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Young children exposed to tuberculosis have a high risk of progression to severe tuberculosis disease, but diagnosis of recent infection is hindered by the poor sensitivity of the tuberculin skin [...]

Rationale: The Xpert (GeneXpert) MTB/RIF, an integrated polymerase chain reaction assay, has not been systematically studied in extrapulmonary and in particular mediastinal tuberculosis (TB).Objectives: To investigate the performance of Xpert MTB/RIF in the diagnosis of intrathoracic nodal TB in a large tertiary urban medical center in the UK.Methods: We collected clinical, cytological, and microbiological data from two cohorts: 116 consecutive patients referred with mediastinal lymphadenopathy with detailed diagnostic information obtained, and an immediately subsequent second cohort of 52 consecutive patients with microbiologically confirmed mediastinal TB lymphadenopathy. All data were derived between January 2010 and October 2012. All patients underwent endobronchial ultrasound and transbronchial needle aspiration (TBNA). The performance of a single Xpert MTB/RIF assay alongside standard investigations, cytology, and microscopy/culture was evaluated against culture-confirmed TB.Measurements and Main Results: Microbiologically confirmed TB mediastinal lymphadenopathy was diagnosed in a total of 88 patients from both cohorts. Three culture-negative cases with associated caseating granulomatous inflammation on TBNA were given a probable diagnosis. A single Xpert MTB/RIF assay demonstrated overall sensitivity for culture-positive TB of 72.6% (62.3-81.0%). Xpert specificity from cohort 1 was 96.3% (89.1-99.1%). The positive predictive value was 88.9% (69.7-97.1%), negative predictive value was 86.5% (76.9-92.1%), and odds ratio was 51.3 (24.0-98.0) for correctly identifying culture-positive disease. Xpert captured all microscopy-positive cases (14 of 14) and the majority of microscopy-negative cases (48 of 71, 67.6%). Among the cases that were culture positive by TBNA, Xpert identified two-thirds of the multiple drug-resistant TB cases, leading to immediate regimen change up to 5 weeks ahead of positive cultures. The use of Xpert combined with cytology increased the sensitivity to 96.6%.Conclusions: Xpert MTB/RIF provides a rapid, useful, and accurate test to diagnose mediastinal nodal TB in intermediate-incidence settings. The additional use of TBNA cytology further enhances the sensitivity of Xpert. This combination can facilitate rapid risk assessment and prompt TB treatment. [ABSTRACT FROM AUTHOR]

We conducted a longitudinal community cohort study of healthy adults in the UK. We found significantly higher incidence of influenza A(H1N1)pdm09 infection in 2010-11 than in 2009-10, a substantial proportion of subclinical infection, and higher risk for infection during 2010-11 among persons with lower preinfection antibody titers. [ABSTRACT FROM AUTHOR]

The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)+ interleukin-2 (IL-2)− CD8+ T cells (r = −0.6, P = 0.004). Within this functional CD8+IFN-γ+IL-2− population, cells with the CD45RA+ chemokine (C-C) receptor 7 (CCR7)− phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8+ T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing tumour necrosis factor (TNF)-α antagonist therapy are at increased risk of latent tuberculosis infection (LTBI) reactivation. The aim of this study was to determine the optimum available screening strategy for identifying patients for tuberculosis (TB) chemoprophylaxis. Methods: We conducted a prospective observational study of consecutive adults with chronic rheumatological disease referred for LTBI screening prior to commencement of TNF-α antagonist therapy. All patients included had calculation of TB risk according to age, ethnicity and year of UK entry, as described in the 2005 British Thoracic Society (BTS) guidelines and measurement of tuberculin skin test (TST) and T.Spot.TB. Results: There were 187 patients included in the study, with 157 patients (84%) taking immunosuppressants. 137 patients would require further risk stratification according to the BTS algorithm, with 110 (80.3%) classified as being at low risk of having LTBI. There were 39 patients (35.5%) who were categorised as low risk but were either TST and/or T.Spot positive and would not have received chemoprophylaxis according to the BTS algorithm. Combination of all three methods (risk stratification and/or positive T.Spot and/or positive TST) identified 66 patients out of 137 who would potentially be offered chemoprophylaxis, which was greater than any single test or two-test combination. Conclusion: Performing both a TST and T.Spot in patients on immunosuppressants prior to commencement of TNF-α antagonist therapy gives an additional yield of potential LTBI compared with use of risk stratification tables alone. Our results suggest that use of all three screening modalities gives the highest yield of patients potentially requiring chemoprophylaxis. [ABSTRACT FROM AUTHOR]

Background: Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection.Methods: A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α).Results: Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPDspecific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone.Conclusions: Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies. [ABSTRACT FROM AUTHOR]

Migration from low- and middle-income countries to high-income countries increasingly determines the severity of tuberculosis (TB) cases in the adopted country. Socially marginalized groups, about whom little is known, may account for a reservoir of TB among the immigrant populations. We investigated the rates of and risk factors for Mycobacterium tuberculosis transmission, infection, and disease in a cohort of 27,358 socially marginalized immigrants who were systematically screened (1991-2010) in an area of Italy with low TB incidence. Overall TB and latent TB infection prevalence and annual tuberculin skin testing conversion rates (i.e., incidence of new infection) were 2.7%, 34.6%, and 1.7%, respectively. Prevalence of both TB and latent TB infection and incidence of infection increased as a function of the estimated TB incidence in the immigrants' countries of origin. Annual infection incidence decreased with time elapsed since immigration. These findings have implications for control policy and immigrant screening in countries with a low prevalence of TB. [ABSTRACT FROM AUTHOR]

Infections with >1 Mycobacterium tuberculosis strain(s) are underrecognized. We show, in vitro and in vivo, how first-line treatment conferred a competitive growth advantage to amplify a multidrug-resistant M. tuberculosis strain in a patient with mixed infection. Diagnostic techniques that identify mixed tubercle bacilli populations are needed to curb the spread of multidrug resistance. [ABSTRACT FROM AUTHOR]

Background: UK tuberculosis (TB) notifications are rising due to disease in the immigrant population. National screening guidelines have been revised but cost-effectiveness analyses are hampered by the lack of data on the comparative performance of tuberculin skin tests (TSTs) and interferon γ release assays (IGRAs) in immigrants.Methods: Three-way evaluation of TSTs and two IGRAs (QuantiFERON Gold in-tube (QFN-GIT) and T-SPOT.TB) in immigrants aged ≥16 years to quantify test positivity, concordance and factors associated with positivity. Yields were computed at different incidence thresholds and the relative cost-effectiveness of screening was estimated using different latent TB infection (LTBI) screening modalities at varying incidence thresholds with or without port-of-arrival chest x-ray (CXR).Results: 231 immigrants were included; median age 29 (IQR 24-37). TSTs were accepted by 80.9%, read in 93.5% and 30.3% were positive - QFN-GIT and T-SPOT.TB positive in 16.6% and 22.5% respectively. Positive TSTs, QFN-GIT and T-SPOT.TB were independently associated with increasing TB incidence in immigrants' countries of origin (p=0.007, 0.007, 0.037 respectively). Implementing current guidance (threshold 40/100 000 per year) would identify 98-100% of LTBIs (depending on test) but entail testing 97-99% of the cohort; screening at 150/100 000 per year would identify 49-71% of LTBIs but only entail screening half the cohort. The two most cost-effective screening strategies were no port-of-entry chest radiography and screen with single-step QFN-GIT at 250/100 000 per year (incremental cost-effectiveness ratio (ICER)) £21 565.3/case averted); and no port-of-entry CXR and screen with single-step QFN-GIT at 150/100 000 per year (averted additional 7.8 TB cases; ICER £31 867.1/case averted).Conclusions: UK immigrant screening could cost-effectively and safely eliminate mandatory CXR on arrival by emphasising systematic screening for LTBI with single-step IGRA. Intermediate incidence thresholds balance the need to identify as many imported LTBIs as possible against limited service capacity. [ABSTRACT FROM AUTHOR]

Background Interferon gamma release assays (IGRAs) are the first new diagnostic tests for latent tuberculosis (TB) infection (LTBI) since the century-old tuberculin skin test (TST). They are cell-mediated immune-based blood tests that have revolutionised LTBI diagnosis and are increasingly recommended by national guidelines. Objectives With the rapid expansion of the IGRA evidence-base in recent years, the limitations of IGRA and uncertainties in clinical interpretation of IGRA results have increasingly come into focus. In LTBI diagnosis these include: prognostic power of IGRAs relative to TST for quantifying risk of progression to active disease, false-negative rates in immunocompromised patients, the clinical meaning of IGRA reversion and the significance of the size of IGRA response. Furthermore, the role of IGRAs in the diagnostic work-up of active TB is unclear, and there is little evidence supporting use of the tests in anti-TB treatment monitoring. Methodological approach On-going large prospective longitudinal clinical endpoint cohort studies of active and latent TB will tackle some of the uncertainties regarding IGRAs. Here we discuss clinical practice and guidance in light of the current uncertainties, based on existing evidence. Conclusions and impact Current and planned clinical research will fill the gaps in the evidence-base, narrowing the areas of uncertainty and informing future policy. Translational research into next-generation IGRAs and new T cell-based diagnostic platforms will likely overcome the limitations of current IGRAs in the near future. [ABSTRACT FROM AUTHOR]

Background UK tuberculosis (TB) notifications are rising due to disease in the immigrant population. National screening guidelines have been revised but cost-effectiveness analyses are hampered by the lack of data on the comparative performance of tuberculin skin tests (TSTs) and interferon ? release assays (IGRAs) in immigrants. Methods Three-way evaluation of TSTs and two IGRAs (QuantiFERON Gold in-tube (QFN-GIT) and T-SPOT.TB) in immigrants aged =16 years to quantify test positivity, concordance and factors associated with positivity. Yields were computed at different incidence thresholds and the relative cost-effectiveness of screening was estimated using different latent TB infection (LTBI) screening modalities at varying incidence thresholds with or without port-of-arrival chest x-ray (CXR). Results 231 immigrants were included; median age 29 (IQR 24-37). TSTs were accepted by 80.9%, read in 93.5% and 30.3% were positive - QFN-GIT and TSPOT. TB positive in 16.6% and 22.5% respectively. Positive TSTs, QFN-GIT and T-SPOT.TB were independently associated with increasing TB incidence in immigrants' countries of origin (p=0.007, 0.007, 0.037 respectively). Implementing current guidance (threshold 40/100 000 per year) would identify 98-100% of LTBIs (depending on test) but entail testing 97-99% of the cohort; screening at 150/100 000 per year would identify 49-71% of LTBIs but only entail screening half the cohort. The two most cost-effective screening strategies were no port-of-entry chest radiography and screen with single-step QFN-GIT at 250/100 000 per year (incremental cost-effectiveness ratio (ICER)) £21 565.3/case averted); and no port-of-entry CXR and screen with single-step QFN-GIT at 150/100 000 per year (averted additional 7.8 TB cases; ICER £31 867.1/ case averted). Conclusions UK immigrant screening could costeffectively and safely eliminate mandatory CXR on arrival by emphasising systematic screening for LTBI with singlestep IGRA. Intermediate incidence thresholds balance the need to identify as many imported LTBIs as possible against limited service capacity. [ABSTRACT FROM AUTHOR]

Background Emerging evidence suggests that Mycobacterium tuberculosis (Mtb) lineage and host ethnicity can determine tuberculosis (TB) clinical disease patterns but their relative importance and interaction are unknown. Methods We evaluated prospectively collected TB surveillance and Mtb strain typing data in an ethnically heterogeneous UK population. Lineage assignment was denoted using 15-loci mycobacterial interspersed repetitive units containing variable numbers of tandem repeats (MIRU-VNTR) and MIRU-VNTRplus. Geographical and ethnic associations of the six global Mtb lineages were identified and the influence of lineage and demographic factors on clinical phenotype were assessed using multivariate logistic regression. Results Data were available for 1070 individuals with active TB which was pulmonary only, extrapulmonary only and concurrent pulmonary-extrapulmonary in 52.1%, 36.9% and 11.0% respectively. The most prevalent lineages were Euro-American (43.7%), East African Indian (30.2%), Indo-Oceanic (13.6%) and East Asian (12.2%) and were geo-ethnically restricted with, for example, Indian subcontinent ethnicity inversely associated with Euro-American lineage (OR 0.23; 95% CI 0.14 to 0.39) and positively associated with the East African-Indian lineage (OR 4.04; 95% CI 2.19 to 7.45). Disease phenotype was most strongly associated with ethnicity (OR for extrathoracic disease 21.14 (95% CI 6.08 to 73.48) for Indian subcontinent and 14.05 (3.97 to 49.65) for Afro-Caribbean), after adjusting for lineage. With East Asian lineage as the reference category, the Euro-American (OR 0.54; 95% CI 0.32 to 0.91) and East-African Indian (OR 0.50; 95% CI 0.29 to 0.86) lineages were negatively associated with extrathoracic disease, compared with pulmonary disease, after adjusting for ethnicity. Conclusions Ethnicity is a powerful determinant of clinical TB phenotype independently of mycobacterial lineage and the role of ethnicity-associated factors in pathogenesis warrants investigation. [ABSTRACT FROM AUTHOR]

The 2009/10 pandemic (p H1 N1) highlighted the need for vaccines conferring heterosubtypic immunity against antigenically shifted influenza strains. Although cross-reactive T cells are strong candidates for mediating heterosubtypic immunity, little is known about the population-level prevalence, frequency, and cytokine-secretion profile of heterosubtypic T cells to p H1 N1. To assess this, p H1 N1 sero-negative adults were recruited. Single-cell IFN-γ and IL-2 cytokine-secretion profiles to internal proteins of p H1 N1 or live virus were enumerated and characterised. Heterosubtypic T cells recognising p H1 N1 core proteins were widely prevalent, being detected in 90% (30 of 33) of p H1 N1-naïve individuals. Although the last exposure to influenza was greater than 6 months ago, the frequency and proportion of the IFN-γ-only-secreting T-cell subset was significantly higher than the IL-2-only-secreting subset. CD8+ IFN-γ-only-secreting heterosubtypic T cells were predominantly CCR7− CD45 RA− effector-memory phenotype, expressing the tissue-homing receptor CXCR3 and degranulation marker CD107. Receipt of the 2008-09 influenza vaccine did not alter the frequency of these heterosubtypic T cells, highlighting the inability of current vaccines to maintain this heterosubtypic T-cell pool. The surprisingly high prevalence of pre-existing circulating p H1 N1-specific CD8+ IFN-γ-only-secreting effector memory T cells with cytotoxic and lung-homing potential in p H1 N1-seronegative adults may partly explain the low case fatality rate despite high rates of infection of the pandemic in young adults. [ABSTRACT FROM AUTHOR]

In industrialized countries, tuberculosis (TB) cases are concentrated among immigrants and driven by reactivation of imported latent TB infection (LTBI). We examined mechanisms used to screen immigrants for TB and LTBI by sending an anonymous, 18-point questionnaire to 31 member countries of the Organisation for Economic Cooperation and Development. Twenty-nine (93.5%) of 31 responded; 25 (86.2%) screened immigrants for active TB. Fewer countries (16/29, 55.2%) screened for LTBI. Marked variations were observed in targeted populations for age (range <5 years of age to all age groups) and TB incidence in countries of origin of immigrants (>20 cases/100,000 population to >500 cases/100,000). LTBI screening was conducted in 11/16 countries by using the tuberculin skin test. Six countries used interferon-γ release assays, primarily to confirm positive tuberculin skin test results. Industrialized countries performed LTBI screening infrequently and policies varied widely. There is an urgent need to define the cost-effectiveness of LTBI screening strategies for immigrants. [ABSTRACT FROM AUTHOR]

A key challenge to greater progress in tuberculosis (TB) control is the reservoir of latent TB infection (LTBI), which represents a huge long-lived reservoir of potential TB disease. In parts of Africa, as many as 50% of 15-year-olds and 77%-89% of adults have evidence of LTBI. A second key challenge to TB control is the human immunodeficiency virus (HIV)-associated TB epidemic, and Africa alone accounts for one-quarter of the global burden of HIV-associated TB. HIV co-infection promotes both reactivation TB from LTBI and rapidly progressive primary TB following recent exposure to Mycobacterium tuberculosis. Preventing active TB and tackling latent infection in addition to the Directly Observed Treatment, Short-Course (DOTS) strategy could improve TB control in high-burden settings, especially where there is a high prevalence of HIV co-infection. Current strategies include intensified case finding (ICF), TB infection control, antiretroviral therapy (ART), and isoniazid preventive therapy (IPT). Although ART has been widely rolled out, ICF and IPT have not. A key factor limiting the rollout and effectiveness of IPT and ICF is the limitations of existing tools to both diagnose LTBI and identify those persons most at risk of progressing to active TB. In this review, we examine the obstacles and consider current progress toward the development of new tools to address this pressing global problem. [ABSTRACT FROM AUTHOR]