Biomarkers to measure severity of disease and treatment ... · Meta-analysis: Horne et al. Lancet...
Transcript of Biomarkers to measure severity of disease and treatment ... · Meta-analysis: Horne et al. Lancet...
Biomarkers to measure severity of TB disease and treatment response
Morten Ruhwald, MD, PhD
Head of Human Immunology
Dept. infectious disease immunology
Statens Serum Institut
Denmark
CONFLICTS OF INTEREST STATEMENTI have no real or perceived conflicts
TB - not like other infectious diseases
• Disease severity• Host’s immune status• Genetic background• Bacterial virulence• Drug resistance• Tx quality
Heyckendorf et al, AJRCCM 2014
Items touched
• Bug• Sputum monitoring
• LAM
• Host• Cytokine biomarkers
• Antigen specific responses
Sputum monitoring during treatment
At least if based on M. tb DNA
Sputum monitoring during treatment
Time to culture conversion• Susceptible: 78 days• MDR: 62-152 days
Time to smear conversion• Susceptible: 23 days• MDR: 83 days
Predictive power of 2m smear positivity (8% MDR) • Relapse: sensitivity 24%, specificity 85%• Failure: sensitivity 57%, specificity 81%
Prediction of 2m culture positivity (8% MDR)• Relapse: sensitivity 40%, specificity 85%• Failure: not sufficient data
Meta-analysis: Horne et al. Lancet ID 2010
Mycobacterial lipoarabinomannan (LAM)
• Abundant mycobacterial cell wall lipopolysaccharide
• Secreted in the urine
• ELISA or LF test
• Poor sensitivity in HIV non-infected
• Modest sensitivity in HIV infected patients with low CD4
Lawn et al. Lancet ID 2012; Lawn et al, BMC ID 2012
Host(excl imaging)
Den Hertog 2011, Plos Path 2011
Riou et al PlosOne 2012
Immunological markers
• IP-10 slide fra Anne Ma
What about IGRAs and IGRA like tests?
ESAT-6
ESAT-6
ESAT-6ESAT-6
ESAT-6
ESAT-6
ESAT-6
ESAT-6ESAT-6 IGR
A p
osi
tive
Denkinger et al JCM 2013
Denkinger et al JCM 2013
Denkinger et al JCM 2013
Denkinger et al JCM 2013
Denkinger et al JCM 2013
• However
…data suggests that “stage specific” antigens exists
Sutherland et al PlosOne 2013
ESAT-6 + CFP10
Disease specific T cell profiles
TBLTBIGeldmacher et al, JEM 2010
TAM AUC
T-cell activation marker-tuberculosis assay (TAM-TB)130 children Tz, 1-12yrs
Portevin et al, Lancet ID 2014
Transcriptomics
• PBMC gene transcriptomic profiling
• 320-transcript specific signature identified in case control study
• Validated prospectively in 29 active TB patients
• 0, 2, 8 and 26 weeks
Berry et al, Nature 2010; Bloom et al Plos One 2012
Further reading
Wallis et al Lancet ID 2013
O’Garra et al, Ann rev. immunol 2013
Thanks to
• Anne Ma Riise, Rigshospitalet Oslo, Norway
• Christoph Lange, Borstel, Germany
• Jan Heyckendorf, Borstel, Germany
• Ioana Olara, Borstel, Germany
• Graham Bothamley, Homerton, UK