Identification of biomarkers for Mycobacterium tuberculosis infection and disease in BCG-vaccinated young children in Southern India

Dhanasekaran, Saravana M.; Jenum, Synne; Stavrum, Ruth; Ritz, Christian; Faurholt‐Jepsen, Daniel; Kenneth, John; Vaz, Mário; Grewal, Harleen M. S.; Doherty, T. Mark; Doherty, Mark; Hesseling, A C; Jacob, Anu; Jahnsen, Frode L.; Kurpad, Anura V; Lindtjørn, Bernt; Macaden, Ragini; Nelson, Jeffrey T.; Selvam, Sumithra; Walker, Robert

doi:10.1038/gene.2013.26

Cited by 34 publications

(36 citation statements)

References 46 publications

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“…Dhanasekaran et al evaluated the response of multiple cytokines for the diagnosis of LTBI in an exposed South Indian population [36]. Anbarasu et al reported IL-6 to be a promising diagnostic marker in the Indian population [37].…”

Section: Discussionmentioning

confidence: 99%

The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India

Bapat

Husain

Daginawala

et al. 2015

Journal of Infection and Public Health

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The tuberculin skin test (TST) and interferon-gamma release assays (IGRA), namely, the QuantiFERON-TB Gold test (QFT), remain the standard immunological diagnostic tools for latent tuberculosis (TB) infection (LTBI). However, the sub-optimal detection rates of both of these tests are major impediments in recognizing the population at risk. This study was aimed at evaluating additional cytokines besides interferon-gamma (IFN-γ) as biomarkers for improving LTBI diagnosis in the tribal population of Melghat, India. Seventy-four close TB contacts were stratified by QFT and TST results into: (i) QFT+/TST+ (n = 26), (ii) QFT+/TST- (n = 12), (iii) QFT-/TST- (n = 35) and (iv) QFT-/TST+ (n = 1) groups. A panel of cytokines (IL-6, IL-10, TNF-α and IL-2R) was then evaluated in antigen-stimulated QFT cell-free culture supernatants using IMMULITE-1000, an automated immunoassay analyzer. Cytokine estimation showed significantly higher levels of IL-6 in the QFT+/TST+ group, while significantly higher levels of IL-10 were found in the QFT-/TST- group. Correlation analysis identified a positive correlation between IL-6 and the QFT response (r = 0.6723, P < 0.0001), while a negative correlation was seen between QFT and IL-10 expression (r = -0.3271, P = 0.0044). Similarly, IL-6 was positively correlated with TST levels (r = 0.6631, P <0 .0001), and conversely, a negative correlation was found between TST and IL-10 expression (r = -0.5698, P < 0.0001). The positive and negative predictive values of IL-6 were found to be 92.59 and 93.33%, respectively, and the positive and negative predictive values of IL-10 were 96.55 and 91.18%, respectively. No significant impact of the demographic characteristics on cytokine positivity was observed. Our preliminary results suggest that the evaluation of additional cytokines in QFT cell-free culture supernatants may be valuable for the identification of LTBI. Combining IL-6 and IL-10 with QFT and/or TST could markedly improve the detection accuracy of LTBI. Our observations require investigation in larger well-characterized cohorts along with follow-up studies to further confirm the study outcome.

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Section: Discussionmentioning

confidence: 99%

The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India

Bapat

Husain

Daginawala

et al. 2015

Journal of Infection and Public Health

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“…Data were analyzed using GeneMapper version 4.0 (Life Technologies, Carlsbad, California, USA) with adjustments of the default peak detection settings if required. The peak areas of replicates were averaged, normalized against GAPDH and log2 transformed as described46.…”

Section: Methodsmentioning

confidence: 99%

BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome

Jenum

Bakken

Dhanasekaran

et al. 2016

Sci Rep

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Biomarkers reflecting the extent of Mycobacterium tuberculosis-induced pathology and normalization during anti-tuberculosis treatment (ATT) would considerably facilitate trials of new treatment regimens and the identification of patients with treatment failure. Therefore, in a cohort of 99 Indian children with intrathoracic tuberculosis (TB), we performed blood transcriptome kinetic analysis during ATT to explore 1) the association between transcriptional biomarkers in whole blood (WB) and the extent of TB disease at diagnosis and treatment outcomes at 2 and 6 months, and 2) the potential of the biomarkers to predict treatment response at 2 and 6 months. We present the first data on the association between transcriptional biomarkers and the extent of TB disease as well as outcome of ATT in children: Expression of three genes down-regulated on ATT (FCGR1A, FPR1 and MMP9) exhibited a positive correlation with the extent of TB disease, whereas expression of eight up-regulated genes (BCL, BLR1, CASP8, CD3E, CD4, CD19, IL7R and TGFBR2) exhibited a negative correlation with the extent of disease. Baseline levels of these transcripts displayed an individual capacity >70% to predict the six-month treatment outcome. In particular, BLR1 and FCGR1A seem to have a potential in monitoring and perhaps tailoring future antituberculosis therapy.

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“…Identification of novel cytokine biomarkers that can improve the performance of IGRAs (independently or in combination with IFN-γ) has been evaluated by several studies [8][9][10]. These studies demonstrated that additional cytokines and cytokine combinations might contribute to the detection of M. tuberculosis infection and active tuberculosis in children [8,[11][12][13]. Furthermore, measurement of alternative cytokines was shown to reduce the number of indeterminate IGRAs [14].…”

Section: Introductionmentioning

confidence: 96%

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

Lundtoft

Awuah

Nausch

et al. 2017

Med Microbiol Immunol

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IFN-γ release assays (IGRAs) often present false-negative or indeterminate results in children with tuberculosis. HIV co-infection may contribute to decreased sensitivity of IGRAs by impairing T-cell IFN-γ expression. Measurement of alternative cytokines in QuantiFERON (QFT) supernatants can circumvent the IFN-γ-dependency and may improve QFT sensitivity. We aimed to identify additional cytokines from QFT supernatants for detection of Mycobacterium tuberculosis infection in children with tuberculosis and HIV co-infection from Ghana. Concentrations of 18 cytokines in QFT supernatants from children (0-16 years) with tuberculosis concomitantly infected with HIV (n = 25) or without HIV (n = 24) from Ghana were measured using cytometric bead array (CBA). 29% of the children showed positive IFN-γ test results, and five cytokines, i.e., IL-6, IL-21, TNF-α, IL-1α and IP-10, detected M. tuberculosis infection with comparable or, for IL-6, with significantly higher sensitivity (59%). Increased age and HIV co-infection were associated with decreased cytokine induction, and especially IL-21 and IP-10 were less prevalent in HIV co-infected children with tuberculosis. Combined cytokine analyses increased proportions of positive tests, and a four-cytokine subset (i.e., IL-6, IL-21, IFN-γ, IL-1α) predicted 78% of the children with tuberculosis correctly. Combined evaluation of IFN-γ and alternative cytokines improved IGRA-sensitivity in children with tuberculosis.

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Identification of biomarkers for Mycobacterium tuberculosis infection and disease in BCG-vaccinated young children in Southern India

Cited by 34 publications

References 46 publications

The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India

The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India

BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

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