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CSF Tests for the Diagnosisof Neurosyphilis in HIV
Christina M. Marra
University of Washington
Seattle, Washington, USA
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07/23/1996 to 06/29/2006
150 have at least one followup visit, 120 HIV+
204 tx for NS
694 in dataset, 507 HIV+
736 enrolled
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Acknowledgements
Lauren Tantalo April Colina
Trudy J ones, ARNP
Rose Fontanilla
Clare Maxwell, MD
Sheila Lukehart, PhD
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Why Care About Neurosyphilis?
12 million cases of syphilis per yearworld-wide
Neurosyphilis can occur at any stage ofsyphilis
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Syphilis and HIV Worldwide
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Neurosyphilis Natural History
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Neurosyphilis Diagnosis
CSF-VDRL specific, not sensitive False negatives 30-70%
Elevated CSF WBCs
Can be hard to distinguish from HIV
CSF-FTA-ABS sensitive, not specific
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Neurosyphilis Diagnosis
CSF-VDRL specific, not sensitive False negatives 30-70%
Elevated CSF WBCs
Can be hard to distinguish from HIV
CSF-FTA-ABS sensitive, not specific May be result of passive diffusion from
serum
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Sensitivity and Specificity ofCSF-VDRL in UW Study
Gold Standard for Diagnosis
CSF WBC>20/ul
SymptomaticNS
Sensitivity of
CSF-VDRL
52% 68%
Specificity ofCSF-VDRL
91% 90%
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Neurosyphilis Diagnosis
CSF-VDRL specific, not sensitive False negatives 30-70%
Elevated CSF WBCs
Can be hard to distinguish from HIV
CSF-FTA-ABS sensitive, not specific May be result of passive diffusion from
serum
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HIV Alone Causes CSFPleocytosis
Wh ite Bloo d Cells/ u l
> 50 - 5
P
ercentofSu
bjects
1 0 0
8 0
6 0
4 0
2 0
0
An tire tro vira l Use
Current
Non e
4 28 8
5 8
1 2
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CSF in HIV Without Syphilis
OR (95% CI) P-value
Current use of ARVs 0.17 (0.05-0.54) 0.003
CD4+ T cells < 200/ul 0.04 (0.006-0.32) 0.002
Plasma HIV RNA > 50/ml 3.27 (1.14-9.39) 0.03
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CSF Abnormalities in Syphilisby ARV Tx
Gold Standard for Diagnosis
Subjects CSF WBC > 20
or +CSF-VDRL
+CSF-VDRL
All 32% 18%
Not on ARVs 44% 21%
On ARVs 15% 12%
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Neurosyphilis DiagnosticTests
Standard diagnostic tests forneurosyphilis all have weaknesses
HIV status influences CSF measures
ARVs CD4
Plasma HIV RNA
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Alternative CSF Tests in HIV
Case-control study of assessment ofCSF B cells as a diagnostic test
47 HIV-infected cases with syphilis
26 HIV-infected controls Well matched by CD4
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Alternative CSF Tests in HIV
% CSF lymphocytes that are B cells CD19+ by FACS
Opted for specificity
Augment CSF-VDRL
Set cut-offs based on values in subjects
with normal CSF measures Elevated CSF % B cells defined as >20%
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CSF Diagnostic Tests
Gold Standard+CSF-VDRL
Sensitivity Specificity
CD19% >20 43% 100%
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Validation Study
Negative Positive
CD19% 129 (90%) 15 (10%)
CSF-VDRL 117 (78%) 33 (22%)
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Validation Study
Gold Standard+CSF-VDRL
Sensitivity Specificity
CD19% >20 21% 93%
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Validation Study
Gold StandardSymptomatic NS
Sensitivity Specificity+CSF-VDRL 64% 89%
CD19% >20 25% 90%
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Neurosyphilis Diagnosis
0
10
20
30
40
50
60
70
80
CSF-VDRL+ CD19+ CSF-VDRL+ or
CD19+
Percentof
Subjects
No NS
NS
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Normalization of CD19%
CSF- VDRL, n = 2 6
Mon ths After Treatm e nt
1 4121 086420
ProportionAbnormal
1 .0
.8
.6
.4
.2
0 .0
CSF CD1 9 % , n = 1 6
Mon ths After Tre atm en t
1 4121 086420
ProportionAbn
ormal
1 .0
.8
.6
.4
.2
0 .0
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Assessment of %CD19+ Cells
Specific but not sensitive
Can augment CSF-VDRL assessment
Not influenced by ARV use Declines after neurosyphilis treatment
Complex, not readily used or available
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Our Diagnostic Approach toNeurosyphilis in HIV+
NS diagnosed if Neurological or ocular sx/signs
Reactive CSF-VDRL
If WBC > 20/ul but nonreactiveCSF-VDRL
Consider ARV tx, CD4, HIV RNA, CSFFTA-ABS, +CD19%
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Point of Care CSF Tests
Immunochromatographic strip tests (ICTs) Detect IgG, IgM and IgA antibodies to recombinanttreponemal proteins
Intended for use on blood
Sensitive (85-97%) and specific (94-98%) in fieldtrials
Goal is specificity over sensitivity
RPR/TRUST Detect IgG and IgM to lipoid material Not recommended for CSF
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ICTs Tested
Optimized and assessed readability ona test CSF panel
SD Bioline Syphilis 3.0 (Korea)
Syphicheck-WB (India)
Visitect (Scotland)
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Bioline Test on CSF
Unused
Negative
Weak Positive
Strong Positive
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CSF ICTs
Gold Standard+CSF-VDRL
Sensitivity Specificity
Bioline 100% 68%
Syphicheck 89% 80%
Visitect 97% 66%
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CSF ICTsGold Standard
Symptomatic NSSensitivity Specificity
Bioline 84% 63%
Syphicheck 84% 79%
Visitect 84% 66%CSF-VDRL 63% 89%
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Bioline Titer >1:8
Gold Standard Sensitivity Specificity
CSF-VDRL+ 67% 98%
Symptomatic NS 60% 96%
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Bioline Test
Gold StandardSymptomatic NS
Sensitivity Specificity
Bioline undiluted 84% 68%
Bioline >1:8 60% 96%
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Normalization of ICTs
Bio lin e ICST, n = 4 1
Mon ths After Treatm en t
1 4121 086420
ProportionAbnormal
1 .0
.8
.6
.4
.2
0 .0
CSF- VDRL, n = 3 1
Mon th s After Treat m en t
1 4121 086420
ProportionAbnormal
1 .0
.8
.6
.4
.2
0 .0
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Future Studies
Determine whether CSF B cells are makingtreponemal antibodies
Complete studies to determine the best ICT
Determine whether titers of treponemalantibodies measured by ICTs decline inserum in parallel with CSF titers
Optimize the RPR/TRUST for use on CSF
Field trial of point of care tests in our STDclinic
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