Cytokine Patterns in Tuberculosis Infection; IL-1ra, IL-2 and IP-10 Differentiate Borderline QuantiFERON-TB Samples from Uninfected Controls

Abstract

BackgroundInterferon gamma release assays (IGRAs) do not discriminate between active tuberculosis (TB) and latent TB infection (LTBI), which limit their use in TB endemic areas. Subjects with QuantiFERON-TB (QFT) results around the diagnostic cut-off more likely show inconsistent results on serial testing which makes the interpretation of the assay difficult. We have studied potential biomarkers in patients with various stages of TB infection and with borderline QFT tests compared to those with higher values.Methods27 soluble biomarkers were analysed in QFT supernatants from patients with active TB (n = 18), individuals with LTBI (n = 48) and from QFT negative controls (n = 16) by the Multiplex bead assay. The LTBI group was classified into two groups according to QFT IFN-γ levels; QFT borderline (0.35–0.70 IU/mL, n = 11) or QFT high (>0.70 IU/mL, n = 36).ResultsThe levels of IL-1ra, IL-2, IL-13, IL-15, IFN-γ, IP-10 and MCP-1 in background corrected TB antigen stimulated supernatants (TBAg-Nil) significantly distinguished both active TB and LTBI QFT high groups from the QFT negative controls (p≤0.004). In addition, IL-1ra, IL-2 and IP-10 significantly differentiated the QFT borderline group from the controls (p≤0.001). Still, in the QFT borderline group the IL-1ra and IP-10 levels were not significant different from neither the QFT high nor the active TB group, whereas the IL-2 levels were lower (p≤0.003). The level of IP-10 showed the best separation between the QFT borderline group and the QFT negative controls (AUC 0.92) and offered 100% sensitivity for active TB.ConclusionIL-1ra, IL-2 and IP-10 differentiate QFT borderline samples from uninfected controls and the majority of QFT borderline subjects were classified as LTBI by these markers. Still, inconsistency was seen, and further studies are needed to examine the performance of alternative markers before concluded if they could be used as diagnostics tools.

Analysis of cellular and soluble profiles in QuantiFERON nonconverters, converters, and reverters in the Gambia

“…In previous studies IL-2 has been shown to enhance diagnosis of LTBI, particularly in those with borderline QFT results. 19 In addition, IL-2 levels are generally higher in LTBI compared with active TB patients. 20 Our results showing elevation of IL-2 before IFN-γ conversion by QFT suggests IL-2 is a likely marker of early infection leading to subsequent conversion.…”

In vitro responses of multiple cytokines to purified protein derivative in healthy and naturally Mycobacterium tuberculosis‐infected rhesus monkeys (Macaca mulatta)

“…In addition to IFN-γ, additional biomarkers have emerged as potential candidates for the evaluation of antigen recognition in whole-blood stimulation assays, such as IP-10, IL1RA, TNF-α and IL17. 14,[17][18][19] This study aimed to evaluate more cytokines as alternative biomarkers of whole-blood stimulation assays in diagnosing nonhuman Panel 1 6 TNF RII, IL19, RANTES, MIF, MPO, Galectin-3 Panel 2 37 IFN-γ, TNF-α, TNF RI, GM-CSF, IL1β, IL1RA, IL1 RII, IL2, IL2 Rα, IL4, IL5, IL6, IL6 Rα, IL8, IL10, IL15, IL17A, IL22, MCP-1, MIP-1β, MCP-3, MCP-4, CCL11, CCL18, CCL22, CCL27, CXCL1, CXCL4, IP-10, CXCL12, CXCL13, CD14, CD27, CD30 been proven to be robust biomarkers of whole-blood stimulation assays. [22][23][24] In our study, IFN-γ and IP-10 were also identified as sensitive markers for the PPD-based whole-blood stimulation assay in nonhuman primates, and IP-10 appeared to be more sensitive than…”

Is interleukin-2 an optimal marker for diagnosing tuberculosis infection? A systematic review and meta-analysis

“…Patient selection bias was unclear for seven articles (7/18), which used cross-sectional design in six articles and did not report the time of patient selection in one article [25,27,28,30,35,37,38]. In addition, the index tests bias was unclear in 13 articles (13/18), because the results of IL-2 cannot be obtained in blinded conditions [26][27][28][29][30][31][32][33][34][36][37][38][39]. The reference standard bias was unclear for one article (1/18), which had intermediate results 33.…”

“…The reference standard bias was unclear for one article (1/18), which had intermediate results 33. Flow and timing bias were unclear for six articles (6/18), in which patients were lost during the analysis of the diagnostic potential of IL-2 [23,25,28,31,33,37]. The bias of applicability concerns was generally low.…”

“…Furthermore, it is notable that the specific IL-2 cannot be detected in Mtb-uninfected contacts [23]. Recent studies have evaluated the auxiliary differentiating value of IL-2 for LTBI [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. However, the results vary (LTBI vs. non-TB controls: 42.9-100% of sensitivity, 91.1-100% of specificity; ATB vs. LTBI: 63.1-100% of sensitivity, 24.14-100% of specificity).…”