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First published online on May 15, 2007
Chest, doi:10.1378/chest.06-2805
doi:10.1378/chest.06-2805
(Chest. 2007; 132:959-965)
© 2007 American College of Chest Physicians
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Usefulness of Whole-Blood Interferon-{gamma} Assay and Interferon-{gamma} Enzyme-Linked Immunospot Assay in the Diagnosis of Active Pulmonary Tuberculosis*

Young Ae Kang, MD; Hye Won Lee, MSc; Seung Sik Hwang, MD; Sang-Won Um, MD; Sung Koo Han, MD; Young-Soo Shim, MD and Jae-Joon Yim, MD

* From the Division of Pulmonary and Critical Care Medicine (Drs. Kang, Um, Han, Shim, and Yim, and Ms. Lee), Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul; and the National Cancer Control Research Institute (Dr. Hwang), National Cancer Center, Goyang, South Korea.

Correspondence to: Jae-Joon Yim, MD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110–744, South Korea; e-mail: yimjj{at}snu.ac.kr

Abstract

Purpose: The aim of this study was to evaluate the usefulness of the whole-blood interferon-{gamma} assay (enzyme-linked immunosorbent assay [ELISA]) and interferon-{gamma} enzyme-linked immunospot assay (ELISPOT) based on early secretory antigenic target 6 and culture filtrate protein 10 in the diagnosis of active pulmonary tuberculosis (TB) in routine clinical practice.

Method: We conducted a prospective study enrolling 144 participants with suspected pulmonary TB in a tertiary referral hospital in Seoul, South Korea, to investigate the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tests. Clinical assessment, tuberculin skin test (TST), whole-blood interferon-{gamma} ELISA (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia), and an ELISPOT assay (T SPOT.TB; Oxford Immunotec; Oxford, UK) were performed. Test results were compared with the final confirmed diagnoses.

Results: Active pulmonary TB was diagnosed in 67 of 144 participants (47%). Sensitivities of QFT-G and T SPOT.TB for active pulmonary TB were 89% (95% confidence interval [CI], 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%; 95% CI, 69 to 93%) and T SPOT.TB (87%; 95% CI, 73 to 96%) were higher than that of TST (64%; 95% CI, 51 to 76%) [p = 0.001 and p < 0.001, respectively].

Conclusion: High NPVs of QFT-G and T SPOT.TB for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB, although the low PPV limits their usefulness in routine clinical practice in South Korea, where the prevalence of latent TB infection is considerable.

Key Words: culture filtrate protein 10 • diagnosis • early secretory antigenic target 6 • interferon-{gamma} • tuberculosis

Tuberculosis (TB) is the most important single infectious cause of mortality and morbidity worldwide, with approximately 2 million deaths annually and 9 million new cases in 2004 reported.123 For the effective and efficient control of TB in developing countries, rapid diagnosis and treatment for active TB patients is the mainstay of the TB control program. However, acid-fast staining of sputum has a sensitivity of only 50 to 60%, and mycobacterial culture usually requires 6 to 8 weeks to be interpretable.456 A rapid diagnosis is crucial not only for patients, but also for TB control in the community.

Recently introduced immunodiagnostic tests for TB infection based on the Mycobacterium tuberculosis-specific antigens early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) include a whole-blood interferon-{gamma} enzyme-linked immunosorbent assay (ELISA) and an enzyme-linked immunospot assay (ELISPOT). A commercial whole-blood interferon-{gamma} ELISA assay (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia) measures the level of interferon-{gamma} in the supernatant of the stimulated whole blood by M tuberculosis-specific antigens ESAT-6 and CFP-10. However, the T SPOT.TB assay (Oxford Immunotec; Oxford, UK) enumerates individual T cells producing interferon-{gamma} among peripheral blood mononuclear cells after M tuberculosis-specific antigenic stimulation using ELISPOT.7 Both tests have shown promising results in the detection of latent TB infection (LTBI).891011 Although these assays were not designed to discriminate between LTBI and active TB disease, the high positive response rates observed in previous studies121314 among patients with active TB disease suggest possible roles for these tests as adjunct diagnostic techniques for active TB disease.

Subsequently, the QFT-G test has been used for the differential diagnosis of active TB in some clinical settings.15 On the basis of these data, the US Food and Drug Administration approved the use of QFT-G for the diagnosis of active TB as well as LTBI.16 The commercially available T SPOT.TB assay also has been approved for diagnostic use in Europe, and its usefulness has been tested in the diagnosis of both LTBI and active TB diseases.1718

Although some clinical data have been reported regarding the diagnostic usefulness of QFT-G and T SPOT.TB assays for active TB disease,121315171920 there has been no report on a direct comparison of QFT-G and T SPOT.TB assays in the diagnosis of active pulmonary TB in patients with clinically suspected TB. The aim of this study was to estimate and compare the usefulness of whole-blood interferon-{gamma} ELISA and ELISPOT assays based on the M tuberculosis-specific antigens ESAT-6 and CFP-10. This was compared with that of the tuberculin skin test (TST) in the diagnosis of active TB disease in routine clinical practice in Korea, where the incidence of active pulmonary TB is intermediate (90/105 cases per year)21 and bacille Calmette-Guérin (BCG) vaccination has been mandatory at birth.

Materials and Methods

Participants
Participants were recruited from December 2004 to December 2005, after the protocol had been approved by the Seoul National University Hospital Ethics Review Committee. All enrolled patients who were suspected of having active pulmonary TB based on clinical symptoms and a radiographic examination were prospectively recruited from the Seoul National University Hospital. After giving written informed consent, each patient was asked to complete a questionnaire about his or her previous TB history, contact with patients known to have TB, family history, and other medical conditions and treatments.

Determination of the Number of Participants
The sample size was determined by the following factors: the incidence of active TB in Korea, previously reported positive response rates to QFT-G and T SPOT.TB assays in patients with active TB,131422 type I error and power, and the expected difference in the positive response rate. We used a value of 80% for the positive response rate for QFT-G and T SPOT.TB assays, with a type I error of 0.05, a power of 0.80, and a 10% expected difference. Using these parameters and assumptions, and a previously described method,23 the minimum sample size was estimated to be 152.

Procedures
We performed a full physical examination of all participants, including chest radiography and sputum microbiological examination. At the same time, 12 mL of peripheral blood were drawn from each subject for the QFT-G and T SPOT.TB assays. After blood sampling, the TST was performed. The results of these tests were compared with the final diagnoses.

Definitions and Diagnoses
Active Pulmonary TB: Final diagnoses were made on the basis of all clinical, radiologic, microbiological, and pathologic information collected after recruitment and during a follow-up of at least 3 months. Active pulmonary TB was confirmed by the culture of M tuberculosis from sputum or by the presence of caseating granuloma in the lung tissues, obtained through the transthoracic needle biopsy, of patients in whom mass-like consolidation was evident from chest radiographs. Patients with high clinical likelihood of active TB and a negative mycobacterial culture finding, but with good clinical and radiographic responses to anti-TB treatment during follow-up were excluded from the final analysis.

Fibrotic TB Sequelae: Fibrotic TB sequelae were defined as "nodulo-streaky" lesions in the upper lobes that had not changed for at least 3 months, with negative mycobacterial culture findings of the sputum.

Nontuberculous Mycobacteriosis: Patients with culture findings positive for nontuberculous mycobacteria (NTM) in their sputum, including both colonization and NTM lung disease, were classified as having nontuberculous mycobacteriosis.

Whole-Blood Interferon-{gamma} Assay: The QFT-G assay was performed in two stages according to the instructions of the manufacturer. First, 1 mL of heparinized whole blood was incubated with aliquots of antigen (ESAT-6, CFP 10, or phytohemagglutinin) or the antigen-free control for 16 to 24 h at 37°C in a CO2 incubator. Then, after overnight incubation, 200 µL of plasma was removed from each well and the concentration of interferon-{gamma} was determined using the assay kit according to the instructions of the manufacturer. The cutoff value for a positive response was 0.35 IU/mL of interferon-{gamma}.813

Interferon-{gamma} ELISPOT Assay: The T SPOT.TB test was performed according to the instructions included in the assay kit. Peripheral blood mononuclear cells were isolated by standard Ficoll-Hypaque density-gradient centrifugation from 8 mL of heparinized blood. Four wells of a 96-well microtitre plate precoated with monoclonal antibodies directed against interferon-{gamma} were seeded with 2 x 105 peripheral blood mononuclear cells per well. The plates were incubated for 16 to 20 h at 37°C in a CO2 incubator with an antigen-free negative control or antigen (ESAT-6, panel A; CFP-10, panel B; and phytohemagglutinin). The plates were then washed with phosphate-buffered saline solution (PBS) and incubated with 50 µL of alkaline-phosphatase-conjugated anti-interferon-{gamma} monoclonal antibody. After 2 h at 4°C, the plates were washed again with PBS, and 50 µL of chromogenic substrate was added for 7 min. The reaction was observed visually and stopped with PBS. Assays were scored using an automated ELISPOT plate reader (AID GmbH; Strassberg, Germany). Test wells were scored as positive if they contained at least five spot-forming cells more than the negative control well, and if this number was at least twice the number in the negative control well.912

TST: After the blood samples were collected for the QFT-G and T SPOT.TB assays, a TST was performed on the volar side of the forearm using the Mantoux method24 with two tuberculin units of purified protein derivative (RT 23; Statens Serum Institut; Copenhagen, Denmark). Any indurations were measured in millimeters 48 to 72 h later using the ball-point method.25 We used the 10-mm induration as a positive cutoff value for the TST.

Statistical Methods
Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio of a positive test result, and likelihood ratio of a negative test result for the diagnosis of active TB disease were calculated for each diagnostic test. Ninety-five percent confidence intervals (CIs) were estimated according to the binomial distribution. A {chi}2 test was used to compare the positive proportions, p values < 0.05 were considered significant, and Bonferroni correction was used for multiple comparisons. Concordance between test results from the TST, QFT-G assay, and T SPOT.TB assay was assessed using {kappa} coefficients ({kappa} > 0.75, excellent agreement; {kappa} < 0.4, poor agreement; {kappa} ≥ 0.04 and ≤ 0.75, fair to good agreement).26 Analyses were performed using statistical software (Stata version 9.2; StataCorp; College Station, TX).

Results

Demographics of the Participants
Overall, 154 patients were recruited. Ten patients were excluded from further analysis because of inconclusive final diagnoses based on clinical evidence. Baseline characteristics for all 144 patients with a presumptive diagnosis of active TB are shown in Table 1 . All participants were HIV negative, although 20 patients had risk factors for immunosuppression, such as transplantation, hematologic malignancy, solid cancer undergoing chemotherapy, and end-stage renal disease. Active TB was diagnosed in 67 patients (47%) [confirmed by bacteriology, n = 58; confirmed by pathology, n = 9]. Of the 58 patients with active pulmonary TB, 25 patients (37%) had positive acid-fast–stained sputum smears.


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  		Table 1.. Demographic and Clinical Characteristics of the 144 Patients With Suspected Diagnosis of Active Pulmonary TB*

 
Results of TST, QFT-G, and T SPOT.TB Assays
TST, QFT-G, and T SPOT.TB results are missing for three, one, and three participants, respectively. The reason for missing results were the omission of second visit for reading of TST result, and the inappropriate handlings of blood sample for QFT-G and T SPOT.TB assays. Of the 143 QFT-G tests performed, five patients (3.5%) had an indeterminate result attributable to a low response to the mitogen included in the kit as a positive control. Among these five patients, three had hematologic or solid cancers and were undergoing courses of anticancer chemotherapy; invasive aspergillosis was diagnosed in one of these patients. Similarly, the T SPOT.TB assay produced four indeterminate results (3%) from 141 tests. Two of these patients also showed an indeterminate result on the QFT-G test, and the other two participants had no risk factors for immunosuppression.

When using 10 mm of induration as the cutoff for a positive TST finding, results were positive in 82 patients (58.2%), 45 of whom had active pulmonary TB diagnosed. Negative TST results were observed in 59 patients (41.8%), 21 of whom had active pulmonary TB diagnosed. QFT-G findings were positive in 95 patients (68.8%), 58 of whom had active pulmonary TB diagnosed; and the results of the assay were negative in 43 patients (31.2%), 7 of whom had active pulmonary TB diagnosed. T SPOT.TB showed positive results in 98 patients (71.5%), 59 of whom had active TB diagnosed. T SPOT.TB results were negative in 39 patients (28.5%), 5 of whom had active TB diagnosed.

Diagnostic Validity of Acid-Fast Staining of Sputa, TST, QFT-G, and T SPOT.TB Assays
Sensitivity of the TST in the diagnosis of active TB, taking a 10-mm induration as the cutoff, was 68% (95% CI, 56 to 79%), and its specificity was 51% (95% CI, 39 to 62%). However, sensitivities of QFT-G and T SPOT.TB in the diagnosis of active pulmonary TB were 89% (95% CI, 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and their specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%, 95% CI; 69 to 93%) and T SPOT.TB (87%, 95% CI; 73 to 96%) in the diagnosis of active pulmonary TB were higher than that of TST (64%, 95% CI; 51 to 76%) [p = 0.001 and p < 0.001, respectively; Table 2 ]


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  		Table 2.. Diagnostic Validity of the Acid-Fast Staining of Sputa, TST, QFT-G, and T SPOT.TB*

 
Clinical Characteristics of Participants With False-Positive or False-Negative Results
The TST gave false-positive results in 37 of 141 patients. The QFT-G and T SPOT.TB tests also produced false-positive results in 37 of 138 participants and in 39 of 137 participants, respectively. More than half of these patients had a history of TB or fibrotic TB sequelae suggesting spontaneously healed TB (Table 3 ).


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  		Table 3.. Clinical Characteristics of Participants With False-Positive Results*

 
Twenty-one participants had false-negative results on the TST, 7 patients had false-negative results on the QFT-G, and 5 patients had false-negative results on the T SPOT.TB. Eight of 21 patients with false-negative TST results had more than one risk factor for false-negative results, such as metabolic derangements or immunosuppressive medication. One patient with a false-negative QFT-G result and three patients with false-negative T SPOT.TB results had one or more risk factors for false-negative results (Table 4 ).


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  		Table 4.. Clinical Characteristics of Participants With False-Negative Results*

 
Concordance Between Tests in TB and Non-TB Patients
Table 5 shows the concordance between the TST, QFT-G, and T SPOT.TB assays. The QFT-G and T SPOT.TB assays showed good agreement in all participants ({kappa} = 0.58) and excellent agreement in those with active pulmonary TB diagnosed ({kappa} = 0.77). However, the overall agreement between TST and QFT-G was poor ({kappa} = 0.37). Similarly, the concordance was poor between the TST and T SPOT.TB assays ({kappa} = 0.27 overall, {kappa} = 0.04 for TB).


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  		Table 5.. Concordance ({kappa}) of TST, QFT-G, and T SPOT.TB

 
Discussion

Our study showed higher sensitivities for the QFT-G (89%) and T SPOT.TB (92%) tests than for the TST (68%) in the diagnosis of active pulmonary TB. Considering the TST has been evaluated for the diagnostic exclusion of active pulmonary TB,272829 the QFT-G and T SPOT.TB tests could be more useful in terms of the differential diagnosis of TB. Especially, the relative high NPVs of QFT-G (84%) and T SPOT.TB (87%) suggest the adjunct role of these tests for the exclusion of the diagnosis of active TB.

However, the low specificities of these two tests, 49% for QFT-G and 47% for T SPOT.TB, limit their usefulness in routine clinical practice, at least in South Korea. Specificities of the tests in this study were poor for active pulmonary TB compared with previously reported data.1314223031 Several factors should be considered to correctly appreciate these lower specificities. First, these results could be explained by the fact that the QFT-G and T SPOT.TB tests do not differentiate active TB disease from LTBI. The high prevalence of LTBI, as high as 30% among Koreans,32 inevitably decreases the specificity of QFT-G and T SPOT.TB for active pulmonary TB. Second, this study was designed to evaluate the diagnostic validity of QFT-G and T SPOT.TB in routine clinical practice, and thus focused on unselected patients with suspected active TB. In this setting, the diagnostic validity tends to be lower than that in studies in which healthy people are enrolled as negative controls and patients with active TB as positive controls.

Although previous studies have reported a higher sensitivity for the T SPOT.TB test relative to that of the QFT-G test,2031 and a higher rate of indeterminate results with the QFT-G test (of 10%, 11%, and 23%)152033 than with the T SPOT.TB test (of 1%, 3%, and 4.7%),172034 the sensitivity and specificity of QFT-G and T SPOT.TB tests were not significantly different in our study, and the rates of indeterminate results were similar for both tests. The frequencies of indeterminate results among immunocompromised hosts were similar in our study (3.5% and 3% for the T SPOT.TB and QFT-G tests, respectively) despite previous studies183334 that have suggested that the T SPOT.TB test produces indefinite results less frequently than the QFT-G test especially among immunocompromised hosts. Our data suggest similar levels of diagnostic values and performances for the two tests in terms of diagnosis of active pulmonary TB.

To appreciate our results correctly, we should consider the limitations of this study. First, this study was performed in an area where BCG vaccination is mandatory and the prevalence of LTBI is considerable. In this context, we should be very cautious to generalize the lower specificity of two assays in the diagnosis of active pulmonary TB. Second, the comparable performances of two assays also could not be concluded because this study included a small number of immunocompromised patients. A study involving more patients with immunocompromised conditions in areas with a low prevalence of LTBI could complement the limitations of our study.

In conclusion, the high NPV of whole-blood interferon-{gamma} ELISA and ELISPOT assays based on the M tuberculosis-specific antigens ESAT-6 and CFP-10 for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB disease. However, high false-positive rates of these tests limit their usefulness in routine clinical practice in South Korea, where the prevalence of LTBI is considerable. In this context, these tests could be more valuable in the diagnosis of active pulmonary TB in areas with a lower prevalence of LTBI.

Acknowledgements

We thank the numerous individuals who volunteered to participate in this study. We also acknowledge the insightful contributions of Young Whan Kim, MD, Chul-Gyu Yoo, MD, Sang Min Lee, MD, and Chang-Hoon Lee, MD. T SPOT.TB test kits were donated by LK BioScience (Seoul, Republic of Korea), and part of the QuantiFERON-TB Gold assay kit was donated by Woongbee Meditech (Seoul, Republic of Korea).

Footnotes

Abbreviations: BCG = bacille Calmette-Guérin; CFP-10 = culture filtrate protein 10; CI = confidence interval; ELISA = enzyme-linked immunosorbent assay; ELISPOT = enzyme-linked immunospot assay; ESAT-6 = early secretory antigenic target 6; LTBI = latent tuberculosis infection; NPV = negative predictive value; NTM = nontuberculous mycobacteria; PBS = phosphate-buffered saline solution; PPV = positive predictive value; QFT-G = QuantiFERON-TB Gold; TB = tuberculosis; TST = tuberculin skin test

This work was performed at the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, South Korea.

The authors have no conflicts of interest to disclose.

Received for publication November 18, 2006. Accepted for publication April 13, 2007.

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