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The Evaluation and Validation of Blood-Derived Novel Biomarkers for Precise and Rapid Diagnosis of Tuberculosis in Areas With High-TB Burden.

ABSTRACT: Tuberculosis (TB) remains a highly contagious public health threat. Precise and prompt diagnosis and monitoring of treatment responses are urgently needed for clinics. To pursue novel and satisfied host blood-derived biomarkers, we streamlined a bioinformatic pipeline by integrating differentially expressed genes, a gene co-expression network, and short time-series analysis to mine the published transcriptomes derived from whole blood of TB patients in the GEO database, followed by validating the diagnostic performance of biomarkers in both independent datasets and blood samples of Chinese patients using quantitative real-time PCR (qRT-PCR). We found that four genes, namely UBE2L6 (Ubiquitin/ISG15-conjugating enzyme E2 L6), BATF2 (Basic leucine zipper transcriptional factor ATF-like), SERPING1 (Plasma protease C1 inhibitor), and VAMP5 (Vesicle-associated membrane protein 5), had high diagnostic value for active TB. The transcription levels of these four gene combinations can reach up to 88% sensitivity and 78% specificity (average) for the diagnosis of active TB; the highest sensitivity can achieve 100% by parallel of BATF2 and VAMP5, and the highest specificity can reach 89.5% through a combination of SERPIG1, UBE2L6, and VAMP5, which were significantly higher than 75.3% sensitivity and 69.1% specificity by T-SPOT.TB in the same patients. Quite unexpectedly, the gene set can assess the efficacy of anti-TB response and differentiate active TB from Latent TB infection. The data demonstrated these four biomarkers might have great potency and advantage over IGRAs in the diagnosis of TB.

SUBMITTER: Gong Z

PROVIDER: S-EPMC8236956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEven though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.Methods & findings2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples).ConclusionsMODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.

Project description:BackgroundTuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities.MethodsWe modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged < 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15-64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis.ResultsAn estimated 195,449 children (95% confidence interval, CI: 189,673-201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146-1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108-243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623-523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591-880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41-2.91), the elderly and adults (RR: 1.40, CI: 0.62-3.16) or men and women (RR: 0.59, CI: 0.25-1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries.ConclusionsThere is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns.

Project description:Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV(+)) individuals with suspected TB from southern Africa and South America with <7 days of TB treatment had 1 sputum specimen tested with Direct LPA, MTBDR-Plus LPA, smear microscopy, MGIT, biochemical identification of mycobacterial species, and culture-based drug-susceptibility testing (DST). Of 639 participants, 59.3% were MGIT M. tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities.

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The Evaluation and Validation of Blood-Derived Novel Biomarkers for Precise and Rapid Diagnosis of Tuberculosis in Areas With High-TB Burden.

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