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Latent Tuberculosis Infection: An Update on Diagnosis. Christopher J. Crnich, MD MS June 13, 2007. TB: Immunopathogenesis. Bacillus Destroyed. Bacillus Multiplies. Distant Spread (Regional Lymph Nodes, Bloodstream). Stage 1. Stage 2 (Logarithmic Growth). Stages of TB Infection.

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latent tuberculosis infection an update on diagnosis

Latent Tuberculosis Infection: An Update on Diagnosis

Christopher J. Crnich, MD MS

June 13, 2007

tb immunopathogenesis
TB: Immunopathogenesis

Bacillus Destroyed

Bacillus Multiplies

stages of tb infection1
Multinucleated Giant Cell

Un-activated Macrophage

Activated Macrophage

Caseous Necrosis

Cytotoxic T-cell

Good CMI Response

Infected & Dying Macrophage

Non-replicating bacillus

Stages of TB Infection

Stage 3:

(Early DTH)

Stage 4a:

(Late DTH)

tb reactivation
Stage 5

(Caseous Liquefaction)

TB: Reactivation
rationale behind diagnosis and treatment of ltbi
Rationale behind diagnosis and treatment of LTBI
  • There are individuals who in whom there is:
    • An increased risk of developing active TB over their lifetime (> 10%)
    • Or, in which the consequences of developing TB, even if the risk of active disease would is low, would be catastrophic
  • Treatment of LTBI reduces risk of developing active infection by 65% to 75%
  • Risk of therapy of LTBI is low in studies published since 1991
    • Hospitalization: 1 in 1,500
    • Death: 1 in 3,300
rates of active tb among selected populations
Rates of active TB among selected populations

ATS, MMWR 2000; 44(RR-6): 1-51

ats guidelines for tst
ATS Guidelines for TST

ATS, MMWR 2000; 44(RR-6): 1-51

effectiveness of isoniazid for treatment of ltbi
Effectiveness of Isoniazid for Treatment of LTBI

Comstock GW. Int J Tuberc Lung Dis 1999; 3(10): 347 - 50

tst using dth to indirectly detect latent tb infection
TST: Using DTH to Indirectly Detect Latent TB Infection
  • Intradermal PPD causes influx of lymphocytes, macrophages & monocytes
  • Local production of cytokines: TNF-alpha, IFN-gamma, IL-10, IL-12
  • Release of serotonin & histamine leads to erythema and induration*
tst and risk of tb
TST and Risk of TB

Palmer & Edwards, JAMA 1969; 205(3): 167-9

tst and risk of tb1
TST and Risk of TB

Comstock et al. AM J Epidemiol 1974; 99(2): 131-8

limitations of tst
Limitations of TST
  • Absolute operating characteristics unknown
  • Significant problems with implementation
    • Requires patient follow-up
    • Significant inter-rater variability
    • Prone to rounding up errors
  • Prone to false-negatives (reduced sensitivity)
    • Anergy
    • Booster phenomenon
    • Active tuberculosis (IL-10 effect)
  • Prone to false-positive (reduced specificity)
    • Due to rounding-up error
    • Due to endemic NTM
    • Due to prior BCG vaccination
false positives due to ntm
False-Positives Due to NTM
  • Cross-reactivity with PPD-B explained 50% of the reactions to PPD-S in the 5-9mm range
  • Cross-reactivity with PPD-B only explained 4% of the reactions to PPD-S in the 10+ range.
  • PPD-B reactions in excess of 15mm seen in only 1.9% of subjects (and many of these may have been due to cross-reactivity with PPD-S)
  • Reactivity to PPD-B decreased the longer the individual had resided in Montreal

Am Rev Respir Dis 1992; 146(3): 752-6

false positive due to ntm
False Positive Due to NTM

Von Reyn et al. Int J Tuberc Lung Dis 2001; 5(12): 1122-8

false positives due to bcg
False Positives Due to BCG

Wang et al. Thorax 2002; 57(9): 804-9

false positives due to bcg1
False Positives Due to BCG

Wang et al. Thorax 2002; 57(9): 804-9

false positives due to bcg2
False Positives Due to BCG

Tissot et al. Clin Infect Dis 2005; 40: 211-7

false positives due to bcg3
False Positives Due to BCG

Wang et al. Thorax 2002; 57(9): 804-9

interferon release assays igra
Interferon- Release Assays (IGRA)

APC

+

T-Cell

Interferon-

+

TB Antigen

commercial igra s
Commercial IGRA’s
  • ELISA-based tests
    • Quantiferon-TB
    • Quantiferon-TB Gold
    • Quantiferon Gold In-Tube Assay
  • ELISPOT-based tests
    • T-SPOT.TB
quantiferon tb gold
QuantiFERON TB - Gold

TB Neg.

TB Pos.

TB Pos.

Indeterm.

Indeterm.

Nil

Mitogen

ESAT-6

CFP-10

quantiferon tb gold1
QuantiFERON TB - Gold

Mazurek et al. MMWR 2005; 54(RR-15): 49-55

performance of igra s
Performance of IGRA’s
  • Animal studies
    • Cattle (M. bovis)
  • Studies of patients with active TB
  • Level of exposure studies
  • Performance in low-prevalence populations
developed in cattle an excellent model for human tb
Developed in Cattle – An Excellent Model for Human TB
  • Bovine TB is an excellent model for human TB
  • Immune response to infection is very similar
  • Most infected cattle have LTBI
  • Active TB disease normally found only in old or undernourished animals

M.bovis PPD injected intradermally and read 72 hrs later

M.avium PPD is used as well for Comparative Testing

sid and igra in cattle
SID and IGRA in Cattle

Sens = 68.2 / Spec = 95.7 / PPV = 20.5 / NPV = 99.5

Sens = 81.8 / Spec = 97.8 / PPV = 37.5 / NPV = 99.7

Wood et al. Vet Microbiol 1992; 31(1): 71-9

igra s in active tb
IGRA’s in Active TB

Menzies et al. Ann Intern Med 2007; 146(5): 340-54

igras exposure level
IGRAs: Exposure Level

Kang et al. JAMA 2005; 293(22): 2756-61

igra s exposure level
IGRA’s: Exposure Level

Ewer et al. Lancet 2003; 361(9364): 1168-73

igra s exposure level1
IGRA’s: Exposure Level

Menzies et al. Ann Intern Med 2007; 146(5): 340-54

igra s exposure level2
IGRA’s: Exposure Level

Arend et al. Am J Respir Crit Care Med 2007; 175(6): 618-27

igra s reduce bcg effect
IGRA’s Reduce BCG Effect

Johnson et al. Clin Diagn Lab Immunol 1999; 6(6): 934-7

specificity of igra s
Specificity of IGRA’s

Menzies et al. Ann Intern Med 2007; 146(5): 340-54

igra s the good
IGRA’s: The Good
  • IGRA’s are more sensitive than TST in patient’s with active TB
    • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity”
    • QFT-G In-Tube may be less sensitive than QFT-G
qft g vs t spot tb
QFT-G vs. T-SPOT.TB

Active TB

Low-Risk

Lee et al. Eur Respir J 2006; 28(1): 24-30

qft g vs t spot tb1
QFT-G vs. T-SPOT.TB

Active TB

Low-Risk

Lee et al. Eur Respir J 2006; 28(1): 24-30

igra s the good1
IGRA’s: The Good
  • IGRA’s are more sensitive than TST in patient’s with active TB
    • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity”
    • QFT-G In-Tube may be less sensitive than QFT-G
igra s the good2
IGRA’s: The Good
  • IGRA’s are more sensitive than TST in patient’s with active TB
    • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity”
    • QFT-G In-Tube may be less sensitive than QFT-G
  • IGRA’s correlate better with level of exposure than TST in contact tracing studies
igra s the good3
IGRA’s: The Good
  • IGRA’s are more sensitive than TST in patient’s with active TB
    • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity”
    • QFT-G In-Tube may be less sensitive than QFT-G
  • IGRA’s correlate better with level of exposure than TST in contact tracing studies
  • IGRA’s do not appear to be influenced by prior BCG status, TST clearly is
igra s the bad
IGRA’s: The Bad
  • No data on predictive ability for the development of TB
  • Few published effectiveness studies
  • Limited data on performance in immunosuppressed patients
  • Limited data on performance in children
  • Problem with indeterminate results
igra s and hiv
IGRA’s and HIV

Rangaka et al. Am J Respir Crit Care Med 2007 (in press)

igra s and hiv1
IGRA’s and HIV

Brock et al. Respir Res 2006; 7: 56-64

igra s in children
IGRA’s in Children

Dogra et al. J Infect 2007; 54(3): 267-76

igra s in children1
IGRA’s in Children

Connell et al. Thorax; 61(7): 616-20

indeterminacy with igra s
Indeterminacy with IGRA’s
  • 318 persons tested with QFT-G at an Italian facility
    • 70% of tests ordered for suspicion of TB or contact with TB
    • 10% ordered for screening prior to immunosuppressive therapy
  • 68/318 (21.4%) of tests were indeterminate

Ferrara et al. Am J Respir Crit Care Med 2005; 172(5): 631-5

indeterminacy by type of igra
Indeterminacy by Type of IGRA

Ferrara et al. Lancet 2006; 367(9519): 1328-34

igra s the ugly
IGRA’s: The Ugly
  • Test variability
    • Conversions
    • Reversions
  • Discordance between different types of IGRA’s
    • QFT-G versus T-SPOT.TB
    • QFT-G versus QFT-IT
igra vs tst conversion
IGRA vs. TST Conversion

Pai et al. Am J Respir Crit Care Med 2006; 174(3): 349-55

igra reversions
IGRA Reversions

Wilkinson et al. J Infect Dis 2006; 193(3): 354-9

are reversions due to wobble around cut point
Are Reversions Due to Wobble Around Cut-Point?

Pai et al. Am J Respir Crit Care Med 2006; 174(3): 349-55

or is it something more fundamentally immunological
Or Is It Something More Fundamentally Immunological?

Leyton et al. Clin Vaccine Immunol 2007; (in press)

summary
Summary
  • IGRA reversions are common
  • Reversions most likely when:
    • There is discordance with the TST (TST-/IGRA+)
    • IGRA near cut-point (0.35 IU/mL for QFT-G and 20 SFC/106 WBCs)
  • Reasons for reversions likely a combination of:
    • Decay of peripheral effector cells
    • Natural biologic wobble
    • Variation due to laboratory procedures
igra agreement
IGRA Agreement

Agreement = 0.75 Kappa = 0.53

Ferrara et al. Lancet 2006; 367(9519): 1328-34

igra agreement1
IGRA Agreement

Agreement = 0.74 Kappa = 0.50

Mahomed et al. Int J Tuberc Lung Dis 2006; 10(3): 310-6

summary1
Summary
  • Discordance between different IGRA tests is very common
  • Reasons?
    • QFT-GIT has an additional antigen (TbA 7.7 in addition to ESAT-6 & CFP-10)
    • Intrinsic differences due to features of the tests (ELISA versus ELISPOT)
    • Misspecification of cut-points
improving concordance
Improving Concordance

Arend et al. Am J Respir Crit Care Med 2007; 175(6): 618-27

my interpretation
My Interpretation
  • IGRA’s can be a useful adjunctive test in:
    • Patients with active TB
    • Contact investigations
  • IGRA’s cannot be used as a rule-out test in these situations, particularly in:
    • Immunosuppressed patients
    • Children
my interpretation1
My Interpretation
  • IGRA’s are not a gold standard for determining the presence of LTBI
    • There is still no way to determine which test is correct when there is discordance
    • IGRA’s have a high rate of conversions and reversions
    • There is significant discordance between different types of IGRA’s
    • The only way to establish the true value of IGRA’s is to perform longitudinal studies to determine who progresses to active TB
my interpretation2
My Interpretation
  • IGRA’s should not replace the TST
  • Using IGRA’s alone for serially surveillance of HCWs may paradoxically increase treatment for LTBI
    • I believe we should still be using the TST
    • If not, looking at absolute increases in IFN level rather than using a threshhold should be done
  • IGRA’s can be a useful supplement to the TST in select populations
    • Patients with h/o BCG
    • Patients with TST between 10-15mm and no risk factors (TST in excess of 18mm should definitely be considered LTBI)
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