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Cryptococcus neoformans and
other Yeast
Dr Sharon Walmsley
University Health Network
Toronto
Organism
• Encapsulated
• Heterobasidiomycetous fungi
• Asexual stage – simple narrow based
budding
• Sexual – bipolar system, in-vitro
• 19 species
Identification
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Routine laboratory media
48-72 hours, 30-35ºC
May be inhibited by cycloheximide
White/cream opaque colonies which
become mucoid with prolonged incubation
Rapid identification
• India ink
• Urease test (ureaammoniapH)
• Laccase activity (diphenolic
compoundsmelanin) – niger seed agar
Rapid Urease Test
Histopathology
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Prominent capsule
Spherical narrow based budding yeast
May have hyphae or pseudohyphae
5-10 mm diameter
• 4 serotypes based on capsule
Ecology
• Saprobe in nature – fruit, trees, rotting
wood, soil
• Bird guano – pigeons, turkey, chickens
Epidemiology
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HIV
Lymphoproliferative disroders
Sarcoidosis
Corticosteroids
Hyper IgM or IgE syndrome
Monoclonal antibodies (infliximab)
SLE
CD4 T-cell lymphoma (idiopathic)
Diabetes
Organ transplant
Peritoneal dialysis
Cirrhosis
• 20% without HIV have no underlying comorbidity
Spectrum of Disease
Colonization  Asymptomatic  Disease
Rates of Disease
Pre-AIDS
1992
HAART
Africa/HIV
.8/10 6/ year
5/10 6/year
1/10 6/year
15-45%
Rates in Transplant
• 18/100,000
• Increased with cell mediated immune
inhibitors
• Highest in kidney and liver
• Rarely carried in through transplanted organ
Serotypes - Cryptococcus neoformans
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A-D
Commercially available antibody tests
Biochemical tests
PCR
Serotypes - Cryptococcus neoformans
Serotype
A – 80% clinical cases
B – tropical, subtropical – S. California,
Hawaii, Brazil, Australia, SE Asia
C – rare
D – Europe – Denmark, Germany, Italy,
France, Switzerland
Pathogenesis
• Inhalation
• Traumatic inoculation
• Human – human – contaminated transplant
tissue
• Zoonosis?
Pathogenicity
• Capsule – polysaccharide
• Melanin
• High temperature growth (37ºC)
Host Response
• Cellular immune response, granulomatous
inflammation
• Th – 1 polarized
• Cytokines – TNF, 1F-8, 1L-2
• Proinflammatory 1L-12, 1L-18, MCP-1,
MIP
• NK cells
Pathogenesis
Host defense
Size of
Inoculation
Virulence of
strain
Clinical Manifestations
Lung
- Portal of entry
- asymptomatic (1/3)  life threatening
pneumonia (ARDS)
- Endobronchial colonization  underlying
chronic lung disease
- Single pulmonary nodule
- Symptomatic – acute, subacute
Pulmonary Cryptococcus
Clinical Manifestations
CNS
- Subacute meningitis or meningo-encephalitis
- Headache, fever, cranial nerve palsies, lethargy,
coma
- Subacute (days)  months
HIV
- Higher yeast burden
-  incidence raised intracranial pressure
- Often disseminated
- Immune reconstitution disease
Cryptococcal meningitis
Cryptococcus- Oral Lesions
Clinical Manifestations
Skin
- Papule with ulcerated center
- Cellulitis, abscess
- Rarely underlying bone lesions
Prostrate
- Asymptomatic (sanctuary)
- Penile, vulvar lesions
Cryptococcus, skin lesions
Cryptococcus, skin lesions
Clinical Manifestations
Eye
- Ocular palsy, papilledema, optic neuritis
- Retinal exudates +/- iritis
- endophthalmitis
Diagnosis
Microscopic
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India Ink (50-80% + CSF)
Gram
Calcoflur white
Silver stain
Culture
– Blood agar
– Routine blood culture
Cryptococcus, India Ink
Diagnosis
Serology
– Latex agglutination, EIA, 90% sensitive &
specific
Radiology
– CXR – infiltrates, nodules, lymphadenopathy,
cavitation, effusion
– CT/MRI – 50% normal, hydrocephalus,
nodules
In vitro susceptibility testing
• Low MICs – amphotericin, flucytosine,
azole
• High MICs – caspofungin
• In vitro R demonstrated but most refractory
cases are relapses
Therapy – Cryptococcal meningitis
• Amphotericin B +/- flucytosine
• Fluconazole
• Amphotercin x 2 wk then fluconazole 400800 mg/d x 8-10 wk
• Chronic suppression fluconazole 200 mg/d
Raised ICP
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CSF OP > 250mm
Rapidly progressive cerebral edema
Repeated LP, shunt
Corticosteroids not useful
Prognosis
• Need to be able to control underlying
disease
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 immunosuppression
 prednisone
HAART
? Adjunctive cytokines – interferon, GCSF
Poor prognosis
 Burden of organism
( + India Ink, crypto Ag > 1:1024, poor CSF
inflammatory response < 20 cells/uL)
 Sensorium
Mortality 10-25%
Prevention
• Fluconazole prophylaxis
• Active immunization- cryptococcal GXMtetanus toxoid conjugate vaccine- in animal
models, no human trials
• Monoclonal antibodies- would require
repeated injections
• Avoid high risk environments
Cryptococcus neoformans (var gattii)
• Initially described in Australia
• Cultured from vegetation around river red
gum trees, eucalyptus trees
• Recent outbreak Vancouver Island
Cryptococcus neoformans var gatti
• Outbreak Vancouver Island, January 02
• N = 59, 2 deaths
Cryptococcus neoformans var gatti
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75% primarily pulmonary disease
25% CNS
58% male, 5.3% Asian
Mean age 60
Certain geographic locations
Never cultured from bird guano
May be associated with certain trees
Cryptococcus neoformans
Cryptococus neoformans
var grubii
var gatti
(now C.gatti)
var enoformans
C.gatti
Vancouver Island
• 1999-2003
– 8.5 – 37/10⁶/year
• Australia - endemic
– 94 cases/million/year
C.gatti
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Usually restricted to tropical, subtropical
Now in temperate zone
Able to identify an environmental reservoir
Identified in sea animals
Cryptococcus
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Global epidemiology
Study – Canada 1984
N = 78
7.7% C.gatti
79.5% C.neoformans v grubii
6.4% C.neoformans v neoformans (serotype D)
6.4% C.neoformans v neoformans (hybid AD)
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