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

Abstract

f Mycobacterium tuberculosis is the major causative agent of tuberculosis (TB). The gamma interferon (IFN-␥) release assay (IGRA) has been widely used to diagnose TB by testing cell-mediated immune responses but has no capacity for distinguishing between active TB and latent TB infection (LTBI). This study aims to identify a parameter that will help to discriminate active TB and LTBI. Whole-blood samples from 33 active TB patients, 20 individuals with LTBI, and 26 non-TB controls were applied to the commercial IFN-␥ release assay, QuantiFERON-TB Gold In-Tube, and plasma samples were analyzed for interleukin-2 (IL-2), IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNF-␣), IFN-␥, monokine induced by IFN-␥ (MIG), interferon gamma inducible protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant (I-TAC), and monocyte chemoattractant protein 1 (MCP-1) by using a commercial cytometric bead array. The Mycobacterium tuberculosis antigen-specific production of most of the assayed cytokines and chemokines was higher in the active TB than in the LTBI group. The mitogen-induced responses were lower in the active TB than in the LTBI group. When the ratio of TB-specific to mitogen-induced responses was calculated, IL-2, IL-6, IL-10, IL-13, TNF-␣, IFN-␥, MIG, and IP-10 were more useful in discriminating active TB from LTBI. In particular, most patients showed higher IP-10 production to Mycobacterium tuberculosis antigens than to mitogen at the individual level, and the ratio for IP-10 was the strongest indicator of active infection versus LTBI with 93.9% sensitivity and 90% specificity. In conclusion, the ratio of the TB-specific to the mitogen-induced IP-10 responses showed the most promising accuracy for discriminating active TB versus LTBI and should be further studied to determine whether it can serve as a biomarker that might help clinicians administer appropriate treatments. M ycobacterium tuberculosis, the major causative agent for tuberculosis (TB), is among the most successful human pathogens, infecting approximately 8.6 million people and leading to 1.3 million deaths each year (1). It is estimated that 2 billion people live with latent TB infection (LTBI) and are therefore a potential source of active TB (2, 3). Identifying LTBI is necessary in order to reduce the risk of development of the disease, while diagnosis of active TB can enable rapid treatment and disease control. To this end, diagnostic biomarkers that can accurately indicate disease status are needed (4, 5).There is presently no diagnostic gold standard for LTBI. Until recently, the tuberculin skin test (TST) involving the intracutaneous injection of purified protein derivative (PPD) into the forearm was the only available method for diagnosing LTBI. However, PPD cross-reacts with nontuberculous mycobacteria as well as with Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine and has poor sensitivity in immunocompromised patients (6). The interferon gamma (IFN-␥) release assay (IGRA) has been widely used in clinical practice a...

Decreased Osteopontin Expression as a Reliable Prognostic Indicator of Improvement in Pulmonary Tuberculosis: Impact of the Level of Interferon-γ-Inducible Protein 10

“…We considered different grouping criteria led to the conflicting results, as in our study, we just recruited patients with smear-positive TB, while patients were divided into minimal, advanced and far advanced TB, irrespective of sputum smear status in their research. Our findings indicate that the expression of IP-10, TNF-α, and IL-12 increases dramatically during the acute inflammatory period of TB, which were supported by previous reports [25,26]. However, changes in the expression of these soluble mediators following the initiation of treatment have not been well explored in smear-positive pulmonary TB patients.…”

“…So tracing changes of OPN is very important during recovery following the treatment initiation. CD4 + Th1 lymphocytes are required for an effective acquired immune response against MTB [25], and Th1-linked chemokines and cytokines may also be involved in disease pathogenesis [26]. IL-12 production by dendritic cells recruited to the site of infection forms an essential early step and triggers the Th1 response [27].…”

Cytokines and Chemokines inMycobacterium tuberculosisInfection

“…Further, antigen-specific IL-10 production is found in pulmonary TB patients (341, 342) and along with TNF-α production can be used to reliably distinguish between latent TB and pulmonary TB (342). In addition, increased accumulation of T REGS expressing IL-10 correlates with increased bacterial burden and more severe TB in an Indian population (343, 344) and a high level of IL-10 at the end of treatment in pulmonary TB patients is associated with TB recurrence (345).…”

The Patterns of Interferon-Gamma and Interleukin-10 Production as a Potential Immunological Biomarker for the Outcome of Mycobacterium Tuberculosis Infection

“…This is a study with limited population size, a limitation shared by many other studies in this area (20)(21)(22)(23)(24)(25). Nonetheless, the differences in the INF-y and IL-10 responses were sufficiently large enough to enable the detection of significant differences between the diagnostic groups and the time-points during treatment.…”