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SINCE 1175. ERS ANNUAL CONGRESS Stockholm September 15-19, 2007 Infections year in review. TUBERCULOSIS: UPDATE ON NEW DIAGNOSTIC METHODS AND TREATMENT APPROACH. OR WHAT WE KNOW TODAY THAT WE DID NOT KNOW JUST ONE YEAR AGO. Luca Richeldi

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TUBERCULOSIS: UPDATE ON NEW DIAGNOSTIC METHODS AND TREATMENT APPROACH

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SINCE 1175

ERS ANNUAL CONGRESS

Stockholm September 15-19, 2007

Infections year in review

TUBERCULOSIS: UPDATE ON NEW DIAGNOSTIC METHODS AND TREATMENT APPROACH

OR WHAT WE KNOW TODAY THAT WE DID NOT KNOW JUST ONE YEAR AGO

Luca Richeldi

Department of Oncology, Hematology and Respiratory Disease

University of Modena and Reggio Emilia, Modena (Italy)

Potential conflicts of interest: LR participated in an advisory board meeting of Oxford Immunotec (T-SPOT.TB) and his Institution received a research grant from the Italian representative of Cellestis (QuantiFERON-TB)


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

  • QuantiFERON-TB Gold (2G) (Cellestis AUS)

    CE marketed, FDA approved: CDC (US) and NICE (UK) guidelines

    • 96 wells plate

    • 2 antigens (ESAT-6 and CFP10) in 2 wells

    • single cut-off at 0.35 IU IFN-g (any antigen)

  • QuantiFERON-TB Gold In Tube (3G) (Cellestis AUS)

    CE marketed, FDA evaluation ongoing

    • 2 (or 3) tubes

    • 3 antigens (ESAT-6, CFP10 and TB 7.7) in one tube

    • single cut-off at 0.35 IU IFN-g (antigens tube)

  • T-SPOT.TB(Oxford Immunotec UK)

    CE marketed, FDA evaluation ongoing: NICE (UK) guideline

    • 96 wells plate

    • 2 antigens (ESAT-6 and CFP10) in 2 wells

    • single cut-off at 6 SFC (any antigen)


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TIGRA PAPERS IN PUBMED

((quantiferon* OR t-spot*) OR (elispot* AND tuberculosis) OR (elisa* AND tuberculosis))

From August to August

As of 31 August 2007


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I apologize with the many Authors (some of them are also good friends) of the excellent papers that I can’t mention here due to time limitations (beware of chairmen!!!)


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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  • TST and QFT-G in:

    • 50 healthy volunteers

    • 50 patients with active TB

    • 100 patients with NTM (ATS criteria)

Clin Infect Dis 2006


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NTM INFECTION

ACTIVE TB

Clin Infect Dis 2006


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“We confirmed that the QFT-TB test is a useful diagnostic method for differentiating active pulmonary TB from NTM, compared with the TST.”

Clin Infect Dis 2006


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  • Retrospective study of QuantiFERON-TB Gold among 242 persons with suspected tuberculosis in San Francisco.

Clin Infect Dis 2007


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  • 64% (95% CI, 48-78%) of 36 TB patients had a positive QuantiFERON-TB Gold. This sensitivity suggests that the blood assay should not be used alone to exclude active tuberculosis.”

Clin Infect Dis 2007


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  • Prospective study of 144 participants with suspected pulmonary TB (47% diagnosed with active disease) tested with QuantiFERON-TB Gold and T-SPOT.TB

Chest 2007


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  • Sensitivity of both QFT-G and T SPOT.TB for active pulmonary TB are high, while specificity is considerably lower.

  • NPV of QFT-G (84%) and T SPOT.TB (87%) are higher than that of TST (64%) (p=0.001 and p<0.001, respectively).

Chest 2007


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  • T-SPOT.TB in 33 patients with culture positive tuberculosisduring anti-TB treatment

J Infect 2007


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  • Significantly more patients in the early rather than the late phase of treatment had positive TIGRA (83% vs 19% p<0.01). In a low burden setting TIGRA may be a promising surrogate marker of mycobacterial disease burden.

J Infect 2007


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

        • more specific than TST (Kobashi)

        • not to be used alone to diagnose TB (Dewan)

        • have high negative predictive value (Kang)

        • longitudinal assessment might be useful (Dheda)


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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  • Prospective study of QuantiFERON-TB Gold In Tube and TST among 294 HIV-infected subjects at risk for TB infection in San Francisco.

Am J Respir Crit Care Med 2007


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  • Subjects with a CD4count of less than 100 cells/mm3 had a RR of an indeterminate result of 4.24 (95% CI 1.55-11.61; p0.003) compared with those with a CD4 count of 100 or more.

  • Overall concordance between QFT and TST was high, but agreement among subjects with positive tests by either modality was low.

Am J Respir Crit Care Med 2007


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  • Prospective study of T-SPOT.TB and TST (N=70) among 201 HIV-infected subjects at risk for TB infection and disease in London.

Clin Exp Immunol 2007


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  • 2.0% indeterminate T-SPOT.TB results: correlation (p=0.017) between CD4 counts and PHA response.

  • Sensitivity for active TB not affected by CD4 counts.

Clin Exp Immunol 2007


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  • Prospective study of T-SPOT.TB, QuantiFERON-TB Gold and TST among 160 individuals screened for HIV-infection (74 HIV+) in a TB endemic South Africa area.

Am J Respir Crit Care Med 2007


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  • TST is negatively affected by HIV infection, while TIGRA are much less (if not at all) affected.

Am J Respir Crit Care Med 2007


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  • TST is negatively influenced by CD4 counts.

  • T-SPOT.TB tends to have more positive results in the lower CD4 group.

Am J Respir Crit Care Med 2007


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  • Fair agreement between TST and TIGRA among HIV-infected. Poor agreement between TST and TIGRA among HIV-uninfected.

More on the meaning of k values in TIGRA studies in the MtP session on LTBI at 1 pm today (room K24)

Am J Respir Crit Care Med 2007


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  • Prospective study of T-SPOT.TB and TST among 203 patients with end stage renal disease in Toronto, Canada. Expert physician panel also evaluated patients for LTBI diagnosis.

Clin J Am Soc Nephrol 2007


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  • T-SPOT.TB scored more positive results, in agreement with the expert physician panel. TST probably highly insensitive in this high-risk group.

Clin J Am Soc Nephrol 2007


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  • Prospective study of T-SPOT.TB and TST among 197 hematological patients and 324 TB contacts in Milan, Italy.

New Microbiol 2007


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  • T-SPOT.TB (36%) scored significantly more positive results than TST (17%) among hematological patients; on the contrary, TST was more positive among TB contacts (60% were BCG vaccinated).

New Microbiol 2007


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

        • Indeterminate QFT-IT in low CD4 HIV (Luetkemeyer)

        • Low QFT-IT vs TST agreement in HIV (Luetkemeyer)

        • Few indeterminate T-SPOT.TB results in HIV (Clark)

        • Low CD4 and positive T-SPOT.TB: active TB (Clark)

        • TIGRA unaffected by HIV infection (Rangaka)

        • Low agreement between TIGRA and TST (Rangaka)

        • TST highly insensitive in ESRD patients (Passalent)

        • TST insensitive in hematological patients (Piana)


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The next F1 world champion

A LOOK INTO THE FUTURE …


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J Immunol 2007

CD4 IFN-g

CD4 IFN-g / IL-2

CD4 IL-2

A LOOK INTO THE FUTURE OF TIGRA

  • Distinct T cell functional signatures suggest a novel immune marker of clinical status in TB infection: dual-cytokine TIGRA?


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

        • QFT-G IT useful in Russian HCWs (Drobniewsky)

        • QFT-G IT and TST disagree in German HCWs (Nienhaus)

        • Very few QFT-G-positive Danish HCWs (Soborg)

      • Children

        • TIGRA more specific than TST in children (Detjen)

        • Retrospective QFT-G in children: NICE GL issue (Taylor)

      • Cost-effectiveness

        • TST and QFT-G are cost-effective in contacts (Diel)

        • TST and T-SPOT.TB are cost-effective in contacts (Diel)


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

      • NAATS useful in excluding AFB+ TB (Greco)

    • Serologic tests

      • No role at the moment (Steingart x 2)

    • High prevalence areas

      • Sputum submission instructions effective(Khan)

      • LAMP robust, easy and promising (Boehme)


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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Proteins 2007

  • Biomarkers

    • IL-23, FoxP3 promising markers(Fletcher)

    • Change in mycobacterial burden (Perrin)

  • New drugs

    • Little data available on rifabutin in HIV(Davies)

    • TMC 207 (diarylquinoline) most promising drug

  • Therapy


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TB CLINICAL DEVELOPMENT PIPELINE

*Institut de Recherche pour le Developement

World Health Organization, Tropical Disease Research

Centers for Disease Control and Prevention

Novel compounds, highlighted in blue italics, are active against MDR/XDR TB

Courtesy Mario Raviglione, WHO


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2015

Science 2006


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  • Diagnosis

    • T-cell interferon-g release assays (TIGRA)

      • Active TB

      • Immunocompromised patients

      • Health care workers

      • Children

      • Cost-effectiveness

    • Nucleic acid amplification assays (NAAT)

    • Serologic tests

    • High prevalence areas

  • Therapy

    • Biomarkers

    • New drugs


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SINCE 1175

ERS ANNUAL CONGRESS

Stockholm September 15-19, 2007

Infections year in review

TUBERCULOSIS: UPDATE ON NEW DIAGNOSTIC METHODS AND TREATMENT APPROACH

Luca Richeldi

Department of Oncology, Hematology and Respiratory Disease

University of Modena and Reggio Emilia, Modena (Italy)


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