1163
The Ecology of Cryptococcus neoformans and the Epidemiology
of Cryptococcosis
Stuart M. Levitz
From the Division of Infectious Diseases, Evans Memorial Department
of Clinical Research and the Department of Medicine, The University
Hospital, Boston University Medical Center, Boston, Massachusetts
The incidence of cryptococcosis, formerly a relatively rare
disease, has markedly increased in recent years due to the
frequent occurrence of the disease in patients with AIDS.
Meningitis and, to a lesser extent, pneumonia are the most
frequent life-threatening manifestations of cryptococcosis, although morbidity due to involvement of virtually any organ
system can occur. While cryptococcosis is greatly increased
in frequency in patients with defective cell-mediated immunity, before the AIDS epidemic f\J50% of all patients with
cryptococcosis had no readily identifiable underlying immune
defect. The vast majority ofcases of cryptococcosis are thought
to result from failure of host defenses to contain the organism after inhalation of aerosolized particles from an environmental source occurs. This review focuses on the ecology of
Cryptococcus neoformans in nature and the epidemiological
features that characterize patients with cryptococcosis.
Readers interested in the clinical manifestations, diagnosis,
and treatment of cryptococcosis are referred to several recent reviews [1-4].
Description of the Pathogen
Although there are 19 known species of the genus Cryptococcus [5], the etiologic agent in virtually all cases of human cryptococcosis is C. neoformans. Rare cases of infection
secondary to Cryptococcus albidus and Cryptococcus laurentii
Received 22 August 1990; revised 4 January 1991.
Reprints and correspondence: Dr. Stuart M. Levitz, Room E540, University Hospital, 88 E. Newton Street, Boston, Massachusetts 02118.
Reviews of Infectious Diseases 1991;13:1163-9
© 1991 by The University of Chicago. All rights reserved.
0162-0886/91/1306-0042$02 .00
have been reported [6, 7]. First described in 1894, C. neoformans is an encapsulated round or oval yeast. In clinical specimens, the yeast cell itself measures f\J4-6 #Lm in diameter,
although considerable heterogeneity in size and shape may
be noted. The surrounding polysaccharide capsule ranges in
size from 1 #Lm to >30 #Lm [2]. In specimens isolated from
nature, the organisms tend to be smaller and poorly encapsulated [8, 9]. A perfect or sexual state of C. neoformans (designated Filobasidiella neoformans) can be demonstrated by
mating the fungus under defined conditions in vitro. Under
such conditions, mycelia (hyphae) are produced, which eventually give rise to spores (basidiospores) [10]. While the small
size (1-3 #Lm) of these basidiospores is ideal for initiating infection by alveolar deposition, the perfect state of C. neoformans has never been demonstrated in nature or in patients.
Thus the contribution, if any, of the perfect state to the
epidemiology of cryptococcosis is undefined.
In general, culture of C. neoformans isolated from clinical
and environmental specimens is not difficult, as the fungus
grows well on various culture media at 25°C and 37°C. However, for specimens that may be heavily contaminated, such
as bird droppings or sputum from patients with AIDS, differentiation of C. neoformans from other yeasts and bacteria can
be time consuming if routine fungal isolation media, such as
Sabouraud dextrose agar, are used. Fortunately, selective media and rapid identification tests have been described that take
advantage of the organism's distinct biochemical profile, including its production of urease, resistance to antibacterial
agents such as chloramphenicol, creatinine assimilation, and
phenoloxidase activity [5, 11, 12]. Phenoloxidase enables C.
neoformans to synthesize melanin from certain catecholamine
precursors. Thus pigmented colonies result when the organism is grown on selective media enriched in catecholamines,
such as birdseed agar. Phenoloxidase activity and melanin
production have been postulated to contribute to the propen-
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The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis are reviewed.
Two varieties of C. neojormans have been recognized. C. neojormans variety neojormans has been
found in nature worldwide,primarily in association with bird droppings, although nonavian sources
have also been found. Most cases of human cryptococcosis are caused by this variety. C. neojormans var. gattii has recently been isolated in nature in association with Eucalyptus trees. Infections caused by this variety occur mainly in tropical and subtropical regions. Because exposure
to C. neoformans is probably common and clinically apparent cases of cryptococcosis in healthy
hosts are rare, it is presumed that most people can mount adequate host defenses upon exposure
to the organism. At least 5%-10% of patients with AIDS become infected with Cryptococcus;
the epidemiology of this infection is different in many respects from that seen in patients without AIDS.
1164
Levitz
RID 1991;13 (November-December)
In contrast to the situation with pigeon droppings, a lower
percentage of soil samples are positive for C. neoformans,
the concentration of organisms in soil tends to be less, and
positivesamplesare often obtained from areas contaminated
by bird excreta. For instance, in a survey of 1,127 soil samples collected from differentgeographic areas of the world,
only 14 (1 %) were positive for C. neoformans. Of those, 10
were from areas frequented by chickens and pigeons [34].
It has been suggested that soil formsan inhospitable environment for C. neoformans. In supportof this, anaerobic conditions,hightemperatures, decreased humidity, direct sunshine,
low pH, and the presence of soil amebae (which devour the
fungi) andother microbes have all beenshownto be detrimental to the survival of C. neoformans in soil [33, 35, 36].
C. neoformans has been isolated from the excrementof a
variety of avian species in addition to pigeons, including
chickens, parrots, sparrows, starlings, turtledoves, canaries,
and skylarks [30, 37-39]. The reason for the high frequency
of C. neoformans in avian excreta is not clear but may be
relatedto the ability of the fungito assimilatexanthine,urea,
uric acid, andcreatinine, all of whichare abundant in thedroppings [37].
As alluded to earlier, C. neoformans is occasionally isolated fromvariousnonaviansources, including fruits, vegetables, dairy products, and the digestive tract of the cockroach
[23, 24, 40,41]. In a study of440 fruit and vegetablesamples
taken from a market in Delhi, India, five (1 %) of the samples
(oneeachof apple, guava,papaya, carrot, and potato) yielded
C. neoformans [40]. Thus far, all isolatescollected from bird
droppings, soil, fruits, vegetables, and milk, whentested,have
been C. neoformans var. neoformans [5, 31, 42]. In a unique
study, C. neoformans was isolated from bagpipes used by a
patient with pulmonary cryptococcosis. However, it is plausiblethatthe patient's sputumcontaminated the bagpipes [43].
Distribution in Nature of C neoformans
var. neoformans
Distribution in Nature of C neoformans yare gattii
C. neoformans wasisolated in nature first from peachjuice
in 1895 and then from milk in 1901 [5, 23, 24]. It was not
isolated again from a saprophytic source until Emmons [25,
26] isolated the organismfrom soil in 1951 and from pigeon
excreta in 1955. Although pigeon droppings commonly are
colonized with C. neoformans, pigeons do not appear to become sick due to cryptococcosis, perhaps becausetheir high
body temperature is detrimental to growth of the organism
[26]. SinceEmmons's originalreports, C. neoformans has been
isolated from soil, pigeonexcrement,and sitescontaminated
by pigeon excrement in various parts of the world. Concentrations of C. neoformans in pigeon droppings often exceed
1Q6 viable organisms per gram, and most investigators have
encountered little difficulty isolating C. neoformans directly
from pigeonexcretaor samplescontaminated by suchexcreta
[27-33].
As opposed to C. neoformans var. neoformans (serotypes
A and D), whose isolation has been reported from numerous
environmental sources worldwide, C. neoformans var. gattii
(serotypesB and C) has been considerably more difficult to
isolate from the environment. An isolate obtained from soil
samples and reported as serotypeC [31] provedsubsequently
to be serotype A [17]. Recently, Ellis and Pfeiffer [44, 45]
extensively tested environmentalsamples from sites in rural
Australia, an area in which C. neoformans var. gattii is endemic. This organismwas isolatedexclusively from material
(including bark, wood, and leaves) collectedunder the canopies of Eucalyptus camaldulensis (river red gum) trees. The
time at which the positive cultures were obtained coincided
with the flowering of the trees. Moreover, air-sampling experimentsdetected airborne fungus in the vicinity of flowering trees but not of nonflowering trees or in other areas.
The distribution of E. camaldulensis is concentrated in trop-
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sity for C. neoformans to invade the CNS, an area rich in
catecholamines [13]. Rareisolatesof urease-negative C. neoformans have been described [14].
On the basis of antigenic determinants on the polysaccharide capsule, four serotypes (A, B, C, and D) of C. neoformans have been recognized; the structures of the major
capsular polysaccharides of these serotypes havebeen determined [15]. Type-specific antiserum used for serotyping is
prepared by immunizing rabbits with formalin-killed yeasts
of a known serotype and then adsorbing the antiserum with
yeastsof heterologous serotypes[16]. Occasional clinicalisolates of C. neoformans are untypeable on the basis of their
failure to agglutinate on exposure to one of the four typespecificantisera [17]. Someisolatesreact to bothtypes A and
D antisera and are designated AD [16]. Individual isolates
of C. neoformans canbe distinguishedby their pattern shown
by pulsed-field gelelectrophoresis, a technique thatmayprove
powerful in studying the molecular epidemiology of cryptococcosis [18].
Geneticand biochemicalstudieshaveestablishedtwovarieties of C. neoformans. C. neoformans var. neoformans includes serotypes A and D, while C. neoformans var. gattii
includes serotypesBand C. In addition to serotyping, which
requires special reagents, the color reaction on various solid
media can be used to distinguishthe twovarietieswith a high
degree of accuracy; these media include creatinine-dextrosebromthymolblue (CDB)agar, canavanine-glycine-bromthymol blue (CGB) agar, and glycine-cyclohexamide-phenol red
(GCP) agar [19-22]. Moreover, C. neoformans var. gattii assimilates L-malate and is relatively temperature sensitive [5,
10]. The morphology of the perfect states of the twovarieties
is also different[10]. As discussed in detail later, distinctive
featurescharacterizethe epidemiologyand ecologyof the individual varieties and serotypes of C. neoformans.
RID 1991;13 (November-December)
Cryptococcosis
ical and subtropical regions; these regions correspond to the
areas of the world in which clinically apparent infections due
to C. neoformans var. gattii are endemic (see next section).
Future studies are needed to determine whether C. neoformans var. gattii is host-specific for E. camaldulensis or
whether other species of Eucalyptus and related plants also
harbor the fungus. It is noteworthy that in California alone
rv150 speciesof Eucalyptus, includingE. camaldulensis, have
been cultivated [46, 47].
Epidemiology of Cryptococcal Varieties and Serotypes
in Patients with Cryptococcosis
There are few published data comparing clinical features
of patients infected with the two varieties of C. neoformans.
In a study published in abstract form only, Henderson et al.
[59]compared nine patientswith cryptococcal meningitis due
to C. neoformans var. gattii with a matched group of patients
infected with C. neoformans var. neoformans. None had severeunderlying immunosuppression. The group infectedwith
C. neoformans var. gattii required a longer course of chemotherapy, leadingthe authorsto speculatethat meningitis caused
by that variety might be more refractory.
It has been suggested that C. neoformans var. gattii has a
relativepredilection for healthyhosts and C. neoformans var.
neoformans for compromised hosts [2]. Two studies examined the in vitro susceptibilities of the two varieties to commonly used antifungal drugs. One found no significant
differences in susceptibilities, while the other found diminishedsensitivityto 5-fluorocytosine in C. neoformans var. gattii [51, 60].
Epidemiological Characteristics of Patients
Infected with C. neoformans
Since C. neoformans is ubiquitous in the environment, exposure to the fungus presumably is commonplace. Few epidemiological studiesattempting to prove this assumption have
been performed. For the most part, these studies consisted
of skin-test surveys using cryptococcin, an antigenic extract
of C. neoformans [61-63]. Results are somewhat difficultto
interpret because the cryptococcin skin test has not beenstandardized, the antigens in the extract are incompletely characterized, and the sensitivity and specificity of the test are
unknown. In a study of 28 pigeon breeders, results for nine
(32%) of 28 who underwent a cryptococcin skin test were
positive, although for none of those tested was there clinical
evidence of past or present infection. In contrast, only one
(4%) of a control group of 24 tested positive [62]. Pigeon
handlers also have a high frequency of cryptococcal antibodies in serum [64, 65]. An increased incidence of reactivity
to cryptococcin among laboratory personnel who work with
C. neoformans has been noted [63].
Despite these findings, which suggest that exposure to C.
neoformans is particularly common in certain groups such
as pigeon breeders and laboratory workers, there is no evidence of an increased incidence of active cryptococcosis
among these groups. Unlike outbreaks of other systemicmycoses, outbreaks of cryptococcosis traced to environmental
sources have not been described. Scattered cases tend to occur worldwide, althougha uniquereport describedthree cases
of cryptococcosis occurring within a IS-month period in the
small town of Kingfisher, Oklahoma [30]. Another case report described pulmonary and hepatic cryptococcosis in a patient who trapped wild pigeons in a building contaminated
with pigeon droppings containing C. neoformans [29]. Because nearly everybody is exposed to birds and bird excreta,
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Kwon-Chung and Bennett [17] reported the varieties and
serotypes of725 clinical isolates of C. neoformans from various parts of the world. Although clinical features of the patients were not given, most isolates were apparently collected
from patients without AIDS. Isolates from regions with temperate climates such as the United States (excluding Southern California andHawaii), Europe, andJapanbelongednearly
exclusivelyto C. neoformans var. neoformans (serotypes A
and D). In contrast, there was a high frequency (35%-100%)
of C. neoformans var. gattii (serotypes B and C) in isolates
from tropicaland subtropicalregionssuchas SouthernCalifornia, Australia, Southeast Asia, Brazil, and Central Africa.
As discussed, the presence of C. neoformans var. gattii predominantly in tropical and subtropical regions may be a
consequence of the association of this variety with E. camaldulensis trees, as such trees are not found in temperate climates [44, 46]. Overall,of the isolates studiedby Kwon-Chung
and Bennett, 70% were serotype A, 16% serotype D or AD,
11 % serotype B, 2 % serotype C, and 1% untypeable. Serotype D was relatively more common in Europe, while nearly
all the serotype C isolates were from Southern California.
Other investigators, studying smaller numbers of clinical isolates, have reported similar trends [22, 48-52].
Even in areas where a relatively high percentage of clinical
isolates from patientswithout AIDS havebeen C. neoformans
var. gattii, nearly all of the isolates from patients with AIDS
have been C. neoformans var. neoformans [49, 50, 53-55].
As of this writing, only four (of >150 tested) isolates from
patients with AIDS reported in the literature were C. neoformans var. gattii [49,50, 53-58]. The reason for this disparity
between isolates from patients with and without AIDS is
speculativebut likely relates to differencesin the pathogenicity or ecology of the isolates. For instance, in Australia 90 %
of patients with AIDS live in a region of the country where
E. camaldulensis trees, a natural reservoir for C. neoformans
var. gattii, are rarely found [44,45]. Thus, if one postulates
that C. neoformans var. gattii is more pathogenic but that exposure to C. neoformans var. neoformans is more common,
one would expect the percentage of cases due to C. neoformans var. neoformans to be higher among patients who are
severely immunocompromised, such as those with AIDS.
1165
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Levitz
been termed signal disease, or malade signal, because it may
herald the presence of an underlying debilitating disease [5].
Those at particularly high risk havedefects in the cell-mediated
arm of the immune system, such as occur in patients with
AIDS, Hodgkin's and non-Hodgkin's lymphomas, and sarcoidosis and in those receiving immunosuppressive therapy (especially with glucocorticoids) [1, 2, 4, 37, 75, 76]. The high
frequency of cryptococcosis among transplant recipients is
probably related to the immunosuppressive therapy given to
prevent rejection rather than a direct effect of the transplant
itself. It is interesting that cyclosporine, which depresses T
cell responses and is used to prevent transplant rejection, has
been shown to have intrinsic anticryptococcal activity in some
systems and may protect against development of active clinical infection [77].
Cryptococcosis also appears to occur with increased frequency in association with leukopenia, diabetes mellitus, rheumatoid arthritis, and hepatic cirrhosis [1, 2,37, 75, 76]. Before
the AIDS epidemic, f\J50 % of cases of cryptococcosis occurred in patients without any obvious immune defects [37,
75, 76], although some may have had subtle defects in their
ability to mount an immune response to cryptococcal antigens [78-80].
In several (but not all) series from the pre-AIDS era, cryptococcosis occurred two to three times more often in men than
in women [75, 76, 81-83]. Estrogens, which have been shown
to have in vitro activity against C. neoformans, may be protective in women [84]; alternatively, however, men may be
more likely to be exposed to the fungus. Among patients with
AIDS in the United States, approximately equal percentages
of each sex are infected with Cryptococcus [85]. Cryptococcosis in patients with AIDS occurs with increased frequency
among blacks, intravenous drug users, and residents of the
southern states immediately east of the Mississippi River
[85, 86].
About 5 %-10% of patients with AIDS in the United States
are reportedly stricken with cryptococcosis, making it one
of the most common life-threatening infections seen in this
group of patients [4, 85]. However, this figure is probably
an underestimate of the true incidence, as infections subsequent to the AIDS-defining infection often are not reported
to public health departments. Moreover, because signs and
symptoms of cryptococcosis can be subtle in cases of AIDS,
the infection may not be diagnosed. It will be important to
see whether the incidence of cryptococcosis in patients with
AIDS increases as patients live longer due to the availability
of primary therapy for the human immunodeficiency virus
and prophylactic therapy for infection due to Pneumocystis
carinii. The prevalence of cryptococcosis in patients with
AIDS in Africa and other developing areas appears to be
higher than that in the United States [87-89]. It is unclear
whether this circumstance is secondary to increased exposure
to saprophytic sources of the fungus [41, 90] or the relative
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it has been difficult to implicate or exonerate the bird as the
main vector responsible for transmission of C. neoformans
var. neoformans, and the possibility remains that at least some
patients acquire infection due to this organism from nonavian sources that remain unrecognized. Since exposure to C.
neoformans is probably common but clinically apparent cases
of cryptococcosis are rare, it is presumed that most people
can mount adequate host defenses when exposed to the organism.
Although it has never been conclusively documented, virtually all cases of cryptococcosis are thought to result initially from inhalation of airborne fungi from an environmental
source. Isolates of C. neoformans measuring 0.6-3.5 Itm in
diameter, a size ideal for alveolar deposition after inhalation,
have been isolated from aerosols generated from soil and pigeon droppings [8, 33, 66]. Samples of air obtained under
flowering E. camaldulensis trees also have grown C. neoformans [44, 45]. Moreover, small pulmonary lesions, consistent with clinically unapparent primary cryptococcosis, have
been incidentally noted in human pathology specimens [3, 67].
The human tracheobronchial tree may become colonized with
C. neoformans, presumably after inhalation of airborne organisms, without development of active cryptococcosis [68, 69].
Rare cases of cutaneous cryptococcosis have occurred after direct inoculation of the organism into the skin [70, 71].
However, most cases of cutaneous cryptococcosis result from
hematogenous dissemination from systemic disease. Although
never documented, the possibility exists that some cases of
cryptococcosis could be the result of dissemination from a
gastrointestinal portal of entry. The occasional findings of contamination of food and human stool with C. neoformans [2,
23, 24, 40, 72] lend support to this possibility. Moreover, in
animal models, disseminated cryptococcosis may be seen after gastrointestinal inoculation of C. neoformans [73].
Two unusual cases of presumed person-to-person transmission of cryptococcosis have been documented. In the first case,
a recipient of a corneal transplant from a donor with cryptococcosis developed cryptococcal endophthalmitis after the
transplant [74]. The other case involved a health care worker
who developed localized cutaneous cryptococcosis after accidentally inoculating himself with blood from a patient with
cryptococcemia [70]. Special precautions, such as isolating
infected patients or wearing masks, are not indicated solely
on the basis of a diagnosis of cryptococcosis, although it would
probably be prudent for patients who are severely immunocompromised to avoid contact with patients who are coughing
and whose sputum is positive for C. neoformans. Veterinary
cases of cryptococcosis occur, but animal-to-person transmission has never been reported.
The prevalence of cryptococcosis is markedly increased
among immunocompromised patients. Moreover, the morbidity, mortality, and frequency of relapse are higher in those
who are severely immunocompromised. Cryptococcosis has
RID 1991;13 (November-December)
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Cryptococcosis
Note Added in Proof
Sincethis articlewasaccepted for publication, C. neoformans var.
gattiihasbeen isolated from E. camaldulensis trees in California[93].
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rarity of other AIDS-related infections, in particular those
caused by P. carinii and the Mycobacterium avium complex,
in those parts of the world [91, 92].
Because patients with AIDS are so exquisitely susceptible
to infection with Cryptococcus it would appear to make empiric sense to counsel them to avoid situations in which exposure to heavy aerosols of C. neoformans might be likely,
such as sweeping a floor contaminated with pigeon droppings
or being in the vicinity of a flowering Eucalyptus tree. However, because of the ubiquity of C. neoformans and the fact
that our knowledge of the circumstances that result in inoculation of the organism is incomplete, it is uncertain whether
such precautions would be beneficial. Moreover, some cases
might arise from reactivation from a latent focus, as has been
shown for other mycoses such as histoplasmosis and coccidioidomycosis. Alternative approaches for the prevention or
early detection of cryptococcosis in patients with AIDS that
merit consideration include prophylaxis with antifungal drugs
and periodic screening for cryptococcal antigen.
Thus, since C. neoformans was first isolated from clinical
and ecologic sources nearly a century ago, knowledge of its
ecology and epidemiology has greatly expanded. However,
despite these significant advances, much still needs to be
learned regarding the circumstances under which patients become infected with this ubiquitous fungus. The challenge
ahead will be to apply this wisdom towards strategies for
reducing the occurrence of cryptococcosis.
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59. Henderson DK, Edwards JE, Dismukes WE, Bennett JE. Meningitis
produced by different serotypes of Cryptococcus neoformans [abstract].
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and Be. Mycopathologia 1986;94:27-30
61. Bennett JE. Cryptococcal skin test antigen: preparation variables and
characterization. Infect Immun 1981;32:373-80
62. Newberry WM Jr, Walter JE, Chandler JW Jr, Tosh FE. Epidemiologic
study of Cryptococcus neoformans. Ann Intern Med 1967;67:724-32
63. Atkinson AJ Jr, Bennett JE. Experience with a new skin test antigen
prepared from Cryptococcus neoformans. Am Rev Respir Dis 1968;
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64. Walter JE, Atchison RW. Epidemiological and immunological studies
of Cryptococcus neoformans. J Bacteriol 1966;92:82-7
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