Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update
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Background: Interferon-γ–release assays (IGRAs) are alternatives to the tuberculin skin test (TST). A recent meta-analysis showed that IGRAs have high specificity, even among populations that have received bacille Calmette–Guérin (BCG) vaccination. Sensitivity was suboptimal for TST and IGRAs. Purpose: To incorporate newly reported evidence from 20 studies into an updated meta-analysis on the sensitivity and specificity of IGRAs. Data Sources: PubMed was searched through 31 March 2008, and citations of all original articles, guidelines, and reviews for studies published in English were reviewed. Study Selection: Studies that evaluated QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. For assessing sensitivity, the study sample had to have microbiologically confirmed active tuberculosis. For assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis. Studies with fewer than 10 participants and those that included only immunocompromised participants were excluded. Data Extraction: One reviewer abstracted data on participant characteristics, test characteristics, and test performance from 38 studies; these data were double-checked by a second reviewer. The original investigators were contacted for additional information when necessary. Data Synthesis: A fixed-effects meta-analysis with correction for overdispersion was done to pool data within prespecified subgroups. The pooled sensitivity was 78% (95% CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB. The pooled specificity for both QuantiFERON tests was 99% among non–BCG-vaccinated participants (CI, 98% to 100%) and 96% (CI, 94% to 98%) among BCG-vaccinated participants. The pooled specificity of T-SPOT.TB (including its precommercial ELISpot version) was 93% (CI, 86% to 100%). Tuberculin skin test results were heterogeneous, but specificity in non–BCG-vaccinated participants was consistently high (97% [CI, 95% to 99%]). Limitations: Most studies were small and had limitations, including no gold standard for diagnosing latent tuberculosis and variable TST methods and cutoff values. Data on the specificity of the commercial T-SPOT.TB assay were limited. Conclusion: The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non–BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.Keywords:
ELISPOT
QuantiFERON
Gold standard (test)
Concordance
Screening and treatment of latent tuberculosis infection (LTBI) prior to anti-tumour necrosis factor alpha (anti-TNF-alpha) therapy has been shown to decrease the incidence of active tuberculosis (TB) by more than 80%, and is recommended by the British Thoracic Society. In the absence of a gold standard test for LTBI, conventional screening currently involves taking a clinical history of risk factors, a chest X-ray and a tuberculin skin test (TST) which can be difficult to interpret in immunosuppressed patients. Alternative cellular immune-based screening tests have been developed to detect Mycobacterium tuberculosis.To examine, evaluate and summarize the quality of evidence on the use of interferon gamma release assay (the ELISpot test) in the diagnosis of latent tuberculosis prior to initiation of anti-TNF-alpha and examine the agreement with the tuberculin skin test.Ovid Medline, Embase and the Cochrane library were searched using search terms that included tuberculosis, each of the current anti-TNF-alpha biological agents, TST and interferon-gamma release assay. Terms were searched using MeSH (medical subject headings) terms and/or free text where relevant.Discordance between tuberculin skin test and ELISpot is greater in individuals who have had the bacillus Calmette-Guérin (BCG) vaccination and are taking corticosteroids. ELISpot technique using CFP-10 and ESAT-6 antigens is more sensitive than TST in detecting M. tuberculosis infection in patients taking corticosteroids. ELISpot avoids cross-reaction with BCG, making it a more specific test in this group of patients. Agreement between the tests was found to be fair (72.8% kappa value=0.38).Tuberculosis resulting from reactivation of latent tuberculosis following treatment with anti-TNF is a continuing problem. Screening reduces the risk but does not eliminate it. Further studies are needed into the cost-effectiveness and sensitivity of ELISpot and the tuberculin skin test in routine clinical practice.
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Background: Detection of latent tuberculosis infection (LTBI) in children, exposed to tuberculosis (TB) infections, followed by appropriate treatment, could be instrumental in reducing TB burden. Interferon Gamma release assays (IGRA) have higher specificity than tuberculin skin tests (TST), hence are more effective option for diagnosis. Hence, the present study was aimed to diagnose the presence of latent TB in children with the help of a new Standard E TB-Feron Enzyme-Linked Immunosorbent Assay (TBF) and evaluating its efficiency as compared to TST and Quantiferon TB Gold plus (QFT Plus). Methods: Diagnosis of LTBI in participants, <18 years old, who were the close household contacts of patients with active TB was carried out employing techniques such as TST, QFT Plus, and TBF. Results: Higher positive results were obtained with IGRA assays QFT Plus and TBF than TST. The perfect agreement was observed between QFT Plus and TBF assays with a Kappa value of 0.9176 whereas TST and TBF assay showed moderate agreement with a Kappa value of 0.42365. The level of cytokines secreted as a result of stimulation by the antigens from QFT Plus tubes was lower in comparison to antigens from TBF tubes. Conclusion: Hence, TBF, which showed similar efficiency as the widely used QFT Plus, can be a useful detection technique for LTBI in children. Moreover, it could prove to be an efficient alternative to expensive IGRAs like QFT Plus.
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To compare the diagnostic efficacy and agreement of the traditional tuberculin skin test with QuantiFERON-Tuberculosis Gold In-Tube test for latent tuberculosis infection in healthcare workers.The cross-sectional analytical study was conducted between March 1 and 31, 2008, at a specialist tuberculosis hospital in Istanbul, Turkey, and comprised healthcare workers who had been employed for at least one year at the hospital and volunteered to take part. Tuberculin skin test and QuantiFERON-Tuberculosis Gold In-Tube test were both performed simultaneously and their results were compared Using SPSS 12.Out of 34 subjects, 20(58.8%) had a positive tuberculin skin test, and 7(20.6%) had a positive QuantiFERON-Tuberculosis Gold In-Tube test. The two tests agreed in only 15(44.1%) cases and disagreed in 19(55.9%). In 16(47.1%) subjects, the QuantiFERON-Tuberculosis Gold In-Tube test was negative and tuberculin skin testwas positive, while in 3(8.8%) participants QuantiFERON-Tuberculosis Gold In-Tube test was positive and tuberculin skin test was negative. Kappa test revealed discordance between the two tests (k=-0.13; p=0.92).Latent tuberculosis infection prevalence was higher based on tuberculin skin test than QuantiFERON-Tuberculosis Gold In-Tube test. The results of the two tests were discordant.
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Background. Correct identification of individuals with latent tuberculosis infection (LTBI) is a crucial element of the elimination strategy, allowing their adequate treatment. In addition to tuberculin skin test (TST), the Quantiferon test (QFT, based on whole blood γ-interferon release) had been recently proposed. Aim of the study is to compare this test to TST for identification of LTBI in a non-selected population, in order to verify their value in identifying truly infected individuals (entitled to receive preventive chemotherapy), and to exclude from treatment those having a positive TST for other reasons (e.g. after BCG vaccination). Methods. 136 consecutive persons (78 males, mean age 34±9 years) referred to the clinic for TST were recruited (78 born in low - or middle - income countries). Based on their history, the cases were divided into 4 groups: 1) recently traced contacts of whom 18 TST negative and 28 TST positive; 2) 22 screening subjects, all TST negative; 3) BCG vaccinated subjects (14); and 4) 54 subjects already undergoing treatment of LTBI for exposure to TB. Results. The overall agreement between TST and QFT was 72% (64% in TST positive and 88.4% in TST negative subjects). The proportion of TST positive/QFT negative BCG vaccinated individuals was 23.1%. The K coefficient was 0.474 in recently traced contacts, 0.366 in BCG vaccinated individuals and 0.451 overall. Conclusions. The study results suggest that agreement between TST and QFT is lower in TST positive than in negative subjects, being lower in individuals treated for LTBI. Quantiferon does not seem to have brought significant improvement in the diagnosis of LTBI.
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Diagnosis of latent tuberculosis infection (LTBI) is currently based on the tuberculin skin test. The enzyme-linked immunospot assay (ELISPOT) is a new blood test to diagnose LTBI.To compare the ELISPOT and the tuberculin skin test for detecting LTBI in contacts of patients with tuberculosis.Prospective study of 413 contacts of patients with tuberculosis.Because there is no gold standard for LTBI, the sensitivity and specificity of the ELISPOT and tuberculin skin test cannot be directly measured. For each contact, we therefore estimated the likelihood of having LTBI by calculating a contact score that quantified exposure to and infectiousness of the index case. We analyzed the relationship of contact score to ELISPOT and tuberculin skin test results. The likelihood of a positive ELISPOT (p = 0.0005) and a tuberculin skin test (p = 0.01) increased significantly with rising contact scores. The contact score was more strongly related to the ELISPOT than to the tuberculin skin test results, although this difference was not statistically significant. Among U.S.-born persons and those who were not vaccinated with bacille Calmette-Guérin, approximately 30% had positive ELISPOT or tuberculin skin test results. Foreign-born, bacille Calmette-Guérin-vaccinated persons were significantly more likely to have a positive tuberculin skin test than a positive ELISPOT result (p < 0.0001).Compared with the tuberculin skin test, the ELISPOT appears to be at least as sensitive for diagnosis of LTBI in contacts of patients with tuberculosis.
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Evaluation for latent tuberculosis infection is advised before organ transplant. The interferon-gamma release assay has been shown to be more specific than the tuberculin skin test for screening for latent tuberculosis infection. We compared the tuberculin skin test and QuantiFERON-TB Gold In-Tube test for screening for latent tuberculosis infection and agreement between the tests in heart and lung transplant recipients before transplant.Fifty-five adult patients who had been evaluated for heart and lung transplant between September 2011 and September 2012 at Masih Daneshvari Hospital in Iran were prospectively enrolled. We performed the tuberculin skin test and QuantiFERON-TB Gold In-Tube test.Of the 55 patients, 3 (5%) had positive tuberculin skin test results, and 11 (20%) had positive QuantiFERON-TB Gold In-Tube test results. Agreement between the tuberculin skin test and QuantiFERON-TB Gold In-Tube test was fair (Kappa=0.061; 95% CI: - 0.185-0.307) (P = .56).The positivity for QuantiFERON-TB Gold In-Tube test was greater than the positivity for the tuberculin skin test, and QuantiFERON-TB Gold In-Tube test more accurately determined the risk for latent tuberculosis infection. However, a further longitudinal study is necessary to verify that the QFT-G test would predict developing tuberculosis after heart and lung transplant.
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Background: Until recently, the tuberculin skin test was the only test for detecting latent tuberculosis (TB) infection, but 2 ex vivo interferon-γ release assays (IGRAs) are now commercially licensed. Purpose: To estimate sensitivity, specificity, and reproducibility of IGRAs (commercial or research versions of QuantiFERON [QFT] and Elispot) for diagnosing latent TB infection in healthy and immune-suppressed persons. Data Sources: The authors searched MEDLINE and reviewed citations of all original articles and reviews for studies published in English. Study Selection: Studies had evaluated IGRAs using Mycobacterium tuberculosis–specific antigens (RD1 antigens) and overnight (16- to 24-h) incubation times. Reference standards had to be clearly defined without knowledge of test results. Data Extraction and Quality Assessment: Specific criteria for quality assessment were developed for sensitivity, specificity, and reproducibility. Data Synthesis: When newly diagnosed active TB was used as a surrogate for latent TB infection, sensitivity of all tests was suboptimal, although it was higher with Elispot. No test distinguishes active TB from latent TB. Sensitivity of the tuberculin skin test and IGRAs was similar in persons who were categorized into clinical gradients of exposure. Pooled specificity was 97.7% (95% CI, 96% to 99%) and 92.5% (CI, 86% to 99%) for QFT and for Elispot, respectively. Both assays were more specific than the tuberculin skin test in samples vaccinated with bacille Calmette–Guérin. Elispot was more sensitive than the tuberculin skin test in 3 studies of immune-compromised samples. Discordant tuberculin skin test and IGRA reactions were frequent and largely unexplained, although some may be related to varied definitions of positive test results. Reversion of IGRA results from positive to negative was common in 2 studies in which it was assessed. Limitations: Most studies used cross-sectional designs with the inherent limitation of no gold standard for latent TB infection, and most involved small samples with a widely varying likelihood of true-positive and false-positive test results. There is insufficient evidence on IGRA performance in children, immune-compromised persons, and the elderly. Conclusions: New IGRAs show considerable promise and have excellent specificity. Additional studies are needed to better define their performance in high-risk populations and in serial testing. Longitudinal studies are needed to define the predictive value of IGRAs.
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The QuantiFERON-TB Gold test was the first blood test to be approved for the diagnosis of latent tuberculosis infection. Although it has been shown to be sensitive and specific in adults, limited data on its performance in children are available.This was a prospective study of children receiving health care in New York, New York. Each child was assessed for risk factors for Mycobacterium tuberculosis infection, underwent tuberculin skin testing, and had a QuantiFERON-TB Gold In-Tube test performed. The concordance between tuberculin skin test and QuantiFERON-TB Gold In-Tube test results was calculated, and the results were analyzed according to the likelihood of exposure to M tuberculosis.Data for 207 children with valid tuberculin skin test and QuantiFERON-TB Gold In-Tube test results were analyzed. There was excellent correlation between negative tuberculin skin test results and negative QuantiFERON-TB Gold In-Tube test results; however, only 23% of children with positive tuberculin skin test results had positive QuantiFERON-TB Gold In-Tube test results. Positive QuantiFERON-TB Gold In-Tube test results were associated with increased likelihood of M tuberculosis exposure, and interferon gamma levels were higher in children with known recent exposure to M tuberculosis, compared with children with older exposure histories. Younger children produced lower interferon gamma levels in response to the mitogen (phytohemagglutinin) control used in the QuantiFERON-TB Gold In-Tube test, but indeterminant results were low for children of all ages. Performance characteristics were similar across all age groups.The QuantiFERON-TB Gold In-Tube test is a specific test for M tuberculosis exposure in children, with performance characteristics similar to those for adults residing in regions with low levels of endemic disease. Concerns about test sensitivity, especially for children <2 years of age, will require additional prospective long-term evaluation.
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Introduction: The purified protein derivative (PPD) skin test is the only widely used method which detects latent tuberculosis infection (LTBI) and is dependent on a normal T cell function. In rheumatoid arthritis (RA) the T cell function is altered, which may result in an inability to develop an adequate PPD reaction. Interferon gamma release tests (IGRA) are now available alternatives to tuberculin skin test (TST) to detect LTBI. Aims: This study compared QuantiFERON-TB Gold In-Tube (QFT-IT) with the TST for the detection of latent tuberculosis infection among patients with RA in an area with a high prevalence of tuberculosis (138%000), where BCG vaccination is mandatory. Methods: A prospective study of patients with received the TST and an IGRA, the QFT-IT, at Pneumophtysiology Ambulatory, Clinical Hospital “Dr.V Babes”, Timisoara, from July 2009-December 2010. Results: Of 194 patients who underwent TST and QFT-IT testing, 101 (52%) had RA. Significantly fewer controls than RA patients had positive TST results (26.7% vs. 65.6%, p Conclusion: In a TB endemic population, the QFT-IT assay seemed to be a more accurate test for detection of LTBI in RA patients compared with the TST, and may potentially improve the targeting of prophylactic therapy before treatment with anti-TNF agents.
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Tuberculosis infection represents a global health problem and a great risk to health care workers. The detection and treatment of latent tuberculosis infection is a key strategy in the control of tuberculosis. The aim of this study was to estimate the usefulness of QuantiFERON-TB Gold In-Tube test which is an interferon-gamma release assay for the detection of latent tuberculosis infection, in a group of Egyptian Health Care Workers in comparison to the tuberculin skin test. A total of 100 Health Care Workers were enrolled. Subjects diagnosed as latent tuberculosis infection by tuberculin were 88% as compared to 36% by quantiferon. Higher tuberculin positive results were associated with direct contact to tuberculosis patients and job categories as physicians and nurses, while higher quantiferon positive results were associated with longer duration of employment and absence of BCG vaccination. The overall agreement between the two tests was poor (k=0.109). The negative discordant results (quantiferon negative/tuberculin positive) were 53% and were found among both contacts and non contact group, which could reflect high number of false positive tuberculin skin test. These data suggest that using IFN-γ method to screen new entrant health care workers for latent tuberculosis infection in our population could be more helpful because it is more specific for detecting latent tuberculosis infection compared to tuberculin skin test. Key words: Tuberculin, gamma-interferon, health care, latent infection.
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