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