1. CRYPTOCOCCAL INFECTIONS IN PATIENTS WITH AIDS Stephen J. Gluckman, M.D. Botswana-UPENN Partnership

2. 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

3. 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

4. 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

5. 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

6. Silver Stain

7. 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

10. 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

11. 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

12. India Ink

13. 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

14. 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

17. Cryptococcal Meningitis Treatment Antifungal agents –Induction –Consolidation –Maintenance Pressure management

18. Anti-Fungal Therapy* * Modified IDSA Guidelines Immunocompetent –asymptomatic, pulmonary Careful observation –symptomatic, pulmonary Fluconazole: 200-400 mg/day x 3-6 months –Cryptococcemia or (+) serum CRAG or (+) urine culture Fluconazole: 200-400 mg/day x 3-6 month –Severe and/or CNS disease Treat as immunosuppressed but for 10 weeks

19. 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 ?

20. 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: ?

21. 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

22. 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