Publications by authors named "Ajit Lalvani"

121 Publications

Defining the Role of Cellular Immune Signatures in Diagnostic Evaluation of Suspected Tuberculosis.

J Infect Dis 2021 Jul 31. Epub 2021 Jul 31.

TB Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown.

Methods: Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry.

Results: All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA-CCR7-CD127- IFNγ -IL-2-TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90-97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects.

Conclusions: Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiab311DOI Listing
July 2021

A conceptual framework to accelerate the clinical impact of evolving research into long COVID.

Lancet Infect Dis 2021 06 22;21(6):756-757. Epub 2021 Apr 22.

NIHR Health Protection Research Unit in Respiratory Infections, National Heart and Lung Institute, Imperial College, London W2 1NY, UK. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(21)00136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062085PMC
June 2021

Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study.

Lancet Infect Dis 2021 03 25;21(3):366-375. Epub 2021 Jan 25.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

Background: Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.

Methods: The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.

Findings: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.

Interpretation: In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.

Funding: National Institute for Health Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(20)30928-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907671PMC
March 2021

CASPA (CArdiac Sarcoidosis in PApworth) improving the diagnosis of cardiac involvement in patients with pulmonary sarcoidosis: protocol for a prospective observational cohort study.

BMJ Open Respir Res 2020 10;7(1)

Interstitial Lung Disease Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK

Introduction: Sarcoidosis is a multisystem disease, predominantly affecting the lungs but can involve the heart, resulting in cardiac sarcoidosis (CS). Patients require MRI/Positron Emission Tomography (PET) scans for diagnosis. Echocardiography, ECG and Holter monitoring may be indicative but not diagnostic alone. Patients can present late with conduction defects, heart failure or sudden death. The CASPA (CArdiac Sarcoidosis in PApworth) study protocol aims to (1) use MRI to identify CS prevalence; (2) use speckle-tracking echocardiography, signal averaged ECG and Holter monitoring to look for diagnostic pathways; and (3) identify serum proteins which may be associated with CS.

Methods And Analysis: Participants with pulmonary sarcoidosis (and no known cardiac disease) from Royal Papworth Hospital will have the following: cardiac MRI with late gadolinium, two-dimensional transthoracic echocardiography with speckle tracking, signal averaged ECG and 24-hour Holter monitor. They will provide a serum sample for brain natriuretic peptide levels and proteomics by liquid chromatography coupled to high-resolution mass spectrometry. All data will be collected on OpenClinica platform and analysed approximately 6 months after final patient recruitment.

Ethics And Dissemination: The Camden & Kings Cross Research Ethics Committee approved the protocol (REC number: 17/LO/0667). Integrated Research Approval System (IRAS) 222 720. Dissemination of findings will be via conference presentations and submitted to peer-reviewed journals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjresp-2020-000608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549466PMC
October 2020

Telemedicine-enabled Accelerated Discharge of Patients Hospitalized with COVID-19 to Isolation in Repurposed Hotel Rooms.

Am J Respir Crit Care Med 2020 08;202(4):508-510

Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli-Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica del Sacro Cuore, Roma, Italy; and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202004-1238OEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427391PMC
August 2020

Removing the handle of the Broad Street pump: measures to slow the spread of covid-19 in primary care teams.

BMJ 2020 05 12;369:m1841. Epub 2020 May 12.

Imperial College London, St Mary's Campus, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m1841DOI Listing
May 2020

Quantitative IFN-γ Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis. A Prospective Cohort Study.

Am J Respir Crit Care Med 2020 04;201(8):984-991

Institute for Global Health.

Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. 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. Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by relinkage to national TB surveillance records (median follow-up 4.7 yr). 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 bacillus Calmette-Guérin [BCG] vaccination). For all tests, incidence rates and rate ratios increased with the magnitude of the test result ( < 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value 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 ≥5 mm vs. 4.3% for ≥15 mm). 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 ≥5 mm vs. 28.1% for ≥15 mm). Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201905-0969OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159430PMC
April 2020

Progress in interferon-gamma release assay development and applications: an unfolding story of translational research.

Ann Transl Med 2019 Jul;7(Suppl 3):S128

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2019.05.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685846PMC
July 2019

Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort.

J Infect Dis 2020 01;221(1):146-155

Institute for Global Health, University College London.

Background: BCG appears to reduce acquisition of Mycobacterium tuberculosis infection in children, measured using interferon-gamma release assays (IGRAs). We explored whether BCG vaccination continues to be associated with decreased prevalence of M. tuberculosis infection in adults.

Methods: We 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.

Results: Of 3453 recent tuberculosis contacts, 27.5% had LTBI. There was strong evidence of an association between BCG and LTBI (adjusted odds ratio = 0.70; 95% confidence interval, .56-.87; P = .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 nonvaccinated participants.

Conclusions: BCG is associated with lower prevalence of LTBI in adult contacts of tuberculosis. These results contribute to growing evidence that suggests BCG may protect against M. tuberculosis infection as well as disease. This has implications for immunization programs, vaccine development, and tuberculosis control efforts worldwide.

Clinical Trials Registration: NCT01162265.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiz430DOI Listing
January 2020

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 Infect Dis 2019 11 27;19(11):1191-1201. Epub 2019 Aug 27.

National Institute for Health Research Health Protection Research Unit in Respiratory Infections, National Heart and Lung Institute, Imperial College London, London, UK; Tuberculosis Unit, TARGET, National Infection Service, Public Health England, London, UK.

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, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001).

Interpretation: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants.

Funding: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(19)30260-9DOI Listing
November 2019

Understanding How BCG Vaccine Protects Against Mycobacterium tuberculosis Infection: Lessons From Household Contact Studies.

J Infect Dis 2020 03;221(8):1229-1231

Department of Medicine, School of Medicine, University of Washington, Seattle.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiz261DOI Listing
March 2020

Interferon gamma release assays for Diagnostic Evaluation of Active tuberculosis (IDEA): test accuracy study and economic evaluation.

Health Technol Assess 2019 05;23(23):1-152

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK.

Background: Interferon 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.

Objectives: To compare the diagnostic accuracy and cost-effectiveness of T-SPOT. (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.

Design: Prospective within-patient comparative diagnostic accuracy study.

Setting: Secondary care.

Participants: Adults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB.

Interventions: The index tests [T-SPOT. and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel 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 Measures: Sensitivity, 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.

Results: A 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. 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. was more sensitive than QFT-GIT (relative sensitivity 1.22, 95% CI 1.14 to 1.31;  < 0.001), but the specificities were similar (relative specificity 1.02, 95% CI 0.97 to 1.08;  = 0.3). For both IGRAs the sensitivity was lower and the specificity was higher for human immunodeficiency virus (HIV)-positive than for HIV-negative patients. The most promising novel antigen was Rv3615c. The added value of Rv3615c to T-SPOT. was a 9% (95% CI 5% to 12%) relative increase in sensitivity at the expense of specificity, which had a relative decrease of 7% (95% CI 4% to 10%). The use of current IGRA tests for ruling out active TB is unlikely to be considered cost-effective if a QALY was valued at £20,000 or £30,000. For T-SPOT., the probability of being cost-effective for a willingness to pay of £20,000/QALY was 26% and 21%, when patients with indeterminate test results were excluded or included, respectively. In comparison, the QFT-GIT probabilities were 8% and 6%. Although the use of IGRAs is cost saving, the health detriment is large owing to delay in diagnosing active TB, leading to prolonged illness. There was substantial between-patient variation in the tests used in the diagnostic pathway.

Limitations: The recruitment target for the HIV co-infected population was not achieved.

Conclusions: Although T-SPOT. was more sensitive than QFT-GIT for the diagnosis of active TB, the tests are insufficiently sensitive for ruling out active TB in routine clinical practice in the UK. Novel assays offer some promise.

Future Work: The novel assays require evaluation in distinct clinical settings and in immunosuppressed patient groups.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3310/hta23230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556820PMC
May 2019

Immunodiagnosis of active tuberculosis.

Expert Rev Respir Med 2019 06 28;13(6):521-532. Epub 2019 May 28.

a Tuberculosis Research Centre, National Heart and Lung Institute , Imperial College London , London , UK.

: 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 -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. : 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. : 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2019.1615888DOI Listing
June 2019

Predicting progression to active tuberculosis: A rate-limiting step on the path to elimination.

PLoS Med 2019 05 24;16(5):e1002814. Epub 2019 May 24.

Tuberculosis Research Centre, National Heart and Lung Institute, St Mary's Campus, Imperial College London, London, United Kingdom.

In a Perspective, Ajit Lalvani and colleagues discuss new approaches to predicting progression to active tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1002814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534286PMC
May 2019

CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

PLoS One 2019 23;14(5):e0217091. Epub 2019 May 23.

Geisel School of Medicine, Hanover, NH, United States of America.

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+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters.

Trial Registration: ClinicalTrials.gov NCT02063555.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532882PMC
January 2020

Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study.

Lancet Infect Dis 2019 02 14;19(2):193-202. Epub 2019 Jan 14.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK. Electronic address:

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 included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, 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 negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis.

Funding: National Institute for Health Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(18)30613-3DOI Listing
February 2019

Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study.

Health Technol Assess 2018 10;22(56):1-96

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK.

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 TST (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 TST [positive if induration is ≥ 6 mm without prior bacillus Calmette-Guérin (BCG) alone, T-SPOT.TB (Oxford Immunotec Ltd, Oxford, UK), TST + T-SPOT.TB, TST + IGRA and the three combination strategies including TST were significantly superior predictors of progression. Compared with the T-SPOT.TB test alone, TST + T-SPOT.TB, TST + QuantiFERON TB Gold In-Tube (QFT-GIT; QIAGEN GmbH, Hilden, Germany) and TST + IGRA were significantly superior predictors of progression and, compared with QFT-GIT alone, T-SPOT.TB, TST + T-SPOT.TB, TST + QFT-GIT, TST + IGRA, TST + T-SPOT.TB, TST + QFT-GIT and TST + IGRA were significantly superior predictors of progression. When evaluating the negative predictive performance of tests and strategies, negative results for TST + QFT-GIT were significantly poorer predictors of non-progression than negative results for TST, T-SPOT.TB and TST + IGRA. The most cost-effective LTBI testing strategies are the dual-testing strategies. The cost and QALY differences between the LTBI testing strategies were small; in particular, QFT-GIT, TST + T-SPOT.TB and TST + QFT-GIT had very similar incremental net benefit estimates.

Conclusion: This study found modest differences between tests, or combinations of tests, in identifying individuals who would go on to develop active TB. However, a two-step approach that combined TST with an IGRA was the most cost-effective testing option.

Implications For Practice And Future Research: The two-step TST strategy, which stratified the TST by prior BCG vaccination followed by an IGRA, was the most cost-effective approach. The limited ability of current tests to predict who will progress limits the clinical utility of tests. The implications of these results for the NHS England/Public Health England national TB screening programme for migrants should be investigated.

Study Registration: This study is registered as NCT01162265.

Funding: The National Institute for Health Research Health Technology Assessment programme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3310/hta22560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216045PMC
October 2018

Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.

Lancet Infect Dis 2018 10 30;18(10):1077-1087. Epub 2018 Aug 30.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK.

Background: Tackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups-ie, people in recent contact with active tuberculosis cases and from high-burden countries.

Method: In this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from-or who frequently travelled to-a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete.

Findings: Between May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6-2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3-2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9-17·4), TST-15 (11·1 per 1000 person-years, 8·3-14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4-13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68-2·34; p<0·0001). However, TST-5 identified a higher proportion of participants who progressed to active tuberculosis (64 [83%] of 77 tested) than all other tests and TST thresholds (≤75%).

Interpretation: IGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk.

Funding: National Institute for Health Research Health Technology Assessment Programme 08-68-01.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(18)30355-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192014PMC
October 2018

Diabetes mellitus and latent tuberculosis infection: baseline analysis of a large UK cohort.

Thorax 2019 01 15;74(1):91-94. Epub 2018 May 15.

Institute for Global Health, University College London, London, UK.

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). TRIAL REGISTRATION NUMBER: PREDICT is registered on clinicaltrials.gov (NCT01162265).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2017-211124DOI Listing
January 2019

Can defective interfering RNAs affect the live attenuated influenza vaccine? - Authors' reply.

Lancet Infect Dis 2017 12;17(12):1235-1236

Department of Medicine, Imperial College, London, UK; NIHR Health Protection Research Unit in Respiratory Infections, Imperial College, London W2 1PG. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(17)30638-2DOI Listing
December 2017

Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways.

PLoS Pathog 2017 Sep 1;13(9):e1006577. Epub 2017 Sep 1.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, St Mary's Campus, London, United Kingdom.

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-myeloid 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1006577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605092PMC
September 2017

Urgent challenges in implementing live attenuated influenza vaccine.

Lancet Infect Dis 2018 01 2;18(1):e25-e32. Epub 2017 Aug 2.

Department of Medicine, Imperial College, London, UK; NIHR Health Protection Research Unit in Respiratory Infections, Imperial College, London, UK. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(17)30360-2DOI Listing
January 2018

Stratification of Latent Mycobacterium tuberculosis Infection by Cellular Immune Profiling.

J Infect Dis 2017 05;215(9):1480-1487

Tuberculosis Research Centre, Respiratory Medicine, National Heart and Lung Institute, Imperial College London, St Mary's Campus.

Background: Recently acquired and remotely acquired latent Mycobacterium tuberculosis infection (LTBI) are clinically indistinguishable, yet recent acquisition of infection is the greatest risk factor for progression to tuberculosis in immunocompetent individuals. We aimed to evaluate the ability of cellular immune signatures that differ between active tuberculosis and LTBI to distinguish recently from remotely acquired LTBI.

Methods: Fifty-nine individuals were recruited: 20 had active tuberculosis, 19 had recently acquired LTBI, and 20 had remotely acquired LTBI. The proportion of mycobacteria-specific CD4+ T cells secreting tumor necrosis factor α (TNF-α) but not interferon γ or interleukin 2 which had a differentiated effector phenotype (TNF-α-only TEFF), and the level of CD27 expression on IFN-γ-producing CD4+ T cells, were detected by flow cytometry.

Results: The TNF-α-only TEFF signature was significantly higher in the group with recently acquired LTBI, compared with the group with remotely acquired LTBI (P < .0001), and it discriminated between these groups with high sensitivity and specificity, with an area under the curve of 0.87. Two signatures incorporating CD27 expression did not distinguish between recently and remotely acquired LTBI. Interestingly, the TNF-α-only TEFF signature in participants with recently acquired LTBI was more similar to that in participants with tuberculosis than that in participants with remotely acquired LTBI, suggesting that recently acquired LTBI is immunologically more similar to tuberculosis than remotely acquired LTBI.

Conclusions: These findings reveal marked biological heterogeneity underlying the clinically homogeneous phenotype of LTBI, providing a rationale for immunological risk stratification to improve targeting of LTBI treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jix107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451604PMC
May 2017

Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis.

PLoS One 2017 23;12(1):e0170285. Epub 2017 Jan 23.

Tuberculosis Research Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4-6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.

Methods: Kv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay.

Results: We observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p<0.0001). This finding was also observed in vimentin stimulation of sarcoidosis PBMCs compared to PBMCs from healthy controls (IFN-γ: 396.6 pg/mL vs. 0.1 pg/mL, p = 0.014; TNF-α: 1139 pg/mL vs 42.29 pg/mL, p = 0.027). No difference was found in cytokine secretion between sarcoidosis and control PBMCs when stimulated with either tubulin or alpha-actinin-4.

Conclusions: Stimulation with both Kveim reagent and vimentin induces a specific pro-inflammatory cytokine secretion from sarcoidosis PBMCs. Further investigation of cellular immune responses to Kveim-specific proteins may identify novel biomarkers to assist the diagnosis of sarcoidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170285PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256960PMC
August 2017

Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

PLoS One 2016 16;11(6):e0157887. Epub 2016 Jun 16.

National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157887PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911124PMC
July 2017

PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection.

PLoS One 2016 12;11(1):e0146905. Epub 2016 Jan 12.

Tuberculosis Research Centre, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146905PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710462PMC
July 2016

Differences in antigen-specific CD4+ responses to opportunistic infections in HIV infection.

Immun Inflamm Dis 2015 Sep 29;3(3):141-53. Epub 2015 Apr 29.

Tuberculosis Research Centre Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London London, UK.

HIV-infected individuals with severe immunodeficiency are at risk of opportunistic infection (OI). Tuberculosis (TB) may occur without substantial immune suppression suggesting an early and sustained adverse impact of HIV on Mycobacterium tuberculosis (MTB)-specific cell mediated immunity (CMI). This prospective observational cohort study aimed to observe differences in OI-specific and MTB-specific CMI that might underlie this. Using polychromatic flow cytometry, we compared CD4+ responses to MTB, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Candida albicans in individuals with and without HIV infection. MTB-specific CD4+ T-cells were more polyfunctional than virus specific (CMV/EBV) CD4+ T-cells which predominantly secreted IFN-gamma (IFN-γ) only. There was a reduced frequency of IFN-γ and IL-2 (IL-2)-dual-MTB-specific cells in HIV-infected individuals, which was not apparent for the other pathogens. MTB-specific cells were less differentiated especially compared with CMV-specific cells. CD127 expression was relatively less frequent on MTB-specific cells in HIV co-infection. MTB-specific CD4+ T-cells PD-1 expression was infrequent in contrast to EBV-specific CD4+ T-cells. The variation in the inherent quality of these CD4+ T-cell responses and impact of HIV co-infection may contribute to the timing of co-infectious diseases in HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/iid3.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578516PMC
September 2015
-->