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Transcript
Meningitis in HIV
Diagnostic and Therapeutic Challenge
Yunus Moosa
AWACC- November 2015
Case: 59 yr. old female- 1st Wk. Feb
Known HIV positive since Oct 2014 on first line treatment
Non specific symptoms- dizziness, malaise, lethargy, fatigue
PMH: Cervical TB lymphadenitis – treated for 9mths(2013)
Chronic medication:
– Tribuss
– Ecotrin
– Epilim CR 400mg bid
Clinically – shotty cervical L/N, otherwise NAD
Investigations
FBC- 13.3/255/4.19
U&E- 136/4.3/100/26/3.2/60 (>89)
LFT- 69/31/2-1/107/19/15/12, CCa 2.3, Mg 0.83, PO4 0.88
HBV sAb positive
HCV negative
HAV negative
RPR – negative, TSH normal, Total cholesterol 3.6, LDL 2.2,
TGA 0.80
CD4- 24 cell/uL, VL 5420 (3.734 Log10)
Chest x-ray: normal.
Management
ATV/r (300/100)- 1 Daily
AZT/3TC (300/150) - 1 bid
Cotrimoxazole- 960 daily
Ecotrin 1 daily
Epilim CR 400mg bid
2 weeks later
Brought in by family: two seizures at home
Disoriented, responded appropriately to commands
no meningism, no focal signs, no papilloedema.
FBC- 14.6/328/7.25, U&E- 133/4.7/97/20/4.8/83 (>89)
LFT- 84/38/17-3/117/23/15/22, CCa 2.28, Mg 0.96, PO4 1.52
Contrast CTS- normal
LP- pressure normal, CRAG > 1:320, AFB negative.
Date
22/02
Appearance
Polys
Xanthochromic 12
L/C
46
RBC Protein Glu Plasma Glu Ratio
0
11.32
1.1 7.1
0.15
What is the most likely diagnosis?
1. Cryptococcal meningitis
2. Tuberculosis
3. Histoplasmosis
4. CM IRIS
5. TB IRIS
6. Histoplasmosis IRIS
7. TB and CM
8. TB IRIS and CM IRIS
Repeat CSF 6 Days later
Treatment was modified and LP repeated
Date
Appearance
Polys L/C
RBC Protein Glu Plasma Glu Ratio
22/02
28/02
Xanthochromic
Blood stained
12
8
0
+++
46
184
11.32
4.27
1.1
0.2
7.1
7.4
0.15
0.03
What is the most likely diagnosis?
1. Cryptococcal meningitis
2. Tuberculosis
3. Histoplasmosis
4. CM IRIS
5. TB IRIS
6. Histoplasmosis IRIS
7. TB and CM
8. TB IRIS and CM IRIS
How would you manage this patient?
1. Continue ATV/r/AZT/3TC and start AMB/FLZ
2. Continue ATV/r/AZT/3TC and start AMB/FLZ and rifafour
3. Discontinue ART and start AMB/FLZ
4. Discontinue ART and start AMB/FLZ and rifafour
5. Change ART to LPV/r/AZT/3TC and start AMB/FLZ
6. Change ART to LPV/r/AZT/3TC and start AMB/FLZ & rifafour
7. Refer to someone who thinks they know more 
Management
ART stopped
Started on AMB
Started on rifafour
Optimized dose of epilim
Continued cotrimoxazole
Continued ecotrin
What do you think is the most central
diagnostic tool for TBM?
1.
2.
3.
4.
5.
6.
7.
8.
Clinical presentation
Blood investigations
Immunologic tests – (IGRAS/PPD skin test)
CSF-chemistry and cell counts
CSF- microbiology
CSF -molecular tests
CSF – adenosine deaminase
Imaging – (CxR/Brain CTS/MRI)
Presentation
Time from symptom to presentation
– Median 10 days
– Range 1 day to 9 months
Symptoms/Signs
– low grade fever, malaise, headache, dizziness, vomiting
– Personality changes, altered mental status
– Stroke, hydrocephalus
– Cranial neuropathies
– Seizures uncommon - should prompt search for alternate
diagnoses
Clinical Staging of TBM
Stage
I (early)
Clinical signs and symptoms
• Non specific symptoms
• Few or no signs of meningism
• Fully conscious and alert
II (intermediate)
• Signs of meningitis
• Drowsiness and lethargy
• Cranial nerve palsies
III (late)
Systemic toxicity
Stupor or coma
Severe neurologic deficit
CSF Cell count and Biochemistry
Abnormalities -not pathognomonic
L/C predominant pleocytosis
Total WCC usually 100 - 500 cells/μL
Earlier -lower counts, neutrophil predominance
Elevated protein levels, typically between 1g/L and 5 g/L
Low glucose usually less than 2.5mmol/L
CSF: plasma ratio <0.5.
Microbiology of CSF
Factors influence sensitivity of smear:
– CSF volume
– Timing delivery to the lab
– Time to analysis
– Technical expertise of lab- (30 min under 1000x)
AFB Smear
– 1 sample sensitivity 20%–40%
– 4 samples sensitivity >85% (10– 15 mL)
Culture sensitivity 40–80%
Important to determine drug susceptibility.
What is the rate of CSF Production?
1. 5mls/day
2. 10mls/day
3. 50mls/day
4. 100mls/day
5. 500mls/day
6. 1000mls/day
What is the total volume of CSF in the CNS?
1. 50-100mls
2. 90-150mls
3. 200-500mls
4. 1000-2000mls
Adenosine Deaminase: ADA
Meta-analysis:
– Sensitivity 79%
– Mean specificity 91%
Specificity is low
–  levels seen in other CNS diseases like neurosarcoid,
meningeal lymphoma, subarachnoid hemorrhage
Not useful in HIV-positive patients.
Journal of Clinical Medicine Research (2010), 2 (5), 220–224,
European Journal of Clinical Microbiology and Infectious Diseases (2004), 23 (6), 471–476
CSF Molecular Tests
Used as a rule in test – positive test confirms TBM
Sensitivity of GXP is ~80% (50% in HIV neg)
Negative test does not exclude TBM
Health Technology Assessment (2007)11 (3), 1–196
Imaging: CTS
Widely used to aid diagnosis of TBM.
Features suggestive of TBM
– Basal meningeal enhancement (Sn34%/Sp75%)
– Hydrocephalus (Sn45%/Sp75%)
– Infarcts (Sn44%/)
– Tuberculoma(s) (Sn31%)
Radiologic interpretations are subjective- inter-radiologists
reliability of findings suggestive of TBM is very poor.
Basal meningeal enhancement was most unreliable feature
PLoS ONE 7(6): e38982. doi:10.1371/journal.pone.00389
Value of CSF as Monitoring Tool
1. Not worth the trouble
2. Somewhat valuable
3. Very valuable
The most useful/reliable objective measure
of response to treatment
1. CSF Pressure
2. CSF Chloride
3. CSF glucose
4. CSF protein
5. CSF pleocytosis
Course
Completed 2 weeks AMB (Cr peaked at 196 µmol/L)
2 weeks into consolidation treatment with FLZ 400mg/d
started LPV/r (200/50) 4 bid, AZT/3TC (300/150) 1 bid
Within 6 days- DILI
Total
protein
Albumi
n
Total bilirubin- conjugate
bilirubin
ALP
GGT
ALT
AST
15/03/15
63
30
5-3
90
41
34
38
20/03/15
64
30
70-60
92
131
354
440
22/03/15
67
31
59-50
119
222
493
879
Cause for DILI
1.
2.
3.
4.
5.
6.
7.
Rifampicin
Isoniazid
PZA
FLZ
LPV/r
AZT
3TC
What ART do we use?
1. LPV/r, AZT, 3TC
2. ATV/r, AZT, 3TC
3. EFV, AZT, 3TC
4. LPV/r, TDF, FTC
5. ATV/r, TDF, FTC
6. EFV, TDF, FTC
TB Treatment should we use?
1. INH, EMB, PZA, Rifampicin
2. INH, EMB, PZA, Rifabutin
3. INH, EMB, PZA, Moxifloxacin
4. INH, EMB, PZA, Streptomycin
Cytochrome P450 enzymes essential for the
metabolism of many drugs
Induction increases synthesis of enzymes  increases
metabolism of target drug therapeutic failure
– Effect is usually delayed
Inhibition  blocks activity of enzymes  toxicity
– Effect usually immediate
– Often used to enhance levels of target drug
Rifampin and CyP450
Not metabolized by the CyP450 enzymes
Potent inducer  affects drugs metabolized by CyP450
Do not modify dose when combined by CyP450 modifiers
Rifabutin and CyP450
Metabolized by the CyP450 enzymes
Requires adjustment when combined with drugs that modify
CyP450
Poor inducer of CyP450  minimal or no adjustment for drugs
metabolized by CyP450
How Dose of Rifabutin when using a PI
1. 450mg daily
2. 300mg daily
3. 150mg daily
4. 150mg 3 x / week
Back to our patient
All treatment stopped from 22/03
31/03:
ATV/r/AZT/3TC/
TMP- SMX/epilim/FLZ/PZA/EMB/INH/Rifabutin/pyridoxine
T/P
15/03
20/03
22/03
31/03
05/05
63
64
67
63
71
Alb
30
30
31
31
34
Total bil- conj bili
5-3
70-60
59-50
9-6
16-4
ALP
GGT
90
92
119
61
64
41
131
222
125
28
ALT
34
354
493
65
14
AST
38
440
879
21
12
Back to our patient
Review 07/09- asymptomatic and well
CD4 64 (24), VL undetectable
Repeated CSF: CRAG 1:80, culture negative
Date
22/02
28/02
07/09
Appearance
Xanthochromic
Blood stained
Xanthochromic
Polys L/C RBC
12
46
0
8
184 +++
0
22
30
Protein
11.32
4.27
2.35
Glu
1.1
0.2
2.0
Plasma Glu
7.1
7.4
4.6
Ratio
0.15
0.03
0.43
Take home message
The diagnosis of TBM is challenging
Diagnosis is often based on clinical and CSF findings
without definitive microbiologic confirmation
CSF lacks sensitivity and specificity
Send at least 6/8mls CSF for proper microbiology evaluation
Imaging is mainly of value in evaluating for complications
and exclude alternate diagnosis
Rifampicin can only be used with LVP/r and not any other PI.
Drug of choice with any other PI is rifabutin