El futuro del diagnostico de la ITL. en tiempos de crisis Taller de TB de Barcelona, Noviembre 2012 Professor Ajit Lalvani FMedSci Chair of Infectious Diseases Department of Respiratory Medicine National Heart and Lung Institute Imperial College London St Mary s TB Service Imperial College Healthcare NHS Trust
Future of latent TB screening: who should be screened? TB contacts: mandatory in low-burden regions, noncontroversial Alongside diagnosis and treatment of active TB, this is a priority for TB control low-burden regions The changing epidemiology of TB in low-burden countries, with increasingly high proportion of total TB cases arising in immigrants from high-burden regions with latent TB infection, has recently focused attention on immigrant screening.
9000 8000 7000 6000 5000 4000 3000 2000 1000 0 UK: highest number of TB cases in Western Europe France Germany Ireland Italy Netherlands Norway Portugal Spain Sweden United Kingdom Denmark Country 2003 2004 2005 2006 2007 Number of cases
Foreign-born TB is a significant proportion of the TB burden in developed countries 100% 241 150 2505 2790 2089 2760 181 277 1904 2308 597 359 243 64 424 2696 2029 4876 381 110 5454 2165 80% 60% 40% 20% 0% Native born Foreign born Percentage of cases* Denmark France Germany Ireland Italy Netherlands Norway Portugal Spain Sweden United Kingdom Country
Reactivation of LTBI plays critical role Data suggests little active TB at time of migration High rates in initial years after migration (newentrants) Molecular studies: limited community transmission Source: HPA 2009, Ormerod 1998, Cohen 2001
Screening migrants arriving in the UK aims to identify active TB but has a low yield
reflected in heterogeneity in practice Pareek M et al, Eur Resp J 2011 UK screening practices highly variable Areas with highest burden least screening Variable screening thresholds used
Screening practices in OECD countries International survey of 31 OECD high-income countries Evaluated screening practices for active and latent TB Where do they screen? Which groups are screened? How do they screen? 29/31 countries responded Pareek et al, Emerg Infect Dis 2012
High-income countries prioritise screening for active TB rather than latent TB 25/29 (86.2%) - active TB 16/29 (55.1%) - latent TB
Immigrant screening for latent TB in high-income countries is limited and inconsistent High-income countries inappropriately prioritise screening for active TB (low yield, 0.1%) LTBI screening, by contrast, is infrequently undertaken practice varies widely, eg in who is screened and how Given the importance of reactivation of imported LTBI in driving the TB burden, we need urgently to define whether immigrant LTBI screening is: effective? cost-effective? who should be screened? how should they be screened?
Pareek M et al Lancet Infectious Diseases 2011 Determine prevalence of LTBI in immigrants and how it varies by region of origin Identify most cost-effective threshold for screening for LTBI (in terms of TB incidence in country of origin)
Methods Immigrant screening data (2008-2010) collated prospectively at three centres Included all migrants screened aged <35 Screened with QuantiFERON-Gold in-tube LTBI=positive IGRA+, normal CXR, no symptoms Data available for 1229 immigrants aged <35 Logistic regression: factors associated with LTBI/positive IGRA
IGRA positivity independently associated with TB incidence in country of origin
Sensitivity analysis: progression from LTBI to active TB most critical Screening thresholds for <16 and 16-35 (UK pound sterling per case averted) Parameter Progression to active TB 2.5% 15% <16 All 16-35 All 208,178.6 31,333.8 <16 40 16-35 40 64,498.4 6,013.6 <16 40 16-35 100 <16 40 16-35 150 47,494.4 3,040.8 <16 40 16-35 200 <16 40 16-35 250 41,823.6 2,049.3 <16 40 16-35 300 <16 40 16-35 350 <16 40 16-35 400 <16 40 16-35 450 <16 40 16-35 500 <16 40 16-35 500+SSA Further reasons why this analysis is an underestimate HIV (higher progression rate) Assumed no prevalent cases (if identified at time of screening likely to be less infectious/less advanced disease)
clinical end-point IGRA studies: >26,000 subjects; median follow-up Prognostic power of IGRA vs TST: 4 years IGRA+: 4-48 cases per 1000 person-years IRR: IGRA 2.1 TST1.6 (Rangaka et al, Lancet Infect Dis 2011) High-burden countries: IGRA = TST Low-burden countries: IGRA > TST, but NNT still too high! Contacts who are positive by both TST and IGRA have greatest risk of progression Immune recognition of additional MTB antigens not in current IGRA likely confers additional prognostic power...
IFN-g responses to novel antigens predict disease progression Novel M tuberculosis Antigen-Spe cific T-Cells Are Early Markers of Infection and Disease Progression Davinder P.S.Dosanjh 1.,Mustafa Bakir 2.,Kerry A.Millington 1,Ahmet Soysal 2,Yasemin Aslan 2,Serpil Efee 2,Jonathan J.Deeks 3,Ajit Lalvani 1 * 1 Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom, 2 Departme nt of Paediatrics, Marmara University School of Medicine, Istanbul, Turkey, 3 Unit of Public Health, Epidemiology and Biostatistics, School of Population Health and Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom IFN-g ELISpot responses to Rv3873 and Rv3879c associated with and preceded TST conversion, identifying these antigens as early targets of CMI following MTB exposure. ELISpot responses to Rv3873 were additionally associated with, and preceded, ESAT- 6/CFP-10-ELISpot conversion: Rv3873 = ultra-early target of CMI Responses to Rv3873 and Rv3878 predicted progression to active disease: Adjusted incidence rate ratios: 3.1 (P=0.04) and 3.3 (P=0.03), respectively. Dosanjh et al, PLoS One 2011
A new molecule as antigenic as ESAT6 and CFP10 Active TB Latent TB PNAS 2011
Transcriptomics Proteomics & Metabolomics Correlates of risk & containment Longitudinal Cohort studies: clinical endpoints
And how do we afford latent TB screening until more prognostic tests become available? For health care systems struggling to afford IGRAs on a routine basis, there is a novel costsaving approach to reduce IGRA usage whilst still benefitting from IGRA accuracy: Calibration of TST against IGRA as reference standard
Bakir et al, Clin Infect Dis 2009
Sensitivity and specificity of TST are a trade-off with each other Children <2y 1 x BCG 2 x BCG Bakir et al, Clin Infect Dis 2009
BCG scars progressively diminish TST specificity ELISpot positive ELISpot negative No BCG 8% 1 x BCG 25% 2 x BCG 63% Bakir et al, Clin Infect Dis 2009
probabilities of false +ve and false ve diagnoses were computed from smoothed ROC curves generated for groups defined by age and BCG status Children <2y 1 x BCG 2 x BCG Bakir et al, Clin Infect Dis 2009
Edvard Munch, 1890 Osler: the outcome of tuberculosis has more to do with what goes on in the patient s mind than what goes on in his lungs