Evaluation of the Diagnostic Potential of IP-10 and IL-2 as Biomarkers for the Diagnosis of Active and Latent Tuberculosis in a BCG-Vaccinated Population

Abstract

BackgroundThe Mycobacterium tuberculosis (Mtb)-specific T-cell interferon gamma release assays (IGRAs) are useful in detecting Mtb infection but perform poorly at distinguishing active tuberculosis disease (ATB) and latent tuberculosis infection (LTBI). This study is aimed at evaluating additional cytokines as biomarkers besides interferon-gamma (IFN-γ) to improve the identification of ATB and LTBI.Methodology/Principal FindingsSixty-six patients with ATB, 73 household contacts (HHC) of ATB patients and 76 healthy controls (HC) were recruited to undergo QuantiFERON TB GOLD in-tube assay (QFT) and the enzyme-linked immunosorbent assay (ELISA) where the release of IFN-γ, IFN-γ inducible protein 10 (IP-10), Interleukin 2 (IL-2) and Tumor Necrosis Factor-α (TNF-α) was determined in the whole blood with or without antigen-stimulation. The positive rates of the QFT, IP-10 and IL-2 tests were 86.4%, 89.4% and 86.4% for the ATB group with no difference between them (p>0.05). However, QFT in combination with IP-10 and IL-2 significantly increased the detection rate to 95.5% in the ATB group (p = 0.03) and the indeterminate rate of all samples decreased from 2.3% (5/215) to 0.4% (1/215). The un-stimulated level of IP-10 was significantly higher in the HHC than the ATB and HC groups. The IP-10 responses were strongly associated with extended Mtb exposure time and the degree of smear-positivity of the index cases. The IL-2/IFN-γ ratio in the antigen-stimulated plasma could discriminate LTBI from ATB with a sensitivity of 77.2% and a specificity of 87.2%.ConclusionThe increased Mtb-specific antigen-stimulated expression of IP-10 and IL-2 may be useful for detecting both ATB and LTBI. Combining the QFT with IP-10 and IL-2 could increase the detection accuracy of active TB over the QFT alone.

IP-10 and MIG Are Compartmentalized at the Site of Disease during Pleural and Meningeal Tuberculosis and Are Decreased after Antituberculosis Treatment

“…Notably, IP-10 alone had an AUC of 0.92 for discriminating active TB from LTBI. In contrast, both unstimulated and M. tuberculosis antigen-stimulated IP-10 in QFT-IT supernatant could not differentiate active TB from LTBI (35,36), although M. tuberculosis antigen-stimulated IP-10 might be more robust for diagnosis of LTBI in young children and in HIV-infected individuals with low CD4 T cell counts (35,37). Since current diagnostic methods, including IGRAs and antigen-specific IP-10 detection, perform well at identifying M. tuberculosis-infected from uninfected people, combining IGRAs or antigen-specific IP-10 detection with plasma IP-10 measurement might have greater utility for the diagnosis of active TB.…”

Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

“…Wang et al reported that the IL-2/IFN-␥ ratio discriminated between active TB and LTBI with a sensitivity of 77.2% and a specificity of 87.2% (24). In addition, Frahm et al reported that the combination of IL-15 and MCP-1 identified active TB and LTBI with a sensitivity of 83% and a specificity of 88% (18).…”

“…The levels of several cytokines, including interleukin-6 (IL-6), IL-10, IL-15, chemokine (C-X-C) motif ligand (CXCL)/interferon gamma-inducible protein 10 (IP-10), and monocyte chemoattractant protein 2 (MCP-2), were significantly higher in TB patients than in healthy controls (7,11,(18)(19)(20)(21); although these finding suggest important roles for these factors in disease pathogenesis, they are not sufficient for diagnosing active as opposed to latent infections. Several studies have also suggested that biomarker combinations such as IFN-␥Ϫtumor necrosis factor alpha (TNF-␣), IFN-␥ϪIL-2, IFN-␥ϪIL-4, and IL-15ϪMCP-1 might be more sensitive than single markers (18,(22)(23)(24). However, a better biomarker to improve the sensitivity and specificity in discriminating between active TB and LTBI is still needed.…”

Association of Genetic Polymorphism of IL-2 Receptor Subunit and Tuberculosis Case

“…결핵균에 감염되 면 T cell이 활성화되어 IL-2를 분비하고 IL-2 receptor를 세 포 표면에 발현한다. 이때 IL-2는 T cell의 증식을 촉진하 고 육아종 형성에 관여하며 결핵 감염에 대한 통제 및 면 역에 핵심적인 역할을 수행한다 (Kaufmann, 2001;Wang et al, 2012;Sharma et al, 2014). IL-2 receptor 중 α chain은 β, γ chain과는 다르게 soluble한 형태로 혈중으로 유리되고 혈 중 IL-2 receptor α (IL-2Rα)의 농도는 유전자의 발현 정도 에 따라 달라진다.…”

“…IL-2 receptor 중 α chain은 β, γ chain과는 다르게 soluble한 형태로 혈중으로 유리되고 혈 중 IL-2 receptor α (IL-2Rα)의 농도는 유전자의 발현 정도 에 따라 달라진다. 따라서 혈중 IL-2Rα의 농도는 T cell 활성의 지표가 되기도 한다 (Rubin et al, 1985;Wang et al, 2012). 또한 결핵균이 잠복 감염된 환자에서 IL-2와 IFN-γ 를 모두 발현하는 T cell의 비율이 현성 감염 환자에 비하 여 높은 것으로 나타났다는 결과를 보고한 연구도 진행되 었다 (Casey et al, 2010;Sester et al, 2011).…”