Scandinavian Journal of Infectious Diseases, 2014; Early Online: 1–7
Original article
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Diagnosis of latent tuberculosis infection before initiation of anti-tumor necrosis factor therapy using both tuberculin skin test and QuantiFERON-TB Gold In Tube assay Ho-Cheol Kim1, Kyung-Wook Jo1, Young Ju Jung1, Bin Yoo2, Chang-Keun Lee2, Yong-Gil Kim2, Suk-Kyun Yang3, Jeong-Sik Byeon3, Kyung-Jo Kim3, Byong Duk Ye3 & Tae Sun Shim1 1Department
of Pulmonary and Critical Care Medicine, 2Department of Rheumatology, and 3Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Abstract Background: Reactivation of latent tuberculosis infection (LTBI) is an important complication in patients treated with tumor necrosis factor-alpha (TNF-a) blocking agents. However, the best method for LTBI detection before initiation of anti-TNF therapy remains to be determined. Methods: From January 2010 to August 2013, anti-TNF therapy was initiated in 426 patients with immune-mediated inflammatory diseases (IMIDs). Tuberculin skin test (TST) and Quantiferon-TB Gold In Tube (QFT-GIT) assay were performed before starting anti-TNF treatment. LTBI was defined as a positive TST (induration 10 mm) or as a positive QFT-GIT result. Patients were followed up until December 2013. Results: The positive TST and QFT-GIT rates were 22.3% (95/426) and 16.0% (68/426), respectively, yielding a total of 27.0% (115/426) of positive LTBI results. LTBI treatment was initiated in 25.1% (107/426) and was completed in 100% (107/107) of patients. During a median 294 days of follow-up, active TB occurred in 1.4% (6/426) of the patients with negative TST and QFT-GIT results at baseline. Conclusion: The either test positive strategy, using both TST and QFTGIT assay, is acceptable for LTBI screening before commencing anti-TNF therapy in patients with IMIDs.
Keywords: latent tuberculosis infection, tuberculin skin tests, QuantiFERON-TB Gold In Tube, tumor necrosis factor
Introduction Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn’s disease (CD), and ulcerative colitis (UC), have been increasingly treated with anti-tumor necrosis factor (TNF)-a antagonists [1]. However, TNF-a antagonists increase the risk of infections such as tuberculosis (TB), which in most cases is the result of reactivation of latent TB infection (LTBI). Therefore, it is important to screen for LTBI before initiating anti-TNF-a therapy [2–4]. The tuberculin skin test (TST) is the traditional TB screening method and has many limitations. It is associated with a higher risk of false-negative results, especially in immunosuppressed subjects,
and false-positive results, especially in BCGvaccinated subjects. In addition, TST requires two hospital visits and has booster effects [5,6]. Recently, interferon-g release assays (IGRAs) were developed to overcome the limitations of TST. They measure interferon-g released by effector T cells responding to Mycobacterium tuberculosisspecific antigens. There are two kinds of IGRA test, including QuantiFERON-TB Gold In Tube (QFTGIT; Cellestis, Carnegie, VIC, Australia) and T-SPOT®. TB (T-SPOT; Oxford Immunotec, Abingdon, UK). These tests have higher specificity than TST, especially in subjects with BCG vaccination, and have higher sensitivity than TST in some immunocompromised subjects [7–10].
Correspondence: Tae Sun Shim MD, Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, South Korea. Tel: 82 2 3010 3892. Fax: 82 2 3010 6968. E-mail: [email protected] (Received 27 March 2014; accepted 18 June 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.938691
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At present, there are no gold standard methods for diagnosing LTBI before initiating anti-TNF-a therapy [9]. Some guidelines suggest that IGRA may replace TST, whereas others suggest that it can be used in combination with TST [2,11]. Previously, at our institution, LTBI was defined as a positive TST (induration 10 mm) and, in cases of borderline TST induration ( 5 mm but 10 mm), a positive T-SPOT result was considered as indicative of LTBI [12]. However, active TB developed in subjects who had negative TST (induration 5 mm) and positive T-SPOT results. Therefore, we changed our screening method to the either test (TST or T-SPOT) positive strategy, which showed lower incidence of TB (0.9%) [13] compared with that (2.1%) of the previous strategy [12]. Although the National Institute of Health and Care Excellence guidelines recommended the concurrent use of TST and QFT-GIT in the screening of LTBI in immunocompromised subjects [14], studies focusing on the performance of the ‘either test positive strategy’ using both TST and QFT-GIT to screen LTBI in a large patient sample before the start of anti-TNF-a therapy are scarce [15], especially in a country with an intermediate TB burden. The aim of the current study was to evaluate the performance of the either test positive strategy using both TST and QFT-GIT for the detection of LTBI in patients due to start anti-TNF-a therapy in Korea, a country with an
intermediate TB burden. The incidence of active TB during follow-up in patients due to begin anti-TNF therapy was also investigated.
Methods Study population From January 2010 to August 2013, a total of 655 patients with IMIDs were screened at the Asan Medical Center. Of these, 426 patients with both TST and QFT-GIT results, and no active TB at baseline, who had been followed up for a minimum of 3 months, and have received anti-TNF therapy were finally enrolled in this study (Figure 1). Their clinical course was followed up until December 2013 and the minimum follow-up duration after initiating anti-TNF therapy was 91 days. This was a retrospective study and thus, written informed consent was waived. The study protocol was approved by the Institutional Review Board of Asan Medical Center.
LTBI screening methods A thorough history was taken during the screening visit, including the presence of any symptoms suggestive of TB, use of disease-modifying anti-rheumatic
Figure 1. Study design. CXR, chest radiography; LTBI, latent tuberculosis infection; NTM, nontuberculosis mycobacterium; QFT-GIT, Quantiferon-TB Gold In Tube; TB, tuberculosis; TNF, tumor necrosis factor; TST, tuberculin skin test.
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LTBI diagnosis before anti-TNF- α therapy
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drugs (DMARDs) or steroids, and previous TB treatments. All patients were checked for the presence of Bacille Calmette-Guerin (BCG) scars. Simple chest radiography, TST, and QFT-GIT were all performed during baseline examination. Any patients with radiographic abnormalities suggestive of TB were further evaluated by sputum acid-fast bacilli smear and culture to rule out active TB or nontuberculous mycobacterial disease. TST was performed using 2TU PPD RT23 (Statens Serum Institute, Copenhagen, Denmark) and the Mantoux approach. Induration size was measured after 48–72 h using the ballpoint method. QFT-GIT was performed using whole blood collected into a heparin-containing tube, stimulated with negative control antigen (Nil), positive control antigen (Mitogen), or TB-specific antigens, and cultured for 16–24 h. Subsequently, the produced interferon-g was measured by enzyme-linked immunosorbent assay (ELISA).
chosen by attending physicians. The anti-TNF-a treatment was immediately stopped in patients who developed active TB.
Criteria for commencing LTBI treatment
Statistical analysis
LTBI treatment was not indicated in patients with a history of previous anti-TB treatment and no further TB exposure. Patients with abnormal chest X-ray findings suggestive of TB (fibronodular findings in upper lobes [16]) and without previous anti-TB treatment history were considered as having LTBI, regardless of the TST or QFT-GIT results, and after excluding active TB, were started on LTBI treatment. In subjects with no history of anti-TB treatment and normal chest radiography, LTBI was defined as a positive TST result (induration 10 mm) or as a positive QFT-GIT result. An interferon-g value of 0.35 IU/ml was considered a positive QFT-GIT result.
Agreement between the TST and QFT-GIT results was examined by kappa (k) coefficients. Comparisons were made using the t test for continuous variables and chi-squared test or Fisher’s exact test for categorical data. All p values were two-tailed, with statistical significance set at p 0.05. Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA).
Treatment of LTBI The Korea Centers for Disease Control and Prevention guidelines recommend three regimens for LTBI treatment: isoniazid (INH) for 9 months; rifampin (RIF) for 4 months; or both INH and RIF for 3 months. The treatment regimen was selected by attending physicians. All patients were tested for liver function at baseline. In patients who developed adverse events, the regimen was switched to another one. Treatment completion was defined as taking over 80% of all prescribed medication within 12 months for INH, 6 months for RIF, and 4 months for INH/RIF. Anti-TNF-a treatment Anti-TNF-a treatment was initiated 3–4 weeks after LTBI treatment. The anti-TNF-a treatment was
Follow-up Anti-TNF-a treatment and LTBI treatment were independently prescribed by attending physicians and pulmonologists, respectively. Regardless of the LTBI status, all patients were followed up by pulmonologists until 6 months after completion of the anti-TNF-a treatment. Chest X-ray was usually performed 3 and 9 months after the initiation of antiTNF-a treatment and thereafter every 12 months. Patients were instructed to visit their physicians if new symptoms or signs suggestive of TB developed. Follow-up duration was calculated until default, transfer to another hospital, death, development of TB, or 6 months following completion of anti-TNF treatment.
Results Baseline clinical characteristics Anti-TNF-a therapy was initiated in 426 eligible patients (Figure 1). The mean age was 41.1 15.8 years and 56.1% (239/426) were male. The other characteristics are presented in Table I. Diagnosis and treatment of latent tuberculosis infection The positivity rates for TST and QFT-GIT were 22.3% (95/426) and 16.0% (68/426), respectively. Based on the either test positive strategy screening results, 115 (27.0%) patients had LTBI and, after adjustments based on chest radiographic findings and anti-TB treatment history, 107 (25.1%) of these patients were started on LTBI treatment (96.3% [103/107] were treated with a combination of isoniazid and rifampin). Although some patients changed the treatment regimen due to adverse events, the LTBI treatment completion rate was 100%. Adverse events occurred in 11 patients during treatment (Table II).
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Table I. Baseline characteristics of 426 patients treated with anti-TNF agents. Value, n (%)
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Characteristic Age (mean), years, SD Gender, male Body mass index, kg/m2 (mean SD) IMIDs Ankylosing spondylitis Rheumatoid arthritis Crohn’s disease Ulcerative colitis Others Combined Comorbid conditions Diabetes mellitus Malignancy Chronic liver disease Chronic lung disease Previous history of anti-TB treatment Positive BCG scar CXR findings suggestive of healed TB Anti-TNF agents used Etanercept Infliximab Adalimumab Anti-inflammatory drugs Steroid DMARDs Steroid DMARDs Immunosuppressant None TST induration size 10 mm 5mm, 10 mm 5 mm QFT-GIT Positive Negative Indeterminate
41.1 15.8 239 (56.1) 22.0 4.0 92 111 160 51 6 6
(21.6) (26.1) (37.6) (12.0) (1.4) (1.4)
15 14 14 11 59 301 43
(3.5) (3.3) (3.3) (2.6) (13.8) (70.7) (10.1)
108 (25.4) 230 (54.0) 88 (20.7) 21 72 39 82 212
(4.9) (16.9) (9.2) (19.2) (49.8)
95 (22.3) 42 (9.9) 289 (67.8) 68 (16.0) 346 (81.2) 12 (2.8)
CXR, chest radiography; DMARD, disease-modifying antirheumatic drug; IMID, immune-mediated inflammatory disease; QFT-GIT, Quantiferon TB-Gold In Tube; TB, tuberculosis; TNF, tumor necrosis factor; TST, tuberculin skin test.
A comparison of TST and QFT-GIT results After excluding 12 indeterminate QFT-GIT results, the baseline TST and QFT-GIT results were compared for 414 patients who had been subjected to both tests (Table III). The agreement between the
Table II. Treatment outcomes of 426 patients on anti-TNF therapy. Characteristic
Value (%)
Median follow-up, days (range, IQR) LTBI treatment regimens (n 107) Isoniazid Rifampin Isoniazid rifampin LTBI treatment outcomes (n 107) Treatment completion Regimen change due to adverse events Adverse event Myalgia Nausea and vomiting Arthralgia Rash Sweating Status of anti-TNF treatment Treatment completion On treatment Default Transfer out Death Development of TB Cause of death Infection other than TB Acute exacerbation of IMID
294 (179–626) 2 (1.9) 2 (1.9) 103 (96.3) 107 (100) 9 (8.4) 11 (10.3) 4 3 2 1 1 27 347 36 14 2 6 2 0
IQR, interquartile range; LTBI, latent tuberculosis infection; TB, tuberculosis; TNF, tumor necrosis factor.
two tests was 84.8% (k value 0.512), and when the TST cut-off was set at 5 mm, the level of agreement was 78.5% (k value 0.434).
Follow-up and development of tuberculosis The median follow-up duration after initiation of anti-TNF-a therapy was 294 days (interquartile range 179–626 days). During follow-up, six patients (1.4%) developed active TB. Their clinical characteristics are presented in Table IV. All six patients had negative TST and QFT-GIT results at baseline screening, and were not given LTBI treatment. In addition, all six patients had extrapulmonary (n 1) or combined pulmonary/extrapulmonary TB (n 5).
Table III. Comparison of TST and QFT-GIT results in 414 patients. TST/QFT-GIT Status TST cut-off 10 mm TST cut-off 5 mm
(6.3) (81.5) (8.5) (3.3) (0.5) (1.4)
Number
/
/2
2/
2/2
Kappa
p value
414 414
48 (11.6) 56 (13.5)
43 (10.4) 77 (18.6)
20 (4.8) 12 (2.9)
303 (73.2) 269 (65.0)
0.512 0.434
0.001 0.001
Values are expressed as numbers (%). QFT-GIT, Quantiferon TB-Gold In Tube; TST, tuberculin skin test.
LTBI diagnosis before anti-TNF- α therapy DA, adenosine deaminase; AS, ankylosing spondylitis; CD, Crohn’s disease; QFT-GIT, Quantiferon TB-Gold In Tube; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor; A TST, tuberculin skin test.
35 Female CD None Yes 0 Negative (0.00) Infliximab None 12 Lung, mediastinal lymph nodes Bacteriological Pan-susceptible Completion 29 Male CD None No 0 Indeterminate Infliximab None 6 Lung, pleural Clinical (high ADA) – On treatment 62 Male RA None No 0 Negative (–0.01) Infliximab None 3 Lung, pleural Bacteriological Pan-susceptible Completion 43 Male CD Yes Yes 0 Negative (0.11) Infliximab None 17 Lung, pericardium Bacteriological Pan-susceptible On treatment 55 Male AS None Yes 5 Negative (0.03) Infliximab None 3 Lung, pleural Bacteriological Pan-susceptible Completion 71 Female RA Yes No 0 Negative (0.00) Adalimumab None 4 Pleural Clinical (high ADA) – Completion Age (years) Gender Underlying disease Previous history of anti-TB treatment Positive BCG scar Baseline TST induration (mm) Baseline QFT-GIT (value, IU/ml) Anti-TNF agents used LTBI treatment Time to TB after start of anti-TNF agent (months) Sites of TB Diagnostic method for TB Drug susceptibility results Outcome of anti-TB treatment
Patient 5 Patient 4 Patient 3 Patient 2 Patient 1 Characteristic
Table IV. Characteristics of six patients who developed active tuberculosis during anti-TNF therapy.
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Patient 6
5
Discussion A number of studies have compared the performance of both TST and QFT-GIT in the diagnosis of LTBI [15,17–19]. Few studies have evaluated LTBI before anti-TNF-a treatment using TST and QFT-GIT. However, these studies were performed in countries with low TB burden and focused on serial QFT-GIT values, not on reactivation of LTBI [15,19]. To the best of our knowledge, this is the first study to evaluate the performance of the either test positive strategy using both TST and QFT-GIT for LTBI screening before anti-TNF-a treatment in a TBprevalent country. Considering the high frequency of reactivation of LTBI after anti-TNF-a treatment, the 1.4% incidence of TB during anti-TNF therapy in our patient sample is acceptable. Anti-TNF-a treatment increases the risk of reactivation of LTBI. Therefore, screening and treatment of LTBI are indicated before the initiation of antiTNF-a treatment [3]. Many studies have suggested that IGRA might have an advantage over TST in diagnosing LTBI. There are no gold standard screening tests for the diagnosis of LTBI but there is a preference for IGRA over TST or for using both TST and IGRA [8,9,20,21]. In a previous study, our institution adopted a strategy using both the TST and the T-SPOT assay to screen for LTBI at baseline before anti-TNF-a therapy. With a median follow-up duration of 884 days, the incidence of TB during anti-TNF therapy was 0.9% (4/430) [13]. In the present study, the median follow-up duration was shorter (294 days) than that of our previous study, but the incidence of TB is still acceptable (6/426, 1.4%). While in the previous study 46.0% (198/430) of the patients were started on LTBI treatment, in the present study only 25.1% (107/426) were started on LTBI treatment, mainly due to lower IGRA positive results (44.2% vs 16.0%, respectively). These findings suggest that some of the positive T-SPOT results might have been false-positive. In our previous study we performed a head-to-head comparison between TST, T-SPOT, and QFT-GIT assays, and found that the T-SPOT assay had lower specificity than QFT-GIT but the difference was not statistically significant [22]. However, due to study design limitations we could not conclude that one IGRA test was better than the other in detecting LTBI before anti-TNF therapy. Prospective, head-to-head comparison, and costeffectiveness studies are needed to resolve these issues. The QFT-GIT uses the ELISA technique to detect interferon-g, while the T-SPOT assay uses the enzyme-linked immunospot (ELISPOT) technique to count the number of interferon-g secreting cells
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[23]. Some studies suggest that T-SPOT is more sensitive than QFT-GIT in detecting TB infection, especially in immunosuppressed patients [24,25]. However, some studies have suggested that the T-SPOT assay is less specific than QFT-GIT in diagnosing TB infection and yields variable results with different observers [20,26–28]. Therefore, the US FDA recommended adopting a borderline result category for interpreting T-SPOT assay results [29]. In our previous study, the cut-off was set at more than eight spot-forming cells, in line with the FDA recommendation [13]. The use of the IGRA test in addition to TST may improve patient outcome. However, the issue of whether to use the QFT-GIT or T-SPOT assay remains to be resolved. Among 95 patients with positive TST ( 10 mm) results, 43 patients (45.3%) showed negative QFTGIT results. This discrepancy may be due to falsepositive TST results due to BCG vaccination or may be due to false-negative QFT-GIT results. If the false-positive TST because of BCG vaccination was a main cause of discrepancy between the two tests, the either test positive strategy can lead to an overtreatment of LTBI. In spite of this point, we adopted the either test positive strategy based on the high risk of TB development and the absence of a gold standard test for diagnosing LTBI in patients receiving anti-TNF agents. Further studies are needed to compare the performance of QFT-GIT alone versus a combined use of TST and QFT-GIT assays. A total of six patients developed active TB after starting anti-TNF-a treatment. Of six patients, two had a history of previous anti-TB medication and therefore LTBI treatment was not indicated in our study. Even though they reported that they had completed anti-TB treatment according to the attending doctor’s decision, it was impossible to identify whether previous treatment was appropriate or not since the treatment had been completed several decades ago. Several previous studies reported that the risk of TB was higher in patients treated with anti-TNF monoclonal antibodies (infliximab or adalimumab) than in patients treated with a soluble TNF receptor (etanercept) [30]. In our study, all six patients who developed active TB had been treated with infliximab (n 5) or adalimumab (n 1) and none had been treated with etanercept. These observations are compatible with previous studies [31,32]. Active TB developed within 6 months of initiating anti-TNF-a therapy in four patients, suggesting that TB develops through reactivation of LTBI. In another two patients, TB developed 17 and 12 months after initiating anti-TNF therapy, respectively, suggesting that TB may develop through a new infection. Further studies with large numbers of patients are needed to find out the role of reinfection in the development
of TB in patients taking anti-TNF agents, especially in a TB-prevalent area. There are several limitations to this study. First, although most subjects were immunocompromised, the TST cut-off was set at 10 mm as described previously [12]. Only 37/426 (8.7%) patients had borderline TST ( 5 mm but 10 mm) and negative QFT-GIT results so that LTBI treatment was not indicated: only one of them developed active TB during follow-up. Second, the number of patients who developed TB was insufficient for predicting TB development, even though we enrolled a large number of patients. Third, the baseline characteristics, anti-TNF agents used, and follow-up duration differed considerably between our previous and current studies, which precluded a meaningful comparison. In conclusion, even though there were some falsenegative results, the either test positive strategy using both TST and QFT-GIT assays is acceptable for LTBI screening before commencing anti-TNF therapy in patients with IMIDs. Further studies are needed to find more accurate and cost-effective methods for LTBI screening before initiating antiTNF-a treatment.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Original article
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Diagnosis of latent tuberculosis infection before initiation of anti-tumor necrosis factor therapy using both tuberculin skin test and QuantiFERON-TB Gold In Tube assay Ho-Cheol Kim1, Kyung-Wook Jo1, Young Ju Jung1, Bin Yoo2, Chang-Keun Lee2, Yong-Gil Kim2, Suk-Kyun Yang3, Jeong-Sik Byeon3, Kyung-Jo Kim3, Byong Duk Ye3 & Tae Sun Shim1 1Department
of Pulmonary and Critical Care Medicine, 2Department of Rheumatology, and 3Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Abstract Background: Reactivation of latent tuberculosis infection (LTBI) is an important complication in patients treated with tumor necrosis factor-alpha (TNF-a) blocking agents. However, the best method for LTBI detection before initiation of anti-TNF therapy remains to be determined. Methods: From January 2010 to August 2013, anti-TNF therapy was initiated in 426 patients with immune-mediated inflammatory diseases (IMIDs). Tuberculin skin test (TST) and Quantiferon-TB Gold In Tube (QFT-GIT) assay were performed before starting anti-TNF treatment. LTBI was defined as a positive TST (induration 10 mm) or as a positive QFT-GIT result. Patients were followed up until December 2013. Results: The positive TST and QFT-GIT rates were 22.3% (95/426) and 16.0% (68/426), respectively, yielding a total of 27.0% (115/426) of positive LTBI results. LTBI treatment was initiated in 25.1% (107/426) and was completed in 100% (107/107) of patients. During a median 294 days of follow-up, active TB occurred in 1.4% (6/426) of the patients with negative TST and QFT-GIT results at baseline. Conclusion: The either test positive strategy, using both TST and QFTGIT assay, is acceptable for LTBI screening before commencing anti-TNF therapy in patients with IMIDs.
Keywords: latent tuberculosis infection, tuberculin skin tests, QuantiFERON-TB Gold In Tube, tumor necrosis factor
Introduction Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn’s disease (CD), and ulcerative colitis (UC), have been increasingly treated with anti-tumor necrosis factor (TNF)-a antagonists [1]. However, TNF-a antagonists increase the risk of infections such as tuberculosis (TB), which in most cases is the result of reactivation of latent TB infection (LTBI). Therefore, it is important to screen for LTBI before initiating anti-TNF-a therapy [2–4]. The tuberculin skin test (TST) is the traditional TB screening method and has many limitations. It is associated with a higher risk of false-negative results, especially in immunosuppressed subjects,
and false-positive results, especially in BCGvaccinated subjects. In addition, TST requires two hospital visits and has booster effects [5,6]. Recently, interferon-g release assays (IGRAs) were developed to overcome the limitations of TST. They measure interferon-g released by effector T cells responding to Mycobacterium tuberculosisspecific antigens. There are two kinds of IGRA test, including QuantiFERON-TB Gold In Tube (QFTGIT; Cellestis, Carnegie, VIC, Australia) and T-SPOT®. TB (T-SPOT; Oxford Immunotec, Abingdon, UK). These tests have higher specificity than TST, especially in subjects with BCG vaccination, and have higher sensitivity than TST in some immunocompromised subjects [7–10].
Correspondence: Tae Sun Shim MD, Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, South Korea. Tel: 82 2 3010 3892. Fax: 82 2 3010 6968. E-mail: [email protected] (Received 27 March 2014; accepted 18 June 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.938691
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At present, there are no gold standard methods for diagnosing LTBI before initiating anti-TNF-a therapy [9]. Some guidelines suggest that IGRA may replace TST, whereas others suggest that it can be used in combination with TST [2,11]. Previously, at our institution, LTBI was defined as a positive TST (induration 10 mm) and, in cases of borderline TST induration ( 5 mm but 10 mm), a positive T-SPOT result was considered as indicative of LTBI [12]. However, active TB developed in subjects who had negative TST (induration 5 mm) and positive T-SPOT results. Therefore, we changed our screening method to the either test (TST or T-SPOT) positive strategy, which showed lower incidence of TB (0.9%) [13] compared with that (2.1%) of the previous strategy [12]. Although the National Institute of Health and Care Excellence guidelines recommended the concurrent use of TST and QFT-GIT in the screening of LTBI in immunocompromised subjects [14], studies focusing on the performance of the ‘either test positive strategy’ using both TST and QFT-GIT to screen LTBI in a large patient sample before the start of anti-TNF-a therapy are scarce [15], especially in a country with an intermediate TB burden. The aim of the current study was to evaluate the performance of the either test positive strategy using both TST and QFT-GIT for the detection of LTBI in patients due to start anti-TNF-a therapy in Korea, a country with an
intermediate TB burden. The incidence of active TB during follow-up in patients due to begin anti-TNF therapy was also investigated.
Methods Study population From January 2010 to August 2013, a total of 655 patients with IMIDs were screened at the Asan Medical Center. Of these, 426 patients with both TST and QFT-GIT results, and no active TB at baseline, who had been followed up for a minimum of 3 months, and have received anti-TNF therapy were finally enrolled in this study (Figure 1). Their clinical course was followed up until December 2013 and the minimum follow-up duration after initiating anti-TNF therapy was 91 days. This was a retrospective study and thus, written informed consent was waived. The study protocol was approved by the Institutional Review Board of Asan Medical Center.
LTBI screening methods A thorough history was taken during the screening visit, including the presence of any symptoms suggestive of TB, use of disease-modifying anti-rheumatic
Figure 1. Study design. CXR, chest radiography; LTBI, latent tuberculosis infection; NTM, nontuberculosis mycobacterium; QFT-GIT, Quantiferon-TB Gold In Tube; TB, tuberculosis; TNF, tumor necrosis factor; TST, tuberculin skin test.
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drugs (DMARDs) or steroids, and previous TB treatments. All patients were checked for the presence of Bacille Calmette-Guerin (BCG) scars. Simple chest radiography, TST, and QFT-GIT were all performed during baseline examination. Any patients with radiographic abnormalities suggestive of TB were further evaluated by sputum acid-fast bacilli smear and culture to rule out active TB or nontuberculous mycobacterial disease. TST was performed using 2TU PPD RT23 (Statens Serum Institute, Copenhagen, Denmark) and the Mantoux approach. Induration size was measured after 48–72 h using the ballpoint method. QFT-GIT was performed using whole blood collected into a heparin-containing tube, stimulated with negative control antigen (Nil), positive control antigen (Mitogen), or TB-specific antigens, and cultured for 16–24 h. Subsequently, the produced interferon-g was measured by enzyme-linked immunosorbent assay (ELISA).
chosen by attending physicians. The anti-TNF-a treatment was immediately stopped in patients who developed active TB.
Criteria for commencing LTBI treatment
Statistical analysis
LTBI treatment was not indicated in patients with a history of previous anti-TB treatment and no further TB exposure. Patients with abnormal chest X-ray findings suggestive of TB (fibronodular findings in upper lobes [16]) and without previous anti-TB treatment history were considered as having LTBI, regardless of the TST or QFT-GIT results, and after excluding active TB, were started on LTBI treatment. In subjects with no history of anti-TB treatment and normal chest radiography, LTBI was defined as a positive TST result (induration 10 mm) or as a positive QFT-GIT result. An interferon-g value of 0.35 IU/ml was considered a positive QFT-GIT result.
Agreement between the TST and QFT-GIT results was examined by kappa (k) coefficients. Comparisons were made using the t test for continuous variables and chi-squared test or Fisher’s exact test for categorical data. All p values were two-tailed, with statistical significance set at p 0.05. Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA).
Treatment of LTBI The Korea Centers for Disease Control and Prevention guidelines recommend three regimens for LTBI treatment: isoniazid (INH) for 9 months; rifampin (RIF) for 4 months; or both INH and RIF for 3 months. The treatment regimen was selected by attending physicians. All patients were tested for liver function at baseline. In patients who developed adverse events, the regimen was switched to another one. Treatment completion was defined as taking over 80% of all prescribed medication within 12 months for INH, 6 months for RIF, and 4 months for INH/RIF. Anti-TNF-a treatment Anti-TNF-a treatment was initiated 3–4 weeks after LTBI treatment. The anti-TNF-a treatment was
Follow-up Anti-TNF-a treatment and LTBI treatment were independently prescribed by attending physicians and pulmonologists, respectively. Regardless of the LTBI status, all patients were followed up by pulmonologists until 6 months after completion of the anti-TNF-a treatment. Chest X-ray was usually performed 3 and 9 months after the initiation of antiTNF-a treatment and thereafter every 12 months. Patients were instructed to visit their physicians if new symptoms or signs suggestive of TB developed. Follow-up duration was calculated until default, transfer to another hospital, death, development of TB, or 6 months following completion of anti-TNF treatment.
Results Baseline clinical characteristics Anti-TNF-a therapy was initiated in 426 eligible patients (Figure 1). The mean age was 41.1 15.8 years and 56.1% (239/426) were male. The other characteristics are presented in Table I. Diagnosis and treatment of latent tuberculosis infection The positivity rates for TST and QFT-GIT were 22.3% (95/426) and 16.0% (68/426), respectively. Based on the either test positive strategy screening results, 115 (27.0%) patients had LTBI and, after adjustments based on chest radiographic findings and anti-TB treatment history, 107 (25.1%) of these patients were started on LTBI treatment (96.3% [103/107] were treated with a combination of isoniazid and rifampin). Although some patients changed the treatment regimen due to adverse events, the LTBI treatment completion rate was 100%. Adverse events occurred in 11 patients during treatment (Table II).
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Table I. Baseline characteristics of 426 patients treated with anti-TNF agents. Value, n (%)
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Characteristic Age (mean), years, SD Gender, male Body mass index, kg/m2 (mean SD) IMIDs Ankylosing spondylitis Rheumatoid arthritis Crohn’s disease Ulcerative colitis Others Combined Comorbid conditions Diabetes mellitus Malignancy Chronic liver disease Chronic lung disease Previous history of anti-TB treatment Positive BCG scar CXR findings suggestive of healed TB Anti-TNF agents used Etanercept Infliximab Adalimumab Anti-inflammatory drugs Steroid DMARDs Steroid DMARDs Immunosuppressant None TST induration size 10 mm 5mm, 10 mm 5 mm QFT-GIT Positive Negative Indeterminate
41.1 15.8 239 (56.1) 22.0 4.0 92 111 160 51 6 6
(21.6) (26.1) (37.6) (12.0) (1.4) (1.4)
15 14 14 11 59 301 43
(3.5) (3.3) (3.3) (2.6) (13.8) (70.7) (10.1)
108 (25.4) 230 (54.0) 88 (20.7) 21 72 39 82 212
(4.9) (16.9) (9.2) (19.2) (49.8)
95 (22.3) 42 (9.9) 289 (67.8) 68 (16.0) 346 (81.2) 12 (2.8)
CXR, chest radiography; DMARD, disease-modifying antirheumatic drug; IMID, immune-mediated inflammatory disease; QFT-GIT, Quantiferon TB-Gold In Tube; TB, tuberculosis; TNF, tumor necrosis factor; TST, tuberculin skin test.
A comparison of TST and QFT-GIT results After excluding 12 indeterminate QFT-GIT results, the baseline TST and QFT-GIT results were compared for 414 patients who had been subjected to both tests (Table III). The agreement between the
Table II. Treatment outcomes of 426 patients on anti-TNF therapy. Characteristic
Value (%)
Median follow-up, days (range, IQR) LTBI treatment regimens (n 107) Isoniazid Rifampin Isoniazid rifampin LTBI treatment outcomes (n 107) Treatment completion Regimen change due to adverse events Adverse event Myalgia Nausea and vomiting Arthralgia Rash Sweating Status of anti-TNF treatment Treatment completion On treatment Default Transfer out Death Development of TB Cause of death Infection other than TB Acute exacerbation of IMID
294 (179–626) 2 (1.9) 2 (1.9) 103 (96.3) 107 (100) 9 (8.4) 11 (10.3) 4 3 2 1 1 27 347 36 14 2 6 2 0
IQR, interquartile range; LTBI, latent tuberculosis infection; TB, tuberculosis; TNF, tumor necrosis factor.
two tests was 84.8% (k value 0.512), and when the TST cut-off was set at 5 mm, the level of agreement was 78.5% (k value 0.434).
Follow-up and development of tuberculosis The median follow-up duration after initiation of anti-TNF-a therapy was 294 days (interquartile range 179–626 days). During follow-up, six patients (1.4%) developed active TB. Their clinical characteristics are presented in Table IV. All six patients had negative TST and QFT-GIT results at baseline screening, and were not given LTBI treatment. In addition, all six patients had extrapulmonary (n 1) or combined pulmonary/extrapulmonary TB (n 5).
Table III. Comparison of TST and QFT-GIT results in 414 patients. TST/QFT-GIT Status TST cut-off 10 mm TST cut-off 5 mm
(6.3) (81.5) (8.5) (3.3) (0.5) (1.4)
Number
/
/2
2/
2/2
Kappa
p value
414 414
48 (11.6) 56 (13.5)
43 (10.4) 77 (18.6)
20 (4.8) 12 (2.9)
303 (73.2) 269 (65.0)
0.512 0.434
0.001 0.001
Values are expressed as numbers (%). QFT-GIT, Quantiferon TB-Gold In Tube; TST, tuberculin skin test.
LTBI diagnosis before anti-TNF- α therapy DA, adenosine deaminase; AS, ankylosing spondylitis; CD, Crohn’s disease; QFT-GIT, Quantiferon TB-Gold In Tube; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor; A TST, tuberculin skin test.
35 Female CD None Yes 0 Negative (0.00) Infliximab None 12 Lung, mediastinal lymph nodes Bacteriological Pan-susceptible Completion 29 Male CD None No 0 Indeterminate Infliximab None 6 Lung, pleural Clinical (high ADA) – On treatment 62 Male RA None No 0 Negative (–0.01) Infliximab None 3 Lung, pleural Bacteriological Pan-susceptible Completion 43 Male CD Yes Yes 0 Negative (0.11) Infliximab None 17 Lung, pericardium Bacteriological Pan-susceptible On treatment 55 Male AS None Yes 5 Negative (0.03) Infliximab None 3 Lung, pleural Bacteriological Pan-susceptible Completion 71 Female RA Yes No 0 Negative (0.00) Adalimumab None 4 Pleural Clinical (high ADA) – Completion Age (years) Gender Underlying disease Previous history of anti-TB treatment Positive BCG scar Baseline TST induration (mm) Baseline QFT-GIT (value, IU/ml) Anti-TNF agents used LTBI treatment Time to TB after start of anti-TNF agent (months) Sites of TB Diagnostic method for TB Drug susceptibility results Outcome of anti-TB treatment
Patient 5 Patient 4 Patient 3 Patient 2 Patient 1 Characteristic
Table IV. Characteristics of six patients who developed active tuberculosis during anti-TNF therapy.
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Patient 6
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Discussion A number of studies have compared the performance of both TST and QFT-GIT in the diagnosis of LTBI [15,17–19]. Few studies have evaluated LTBI before anti-TNF-a treatment using TST and QFT-GIT. However, these studies were performed in countries with low TB burden and focused on serial QFT-GIT values, not on reactivation of LTBI [15,19]. To the best of our knowledge, this is the first study to evaluate the performance of the either test positive strategy using both TST and QFT-GIT for LTBI screening before anti-TNF-a treatment in a TBprevalent country. Considering the high frequency of reactivation of LTBI after anti-TNF-a treatment, the 1.4% incidence of TB during anti-TNF therapy in our patient sample is acceptable. Anti-TNF-a treatment increases the risk of reactivation of LTBI. Therefore, screening and treatment of LTBI are indicated before the initiation of antiTNF-a treatment [3]. Many studies have suggested that IGRA might have an advantage over TST in diagnosing LTBI. There are no gold standard screening tests for the diagnosis of LTBI but there is a preference for IGRA over TST or for using both TST and IGRA [8,9,20,21]. In a previous study, our institution adopted a strategy using both the TST and the T-SPOT assay to screen for LTBI at baseline before anti-TNF-a therapy. With a median follow-up duration of 884 days, the incidence of TB during anti-TNF therapy was 0.9% (4/430) [13]. In the present study, the median follow-up duration was shorter (294 days) than that of our previous study, but the incidence of TB is still acceptable (6/426, 1.4%). While in the previous study 46.0% (198/430) of the patients were started on LTBI treatment, in the present study only 25.1% (107/426) were started on LTBI treatment, mainly due to lower IGRA positive results (44.2% vs 16.0%, respectively). These findings suggest that some of the positive T-SPOT results might have been false-positive. In our previous study we performed a head-to-head comparison between TST, T-SPOT, and QFT-GIT assays, and found that the T-SPOT assay had lower specificity than QFT-GIT but the difference was not statistically significant [22]. However, due to study design limitations we could not conclude that one IGRA test was better than the other in detecting LTBI before anti-TNF therapy. Prospective, head-to-head comparison, and costeffectiveness studies are needed to resolve these issues. The QFT-GIT uses the ELISA technique to detect interferon-g, while the T-SPOT assay uses the enzyme-linked immunospot (ELISPOT) technique to count the number of interferon-g secreting cells
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[23]. Some studies suggest that T-SPOT is more sensitive than QFT-GIT in detecting TB infection, especially in immunosuppressed patients [24,25]. However, some studies have suggested that the T-SPOT assay is less specific than QFT-GIT in diagnosing TB infection and yields variable results with different observers [20,26–28]. Therefore, the US FDA recommended adopting a borderline result category for interpreting T-SPOT assay results [29]. In our previous study, the cut-off was set at more than eight spot-forming cells, in line with the FDA recommendation [13]. The use of the IGRA test in addition to TST may improve patient outcome. However, the issue of whether to use the QFT-GIT or T-SPOT assay remains to be resolved. Among 95 patients with positive TST ( 10 mm) results, 43 patients (45.3%) showed negative QFTGIT results. This discrepancy may be due to falsepositive TST results due to BCG vaccination or may be due to false-negative QFT-GIT results. If the false-positive TST because of BCG vaccination was a main cause of discrepancy between the two tests, the either test positive strategy can lead to an overtreatment of LTBI. In spite of this point, we adopted the either test positive strategy based on the high risk of TB development and the absence of a gold standard test for diagnosing LTBI in patients receiving anti-TNF agents. Further studies are needed to compare the performance of QFT-GIT alone versus a combined use of TST and QFT-GIT assays. A total of six patients developed active TB after starting anti-TNF-a treatment. Of six patients, two had a history of previous anti-TB medication and therefore LTBI treatment was not indicated in our study. Even though they reported that they had completed anti-TB treatment according to the attending doctor’s decision, it was impossible to identify whether previous treatment was appropriate or not since the treatment had been completed several decades ago. Several previous studies reported that the risk of TB was higher in patients treated with anti-TNF monoclonal antibodies (infliximab or adalimumab) than in patients treated with a soluble TNF receptor (etanercept) [30]. In our study, all six patients who developed active TB had been treated with infliximab (n 5) or adalimumab (n 1) and none had been treated with etanercept. These observations are compatible with previous studies [31,32]. Active TB developed within 6 months of initiating anti-TNF-a therapy in four patients, suggesting that TB develops through reactivation of LTBI. In another two patients, TB developed 17 and 12 months after initiating anti-TNF therapy, respectively, suggesting that TB may develop through a new infection. Further studies with large numbers of patients are needed to find out the role of reinfection in the development
of TB in patients taking anti-TNF agents, especially in a TB-prevalent area. There are several limitations to this study. First, although most subjects were immunocompromised, the TST cut-off was set at 10 mm as described previously [12]. Only 37/426 (8.7%) patients had borderline TST ( 5 mm but 10 mm) and negative QFT-GIT results so that LTBI treatment was not indicated: only one of them developed active TB during follow-up. Second, the number of patients who developed TB was insufficient for predicting TB development, even though we enrolled a large number of patients. Third, the baseline characteristics, anti-TNF agents used, and follow-up duration differed considerably between our previous and current studies, which precluded a meaningful comparison. In conclusion, even though there were some falsenegative results, the either test positive strategy using both TST and QFT-GIT assays is acceptable for LTBI screening before commencing anti-TNF therapy in patients with IMIDs. Further studies are needed to find more accurate and cost-effective methods for LTBI screening before initiating antiTNF-a treatment.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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