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

SP age 69 years – lung biopsy (PAS)

Clinical features of TBM and fungal meningitis Subacute presentation 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 or2) AmB 0.3mg/kg/d + 5FC for 6 wks Resp (%)Relapse (%) Died (%) AmB 10 wks AmB +5FC 6 wks 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 or2) AmB 0.7mg/kg/d + 5FC for 10 wks Resp (%) Died (%) Pos CSF (d) Flu AmB +5FC 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) or2) AmB <7d, then ITZ (n=12) CR (%) PR (%) Fail / UE (%) ITZ alone AmB then ITZ 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 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 AmB + 5FC * * p=0.06 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 or2) ITZ 400mg/d for 8 wks Resp (%) Died (%) Pos CSF (%) Flu ITZ 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 p value RR (95% CI) ITZ Rx (0.9,19.8) No prior 5FC (1.3, 27.1)  serum CRAG (1, 1.38) Saag et al, Clin Infect Dis 1999;28:291

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

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

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

Choice of initial antifungal therapy for cryptococcal meningitis Priority sequence Amphotericin B ( 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 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