Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting

Sudbury, Eva; Otero, Larissa; Tebruegge, Marc; Messina, Nicole L.; Seas, Carlos; Montes, Martín; Rìos, Julia; Germano, Susie; Gardiner, Kaya; Clifford, Vanessa; Gotuzzo, Eduardo; Curtis, Nigel

doi:10.1016/j.jctube.2019.100102

Cited by 23 publications

(17 citation statements)

References 39 publications

(48 reference statements)

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“…The serum biosignature consisting of 16 proteins (APRIL/TNFSF13, sCD30/TNFRSF8, chitinase 3-like 1, sIL-6Rα, IL-8, IL-11, IL-12(p70), IL-19, IL-28A/IFN-λ2, LIGHT/TNFSF14, MMP-1, MMP-2, MMP-3, OPN, PTX-3, TWEAK/TNFSF12) was found informative for the differentiation between the TB and HC groups, while the panel of 15 proteins (IL-6, APRIL/TNFSF13, sCD30/TNFRSF8, gp130/sIL-6β, IL-2, sIL-6Rα, IL-8, IL-29/IFNλ1, IL-35, MMP-2, MMP-3, OPN, PTX-3, sTNF-R2, TWEAK/TNFSF12) distinguished the HC group from the LTBI cohort. Currently, a number of studies have demonstrated a potential of blood-derived host protein biomarkers in the diagnosis of active TB [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. A 6-marker serum protein biosignature consisting of CRP (c-reactive protein), IFN-γ, IP-10 (human interferon-inducible protein 10), CFH (complement factor H), Apo-AI (apolipoprotein AI), and SAA (serum amyloid A) showed a potential in the diagnosis of childhood tuberculous meningitis48.…”

Section: Discussionmentioning

confidence: 99%

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

et al. 2021

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None of the currently used diagnostic tools are efficient enough in diagnosing Mycobacterium tuberculosis (M.tb) infection in children. The study was aimed to identify cytokine biosignatures characterizing active and latent tuberculosis (TB) in children. Using a multiplex bead-based technology, we analyzed the levels of 53 Th17-related cytokines and inflammatory mediators in sera from 216 BCG-vaccinated children diagnosed with active TB (TB) or latent TB (LTBI) as well as uninfected controls (HC). Children with active TB, compared to HC children, showed reduced serum levels of IL-17A, MMP-2, OPN, PTX-3, and markedly elevated concentrations of APRIL/TNFSF13. IL-21, sCD40L, MMP-2, and IL-8 were significantly differentially expressed in the comparisons between groups: (1) HC versus TB and LTBI (jointly), and (2) TB versus LTBI. The panel consisting of APRIL/TNFSF13, sCD30/TNFRSF8, IFN-α2, IFN-γ, IL-2, sIL-6Rα, IL-8, IL-11, IL-29/IFN-λ1, LIGHT/TNFSF14, MMP-1, MMP-2, MMP-3, osteocalcin, osteopontin, TSLP, and TWEAK/TNFSF12 possessed a discriminatory potential for the differentiation between TB and LTBI children. Serum-based host biosignatures carry the potential to aid the diagnosis of childhood M.tb infections. The proposed panels of markers allow distinguishing not only children infected with M.tb from uninfected individuals but also children with active TB from those with latent TB.

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Section: Discussionmentioning

confidence: 99%

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

et al. 2021

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“…TST, QFT assays and T-SPOT.TB assays had sensitivities of ∼80% or below, indicating that approximately one in five children with TBM have a false-negative result when a single immunological test is performed, irrespective of which test is used. Several recent studies, including in patients with TBM, have investigated novel immune-based TB biomarkers in blood that have the potential to improve the diagnosis of TB in children, but additional studies will be required to confirm their findings [ 24 – 26 ]. Interestingly, our multivariate logistic regression analyses indicate that false-negative TST results were more common in children with more severe TBM.…”

Section: Discussionmentioning

confidence: 99%

Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study

et al. 2020

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IntroductionTuberculous meningitis (TBM) is often diagnostically challenging. Only limited data exist on the performance of interferon-γ release assays (IGRA) and molecular assays in children with TBM in routine clinical practice, particularly in the European setting.MethodsMulticentre, retrospective study involving 27 healthcare institutions providing care for children with tuberculosis (TB) in nine European countries.ResultsOf 118 children included, 54 (45.8%) had definite, 38 (32.2%) probable and 26 (22.0%) possible TBM; 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Of 108 patients who underwent cranial imaging 90 (83.3%) had at least one abnormal finding consistent with TBM. At the 5-mm cut-off the tuberculin skin test had a sensitivity of 61.9% (95% CI 51.2–71.6%) and at the 10-mm cut-off 50.0% (95% CI 40.0–60.0%). The test sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 71.7% (95% CI 58.4–82.1%) and 82.5% (95% CI 58.2–94.6%), respectively (p=0.53). Indeterminate results were common, occurring in 17.0% of QuantiFERON-TB assays performed. Cerebrospinal fluid (CSF) cultures were positive in 50.0% (95% CI 40.1–59.9%) of cases, and CSF PCR in 34.8% (95% CI 22.9–43.7%). In the subgroup of children who underwent tuberculin skin test, IGRA, CSF culture and CSF PCR simultaneously, 84.4% had at least one positive test result (95% CI 67.8%–93.6%).ConclusionsExisting immunological and microbiological TB tests have suboptimal sensitivity in children with TBM, with each test producing false-negative results in a substantial proportion of patients. Combining immune-based tests with CSF culture and CSF PCR results in considerably higher positive diagnostic yields, and should therefore be standard clinical practice in high-resource settings.

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“…Figure 5 demonstrates this effect graphically by showing that biomarker panels lacking CXCL1, CXCL2, or MMP8 have lower AUC values than the biomarker sets that contain at least 1 of these 3. [31][32][33][34][35][36][37][38][39] . Only one study reported MMP8 performance as a biomarker in children (<25 per diagnostic category) and three studies measured CXCL1 [41][42][43] .…”

Section: Two Different Biomarker Panels Are Identified Using Machine mentioning

confidence: 99%

Tuberculosis biomarkers discovered using Diversity Outbred mice

Koyuncu

Niazi

Tavolara

et al. 2021

Preprint

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BackgroundBiomarker discovery for pulmonary tuberculosis (TB) may be accelerated by modeling human genotypic diversity and phenotypic responses to Mycobacterium tuberculosis (Mtb). To meet these objectives, we use the Diversity Outbred (DO) mouse population and apply novel classifiers to identify informative biomarkers from multidimensional data sets.MethodTo identify biomarkers, we infected DO mice with aerosolized Mtb confirmed a human-like spectrum of phenotypes, examined gene expression, and inflammatory and immune mediators in the lungs. We measured 11 proteins in 453 Mtb-infected and 29 non-infected mice. We have searched all combinations of six classification algorithms and 239 biomarker subsets and independently validated the selected classifiers. Finally, we selected two mouse lung biomarkers to test as candidate biomarkers of active TB, measuring their diagnostic performance in human sera acquired from the Foundation for Innovative New Diagnostics.FindingsDO mice discovered two translationally relevant biomarkers, CXCL1 and MMP8 that accurately diagnosed active TB in humans with > 90% sensitivity and specificity compared to controls. We identified them through the two classifiers that accurately diagnosed supersusceptible DO mice with early-onset TB: Logistic Regression using MMP8 as a single biomarker, and Gradient Tree Boosting using a panel of 4 biomarkers (CXCL1, CXCL2, TNF, IL-10).InterpretationThis work confirms that the DO population models human responses and can accelerate discovery of translationally relevant TB biomarkers.FundingSupport was provided by NIH R21 AI115038; NIH R01 HL145411; NIH UL1-TR001430; and the American Lung Association Biomedical Research Grant RG-349504.

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Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting

Cited by 23 publications

References 39 publications

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

Cytokine Biosignature of Active and Latent Mycobacterium Tuberculosis Infection in Children

Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study

Tuberculosis biomarkers discovered using Diversity Outbred mice

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