A simple TB blood test could accurately identify TB among patients with varying degrees of exposure to the disease, according to research presented at the Association for Diagnostics & Laboratory Medicine (ADLM) annual meeting, which took place last week in California.
The journal Respiratory Therapy reports that if confirmed, the researchers say the results could help save millions of lives and curtail a global health emergency.
“Every week of delay in diagnosing TB matters – so that early identification may allow treatment to begin sooner and potentially reduce transmission,” said Dr Sheng-Wei Pan, a physician in the department of chest medicine at Taipei Veterans General Hospital in Taiwan and the study’s lead author.
According to the WHO, a quarter of the global population is estimated to have been infected with the TB bacteria (Mycobacterium tuberculosis), and 5%-10% will go on to develop active disease.
TB is almost always curable with antibiotic therapy when M. tuberculosis is detected in initial stages of disease progression. It is typically diagnosed by assessing samples of patients’ sputum.
“However, not all patients can produce sputum when they first seek medical care, especially those with early disease or those with low bacterial burden,” Pan said. For that reason, non-sputum-based diagnostic tools are urgently needed.
The researchers evaluated a blood marker produced by the bacteria called 6-kDa early secreted antigenic target (ESAT-6). While ESAT-6 has been studied before, most sensors used to detect it have not been sensitive enough to distinguish active pulmonary TB from latent TB infection, TB exposure, or other lung diseases.
Pan’s team used a new biosensor that overcame this limitation.
“The novelty of our study lies in the highly sensitive quantification of circulating ESAT-6,” Pan said.
The researchers quantified ESAT-6 levels in blood samples from 217 patients who either had an active pulmonary TB infection (cases) or did not (controls). The control group was further classified into patients with lung disease caused by different Mycobacterium species than the one that causes TB, those with lung cancer, people infected with latent TB (no symptoms) after being exposed to a contact with TB, uninfected people who were exposed to a TB contact, and healthy people with no known TB contacts.
The ESAT-6 marker did an excellent job of differentiating between TB- and non-TB patients. Moreover, the researchers noted a stepwise increase in the blood concentration of the marker across the spectrum of TB infection, with the lowest levels in uninfected people with TB contacts, medium amounts in those with latent TB, and the highest levels in patients with active TB.
This strong, independent association held true even after the researchers accounted for other factors that could impact patients’ TB status, such as age, sex, and the presence of diabetes.
Unlike biomarkers that measure the body’s immune response to infection, ESAT-6 is derived directly from the TB bacteria. “We believe this is one reason why it performs so well in identifying active TB,” Pan said. The study found ESAT-6 did a better job discriminating among TB patient groups than two common blood-based markers.
Because the study used a design in which patients’ disease status was known from the outset, further research is needed to confirm that ESAT-6 can predict TB status in real time.
“We are currently planning a prospective study to further evaluate if this can be used in a real-world clinical setting,” added Pan.
Although sputum cultures remain essential for verifying TB and providing information about drug resistance, ESAT-6 holds promise as a practical tool for triaging patients in instances when sputum-based diagnostics are limited or delayed.
Study details
Quantitative assessment of circulating blood ESAT-6 for non-sputum identification of pulmonary tuberculosis
Sheng-Wei Pan, Mei-Lin Ho, Xiu-An Ye et al.
Abstract
Background
Non-sputum diagnostic tools for pulmonary tuberculosis (PTB) are urgently needed, particularly as triage tests in patients unable to produce sputum or with paucibacillary disease. The 6-kDa early secreted antigenic target (ESAT-6), a Mycobacterium tuberculosis-specific secreted antigen, represents a pathogen-derived blood biomarker. We evaluated whether circulating ESAT-6 levels can discriminate PTB and reflect the tuberculosis infection spectrum, with a focus on its potential use as a blood-based triage test in clinical settings where sputum-based diagnostics are limited or delayed.
Methods
n this case-control study, plasma ESAT-6 concentrations were quantified using a validated quantitative immunoassay, in triplicate. Mean values were used for analysis to minimise intra-assay variability. Study populations were PTB group and control groups comprising non-tuberculous mycobacterial lung disease, lung cancer, TB contacts with latent TB infection (LTBI) and without LTBI (non-LTBI), and healthy controls. Diagnostic performance for PTB was evaluated using receiver operating characteristic (ROC) analysis. Optimal cut-off values were determined to assess sensitivity and specificity. Associations between ESAT-6 levels and PTB were examined using multivariable logistic regression.
Results
Plasma ESAT-6 levels were significantly higher in PTB (n=83; median [IQR], 113.6 [104.3-122.0] ng/mL) than in all non-PTB control groups (combined n=130) (all p< 0.001). A stepwise increase in ESAT-6 concentrations was observed across the TB infection spectrum, with the highest levels in PTB, intermediate levels in LTBI (73.0 [64.8-86.2] ng/mL), and the lowest levels in non-LTBI TB contacts (49.8 [39.0-63.3] ng/mL) (all inter-group p<0.001). ESAT-6 demonstrated excellent discriminative performance for PTB (area under the ROC curve [AUC], 0.976; 95% CI, 0.960-0.992), exceeding that of blood monocyte-to-lymphocyte ratio (AUC, 0.656; 95% CI, 0.573-0.739) and C-reactive protein (AUC, 0.683; 95% CI, 0.595-0.772), and remained independently associated with PTB after adjustment for clinical cofactors. Using an optimised cut-off of 95.0 ng/mL, ESAT-6 achieved a sensitivity of 95.2% and a specificity of 90.8%. Diagnostic performance of ESAT-6 remained robust across clinically relevant subgroups, including culture-negative PTB.
Conclusion
Quantitative blood ESAT-6 levels reflect the TB infection spectrum and show high accuracy for identifying PTB, supporting its potential role as a pathogen-derived, non-sputum blood-based triage biomarker within clinical laboratory-based diagnostic workflows.
Association for Diagnostics & Laboratory Medicine(ADLM) Annual Meeting
Respiratory Therapy article – New TB Blood Test Could Help Early Detection (Open access)
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