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de Lusignan S, Carlyon T, Lalvani A, 2020, Removing the handle of the Broad Street pump: measures to slow the spread of covid-19 in primary care teams., BMJ, Vol: 369
Lalvani A, Seshadri C, 2020, Understanding how BCG vaccine protects against Mycobacterium tuberculosis infection: Lessons from household contact studies, Journal of Infectious Diseases, Vol: 221, Pages: 1229-1231, ISSN: 0022-1899
Katelaris AL, Jackson C, Southern J, et al., 2020, Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: a cross-sectional analysis of a UK-based cohort, The Journal of Infectious Diseases, Vol: 221, Pages: 146-155, ISSN: 0022-1899
BackgroundBCG appears to reduce acquisition of Mycobacterium tuberculosis (Mtb) infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of Mtb infection in adults.MethodsWe conducted a cross-sectional analysis of data from adult contacts of tuberculosis cases participating in a UK cohort study. Vaccine effectiveness (VE) of BCG, ascertained based on presence of a scar or vaccination history, against latent tuberculosis infection (LTBI), measured via IGRA, was assessed using multivariable logistic regression. The effects of age at BCG and time since vaccination were also explored.ResultsOf 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (aOR=0.70, 95% CI 0.56-0.87, p=0.0017) yielding a VE of 30%. VE declined with time since vaccination, but there was evidence that LTBI prevalence was lower amongst vaccinated individuals even >20 years after vaccination, compared with non-vaccinated participants.ConclusionBCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against Mtb infection as well as disease. This has implications for immunisation programmes, vaccine development and tuberculosis control efforts worldwide.
Gupta RK, Lipman M, Jackson C, et al., 2019, Quantitative interferon gamma release assay and tuberculin skin test Results to predict incident tuberculosis: a prospective cohort study., American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 984-991, ISSN: 1073-449X
RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p<0.0001). Over three years' follow-up, there was a modest increase in positive predictive value (PPV) with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/mL vs. 3.6% for ≥4.00 IU/mL; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5mm vs. 4.3% for ≥15mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/mL vs. 23.2% for ≥4.00 IU/mL; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5mm vs. 28.1% for ≥15mm). CONCLUSIONS: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB and TST modestly increases PPV for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Berrocal-Almanza LC, Harris R, Lalor MK, et al., 2019, Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study., Lancet Infectious Diseases, Vol: 19, Pages: 1191-1201, ISSN: 1473-3099
BACKGROUND: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population. METHODS: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System. FINDINGS: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, an
Gupta R, Lipman M, Jackson C, et al., 2019, Do higher quantitative interferon gamma release assay or tuberculin skin test results help to predict incident tuberculosis? Data from the UK PREDICT study, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Yang Y, Walker TM, Walker AS, et al., 2019, DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis, Bioinformatics, Vol: 35, Pages: 3240-3249, ISSN: 1367-4803
MotivationResistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages.ResultsWe used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data. The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs [i.e. isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)], multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. t-SNE visualization shows that DeepAMR_cluster captures lineage-related clusters in the latent space.Availability and implementationThe details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php.
Lalvani A, Whitworth HS, 2019, Progress in interferon-gamma release assay development and applications: an unfolding story of translational research, ANNALS OF TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 2305-5839
Introduction: There is an unmet clinical need for improved diagnostic tests for active tuberculosis (TB) to provide high sensitivity for all cases, accelerate time to diagnosis and ensure timely and appropriate treatment. Whilst the measurement of M.tb-specific immune responses is widely used for detecting infection in the absence of TB symptoms (i.e. latent TB infection), there is currently no role for immunodiagnostics in active TB disease. This is primarily due to insufficient sensitivity, and an inability to discriminate between active disease and controlled, latent TB infection. Areas covered: In this review, we focus on recent developments in the use of immune-based tests to provide a point of care test for the rule-in or rule-out of active TB. Expert opinion: Recent studies have demonstrated that second-generation IGRAs have the potential to rule-out active TB, particularly in low burden settings. Newer technological platforms, including systems serology and flow cytometry, offer the means to measure specific M.tb specific immune signatures which have been shown to have a high level of accuracy for active TB. However, it is now crucial that new and promising test undergo validation in clinically relevant cohorts which include the full spectrum of TB patients and differential diagnoses.
Masonou T, Hokey DA, Lahey T, et al., 2019, CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial, PLoS ONE, Vol: 14, ISSN: 1932-6203
BACKGROUND: DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo. METHODS: We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining. RESULTS: DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses. CONCLUSION: DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ c
Lalvani A, Berrocal Almanza L, 2019, Engaging with civil society to improve access to LTBI screening for new-entrant migrants in England: a qualitative study, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, Vol: 23, Pages: 563-570, ISSN: 1027-3719
Setting The LTBI programme offers testing and treatment to new entrant migrants from high incidence countries in England. However, the rates of LTBI testing, treatment acceptance and completion are suboptimal and appropriate access must be improved. Objective: To gain insights from the community, community-based organisations (CBOs), and public sector stakeholders on interventions that facilitate collaboration to improve health care outreach and delivery. Design Three stakeholder meetings and five focus group discussions were held using thematic analysis to identify themes arising from the participants’ perspectives. Results Four overarching themes emerged from the discussions. These were capacity, collaboration, culture and trust. These highlighted the complementary skills sets different sectors bring to collaboration, as well as the barriers that need surmounting.Stigma could be reduced by making LTBI testing routine, and community members could act as champions for health promotion raising awareness on LTBI testing, and providing a bridge between communities and primary care services. Conclusion Public service providers, community members and CBOs have a willingness to collaborate to support primary care delivery of testing for LTBI and other communicable and non-communicable diseases. Policy and commissioning support are needed to facilitate such workings.
Takwoingi Y, Whitworth H, Rees-Roberts M, et al., 2019, Interferon gamma release assays for diagnostic evaluation of active tuberculosis (IDEA): test accuracy study and economic evaluation, Health Technology Assessment, Vol: 23, ISSN: 1366-5278
BackgroundInterferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice.ObjectivesTo compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB® (Oxford Immunotec, Abingdon, UK) and QuantiFERON® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs.DesignProspective within-patient comparative diagnostic accuracy study.SettingSecondary care.ParticipantsAdults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB.InterventionsThe index tests [T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results.Main outcome measuresSensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test.ResultsA total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT.TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT.TB was mor
Lalvani A, Berrocal-Almanza LC, Halliday A, 2019, Predicting progression to active tuberculosis: a rate-limiting step on the path to elimination, PLoS Medicine, Vol: 16, ISSN: 1549-1277
In a Perspective, Ajit Lalvani and colleagues discuss new approaches to predicting progression to active tuberculosis.
Whitworth HS, Badhan A, Boakye AA, et al., 2019, Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study, Lancet Infectious Diseases, Vol: 19, Pages: 193-202, ISSN: 1473-3099
BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were eligible and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negati
Halliday A, Jain P, Hoang L, et al., Validation of new technologies for the diagnostic evaluation of active tuberculosis (VANTDET), Efficacy and Mechanism Evaluation, ISSN: 2050-4365
Background: Tuberculosis (TB) is a devastating disease for which new diagnostic tests are desperately needed. Objective: To validate promising new technologies (namely whole blood transcriptomics, proteomics, flow cytometry and qRT-PCR) and existing signatures for detection of active TB in samples obtained from individuals suspected of active TB. Design: Four sub-studies, each of which used the samples from biobank collected as part of the IDEA study, which was a prospective cohort of patients recruited with suspected TB. Setting: secondary care Participants: Adults (aged ≥ 16 years old) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB. Interventions: New tests using either: genome-wide gene expression microarray (transcriptomics); SELDI TOF/ LC-MS (proteomics), flow cytometry, qRT-PCR. Main outcome measures: Area under the curve (AUC), sensitivity and specificity, were calculated to determine diagnostic accuracy. Positive and negative predictive values were calculated in some cases. A decision tree model was developed to calculate the incremental costs and quality-adjusted life-years (QALYs) of changing from current practice to using the novels tests. Results: The project and 4 sub-studies which assessed the previous published signatures measured using each of the new technologies, and a health economic analysis where the best performing tests were evaluated for cost effectiveness. The diagnostic accuracy of the transcriptomic tests ranged from AUC=0.81-0.84 for detecting all TB in our cohort. The performance for detecting culture confirmed TB or pulmonary TB (PTB) was better than for highly probable TB or extrapulmonary TB (EPTB) respectively, but not high enough to be clinically useful. None of the previously described serum proteomic signatures for active TB provided good diagnostic accuracy, not did the candidate rule-out tests. Four of six previously described cell
Southern J, Sridhar S, Tsou C-Y, et al., 2019, Discordance in latent tuberculosis (TB) test results in patients with end-stage renal disease, Public Health, Vol: 166, Pages: 34-39, ISSN: 0033-3506
ObjectivesThis natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up.Study designClose contacts of people with sputum smear–positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for ≥8 h.MethodsPatients were informed and invited for screening 8–10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON®-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT®-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing.ResultsOf 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease.ConclusionThis study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy.
Drobniewski FA, jackson C, southern J, et al., 2018, Diabetes mellitus and latent tuberculosis infection: baseline analysis of a large UK cohort, Thorax, Vol: 74, Pages: 91-94, ISSN: 1468-3296
We conducted a cross-sectional analysis of baseline data from a UK cohort study which enrolled participants at risk of latent tuberculosis infection (LTBI, defined as a positive result for either of the two interferon gamma release assays). Binomial regression with a log link was used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the relationship between diabetes mellitus (DM) and LTBI. Adjusted for age, sex, ethnicity, body mass index and the presence of other immunocompromising conditions, DM was associated with a 15% higher prevalence of LTBI (adjusted PR=1.15, 95% CI 1.02 to 1.30, p=0.025).
Whitworth HS, Badhan A, Boakye AA, et al., An observational cohort study to evaluate the clinical utilty of current and second-generation interferon-gamma release-assays in diagnostic evaluation of tuberculosis, Lancet Infectious Diseases, ISSN: 1473-3099
BackgroundThe role of interferon-gamma release assays (IGRAs) in diagnosis of active tuberculosis (TB) is unclear, yet they are commonly used in low-TB-incidence countries. This study sought to resolve this clinical uncertainty by determining the diagnostic accuracy and role of current and second-generation IGRAs in the diagnostic assessment of suspected TB in a low-incidence setting. MethodsThis was a prospective cohort study of 1,060 adults with suspected TB, conducted in routine secondary care in England. Patients were tested for M. tuberculosis (Mtb) infection at baseline using current and second-generation IGRAs, the latter incorporating novel Mtb antigens, and followed up for 6-12m to establish definitive diagnoses. Sensitivity, specificity and positive and negative likelihood ratios (LRs) and predictive values (PVs) of the tests for TB were determined.FindingsTB was diagnosed in 363 (43%) of 845 patients included in analyses. Sensitivity of T-SPOT.TB was 81.4% (95%CI 76.6-85.3%), higher than Quantiferon-Gold In-Tube at 67.3% (95%CI 62.0-72.1%). Second-generation IGRA had higher sensitivity than current tests, at 94.0% (95%CI 90.0–96.4%) for culture-confirmed TB and 89.2% (95%CI 85.2–92.2%) when including highly-probable TB, giving a negative LR for all TB of 0.13 (95%CI 0.10-0.19). Specificity ranged from 86.2% (95%CI 82.3-89.4%) for T-SPOT.TB to 80.0% (95%CI 75.6-83.8%) for second-generation IGRA.InterpretationCurrently-available IGRAs lack sufficient accuracy for diagnostic evaluation of suspected TB. Second-generation tests, however, may have sufficiently high sensitivity, low negative LR and correspondingly high negative PV in low-incidence settings to facilitate prompt rule-out of TB.
Abubakar I, Drobniewski FA, Southern J, et al., 2018, Prognostic value of interferon gamma release assays and tuberculin skin test in predicting the development of active tuberculosis: The UK PREDICT TB Cohort Study, Lancet Infectious Diseases, Vol: 18, Pages: 1077-1087, ISSN: 1473-3099
BackgroundTackling tuberculosis (TB) requires testing and treatment latenttuberculosis in high-risk groups. The aim of this study was to estimatethe predictive values of the tuberculin skin test (TST) and interferongamma release assays (IGRAs) for development of active TB .MethodA cohort of migrants and contacts of active TB patients wereprospectively recruited in clinics, the community and primary care. Eachparticipant received three tests (Quantiferon Gold In-Tube [QFT-GIT], TSPOT.TBand TST). A positive TST was reported using three thresholds: 5mm(TST5), 10mm (TST10), and 5mm in BCG-naïve or 15mm in vaccinated (TST15).Participants were followed for a median of 2.9 years. Incident TB caseswere identified by national TB databases, telephone interview, andmedical note review. Outcomes were ratio of incidence rate ratios andpredictive values for TB development.FindingsNinety-seven (1.0%) of 9,610 participants developed active TB (77 of6,380 with results for all 3 tests). In all tests, TB incidence was verylow in test-negatives (1.2-1.6 per 1000 per year). Incidence rates intest-positives were highest for T-SPOT.TB (13.2, 95%CI: (9.9,17.4)),TST15 (11.1 (8.3,14.6)) and QFT-GIT (10.1 (7.4,13.4)). Positive resultsfor these tests were significantly more predictive of progression than TST10 and TST5. However, TST5 identified a higher proportion ofprogressors than TST10, TST15, T-SPOT.TB and QFT-GIT.Interpretation IGRA-based or TST15 strategies appear most suited forscreening. Although TST5 and TST10 detect more TB cases, they alsoclassify more individuals who are unlikely to develop TB as testpositive.Funding source: National Institute for Health Research Health TechnologyAssessment Programme 08-68-01.
Abubakar I, Lalvani A, Southern J, et al., 2018, Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study, Health Technology Assessment, Vol: 22, Pages: 1-95, ISSN: 1366-5278
BACKGROUND: Despite a recent decline in the annual incidence of tuberculosis (TB) in the UK, rates remain higher than in most Western European countries. The detection and treatment of latent TB infection (LTBI) is an essential component of the UK TB control programme. OBJECTIVES: To assess the prognostic value and cost-effectiveness of the current two interferon gamma release assays (IGRAs) compared with the standard tuberculin skin test (TST) for predicting active TB among untreated individuals at increased risk of TB: (1) contacts of active TB cases and (2) new entrants to the UK from high-TB-burden countries. DESIGN: A prospective cohort study and economic analysis. PARTICIPANTS AND SETTING: Participants were recruited in TB clinics, general practices and community settings. Contacts of active TB cases and migrants who were born in high-TB-burden countries arriving in the UK were eligible to take part if they were aged ≥ 16 years. MAIN OUTCOME MEASURES: Outcomes include incidence rate ratios comparing the incidence of active TB in those participants with a positive test result and those with a negative test result for each assay, and combination of tests and the cost per quality-adjusted life-year (QALY) for each screening strategy. RESULTS: A total of 10,045 participants were recruited between May 2010 and July 2015. Among 9610 evaluable participants, 97 (1.0%) developed active TB. For the primary analysis, all test data were available for 6380 participants, with 77 participants developing active TB. A positive result for TSTa (positive if induration is ≥ 5 mm) was a significantly poorer predictor of progression to active TB than a positive result for any of the other tests. Compared with TSTb [positive if induration is ≥ 6 mm without prior bacillus Calmette-Guérin (BCG) alone, T-SPOT®.TB (Oxford Immunotec Ltd, Oxford, UK), TSTa + T-SPOT.TB, TSTa + IGRA and the three combination
Pareek M, Pollock KM, Lalvani A, 2018, Diagnosis in suspected infective disease, Diagnosis and Treatment in Internal Medicine, Editors: Davey, Sprigings, ISBN: 9780199568741
Uniquely, this new book shows readers how to turn symptoms into a list of diagnoses ordered by probability - a differential diagnosis.
Pollock KM, Lalvani A, 2018, Defences against infection, Diagnosis and Treatment in Internal Medicine, Editors: Davey, Sprigings, ISBN: 9780199568741
Uniquely, this new book shows readers how to turn symptoms into a list of diagnoses ordered by probability - a differential diagnosis.
Singanayagam A, Zambon M, Lalvani A, et al., 2017, Can defective interfering RNAs affect the live attenuated influenza vaccine? Reply, Lancet Infectious Diseases, Vol: 17, Pages: 1235-1236, ISSN: 1473-3099
Jarvis H, Thwaites R, Tunstall T, et al., 2017, Isolated mediastinal lymph node tuberculosis (IMLNTB) is characterised by elevation in systemic and bronchial IL-12 pathway mediators compared to pulmonary TB
Abubakar I, Drobniewski F, Southern J, et al., 2017, PROGNOSTIC VALUE OF INTERFERON GAMMA RELEASE ASSAYS AND TUBERCULIN SKIN TEST IN PREDICTING THE DEVELOPMENT OF ACTIVE TUBERCULOSIS: THE UK PREDICT TB COHORT STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A22-A22, ISSN: 0040-6376
Berrocal-Almanza LC, OConnell AM, Muzyamba MC, et al., 2017, IS THE NEW NATIONAL LTBI SCREENING PROGRAM REACHING THE TARGET POPULATION? A POPULATION-BASED COHORT STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A21-A22, ISSN: 0040-6376
Reuschl AK, Edwards MR, Parker R, et al., 2017, Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways, PLoS Pathogens, Vol: 13, ISSN: 1553-7366
Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myleoid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.
Singanayagam A, Zambon M, Lalvani A, et al., 2017, Urgent challenges in implementing live attenuated influenza vaccine., Lancet Infectious Diseases, Vol: 18, Pages: e25-e32, ISSN: 1473-3099
Conflicting reports have emerged about the effectiveness of the live attenuated influenza vaccine. The live attenuated influenza vaccine appears to protect particularly poorly against currently circulating H1N1 viruses that are derived from the 2009 pandemic H1N1 viruses. During the 2015-16 influenza season, when pandemic H1N1 was the predominant virus, studies from the USA reported a complete lack of effectiveness of the live vaccine in children. This finding led to a crucial decision in the USA to recommend that the live vaccine not be used in 2016-17 and to switch to the inactivated influenza vaccine. Other countries, including the UK, Canada, and Finland, however, have continued to recommend the use of the live vaccine. This policy divergence and uncertainty has far reaching implications for the entire global community, given the importance of the production capabilities of the live attenuated influenza vaccine for pandemic preparedness. In this Personal View, we discuss possible explanations for the observed reduced effectiveness of the live attenuated influenza vaccine and highlight the underpinning scientific questions. Further research to understand the reasons for these observations is essential to enable informed public health policy and commercial decisions about vaccine production and development in coming years.
Shaikh N, Gupte A, Dharmshale S, et al., 2017, Novel interferon-gamma assays for diagnosing tuberculosis in young children in India., Int J Tuberc Lung Dis, Vol: 21, Pages: 412-419
SETTING: The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are used as supportive evidence to diagnose active tuberculosis (TB). Novel IGRAs could improve diagnosis, but data are lacking in young children. DESIGN: Children (age 5 years) with suspected TB were prospectively screened at a tertiary hospital in Pune, India; the children underwent TST, and standard (early secretory antigenic target 6 and culture filtrate protein 10) and enhanced (five additional novel antigens) enzyme-linked immunospot (ELISpot) assays. RESULTS: Of 313 children (median age 30 months) enrolled, 92% had received bacille Calmette-Guérin vaccination, 53% were malnourished and 9% were coinfected with the human immunodeficiency virus (HIV); 48 (15%) had TB, 128 (41%) did not, and TB could not be ruled out in 137 (44%). The sensitivity of enhanced (45%) and standard (42%) ELISpot assays for diagnosing TB was better than that of TST (20%) (P 0.03); however, enhanced ELISpot was not more sensitive than the standard ELISpot assay (P = 0.50). The specificity of enhanced ELISpot, standard ELISpot and TST was respectively 82% (95%CI 74-89), 88% (95%CI 81-94) and 98% (95%CI 93-100). Rv3879c and Rv3615c, previously reported to be promising antigens, failed to improve the diagnostic performance of the ELISpot assay. CONCLUSION: The TST and the standard and novel ELISpot assays performed poorly in diagnosing active TB among young children in India.
Halliday A, Whitworth H, Hermagild Kottoor S, et al., 2017, Stratification of latent tuberculosis infection by cellular immune profiling., Journal of Infectious Diseases, Vol: 215, Pages: 1480-1487, ISSN: 1537-6613
Background: Recently-acquired and remotely-acquired latent tuberculosis (TB) infection (LTBI) are clinically indistinguishable, yet recent acquisition of infection is the greatest risk factor for progression to active TB (ATB) in immunocompetent individuals. We aimed to evaluate the ability of cellular immune signatures which differ between ATB and LTBI, to distinguish recently from remotely acquired LTBI. Methods: Fifty-nine individuals were recruited: ATB (n=20); recent LTBI (n=19); remote LTBI (n=20). The proportion of mycobacteria-specific TNFα+IFNγ-IL-2-- secreting CD4+ T cells with a differentiated effector phenotype (TNFα-only TEFF), and the level of CD27 expression on IFNγ-producing CD4+ T cells, were detected by flow-cytometry. Results: The TNFα-only TEFF signature was significantly higher in recent compared to remote LTBI (p<0.0001), and discriminated between these groups with high sensitivity and specificity, with an area under the curve (AUC) = 0.87. Two signatures incorporating CD27 expression did not distinguish between recent and remote LTBI. Interestingly, the TNFα-only TEFF signature in recent LTBI was more similar to ATB than remote LTBI, suggesting that recent LTBI is immunologically more similar to ATB than remote LTBI. Conclusions: These findings reveal marked biological heterogeneity underlying the clinically homogeneous phenotype of LTBI, providing a rationale for immunological risk-stratification for improved targeting of LTBI treatment.
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