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BACKGROUND Reduced sensitivity of tuberculosis (TB) interferon-γ release assays (IGRAs) among the elderly has been reported, which is presumably due to diminished immune function. We evaluated the clinical performance of QuantiFERON®-TB Gold plus (QFT-Plus) compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) and T-Spot®.TB (T-SPOT) in the elderly. METHODS Blood samples for all three IGRAs were drawn at the same time from all the participants. Both CD4 and CD8 T-cell counts in patients' peripheral blood were also measured. RESULTS A total of 142 active pulmonary TB patients (median age: 84, interquartile range; 76-89 years) were recruited. The sensitivities of the tested IGRAs (excluding invalid/indeterminate cases) were as follows: QFT-Plus, 93.6%; QFT-GIT, 91.4%; and T-SPOT 68.1%. QFT-Plus displayed significantly higher sensitivity than T-SPOT (p

Objectives This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. Methods Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. Results IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82–0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. Conclusion Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.

This study aimed to determine whether increased cut-off of the T-SPOT.TB could aid in diagnosing active tuberculosis (ATB).Patients suspected of having TB were enrolled to derive a T-SPOT.TB threshold value to help diagnose ATB, which was subsequently validated in real-world clinical practice.In total, 701 adult patients suspected of having tuberculosis who had undergone the T-SPOT.TB assay were included in the derivation cohort. The numbers of ESAT-6 (U = 43583, P = 0.0002) and CFP-10 (U = 41753, P 0.0001) spot-forming cells (SFCs) significantly increased in the ATB group compared with the Latent tuberculosis infection (LTBI) group. According to receiver operating characteristic analysis, when a cut-off of 37.5 SFCs/2.5 × 10In high-burden countries, a higher threshold value of 173.5 SFCs/2.5 × 10

Diagnosing latent tuberculosis (TB) infection (LTBI) is important globally for TB prevention. LTBI diagnosis requires a positive test for infection and negative evaluation for active disease. Current tests measure an immunologic response and include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), T-SPOT.TB and QuantiFERON. The IGRAs are preferred in bacille Calmette-Guérin-vaccinated populations. The TST is still used when cost or logistical advantages over the IGRAs exist. Both TST and IGRAs have low positive predictive values. Tests that differentiate the TB spectrum and better predict future TB risk are needed.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and developing active tuberculosis. QuantiFERON®-TB Gold Plus (QFT-Plus) has two TB-specific antigens tubes (TB1 and TB2). TB1 elicits CD4 T-cell response, and TB2 elicits both CD4 and CD8 T-cells responses, with expected increased sensitivity. The aim of this study was to estimate the prevalence of LTBI in renal transplant recipients in Japan. We conducted a cross-sectional study by using two interferon-γ release assays (IGRAs), QFT-Plus and T-SPOT®.TB (TSPOT). One hundred thirty-five recipients were prospectively enrolled. The median age was 49 years (range: 20 to 79). The positivity rates of QFT-Plus and TSPOT were 5.9% (95%CI 3.0-11.3) and 3.7% (95%CI 1.6-8.4), respectively, with no significant difference. The concordance rate was 95.5% (κ coefficient, 0.76). Age of 60 years and higher was related to the higher positivity rate in both QFT-Plus and TSPOT. The positivity rates of TB1 and TB2 were 5.1% (95%CI 2.5-10.2) and 5.9% (95%CI 3.0-11.2), respectively, with no significant difference. The concordance rate was 99.3% (κ coefficient, 0.93). TB2 did not show a higher positivity rate compared with TB1. The estimated prevalence of LTBI by using the both IGRAs was 3.7-5.9% in renal transplant recipients. These results were equivalent to the IGRAs positivity rate in the general Japanese population, even under the condition of immunosuppressive therapy. In consideration of the higher risk of developing active TB from LTBI, we can use both IGRAs as acceptable tools for LTBI diagnosis in renal transplant recipients.

Summary Objectives To evaluate the performance of QuantiFERON-TB Gold Plus (QFT-Plus) on Mycobacterium tuberculosis (MTB) infection test among registered village doctors from China. Methods MTB infection of the registered village doctors in Zhongmu County were tested using QFT-Plus and two other interferon-gamma release assays (IGRAs) in parallel: QuantiFERON-TB Gold In-Tube (QFT) and T-SPOT.TB (T-SPOT). Retests were carried out for baseline positives at 3 and 6 months later, respectively. Results A total of 616 village doctors were included in the baseline examination. The positivity of QFT, QFT-Plus and T-SPOT was 27.91% (168/602), 31.22% (187/599) and 27.70% (169/610), respectively. The concordance between QFT and QFT-Plus was 94.81% (Kappa coefficient: 0.87) and between T-SPOT and QFT-Plus was 88.93% (Kappa coefficient: 0.73). Reversions were frequently observed for all three assays. With respect to QFT-Plus, the quantitative results of reversions in the serial testing were mostly distributed in an “uncertain range” zone (0.2-0.7 IU/mL). Similar patterns of distribution were observed for QFT and T-SPOT as well. Conclusion Village doctors should gain more attention as an at-risk group for TB infection control in rural China. Our results support, by means of serial testing, a good agreement between QFT-Plus and QFT in Chinese population.

Summary Objectives Tuberculosis (TB) is a serious infectious disease with high mortality for solid-organ transplantation. Preventive therapy of latent tuberculosis infection (LTBI) has been considered to reduce TB risk and improve outcomes of transplantation. The aim of this study was to evaluate the cost-effectiveness of the interferon-gamma release assays (IGRAs); QuantiFERON®-TB Gold in-Tube (QFT) and T-SPOT®.TB (TSPOT)), for kidney, liver and lung transplant recipients in low TB incidence countries. Methods Decision trees and Markov models were developed for four strategies; QFT, TSPOT, the tuberculin skin test (TST) and no screening. Targeted populations were hypothetical cohorts of kidney, liver and lung transplant recipients aged 40 years using a societal perspective on a lifetime horizon. Per-person costs, effectiveness and incremental cost effectiveness ratios were calculated and compared. Results QFT was the most cost-effective (Kidney; US$ 5679, 3.026 QALYs, Liver; US$ 5914, 2.365 QALYs, Lung; US$ 6092, 3.761 QALYs). No screening was the least effective. Cost-effectiveness was not sensitive to BCG vaccination rate, and the costs of screening tests and treatment. Conclusions TB screening using IGRA with individualized TB risk assessment and follow-up monitoring of drug toxicity during LTBI treatment is recommended for solid organ transplantation, on the basis of the benefits and cost-effectiveness.

Background: Tuberculosis (TB) is a leading cause of fever of unknown origin (FUO). In recent years, interferon-γ release assays (IGRAs) have been widely utilized and the cut-off values given by the manufacturers are set in countries where rates of TB are not as high. Methods: A prospective cohort study was conducted in a Chinese general hospital to evaluate the diagnostic performance of T-SPOT.TB (T-SPOT) and QuantiFERON-TB Gold (QFT) in detecting active TB (ATB) in a high TB endemic area. Test results were compared with the culture and clinically confirmed diagnosis. Further, we explored an alternative method of interpreting IGRAs by increasing the cut-off values. Results: The sensitivity and specificity of T-SPOT in detecting ATB were 85.3% (95% CI 81.6–94.0%) and 71.8% (95% CI 67.3–76.0%), respectively. The sensitivity and specificity of QFT were 72.3% (95% CI 62.8–80.1%) and 77.0% (95% CI 72.7–80.8%), respectively. Receiver operating characteristic analysis was used for evaluation of different cut-off values. When the cut-off values were adjusted as 125 spot-forming cells (SFCs)/ 2.5*105 cells for T-SPOT and 4.0 IU/ml for QFT, the specificity could be improved to > 90.0% (90.3% and 94.1%, respectively), and the sensitivity were 43.1% and 41.6%, respectively. The new adjusted cut-off values were validated in another independent validation cohort. Conclusion: The adjusted cut-off values of the two assays considerably improved the diagnostic value when applied to FUO patients in clinical settings.

Background T-SPOT.TB may yield indeterminate results, including high nil responses and insufficient mitogen responses. We explored the incidence and risk factors of high nil responses. Methods A 1:1 matched case-control study of patients who underwent T-SPOT.TB tests in Peking Union Medical College Hospital from Jan 1, 2015 to Apr 30, 2017 was conducted. High nil responses were defined as >10 spots in negative control wells. Cases and controls were matched based on when the tests were performed. Demographic, clinical and laboratory data were obtained from the Medical Record System. Results A total of 644 out of 36,316 (1.76%, 95% CI: 1.63%–1.90%) patients presented with high nil responses (280 cases and 280 controls were enrolled). Multivariate analysis revealed that male (OR = 1.882, 95% CI: 1.222–2.899), Behcet's disease (OR = 7.764, 95% CI: 1.714–35.167), heavy use of corticosteroids within a month (OR = 0.357, 95% CI: 0.138–0.921, for >1000 mg group) and hypoalbuminemia (OR = 0.385, 95% CI: 0.241–0.615) are significantly associated with high nil responses. Conclusions High nil responses in T-SPOT.TB assays are quite rare. Male gender and Behcet's disease are suggested as independent risk factors, while recent excessive use of corticosteroids and hypoalbuminemia seem to be independent protective factors.

The IGRA-ELISA and T-SPOT.TB are widely used in China. The aim of the study was to evaluate the performance of the two assays in diagnosis Mycobacterium tuberculosis infection.Of the 3727 patients in the study, 204 underwent testing using both the T-SPOT.TB and IGRA-ELISA, 1794 were tested using the T-SPOT.TB only, and 1729 were tested using the IGRA-ELISA only. The positive rate and consistency of the two assays were analyzed, and their sensitivity and specificity for diagnosing active tuberculosis were compared.There were no significant differences in the positive rate between the T-SPOT.TB test (25.8%) and IGRA-ELISA (28.6%), p = .065. The two assays were highly consistent, with a kappa value of 0.852 (p .0001) and a total coincidence rate of 92.7%. For the diagnosis of active tuberculosis, the sensitivity and specificity values of the T-SPOT.TB test were 82.9% (107/129) and 78.6% (1309/1665), respectively, and those of IGRA-ELISA were 81.7% (94/115) and 75.2% (1214/1614), respectively. There were no significant differences in sensitivity (p .05), but the specificity of the T-SPOT.TB test was slightly higher than that of IGRA-ELISA (p = .023).Both in terms of diagnosing M. tuberculosis infection and ruling out active tuberculosis, the performance of the IGRA-ELISA-a simple, almost labor-free assay that allows simultaneous processing of a very large number of samples-was well-matched with that of T-SPOT.TB test. However, IGRAs cannot be used as the only test to diagnose active tuberculosis.

Background The QuantiFERON-TB Gold Plus (QFT-Plus) was introduced in 2015 as a new generation of interferon-gamma release assays (IGRAs) designed to detect Mycobacterium tuberculosis infection (TB). Examination of its diagnostic accuracy is crucial before it is launched in Japan. Method We examined 99 patients with laboratory-confirmed active TB (patients) and 117 healthy volunteers with no risk of TB infection (controls) at a medical center in Tokyo, Japan. Blood samples were collected from both the patients and controls and tested using three types of IGRAs: the QFT-Plus, the QuantiFERON-TB Gold In-Tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). The sensitivity and specificity of each IGRA were examined and compared. Results The sensitivity of the QFT-Plus was 98.9% (95% confidence interval [CI], 0.934–0.998) and similar to that of the QFT-GIT (97.9%; 95% CI, 0.929–0.998) and T-SPOT (96.9%; 95% CI, 0.914–0.994). The specificity of the QFT-Plus was the same as that of the QFT-GIT and T-SPOT (98.1%; 95% CI, 0.934–0.998). One patient with uncontrolled diabetes mellitus showed negative results on all three IGRAs. Conclusions The QFT-Plus showed a high degree of agreement with the QFT-GIT and T-SPOT, with high sensitivity and specificity. Severe diabetes mellitus may influence the results of IGRAs. Larger studies are needed to validate the accuracy of the GFT-Plus and determine whether it can contribute as adjunctive method for the early diagnosis of active TB in Japan.

Rheumatoid arthritis (RA) is an immune mediated inflammatory disorder, and immune suppressive drugs are prescribed. RA patients receiving treatments are in a kind of immunosuppressive condition that presents increased risk of developing active tuberculosis. Accurate diagnosis of latent tuberculosis infection (LTBI) is recommended for RA. QuantiFERON®-TB Gold Plus (QFT-Plus), a novel IGRA, has two tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses, with expected increased sensitivity. We conducted a cross-sectional study to compare two IGRAs, QFT-Plus and T-SPOT®.TB (TSPOT), in RA. One hundred fifty-two RA patients (median age: 66.5 yrs) were enrolled. QFT-Plus and TSPOT were concurrently conducted. Lymphocyte subsets (CD4 T-cell and CD8 T-cell) were also measured. The positivity rates of QFT-Plus and TSPOT were 9.7% and 4.5%, respectively, with the difference being significant (P

Background Accurate identification of individuals with TB infection, is required to achieve the WHO's End TB Strategy goals. While there is general acceptance that the T-SPOT.TB test borderline category provides an opportunity to increase test resolution of results around the test cut-off point, this has not been investigated. Methods 645,947 tests were analyzed to determine frequency of borderline results, effect of age and time between tests and associations between subjects' clinical risk factors and retest results. Results 645,947 tests produced 93.5% negatives, 4% positives, 0.6% invalids, and 1.8% borderlines. Within the borderline results, 5044 were repeated, with 59.2%, 20.0% and 20.2% resolving to negative, positive and borderline, respectively. Age of subject did not affect retest results; however, time between tests indicated that retest resolution occurred with greatest frequency after 90 days. TB risk factors were provided for 2640 subjects and 17% of low risk subjects with a high initial borderline resolved to negative while 27.6% of subjects with high risk and an initial low borderline resolved to positive, suggesting that these subjects could have been inappropriately classified if using a single cut-off point test with no borderline category. Conclusion This study demonstrates the utility of the T-SPOT.TB test's borderline category to increase test resolution around the test cut-off point.

Summary Objectives Biologic agents are used against rheumatic diseases, however, they increase the risk of developing severe infections and diseases such as tuberculosis. We aimed to determine the benefits of IP-10 detection to diagnose latent tuberculosis infection (LTBI) in patients with inflammatory rheumatic diseases on different immunosuppressive drug regimens, and compare these results with IFN-γ detection. Materials and methods We included 64 patients with inflammatory rheumatic diseases. We used QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB to detect IFN-γ production, and an in-house ELISA for IP-10 detection from the previous QFN-G-IT stimulated samples. We assessed the combined use of IFN-γ release assays (IGRAs) and IP-10 test, and analyzed the influence of immunotherapy on the tests performance. Results We obtained 34.9% positive results by T-SPOT.TB, 25.0% by QFN-G-IT and 31.3% by IP-10 test. The combined use of IGRAs and IP-10 detection increased significantly the amount of positive results ( p in vitro tests ( p > 0.05). Conclusions IP-10 and IFN-γ detection is comparable and their combined use could increase the number of positive results in the diagnosis of LTBI in rheumatic patients. The tested assays were not influenced by rheumatoid immunosuppressive therapy. Thus, IP-10 could be of use in the development of new and improved LTBI diagnostic tools.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and progressing to active tuberculosis (TB). This study was conducted in National hospital for tuberculosis and renal transplantation (RT) in Japan. The purpose is to compare two interferon-γ release assays (IGRAs), QuantiFERON®-TB Gold in Tube (QFT) and T-SPOT®.TB (TSPOT), in patients after renal transplantation for detecting latent TB infection (LTBI). Total 92 renal transplant recipients (median age 46 years, range 17-75) were prospectively enrolled, and QFT and TSPOT were concurrently examined. Total subjects were 92 patients (median age 46 years, range 17-75). The positive rate in QFT and TSPOT were 6.5% (95% confidence interval (CI) 3.0-13.5) and 2.2% (95% CI 1.0-7.6), respectively. There was a significant difference in IGRAs positivity (P

Utility of the in-vitro immunodiagnostic methods, based on the detection of interferon-γ released by T-cells after specific Mycobacterium tuberculosis antigen stimulation (IGRA), has been an improvement in the accuracy of the latent tuberculosis infection diagnosis. IGRA have a well-known higher specificity than the tuberculin skin testing (TST). Moreover, they can obtain a larger number of positive results than the TST in immunocompromised patients. IGRA have shown a high correlation with M. tuberculosis exposure, but their positive and negative predictive value are similar than those obtained by TST. Nevertheless, given their high specificity, they allow reducing number of unnecessary preventive treatments. In addition, these in-vitro techniques are less affected than TST by the different immunosuppressing status. In this review is discussed up-to-date applicability of IGRA in different patient groups: contact studies, pediatric population, immunosuppressed patients, health care workers and active tuberculosis patients. Furthermore, it has been included possible future directions for latent tuberculosis infection and active tuberculosis diagnosis.

Summary Objective In this study, we have performed a direct comparison between both T-cell based assays (QFN-G-IT and T-SPOT.TB) and TST in patients with psoriasis taking different immunosuppressant drug-regimens. Methods We have prospectively studied 103 patients with moderate-to-severe psoriasis who required latent tuberculosis infection (LTBI) screening before starting systemic immunosuppressive treatment or during its sustained use. Results Overall number of positive results was 16.5%, 17.5% and 8.7% using T-SPOT.TB, QFN-G-IT and TST, respectively. Differences in the percentage of positive results between TST with T-SPOT.TB and QFN-G-IT were significant ( p = 0.005 and p = 0.008, respectively). A total of 24.3% of the subjects enrolled were positive for at least one of the three tests performed. Sixteen patients with negative TST (17%) were positive for one of the two IGRAs. We obtained seven indeterminate results by T-SPOT.TB and two by QFN-G-IT. Seven patients with negative TST presented indeterminate results by either of two IFN-γ assays. Positive TST, T-SPOT.TB and QFN-G-IT results were not affected by clinical therapeutic profile. Conclusions Our results reveal that in vitro assays are useful methods for LTBI diagnosis in patients with psoriasis, suggesting that they might be less influenced by immunosuppression than TST.

Background The relative diagnostic accuracy of interferon γ release assays (IGRAs; based on ELISA [enzyme-linked immunosorbent assay] or ELISPOT [enzyme-linked immunosorbent spot], ie, the QuantiFERON and T-SPOT.TB tests, respectively) and the tuberculin skin test (TST) for latent tuberculosis (TB) infection in people with end-stage kidney disease is uncertain and national guidelines for their use are inconsistent. Study Design Systematic review. Selection Criteria for Studies Evaluated performance of tests for latent TB with clinical risk-factor assessment. Setting & Population People with end-stage kidney disease (chronic kidney disease stage 5 [eGFR Index Tests ELISA- or ELISPOT-based IGRAs, TST, assays to detect antimycobacterial antibodies, and flow cytometry–based tests. Outcomes Odds of test positivity with clinical risk factor for latent TB, expressed as ORs and relative ORs (RORs). Results 47 studies (6,828 participants) were included, but only 30 studies (4,546 participants) contained sufficient data to contribute to meta-analysis. Studies were predominately in the dialysis population (23/30; 3,700 participants) in countries with low to moderate TB prevalence (0.0-50.0 cases/105 persons). BCG vaccination rate was variable (2.7%-100.0%). 9 studies compared IGRAs with the TST directly, 17 studies evaluated the TST only, and the other 4 studies evaluated other tests. Compared to a positive TST result, a positive ELISA-based IGRA result was associated more strongly with radiologic evidence of past TB (ROR, 4.29; 95% CI, 1.83-10.3; P = 0.001) and contact with active TB (ROR, 3.36; 95% CI, 1.61-7.01; P = 0.001). Compared to a negative TST result, a negative ELISA-based IGRA result was associated more strongly with BCG vaccination (ROR, 0.30; 95% CI, 0.14-0.63; P = 0.002). There were insufficient data to compare performance of the ELISPOT-based IGRA with the TST or ELISA-based IGRA. Limitations 17 of 47 included studies (36.2%) did not contain sufficient data to contribute to meta-analysis. Conclusions Compared to the TST, the ELISA-based IGRA was associated more strongly with risk factors for latent TB in end-stage kidney disease.

Summary Background There is limited information on the prevalence of latent tuberculosis infection (LTBI) and the risk factors among contacts of pulmonary TB, which might contribute significantly to TB burden and therefore become the major concern for TB control in Shanghai, China. Methods A total of 45 diagnosed TB patients from each of 7 Shanghai districts were chosen and approximately 3 contacts per case were randomly selected. A structured questionnaire was used to acquire socio-demographic information and to assess the degree of exposure to index cases. LTBI screening was performed by T-SPOT. TB assay. Results Of 969 enrolled contacts, 39% were men, average age was 45 ± 19.1 years, and 76.3% were household contacts. LTBI was identified in 29.6% of subjects. Those contacting smear-positive TB patients were 2.24 times (95%CI, 1.586–3.162) more likely to develop LTBI than those otherwise; household contact significantly increased the likelihood of LTBI by 1.52 times (95%CI, 1.061–2.180). Furthermore, among household contacts, the risk of LTBI was higher in spouses and first-degree relatives and increased with age and contact duration. Conclusions A high prevalence of LTBI was observed among the TB contacts in Shanghai, highlighting the need of intervention among the household contacts and those contacting smear-positive TB patients.

Introduction The diagnosis of latent tuberculosis (LTB) in patients with rheumatoid arthritis (RA) has become important with the introduction of anti-tumor necrosis factor (anti-TNF-α) agents and the appearance of active tuberculosis cases in these patients. The tuberculin skin test (TST) has limited value in patients with RA. Tests based on the release of interferon-gamma (IFN-γ) are being studied, but their role has not been well established for this group of patients. Objectives To compare the diagnosis of LTB in patients with RA by using cellular immune response to the TST and T.SPOT-TB. Additionally, findings of tomography studies compatible with LTB were used. Methods Clinical evaluation, TST, T.SPOT-TB and high-resolution computed tomography (HRCT) in a group of patients with RA at the University Hospital of the Federal University of Goias. Results Response to the TST was lower in patients with RA (13.5%) compared to the predicted values of the general population. T.SPOT-TB identified a higher number of patients with LTB than the TST (36.8%). HRCT showed changes compatible with LTB in 52.9% of the patients, including 8 of the 11 patients with negative TST and T.SPOT-TB. Conclusions The TST by itself is insufficient to diagnose LTB. A higher number of positive results were obtained with T.SPOT-TB when compared to the TST. Nevertheless, it was negative in a large percentage of patients with tomography findings consistent with LTB. HRCT is readily available in most large health-care centers and it could be incorporated into the diagnostic strategy for LTB in patients with RA.

Summary Objectives Longitudinal studies in household contacts to identify subgroups at risk of active tuberculosis are lacking. Methods Household contacts of pulmonary tuberculosis patients were prospectively enrolled to receive chest radiography, sputum studies, and T-SPOT. TB assay at initial visit. Repeat examinations every 6 months for 3 years, and 4-month rifampin preventive therapy for T-SPOT. TB -positive contacts were provided. We investigated factors predicting T-SPOT. TB -positivity and active pulmonary tuberculosis. Results 583 contacts were enrolled with a follow-up duration of 20.7 ± 9.4 months. 176 (30.2%) were T-SPOT. TB -positive initially and 32 (18.2%) of them received preventive therapy. Old age, living in the same room/house with the index case, the index case having a high smear grade (3+ ∼ 4+) and pulmonary cavitation were associated with T-SPOT. TB -positivity. Active tuberculosis developed in 9 T-SPOT. TB -positive contacts; risk factors included T-SPOT. TB -positivity without preventive therapy, living in the same room, and the index case being ≤50 years or female. 108 (61.4%) T-SPOT. TB -positive contacts had repeat examinations. Forty-five had T-SPOT. TB reversion and none of them developed active tuberculosis. Conclusion Household contacts who are T-SPOT. TB -positive and live in the same room as the index case are at risk of active tuberculosis and require preventive therapy and close follow-up.

Summary Background The clinical manifestations of extrapulmonary tuberculosis (E-TB) vary according to site of disease, so we tested the hypothesis that IFN-γ producing T-cell responses also vary in parallel. Therefore we conducted a prospective, blinded, observational study to evaluate the diagnostic performance of blood T-SPOT.TB according to the various sites of E-TB. Methods From April 2008 to August 2010, all patients with suspected E-TB were enrolled at a tertiary hospital in an intermediate TB-burden country. Final diagnosis in patients with suspected E-TB was classified by clinical category. Results A total of 368 patients with suspected E-TB were enrolled; 196 (53%) were classified as having TB, including 119 (32%) with confirmed TB, 34 (9%) probable TB, and 43 (12%) possible TB; the remaining 172 (47%) were classified as not having TB. After excluding patients with possible TB, the T-SPOT. TB was more sensitive in patients with chronic forms of E-TB such as lymph node or osteoarticular TB (93%, 95% CI 83%–97%) than in patients with acute forms of E-TB such as TB meningitis or miliary TB (79%, 95% CI 66%–87%, P = 0.03). Conclusions The diagnostic performance of the blood T-SPOT. TB differs among patients with various clinical manifestations of E-TB.

One-third of the world-wide population currently presents latent tuberculosis infection (LTI). In Spain, TB is situated as the third disease of mandatory notification. The standard technique for the diagnosis of ITL is the tuberculin test (PPD), although its most important drawback is its specificity since the proteins used are not specific for Mycobacterium tuberculosis. In recent years, research has been done and new diagnostic methods have been approved based on the in vitro quantification of the immune cell response, the so-called interferon gamma release assays (IGRA). Compared with PPD, the main difference is that IGRAs detect the release of interferon-gamma in response to specific tuberculous antigens. In the absence of a true reference test for the diagnosis of tuberculosis infection, it is difficult to establish the sensitivity and specificity of these new diagnostic techniques. IGRAs have been used in the detection of ITL in subjects with immune system alterations (HIV, EEI, IRC, rheumatologic diseases) with good results. They are also being extensively used in the study of contacts. In recent studies involving serial controls of said tests, they were observed to present conversions and reversions that occur after exposure to M. tuberculosis. Today and with the current knowledge, it seems that IGRAs can complement PPD, but not substitute them.

The aim of this study was to compare the diagnostic performance of 2 interferon-γ release assays, an enzyme-linked immunospot assay (T-SPOT.TB; Oxford Immunotec Ltd., Oxford, UK) and the QuantiFERON-TB Gold in-Tube assay (QFT-GIT; Cellestis Ltd., Carnegie, Australia), in patients with suspected active tuberculosis (TB). From October 2009 to October 2011, a total of 200 patients with suspected TB were enrolled. Clinical and microbiological characteristics of the patients were collected and blood samples were obtained for T-SPOT.TB and QFT-GIT assays. Among the 200 subjects, 98 (49%) had culture-confirmed TB, 18 (9%) had probable TB, and the remaining 84 (42%) subjects did not have TB. The sensitivity, specificity, positive predictive value, and negative predictive value for active TB diagnosis by the T SPOT. TB were 83%, 71%, 81%, and 75%, respectively. For QFT-GIT, the sensitivity, specificity, positive predictive value, and negative predictive value for active TB diagnosis were 66%, 76%, 80%, and 62%, respectively. The QFT-GIT assay resulted in more indeterminate and false-negative results than the T-SPOT.TB assay, especially in immunocompromised patients. In conclusion, T-SPOT.TB had a higher sensitivity and resulted in fewer indeterminate results than the QFT-GIT assay for diagnosing active TB.

Summary Objectives To determine the diagnostic value of a blood interferon-gamma release assay in suspected active tuberculosis (TB). Methods 136 subjects with suspected pulmonary TB (pTB) at a single London centre with intermediate TB incidence, were clinically graded into low ( 75%) likelihood of active pTB and then tested by T-SPOT ® .TB assay. The diagnosis was confirmed by culture ( n = 33), treatment response ( n = 13) or a firm alternative diagnosis ( n = 90). Results Overall, the T-SPOT. TB sensitivity was 74% (95% confidence intervals 60–84%), positive predictive value (PPV) 56% (43–68%), negative predictive value (NPV) 83% (71–90%), positive likelihood ratio (PLR) 1.75 and negative likelihood ratio (NLR) 0.45. Results for high pTB likelihood subjects: PPV 100%, NPV 25% (7–60%), PLR >69, NLR 0.31. Results for intermediate pTB likelihood subjects: PPV 67% (41–85%), NPV 88% (65–96%), PLR 2.39, NLR 0.26. Results for low pTB likelihood subjects: PPV 15% (6–34%), NPV 92% (79–97%), PLR 1.23, NLR 0.80. False negatives occurred in 24% of cases of active tuberculosis (4 smear and culture-positive, 3 smear negative and culture-positive, and 4 culture negative). Conclusions The predictive values and likelihood ratios show the T-SPOT. TB test does not assist in confidently confirming or excluding active TB, regardless of the pre-test probability of disease.

Test accuracy of interferon-γ release assays (IGRAs) for diagnosing TB differs when using older or precommercial tools and inconsistent diagnostic criteria. This metaanalysis critically appraises studies investigating sensitivity and specificity of the commercial T-Spot. TB and the QuantiFERON-TB Gold In-Tube Assay (QFT-IT) among definitely confirmed TB cases. We searched Medline, EMBASE, and Cochrane bibliographies of relevant articles. Sensitivities, specificities, and indeterminate rates were pooled using a fixed effect model. Sensitivity of the tuberculin skin test (TST) was evaluated in the context of IGRA studies. In addition, the rates of indeterminates of both IGRAs were assessed. The pooled sensitivity of TST was 70% (95% CI, 0.67-0.72) compared with 81% (95% CI, 0.78-0.83) for the QFT-IT and 88% (95% CI, 0.85-0.90) for the T-Spot. TB . Sensitivity increased to 84% (95%CI, 0.81-0.87) and 89% (95% CI, 0.86-0.91) for the QFT-IT and T-Spot. TB , respectively, when restricted to performance in developed countries. In contrast, specificity of the QFT-IT was 99% (95% CI, 0.98-1.00) vs 86% for the T-Spot. TB (95% CI, 0.81-0.90). The pooled rate of indeterminate results was low, 2.1% (95% CI, 0.02-0.023) for the QFT-IT and 3.8% (95% CI, 0.035-0.042) for the T-Spot. TB , increasing to 4.4% (95% CI, 0.039-0.05) and 6.1% (95% CI, 0.052-0.071), respectively, among immunosuppressed hosts. The newest commercial IGRAs are superior, in comparison with the TST, for detecting confirmed active TB disease, especially when performed in developed countries.

Background: Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their management is hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-γ release blood assays T-SPOT.TB (TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy for latent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown. Methods and results: Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneously performed, their results were compared, and intertest agreement was evaluated. Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p < 0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (κ = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (κ = 0.16) or QFT-IT (κ = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001). Conclusions: Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based on these results, we recommend tailoring application of the new blood IFN-γ assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

Rationale Mycobacterium tuberculosis (MTB)-specific interferon-γ release assays (IGRAs) are an alternative or adjunct to the tuberculin skin test (TST) in identifying recent contacts with latent tuberculosis infection (LTBI), but there are scarce data directly comparing performance of the tests. Objective To evaluate the agreement between both IGRAs and to determine which contacts were most likely to represent LTBI, the QuantiFERON-TB-Gold In Tube assay (QFT) and the T-Spot. TB test (T-Spot) were compared in TST-positive persons recently exposed to pulmonary tuberculosis cases. Methods Prospectively enrolled close contacts (n = 812) of 123 culture-confirmed tuberculosis source cases underwent IGRA testing using standardized collected data. Factors independently influencing the risk of MTB infection and their interactions with each other were evaluated by multivariate analysis. Results Five variables were found to significantly predict a positive IGRA test result (age, source case acid-fast bacilli positive and/or coughing, cumulative exposure time, foreign origin). There was excellent agreement between the two IGRAs (93.9%, κ = 0.85), with QFT finding 30.2% of contacts positive and T-Spot finding 28.7%. Assuming positivity to both IGRAs as true infection, sensitivity of the TST at > 10 mm was 72% and at > 15 mm was 39.7%. The use of either IGRA as a replacement for the TST would decrease the number of LTBI suspects to be investigated by approximately 70%. Conclusions IGRAs are a more accurate indicator of the presence of LTBI than the TST. Both QFT and T-Spot appear to be valuable public health tools, showing excellent agreement with each other.

Healthcare workers have an increased risk of tuberculosis infection compared with the general population. There have been few attempts to quantify the prevalence of latent tuberculosis infection amongst German healthcare workers, due to inadequacy of the current tuberculin skin test (TST). Therefore, it was our aim to investigate the prevalence of latent tuberculosis in this cohort using a tuberculosis-specific ELISpot (T-SPOT.TB) test and to compare the performance of this test to that of the TST. Ninety-five healthy participants working in departments of radiology were examined by ELISpot, lymphocyte transformation test and TST. For cellular in-vitro tests, tuberculosis-specific peptides and purified protein derivate (PPD) were used as antigens. These tests were combined with a questionnaire on prior tuberculosis exposure. Out of 95 healthcare workers, only one (1%) was defined as positive by T-SPOT.TB, 92 (97%) by PPD-ELISpot, 78 (82%) by PPD-lymphocyte transformation test and 32 (34%) by TST. Multivariate analysis showed that the TST was significantly affected (P

Until recently, the tuberculin skin test was the only test for detecting latent tuberculosis (TB) infection with a lack of specificity and reliability. Since 2005, new tests are available. Those tests are based on interferon gamma released (IGRAs) by T lymphocytes after mycobacterium tuberculosis antigen specific exposure. The new tests are able to modify our understanding of natural history of tuberculosis. Longitudinal studies are needed to define the predictive value of IGRAs.

Resume Le developpement de tests sanguins in vitro, mesurant la reponse d'hypersensibilite retardee observee a l'issue d'un contage tuberculeux, va progressivement modifier le diagnostic de l'infection par Mycobacterium tuberculosis . Ces tests sanguins (Quantiferon TB Gold TM , Cellestis, Australia ; T-SPOT.TB TM , Oxford Immunotec, Angleterre) utilisent des antigenes specifiques de M. tuberculosis complex : ESAT-6, et CFP-10, comparativement a l'intradermoreaction a la tuberculine (IDR) qui est un melange complexe de plus de 200 antigenes mycobacteriens. ESAT-6 et CFP-10 sont absents de toutes les souches vaccinales de BCG utilisees dans le monde. Une amelioration significative de la specificite de ces tests, associee a une sensibilite identique ou superieure vis-a-vis de l'IDR, dans le diagnostic de la tuberculose–infection feront que ces tests sanguins remplaceront dans le futur l'IDR.

Resume Le developpement de tests sanguins in vitro, mesurant la reponse d'hypersensibilite retardee observee a l'issue d'un contage tuberculeux, va progressivement modifier le diagnostic de l'infection par Mycobacterium tuberculosis . Ces tests sanguins (Quantiferon TB Gold TM , Cellestis, Australia ; T-SPOT. TB TM , Oxford Immunotec, United Kingdom) utilisent des antigenes specifiques de M. tuberculosis complex : ESAT-6 et CFP-10, comparativement a l'intradermoreaction a la tuberculine (IDR) qui est un melange complexe de plus de 200 antigenes mycobacteriens. ESAT-6 et CFP-10 sont absents de toutes les souches vaccinales de BCG utilisees dans le monde. Une amelioration significative de la specificite de ces tests, associee a une sensibilite identique ou superieure vis-a-vis de l'IDR, dans le diagnostic de la tuberculose–infection feront que ces tests sanguins remplaceront dans le futur l'IDR.

A major challenge in tuberculosis control is the diagnosis and treatment of latent tuberculosis infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent tuberculosis. However, an alternative has now emerged in the form of a new in-vitro test: the interferon-gamma assay. We did a systematic review to assess the performance of interferon-gamma assays in the immunodiagnosis of tuberculosis. By searching databases, contacting experts and test manufacturers, we identified 75 relevant studies. The results suggest that interferon-gamma assays that use Mycobacterium tuberculosis-specific region of difference 1 (RD1) antigens (such as early secretory antigenic target 6 and culture filtrate protein 10) may have advantages over the TST, in terms of higher specificity, better correlation with exposure to M tuberculosis, and less cross-reactivity due to BCG vaccination and non-tuberculous mycobacterial infection. However, interferon-gamma assays that use RD1 antigens in isolation may maximise specificity at the cost of sensitivity. Assays that use cocktails of RD1 antigens seem to overcome this problem, and such assays have the highest accuracy. RD1-based interferon-gamma assays can potentially identify those with latent tuberculosis who are at high risk for developing active disease, but this requires confirmation. There is inadequate evidence on the value of interferon-gamma assays in the management of immunocompromised individuals, children, patients with extrapulmonary or non-tuberculous mycobacterial disease, and populations in countries where tuberculosis is endemic. Current evidence suggests that interferon-gamma assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realised in practice remains to be confirmed in well designed, long-term studies.

Childhood tuberculosis often presents non-specifically and is a common differential diagnosis in high prevalence areas. Current diagnostic tools have poor sensitivity and cannot reliably exclude tuberculosis, so overdiagnosis is common. HIV co-infection exacerbates this problem and accounts for an increasing proportion of paediatric tuberculosis worldwide.We assessed the usefulness of a T-cell-based rapid blood test for Mycobacterium tuberculosis infection, the enzyme-linked immunospot assay (ELISPOT), in routine clinical practice. We did a prospective blinded study of 293 African children with suspected tuberculosis in kwaZulu-Natal, a region with high HIV prevalence. Children had full clinical assessment, ELISPOT, and a tuberculin skin test. Test results were compared with final clinical and microbiological diagnoses.In children with tuberculosis, sensitivity of ELISPOT was 83% (95% CI 75-89, n=133), significantly higher (p0.001) than the 63% (54-72) sensitivity of tuberculin skin test (n=116). Sensitivity of tuberculin skin test fell significantly in children younger than 3 years (to 51%), with HIV co-infection (36%), or with malnutrition (44%). Sensitivity of ELISPOT, which was not significantly adversely affected by these factors, was 85%, 73%, and 78%, respectively in these subgroups. In 116 children with both test results available, sensitivity of the two tests combined was 91% (85-95).Diagnostic sensitivity of ELISPOT is higher than that of the skin test and is less affected by factors frequently associated with childhood tuberculosis in developing countries. Used together with the skin test, ELISPOT provides a clinically useful diagnostic sensitivity in African children with suspected tuberculosis.

Summary Current diagnostic tests for tuberculosis based on tuberculin have poor specificity, and both BCG vaccination and exposure to non-tuberculosis mycobacteria produce a response similar to that induced by infection with Mycobacterium tuberculosis . The identification of regions of the M tuberculosis genome that are not present in BCG and non-tuberculous mycobacteria provides a unique opportunity to develop new highly specific diagnostic reagents. We describe the current status of attempts to exploit this information and summarise recent research that has used defined antigens for an accurate and rapid test for tuberculosis infection based on the detection of T cells sensitised to M tuberculosis either by blood tests in vitro or skin tests in vivo.