CRYPTOCOCCAL INFECTIONS
IN PATIENTS WITH AIDS
Stephen J. Gluckman, M.D.
Botswana-UPENN Partnership
Microbiology
• Encapsulated yeast
• 4 serotypes
– A (C. neoformans v grubii)
– B and C ( C. gatti)
– D (C. neoformans v neoformans)
• All types can cause human disease
• Life cycle
– Asexual: yeast that reproduce by budding
• Human infections
– Sexual: only seen in the laboratory
Ecology and Epidemiology
• World wide
– C. neoformans associated with bird droppings
– C. gatti not associated with birds, associated with
eucalyptus trees
• Generally an infection of immunocompromised
but can cause clinical disease in healthy
persons
– Decreased Cell-mediated immunity
• AIDS – CD 4 usually < 100
• Prolonged corticosteroids
• Organ transplant
Ecology and Epidemiology
• 15-30% of AIDS patients in Sub-Saharan
Africa*
• Much less common in children
• No person to person transmission
*Powderly, WG Clin Infect Dis 1993
Clinical Presentations
• Pulmonary
– Asymptomatic nodule
– Symptomatic: not distinguishable from other
causes
• History, PE, routine laboratory testing does not produce
features peculiarly suggestive of cryptococcal infection
– Diagnosis
• Staining of biopsy specimen
• Culture of sputum and/or blood
• Serum cryptococcal antigen (CRAG)
– All patients with pulmonary disease need a CSF
examination to r/o sub clinical meningitis
Silver Stain
Clinical Presentations
• Cutaneous
– Disseminated disease
– Looks similar to molluscum contageosum
– Diagnosis:
• Unroofing a lesion and making a smear and culture
• Serum CRAG
– All patients with cutaneous disease need a
CSF examination to r/o sub clinical meningitis
Clinical Presentations
• Cryptococcal Meningitis
– Typical
• Subacute onset of fever and headache
• Photophobia and/or meningeal signs in only 25%
– Less typical
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Seizures
Confusion
Progressive dementia
Visual or hearing impairment
FUO
– Diagnosis
• CSF
• Serum CRAG: > 99% sensitive in AIDS patients
Cryptococcal Meningitis
• In 2003 there were 193 (+) CSF cultures for
cryptococcus from PMH *
– Leucocytes
• No leucocytes in 31%
• Only 1-10 leucocytes in 23%
• 7% had > 250 leucocytes
– 30% of these had predominately PMN’s
– 95% (+) India Ink
– 1% (-) cryptococcal antigen
• Literature
– Sensitivity: 93-100%
– Specificity: 93-98 %
*Bisson et al
India Ink
Prognosis for Cryptococcal
Meningitis
• Prior to 1950 it was uniformly fatal
• Amphotericin B introduced and mortality fell to the 3040% range
• In 1970’s 5-FC was released
– Not for monotherapy
– Decreased relapse rate when used with Amphotericin B
• Mortality with current regimens: 10%
• Predictors of death
– Altered mental status
– CSF CRAG > 1024
– CSF cell count < 20
• Changes in serum CRAG titer do not correlate with
clinical outcome. So no need to follow
Summary of Diagnostic Options
• Culture
– White mucoid colonies within 48hours
– Blood cultures often (+) in immunosuppressed
patients
• 2/3rds with meningitis
• Tissue
– Silver or mucicarmine stain
• India Ink for CSF
• Cryptococcal antigen
– Serum and CSF are 99% sensitive in AIDS patients
– Serum is less sensitive in normal hosts
Cryptococcal Meningitis
Treatment
• Antifungal agents
– Induction
– Consolidation
– Maintenance
• Pressure management
Treatment*
*Modified IDSA Guidelines
– Immunosuppressed (pulmonary, cutaneous,
or meningitis)
• Induction
– Amphotericin B 0.7-1 mg/kg/day plus 5-flucytosine
100mg/kg/day x 2 weeks then
• Consolidation
– Fluconazole 400 mg/day x 6-10 weeks then
• Suppression
– Fluconazole 200 mg/day x ?
Cryptococcal Meningitis
Treatment
One More Thing
• Anti-fungal: induction, consolidation, maintenance
• Pressure management
– Elevated pressure
• 75% > 200
• 25% > 350
– Repeated lumbar punctures
• Increased pressure: daily until normal x several days
• Normal pressure: recheck at 2 weeks prior to switching to
fluconazole
– Lumbar drain
– VP shunt: if still elevated at 1 month
– No role for
• acetazolamide, mannitol
– Steroids: ?
Treatment
• Other options
– Fluconazole induction
• Increased mortality
• Not IDSA first choice
– 5 FC monotherapy
• Not an option because of resistance
– 5-FC plus Fluconazole
• Increased long term toxicity but an option
– Caspofungin
• No efficacy
– Voriconazole
• Good in vitro activity but little clinical experience
Summary
• Cryptococcal infections are common in patients
with AIDS
• In patients with AIDS cryptococcal infections are
seen in patients with the lowest CD 4 (+) cell
counts
• Prolonged therapy and secondary prophylaxis is
necessary
• For meningitis both anti-fungal therapy and
aggressive pressure management are required