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

http://admerk.com/janco/flags/flagimages/admerk_botswana_flag_jpg.jpg

http://admerk.com/janco/flags/flagimages/admerk_botswana_flag_jpg.jpg

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 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 30-

40% 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 MeningitisTreatment

• 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 MeningitisTreatment

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