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Clinical Reevaluation of the QuantiFERON TB-2G Test as a Diagnostic Method for Differentiating Active Tuberculosis from Nontuberculous Mycobacteriosis

  1. Yoshihiro Kobashi,
  2. Yasushi Obase,
  3. Minoru Fukuda,
  4. Kouichiro Yoshida,
  5. Naoyuki Miyashita, and
  6. Mikio Oka
  1. Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan
  1. Reprints or correspondence: Dr. Yoshihiro Kobashi, Div. of Respiratory Diseases, Dept. of Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan 701-0192 (yoshihiro{at}med.kawasaki-m.ac.jp).
 
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Abstract

Introduction. We reevaluated the usefulness of a whole-blood interferon-γ enzyme-linked immunosorbent assay (QuantiFERON TB-2G [QFT-TB]; Cellestis) in obtaining a differential diagnosis between active tuberculosis (TB) and nontuberculous mycobacteriosis (NTM).

Methods.The subjects were 50 healthy volunteers, 50 patients with active TB, and 100 patients with NTM who satisfied the diagnostic guidelines of the American Thoracic Society from April 2005 through June 2006. The tuberculin skin test (TST) and the QFT-TB test were performed for all subjects. The QFT-TB test was performed every 2 months.

Results. Of the healthy volunteers, 64% had a negative TST result and 94% had a negative QFT-TB test result. Of the patients with active TB, 64% had a positive TST result and 4% had a negative QFT-TB test result. Of the patients with pulmonary Mycobacterium avium complex disease, 60% had a positive TST result and 7% had a positive QFT-TB test result. The QFT-TB test had a mean sensitivity of 86% and a mean specificity of 94%. The QFT-TB test results for patients with active TB transiently decreased during treatment involving antituberculous drugs. The rate of positive QFT-TB test results was 86% at the initiation of treatment, 48% 6 months later, and 33% 12 months later.

Conclusions. We confirmed that the QFT-TB test is a useful diagnostic method for differentiating active pulmonary TB from NTM, compared with the TST. However, because it is possible that the effect of the QFT-TB test may be long lasting after treatment and may not be resolved over time, even with treatment, as in this study, it may not provide any level of certainty regarding cure of infection.

The standard immunological diagnostic tool for the diagnosis of tuberculosis (TB), the tuberculin skin test (TST), has many well-known shortcomings. Two health care visits are required to complete the test. In addition, because the PPDs of tuberculin contain many antigens that are shared with other bacteria, the TST does not reliably distinguish TB resulting either from previous immunization with the bacille Calmette-Guérin (BCG) vaccine or from most nontuberculous mycobacteria [1]. This is a major problem in Japan, because a growing proportion of individuals with TB are foreign-born persons from developing countries that have a high incidence of TB and are affected by the HIV pandemic, and most of these individuals received BCG vaccination during childhood [2, 3]. A more immunologically accurate and convenient test for the diagnosis of TB would greatly enhance efforts regarding tuberculosis control [4].

Tests can detect T cells that produce IFN-γ in response to early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10), with an ELISA used to measure IFN-γ concentrations in supernatants (QuantiFERON TB-2G [QFT-TB]; Cellestis) or an enzyme-linked immunospot assay used to detect individual T cells producing IFN-γ (T SPOT-TB; Oxford Immunotec) [5–8]. The US Food and Drug Administration has approved the QFT-TB test and is evaluating the T SPOT-TB test, which has been approved for use in Europe. These tests reveal a positive result for most persons with a high likelihood of TB and a negative result for BCG-vaccinated individuals with a low likelihood of TB. Of these tests, the QFT-TB test was first used commercially in Japan in April 2005 for the diagnosis of TB. However, there was no reference standard interpretation of QFT-TB test results for IFN-γ concentrations in test samples. Thereafter, in December 2005, the Centers for Disease Control and Prevention proposed guidelines for using the QFT-TB test to detect TB infection in the United States [9]. Therefore, we reevaluated the specificity and sensitivity of the QFT-TB test for the identification of patients with active TB and healthy volunteers without TB, in a predominantly BCG-vaccinated population in Japan, according to the guidelines proposed by the Centers for Disease Control and Prevention [9].

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Subjects and Methods

Study population. The study was approved by the ethics committee at Kawasaki Medical School. Fifty patients who had active TB that was confirmed by culture of sputum, bronchoalveolar lavage fluid, or pleural fluid samples to be positive for TB, as well as 100 patients with nontuberculous mycobacteriosis (NTM) that satisfied the diagnostic criteria of the American Thoracic Society [10], were prospectively enrolled from April 2005 through June 2006. Fifty Kawasaki Medical School students (age, 22–26 years) participated in this study as healthy control subjects. The patients received their diagnosis at Kawasaki Medical School Hospital (1072 beds), Kawasaki Medical School Kawasaki Hospital (650 beds), or Asahigaoka Hospital (90 beds). We obtained written, informed consent from all participants in this study. Healthy volunteers (28% of patients), patients with active TB (74%), and patients with NTM (76%) had negative results of serological tests for HIV or had no obvious risk factors for HIV infection. From the healthy volunteers, we collected demographic data regarding (1) any history of previous TB or exposure to a person with TB, (2) other risk factors for TB (i.e., HIV infection, leukemia, lymphoma, diabetes mellitus, or renal failure), and (3) receipt of immunosuppressive drugs within the 3 months before enrollment in this study. Information regarding any previous Mantoux TST results and BCG NTM, as well as information about clinical symptoms and laboratory findings, was collected at the time of enrollment. Sputum or other appropriate respiratory samples were collected from all patients, and culture samples were obtained for the detection for mycobacteria.

Sample collection and TST. Each subject had a heparinized blood sample collected by venipuncture for the whole-blood IFN-γ assay. Blood samples were collected before administration of the Mantoux TST. For the TST, 0.1 mL of tuberculin PPD (Nippon BCG; equivalent to ∼3 tuberculin units of PPD solution) was injected intradermally into the volar aspect of the forearm, and the transverse induration diameter was measured 48 h later.

QFT-TB test. The QFT-TB test was performed according to the recommendations of the manufacturer (Cellestis). In brief, the test consisted of a negative control (a nil well [i.e., whole blood without antigens or mitogen]), a positive control (a mitogen well [i.e., whole blood stimulated with the mitogen photohemaggulutinin]), and 2 sample wells (i.e., whole blood stimulated with either ESAT-6 or CFP-10). Whole blood specimens were incubated for 18 h (overnight) at 37°C in a humidified atmosphere. The IFN-γ level of the nil well was considered to be the background value and was subtracted from the values for the mitogen well and the antigen-stimulated wells. The test result was considered to be positive if the IFN-γ level in the sample well after stimulation with ESAT-6 and/or CFP-10 was ⩾0.35 IU/mL (after subtraction of the value for the nil well), irrespective of the result for the positive control well. The test result was considered to be negative if the IFN-γ level was <0.35 IU/mL and if the IFN-γ level of the positive control well (after subtraction of the value for the nil well) was ⩾0.5 IU/mL. The test result was considered to be indeterminate if the IFN-γ level was <0.35 IU/mL in both antigen wells and <0.5 IU/mL in the positive control well. The QFT-TB test was performed for all patients before initiation of administration of antituberculous drugs and was performed again 2, 4, 6, 9, and 12 months later during the treatment of active TB.

Statistical analysis. Information from the questionnaires, TST results, and whole blood IFN-γ assay results were entered into Excel 2000 software (Microsoft) and then were transferred to Santa software, version 7.0 (Santa), for statistical analysis. The analysis consisted of the Student's t test, for evaluating differences in means on the basis of logarithmic transformation of the IFN-γ measurements; the χ2 test, for testing the difference in proportions; exact binomial methods, to compute confidence intervals for proportions; and maximum-likelihood logistic regression, to estimate the strength of the association between the duration of antituberculous treatment and the results of the whole blood IFN-γ assay and the TST. The sensitivity, specificity, positive predictive value, and negative predictive value (and 95% CIs) of the QFT-TB test (with CFP-10 and ESAT-6) were calculated by comparing individuals with active TB with a control group of patients with NTM.

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Results

The subjects were enrolled in the study from April 2005 through June 2006. Fifty Kawasaki Medical School students (32 men and 18 women) participated as healthy volunteers (74% of these volunteers received BCG vaccination). The mean age of the healthy volunteers was 24 years (range, 22–26 years). None of these subjects had any history of previous TB infection or had experienced such immunosuppressive conditions as HIV infection, leukemia, lymphoma, diabetes mellitus, or renal failure. There were 50 patients with active TB (31 had pulmonary TB, 6 had pulmonary tuberculoma, 4 had tuberculous pleuritis, 4 had pulmonary TB and tuberculous pleuritis, 3 had cervical tuberculous lymphangitis, and 2 had tuberculous peritonitis). Acid-fast smear results for sputum, bronchoalveolar lavage fluid, or pleural fluid samples were positive for 28 of 50 patients with culture-positive TB (i.e., active TB). The remaining 22 patients had acid-fast smear–negative and culture-positive results for TB. A total of 100 patients (31 men and 69 women) had NTM that satisfied the diagnostic criteria of the American Thoracic Society guidelines (the causative microorganism was Mycobacterium avium in 50 patients, Mycobacterium intracellulare in 44, Mycobacterium kansasii in 4, and Mycobacterium marinum in 2). The mean age of the patients with pulmonary NTM was 59 years (range, 34–78 years). There was a significant difference in the sex distribution between the patients with active TB and the patients with NTM (table 1).

Table 1
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Table 1

Characteristics of 50 patients with active tuberculosis (TB) and 100 patients with pulmonary nontuberculosis mycobacteriosis (NTM).

Thirty-seven subjects (74%) reported having received BCG vaccination at least once by the time of graduation from junior high school. The TST result was positive for 36% of the healthy volunteers, and all of them had been vaccinated with BCG. However, no healthy volunteers had a positive QFT-TB test result. Ninety-four percent of the volunteers had negative results, and 6% of them had indeterminate results (table 2).

Table 2
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Table 2

Comparison between results of the QuantiFERON TB-2G (QFT-TB) test and the tuberculin skin test (TST) for 50 healthy volunteers.

The TST result was positive for 64% but negative for 36% of 50 patients with active TB. Patients with active TB had a rate of positive results of the QFT-TB test (86%) that was significantly higher than that of the TST (64%) (P < .05) (table 3). Twenty-five (89%) of 28 patients who were smear positive for TB also had positive QFT-TB results. Eighteen (82%) of 22 patients who were smear negative and culture positive for TB showed QFT-TB results before culture results. Those results were negative for 2 patients (4%) and indeterminate for 5 patients (12%). The rate of false-negative results of the QFT-TB test (4%) was also significantly lower than that of the TST (36%) (P < .05). Two patients who had a false-negative QFT-TB result and 4 patients who had an indeterminate QFT-TB result were immunocompromised hosts who had a severe underlying disease, and severe lymphocytopenia was recognized in the peripheral blood of these patients (table 4). However, they had negative results of serological tests for HIV. Two patients were considered to have negative results because the positive control of the QFT-TB test was >0.5 IU/mL for either ESAT-6 or CFP-10 (one was 0.65 IU/mL for ESAT-6, and the other was 0.84 IU/mL for ESAT-6). The results were considered to be indeterminate for 4 patients because the positive control for the QFT-TB test was <0.5 IU/mL for both ESAT-6 and CFP-10. Only 1 patient was immunocompetent and had positive TST results, and he also had negative results of serological tests for HIV. For this patient, a diagnosis of pulmonary tuberculoma was made by bronchoscopy (table 4).

Table 3
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Table 3

Comparison between results of the QuantiFERON TB-2G (QFT-TB) test and the tuberculin skin test (TST) for 50 patients with active tuberculosis.

Table 4
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Table 4

Clinical findings for patients with tuberculosis (TB) who had false-negative or indeterminate QuantiFERON TB-2G (QFT-TB) test results.

As for the specificity, sensitivity, positive predictive value, and negative predictive value of CFP-10 and ESAT-6 for the diagnosis of active TB, by use of the cutoff value (0.35 IU/mL), the mean specificities (with 95% CIs) of CFP-10 and ESAT-6 were 93.0% (92.0%–95.6%) and 94.6% (92.6%–96.0%), respectively; the mean sensitivities were 74.8% (68.6%–81.4%) and 81.7% (74.5%–88.0%), respectively; the mean positive predictive values were 27.5% (17.6%–38.0%) and 34.1% (24.3%–44.9%), respectively; and the mean negative predictive values were 92.0% (88.3%–94.8%) and 95.2% (91.7%–97.8%), respectively. If the data from CFP-10 and ESAT-6 were combined and a person was found to be positive for at least 1 of 2 antigens, he or she was judged to have a positive test result; the mean sensitivity was 86.0% (95% CI, 82.2%–90.5%), the mean specificity was 94.0% (95% CI, 92.1%–96.8%), the mean positive predictive value was 16.7% (95% CI, 11.8%–22.8%), and the mean negative predictive value was 96.1% (95% CI, 92.5%–98.3%).

The rate of positive results, according to causative microorganism detected, was 8% for M. avium, 7% for M. intracellulare, 100% for M. kansasii, and 100% for M. marinum (table 5). The rate of positive results associated with the TST (60%) was significantly higher than that associated with the QFT-TB test (7%) for patients with pulmonary M. avium complex (MAC) disease, and most of these patients had received BCG vaccination (table 6). Five of 7 patients with positive QFT-TB results had a history of previous healed pulmonary TB. Although the details of treatment were unknown, the patients had received treatment for pulmonary TB. Two of them had received antituberculous treatment within 2–3 years, 1 had received antituberculous treatment within 5 years, and the remaining 2 had received antituberculous treatment within 10 years.

Table 5
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Table 5

Results of the QuantiFERON TB-2G (QFT-TB) test performed for patients with nontuberculous mycobacteriosis (NTM).

Table 6
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Table 6

Comparison of QuantiFERON TB-2G (QFT-TB) and tuberculin skin test (TST) results for 94 patients with nontuberculous mycobacteriosis (Mycobacterium avium complex disease).

Finally, in investigating transitional changes in the QFT-TB test results for the patients with active TB after the initiation of treatment involving antituberculous drugs, the rate of positive QFT-TB results first slightly increased and then gradually decreased, with a rate of 86% noted before treatment, 90% 2 months later, 69% 4 months later, 50% 6 months later, 43% 9 months later, and 33% 12 months later (table 7). Regarding the clinical course of disease in patients with TB who had completed treatment and who had the QFT-TB test performed during a 12-month period, all 21 patients had a good response to the treatment involving antituberculous drugs. Despite the good clinical effects noted, however, 7 patients still had a positive QFT-TB test result.

Table 7
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Table 7

Transitional change of QuantiFERON TB-2G (QFT-TB) test results for patients with active tuberculosis receiving treatment involving antituberculous drugs.

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Discussion

Regarding the specificity and sensitivity of the QFT-TB test, Mori et al. [6] reported a sensitivity of 89% in a selected population of patients with clinical signs suggestive of TB. They reported a specificity of 98% in low-risk subjects who had been vaccinated with BCG and who were assumed to be truly free of TB. Although another blind prospective study involving 82 patients with a high level of clinical suspicion for active TB showed that the QuantiFERON TB-2G test encoded by the gene located within the region of difference 1 (QFT-RD1 test) was 85% sensitive for active TB, ∼10% of these patients had indeterminate QFT-TB results [11]. In the present study, when we made use of an IFN-γ cutoff value for positive and negative judgment according to the guidelines proposed by the Centers for Disease Control and Prevention [9], the specificity (94.0%) and sensitivity (86.0%) of the QFT-TB test were much better than those associated with the TST [12]. These results were as excellent as the results of Mori et al. [6], when compared with the results of the TST [12], even though there were many BCG-vaccinated volunteers and patients with active TB or NTM. As reported elsewhere [6, 10, 13], the QFT-TB test has not been influenced by BCG vaccination status. Our results also confirmed that the QFT-TB test had a higher specificity and supported the usefulness of the QFT-TB test in BCG-vaccinated individuals. The present study was also designed to assess the specificity of the QFT-TB test after exposure to nontuberculous mycobacteria. Given the reported specificity of ESAT-6 and CFP-10 for mycobacterial species [14], however, the assay is likely to be negative for infection with MAC, which is a major source of infection with nontuberculous mycobacteria. This finding is compatible with our study's finding that the IFN-γ response for both ESAT-6 and CFP-10 was negative in all patients who were negative for Mycobacterium tuberculosis and were positive for MAC, except in 7 patients. Five of the 7 patients with MAC who had a positive IFN-γ response could have had coinfection with TB. On the other hand, positive reactions can be expected from patients with M. kansasii or M. marinum infection, because the genes encoding both ESAT-6 and CFP-10 are present in these nontuberculous mycobacteria [15]. In the present study, all patients with NTM (due to M. kansasii in 4 patients and M. marinum in 2) had positive results for both ESAT-6 and CFP-10.

We studied the reason that there were indeterminate QFT-TB test results for 5 patients with active TB and false-negative QFT-TB test results for 2 patients with active TB. Four of the 5 patients with indeterminate QFT-TB results had moderate lymphocytopenia (lymphocyte count, <1000 lymphocytes/µL) due to underlying diseases (table 4). Actually, this QFT-TB test depends on the elaboration of inflammatory cytokines by T cells previously sensitized to M. tuberculosis–specific antigens. In the blood, mononuclear cells from the peripheral blood are stimulated in vitro, and the production of IFN-γ from sensitized T cells is measured by ELISA [14]. Therefore, we thought that lymphocytopenia caused both the decrease in the production of IFN-γ and the lower mitogen QFT-TB levels (<0.5 IU/mL). However, although 1 patient had a lymphocyte count within the normal limit, he had an indeterminate QFT-TB test result. Whether this was the result of the small size of the lesion, localization, or the absence of a cavity lesion is unknown. Despite the fact that 2 patients who had false-negative results had severe lymphocytopenia, these patients presented with mitogen QFT-TB levels of >0.5 IU/mL. Therefore, we had to consider their QFT-TB test result to be negative according to the guidelines of the Centers for Disease Control and Prevention [9]. We think that it is difficult to evaluate the QFT-TB test through the findings of this study alone. Both patients with indeterminate QFT-TB results and false-negative QFT-TB results had negative results of serological tests for HIV.

We also studied transitional changes in the QFT-TB test results from the time of initiation of antituberculous treatment in patients with active TB. Subsequently, although the rate of positive results (for ESAT-6 and/or CFP-10) first slightly increased, it then decreased from 86% (before treatment) to 33% (12 months later), and the mean IFN-γ levels also decreased (table 7). Antituberculous treatment was clinically effective in all patients with a decrease in the IFN-γ levels. We think that this may be because of the time lag from the death of M. tuberculosis to the decrease in IFN-γ production due to T cells. In previous reports, although the enzyme-linked immunospot assay has been mentioned as being useful in the monitoring of antituberculous chemotherapy for active TB [11, 16], there have been no reports regarding transitional changes in the QFT-TB test. We think that the QFT-TB test may be useful as a marker of successful antituberculous therapy. However, although all 21 patients with active TB who completed treatment and underwent a periodical QFT-TB test within 12 months had a good response to the treatment, 7 patients (33%) continued to have a positive QFT-TB test result. Because the effects of the QFT-TB test may be long lasting after treatment and may not be resolved over time, even with treatment, as in this study, a long follow-up of transitional changes in QFT-TB test results should be performed carefully over 1 year. Otherwise, among patients with pulmonary MAC disease, 5 patients who had a past history of healed pulmonary TB had positive QFT-TB results. Because these positive results may also indicate that the findings of the QFT-TB test may be long lasting after the completion of treatment and may not resolve over time, even with treatment, the QFT-TB test may not provide any level of certainty regarding cure of infection.

In conclusion, our study demonstrated the usefulness of the QFT-TB test as an immunological diagnostic method for the detection of TB, on the basis of its excellent specificity and sensitivity. However, several false-negative or indeterminate QFT-TB test results were encountered for patients with active TB who had a severe underlying disease with lymphocytopenia. Although the QFT-TB test may be useful as a marker for monitoring clinical effectiveness, it may not provide any level of certainty regarding cure of infection, because it is possible that the responses to the effects of this method may be long lasting and may not resolve over time, even with treatment, as in this study.

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Acknowledgments

We thank T. Matsushima (Asahigaoka Hospital, Okayama City, Japan) and N. Okimoto (Kawasaki Medical School, Kawasaki Hospital, Kurashiki, Japan) for their helpful comments.

Potential conflicts of interest. All authors: no conflicts.

  • Received April 17, 2006.
  • Accepted July 31, 2006.
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  1. Clin Infect Dis. (2006) 43 (12): 1540-1546. doi: 10.1086/509327
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