IGRAs in Diagnosis of Childhood LTBI and Active TB: Yes

Transcription

1 IGRAs in Diagnosis of Childhood LTBI and Active TB: Yes Professor Ajit Lalvani Director, Tuberculosis Research Unit National Heart and Lung Institute Imperial College London Conflict of Interest Statement: AL is inventor for several patents underpinning T cell-based diagnosis. IFN-g ELISpot was commercialised by an Oxford University spin-out company (T-SPOT.TB, Oxford Immunotec) in which Oxford University and AL have minority shares of equity and royalty entitlements

2 IGRA and TST both measure the wrong thing but IGRA do it more specifically Hans Rieder IUATLD Europe Conference Dubrovnik May 2009

3 Diagnosis of Childhood TB Infection LTBI Why is it important? Individual child - Risk of progression to active TB is high Community - Sentinel of Mtb transmission in the community as infection is almost always recent

4 Diagnosis of Childhood TB Infection Active TB Why is it important? High morbidity and mortality - CNS disease... - Disseminates... Difficult to diagnose - Often paucibacillary - Children don t expectorate

5 Diagnosis of Childhood TB Infection Clinical consequences of missing a case of LTBI or active TB are high Better to err on side of caution and maximise sensitivity at cost of specificity in the diagnostic testing strategy If this assumption/principle is correct, then I suggest that the evidence shows that I am right, i.e. that: IGRA and TST is better than TST alone

6 IGRAs in Diagnosis of Childhood LTBI No gold standard for LTBI...

7 Surrogate reference standard Proximity Duration Relationship Infectivity TSPOT.TB QFT-GIT Index case Exposure Contact

8 Completed at Muenchenwiller March 2003 Superiority of a new test for LTBI (Lancet, April 2003)

9 Correlation with Exposure -Low burden setting Reference Setting Population Assay(s) used Conclusion Ewer_Lalvani. Lancet (2003) School TB outbreak, UK 535 students (11-15y) ELISpot TST and ELISpot were positive in similar numbers, but TSPOT correlated more strongly with exposure than TST on the basis of proximity and duration. Richeldi_Lalvani. Am J Respir Crit Care Med (2004) Altet-Gomez_ Dominiguez. Eur Respir J (2011) Cruz_Smith. Paed (2011) Pavic_Dodig. Paed Infect Dis (2011) Neonatal ward contact tracing, Italy Contact tracing and public health screening, Spain Screening within paediatric TB clinic setting, US TB contact screening in hospital setting, Croatia 92 participants 51 adults; 41 newborns 166 children 98 contacts; 68 health screened (mean 9y) 210 children (1m-18y) 179 with query LTBI; 31 with ATB 142 BCG vaccinated children ( 5y) ELISpot TSPOT and QFT-GIT TSPOT QFT-GIT ELISpot was positive in more cases than TST. ELISpot (but not TST) positivity correlated with degree of exposure. Equivalent numbers of positive cases by QFN-GIT and TSPOT. Risk of positive TSPOT or QFT-GIT higher with increasing exposure. TSPOT was more likely to be positive with increased risk of LTBI (based on risk factors and/or known source case) Numbers of TST and QFT-GIT positive cases equivalent. Higher risk of either being positive with increasing if index case is C+ or has cavity lesions.

10 Correlation with Exposure - Moderate-High burden setting Reference Setting Population Assay(s) used Conclusion Soysal_Lalvani. Lancet (2005) Household contact screening, Turkey 979 children (0-16y) ELISpot TST positive in slightly higher number of cases than ELISpot, but ELISpot positivity was associated with increased exposure. Nakaoka_Cuevas. Emerg Infect Dis (2008) Hill_McAdam. Paed (2006) Okada_Chhour. Epid Infect (2008) Petrucci_Cuevas. Paed Infect Dis (2008) Household contact screening, Nigeria Household contact screening, The Gambia Household contact screening, Cambodia Household contact screening, Nepal and Brazil 207 children 46 with control index case; 83 with S- TB index case; 78 with S+ TB index case QFT-GIT Numbers of positive tests equivalent for TST and QFT-GIT in contacts of controls and S- TB index case, but QFT-GIT positive more often in contacts of S+ TB. 856 children (6m-14y) ELISpot Numbers of TST and ELISpot positive cases equivalent. Higher risk of either being positive with increasing exposure, particularly for TST. 195 children ( 5y) QFT-G Slightly higher numbers of TST positive cases than QFT-GIT. Higher risk of either test being positive with increasing smear grade of index case, particularly for QFN-GIT. 259 children (0-15y) 146 in Nepal; 113 in Brazil QFN-GIT Numbers of positive TST and QFT-GIT equivalent. Higher numbers of cases positive for both tests, but particularly TST, in children from Nepal, who were exposed to index cases with higher smear grades than in Brazil.

11 Correlation with Exposure -Moderate-high burden setting (continued) Reference Setting Population Assay(s) used Conclusion Kasambira_Dorm an. Int J Tuberc Lung Dis (2011) Household contact screening, South Africa 270 children (median 6y) QFT-GIT Equivalent numbers of cases TST* and QFT-GIT positive. Higher risk of positive QFT-GIT or TST with increasing smear grade of index case. Hesseling_Walzi. Thorax (2009) Chun_Kim. Diag Microbiol Intect Dis (2008) Adetifa_Hill. Paed Infect Dis (2010) Household contact screening, South Africa Screening within hospital setting, South Korea Household contact screening, The Gambia 82 participants 29 children; 53 adults QFT and TSPOT 227 BCG vaccinated QFT-GIT children (<15y) 42 close contacts; 29 casual contacts; 65 controls 285 children (6m-14y) QFT-GIT and TSPOT Numbers of positive children approximately equivalent for TST and QFT-GIT, and higher for TSPOT. High risk of positive QFT-GIT or TSPOT with increasing exposure, particularly for TSPOT. Higher number of contact cases positive with TST than QFT-GIT. Higher risk of either test in close compared to casual contacts, particularly for QFT-GIT. Numbers of cases positive equivalent for TST, TSPOT and QFT-FIT. All tests responded to gradient of sleeping proximity to index case. Combining TST and IGRA increased sensitivity by 10%, but reduced specificity. *Conclusion is based on TST cut off of 5mm. However, most (95%) participants were BCG vaccinated). If use cut-off of 10mm, QFT-GIT is positive in higher number of cases than TST.

12 Correlation with Exposure -Conclusions Low burden countries: IGRA (particularly TSPOT/ELISpot) results correlate more strongly than TST with degree of TB exposure, but are independent of BCG vaccination status Moderate-high burden countries: IGRA results correlate more strongly than TST with degree of TB exposure, but are independent of BCG vaccination status

13 Risk of progression: definitive reference standard No active TB TSPOT.TB QFT-GIT Longitudinal follow-up Contact/ high risk patient Active TB

14 Dice (Opt:1.00%) (Tol 2.0%-2.0%) (H>0.0% S>0.0%) [0.0%-100.0%] Do IGRA predict progression to active TB? The first case... ESAT6 CFP10 RFLP analysis of MTB isolate from bronchoalveolar lavage: identical strain to that of the mother IS6110 RFLP IS6110 RFLP 100 Mycobacterium Mycobacterium tuberculosis tuberculosis 314 Modena 201Modena Pediatrics 2007

15 Correlation with Progression -Low burden setting Reference Setting Population Assays used Diel_Nienhaus. Am J Respir QFT-GIT Crit Care Med (2011) Higuchi_Harada. J Infect (2009) Nsutebu_Watson. Public Health (2008) Contact screening, Germany Primary school contact tracing, Japan High school screening, UK 954 participants 848 adults; 106 children (0-15y; 2 given preventative therapy) 313 students (8-12y) 41 close contacts; 272 casual contacts (99% BCG) QFT-G Conclusion Equivalent numbers of children positive by QFT- GIT and TST when using TST cut-off of 10mm. All of 6 children who progressed to ATB had positive QFT-GIT at baseline. Four had TST 10mm, and 6 had TST 5mm. Higher numbers of cases positive by TST than by QFT-GIT. Treatment based predominantly on QFN+, and no progression to ATB observed at follow up. 190 children (13-14y) QFT-GIT Of 28 children with positive TST, none were QFT-GIT positive. At follow up, no children had progressed to active TB.

16 Correlation with Progression -Moderate-high burden setting Reference Setting Population Assays used Conclusion Bakir_Lalvani. Ann Int Med 908 children (mean ELISpot (2008) 7.5y) Hill_Adegbola. Plos one (2008) Shah_Dorman. PLoS One (2011) Community-based contact screening, Turkey Contact screening, The Gambia Household contact screening, South Africa 2348 participants y, 599 >25y 270 children (6m-16y) 196 followed up for 6m ELISpot QFT-GIT Higher number of cases positive with TST than ELISpot at baseline, but positivity of tests equally associated with progression to active TB. Of cases (0-25y) who progressed to ATB, over half had positive ELISpot and almost 70% had positive TST at baseline. At least one test was positive in 82% of progressors. Equivalent numbers of cases positive by TST and QFT-GIT at baseline. 39 cases progressed to active TB, but TST and QFT data not shown for these patients.

17 Correlation with Progression -Conclusions Low burden countries: Insufficient numbers of incident cases (n=6) to compare either IGRA vs TST Positive QFT results associated with risk of progression (and QFT negativity associated with lack for progression) Moderate-high burden countries: Insufficient numbers of incident paediatric cases (n = 22) to compare either IGRA vs TST Positive ELISpot results associated with risk of progression IGRA and TST better than either alone

18 Clinical utility in LTBI Rule-in test LTBI??? HIV Young kids Other immunosuppression Uninfected BCG vaccinated Sensitivity in young children and immunosuppressed populations is better than TST but we do not know the false-negative rates in these subgroups: hence rule-out is difficult High specificity lessens the number of people inappropriately treated on the basis of false-positive TST Tuberculosis Research Unit

19 -Immunocompetent adults -Children Suspected LTBI TST and IGRA TST + IGRA + TST + IGRA - TST IGRA+ TST IGRA - X-ray changes or strongly +ve TST LTBI Uninfected LTBI Uninfected Immunosuppressed Immunosuppressed LTBI LTBI LTBI?

20 Highest risk or progression = dual-positive (IGRA+TST) Prospective longitudinal cohort study in communitybased contact investigations 443 index patients with sputum smearpositive pulmonary tuberculosis 1024 child contacts enrolled at central study clinic 965 child contacts with complete baseline data 15 incident cases active TB over 2 years follow-up N=57 Never attended follow-up 908 child contacts 337 ELISpot-positive TST-positive 317 (94%) received IPT 44 ELISpot-positive TST-negative 18 (41%) received IPT 213 ELISpot-negative TST-positive 140 (66%) received IPT 314 ELISpot-negative TST-negative 146 (47%) received IPT Bakir et al, Ann Intern Med 2008 Tuberculosis Research Unit

21 Additional antigens may enhance prognostic power Responses to Rv3873 and Rv3878 predicted progression independently of conventional IGRA antigens

22 IGRAs in Diagnosis of Childhood Active TB TSPOT.TB QFT-GIT

23 Active TB -Low burden setting Reference Bamford_ Kampmann. Arch Dis Child (2010) Kampmann_ Anderson. Eur Respir J (2009) Hermann_ Lagrange. PLoS One (2009) Study design/setting Retrospective analysis, routine clinical practice, UK Prospective cohort study in routine clinical practice, UK Prospective cohort study, France Population Assay used No all TB / sens of IGRA in all TB 333 children with suspected active TB (0-16y) 209 children with suspected active TB (2m-16y) TSPOT.TB and QFT-GIT QFT-GIT and TSPOT.TB 195 / 46% for TSPOT; 59% for QFT; 63% for TST 15mm 63 / 50% for TSPOT; 64% for QFT; 71% TST 10mm No C+ TB / sens of IGRA in C+ TB 49 / 67% for TSPOT; 78% for QFT; 82% for TST 15mm 25 / 58% for TSPOT; 80% for QFT; 88% for TST 131 children (0-17y) QFT-GIT 32 / 78% 15 / Data not shown No C- TB / sens of IGRA in C- TB 146 / 38% for TSPOT; 52% for QFT; 56% for TST 15mm 38 / 45% for TSPOT; 53% for QFT; 62% for TST 17 / Data not shown No non-tb / spec of IGRA in non-tb 138 / Data not shown Data not shown 31 / 70%

24 Active TB -Moderate-high burden setting Study design/setting Lieberschuetz_ Lalvani. Lancet (2004) Davies_Nicol. AIDS (2009) Nicol_Hussey. Paediatrics (2009) Study design/setting Population Assay used No all TB / sens of IGRA in all TB Prospective cohort study in routine clinical practice, South Africa Prospective cohort South Africa Prospective cohort study, South Africa 293 children with suspected active TB (0-14y) 188 children (median 20m) 139 HIV positive 243 children with suspected active TB (median 18m) ELISpot 133 / 83% for ELISpot; 65% for TST ELISpot 39 HIV pos / 64% for ELISpot; 29% for TST TSPOT.TB 58 / 50% for TSPOT; 80% for TST No C+ TB / sens of IGRA in C+ TB 57 / 81% for ELISpot; 37% for TST 21 HIV pos / 66% for ELISpot 10 / 40% for TSPOT; 52% for TST No C- TB / sens of IGRA in C- TB 64 / 84% for ELISpot; 81% for TST 18 HIV pos / 61% for ELISpot 48 / Data not shown No non-tb / spec of IGRA in non-tb 13 / 69% for ELISpot; 100% for TST 50 / 84% for both tests Warier_Bose. Indian Paed (2010) Moyo_Mahomed. Int J Tuberc Lung Dis (2011) Sun_Shen. Chin Med J (2010) Prospective study, India Longitudinal cohort study follow up, South Africa Prospective study, China 143 children (0-18y) 400 children (9-34m) 74 children with active TB and 51 controls (mean 7y) ELISpot 53 / 42% 15 / 53% 38 / 37% 47 / 98% QFT-GIT TSPOT.TB 38 / 39% for QFT; 35% for TST 74 / 89% for TSPOT; 77% for TST 3 / Data not shown 18 / 83% for TSPOT; 61% for TST 35 / Data not shown 56 / 91% for TSPOT; 82% for TST 80% for QFT; 84% for TST 51 / 94% for TSPOT; 71% for TST

25 Literature review: Active TB: Conclusions - IGRA performance much more variable in children than adults. Likely reflects heterogeneity in Th1-type cellular immunity between children of different ages, different ethnicity, different environments (nutrition, coinfection) - TST performance worse in high-burden regions vs low-burden regions Low burden countries: IGRA and TST broadly similar sensitivity in culture-confirmed TB Specificity of both IGRA and TST is high, but IGRA higher Moderate-high burden countries: IGRA and TST broadly similar sensitivity ELISpot more sensitive than TST Specificity higher for IGRA than TST IGRA and TST better than either alone

26 Diagnosing active TB in children with HIV in resource-constrained setting Study population: 293 children with suspected TB in routine practice 25-30% prevalence of HIV infection and malnutrition Unlike TST, sensitivity of ELISpot was independent of Young age (85% vs 51%) HIV co-infection (73% vs 36%) Malnutrition (78% vs 44%) Liebeschuetz et al, Lancet 2004 Overall diagnostic sensitivity: ELISpot: 83% TST: 63% ELISpot and TST: 91% Tuberculosis Research Unit

27 Clinical utility for evaluation of TB suspects Large prospective blinded studies of IGRA vs TST in TB suspects Neither IGRA is a reliable rule-out Maximum sensitivity: IGRA &TST in combination Liebeschuetz et al Lancet 2004 (Children, HIV, malnutrition) Dosanjh et al Ann Intern Med 2008 Golletti et al PLoS ONE 2008 Sensitivity IGRA 83% (ELISpot) 91% 85% (ELISpot) 97% 85% (T-SPOT) 78% (QFT) Sensitivity IGRA and TST 97% Pre-test probability 50% Dosanjh et al Ann Intern Med 2008 ELISpot Sensitivity 85% LR 0.21 Post-test probability 12% TST Sensitivity 81% LR 0.20 Post-test probability 3% Sensitivity 97% LR 0.04 Also: Ravn et al Clin Diagn Lab Immunol 05; Ferrara et al Lancet 06; Kang et al Chest 07 Tuberculosis Research Unit

28 Clinical utility in active TB TB Infection Asymptomatic: LTBI Symptomatic: Active TB Uninfected Immune-based tests are tests of infection, not active disease: cannot distinguish between the two TB infection is a prerequisite for TB disease But by ruling out infection, you can rule-out active TB Requires test of very high diagnostic sensitivity: higher than either of the current IGRAs Sensitivity in real-life routine practice is only around: 75%(QFT) to 85%(T-SPOT) But in a child with compatible symptoms, a positive result strongly suggests active TB = rule-in Tuberculosis Research Unit

29 Suspected active tuberculosis TST and IGRA TST + IGRA + TST + IGRA - TST - IGRA + TST IGRA Active TB strongly suggested Discordant results: TB is possible Active TB unlikely

30 Next-generation IGRA: enhanced sensitivity Cultureconfirmed & highly probable TB TST ( 15 mm) ELISpot (ESAT-6, CFP-10) ELISpot PLUS (ESAT-6, CFP-10 Rv3879c) ELISpot/ TST ELISpot PLUS / TST Sensitivity % (95% CI) Specificity % (95% CI) 80 (72, 85) 85 (79, 90) 89 (84, 93) 97 (93, 99) 99 (95, 100) P= (64, 97) 84 (60, 97) Negative Likelihood ratio 0.25 (0.19, 0.35) 0.21 (0.15, 0.30) 0.15 (0.10, 0.24) 0.04 (0.02, 0.12) 0.02 (0.005, 0.09) ELISpot PLUS boosts diagnostic sensitivity without compromising specificity ELISpot PLUS used in combination with TST enables rule-out of TB Dosanjh et al, Ann Intern Med 2008 Tuberculosis Research Unit

31 Summary of Debate: messages for clinical practice Latent TB and active TB Diagnostic sensitivity is the priority Maximise this by using IGRA and TST where both are available If both not available, IGRA is preferable to TST IGRA very reliable as rule-in test for infection (and, in young children in low burden countries, for disease) IGRA are not a reliable rule-out for infection or disease in young children: but next-generation tests have higher sensitivity Distinguishing latent from active TB: detailed T cell analysis

32 Tuberculosis Research Unit Imperial College London Hilary Whitworth Saranya Sridhar Manish Pareek Suzie Hingley-Wilson Damien Montamat-Sicotte Muhunthan Thillai Christian Eberhardt Hilary Whitworth Katrina Pollock David Connell Sarah Hackforth Samuel Bremang Lee Potiphar Lisa Grass Donald Mitchell Shaima Begom Elihu Aranday-Cortes Davinder Dosanjh Tim Hinks Kerry Millington Conflict of Interest Statement: AL is inventor for several patents underpinning T cell-based diagnosis. IFN-g ELISpot was commercialised by an Oxford University spin-out company (T-SPOT.TB, Oxford Immunotec) in which Oxford University and AL have minority shares of equity and royalty entitlements.

33 Recent exposure/ Contact tracing: -Contacts -HCWs Suspected LTBI TST and IGRA TST + IGRA + TST + IGRA - TST IGRA+ TST IGRA - LTBI Uninfected Uninfected