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Exciting Developments Towards Non-Sputum Based Diagnosis of TB
Niaz Banaei MDProfessor of Pathology and Medicine
Stanford University [email protected]
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Active TB
Latent Infection
10 million cases estimated
1/4 of world’s population
Global Burden of M. tuberculosis
WHO 2018
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Active TB
Latent Infection
10 million cases estimated6.4 million reported3.6 million diagnostic gap
1/4 of world’s population
Global Burden of M. tuberculosis
WHO 2018
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Contributors to Global Diagnostic Gap
Pediatric ExtrapulmonaryHIV/AIDSUnproductive
1 million 0.9 million
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Active TB
Latent Infection
Incipient TB
10 million cases estimated6.4 million reported3.6 million global gap
1/4 of world’s population
Global Burden of M. tuberculosis
WHO 2018
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Recent and Projected Trends in Global TB Incidence Cases
Dye et al Annu Rev Public Health 2013
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Active TB
Latent Infection and
Incipient TB
Sputum: Culture & NAATBlood: IGRA, RNA signature, biomarkersUrine: biomarkers (LAM)Breath: biomarkers
Blood: IGRA, RNA signature
Diagnostic Tools for M. tuberculosis
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Active TB
Latent Infection and
Incipient TB
Blood: IGRA
Blood: IGRA
Diagnostic Tools for M. tuberculosis
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‘A 21st Century Solution for Latent TB Detection’
IGRAs entered the scene with a lot of promise
More sensitive and specific than TSTMore reproducible/objective
More predictive
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Active TB
Sensitivity and Predictive Value of IGRAs
Pai et al. Clin Micro Rev 2014
Diel et al. Chest 2010
Sensitivity: 80-90s%Specificity: low due to LTBI
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Latent Infection
Sensitivity and Predictive Value of IGRAs
Pai et al. Clin Micro Rev 2014
Diel et al. Chest 2010
Sensitivity: 40-70%Specificity: >90%Predictive value: <10%
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Incipient TB
Sensitivity and Predictive Value of IGRAs
Pai et al. Clin Micro Rev 2014
Diel et al. Chest 2010
Sensitivity: 40-70%Specificity: low due to LTBIPredictive value: <10%
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Active TB
Latent Infection
Incipient TB
Sensitivity and Predictive Value of IGRAs
Pai et al. Clin Micro Rev 2014
Diel et al. Chest 2010
Sensitivity: 80-90s%Specificity: low due to LTBI
Sensitivity: 40-70%Specificity: >90%Predictive value: <10%
Sensitivity: 40-70%Specificity: low due to LTBIPredictive value: <10%
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‘A 21st Century Solution for Latent TB Detection’
IGRAs entered the scene with a lot of promise
More sensitive and specific than TSTMore reproducible/objective
More predictive
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TB Ag Tube 1 (TB1): ESAT-6 and CFP-10 peptides for CD4 T Cells
TB Ag Tube 2 (TB2): ESAT-6 and CFP-10 peptides for CD4 and CD8
T Cells
QuantiFERON®-TB Gold Plus
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TB1 +
TB2 +
+- +
-
-
-
• Interpretation of QFT-Plus using
manufacturer’s interpretation
Interpretation of QFT-Plus Results
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• Evidence for role of CD8+ T cells in TB immunity
• IFN- positive Mtb-specific CD8+ T cells
– Associated with recent exposure to TB
– More frequently detected in active TB vs. latent infection
– Mycobacterial burden-dependent
– Detectable in active TB subjects with HIV co-infection
and young children
– Decline after anti-tuberculosis treatment
Why Target CD8 T Cells in QFT-Plus?
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Does QFT-Plus have a higher sensitivity
than QFT-GIT for recent exposure to Mtb?
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Barcellini et al ERJ 2016
Study Design
QFT-Plus vs. QFT-GIT
Prospective contact screening
Location: Milan, Italy
Contacts: Tested 119 adults with newly positive TST (≥5mm)
Included immunocompromised (9%)
Retested 10-12 weeks if negative
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• QFT-Plus: 57.1% (68/119) vs. QFT-GIT: 47.1% (56/119)
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QuantiFERON-TB Gold Plus performance in a high-risk population in the United States: a comparison with QuantiFERON-TB Gold In-tube, tuberculin skin test and T-SPOT.TBCDC Tuberculosis Epidemiologic Studies Consortium II (TBESCII)
Study Design
QFT-Plus vs. QFT-GIT
Prospective cross-sectional study
Location: 12 clinics in the U.S.
Contacts: Tested 508 individuals (adult and children) at high
risk for LTBI
Venkatappa et al JCM 2019
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94%
99%
98%
Agree-
ment
QuantiFERON-TB Gold Plus performance in a high-risk population in the United States: a comparison with QuantiFERON-TB Gold In-tube, tuberculin skin test and T-SPOT.TBCDC Tuberculosis Epidemiologic Studies Consortium II (TBESCII)
Venkatappa et al JCM 2019
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In 44 children with household
TB exposure, agreement
between the QFT-GIT and
QFT-Plus was 96%.
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Does QFT-Plus have a higher sensitivity
than QFT-GIT for recent exposure to Mtb?
Answer: No. Differences observed are
due to antigen formulation and not
immunological response.
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Does QFT-Plus have a higher sensitivity
than QFT-GIT in patients with active TB?
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Does QFT-Plus have a higher sensitivity
than QFT-GIT in patients with active TB?
QFT-GIT QFT-Plus P value TB Ag TB1 TB2 QFT-GIT QFT-Plus
Petruccioli et al
Tuberculosis 2017Italy Adult ≤7 days 0% 69 88% 90% <0.05 2.6 1.9 2.5 19 100% 100%
24 96% 96% >0.05
33 clin 85% 85% >0.05
Yi et al Sci Rep 2016 Japan Adult ≤14 days 4% 162 96% 96% >0.05 4.23 2.36* 2.85* 212 99% 97%
Horne et al IJTLD 2018 US & Japan Adult ≤14 days 2% 164 94% 93% >0.05 4.45 3.07* 3.56** ND --- ---
5 100% 100% >0.05 ND --- ---
7 clin 25% 25% >0.05 ND --- ---
87%4.67
Controls
77Germany 90%3.1* 3.7*
Sensitivity Specificity Country Age Abx Tx HIV+/ICH CasesMedian or Mean (IU/ml)
Hoffmann et al
Clin Microb Inf 2016Adult
Not
provided5%
Study
Kay et al AJTMH 2019 Eswatini Pediatric 0 days 42%Not
provided
Not
provided
Not
provided
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Does QFT-Plus have a higher sensitivity
than QFT-GIT in HIV+ patients with active
TB?
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Study Design
Single arm
Prospective
Location: Zambia
TB Patients: Smear+ or Xpert+
68 HIV+
<3 days of anti-TB therapy
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HIV-
HIV+
Prior study on QFT-GIT
Sensitivity: 63%
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Active TB
Incipient TB
Blood: RNA signature
Blood: RNA signature
WHO 2018
Diagnostic Tools for M. tuberculosis
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Nature 2010
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IFN I/II signalling and complement transcripts up 18 months
before TB diagnosis, while changes in myeloid , lymphoid,
monocyte and neutrophil responses occurred more proximally
Scriba PLoS Pathogens 2017
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GBP5 promotes inflammasome assembly
DUSP3 regulator of JNK and ERK signalling
KLF2 anti-inflammatoryLANCET RM 2016
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GBP5 promotes inflammasome assembly
DUSP3 regulator of JNK and ERK signalling
KLF2 anti-inflammatoryLANCET RM 2016
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Genes comprising the 8
best signatures for
incipient TB
LANCET RM 2020
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Diagnostic Accuracy of the 8 Best
Signatures for Incipient TB
LANCET RM 2020
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Diagnostic Accuracy of the 8 Best
Signatures for Incipient TB
LANCET RM 2020
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LANCET RM 2020
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Active TB
Incipient TB
Urine: biomarker (LAM)
WHO 2018
Diagnostic Tools for M. tuberculosis
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Urinary LAM Detection with Lateral Flow
(LAM)
Lipoarabinomannan (LAM)
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Urinary LAM Detection with Lateral Flow
Alere Determine TB LAM Ag (AlereLAM)
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≤100 101-200 >200CD4
Schiller Cochrane 2019
Sensitivity Specificity
≤100 101-200 >200CD4
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WHO 2020
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Novel Fujifilm SILVAMP TB LAM (FujiLAM)
Lancet Infect Dis 2019
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Lancet Infect Dis 2019
Inpatients with HIV
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OFID 2020
Inpatients and outpatients with HIV
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Sensitivity 95%
Specificity 80%
2017
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Active TB
Urine: biomarkersBreath: biomarkers
WHO 2018
Diagnostic Tools for M. tuberculosis
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Infectious Diseases Have Metabolic Signatures Need for Technological Innovation to Detect Them
Colorimetric Sensor Array
Urine
Breath
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Colorimetric Array for Detection
of Volatile Signatures
• Digitally image before & after exposure & subtract.
After Exposure
ammonia
• Difference Map is a “molecular fingerprint”:
a unique 108-dimensional vector (36 ΔR, ΔG, ΔB).
(center avg.
300 pixels)
Difference Map
|Rafter- Rbefore|,|Gafter- Gbefore|,|Bafter- Bbefore|
• Printed array of chemically responsive dyes.
Before Exposure
Biggest color changesare boxed in gray.
9
mm
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Urine collected
Gold StandardCases: Culture+/NAAT+Controls: Culture-/NAAT-
Sputum
Analysis
Difference
Diagnosis of Tuberculosis from Analysis of
Urine Volatile Organic Compounds
Highland Study
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Correlation matrix indicates similarities between patients of the same category
TB
N=39
Non-TB
N=25
Sensitivity: 86.9%
Specificity: 87.6%
Lim et al ACS Sensors 2016
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Urine collected
Kenya Study at KEMRI
TB: 200 Non-TB: 200
2 hr
Gold StandardCasesGeneXpert+ &or Cx+Controls: GeneXpert- & Cx-
Sputum
Analysis
Difference
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Principal Component Analysis Score plots
Sensitivity: 78.3%
Specificity: 69.2%
Sensitivity: 57.9%
Specificity: 63.1%
Sandlund et al DMID 2018
HIV- Group HIV+ Group
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Active TB
Blood: cfDNA Urine: cfDNA
WHO 2018
Diagnostic Tools for M. tuberculosis
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Application of cf DNA in Diagnostics
Fetal aneuploidy Cancer mutations Organ rejection
Microbial cf DNA
Infectious diseases
- EBVnasopharyngeal CA (Cancer Res 1999)
- Invasive fungal infection (CID 2013)
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Biology of Cell-Free DNA
Discovered in 1948
(Mandel & Metais)
Removed by liver
Half-life 10-15min
Apoptosis: 180-1000bp
Necrosis: 10,000bp
Trans-renal
150-200bp
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Target Population for cfDNA TB Diagnosis
Pediatric ExtrapulmonaryHIV/AIDSUnproductive
1 million 0.9 million
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Accuracy of Plasma cf DNA for TB Diagnosis
IS611065%
(21/33)
93%
(18/19)
gyrB29%
(10/33)
100%
(19/19)Click et al
Scientific
Reports 2018
>18 yo Kenya PTB 43 ND PCR IS611044%
(19/43)ND
Brazil PTB 4974%
(34/49)
USA EPTB 875%
(6/8)
Stanford/GG/
IV>18 yo Uganda PTB 54 40 PCR IS6110
46%
(25/54)
100%
(40/40)
GWiS
Target Specificity
Digital
PCR
Cases Controls
Hogan et al
In
preparationPCR
PCR69
Method Sensitivity
Ushio et al
Tuberculosis
2016
Age
19
CountryTB
Type
53%
(8/15)
100%
(69/69)
33PTB
GWiS100%
(15/15)PTB 15 15
Vietenam
& SA>18 yo
>18 yo
Japan>18 yo
Bilateral vsUnilateral PTB
PTB+EPTB vs. PTB
↑cfDNA ↑cfDNA
Day14 Day0+1484% 94%
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Accuracy of Urine cf DNA for TB Diagnosis
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Miliary Multifocal LAN Pleural Joint90%(9/10)
67%(16/24)
72%(18/25)
33%(1/3)
45%(5/11)
Accuracy of Urine cf DNA for TB Diagnosis
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Accuracy of Urine cf DNA for TB Diagnosis
vsRadiology vsSmear+ vsTTCxP Wk1 Wk12
écfDNA None None écfDNA 9/11Neg*100% with
retesting
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Cannas et al
IJTLD 2008>18 yo Italy PTB 43 23
Nested
PCRIS6110
79%
(34/43)
100%
(23/23)
EPTB 82 70%
(57/82)
PTB 2518%
(5/25)
Labugger et al
Infection 2017>18 yo Germany PTB 11 8 PCR IS6110
64%*
(7/11)
100%
(8/8)
Stanford/GG/
IV>18 yo Uganda PTB 75 59 PCR IS6110
32%
(24/75)
98%
(58/59)
Fortun et al
IJTLD 2014
Sensitivity SpecificityTB
TypeTargetCases Method
TMA16S
rRNA
Not
Done>18 yo
CountryAge
0Spain
Controls
Accuracy of Urine cf DNA for TB Diagnosis
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Pediatric ExtrapulmonaryHIV/AIDS
Potential of cf DNA in Diagnosis of TB
Cell-free DNA
in Urine
Accuracy
Sensitivity 40%-70%
Specificity ≈100%
Unproductive
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Accuracy of Urine cf DNA for TB Diagnosis
Hogan
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Preanalytical Variables Impacting
Pathogen cfDNA in Blood and Urine
Murugesan JCM 2019 PMID:31511335
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Optimization of Variables Impacting Plasma cfDNA Detection
Murugesan JCM 2019 PMID:31511335
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Comparison of Blood Collection Tubes
Murugesan JCM 2019 PMID:31511335
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Comparison of Urine Collection Preservatives
Murugesan JCM 2019 PMID:31511335
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Comparison of Blood Collection Tubes andUrine Preservatives in Patients with TB
Murugesan JCM 2019 PMID:31511335
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Optimization of Variables Impacting Plasma cfDNA Detection
Murugesan JCM 2019 PMID:31511335
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Comparison of Plasma Processing Delay
Murugesan JCM 2019 PMID:31511335
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Comparison of Urine Processing Delay
Murugesan JCM 2019 PMID:31511335
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Optimization of Variables Impacting Plasma cfDNA Detection
Murugesan JCM 2019 PMID:31511335
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Comparison of 1 spin vs 2 spin Plasma Collection
Murugesan JCM 2019 PMID:31511335
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Comparison of Whole vs 1 Spin Urine Processing
Murugesan JCM 2019 PMID:31511335
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Optimization of Variables Impacting Plasma cfDNA Detection
Murugesan JCM 2019 PMID:31511335
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Comparison of Fresh vs. Frozen Plasma
Murugesan JCM 2019 PMID:31511335
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Comparison of Fresh vs. Frozen Urine
Murugesan JCM 2019 PMID:31511335
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Optimization of Variables Impacting Plasma cfDNA Detection
Murugesan JCM 2019 PMID:31511335
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Comparison of Plasma and Urine Volume
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Preanalytical Variables Impacting
Pathogen cfDNA in Blood and Urine
Higher volume
more sensitive
EDTA is adequate
Murugesan JCM 2019 PMID:31511335
Up to 24 hr delay
is adequate
1 spin is adequate for plasma
No spin needed for urine
Freeze thaw
has no impact
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Promega
OmegaQiagen
Thermo
Plasma
ccfDNA extraction
DNA spiking
Sample collection
tube
Processing delay
Centrifugation
Sample storage
Promega &Maxwell
KingFisher &Omega
KingFisher &Thermo
QiaSymphony &Qiagen
Optimization of Variables Impacting Plasma cfDNA Detection
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Mtb cfDNA Testing is Promising
Optimize extraction of cfDNA from plasma and urine
Short cfDNA fragments
At lower limit of detection
Assess sensitivity of TB cf-DNA using optimized pre-
analytics in adult and pediatric cohorts
Develop sample-to-answer assay
GeneXpert Ultra
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Active TB
Latent Infection and
Incipient TB
Sputum: Culture & NAATBlood: IGRA, RNA signature, biomarkersUrine: biomarkers (LAM)Breath: biomarkers
Blood: IGRA, RNA signature
Diagnostic Tools for M. tuberculosis
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Acknowledgements
Stanford University
Kanagavel Murugesan
Rajiv Gaur
Fiona Senchyna
Hee-Won Moon
Catherine Hogan
Jason Andrews
Juan Santiago
Nobuyuki Futai
Global Good/IVL
UCSF/Uganda
Adithya Cattamanchi
Uganda Team
Stellenbosch University
Grant Theron
Funding
Stanford Global Health
Global Good/IVL, ChEM-H