Cryptococcus neoformans infections

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Cryptococcus neoformans infections

• Dr R Pickles
• Staff Specialist
• Immunology Infectious Diseases
• John Hunter Hospital

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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

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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

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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 gt 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

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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

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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 lt 200
• Incidence has declined in Australia since advent
  HAART
• Prolonged steroid therapy
• Organ transplantation
• Malignancy
• Sarcoidosis

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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.

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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

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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

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Diagnosis

• High index of suspicion needed
• Lumbar pucture
• Measure record opening pressure
• Repeat at least fortnightly during therapy and
  daily if pressure gt 25 cmH2O
• India ink examination
• CSF WCC (usually mononuclears) typically low (lt
  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

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Diagnosis

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

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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

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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

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Poor prognostic factors

• CSF WBC lt 20/uL ()
• Initial CSF or serum antigen titre gt 132 ()
• Extraneural sites involved additionally ()
• Raised opening pressure ()
• Persistently low CSF glucose