Abstract
ABSTRACTThe tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-γ), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B (P <0.00001). In addition, antigen stimulation increased the expression of heparin-binding EGF-like growth factor (HB-EGF) and activin AB in LTBI samples. In nil tubes, LIGHT was the most significant marker (P <0.0001) and was elevated in LTBI subjects. Other prominent markers in nonstimulated QFT-GIT supernatants were the complement-3 components C3b, iC3b, and C3d, which were upregulated in LTBI and markedly decreased upon stimulation. We found known and novel proteins that warrant further studies for developing improved tests for LTBI, for predicting progression to active disease, and for discriminating LTBI from active TB.
Highlights
The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations
In the nil tube supernatants of the study subjects, the median IFN-␥ signal was 1,434 relative fluorescence units (RFU), and no significant differences were noted between LTBI (1,494 RFU) and healthy controls (HC) (1,414 RFU)
In the supernatants of the stimulated tubes, the median IFN-␥ signal was elevated for LTBI subjects (3,589 RFU) compared with that of HC subjects (1,419 RFU)
Summary
The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Until the commercial IGRAs were available, the TST was the only test for diagnosing LTBI but with several well-described limitations, for example, the need for two visits, the subjective quality of the results, the low sensitivity for active TB, and the occurrence of false-positive results due to prior BCG vaccination or nontuberculous mycobacteria (NTM) infection [3,4,5]. Since the multiplexed platform has not been validated using matrices such as supernatants from extended stimulation tubes and controls, we studied how reliable such a matrix is for biomarker discovery Toward these aims, we utilized residual QFT-GIT samples from the TB Epidemiologic Studies Consortium (TBESC) parent study in a feasibility study to determine the performance of the SOMAscan assay with heparin plasma from both the nil and M. tuberculosis antigen (Mtb)-stimulated tubes
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