1. Cryptococcus neoformans infections
Dr R Pickles
Staff Specialist
Immunology & Infectious Diseases
John Hunter Hospital

2. Cryptococcus - microbiology
Invasive fungal infection increasingly prevalent with increasing numbers of immunocompromised patients.
An encapsulated yeast
C. neoformans the major pathogenic member of the genus
Subclassified into 4 serotypes and 2 varieties
Serotypes based upon capsular agglutination reactions, types A, B, C, D
Serotype A now classified as variety grubii
Serotypes B + C variety gattii
Serotype D variety neoformans

3. Cryptococcus - lifecycle
Exists in asexual and sexual forms, with the asexual form existing as a yeast, which reproduces by budding. This is the only form associated with human infection.
Produces white mucoid colonies in vitro which become visible within 48 hours
Thick capsule visible in India ink suspension .
Capsule has important antiphagocytic properties

6. Cryptococcus - ecology
Var grubii and var neoformans
Found worldwide in soil contaminated by bird droppings (esp chickens and pigeons), roosting sites and rotting vegetation
Pigeons do not become infected, ? Inhibited by body temperature of > 40 o C
Cryptococcus can be found in pigeon GI tract
Outbreaks of disease not associated with pigeon roosting areas
? Infection via ingestion of contaminated vegetation

7. Cryptococcus - ecology
var gattii
Never cultured from bird guano
Flowering river red gums (Eucalyptus camaldulensis) and forest red gums (E. tereticornis)
These trees have been widely exported around the world

8. Cryptococcus - epidemiology
Increasing proportions of patients have an underlying immune deficiency – virtually all var neoformans or var grubii
HIV/AIDS
Accounts for up to 50% cryptococcal infections
CD 4 < 200
Incidence has declined in Australia since advent HAART
Prolonged steroid therapy
Organ transplantation
Malignancy
Sarcoidosis

9. Cryptococcus neoformans var gattii
In contrast to var neoformans, var gattii geographically restricted:
Australia, PNG
N. Africa and Mediterranean
India, SE Asia
Mexico, Brazil, Paraguay, S California
Commonly non-immunocompromised hosts
Large mass lesions (cryptococcomas) common, resulting in significant morbidity.

10. Clinical Manifestations
Pulmonary cryptococcosis
Asymptomatic carriage may occur in healthy people as well as those with chronic lung disease
May experience a self limited pneumonia
Invasive chronic pulmonary disease may occur and may disseminate to the CNS
CNS disease
Meningitis (85%), meningoencephalitis, cryptococcoma
Generally symptoms more insidious and of longer duration in the non-immunosuppressed
Higher burden of organisms in AIDS, with variable inflammatory response, which parallels degree of immunosuppression

11. Clinical manifestations
Cutaneous cryptococcosis
Ulcerated or nodular lesions – usually portend poor prognosis in disseminated disease
cellulitis
Bone and joint disease
Lytic lesions in up to 10% with disseminated disease
Ocular cryptococcosis
Rare, other than pressure effects
Genitourinary disease
Prostate acts as sanctuary site in immunosuppressed

12. Diagnosis High index of suspicion needed Lumbar pucture
Measure + record opening pressure
Repeat at least fortnightly during therapy and daily if pressure > 25 cmH2O
India ink examination
CSF WCC (usually mononuclears) typically low (< 50) in those with advanced immunosuppression
CSF glucose + protein often only minimally abnormal
Cryptococcal antigen assay
Rapid diagnostic test
Rare false positives
Titre generally correlates to organism burden
Serum assay useful screen in AIDS patients

13. Diagnosis Extraneural cultures Radiology
Occasionally positive from another site
Full evaluation needed to exclude disseminated disease, or CNS disease
Radiology
Detection of cryptococcomas
May detect hydrocephalus -> need for shunt

14. Treatment CNS disease uniformly fatal without Rx
Immunocompromised patients need longterm suppressive therapy, unless immune status substantially recovers
Aim for complete eradication of organism in the nonimmunosuppressed:
Amphotericin B mg/kg/d + flucytosine mg/kg/d for 6 weeks followed by fluconazole 400 mg/d for 3-6 months+
Debate re switch to fluconazole after 2 weeks if favourable clinical(including LP) response

15. Treatment
In HIV/AIDS most switch early to oral therapy, or use high dose oral fluconazole from the outset if mild disease
Liposomal amphotericin if develop toxicity
? New azoles
Echinocandins have no anticryptococcal activity
Management of raised intracranial pressure often the most problematic issue
Large volume (30-50 mL) CSF removal up to daily
Shunt or drain placement (does not prevent clearance of infection)
Steroids generally of no use in management of pressure, except where oedema associated with cryptococcomas

16. Poor prognostic factors
CSF WBC < 20/uL (*)
Initial CSF or serum antigen titre > 1:32 (*)
Extraneural sites involved additionally (*)
Raised opening pressure (*)
Persistently low CSF glucose