Browsing by Author "Jenum, Synne"
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- ItemCCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries(ElsevierLtd, 2021-10) Chendi, Bih H.; Tveiten, Hallgeir; Snyders, Candice I.; Tonby, Kristian; Jenum, Synne; Nielsen, Susanne Dam; Hove-Skovsgaard, Malene; Walzl, Gerhard; Chegou, Novel N.; Dyrhol-Riise, Anne MObjectives: To evaluate the performance of selected host immunological biomarkers in differentiating tu- berculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries. Design: Participants with TB disease ( N = 85) and LTBI ( N = 150) were recruited from prospective co- horts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status. Results: Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1 + RANTES + CRP + MIP-1 α) derived from a training set ( n = 155) differentiated TB disease from LTBI in the test set ( n = 67) with a sensitivity of 56.0% (95% CI, 34.9–75.6) and a specificity of 85.7% (95% CI, 71.5–94.6). A 5-marker signature derived from the HIV uninfected group (CCL1 + RANTES + MIP- 1 α+ procalcitonin + IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a speci- ficity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1 + TNF- α) identified in HIV- infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respec- tively in the test set. Conclusions: Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration.
- ItemCombining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes(Springer Nature, 2020) Sivakumaran, Dhanasekaran; Jenum, Synne; Vaz, Mario; Selvam, Sumithra; Ottenhoff, Tom H. M.; Haks, Marielle C.; Malherbe, Stephanus T.; Doherty, Mark; Ritz, Christian; Grewal, Harleen M. S.Tuberculosis (TB) is a global health concern. Treatment is prolonged, and patients on anti-TB therapy (ATT) often experience treatment failure for various reasons. There is an urgent need to identify signatures for early detection of failure and initiation of a treatment switch.We investigated how gene biomarkers and/or basic patient characteristics could be used to define signatures for treatment outcomes in Indian adult pulmonary-TB patients treated with standard ATT. Using blood samples at baseline, a 12-gene signature combined with information on gender, previously-diagnosed TB, severe thinness, smoking and alcohol consumption was highly predictive of treatment failure at 6 months. Likewise a 4-protein biomarker signature combined with the same patient characteristics was almost as highly predictive of treatment failure. Combining biomarkers and basic patient characteristics may be useful for predicting and hence identification of treatment failure at an early stage of TB therapy.
- ItemEffect of non-tuberculous mycobacteria on host biomarkers potentially relevant for tuberculosis management(PLoS, 2014-10-16) Dhanasekaran, S.; Jenum, Synne; Stavrum, Ruth; Wiker, Harald G.; Kenneth, John; Vaz, Mario; Doherty, T. Mark; Grewal, Harleen M. S.; Hesseling, A. C.Background: Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens. Methodology and Principle Findings: The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged , 3 years evaluated for TB using dual-colour-Reverse-Transcriptase-Multiple-Ligation-dependent-Probe-Amplification (dcRTMLPA) and Bio-Plex assays. The children were classified based on clinical examination, chest X-rays and mycobacterial culture reports as either: 1) TB disease, 2) NTM present and 3) controls. The study shows a down-regulation of RAB33A (p, 0.001) and up-regulation of TGFb1, IL-2 and IL-6 (all p,0.05) in children with TB disease, and that RAB33A, TGFBR2 and IL-10 (all p,0.05) were differentially expressed in children with NTM present when compared to children that were culture negative for MTB and NTM (controls). Conclusions and Significance: Carriage of NTM may reduce the specificity of future diagnostic and predictive immune biomarkers relevant to TB management.
- ItemThe frequencies of IFNγ+IL2+TNFα+ PPD-specific CD4+CD45RO+ T-cells correlate with the magnitude of the QuantiFERON® Gold In-Tube response in a prospective study of healthy Indian adolescents(PLoS, 2014-07-03) Jenum, Synne; Grewal, Harleen M. S.; Hokey, David A.; Kenneth, John; Vaz, Mario; Doherty, Timothy Mark; Jahnsen, Frode Lars; Hesseling, A. C.Background: QuantiFERON-TB Gold In-Tube (QFT) is an IFNγ-release assay used in the diagnosis of Mycobacterium tuberculosis (MTB) infection. The risk of TB progression increases with the magnitude of the MTB-specific IFNγ-response. QFT reversion, also associated with low Tuberculin Skin Test responses, may therefore represent a transient immune response with control of M. tuberculosis infection. However, studies at the single cell level have suggested that the quality (polyfunctionality) of the T-cell response is more important than the quantity of cytokines produced. Objective: To explore the quality and/or magnitude of mycobacteria-specific T-cell responses associated with QFT reversion and persistent QFT-positivity. Methods: Multi-color flowcytometry on prospectively collected peripheral blood mononuclear cells was applied to assess mycobacteria-specific T-cell responses in 42 QFT positive Indian adolescents of whom 21 became QFT negative (reverters) within one year. Ten QFT consistent negatives were also included as controls. Results: There was no difference in the qualitative PPD-specific CD4+ T-cell response between QFT consistent positives and reverters. However, compared with QFT consistent positives, reverters displayed lower absolute frequencies of polyfunctional (IFNγ+IL2+TNFα+) CD4+ T-cells at baseline, which were further reduced to the point where they were not different to QFT negative controls one year later. Moreover, absolute frequencies of these cells correlated well with the magnitude of the QFT-response. Conclusion: Whereas specific polyfunctional CD4+ T-cells have been suggested to protect against TB progression, our data do not support that higher relative or absolute frequencies of PPD-specific polyfunctional CD4+ T-cells in peripheral blood can explain the reduced risk of TB progression observed in QFT reverters. On the contrary, absolute frequencies of these cells correlated with the QFT-response, suggesting that this readout reflects antigenic load.
- ItemIdentification of subclinical tuberculosis in household contacts using exposure scores and contact investigations(BMC (part of Springer Nature), 2020-01-31) Bekken, Gry K.; Ritz, Christian; Selvam, Sumithra; Jesuraj, Nelson; Hesseling, Anneke C.; Doherty, T. M.; Grewal, Harleen M. S.; Vaz, Mario; Jenum, SynneBackground: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as “asymptomatic, early pre-clinical disease during which pathology evolves”. Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence. Methods: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010–2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtbculture positivity in sputum or gastric aspirate (subjects < 5 years) specimen. Results: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: ORTST 1.16, 95% CI: 1.01, 1.33; ORQFT 1.33 95% CI: 1.16, 1.51. Infectivity Score: ORTST 1.39, 95% CI: 1.10, 1.76; ORQFT 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70). Conclusions: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.