Complex OIs of the CNS

David R Boulware MD, MPH, CTropMed

Lois & Richard King Distinguished Assoc. Professor

University of Minnesota

boulw001@umn.edu

Warm Up: What is the diagnosis?

Warm Up: What is the diagnosis?1.Cryptococcosis2.Emmonsiosis3.Histoplasmosis4.Molluscum

Case 1

• 35yo M presents to hospital• Fever, Headache, Photophobia of 1 day

duration• Cough for ~5 days• Known HIV+, not in care

Statistically, what is the most probable etiology of meningitis?

1. Cryptococcal

2. Meningococcal

3. Pneumococcal

4. TB

Case 2

• 35yo F wife presents to hospital• Headache of 10 days duration• Cough for ~5 days• Known HIV+, not in care

Statistically, what is the most probable etiology of meningitis?

1. Cryptococcal

2. Meningococcal

3. Pneumococcal

4. TB

What would be the first test you would order on CSF?

1. BACTEC MGIT culture

2. CSF Culture

3. Cryptococcal Antigen

4. Gram’s Stain

5. India ink

6. Xpert MTB/Rif

7. Z-N Stain for AFB

Hospital CountrySample

SizeHIV

infected

Meningitis Prevalence

Bacterial / Pyogenic

Tuberculosis CryptococcalAseptic / Viral

Meningitis

Mulago and Mbarara1 Uganda 416 98% 4% 8% 59% 29%

GF Jooste 2South Africa

1,737 96% 19% 13% 30% 38%

Queen Elizabeth Central 3

Malawi 263 77% 20% 17% 43% 20%

Harare Central and Parirenyatwa 4

Zimbabwe 200 90% 16% 12% 45% 28%

Univ. Teaching Hospital

Zambia 331 100% 3% 14.5% 27.5% † 55%

Pooled Average   2616 93%9.3%

(8.2-10.5%)12.7%

(11-14%)37%

(35-39%)41%

(40-43%)

Etiologies of Meningitis in Africa

Durski K et al. J AIDS 2013

72% in 2014

Cryptococcus

TB

Bacterial

Aseptic/Viral

Cryptococcus

TB

Bacterial

Aseptic/Viral

Cape Town, South Africa Kampala, Uganda

Jarvis J et al. BMC Inf Dis 2010

Etiologies of Meningitis in Africa

Durski K et al. JAIDS 2013

Only Modest reduction of Cryptococcosis with ART Roll Out

Jarvis J, et al. AIDS 2009

Incidence of cryptococcosis (n=17,005*) vs. number of persons on antiretroviral treatment (ART)** by year,

Gauteng Province, 2002-2010

0

5

10

15

20

25

2002n=1,194

2003n=1,511

2004n=1,539

2005n=2,000

2006n=2,253

2007n=2,109

2008n=2,141

2009n=2,141

2010n=2,117

YearIn

cid

ence

(ca

ses

per

100

,000

p

op

)

0

50000

100000

150000

200000

250000

300000

Nu

mb

er of p

erson

s on

an

tiretroviral treatm

ent

Incidence

ART

Govender N et al, GERMS 2010

Shift from HIV-status unknown to known HIV+In Uganda, 95% known HIV+ status at meningitis presentation.

Cryptococcal Meningitis Incidence per100,000 HIV-infected persons, 2014

What is the most sensitive test for cryptococcal meningitis?

1. India ink

2. CSF Culture

3. CrAg – latex (CLAT)

4. CrAg – lateral flow assay

5. BACTEC MGIT culture

Diagnostics

Cryptococcal Antigen

Lateral Flow Assay

US$100 = ZAR 700 = 50 tests

What is the least sensitive test for cryptococcal meningitis?

1. India ink

2. CSF Culture

3. CrAg – latex (CLAT)

Performance of CrAg LFAKampala, Mbarara, Cape Town

Boulware et al Emerg Infect Dis 2014

Diagnostic Test n Sensitivity SpecificityPositive Predictive

ValueNegative Predictive

Value

CRAG LFA 619 99.0% (406/410) 99.0% (207/209) * 99.5% (406/408) 98.1% (207/211)

                   

CSF Culture † 761 90.7% (438/483) 100% (278/278) 100% (438/438) 86.1% (278/323)

100 mL CSF volume 479 95.7% (288/301) 100% (178/178) 100% (288/288) 93.2% (178/191)

10 mL CSF volume 282 82.4% (150/182) 100% (100/100) 100% (150/150) 75.8% (100/132)

                   

India Ink 758 86.0% (413/480) 97.1% (270/278) 98.1% (413/421) 80.1% (270/337)

                   

CRAG-latex (Meridian) 279 97.8% (176/180) 85.9% (85/99) 92.6% (176/190) 95.5% (85/89)

CRAG-latex (Immy) 668 96.5% (413/428) 99.6% (239/240) 99.8% (413/414) 94.1% (239/254)

Cryptococcal Meningitis: in the first week of therapy, which has largest impact on improving survival among all patients receiving amphotericin.

1. Adjunctive flucytosine (5FC)

2. Adjunctive fluconazole

3. Intracranial pressure management

4. Liposomal Amphotericin

Intracranial Pressure Control• >200 mm H2O is High

– 50% prevalence in US– 80% prevalence in Uganda

• >250 mm, Repeat LP daily

• Yeast obstruct CSF outflow cause ↑ICP– Minimal inflammation in HIV-

associated cryptococcosis– Not cerebral edema

< 250 mm

> 250 mm

CSF Opening Pressure

Days after Diagnosis

Cu

mu

lativ

e S

urv

iva

l

Survival by Baseline Intracranial Pressure in Uganda

Unpublished from the cohort of:Kambugu et al. Clin Inf Dis 2008; 46: 1694-1701.

Benefit of therapeutic LPsCOAT Trial Sub-Study

• 248 Persons with Cryptococcus screened for the COAT trial

• COAT Protocol: scheduled LPs at Day 1,~8,14 and therapeutic LPs recommended when ICP >250

• 56% with ICP >250mm H2O

• 30% received therapeutic LPs

• 69% relative reduction in ~10 day mortality, regardless of baseline pressure (95% CI: 18%-88%). 1.3 vs. 2.4 deaths per 100 person days

Rolfes MA et al CID 2014; 59:1607-14.

Benefit of therapeutic LPsCOAT Trial Sub-Study

• 248 Persons with Cryptococcus screened for the COAT trial

• 69% relative reduction in ~10 day mortality, regardless of baseline pressure (95% CI: 18%-88%).

Baseline CSF ICP <250 mm H2O• 0% (0/21) vs. 16% (11/77) mortality

Baseline CSF ICP >250 mm H2O• 8% (4/48) vs. 17% (12/69) mortality

Rolfes MA et al CID 2014; 59:1607-14.

1.3 vs. 2.4 deaths per 100 person days

Timing of 1st Therapeutic LP

Level of Care

Kate BirkenkampRadha Rajasingham

At time of initial cryptococcal diagnosis, the median amount of CSF volume needed to be removed to normalize intracranial pressure (<20 cm H2O) is?

1. 5 mL

2. 10 mL

3. 15 mL

4. 20 mL

Case 3

• 35yo M brother presents to hospital• Headache of 10 days duration• Cough for ~5 days• Known HIV+, not in care• CSF Cryptococcal Antigen LFA negative• CSF: 65 white cells, 100% lymphocytes• 2mL of CSF collected

What would be the next test you would order?

1. MGIT culture

2. CSF Culture

3. Cryptococcal Antigen, blood

4. Gram’s Stain

5. India ink

6. Xpert MTB/Rif

7. Z-N Stain for AFB

Suspected Meningitis

n=207

CSF Culture Positiven=126

Williams D Clin Infect Dis 2015

Fingerstick Testing of Cryptococcal Antigen

72%

CrAg LFA is negative in blood, what would be the next test you would order?

1. MGIT culture

2. CSF Culture

3. India ink

4. Xpert MTB/Rif

5. Z-N Stain for AFB

6. Repeat large volume LP

What would be the next test you would order?

1. MGIT culture 4-6 weeks to result

2. CSF Culture 5-14 days to result

3. Cryptococcal Antigen, blood ZAR ~45

4. Gram’s Stain Case = 10 days of symptoms

5. India ink Less sensitive than CrAg

6. Xpert MTB/Rif ZAR ~370

7. Z-N Stain for AFB Poor sensitivity

WHO, Oct 2014

Strong recommendation: • Xpert MTB/RIF should be used as the

initial diagnostic test in testing cerebrospinal fluid specimens from patients presumed to have TB meningitis

Uganda TBM Results

CSF Test N Sensitivity Specificity Positive Predictive Value

Negative Predictive Value

Xpert 2mL un-centrifuged CSF 107

28%(5/18)

100%(89/89)

100%(5/5)

87%(89/102)

Xpert centrifuged CSF 95

72%(13/18)

100%(77/77)

100% (13/13)

94%(77/82)

Culture 8071%

(12/17)100%

(63/63)100%

(12/12)93%

(63/68)

AFB Smear by Microscopy 107

22%(4/18)

100%(89/89)

100%(4/4)

86%(89/103)

Bahr NC. Intl J TB Lung Dis; 2015; 19:1209-15

Xpert Protocols: P=0.008 by McNemar’s test

MGITCulture

Xpert MTB/Rif 2mL raw CSF

AFB Smear

Xpert MTB/Rif Centrifuged CSF

Median 6 mL

03

1

1

1

3

5

4

Bahr NC. Intl J TB Lung Dis; 2015; 19:1209-15

TBM Clinical Case Definition Diagnostic Score1. Clinical criteria (maximum category score =6)

Symptoms duration of more than 5 days 4TB Systemic symptoms: cough for > 2 weeks, weigh loss, night sweats 2Focal neurological deficit 1Cranial nerve palsy 1Altered consciousness 12 . CSF criteria (maximum category score = 4)

Clear appearance 1Cells 10-500/ul 1Lymphocyte predominance (>50%) 1Protein concentration >1g/L 1CSF to plasma glucose ratio <50% or absolute glucose concentration of <2.2 mmol/l 13. Evidence of TB elsewhere (maximum category score= 4)

CXR suggestive of TB=2, millary =4 2/4AFBs from sputum, lymph node, 4Abdominal Ultrasound evidence for TB 24.Exclusion of alternative diagnoses

Final diagnosis Probable TBM ≥ 10Possible TBM 6-9Not TBM ≤ 5

Cryptococcus vs. TBM Case Definition Diagnostic Score1. Clinical criteria (maximum category score =6)

Symptoms duration of more than 5 days 4TB Systemic symptoms: cough for > 2 weeks, weigh loss, night sweats 2Focal neurological deficit 1Cranial nerve palsy 1Altered consciousness 12 . CSF criteria (maximum category score = 4)

Clear appearance 1Cells 10-500/ul 1Lymphocyte predominance (>50%) 1Protein concentration >1g/L 1CSF to plasma glucose ratio <50% or absolute glucose concentration of <2.2 mmol/l 13. Evidence of TB elsewhere (maximum category score= 4)

CXR suggestive of TB=2, miliary =4 2/4AFBs from sputum, lymph node, 4Abdominal Ultrasound evidence for TB 24. Exclusion of alternative diagnosesFinal diagnosis Probable TBM ≥ 10Possible TBM 6-9Not TBM ≤ 5

8-9Crypto

Case 4

• 32yo M cousin presents to hospital• Headache of 2 days duration, Seizure• Known HIV+, CD4=50 cells/mL• Started ART ~4 weeks ago• Receiving TMP/SMZ (Septrin) ~1 year

Head CT

Head CT

What is your testing/therapy?

1. Biopsy by Neurosurgery

2. CrAg on blood

3. Empiric TB therapy

4. Diagnostic LP

5. Pyrimethamine, sulfadiazine

6. Toxoplasma IgG

Pyrimethamine, sulfadiazine prescribed

Unmasking Cryptococcosis on ART

• Accelerated presentation on ART• Can present with cryptococcomas

– Rare in ART-naïve persons– Looks like Toxoplasmosis

• Unmasking of Toxo on ART, very rare when receiving TMP/SMZ prophylaxis.

Unmasking Cryptococcosis on ART,How can this be prevented?

1. Fluconazole prophylaxis for CD4<100

2. Pre-ART CrAg screening if CD4<100

3. Lumbar Puncture, if CrAg-positive

CR

AG

+ P

reva

lenc

e ~7.2% average CRAG+ prevalence in CD4<100

NHLS CrAg+ Prevalence in CD4<100

Prince Mshiyeni Memorial Hospital (PMMH) in

Umlazi, KZN started CrAg Screening in June 20154.4% CrAg+ (n=3501)

Meya DB, et al. Clin Infect Dis 2010; 51:448-453

N=33All CD4 CRAG+

200-400mg 2-4 weeks

CRAG Screening + Adherence SupportTanzania & Zambia, CD4<200

Mfinanga et al. Lancet 2015, 385:2173-82.

For asymptomatic CrAg+ person, what is the initial therapy?

1. Immediate ART if asymptomatic

2. Fluconazole 800mg/d x 2 wk

3. Fluconazole 400mg/d x 8 wk

4. Fluconazole 200mg/d x 26 wk

5. Amphotericin x1 week

* Lateral Flow Assay (LFA) can be performed as a reflex test on plasma samples collected for CD4 testing (or serum samples). Latex agglutination can be performed on serum samples only.

Figure 3: Algorithm for CRAG screening upon entry into HIV care

+ LP

If CD4≤100, and ART naïve, perform CRAG

screening*

CRAG Negative CRAG Positive

Signs or symptoms of CNS infection

Routine medical care Initiate ART at 2 weeks

Asymptomatic

Treat with fluconazole 800mg x2 weeks, then

400mg x8 weeks

Diagnostic lumbar puncture

Return to physician for evaluation

Entry into HIV care Perform CD4 count

Treat for cryptococcal meningitis per WHO

guidelines31

- LP