scholarly journals Multi-country evaluation of RISK6, a 6-gene blood transcriptomic signature, for tuberculosis diagnosis and treatment monitoring

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rim Bayaa ◽  
Mame Diarra Bousso Ndiaye ◽  
Carole Chedid ◽  
Eka Kokhreidze ◽  
Nestani Tukvadze ◽  
...  
Keyword(s):  
Characteristic Curve ◽  
Treatment Monitoring ◽  
Tb Treatment ◽  
Healthy Donors ◽  
End Of Treatment ◽  
Product Profile ◽  
Transcriptomic Signature ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Nested Case Control

AbstractThere is a crucial need for non-sputum-based TB tests. Here, we evaluate the performance of RISK6, a human-blood transcriptomic signature, for TB screening, triage and treatment monitoring. RISK6 performance was also compared to that of two IGRAs: one based on RD1 antigens (QuantiFERON-TB Gold Plus, QFT-P, Qiagen) and one on recombinant M. tuberculosis HBHA expressed in Mycobacterium smegmatis (IGRA-rmsHBHA). In this multicenter prospective nested case–control study conducted in Bangladesh, Georgia, Lebanon and Madagascar, adult non-immunocompromised patients with bacteriologically confirmed active pulmonary TB (ATB), latent TB infection (LTBI) and healthy donors (HD) were enrolled. ATB patients were followed-up during and after treatment. Blood RISK6 scores were assessed using quantitative real-time PCR and evaluated by area under the receiver-operating characteristic curve (ROC AUC). RISK6 performance to discriminate ATB from HD reached an AUC of 0.94 (95% CI 0.89–0.99), with 90.9% sensitivity and 87.8% specificity, thus achieving the minimal WHO target product profile for a non-sputum-based TB screening test. Besides, RISK6 yielded an AUC of 0.93 (95% CI 0.85–1) with 90.9% sensitivity and 88.5% specificity for discriminating ATB from LTBI. Moreover, RISK6 showed higher performance (AUC 0.90, 95% CI 0.85–0.94) than IGRA-rmsHBHA (AUC 0.75, 95% CI 0.69–0.82) to differentiate TB infection stages. Finally, RISK6 signature scores significantly decreased after 2 months of TB treatment and continued to decrease gradually until the end of treatment reaching scores obtained in HD. We confirmed the performance of RISK6 signature as a triage TB test and its utility for treatment monitoring.

scholarly journals Age-Related Immunoreactivity Profiles to Diverse Mycobacterial Antigens in BCG-Vaccinated Chinese Population

2021 ◽  
Vol 11 ◽  
Author(s):  
Qing-yuan Yang ◽  
Yu-tong Zhang ◽  
Jia-ni Xiao ◽  
Yu-shuo Liang ◽  
Ping Ji ◽  
...  
Keyword(s):  
Elispot Assay ◽  
Vaccine Development ◽  
Age Related ◽  
Healthy Donors ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Mycobacterial Antigens ◽  
Selection Of

Long-term immunoreactivity to mycobacterial antigens in Bovis Calmette-Guérin (BCG)-vaccinated population is not well investigated. Herein, 361 volunteer healthy donors (HDs) with neonatal BCG vaccination from Shanghai region (China) were enrolled. They were subdivided into ESAT-6/CFP10- (E6C10-) and ESAT-6/CFP10+ (E6C10+) groups based on gamma-interferon release assays (IGRAs). Three mycobacterial antigens, including Rv0934, Rv3006, and Rv3841, were subjected to the determination of immunoreactivity by ELISPOT assay. The immunoreactivities to three mycobacterial antigens were firstly compared among TB patients (N=39), E6C10+ HDs (N=78, 21.61% of HDs) and E6C10- HDs (N=283, 78.39% of HDs). It was revealed that Rv3006 was dominant upon M.tb infection, while Rv3841 was likely to be more responsive upon latent TB infection. In E6C10- population, the immunoreactivity to Rv3841 maintained along with aging, whereas those to Rv3006 and Rv0934 attenuated in E6C10- HDs older than 45 years old. Our study implies the shift of dominant antigens at different infection statuses, providing the clues for the selection of mycobacterial antigens in vaccine development and precision revaccination in the future.

scholarly journals Evaluation of Gamma Interferon Release Assays Using Mycobacterium tuberculosis Antigens for Diagnosis of Latent and Active Tuberculosis in Mycobacterium bovis BCG-Vaccinated Populations

2010 ◽  
Vol 17 (12) ◽  
pp. 1985-1990 ◽  
Author(s):  
Shu Zhang ◽  
Lingyun Shao ◽  
Ling Mo ◽  
Jiazhen Chen ◽  
Feifei Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Gamma Interferon ◽  
Sputum Smear ◽  
Purified Protein Derivative ◽  
Tb Treatment ◽  
Latent Tb ◽  
Specific Antigens ◽  
Latent Tb Infection

ABSTRACT T-cell-based gamma interferon (IFN-γ) release assays (IGRAs) using Mycobacterium tuberculosis-specific antigens have shown higher sensitivity and specificity than the routine tuberculin skin test (TST). However, the effects of Mycobacterium bovis BCG vaccination and anti-tuberculosis (TB) treatment on dynamic T-cell responses to M. tuberculosis-specific antigens in active TB cases have rarely been investigated in regions where TB is endemic. Eighty-nine patients with active pulmonary TB (ATB) and 57 healthy controls (HC) from China were recruited and tested by sputum smear and culture, TSTs, and IGRAs with M. tuberculosis-specific antigens ESAT-6 and CFP-10 (T-SPOT.TB) as well as purified protein derivative (PPD) stimulation. All 146 participants were screened by the T-SPOT.TB assay at recruitment. T-SPOT.TB-positive rates in ATB and HC groups were 87.6% (78/89) and 21.1% (12/57), respectively. Of 38 ATB patients who were both TST and T-SPOT.TB tested, the positive rates were 73.7% (28/38) and 94.7% (36/38), respectively (P = 0.0215), and those in the HC group were 62.3% (33/53) and 18.9% (10/53), respectively (P < 0.0001). The T-SPOT.TB-positive rates declined during TB treatment and were 94.4% (51/54), 86.4% (19/22), and 61.5% (8/13) for ATB patients receiving 0- to 1-month, 1- to 3-month, and 3- to 6-month anti-TB treatment, respectively. The IGRA is a most promising test for both active TB and latent TB infection (LTBI) diagnosis due to the improvement of its specificity and convenience, especially in the Mycobacterium bovis BCG-vaccinated population. Furthermore, the T-SPOT.TB assay using ESAT-6 and CFP-10 in ATB patients during anti-TB treatment could serve as a potential predictor of therapeutic efficacy.

Quantification of neutrophil and monocyte CD64 expression: a predictive biomarker for active tuberculosis

2020 ◽  
Vol 24 (2) ◽  
pp. 196-201 ◽  
Author(s):  
A. Gatti ◽  
C. Ceriani ◽  
M. De Paschale ◽  
C. Magnani ◽  
M. Villa ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Binding Capacity ◽  
Characteristic Curve ◽  
Predictive Biomarker ◽  
Assay Sensitivity ◽  
Fcgamma Receptor ◽  
Quantitative Expression ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Culture Positive

SETTING: QuantiFERON TB assay (QFT) is used to screen tuberculosis (TB) infection, but it cannot distinguish active TB from latent TB infection (LTBI).OBJECTIVE: To evaluate the quantitative expression of the high-affinity FCgamma receptor I (CD64) on neutrophils (NE) and monocytes (MO) in peripheral blood using flow cytometry, measured in antibody binding capacity (ABC) units as a predictive biomarker of TB.DESIGN: Fifty-two patients were enrolled (45 QFT-positive and 7 QFT-indeterminate). Cultures and molecular analyses were performed.RESULTS: Of the 45 QFT-positive patients, 29 were culture-positive (active TB) and 16 were negative (LTBI). The median NE CD64 ABC and MO CD64 ABC expression was significantly higher (P < 0.001) in culture-positive patients. The NE CD64 and MO CD64 area under the receiver operating characteristic curve values were respectively 0.948 (95%CI 0.838–0.992) and 0.989 (0.901–1.000). By setting the cut-off NE CD64 value at >2400 ABC or MO CD64 value >25 800 the assay sensitivity increased to 95.5% with 100% specificity and 100% positive predictive value. In the QFT-indeterminate group, five culture-positive cases had NE CD64 >2400 ABC or MO CD64 value >25 800; two culture-negative cases had lower values.CONCLUSION: The CD64 quantitative expression on peripheral blood cells may be used as a predictive biomarker for active TB.

scholarly journals A novel blood-based assay for treatment monitoring of tuberculosis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Alexandra J. Zimmer ◽  
Samuel G. Schumacher ◽  
Erik Södersten ◽  
Anna Mantsoki ◽  
Romain Wyss ◽  
...  
Keyword(s):  
Early Identification ◽  
Treatment Initiation ◽  
Fold Increase ◽  
Gene Signature ◽  
Treatment Monitoring ◽  
Pulmonary Tb ◽  
Transcriptional Signature ◽  
Tb Treatment ◽  
End Of Treatment ◽  
Sequencing Platforms

Abstract Objectives A novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) has been validated for tuberculosis (TB) treatment monitoring using laboratory-based RNA sequencing platforms. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instrument. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment. Results The 3-gene signature expression level (TB score) changed significantly over time with respect to baseline among 31 pulmonary TB patients. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54–1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03–2.33]). The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with larger prospective treatment monitoring studies.

scholarly journals A Novel Blood-Based Assay for Treatment Monitoring of Tuberculosis

2021 ◽  
Author(s):  
Alexandra Jaye Zimmer ◽  
Samuel G Schumacher ◽  
Erik Södersten ◽  
Anna Mantsoki ◽  
Romain Wyss ◽  
...  
Keyword(s):  
Early Identification ◽  
Treatment Initiation ◽  
Fold Increase ◽  
Gene Signature ◽  
Treatment Monitoring ◽  
Transcriptional Signature ◽  
Tb Treatment ◽  
End Of Treatment ◽  
Baseline Levels ◽  
Over Time

Abstract ObjectivesA novel 3-gene host transcriptional signature (GBP5, DUSP3 and KLF2) that has been validated for TB diagnosis. The signature was recently translated by Cepheid into a prototype cartridge-based test that can be run on the GeneXpert instruments. In this study, we prospectively evaluated the change in the expression of the cartridge-based 3-gene signature with time following treatment initiation among pulmonary TB patients who were microbiologically cured at the end of treatment. ResultsOur results show that the 3-gene signature expression level (TB score) changes significantly over time with respect to baseline levels. The greatest increase in TB score occurred within the first month of treatment (median fold-increase in TB score: 1.08 [IQR 0.54-1.52]) and plateaued after 4 months of treatment (median TB score: 1.97 [IQR: 1.03-2.33]. The rapid and substantial increase of the TB score in the first month of treatment holds promise for the early identification of patients that respond to TB treatment. The plateau in TB score at 4 months may indicate early clearance of disease and could direct treatment to be shortened. These hypotheses need to be further explored with large prospective treatment monitoring and test of cure studies.

scholarly journals Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2704
Author(s):  
Leonardo S. de de Araujo ◽  
Marcelo Ribeiro-Alves ◽  
Matthew F. Wipperman ◽  
Charles Kyriakos Vorkas ◽  
Frank Pessler ◽  
...  
Keyword(s):  
External Validation ◽  
Significant Differential Expression ◽  
Tb Treatment ◽  
The United Kingdom ◽  
Host Genetic ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
New Biomarkers ◽  
Monitor Treatment Response ◽  
And Control

External validation in different cohorts is a key step in the translational development of new biomarkers. We previously described three host mRNA whose expression in peripheral blood is significantly higher (NPC2) or lower (DOCK9 and EPHA4) in individuals with TB compared to latent TB infection (LTBI) and controls. We have now conducted an independent validation of these genes by re-analyzing publicly available transcriptomic datasets from Brazil, China, Haiti, India, South Africa, and the United Kingdom. Comparisons between TB and control/LTBI showed significant differential expression of all three genes (NPC2high p < 0.01, DOCK9low p < 0.01, and EPHA4low p < 0.05). NPC2high had the highest mean area under the ROC curve (AUROC) for the differentiation of TB vs. controls (0.95) and LTBI (0.94). In addition, NPC2 accurately distinguished TB from the clinically similar conditions pneumonia (AUROC, 0.88), non-active sarcoidosis (0.87), and lung cancer (0.86), but not from active sarcoidosis (0.66). Interestingly, individuals progressing from LTBI to TB showed a constant increase in NPC2 expression with time when compared to non-progressors (p < 0.05), with a significant change closer to manifestation of active disease (≤3 months, p = 0.003). Moreover, NPC2 expression normalized with completion of anti-TB treatment. Taken together, these results validate NPC2 mRNA as a diagnostic host biomarker for active TB independent of host genetic background. Moreover, they reveal its potential to predict progression from latent to active infection and to indicate a response to anti-TB treatment.

scholarly journals Screening for Mycobacterium tuberculosis Infection Using Beijing/K Strain-Specific Peptides in a School Outbreak Cohort

2021 ◽  
Vol 11 ◽  
Author(s):  
Ji Young Hong ◽  
Ahreum Kim ◽  
So Yeong Park ◽  
Sang-Nae Cho ◽  
Hazel M. Dockrell ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Tuberculosis Infection ◽  
Tb Treatment ◽  
Diagnostic Potential ◽  
Tnf Α ◽  
Latent Tb ◽  
Ifn Γ ◽  
Latent Tb Infection ◽  
Tb Diagnostics ◽  
Active Disease

BackgroundThe Beijing strain of Mycobacterium tuberculosis (M. tb) has been most frequently isolated from TB patients in South Korea, and the hyper-virulent Beijing/K genotype is associated with TB outbreaks. To examine the diagnostic potential of Beijing/K-specific peptides, we performed IFN-γ release assays (IGRA) using a MTBK antigen tube containing Beijing/K MTBK_24800, ESAT-6, and CFP-10 peptides in a cohort studied during a school TB outbreak.MethodsA total of 758 contacts were investigated for M. tb infection, and 43 contacts with latent TB infection (LTBI) and 25 active TB patients were enrolled based on serial screening with QuantiFERON-TB Gold In-Tube tests followed by clinical examinations. Blood collected in MTBK antigen tubes was utilized for IGRA and multiplex cytokine bead arrays. Immune responses were retested in 24 patients after TB treatment, and disease progression was investigated in subjects with LTBI.ResultsTotal proportions of active disease and LTBI during the outbreak were 3.7% (28/758) and 9.2% (70/758), respectively. All clinical isolates had a Beijing/K M. tb genotype. IFN-γ responses to the MTBK antigen identified M. tb infection and distinguished between active disease and LTBI. After anti-TB treatment, IFN-γ responses to the MTBK antigen were significantly reduced, and strong TNF-α responses at diagnosis were dramatically decreased.ConclusionsMTBK antigen-specific IFN-γ has diagnostic potential for differentiating M. tb infection from healthy controls, and between active TB and LTBI as well. In addition, TNF-α is a promising marker for monitoring therapeutic responses. These data provide informative readouts for TB diagnostics and vaccine studies in regions where the Beijing/K strain is endemic.

Comparison of Screening Procedures for Mycobacterium tuberculosis Infection Among Patients with Inflammatory Diseases

2009 ◽  
Vol 36 (9) ◽  
pp. 1876-1884 ◽  
Author(s):  
BOLETTE SOBORG ◽  
MORTEN RUHWALD ◽  
MERETE LUND HETLAND ◽  
SØREN JACOBSEN ◽  
AASE BENGAARD ANDERSEN ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mycobacterium Tuberculosis ◽  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Mycobacterium Tuberculosis Infection ◽  
Tb Treatment ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
High Degree

Objective.To test if Mycobacterium tuberculosis screening results differ among patients with inflammatory disease depending on whether the QuantiFeron TB-Gold test (QFT) or tuberculin skin test (TST) is used; and to evaluate if a possible difference is influenced by the presence of risk factors or immunosuppression.Methods.The interferon-γ response to in vitro stimulation of M. tuberculosis-specific antigens was measured with QFT and results were compared with TST. Associations to bacillus Calmette-Guerin (BCG) vaccination, risk factors, and immunosuppression were analyzed for both tests.Results.QFT and TST results were available for 294/302 and 241/302 patients, respectively; 234 had results from both tests. Twenty-one (7%) tested positive with QFT and 45 (19%) with TST. A positive QFT was associated with risk factors for M. tuberculosis infection: i.e., birth or upbringing in a TB-endemic area [risk ratio (RR) = 7.8, 95% CI 1.5–18.2, p < 0.001], previous TB treatment (RR 4.7, 95% CI 1.6–13.5, p = 0.005), and any latent TB infection risk factor (RR 4.7, 95% CI 2.1–11.0, p = 0.0002). Treatment with corticosteroids increased the risk for an inconclusive QFT result (RR 4.2, 95% CI 1.6–10.7, p = 0.04) and decreased the risk for a positive TST result (RR 0.4, 95% CI 0.1–1.0, p = 0.04). Agreement between the tests was low (kappa 0.2, 95% CI 0.02–0.3, p = 0.002).Conclusion.The study documented a high degree of discordant positive QFT and TST results. A positive QFT was more closely associated with risk factors for M. tuberculosis infection than the TST. The use of corticosteroids affected test outcome by increasing the risk for an inconclusive QFT result and decreasing the risk for a positive TST result.

scholarly journals Modelling the Impact of Different Tuberculosis Control Interventions on the Prevalence of Tuberculosis in an Overcrowded Prison

2018 ◽  
Vol 30 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Herlianna Naning ◽  
Haider Abdulrazzaq Abed Al-Darraji ◽  
Scott McDonald ◽  
Noor Azina Ismail ◽  
Adeeba Kamarulzaman
Keyword(s):  
Treatment Strategy ◽  
Treatment Strategies ◽  
Ventilation Rate ◽  
Transmission Model ◽  
Tuberculosis Control ◽  
High Turnover ◽  
Tb Treatment ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
The Impact

The aim of this study was to simulate the effects of tuberculosis (TB) treatment strategies interventions in an overcrowded and poorly ventilated prison with both high (5 months) and low (3 years) turnover of inmates against improved environmental conditions. We used a deterministic transmission model to simulate the effects of treatment of latent TB infection and active TB, or the combination of both treatment strategies. Without any intervention, the TB prevalence is estimated to increase to 8.8% for a prison with low turnover of inmates but modestly stabilize at 5.8% for high-turnover prisons in a 10-year period. Reducing overcrowding from 6 to 4 inmates per housing cell and increasing the ventilation rate from 2 to 12 air changes per hour combined with any treatment strategy would further reduce the TB prevalence to as low as 0.98% for a prison with low inmate turnover.

scholarly journals Recommendations for tuberculosis screening before and during treatment with tumour necrosis factor inhibitors

2009 ◽  
Vol 137 (3-4) ◽  
pp. 211-216
Author(s):  
Dragana Mandic ◽  
Radmila Curcic ◽  
Gordana Radosavljevic ◽  
Nemanja Damjanov ◽  
Dusan Stefanovic ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Tnf Alpha ◽  
Tuberculosis Screening ◽  
Tb Treatment ◽  
Immunocompromised Status ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Alpha Therapy ◽  
Necrosis Factor

Patients with an autoimmune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, uveitis or psoriasis, and treated with the anti-tumour necrosis factor (TNF) alpha inhibitors are at high risk of developing various infections including tuberculosis (TB). Serious infections are the result of the patients' immunocompromised status that is caused by the primary disease itself, as well as by previous immunosuppressive therapy. In order to decrease the risk of developing TB, prior to the introduction of the anti-TNF alpha therapy, all patients should undergo screening for TB. Experiences from the countries that have already implemented recommendations for TB screening show a significant decrease in TB occurrence in the anti-TNF alpha treated patients. The PPD skin test result is considered positive if induration is of size ?5 mm. The BCG vaccine applied at birth has no effect on interpretation of PPD test results in adults. The diagnosis of active TB is contraindicated for the introduction of the anti-TNF alpha therapy; first, such patients should receive the TB treatment; and 6 months after the completion of the TB treatment, the introduction of the anti-TNF alpha therapy may be considered. The patients with the diagnosis of the latent TB infection (LTBI) should not immediately start with the anti-TNF alpha therapy, but they should first receive the TB chemoprophylaxis; not earlier than a month upon the introduction of the TB chemoprophylaxis, the anti-TNF alpha therapy may be introduced. The first TB follow-up screening during the anti-TNF alpha therapy is recommended 6 months after the anti-TNF alpha therapy has been introduced and the next one should be scheduled after 12 months.

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