1. Cryptococcal pneumonia and meningitis

2. Cryptococcus neoformans

3. Cryptococcus gattii or grubii - serotype B or C

4. Pulmonary cryptococcosis - large nodule

5. SP age 69 years

6. Pulmonary cryptococcosis - cavitating nodule

7. Pulmonary cryptococcosis - cavitating nodule

8. Pulmonary cryptococcosis - cavitating pneumonia

9. Pulmonary cryptococcosis - consolidation

10. Pulmonary cryptococcosis - bilateral atelectasis

11. Pulmonary cryptococcosis - ‘atypical pneumonia’

12. Pulmonary cryptococcosis - cavitating pneumonia

13. Pulmonary cryptococcosis -IDSA guidelines

15. SP age 69 years – lung biopsy (PAS)

16. Clinical features of TBM and fungal meningitis Subacute presentation - 1-4 weeks Headache, confusion / reduced acuity, vomiting common Focal signs, hydrocephalus and extrameningeal features, occasional Neck stiffness uncommon in immunocompromised Differential diagnosis is wide, including non-infectious causes

17. Investigations - immunocompromised patient TB and fungal blood culture MR scan of brain (better than CT) CSF with opening pressure CSF analysis - microscopy for TB and yeast cells (India Ink), and bacteria

18. India ink for cryptococcal meningitis

19. Investigations - immunocompromised patient TB and fungal blood culture MR scan of brain (better than CT) CSF with opening pressure CSF analysis - microscopy for TB and yeast cells (India Ink), and bacteria - routine, fungal and TB culture - Viral culture and PCR for HSV and CMV - cells, protein and glucose - TB PCR - Aspergillus antigen / PCR Chest Xray

20. Cryptococcal meningitis in AIDS, a disseminated disease

21. First randomised study of cryptococcal meningitis 51 pts received either 1) AmB 0.4mg/kg/d for 10 wks or2) AmB 0.3mg/kg/d + 5FC for 6 wks Resp (%)Relapse (%) Died (%) AmB 10 wks 41 1847 AmB +5FC 6 wks 67 424 Bennett et al, NEJM 1979;301:126

22. Randomised study of cryptococcal meningitis in AIDS 21 pts received either 1) Flu 400mg/d for 10 wks or2) AmB 0.7mg/kg/d + 5FC for 10 wks Resp (%) Died (%) Pos CSF (d) Flu 42 2841 AmB +5FC 100 016 Larsen et al, Am J Med1990;113:182

23. Open study of cryptococcal meningitis in AIDS with itraconazole 37 pts received either 1) ITZ 400mg/d (n = 25) or2) AmB <7d, then ITZ (n=12) CR (%) PR (%) Fail / UE (%) ITZ alone 40 24 36 AmB then ITZ 83 8 8 Denning et al, Mycoses in AIDS 1990;305.

24. Randomised study of cryptococcal meningitis in AIDS 381 pts received either 1) AmB 0.7mg/d for 2 wks or2) AmB 0.7mg/kg/d + 5FC 2 wks, then re-randomised to ITZ or FLU 400mg/d for 8 weeks Resp (%) Died (%) Pos CSF (%) AmB 83 5 40 AmB + 5FC 78 6 49* * p=0.06 van der Horst et al, NEJM 1997;331:15

25. Randomised study of cryptococcal meningitis in AIDS 306 pts received either 1) FLU 400mg/d for 8 wks or2) ITZ 400mg/d for 8 wks Resp (%) Died (%) Pos CSF (%) Flu 68 1 3 ITZ 70 3 5 van der Horst et al, NEJM 1997;331:15

26. Randomised study of maintenance of cryptococcal meningitis in AIDS Cox proportional hazards model Risk of relapse p value RR (95% CI) ITZ Rx0.06 4.32 (0.9,19.8) No prior 5FC0.045.88 (1.3, 27.1)  serum CRAG0.081.2 (1, 1.38) Saag et al, Clin Infect Dis 1999;28:291

27. Jarvis et al, BMC Infect Dis 2010;10:67 Meningitis in subsarahan Africa Cape Town 3 years sequential LPs

28. Nussbaum et al, Clin Infect Dis 2010;50:338 HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive 14 days of - fluconazole (1200 mg/d) alone (A) or - fluconazole (1200 mg/d) alone + flucytosine (100 mg/kg/d) (B) followed by fluconazole (800 mg/d) Cryptococcal meningitis Rx P <0.001

29. Nussbaum et al, Clin Infect Dis 2010;50:338 Cryptococcal meningitis Rx

30. Choice of initial antifungal therapy for cryptococcal meningitis Priority sequence Amphotericin B (0.7- 1.0 mg/Kg/d) or AmBisome 3-4mg/Kg/d) + flucytosine (100 mg/kg/d) Fluconazole >800mg/d + flucytosine (100 mg/kg/d) Perfect et al, IDSA Guidelines. Clin Infect Dis 2010;50:291

31. Management of cryptococcal meningitis LP essential, CT / MR scan desirable, but not essential Initiate Rx - Amphotericin B 0.7mg/kg/d or Liposomal amphotericin B 4mg/kg/d + Flucytosine 25mg/kg/dose tid If CSF pressure >250, repeat LP in 2 days and drain CSF IF CSF pressure >250 for several days use acetazolamide, (not steroids) and consider lumbar shunt If patient responding, switch to fluconazole 400mg/d. Stop therapy if HARRT Rx successful for >6m, or, in non-AIDS CSF antigen <1:8after at least 6m Rx

32. Coccidioidal meningitis Pointers Travel history Extra-meningeal disease No suggestions of TB Lack of response to TB treatment Essential tests CSF coccidioidal antibody Treatment High dose azole or intrathecal amphotericin B Lifelong

33. Aspergillus Aspergillus meningitis >40 cases reported Pointers Neutrophil predominant CSF Immunocompromised, neurosurgery / IT antibiotics, IVDA, or extension from Aspergillus sinusitis Essential tests CSF Aspergillus antigen (galactomannan) Aspergillus PCR, fungal culture Treatment IV itraconazole or voriconazole or amphotericin B No steroids Outcome reasonable, if diagnosis made WWW.aspergillus.org.uk