Cryptococcus

Background

• Genus of yeast within the family Cryptococcaceae
• Only Cryptococcus neoformans and Cryptococcus gattii cause infections in humans

Epidemiology

• The majority of cases occur in patients with advanced HIV or other severely immunocompromising conditions

Pathophysiology

• Initially acquired by inhalation, followed by hematogenous dissemination with strong neurotropism

Clinical Manifestations

• Infects CNS, lung, and bloodstream
• Cryptococcal meningitis is the most common clinical manifestation
• Pulmonary infection more common with Cryptococcus gattii while CNS infection and fungemia were more common with Cryptococcus neoformans

Cryptococcal Meningitis

• Typically subacute presentation over 1-2 weeks (in HIV) or 6 to 12 weeks (non-HIV)
• Headache (most common sign, near-universal), altered cognition (50%), lethargy, fever (50-70%), nuchal rigidity, nausea/vomiting (in about 70%), seizure (15%)
• Visual symptoms include diplopia and photophobia, followed by decreased visual acuity
• Can also develop ataxia, aphasia, seizures, and chorea
• Symptoms in advanced HIV can be subtle or absent

Differential Diagnosis

• Other causes of meningoencephalitis and CNS mass lesions in immunocompromised patients

Investigations

• Lumbar puncture for CSF
  • High opening pressure >18 (in around 80%)
    • >25 cm H₂O is a poor prognostic sign
  • Low glucose (can be undetectably low) and elevated protein
  • WBC count can be normal; when elevated (usually in the tens to hundreds), typically lymphocytic pleocytosis
  • Cryptococcal antigen (CRAg); or India ink staining if CrAg unavailable
• Cryptococcal antigen (CRAg) can also be sent serum
• CT chest for pulmonary infection
  • Most commonly shows clustered nodular pattern
  • May also show solitary pulmonary nodule/mass with or without cavitation, scattered nodules, or peribronchovascular consolidation

Diagnosis

• Made with cryptococcal antigen from CSF or blood, India ink staining, or fungal culture

Management

Patients with HIV

CNS Disease

• Induction (first 2+ weeks): liposomal amphotericin B (3-4 mg/kg IV daily) plus flucytosine (100 mg/kg per day orally in 4 divided doses)
  • IV formulations may be used in severe cases and in those without oral intake where the preparation is available) for at least 2 weeks
• Consolidation: fluconazole (400 mg [6 mg/kg] per day orally) for a minimum of 8 weeks
• Maintenance:
  • Fluconazole (200 mg per day orally) or itraconazole (200 mg twice per day orally; drug-level monitoring strongly advised)
  • Start HAART 2–10 weeks after starting antifungals
  • Consider stopping antifungals once CD4 >= 100 for 3 months

Fungemia

• First, rule out meningitis with an LP
• If no meningitis, can treat with fluconazole 400 mg po daily until immune reconstitution

Organ Transplant Patients

• Always consider decreasing immunosuppression if able to

CNS, Severe, or Disseminated Disease

• Induction (first 2+ weeks): liposomal amphotericin B (3–4 mg/kg per day IV) plus flucytosine (100 mg/kg per day in 4 divided doses)
  • If not including flucytosine, then extend induction to 4-6 weeks
• Consolidation: fluconazole (400–800 mg [6–12 mg/kg] per day orally) for 8 weeks, then by fluconazole (200–400 mg per day orally) for 6–12 months (B-II)

Mild-to-Moderate Non-CNS Disease

• Includes mild-to-moderate pulmonary disease
• Fluconazole (400 mg [6 mg/kg] per day) for 6–12 months

Patients Without HIV or Organ Transplant

• Induction (first 4+ weeks): amphotericin B deoxycholate (0.7–1.0 mg/kg per day IV) plus flucytosine (100 mg/kg per day orally in 4 divided doses)
  • If neurological complications or positive CSF cultures after 2 weeks of treatment, consider extending to 6 weeks total
  • If not including flucytosine, then extend induction by 2 weeks
  • If there is amphotericin B deoxycholate toxicity, liposomal amphotericin B may be substituted in the second 2 weeks
• Consolidation: fluconazole (400 mg per day) for 8 weeks
• Maintenance: fluconazole (200 mg [3 mg/kg] per day orally) for 6–12 months

Pregnant Patients

• See review at [1]
• In short, amphotericin B monotherapy is recommended, since fluconazole is teratogenic

Further Reading

• IDSA Guidelines 2010