Meningitis in HIVDiagnostic 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 laterBrought 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 Appearance Polys L/C RBC Protein Glu Plasma Glu Ratio

22/02 Xanthochromic 12 46 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 Xanthochromic 12 46 0 11.32 1.1 7.1 0.15

28/02 Blood stained 8 184 +++ 4.27 0.2 7.4 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. Clinical presentation

2. Blood investigations

3. Immunologic tests – (IGRAS/PPD skin test)

4. CSF-chemistry and cell counts

5. CSF- microbiology

6. CSF -molecular tests

7. CSF – adenosine deaminase

8. Imaging – (CxR/Brain CTS/MRI)

PresentationTime 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 Clinical signs and symptoms

I (early)• 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 toxicityStupor or comaSevere 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: CTSWidely 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.0038982

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

Albumin

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. Rifampicin

2. Isoniazid

3. PZA

4. FLZ

5. LPV/r

6. AZT

7. 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 CyP450Metabolized 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 Alb Total bil- conj bili ALP GGT ALT AST

15/03 63 30 5-3 90 41 34 3820/03 64 30 70-60 92 131 354 44022/03 67 31 59-50 119 222 493 87931/03 63 31 9-6 61 125 65 2105/05 71 34 16-4 64 28 14 12

Back to our patientReview 07/09- asymptomatic and well

CD4 64 (24), VL undetectable

Repeated CSF: CRAG 1:80, culture negative

Date Appearance Polys L/C RBC Protein Glu Plasma Glu Ratio

22/02 Xanthochromic 12 46 0 11.32 1.1 7.1 0.15

28/02 Blood stained 8 184 +++ 4.27 0.2 7.4 0.03

07/09 Xanthochromic 0 22 30 2.35 2.0 4.6 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