Abstract
BackgroundWe previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated culture supernatants.MethodsWe recruited 15 culture confirmed TB cases and 15 non-TB cases from a high-TB endemic community in Cape Town, South Africa into a pilot case-control study from an on-going larger study. Blood samples collected from study participants were stimulated with 4 M.tb antigens that were previously identified as promising (ESAT6/CFP10 (early secreted), Rv2029c (latency), Rv2032 (latency) and Rv2389c (rpf)) in a 7-day or overnight culture assay. Supernatants were also collected form the standard QuantiFERON In Tube (QFT-IT) test. The levels of 26 host markers were evaluated in the three culture supernatants using the Luminex platform.ResultsThe unstimulated levels of CRP, Serum amyloid P (SAP) and serum amyloid A (SAA) and ESAT-6/CFP-10 specific IP-10 and SAA were amongst the best discriminatory markers in all 3 assays, ascertaining TB with AUC of 72–84%. Four-marker models accurately classified up to 92%, 100% and 100% of study participants in the overnight, 7-day and Quantiferon culture supernatants, respectively, after leave-one-out cross validation.ConclusionUnstimulated and antigen-specific levels of CRP, SAA, IP-10, MMP-2 and sCD40L hold promise as diagnostic candidates for TB disease in short-term stimulation assays. Larger studies are required to validate these findings but the data suggest that antigen-specific cytokine production and in particular mutimarker biosignatures might contribute to future diagnostic strategies.
Highlights
We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants
Alternative M.tb specific antigens [12,13], and alternative host markers other than IFN-c in M.tb-specific antigenstimulated whole blood culture assays have been investigated for TB diagnostic purposes [14], [15]. In one of these studies [15] we showed that the measurement of many host markers (including interferon-inducible protein (IP)-10, tumour necrosis factor (TNF)a, IFN-c, interleukin (IL)-12p40, transforming growth factor (TGF)-a, vascular endothelial growth factor (VEGF) and RANTES (CCL5)) upon stimulation with novel M.tb infection phase-dependent antigens in culture supernatants showed potential in the diagnosis of TB disease [15]
Utility of host markers detected in 7-day antigenstimulated culture supernatants in the diagnosis of TB disease
Summary
We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. Sputum culture remains the gold standard method for TB diagnosis but fails to deliver results in a time effective manner [4]. Cost effectiveness of the GeneXpert test remains one of the major impediments to the large-scale roll-out of the test in high burden but resourceconstrained settings [7,5]. Alternative methods such as serological, urine based [8,9], and other immunological tests have been investigated but these tests do not yield consistent results. The use of the available commercial serological tests was subsequently discouraged by the WHO [1]
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