Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study

Turner, Chris; Rk, Gupta; Tsaliki, Evdokia; Roe, Jennifer; Mondal, Prasenjit; Nyawo, Georgina; Palmer, Zaida; Miller, R F; Reeve, Byron W P; Theron, Grant; Noursadeghi, Mahdad

doi:10.1016/s2213-2600(19)30469-2

Cited by 105 publications

(118 citation statements)

References 33 publications

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“…Subsequently, Warsinke HC et al ( 25 ) evaluated the performance of the 3-gene TB score in three different TB cohorts ( 25 – 27 ) and found that outcomes approached the WHO TTP benchmarks for a non-sputum-based triage test, with a high negative predictive value. Further, a very recent study evaluated 27 eligible identified signatures in a systematic meta-review, from which four signatures (Sweeney3, Kaforou25, Roe3, and BATF2) fulfilled the WHO minimum diagnostic accuracy parameters required for a TB triage test ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

et al. 2021

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To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible.

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Section: Introductionmentioning

confidence: 99%

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

et al. 2021

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“…Nonetheless, more than half of PTB in developing countries and about 20% in developed countries lack bacteriological con rmation [1,10]. In addition, there are some other limitations of those principal techniques, the time delay of Mtb culture and the high cost of Xpert tests [11,12]. Therefore, more accurate, rapid, and costeffective triage tests based on biomarkers are needed to improve case detection, especially to indicate progression from latent infection to clinical disease [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…New diagnostic innovations of rapid biomarker-based, non-sputum tests are critical for detecting active TB, ruling out disease or referring patients to the more expensive and accurate molecular testing for con rmation [11,[13][14][15][16]. However, few biomarkers progress to a further developmental stage and none has so far led to a diagnostic test that meets the optimum performance requirements of the target product pro les [15,16].…”

Section: Introductionmentioning

confidence: 99%

Soluble CD14 and Th 17-Related Interleukins in Bronchoalveolar Lavage Fluid are Potential Triage Biomarkers for Pulmonary Tuberculosis

Liu¹,

Li²,

Dong³

et al. 2021

Preprint

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Background: Soluble CD14 (sCD14) and T helper 17-related interleukins (IL-17 and IL-22) in bronchoalveolar lavage fluid (BALF) are preliminarily reported to be increased in pulmonary tuberculosis (PTB). Their significances to the bacteriological confirmation and activity differentiation of PTB, however, are not completely clarified. Methods: A observational study was conducted in 154 consecutive adult patients who were primarily diagnosed with PTB based on radiographic abnormalities. Bacteriological confirmation was made using sputum/BALF smearing, TB-DNA, Xpert test and Mycobacterium tuberculosis (Mtb) culture. BALF and serum sCD14, IL-17 and IL-22 were measured using ELISA assays. Their associations with clinical/bacteriological characteristics were analyzed. Results: Finally, 103, 16, 7 and 28 patients were diagnosed with active, inactive, gray zone and non-PTB, respectively. Among active PTB patients, 82 (79.6%) cases, 33 (32.0%) based on sputum and additional 49 (47.6%) depended on BALF were bacteriologically confirmed. BALF levels of sCD14, IL-17 and IL-22 were similar between patients with PTB and non-PTB, but significantly higher in active PTB and bacteriologically-confirmed patients. The BALF levels of these biomarkers to some extent predicted bacteriological confirmation failure (AUC of IL-22 = 0.866), nonresponders to empiric antibacterial therapy, Xpert test (AUC of IL-22 = 0.760) and Mtb cultures. When the sensitivities were set at ³ 90% (WHO's minimal requirement for a triage test), the specificities of bacteriological confirmation failure prediction and empiric antibacterial therapy nonresponder prediction in interferon-g release assay-positive patients were about 67%, very close to the WHO's minimal requirement (³ 70%) for a triage test. In addition, serum levels of sCD14, IL-17 and IL-22 were relatively lower and had no predictive values. Conclusions: BALF levels of sCD14, IL-17 and IL-22, superior to their serum levels, are potential triage biomarkers and may be used to replace the expensive Xpert test in particular occasions or refer proper patients to conduct lung biopsy and expensive molecular tests in the first week or to start nondelayed anti-TB therapy bypassing empiric antibacterial therapy and time-consuming Mtb culture.

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“…Currently, microbiological culture and sputum smear microscopy are utilized for the routine diagnosis of PTB. [ 6 ] However, these approaches have various drawbacks, including the time delay for positive culture and poor sensitivity (20%–60%) of microscopy. [ 7 , 8 ] The Xpert MTB/RIF assay is recommended by the World Health Organization for the diagnosis of PTB.…”

Section: Introductionmentioning

confidence: 99%

Monokine induced by gamma interferon for detecting pulmonary tuberculosis

Dan²,

Che³

et al. 2020

Medicine

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Backgrounds: Pulmonary tuberculosis (PTB) is an oldest-known and most formidable disease. The standard microbiology culture is time-wasting. Monokine induced by gamma interferon (MIG) has been reported as a new biomarker to auxiliarily detect PTB. In our study, we used meta-analysis to assess the diagnostic value of MIG for PTB. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched for relative records up to April 2, 2020. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the curve, and summary receiver operating characteristic curve were estimated. Results: Eight studies including 1487 participants were included. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of MIG for detecting PTB were 84%, 84%, 5.19, and 0.19, respectively. The diagnostic odds ratio and area under the curve were 27.88 and 0.90, respectively, indicating a good diagnostic ability of MIG. Meta-regression analysis showed that human immunodeficiency virus status might be a source of heterogeneity (P = .02). Conclusions: Our results showed that MIG had a good diagnostic value for PTB.

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Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study

Cited by 105 publications

References 33 publications

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

Soluble CD14 and Th 17-Related Interleukins in Bronchoalveolar Lavage Fluid are Potential Triage Biomarkers for Pulmonary Tuberculosis

Monokine induced by gamma interferon for detecting pulmonary tuberculosis

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