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

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 PMNs

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 1970s 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