Cryptococcal pneumonia and
meningitis
Cryptococcus neoformans
Cryptococcus gattii or grubii serotype B or C
Pulmonary cryptococcosis
- large nodule
SP age
69
years
Pulmonary cryptococcosis
- cavitating nodule
Pulmonary cryptococcosis
- cavitating nodule
Pulmonary cryptococcosis
- cavitating pneumonia
Pulmonary cryptococcosis
- consolidation
Pulmonary cryptococcosis
- bilateral atelectasis
Pulmonary cryptococcosis
- ‘atypical pneumonia’
Pulmonary cryptococcosis
- cavitating pneumonia
Pulmonary cryptococcosis -IDSA guidelines
Pulmonary cryptococcosis -IDSA guidelines
SP age 69 years – lung biopsy (PAS)
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
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
India ink for cryptococcal meningitis
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
Cryptococcal meningitis in AIDS, a
disseminated disease
First randomised study of
cryptococcal meningitis
51 pts received either
1) AmB 0.4mg/kg/d for 10 wks
or
2) AmB 0.3mg/kg/d + 5FC for 6 wks
Resp (%)
AmB 10 wks
AmB +5FC 6 wks
41
67
Relapse (%) Died (%)
18
4
47
24
Bennett et al, NEJM 1979;301:126
Randomised study of cryptococcal
meningitis in AIDS
21 pts received either
1) Flu 400mg/d for 10 wks
or
2) AmB 0.7mg/kg/d + 5FC for 10 wks
Flu
AmB +5FC
Resp (%)
42
100
Died (%)
28
0
Pos CSF (d)
41
16
Larsen et al, Am J Med1990;113:182
Open study of cryptococcal meningitis in
AIDS with itraconazole
37 pts received either
1) ITZ 400mg/d (n = 25)
or
2) AmB <7d, then ITZ (n=12)
CR (%)
ITZ alone
AmB then ITZ
40
83
PR (%)
24
8
Fail / UE (%)
36
8
Denning et al, Mycoses in AIDS 1990;305.
Randomised study of cryptococcal
meningitis in AIDS
381 pts received either
1) AmB 0.7mg/d for 2 wks
or
2) AmB 0.7mg/kg/d + 5FC 2 wks, then re-randomised to ITZ or FLU
400mg/d for 8 weeks
Resp (%)
AmB
AmB + 5FC
* p=0.06
83
78
Died (%)
5
6
Pos CSF (%)
40
49*
van der Horst et al, NEJM 1997;331:15
Randomised study of cryptococcal
meningitis in AIDS
306 pts received either
1) FLU 400mg/d for 8 wks
or
2) ITZ 400mg/d for 8 wks
Flu
ITZ
Resp (%)
68
70
Died (%)
1
3
Pos CSF (%)
3
5
van der Horst et al, NEJM 1997;331:15
Randomised study of maintenance of
cryptococcal meningitis in AIDS
Cox proportional hazards model
Risk of relapse
ITZ Rx
No prior 5FC
 serum CRAG
p value
0.06
0.04
0.08
RR (95% CI)
4.32 (0.9,19.8)
5.88 (1.3, 27.1)
1.2
(1, 1.38)
Saag et al, Clin Infect Dis 1999;28:291
Meningitis in
subsarahan Africa
Cape Town
3 years sequential
LPs
Jarvis et al, BMC Infect Dis 2010;10:67
Cryptococcal meningitis Rx
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)
P <0.001
Nussbaum et al, Clin Infect Dis 2010;50:338
Cryptococcal meningitis Rx
Nussbaum et al, Clin Infect Dis 2010;50:338
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
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
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
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