Evidence-based use of the new diagnostic tools for TB-infection Roland Diel, MD, MPH German Central Committee against Tuberculosis, Germany 20. Tuberkulose-Symposium in Münchenwiler, 24 th March 2011 1
Why new diagnostic tools (IGRAs) for TB infection? Different cut offs for TST positivity in different countries (e.g. contact tracing: USA 5mm, Germany >5mm, Switzerland >10mm) TST >15 mm do not necessarily represent latent TB infection (Tissot et al. 2005) Increased probability of false-positives in BCG-vaccinated or in NTM-infected persons (inconstant specificity) Increased risk of false-negative results due to application failures and in immunocompromised people Booster phenomenon in serial testing (e.g. of healthcare workers) Better compliance to chemoprevention than with the TST achievable? 2
Background for IGRA research Experts remain divided over the replacement of TST by IGRAs Current evidence about accuracy of IGRAs and the TST must be assessed Sensitivity (for diagnosis of active TB as surrogate for sensitivity of LTBI) Specificity Influence of exposure gradients on test results Negative and positive predictive values for progression Assessment should be focussed on the newest commercial IGRAs (QFT-IT, T-Spot.TB) 3
Definitions Specificity calculations ability of a test to give a negative result if a person is not infected healthy subjects with no known TB risk in low-burden countries required Negative Predictive Value for progression Proportion of IGRA/TST score-negative persons that do not progress to active TB in a longitudinal, follow-up study Positive Predictive Value for progression Proportion of IGRA/TST score-positive persons that develop active TB in a longitudinal, follow-up study 4
Sensitivity of IGRAs and TST as a surrogate parameter for latent TB in Pai s meta-analysis Pai M, Zwerling A, Menzies D. Systematic Review: T-Cell-based assays for the diagnosis of latent tuberculosis infection: An update. Ann Int Med 2008; 149:177-184 5
New meta-analysis only on commercial IGRAs 6
Studies included in the meta-analysis Commercial formats of QFT-In Tube or T-Spot.TB test only Excludes Liquid antigen QFT-Gold (2G) and pre-commercial ELISpot Studies with original data only For T-Spot.TB, used 6 spot cut-off (European, not the FDA-approved criteria) Studies excluded where mitogen control not used Sensitivity calculations - positive culture, PCR, or histology required Excluded if treated for more than 2 weeks PPD interpreted using cut-off employed in the respective papers 7
Sensitivity of TST in Diel et al. 25 Studies (10 studies more than in Pai) 8
Sensitivity of QFT-IT in Diel et al. 16 Studies 9
Sensitivity of T-Spot.TB in Diel et al. 17 Studies 10
Sensitivity of TST and QFT-IT in blood Sester et al. ERJ 2010 TST 12 Studies QFT-IT 8 Studies 11
Sensitivity of T-Spot.TB in blood/extrasanguinously Sester et al. ERJ 2010 Blood 15 Studies Extrasanginous samples 7 Studies 12
Are IGRAs suitable for diagnosis of active TB? IGRAs are not rule out tests for active TB They lack the required sensitivity A positive IGRA is not proof of TB disease provides no information as to the source of an observed pathology low specificity for active TB (no differentiation between latent and active TB) designed for LTBI detection Can be used to aid diagnosis in special cases (unclear conclusions from other tools, suspected extrapulmonary TB, acutely symptomatic children) 13
New technology for active TB testing PCR-based molecular test Xpert MTB/RIF (Cepheid) outperforms IGRAS in diagnosis of active TB identifies 98.2% of all culture-confirmed TB cases and 72.5% of AFB-negative patients specific in 99.2% of controls 14
Specificity for LTBI diagnosis in individuals with low risk for LTBI Study Country Type of participants No. subjects No. subjects scored negative/ all tested* No. subjects considered false positive Specificity of IGRA(s) Specificity of TST Detjen 2007 Germany (Low burden) Children with confirmed non TB lymphadenitis or respiratory infections 45 T SPOT: 39/40 QFT: 40/40 TST: 22/40 T SPOT: 1 QFT: 0 TST: 18 (all 18 with NTM lymphadenitis) T SPOT: 98% QFT: 100% 55% Franken 2007 Netherlands (Low burden) Dutch Armed Forces personnel 171 QFT: 166/168 TST: 136/145 QFT:2 TST: 9 QFT: 99% 94% Palazzo 2008 Italy (Low burden) Healthy blood donors as controls for TB suspects 24 QFT: 14/14 TST: N.A. QFT: 0 QFT: 100% N.A. Ruhwald 2008 Denmark (Low burden) 86 high school students and 38 high school staff 124 QFT:124/124 TST: 116/124 QFT: 0 TST: 8 (10mm cutoff) QFT: 100% 95% Wang 2010 USA (low burden) 97 adult university volunteers and 11 hospital children 108 T Spot ( European cutoff):105/108 T Spot : 3 T Spot: 97% N.A. *after subtraction of invalid results/indeterminates N.A.: not assessed Pooled specificity QFT: 99.4% [95% CI 97.9 99.9%] Pooled specificity TST: 88.7% [95% CI 84.6 92.0%] Specificity T Spot: 97.2% 97.5% 15
Interpretation of a TST-result given 72% sensitivity, 89% specificity and 20% LTBI prevalence 1000 contacts tested 200 with LTBI 800 without LTBI 144 TP 56 FN 712 TN 88 FP Probability of LTBI in a contact with a positive TST result (PPV): 144/232 = 62.1% Probability of no LTBI in a contact with a negative TST result (NPV): 712/768 = 92.7% 16
Interpretation of an IGRA-result given 85% sensitivity, 99% specificity and 20% LTBI prevalence 1000 contacts tested 200 with LTBI 800 without LTBI 170 TP 30 FN 792 TN 8 FP Probability of LTBI in a contact with a positive IGRA result (PPV): 170/178 = 95.5% Probability of no LTBI in a contact with a negative IGRA result (NPV): 792/822 = 96.4% 17
Exposure and test positivity indirect approach to specificity Study Country No. and type of participants No. BCG vaccinees No. IGRA positives/ total tested IGRA (Odds Ratio) No. TST positives/ total tested TST (Odds Ratio) Bartalesi 2009 Casas 2009 Italy 398 IMID subjects Spain 147 HCWs 15.6% 4.1% 13.1% QFT: 5.3 23.2% 6.5 T SPOT: 38.8% QFT: 29.3% T SPOT: 2.1 QFT: n.s. 70.1% n.s* Hesseling 2009 South Africa 82 close contacts (29 children and 53 adults) 75.6% T Spot: 74.1% T SPOT: 38.40 QFT: 39.2% QFT: 14.94 69.2% 3.83 Laffitte 2009 Lien 2009 Matulis 2008 Switzerland 50 anti TNFalpha treatment candidates 92.8% 20% T Spot: 5.67 (Contact history) T-Spot: 25.3 (Lesions in CXR) 40.0% n.s. Vietnam 300 HCWs > one third 47.3% QFT: 1.94 61.1% not calculated Switzerland 142 rheumatic patients 83.1% 12.0% QFT: 17.8 (Contact history) QFT: 66.8 (Lesions in CXR) 40.0% 6.23 *n.s.: not significant 18
Exposure and test positivity (continued) Study Country No. and type of participants Seyhan 2010 Turkey 100 hemodialysis patients No. BCG vaccinees 72.0% 43% No. IGRA positives/ total tested IGRA (Odds Ratio) QFT: 5.08 (Contact history) QFT: 3.06 (Lesions in CXR) No. TST positives/ total tested TST (Odds Ratio) 34.0% not calculated Triverio 2009 Switzerland 62 ERDS patients 22.6% T SPOT: 29.0% T SPOT: 1.2 QFT: 21.0% QFT: 4.6 19.4% n.s. Vinton 2009 Australia 481 hospital staff members 78.0% 8.4% QFT: 5.6 33.0% n.s. Zellweger 2005 Switzerland 91 contact persons 85.7% 16.5% T Spot: 5.0 44.0% n.s. *n.s.: not significant 19
IGRAs and PPV for progression IGRAs do detect more accurately those subjects who are truly infected Much more specific, sensitive (proven in active TB patients) Stronger correlation with risk factors for LTBI But : Do the IGRAs single out those most likely to progress to active TB after an exposure? Do they have a higher predictive value for progression than does the TST? 20
Theoretical considerations Comparing TST and IGRA testing with respect to PPV for infection, simple analysis of sensitivity and specificity estimates tells us that: IGRAs should be more accurate and higher than the TST at predicting who develops TB! TST IGRA But what do the data published to date tell us? denotes no. of false-positive, uninfected contacts 21
Positive predictive value for progression Diel et al. ERJ 2010 / Leung et al. AJRCCM 2010 Study Number and type of participants Country Performance of IGRA(s)/TST testing Follow up period (months) No. later TB cases among untreated IGRA positives No. later TB cases among untreated TST positives Clark 2007 201 immunodeficient HIV 1 +ve adults UK (Low burden) N.A.* 24 T Spot: 10% Not assessed Diel 2008 601 close contacts of AFB +ve TB cases Germany (Low burden) Simultaneously with TST 24 (mean) QFT: 14.6% TST >5mm: 2.3% Aichelburg 2009 830 HIV 1 +ve adults Austria (Low burden) IGRA first, TST only if QFT +ve 19 (mean) QFT: 8.3% Not assessed Kik 2010 433 adult close immigrant and BCG vaccinated Dutchborn contacts The Netherlands (Low burden) TST first, IGRAs only if TST +ve 22 (median) QFT: 2.8% T SPOT: 3.3% TST 10mm: 3.1% Leung 2010 308 male adult silicosis patients (most patients BCG unvaccinated) Hong Kong (Intermediat eburden) Simultaneously with TST 30 (mean) T SPOT: 4.5% TST 10mm: 1,64% (difference TST + / TSTnot significant 22
Selection bias in progression studies No. of contacts developing TB during the study period (nominator) Contacts at risk initially included (intended denominator) Contacts at the end of the study period (definite denominator) time Progression rate (nominator/denominator) depends on assessment of drop outs! 23
Predictive value of QFT-IT Diel et al. AJRCCM 2010 1404 close contacts 79 without TST, 3 indeterminate 381 moved 954 close contacts 198 QFT positive 606 TST positive 759 QFT negative 348 TST negative 147 refused INH/RIF 51 with INH/RIF 555 without INH/RIF Follow up: 2.85 12.9% Person-years 0% 3.1% 0% 0.6% 19 developed active TB 0 developed active TB 17 developed active TB 0 active TB 2 active TB 24
A recent study on progression to active TB An analysis of 2,204 tuberculosis contacts using QuantiFERON TB Gold In-Tube and PPD P Haldar, H Thuraisingham, W Hoskyns, G Woltmann University Hospitals of Leicester, UK Abstract presented: British Thoracic Society, 2009 25
Screening TB contacts in Leicester, UK Haldar et al. Thorax 2009 2,204 close contacts 1039 QFT Gold In-Tube 1165 no QFT 204 QFT positive 835 QFT negative* Approx # 110 no (or unfinished) chemoprevention Approx # 90 with chemoprevention No chemoprevention 17.2% Follow up: 445 days average 4.7% 1.6% 19 developed active TB 1 developed active TB No active TB cases 19 active TB * Indeterminates not reported # Approximate estimates only, as actual number are not reported 26
Results of progression studies IGRAs predict progression with high variability - at least in low and intermediate incidence countries There are only very few studies unconditionally comparing TST and IGRAs Progression rates also depend on individual or social risks - risk levels are probably different between natives (or naturalised subjects) and recent immigrants A universal progression rate can simply not be determined; studies different in design and done on different subjects/groups will have different outcomes 27
Rate of progression to TB for contacts scored positive Diel et al. AJRCCM 2010 QFT No. untreated contacts Progressed to active TB Progression rate Positive 147 19 12.9% Negative 756 0 0% TST (mm) 0-5 348 # 2 0.6% > 5 555 17 3.1% > 10 207 10 4.8% > 15 63 2 3.2% p < 0.0001 p < 0.01 p < 0.05 * for the untreated 903 subjects who had QFT and TST results and remained in Hamburg. 28
Implications for preventive therapy Diel et al. AJRCCM 2010 Number of people needed to treat to stop 1 case of active TB: QFT = 8 With all cases detected TST @>5mm = 33 With ~10% of cases missed TST @>10mm = 21 With ~50% of cases missed Higher accuracy makes identification and treatment of LTBI: More effective Less expensive - as fewer people require treatment Practical 29
Multiple logistic regression analysis for progression to TB Diel et al. AJRCCM 2010 Progression to TB Odds ratio 95% CI Interval p IFN- level (IU/mL)* 1.93 1.55.1-2.40 < 0.0001 TST induration diameter (mm) 0.89 0.78-1.01 0.08 (n.s.) Age (yrs) 0.94 0.89-0.99 < 0.02 Gender 0.75 0.23-2.44 0.63 (n.s.) Origin outside Germany 1.88 0.52-6.75 0.33 (n.s.) BCG vaccination 0.76 0.22-2.61 0.66 (n.s.) Cumulative exposure time (hrs) 1.002 0.998-1.005 0.29 (n.s.) * for the untreated 903 subjects who had QFT and TST results and remained in Hamburg. 30
Negative predictive value of IGRAs Diel et al. ERJ 2010 Study, Year Clark et al. 2007 Diel et al. 2008 Aichelburg et al. 2009 Kik et al. 2009 Lee et al. 2009 (Infection) Silverman et al. 2007 No. study members 47 UK (Low burden) 601 Germany (Low burden) 830 Austria (Low burden) 327 Netherlands (Low burden) 32 Taiwan (Intermediate burden) 23 Canada (Low burden) Country Type Duration of follow up (mo.) HIV- 1 positive individuals Close contacts of smear positive TB cases HIV-1 positive adults Close immigrant contacts of smear positive TB cases ERDS patients and healthy controls Visitors of BCG vacc. bladder cancer patients IGRA (s) used Mean age (yrs S D) 24 T-Spot median 40 (range: 33 46) 24 (mean) QFT 27.7 ( 12.0) 19 (mean) QFT 39 (range: 32 47) 22 (median) T-Spot/ QFT 24 T-Spot 52.7 7.0 24 QFT 57.7 13.4 No. TB cases developed in testnegative subjects No. false negative cases NPV (%, CI 95%) a 0 0 100% [0.94 1.00] 0 0 100% [0.99 1.00] 0 0 100% [0.996 1.00] N.A. T-Spot/QFT:5 T-Spot: 2; QFT: 3 T-Spot: 98.3% [0.94 1.0]; QFT: 98.0% [0.94 1.0] 2 2 88.2% [0.64 0.99] 0 0 100% [0.86 1.0] 31
NPV for progression of QFT-IT and T-Spot.TB Pooled values - Diel et al. ERJ 2010 NPV (95% CI) Patients n/n Aichelburg et al. 2009 19 1.00 (1.00-1.00) 738/738 Diel et al. 2008 20 1.00 (0.99-1.00) 535/535 Kik et al. 2010 21 0.98 (0.94-1.00) 146/149 Silvermann et al. 2007 45 1.00 (0.83-1.00) 20/20 0 0.2 0.4 0.6 0.8 1 Pooled NPV (QFT-G-IT) = 0.998 (0.994 to 1.0) Chi-square = 13.67; df = 3 (p = 0.0034) Inconsistency (I-square) = 78.1 % Negative predictive value for progression NPV (95% CI) Patients n/n Clark et al. 2007 22 1.00 (0.92-1.00) 47/47 Kik et al. 2010 21 0.98 (0.94-1.00) 116/118 Lee et al. 2009 41 0.88 (0.64-0.99) 15/17 0 0.2 0.4 0.6 0.8 1 Pooled NPV (T-Spot.TB) = 0.98 (0.94 to 0.99) Chi-square = 5.86; df = 2 (p = 0.0533) Inconsistency (I-square) = 65.9 % Negative predictive value for progression 32
How do IGRAs perform in children? 33
IGRA testing in children: Factors for consideration Young children are at increased risk of progressing to TB if infected TB often takes appears in very serious forms in children Very young children may not be immunocompetent Evidence has been collected for decades on the use of TST in children Poor specificity in those BCG-vaccinated and carrying NTM infections To date, only limited data on sensitivity of IGRAs (for detecting active TB) in children, not only in those <5 years! 34
IGRA and TST sensitivity in detecting active TB in children Study Country; IGRA used Mean Age (range) Bamford et al. 2009 Bianchi et al. 2009 Connell et al. 2008 Cruz et al. 2011 Detjen et al. 2007 Kampmann et al. 2009 Nichol et al. 2009 TST -Sensitivity n/n (%) GB; QFT/T-Spot 10.1 (0.6-16) yrs 37/45 (82.2) Italy; QFT Australia; QFT/T-Spot USA; T-Spot Germany; QFT/T-Spot 54.0 (31.2-81.7) months 8.2 (1.8-13.6) yrs 7/9 (77.8) IGRA-Sensitivity n/n (%) QFT: 36/46 (78.3) T-Spot: 18/27 (66.7) 14/16 (87.5) 15/16 (93.8) QFT:8/9 (88.9) T-Spot: 9/9 (100.0) 8.6 (0.1-18) yrs 10/13 (76.9) 12/13 (92.3) 28 (4-85) months 28/28 (100.0) GB; QFT/T-Spot 9,2 (0.5-15) yrs 20/25 (80.0) South Africa; T-Spot Median 18 months, (interquartil range 14-24 months) Pooled Sensitivity: TST: 124/146; 84.9% [95% CI 78.1%-90.3%] QFT: 105/124; 84.6% [95% CI 77.1%-90.5%] T-Spot: 84/112; 75.0% [95% CI 65.9%-82.7%] QFT and T-Spot: 26/28 (92.9) QFT: 20/25 (80.0) T-Spot: 14/25 (56.0) 8/10 (80.0) 5/10 (50.0) 35
Diel et al. AJRCCM 2010: Data from children 104 close contact children Mean age 10.4 ± 4.3 years 36% BCG vaccinated 6 progressed to active TB 6/21 QFT positive (29%) developed TB None of the 83 QFT negative children developed TB 6/40 (15%) TST positive @5mm developed TB 2 of the 6 would have been missed by TST @10mm IGRA detects those likely to progress to active TB 36
A recent review of published literature: The Use of Interferon-gamma Release Assays in HIV positive Individuals Matthias Hoffmann and Pernille Ravn European Infectious Diseases 2010;4: 23-29 37
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Rate of indeterminate IGRA results stratified by CD4+ count in HIV-positive individuals without active tuberculosis Indeterminate responses correlate with CD4+ count 39
IGRAs in HIV positives Superior sensitivity in HIV positive compared to TST But lower than in HIV negative Patients with CD4 >200 cells/ L have performance comparable to HIV negative More indeterminates than in HIV-negatives Indeterminate responses associated with low CD4 cell count Not a rule out - test (up to 35% false negative for active TB) - But better than the TST 40
Iatrogenic immunosuppression (especially anti-tnf-α therapy) 41
Comparison of QFT and TST in RA patients in Peru Ponce De Leon et al. J Rheumatol 2008 Objectives: Compare TST and QFT positivity in RA patients with matched controls Determine the level of agreement between these tests Determine the performance of both tests by age groups Methods: 101 outpatients with Rheumatoid Arthritis 93 immunocompetent controls Matched by age, gender Osteoporosis, osteoarthritis, mechanic lumbar pain and tendinitis Positive TST 5mm for RA patients and 10 mm for Controls QFT-IT performed as per manufacturer s instructions 42
Responses in controls vs RA patients Ponce De Leon et al. J Rheumatol 2008 Highly significant drop in TST sensitivity for RA patients Less effect for IGRA 43
LTBI testing and IGRAs-Conclusions With IGRAs, what has changed in the way we look at TB? IGRAs are more specific and more sensitive (in adults) than PPD What does this mean in practical terms? IGRAs allow the exclusion of M. tuberculosis infection with higher reliability In longitudinal studies in low prevalence countries NPV for progression was high for both IGRAs IGRA positivity is clearly associated with exposure to infectious TB cases Odd ratios of IGRA positivity usually exceeds those for the TST 44
LTBI testing and IGRAs-Conclusions. IGRAs are likely more predictive of future TB This should change our attitudes to screening and treating LTBI But: More larger-sized and better designed studies needed to evaluate Sensitivity of IGRAs in Children Predictive values of IGRAs in immune-deficient hosts and children 45