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

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

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

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

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

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

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.

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

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

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

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

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 0.5-0.7 mg/kg/d + flucytosine 100-150 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

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

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