commonly observed in the 171 method for the rapid diagnosis of cryptococcosis. For this
cases were cough and dyspnea, while the main symptom technique, fluid samples are usually stained with India ink
involving the CNS was headache [21]. Similarly, the usual while tissue samples may be stained with hematoxylin and
symptoms in the Pacific west coast case reports were cough eosin (H&E), mucicarmine, or other stains [12, 20, 91].
and shortness of breath, although some patients developed In both cases, cryptococcal cells appear round to oval in
nausea, fever, headache, muscle pain, and loss of appetite. It shape, surrounded by a wide capsule. Infrequently, one may
is important to recognize that the clinical presentation of C. visualize nonencapsulated cryptococci under the microscope
gattii infection may be quite subtle. For example, patients [12]. In the laboratory, both C. neoformans and C. gattii
3 and 9 were asymptomatic while patient 6 experienced readily grow as round cream-colored mucoid colonies on
only a nonspecific cough [22, 24, 114]. The most common Sabouraud dextrose agar, a selective medium that is widely
pathology observed in these patients was nodules of the used for the isolation of yeast [12]. Alternatively, malt
lung in the form of cryptococcomas. Interestingly, patient 7 extract agar may be used to selectively isolate fungi [12, 47].
presented with pulmonary ground-glass opacities, a pattern Differential microbial media such as Staib agar or birdseed
that is quite distinct from circumscribed nodules and agar may be used to distinguish dark brown colonies of C.
rarely observed in the clinic [25]. The specific pulmonary neoformans or C. gattii from other fungi [47, 124]. Further
pathology for patient 4 was not reported [22]. Meanwhile, differentiation of cryptococcal species can be accomplished
CNS pathology was documented in four patients: patient on L-canavanine-glycine-bromthymol blue (CGB) agar; C.
1 had cerebral cryptococcomas and patients 5, 7, and 12 gattii colours the medium blue while C. neoformans does not
presented with meningitis [22, 25, 114]. (medium remains yellow) [125]. Though not required for
All 171 C. gattii cases from the BC Cryptococcal Working clinical management, the fungus may be viewed in its sexual
Group study were caused by C. gattii serotype B [21]. This state by growing the cells on V8 medium in the dark followed
finding is consistent with the fact that serotype B exists at by fixation and staining to visualize the hyphae, nuclei, and
a much higher frequency in the environment compared to septa [101]. Finally, it is possible to determine the exact
serotype C. In fact, the identification of C. gattii serotype C serotype of a cryptococcal isolate using a slide agglutination
in the environment had not been described prior to 1998 [50, assay although commercial kits for this purpose are not
122]. It also appears that the C. gattii major genotype VGIIa is currently available [22, 25].
highly associated with human disease: 82% of the cases were In vitro activity of antifungal agents may be helpful
VGIIa, while the others were VGIIb (9%) and VGI (6%) [21]. in guiding the clinical management of severe cryptococcal
Similarly, 5 of the 12 case reports from the Pacific west coast infection including meningoencephalitis [126]. A slower
were VGIIa, one was VGIIb, and another was VGI, while the clinical response of C. gattii to antifungal therapy has
8 Interdisciplinary Perspectives on Infectious Diseases

Table 2: Summary of case reports of C. gattii infection.

Health Pathology
Age (sex) Residence Exposure Symptoms (molecular type)
conditions
Cough, chills, night
BC mainland Chronic sweats, nausea, Lung/brain
Yard/landscaping
1 [22] 47 (M) (on coast north hepatitis C, drug muscular pain, nodules (VGI)
work at residence
of VI) addiction headache, appetite
loss, stiff neck
Dyspnea, fever, chills,
Deforestation near
headache, night
BC (lower residence, yard Lung mass (VGIIa)
2 [22] 48 (F) None sweats, appetite loss,
mainland) work, last visited
nausea, muscular
VI 4 years ago
pain
Chronic renal
Little outdoor
failure, lung Lung nodule
exposure, last
3 [22] 73 (F) BC disease, breast None (VGIIa)
visited VI 14 years
cancer, hip
ago
surgery
Cough, dyspnea,
Scarred lung Not specified
No travel out of fever, chills, nausea,
4 [22] 59 (M) OR tissue (due to (VGIIa)
OR in last year weight loss, muscular
occupation)
pain
Chronic
Travel to parts of lymphocytic Fever, weight loss, Meningitis
5 [22] 87 (M) OR (VGIIb)
OR, WA & CO leukemia (oral appetite loss
steroid)
Large granular
lymphocytic Lung nodule
WA (Puget Travel to south CA
6 [24] 74 (M) leukemia Cough (VGIIa)
Sound) and HI in last year
(steroid and
hormone)
Headache, blurred Lung opacities,
Holidays spent on vision, airspace disease,
7 [25] 45 (F) Alberta southeast shore of None photosensitivity, meningitis (not
VI, park visits nausea, vomiting, specified)
cough
Psoriatic gout
Travel to Victoria
(nonsteroidal 3 large nodular
and VI east coast Chest pain, fever,
8 [103] 51 (M) Denmark anti- infiltrates (VGIIa)
for 7 days, garden cough, dyspnea
inflammatory
visits
drug)
Bradycardia,
acute Lung opacity (not
9 [114] 54 (M) Not specified Not specified myocardial None specified)
infarction,
smoker
Lung nodules (not
10 [114] 62 (M) Not specified Not specified Previous smoker Chest pain
specified)
Previous
smoker, total Cavitary lesion
Exposure to
11 [114] 69 (F) Not specified colectomy due Cough, dyspnea (not specified)
tuberculosis
to ulcerative
colitis
Previous Lung opacity,
Occupational smoker, mild meningitis (not
12 [114] 65 (M) Not specified Not specified
(painter) recurrent specified)
hemoptysis

Legend: BC: British Columbia, CA: California, CO: Colorado, HI: Hawaii, OR: Oregon, VI: Vancouver Island, WA: Washington.
Interdisciplinary Perspectives on Infectious Diseases 9

been attributed to serotype-specific differences in antifungal MacDougall et al., C. gattii was isolated from environments
activity though there are no consistent or predictable data outside of Vancouver Island including the British Columbia
to support this hypothesis [127, 128]. To evaluate this mainland, the Gulf islands, and Washington state, but no
possibility further, a recently published study compared positive environmental samples were found in Oregon [22].
the susceptibility of 86 C. neoformans and 42 C. gattii In the clinic, C. gattii has been isolated in Seattle (1975),
isolates to various antifungal drugs including amphotericin Vancouver Island, and the British Columbia mainland, and
B, flucytosine, fluconazole, posaconazole, voriconazole, and most recently in Oregon, Washington, and Alberta [22–
isavuconazole [129]. The major finding was that all anti- 25, 63].
fungal agents tested retained activity against all cryptococcal
isolates with the newer azoles exhibiting greater potency
compared to fluconazole and flucytosine. In this report, no
12. Conclusion
significant differences in drug potency were observed for C. The recent outbreak of C. gattii infection in the Pacific
gattii serotypes B or C compared to other serotypes. Northwest highlights the fact that this fungus is an impor-
tant emerging pathogen that can adapt to new potential
environmental niches. C. gattii isolates found on Vancouver
11. Spread of the Vancouver Island Island appear to be hypervirulent, as the number of infected
C. gattii Outbreak individuals per million people per year between 2002 and
2005 was more than 36 times higher on Vancouver Island
The colonization of C. gattii on Vancouver Island, and compared to endemic regions such as Australia [22, 23].
possibly other adjacent regions, indicates that this fungus It is in the interest of scientists and clinicians alike to
has the ability to adapt to new environmental conditions. It better understand the pathogenesis of C. gattii disease
has been suggested by Kidd et al. that the temperate climate in order to discover effective prevention and treatment
of Vancouver Island may provide a favorable niche for the strategies, including measures to limit human exposure to
survival and dispersal of C. gattii [23]. Global warming this pathogenic fungus. Employing C. neoformans as a model
has also been proposed to favor C. gattii colonization of organism to understand the disease-causing potential of C.
new geographic regions [23]. Studies in Colombia have also gattii is no longer sufficient since fundamental disparities
suggested a correlation between climate and distribution such as differences in host tropism and the expression of
of cryptococcal serotypes A to C. Specifically, differential certain virulence factors exist between the two species.
tolerance of climatic and possibly other environmental
conditions by individual serotypes may affect their geo-
graphic and ecological distribution [37, 130]. The modes Acknowledgments
of dispersal of C. gattii have been studied on Vancouver
This work was supported in part by the Research Institute of
Island. Some trees in the region show intermittent positivity,
the McGill University Health Centre, the Quebec Respiratory
suggesting the movement of fungal spores [121]. High C.
Health Training Program (SC), a Burroughs Wellcome
gattii levels exist in public areas such as park entrances,
Career Award in the Biomedical Sciences (SQ), and a Canada
parking lots, and beaches despite the fact that these areas
Research Chair (SQ).
are characterized by low tree density [47, 121]. A significant
amount of C. gattii dispersal appears to be mediated by
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