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Original Research: Chest Infections |

A TB Antigen-Stimulated CXCR3 Ligand Assay for the Diagnosis of Active Pulmonary TBCXCR3 Ligand Assay in Pulmonary TB FREE TO VIEW

Wou Young Chung, MD; Keu Sung Lee, MD; Yun Jung Jung, MD; Hye Lim Lee, MS; Young Sun Kim, PhD; Joo Hun Park, MD, PhD; Seung Soo Sheen, MD; Kwang Joo Park, MD, PhD
Author and Funding Information

From the Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea.

CORRESPONDENCE TO: Kwang Joo Park, MD, PhD, Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon 443-721, South Korea; e-mail: parkkj@ajou.ac.kr


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):283-291. doi:10.1378/chest.13-1855
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BACKGROUND:  The ligands for CXC chemokine receptor 3 (CXCR3) recruit T-helper type 1 cells, which play a major role in cell-mediated immunity in TB.

METHODS:  A total of 409 subjects were enrolled. The study population comprised 186 patients with active TB, 58 patients with non-TB pulmonary diseases, 50 control subjects with a positive interferon (IFN)-γ release assay (IGRA) result, and 115 control subjects with a negative IGRA result. Whole-blood samples were collected using IGRA methodology. After incubation, plasma IFN-γ levels and two CXCR3 ligands, IFN-inducible T-cell α-chemoattractant (I-TAC, CXCL11) and monokine induced by IFN-γ (MIG, CXCL9), were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) analysis was performed. Sensitivity and specificity were based on cutoff values selected to maximize the Youden index.

RESULTS:  The TB antigen-stimulated levels of IFN-γ, I-TAC, and MIG were significantly increased in the active pulmonary TB group compared with all other groups. From ROC analysis, for the diagnosis of active TB, I-TAC and MIG outperformed IFN-γ in all comparisons with the IGRA-positive and -negative control groups and the non-TB pulmonary disease group. The areas under the curve (95% CI) for differentiating active pulmonary TB from all other groups were 0.893 (0.864-0.924) for IFN-γ, 0.962 (0.946-0.978) for I-TAC, and 0.944 (0.922-0.965) for MIG. Sensitivity and specificity were 90.3% and 90.7%, respectively, for I-TAC; 92.5% and 85.2% for MIG; and 84.9% and 79.8% for IFN-γ.

CONCLUSIONS:  TB antigen-stimulated assays of I-TAC and MIG may be useful surrogate markers in the diagnosis of active pulmonary TB.

Figures in this Article

TB has long been one of the most important public health concerns worldwide.1 Effective control of TB relies on early detection and adequate treatment of the infection. However, it is difficult to achieve these goals using conventional laboratory tests.2

Because of the need for better diagnostic tools, the interferon (IFN)-γ release assay (IGRA) was developed as an alternative to the classic, century-old methodology, the tuberculin skin test (TST).3,4 Many studies have reported that the IGRA has superior sensitivity and specificity to TST for the diagnosis of active TB infection and latent TB infection (LTBI).58 However, IGRA fails to differentiate between active TB infection and LTBI, as is the case for TST.2,8,9 This limitation may be more problematic in high-endemic countries, where LTBI is prevalent and difficulties in treatment decisions are often encountered.10 Furthermore, despite earlier expectations that IGRA would possess high diagnostic accuracy, a meta-analysis revealed increasingly unsatisfactory results, including in countries with various levels of TB prevalence.8 According to this report, pooled sensitivity and specificity were 80% and 79%, respectively.

Cell-mediated immunity, particularly the T-helper type 1 (Th1) lymphocyte pathway is closely related to the pathogenesis of TB.1113 CXC chemokine receptor 3 (CXCR3) ligands act downstream of IFN-γ and more specifically toward the Th1 pathway.14,15 CXCR3 ligands comprise three chemokines: IFN-γ-inducible 10-kDa protein (IP-10, CXCL10), monokine induced by IFN-γ (MIG, CXCL9), and IFN-inducible T-cell α-chemoattractant (I-TAC, CXCL11). IP-10 has been evaluated in a whole-blood release assay in patients with TB but was not superior to IFN-γ for the diagnosis of active TB.12,16 I-TAC exhibits the most potent activity but has not been assessed in patients with TB.17 We screened the blood of the patients with TB for Th1-related chemokines and found higher levels of I-TAC and MIG than of IP-10.

We evaluated the clinical utility of I-TAC and MIG in patients suspected of having TB as well as in a control group. The former was categorized into TB and non-TB groups and the latter into IGRA-positive and -negative groups. We evaluated the diagnostic utility of these markers in Korea, where the prevalence of both active TB and LTBI remains high.18

Subjects

This study was conducted at Ajou University Hospital from January 2010 to April 2012. In total, 252 patients with suspected pulmonary TB were enrolled consecutively. The control group comprised 165 volunteer subjects who received a general health examination. All subjects were without HIV. All samples were collected from patients before the initiation of treatment. The study was approved by the Ajou University Hospital Institutional Review Board (approval number MED-SMP-12-068), and all subjects provided written informed consent.

A diagnosis of active pulmonary TB was made when Mycobacterium tuberculosis was identified in clinical specimen cultures, or in the case of negative culture results, when suggestive clinicoradiologic features were reinforced by responses to anti-TB therapy. TB lymphadenitis was diagnosed based on the presence of M tuberculosis or observation of typical pathologic findings with an appropriate response to treatment. TB pleural effusion was diagnosed based on the presence of M tuberculosis, observation of typical pathologic findings in pleural tissues, or compatible findings in cellular and biochemical analyses of the pleural fluid with an appropriate response to treatment. The diagnosis of meningeal TB was supported by cerebrospinal fluid biochemical findings. Chest CT scan was performed in 220 patients with suspected TB. The patients were assigned to a non-TB pulmonary disease group if they did not have active TB infection. The diagnosis of active TB was initially made by the physician in charge and two other investigators. The patients were followed continuously until October 2013, and the cases were independently reviewed by one radiologist and two other respiratory medicine specialists; a final decision was made by consensus.

The presence of a fibrotic lesion denotes preexisting, inactive TB. Subjects in this group presented with chest roentgenograms showing fibrotic sequelae, which were verified as stable for at least 6 months and if the sputum culture for M tuberculosis was negative. Of the control subjects, one had a history of treatment for TB, and four had fibrotic lesions.

The control subjects were subdivided into IGRA-positive and -negative groups according to their IGRA results from QuantiFERON-TB Gold In-Tube tests (Cellestis, a QIAGEN Company). To support the diagnosis of LTBI in the control subjects, the contact history of TB was assessed and stratified according to the epidemiologic risk of infection.19

Whole Blood Stimulation

Blood (1 mL) was drawn and placed into three vacutainer tubes from the QuantiFERON-TB Gold In-Tube test. The tubes were precoated with three components: saline (nonstimulated; nil tube); M tuberculosis ESAT-6, CFP10, and TB 7.7 antigens (stimulated; TB-antigen tube); or phytohemagglutinin (nonspecific positive control; mitogen tube). The tubes were incubated for 20 to 24 h at 37°C, and plasma was harvested and frozen until further analysis.

Measurement of Biomarkers

I-TAC and MIG were measured in the samples collected using the Quantikine ELISA Kit (R&D Systems, Inc). IFN-γ levels were measured using the QuantiFERON-TB Gold In-Tube ELISA (enzyme-linked immunosorbent assay).20

Statistical Analysis

Data were analyzed with SPSS, version 18 (IBM) and MedCalc, version 12.3.0.0 (MedCalc Software bvba) software. Nonnormal data are presented as median (interquartile range), unless otherwise indicated. The Kruskal-Wallis test was used for comparisons among groups, followed by Dunn post hoc test for pairwise multiple comparisons. The predictive performance was evaluated using nonparametric receiver operating characteristic (ROC) analysis. The optimal cutoff values were determined to maximize the Youden index. The Youden index is based on selecting a point that maximizes the number of subjects who are classified correctly and gives equal weight to sensitivity and specificity.21P < .05 was considered statistically significant.

Clinical Characteristics

Of 252 patients with suspected TB, eight were excluded for the following reasons: One patient died, six were lost too early in the treatment course to determine changes in their radiographic findings, and one was excluded because the final pathologic examination revealed secondary atelectasis by a subdiaphragmatic dermoid cyst. In total, there were 186 patients with TB and 58 with non-TB pulmonary disease, including pneumonia (n = 16; two with parapneumonic effusion), bronchiectasis with or without pneumonia (n = 10), stable fibrotic lesions (n = 14), lung adenocarcinoma with miliary metastasis (n = 1), and nontuberculous mycobacterial infection (n = 17).

Patient demographics and clinical features are described in Table 1. Of the 186 patients with active pulmonary TB, the acid-fast bacilli smear was positive in 104, and the M tuberculosis culture was positive in 158. Extrapulmonary TB was concurrent in 41 patients (tuberculous pleural effusion [n = 28], cervical lymphadenopathy [n = 12], meningitis [n = 1]). Four patients showed miliary dissemination patterns. Regarding the IGRA results, 178 were positive, seven were negative, and one was indeterminate in the active TB group. In the control group, 50 were positive and 115 negative. In the nontuberculous pulmonary diseases group, 30 subjects had positive and 28 had negative results.

Table Graphic Jump Location
TABLE 1  ] Study Population Characteristics

Data are presented as counts, mean ± SD, or No. (%). IGRA = interferon-γ release assay.

The results of the TB contact investigation are described in the Table 1. The low-priority community contact was not included because the accuracy of the information was considered very limited.

Assessment of CXCR3 Ligand Levels

TB antigen-stimulated IFN-γ, I-TAC, and MIG levels were all significantly higher in the active pulmonary TB group than in all other groups (Fig 1). To evaluate TB antigen-induced release of CXCR3 ligands, TB antigen-stimulated levels minus nonstimulated levels (TB antigen tube levels − nil tube levels) were obtained according to the IGRA interpretation strategy. According to this methodology, overall significance was less than these total levels (Fig 2). IFN-γ and CXCR3 ligand levels in patients with active TB did not show significant differences according to M tuberculosis culture positivity, drug resistance, treatment response, or the presence of extrapulmonary TB.

Figure Jump LinkFigure 1  A-C, Comparison of TB antigen-stimulated IFN-γ (Α), I-TAC (B), and MIG (C) levels between the patient and the control groups. Horizontal lines indicate median values. Medians and IQRs are indicated in the tables. Active TB = active pulmonary TB group; IFN = interferon; IGRA = interferon-γ release assay; IGRA + Cont = IGRA-positive control group; IGRA-Cont = IGRA-negative control group; IQR = interquartile range; I-TAC = interferon-inducible T-cell α-chemoattractant; IU = International Unit; MIG = monokine induced by interferon-γ; non-TB = non-TB pulmonary disease group.Grahic Jump Location
Figure Jump LinkFigure 2  A-C, Comparison of TB antigen-induced release (TB antigen-stimulated − nonstimulated levels) of IFN-γ (A), I-TAC (B), and MIG (C) levels between the patient and control groups. Horizontal lines indicate median values. Medians and IQRs are indicated in the table. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
ROC Analysis of CXCR3 Ligands

From ROC analysis of TB antigen-stimulated levels of CXCR3 ligands for the diagnosis of active TB, I-TAC and MIG outperformed IFN-γ in all respects. The areas under the curve (AUCs) of I-TAC and MIG were significantly higher than that of IFN-γ (P < .0001 and P < .0008, respectively), and I-TAC showed a higher AUC than MIG (P < .045). The diagnostic performance parameters are shown in Tables 2 and 3.

Table Graphic Jump Location
TABLE 2  ] Diagnostic Performance of TB Antigen-Stimulated Levels of Markers for the Differentiation of the Active Pulmonary TB Group From Other Groups

AUC = area under the curve; IFN = interferon; I-TAC = interferon-inducible T-cell α-chemoattractant; MIG = monokine induced by interferon-γ.

Table Graphic Jump Location
TABLE 3  ] Diagnostic Performance of TB Antigen-Stimulated Levels of the Markers for the Differentiation of 158 Patients With Culture-Positive Pulmonary TB From Those in Other Groups

See Table 2 legend for expansion of abbreviations.

By comparison, the ROC analysis of TB antigen-induced release levels of the markers showed less significant differences. For differentiating active TB from all other groups, the AUC of I-TAC release was 0.936 (95% CI, 0.905-0.959), and sensitivity and specificity were 89.8% and 86.1%, respectively, at a cutoff value of 497.8 pg/mL. For MIG release, the AUC was 0.918 (95% CI, 0.885-0.945), and sensitivity and specificity were 91.4% and 83.6%, respectively, at a cutoff value of 804.1 pg/mL. For IFN-γ release, the AUC was 0.897 (95% CI, 0.861-0.927), and sensitivity and specificity were 87.1% and 80.6%, respectively, at a cutoff value of 1.21 units/mL. Similar results were found for patients with positive cultures.

For differentiation of active TB from LTBI, TB contact histories as well as IGRA results were considered. Considering the lack of a definitive gold standard for LTBI, the LTBI was defined according to the various possible settings, and related ROC analysis results are shown in Table 4.

Table Graphic Jump Location
TABLE 4  ] Diagnostic Performance of TB Antigen-Stimulated Levels of the Markers for the Differentiation of Patients With Active Pulmonary TB From LTBI According to the Various Categorizations

LTBI = latent TB infection. See Table 1 and 2 legends for expansion of other abbreviations.

For differentiating control subjects with IGRA-positive results from those with IGRA-negative results, TB antigen-stimulated MIG levels had an AUC of 0.897 (95% CI, 0.840-0.939) with a sensitivity of 90% and specificity of 76% (cutoff, 800.8 pg/mL). I-TAC levels had an AUC of 0.800 (95% CI, 0.731-0.858) with a sensitivity of 70% and specificity of 78% (cutoff, 630.2 pg/mL). By comparison, TB antigen-induced release levels of MIG had an AUC of 0.943 (95% CI, 0.896-0.973) with a sensitivity of 90% and specificity of 90% (cutoff, 146.4 pg/mL). I-TAC release levels had an AUC of 0.881 (95% CI, 0.822-0.926) with a sensitivity of 80% and specificity of 85% (cutoff, 131.2 pg/mL).

The central finding of this study was that the CXCR3 ligands I-TAC and MIG were useful markers of TB using a TB antigen-stimulated whole-blood assay methodology. They provided superior differentiation of subjects with active TB from control subjects with IGRA-positive results, which generally signifies LTBI. Furthermore, these two chemokines better differentiated active TB from non-TB pulmonary diseases.

We acknowledge an important caveat to our study. We suggest a significant role for CXCR3 ligands as promising markers for the diagnosis of active TB, particularly for differentiation from LTBI. However, an exact diagnosis of LTBI is impossible with current technology.22 We attempted to obtain detailed epidemiologic data for TB contact history to support the diagnosis of LTBI. However, the diagnostic accuracy of LTBI is limited in that the contact investigation is a retrospective assessment, and our study setting, which has a high TB prevalence, further confounds the results. We applied possible settings of categorization criteria to define the LTBI group while considering the misclassification possibilities. The exclusion of low-priority community contact may underestimate the size of the LTBI group. For better determination of LTBI, a future epidemiologic study should follow a longitudinal cohort. Furthermore, the more significant differences in CXCR3 ligands than IFN-γ levels between the active TB and IGRA-positive control groups should be interpreted with caution because these two groups were originally classified based on high IFN-γ levels. Additionally, the optimal cutoffs were determined by the Youden index, which produces a balanced maximum of sensitivity and specificity. However, in the case of active TB, weighing sensitivity more than specificity may be preferred.

The superiority of CXCR3 ligands over IFN-γ may be explained by previous reports. IFN-γ exerts pleiotropic effects on the immune system, especially in the initial steps of numerous reactions. Those functions encompass a broad stimulation of macrophages, natural killer cells, and even neutrophils as well as activation of Th1 immune responses.23 CXCR3 ligands, induced by IFN-γ, target the Th1 response by binding to CXCR3 expressed on Th1 lymphocytes.14 Furthermore, CXCR3 ligands antagonize the T-helper cell type 2 response by acting on CCR3.24 The concentrations of I-TAC and MIG were 10- to 20-fold higher than the transformed concentrations of IFN-γ, with a ratio of 1 International Unit/L to 50 pg/mL. These concentration differences could also enhance their utility as clinical markers.

Of the three CXCR3 ligands, IP-10 has been most often evaluated in TB antigen-stimulated whole-blood samples. Although the utility of IP-10 was comparable to that of IGRA, it showed only limited value for the differentiation of active and LTBI.12,25 One study showed the significance of TB antigen-stimulated MIG levels for the diagnosis of active TB.13 The present results confirm the significance of MIG in a larger number of patients with active TB and control subjects with mixed IGRA positivity. I-TAC, which has not been previously evaluated using TB antigen-stimulated blood samples, showed greater discriminatory power for active TB. Previous biochemical studies showed that I-TAC had the highest potency and affinity for CXCR3 among the three ligands.23,24 Although all three CXCR3 ligands bind to CXCR3, they have nonredundant mechanisms of action.14,26,27 IP-10 is more sensitive to innate stimuli, such as type 1 IFNs (IFN-α/β) and nuclear factor-κB induction, but less dependent on IFN-γ.14

The IGRA interpretation strategy uses TB antigen-stimulated release of IFN-γ to determine positivity. For the diagnosis of active TB, however, the TB antigen-stimulated levels, which represent total augmented levels, were found to be more valid. Nonstimulated I-TAC and MIG levels were already increased in patients with TB, and consideration of only the released levels negated the already high blood levels. This approach is plausible when the theoretical background is considered. CXCR3 is expressed at high levels on activated T cells, memory T cells, and natural killer cells.28 In active TB, activated T cells are abundant due to ongoing immunologic stimulation by mycobacteria. Thus, baseline levels of CXCR3 ligands should be elevated. In contrast, in LTBI, memory T cells are more involved in immunologic manifestations.29 The incubation step in the IGRA methodology involves induction of memory T cells. Thus, in LTBI, TB antigen-induced release levels may be more valid, but this should be verified by further studies. The mitogen-stimulated CXCR3 ligand levels were mostly very high without significant intergroup differences. Thus, we measured only IFN-γ levels for the IGRA determination.

This study had some limitations. First, despite our efforts, the control group was not well matched for previous medical conditions and TB-related history. Additionally, the TB and non-TB groups had differences in demographic features, which may bias the statistical comparisons. Second, TST, a well-known test for TB latency, was not performed. However, Bacillus Calmette-Guérin vaccination is routinely given during infancy in Korea, so the validity of the TST is low. Third, patients with HIV infection were excluded from the study because of their rarity. Subjects with HIV may show different results because of their altered immune status. Finally, active TB was diagnosed from clinical findings in some patients with negative cultures. The possibility of misclassification exists, regardless of the efforts made. However, culture-proven cases showed similarly significant results when analyzed separately. Furthermore, in the clinical setting, it is more realistic to include such cases because a sizable portion is diagnosed from clinical findings, especially in countries with a high TB prevalence, and treatment is important for the control of TB.

The CXCR3 ligands I-TAC and MIG in conjunction with a TB antigen-stimulation assay methodology are superior to the IGRA method and show promise as clinical markers for the diagnosis of active pulmonary TB.

Author contributions: K. J. P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. W. Y. C. and K. J. P. contributed to study design; W. Y. C., K. S. L., Y. J. J., H. L. L., Y. S. K., J. H. P., and K. J. P. contributed to data collection; K. S. L., Y. J. J., and J. H. P. contributed to clinical assessment and management of the patients; H. L. L. and Y. S. K. contributed to sample processing and data analysis; S. S. S. contributed to the collective processing of data and statistical analysis; K. J. P. contributed to clinical evaluation and data analysis; W. Y. C. and K. J. P. contributed to the writing and revision of the manuscript; W. Y. C., K. S. L., Y. J. J., H. L. L., Y. S. K., J. H. P., and S. S. S. contributed to the approval of the article; and K. J. P. contributed to the final approval of the article.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

AUC

area under the curve

CXCR3

CXC chemokine receptor 3

IFN

interferon

IGRA

interferon-γ release assay

IP-10

interferon-γ-inducible 10-kDa protein

I-TAC

interferon-inducible T-cell α-chemoattractant

LTBI

latent TB infection

MIG

monokine induced by interferon-γ

ROC

receiver operating characteristic

Th1

T-helper type 1

TST

tuberculin skin test

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Figures

Figure Jump LinkFigure 1  A-C, Comparison of TB antigen-stimulated IFN-γ (Α), I-TAC (B), and MIG (C) levels between the patient and the control groups. Horizontal lines indicate median values. Medians and IQRs are indicated in the tables. Active TB = active pulmonary TB group; IFN = interferon; IGRA = interferon-γ release assay; IGRA + Cont = IGRA-positive control group; IGRA-Cont = IGRA-negative control group; IQR = interquartile range; I-TAC = interferon-inducible T-cell α-chemoattractant; IU = International Unit; MIG = monokine induced by interferon-γ; non-TB = non-TB pulmonary disease group.Grahic Jump Location
Figure Jump LinkFigure 2  A-C, Comparison of TB antigen-induced release (TB antigen-stimulated − nonstimulated levels) of IFN-γ (A), I-TAC (B), and MIG (C) levels between the patient and control groups. Horizontal lines indicate median values. Medians and IQRs are indicated in the table. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Study Population Characteristics

Data are presented as counts, mean ± SD, or No. (%). IGRA = interferon-γ release assay.

Table Graphic Jump Location
TABLE 2  ] Diagnostic Performance of TB Antigen-Stimulated Levels of Markers for the Differentiation of the Active Pulmonary TB Group From Other Groups

AUC = area under the curve; IFN = interferon; I-TAC = interferon-inducible T-cell α-chemoattractant; MIG = monokine induced by interferon-γ.

Table Graphic Jump Location
TABLE 3  ] Diagnostic Performance of TB Antigen-Stimulated Levels of the Markers for the Differentiation of 158 Patients With Culture-Positive Pulmonary TB From Those in Other Groups

See Table 2 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4  ] Diagnostic Performance of TB Antigen-Stimulated Levels of the Markers for the Differentiation of Patients With Active Pulmonary TB From LTBI According to the Various Categorizations

LTBI = latent TB infection. See Table 1 and 2 legends for expansion of other abbreviations.

References

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