Teste de liberação interferon-gama (interferon gamma release assay - IGRA) para detecção de tuberculose latente em pacientes imunocomprometidos / Gamma interferon release test (interferon gamma release assay - IGRA) for tuberculosis detection latent in immunocompromised patients

INTRODUÇÃO: A ILTB é definida como um estado de resposta imune persistente à estimulação por antígenos de Mycobacterium tuberculosis sem evidência, sintomas clínicos ou achados radiológicos de doença ativa. Estima-se que um terço da população mundial possua ILTB. A importância de diagnosticar a ILTB reside no potencial de reativação para a doença ativa e transmissível quando o indivíduo estiver imunossuprimido com comorbidades ou em terapia biológica. Quando identificado o potencial de desenvolvimento de doença ativa em um indivíduo com ILTB é recomendada a realização do tratamento preconizado, de forma a impedir que ocorra a reativação. A identificação e tratamento da ILTB constituem estratégias fundamentais para reduzir a carga global de tuberculose, especialmente em países em desenvolvimento. TECNOLOGIA: Teste de liberação de interferon-gama (do inglês interferon gamma release assay - IGRA). PERGUNTAS DE PESQUISA: O uso de IGRA apresenta maior acurácia na detecção de ILTB e capacidade para prever o desenvolvimento de tuberculose ativa, em comparação ao PPD, em pacientes imunocomprometidos? EVIDÊNCIAS CLÍNICAS: Foram analisadas dez revisões sistemáticas que avaliaram o desempenho do IGRA

Is interleukin-2 an optimal marker for diagnosing tuberculosis infection? A systematic review and meta-analysis.

BACKGROUND: Latent tuberculosis infection (LTBI) is a huge reservoir for the deadlier TB disease. Accurate identification of LTBI is a key strategy to eliminate TB. Therefore, a systematic review and meta-analysis approach was used to assess diagnostic potential of IL-2 for LTBI. METHODS: PubMed, Web of Science, the Cochrane Library and Embase were searched. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the summary receiver operating characteristic curve (AUROC) and hierarchical summary receiver operating characteristic curve (HSROC) were estimated by bivariate and HSROC models. RESULTS: Twenty-seven studies including 1404 participants and 1986 samples met the inclusion criteria. The pooled sensitivity, specificity, PLR, NLR, DOR and AUROC of IL-2 were separately as 87%, 98%, 34.78, 0.14, 256.41 and 0.98, indicating a very powerful differentiating ability of IL-2 for LTBI from non-TB controls. For differentiating ATB from LTBI, the pooled sensitivity, specificity, PLR, NLR, DOR and AUROC of IL-2 were 83%, 76%, 3.41, 0.22, 15.47 and 0.87, respectively, suggesting a good differentiating ability of IL-2. CONCLUSIONS: These findings showed that IL-2 is a powerful marker for differentiating LTBI from non-TB controls and a good marker for differentiating ATB from LTBI individuals.

First assessment of interferon gamma release assay results among healthcare workers at a general hospital in China.

INTRODUCTION: China has a very high tuberculosis (TB) burden. The interferon-gamma release assay (IGRA) is more specific for the diagnosis of latent tuberculosis infection (LTBI) than the tuberculin skin test, especially among populations with a high degree of coverage by the BCG vaccine. OBJECTIVES: To evaluate the first screening of healthcare workers (HCW) for LTBI using the IGRA at a general hospital in Beijing. METHODS: A pilot screening program for LTBI was triggered by accidental contact between HCW and two patients with active TB in the emergency department (ED). Given the necessity of estimating the overall LTBI prevalence in the institution, a sample of 518 HCW was enrolled in our cross-sectional study. The second IGRA was repeated with 43 of the 121 HCW in the ED after exposure to index TB cases. Data on putative risk factors were collected with a self-administered questionnaire. RESULTS: The prevalence of LTBI in the targeted population was 21.8%. Differences in the prevalence of LTBI were significantly related to age, employment duration, and history of occupational exposure. A lack of childhood BCG vaccination was independently associated with the prevalence of LTBI (adjusted OR: 1.686, 95% CI: 1.045-2.723, P = .0325). No new LTBI was diagnosed 12 weeks postexposure. No HCW adopted the preventive treatment for LTBI. CONCLUSIONS: Considering the high morbidity of LTBI among HCW even in general hospitals, it is essential to formulate government policies and institutional operation protocols for the systematic screening, registration, and administration of prophylaxes for the control of LTBI.

Cost-effectiveness analysis of strategies using new immunological diagnostic tests of latent tuberculosis infection before TNF-blockers therapy.

Several tests have been proposed to detect latent tuberculosis (LTB). OBJECTIVE: To evaluate the cost-effectiveness of different interferon-gamma release assays based strategies used to screen LTB before tumour necrosis factor (TNF) blockers initiation. METHODS: Consecutive patients with rheumatoid arthritis, spondyloarthritis or Crohn's disease for whom TNF-blockers were considered, were recruited in 15 tertiary care centres. All were screened for LTB with tuberculin skin test (TST), QuantiFERON TB Gold® in tube (QFT) and T-SPOT.TB® (TSpot) on the same day. Cost-minimization and cost-effectiveness analysis, testing 8 screening test combinations, were conducted. Effectiveness was defined as the percentage of LTB treatment avoided and compared with TST alone. Cost were elicited in the payer perspective, included all the costs related to the screening procedure. RESULTS: No tuberculosis reactivation was observed after TNF-blocker initiation. TST followed by QFT if TST was positive was found as the best screening strategy, i.e. the less costly (-54€ compared to reference) and most effective (effectiveness 0.93), resulting in an incremental cost-effectiveness ratio of -192€ per treatment avoided. A probabilistic sensitivity analysis confirmed this result in 72.3% of simulations. CONCLUSION: TST followed by QFT if TST was positive is the most cost-effective strategy in screening for LTB in patients before starting anti-TNF therapy. TRIALREGNO: NCT00811343.

Assessment of an ultra-sensitive IFNγ immunoassay prototype for latent tuberculosis diagnosis.

Worldwide there are about 1.7 billion individuals with latent tuberculosis infection (LTBI) and only 5% to 15% will develop active tuberculosis (TB). It is recommended to treat only those most at risk of developing active TB to avoid problems of drug resistance. LTBI diagnosis involves reviewing the individual's medical history, physical examination, and biological tests. Interferon gamma release assays (IGRA) can yield "undeterminate" or "uncertain" results, which makes clinical management decisions difficult. We assessed an ultra-sensitive immunoassay prototype based on single molecule array (SiMoA) technology to evaluate its overall performance, and in particular, its performance for indeterminate and uncertain positive or negative samples, as classified by the results from the current ELISA technique used for IFNγ quantification. We analyzed samples from hospitalized or consulting patients and healthcare workers from three hospitals in Paris, previously classified as negative (n = 30), positive (n = 35), uncertain negative (n = 25), uncertain positive (n = 31), or indeterminate (n = 30). We observed that with the SiMoA assay 83.3% of the indeterminate samples became interpretable and could be classified as negative, whereas 74% of uncertain positive samples were classified as positive. Most uncertain negative samples (72%) were reclassified as uncertain positive (68%) or positive (4%). The results suggest that the ultra-sensitive SiMoA IFNγ assay could represent a useful tool for the identification of true positive and negative samples among those giving indeterminate or uncertain results with the TB IGRA assay currently used.

Preventive therapy for latent tuberculosis infection-the promise and the challenges.

Around one third of the world's population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed.

A systematic review of economic models used to assess the cost-effectiveness of strategies for identifying latent tuberculosis in high-risk groups.

BACKGROUND: Timely diagnosis and treatment of latent tuberculosis infection (LTBI) through screening remains a key public health priority. Although globally it is recommended to screen people at high risk of developing TB, the economic evidence underpinning these recommendations is limited. This review critically appraised studies that had used a decision-analytical modelling framework to estimate the cost-effectiveness of interferon gamma release assays (IGRAs) compared to tuberculin skin test (TST) for detecting LTBI in high risk populations. METHODS: A comprehensive search of MEDLINE, EMBASE, NHS-EED was undertaken from 2009 up to June 2015. Studies were screened and extracted by independent reviewers. The study quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and the Philips' checklist, respectively. A narrative synthesis of the included studies was undertaken. RESULTS: Ten studies were included in this review. Two economic evaluations were conducted in a child population, six in an immunocompromised population and two in a recently arrived population from a country with a high incidence of TB. Most studies (n = 7) used a decision tree structure with Markov nodes. In general, all models were clearly described in terms of reporting quality, but were subject to limitations to structure and model inputs. Models have not elaborated on their setting or the perspective of the studies was not consistent with their analyses. Other concerns were related to derivation of prevalence, test accuracy and transition probabilities. CONCLUSION: Current methods available highlight limitations in the clinical effectiveness literature, model structures and assumptions, which impact on the robustness of the cost-effectiveness results. These models available are useful, but limited on the information that can be used to inform on future cost-effectiveness analysis. Until consideration is given on deriving the performance of tests used to identify LTBI that progresses to active TB, and the development of more comprehensive models, the economic benefit of LTBI testing with TST/IGRAs in high risk populations will remain unanswered.

Methods Used in Economic Evaluations of Tuberculin Skin Tests and Interferon Gamma Release Assays for the Screening of Latent Tuberculosis Infection: A Systematic Review.

BACKGROUND: Latent tuberculosis infection (LTBI) provides a constant pool of new active tuberculosis cases; a third of the earth's population is estimated to be infected with LTBI. OBJECTIVE: The objective of this systematic review was to assess the quality and summarize the available evidence from published economic evaluations reporting on the cost-effectiveness of tuberculin skin tests (TSTs) compared with interferon gamma release assays (IGRAs) for the screening of LTBI. METHODS: An extensive systematic review of the published literature was conducted. A two-step process was adopted to identify relevant articles: information was extracted into evidence tables and then analyzed. The quality of the publications was assessed using a 10-item checklist specific for economic evaluations. RESULTS: Twenty-eight studies were identified for inclusion in this review. Most of the studies found IGRAs to be more cost-effective than TSTs; however, the conclusions from the studies varied significantly. Most studies scored highly on the checklist although only one fulfilled all the stipulated criteria. A wide variety of methodological approaches were documented; identified differences included the type of economic evaluation and model, time horizon, perspective, and outcomes measures. CONCLUSIONS: The lack of consistent methods across studies makes it difficult to draw any firm conclusions about the most cost-effective option between TSTs and IGRAs. This problem can be solved by improving the quality of economic evaluation studies in the field of LTBI screening, through adherence to quality checklists.

Mycobacterium Tuberculosis Infection, Immigration Status, and Diagnostic Discordance: A Comparison of Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube Test Among Immigrants to the U.S.

OBJECTIVE: We used a recent source of nationally representative population data on tuberculosis (TB) infection to characterize concordance between the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) blood test for immigrants in the United States. METHODS: We used TB screening data from the 2011-2012 National Health and Nutrition Examination Survey to examine concordance between the TST and QFT-GIT--an interferon-gamma release assay (IGRA) blood test--for 7,097 U.S. natives, naturalized citizens, and noncitizens. RESULTS: Consistent with prior findings, one in five immigrants in the survey was identified with latent TB infection (LTBI), a rate 14 times higher than for U.S. natives. We also found higher rates of discordant TST/IGRA results among immigrants than among U.S. natives. Unadjusted discordance between TST and IGRA was 3% among U.S. natives (weighted N=5,684,274 of 191,179,213) but ranged up to 19% for noncitizens (weighted N=3,722,960 of 19,377,147). Adjusting for age, sex, and race/ethnicity, noncitizens had more than nine times the odds of having a positive TST result but negative QFT-GIT result compared with U.S. natives. CONCLUSIONS: Our findings suggest that whether and how either of these tests should be deployed is highly context sensitive. Significant discordance in test results when used among immigrants raises the possibility of missed opportunities for harm reduction in this already at-risk population. However, we found little distinction between the tests in terms of diagnostic outcome when used in a U.S. native population, suggesting little benefit to the adoption and use of the QFT-GIT test in place of TST on the basis of test performance alone for this population.

Assessment of CD27 expression as a tool for active and latent tuberculosis diagnosis.

UNLABELLED: There are still no reliable tests to distinguish active tuberculosis (TB) from latent TB infection (LTBI). Assessment of CD27 modulation on CD4⁺ T-cells has been suggested as a tool to diagnose different TB stages. OBJECTIVES: To use several cytometric approaches to evaluate CD27 expression on Mycobacterium tuberculosis (Mtb)-specific CD4⁺ T-cells to differentiate TB stages. METHODS: 55 HIV-uninfected subjects were enrolled: 13 active TB; 12 cured TB; 30 LTBI. Whole blood was stimulated with RD1-proteins or Cytomegalovirus-lysate (CMV). Interferon (IFN)-γ response was evaluated by cytometry. The proportion of CD27(±) within the IFN-γ⁺ CD4⁺ T-cells or RATIO of the CD27-median fluorescence intensity (MFI) of CD4⁺ T-cells over the CD27 MFI of IFN-γ⁺ CD4⁺ T-cells was evaluated. RESULTS: The greatest diagnostic accuracy in discriminating active TB vs. LTBI or cured TB was reached by evaluating the CD27(+) CD45RA(-) cells within the IFN-γ⁺ CD4⁺ T-cell subset (76.92 sensitivity for both, and 90% and 91.67% specificity, respectively), although the use of the CD27 MFI RATIO allows for stricter data analysis, independent of the operator. CONCLUSIONS: the study of CD27 expression using different approaches, whether it involves evaluation of CD45RA expression or not, is a robust biomarker for discriminating TB stages.

Added value of interferon-gamma release assays in screening for tuberculous infection in the Netherlands.

BACKGROUND: Interferon-gamma release assays (IGRAs) are reported to be more specific for the diagnosis of latent tuberculous infection (LTBI) than the tuberculin skin test (TST). The two-step procedure, TST followed by an IGRA, is reported to be cost-effective in high-income countries, but it requires more financial resources. OBJECTIVE: To assess the added value of IGRA compared to TST alone in the Netherlands. METHODS: Test results and background data on persons tested with an IGRA were recorded by the Public Municipal Health Services in a web-based database. The number of persons diagnosed with LTBI using different screening algorithms was calculated. RESULTS: In those tested with an IGRA, at least 60% of persons who would have been diagnosed with LTBI based on TST alone had a negative IGRA. Among those with a TST reaction below the cut-off for the diagnosis of LTBI, 13% had a positive IGRA. For 41% of persons tested with an IGRA after TST, the IGRA influenced whether or not an LTBI diagnosis would be made. CONCLUSION: With the IGRA as reference standard, a high proportion of persons in low-prevalence settings are treated unnecessarily for LTBI if tested with TST alone, while a small proportion eligible for preventive treatment are missed. Incremental costs of the two-step strategy seem to be balanced by the improved targeting of preventive treatment.

Optimizing screening for tuberculosis and hepatitis B prior to starting tumor necrosis factor-α inhibitors in Crohn's disease.

BACKGROUND AND AIMS: Treatment with tumor necrosis factor-α (TNF-α) inhibitors in patients with Crohn's disease (CD) is associated with potentially serious infections, including tuberculosis (TB) and hepatitis B virus (HBV). We assessed the cost-effectiveness of extensive TB screening and HBV screening prior to initiating TNF-α inhibitors in CD. METHODS: We constructed two Markov models: (1) comparing tuberculin skin test (TST) combined with chest X-ray (conventional TB screening) versus TST and chest X-ray followed by the interferon-gamma release assay (extensive TB screening) in diagnosing TB; and (2) HBV screening versus no HBV screening. Our base-case included an adult CD patient starting with infliximab treatment. Input parameters were extracted from the literature. Direct medical costs were assessed and discounted following a third-party payer perspective. The main outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity and Monte Carlo analyses were performed over wide ranges of probability and cost estimates. RESULTS: At base-case, the ICERs of extensive screening and HBV screening were €64,340 and €75,760 respectively to gain one quality-adjusted life year. Sensitivity analyses concluded that extensive TB screening was a cost-effective strategy if the latent TB prevalence is more than 12 % or if the false positivity rate of TST is more than 20 %. HBV screening became cost-effective if HBV reactivation or HBV-related mortality is higher than 37 and 62 %, respectively. CONCLUSIONS: Extensive TB screening and HBV screening are not cost-effective compared with conventional TB screening and no HBV screening, respectively. However, when targeted at high-risk patient groups, these screening strategies are likely to become cost-effective.

[Immunodiagnosis and biomarkers in tuberculosis]. / Inmunodiagnóstico y biomarcadores en tuberculosis.

Based on the tuberculin skin test it is estimated that latent tuberculosis infection is present in one-third of the world's population. The new strategies in public health and research are aimed to reduce and eradicate this enormous reservoir. However, the absence of effective biomarkers for diagnosis and treatment of latent tuberculosis limits the development of new drugs and vaccines. Some components are present in both, the PPD (used in the tuberculin skin test) and the BCG vaccine. This increases the number of false positives in vaccinated individuals. Nowadays, there is not an immune diagnostic method that can differentiate latent tuberculosis and tuberculosis disease. New studies have addressed some strategies including specific antibodies, new cytokines and / or antigens as candidates for biomarkers. However, the high costs of these studies, the low number of participants and their different methodology make difficult a future meta-analysis and more conclusive results.

Cost effectiveness of interferon-gamma release assay versus chest X-ray for tuberculosis screening of BCG-vaccinated elderly populations.

BACKGROUND: The prevalence of tuberculosis (TB) in the elderly is higher than that in the general population, and elderly populations are considered a high-risk group. Currently, annual TB screening of Bacille Calmette-Guérin (BCG)-vaccinated people aged over 65 years is performed by an annual chest x-ray examination (CXR) in Japan. Interferon-gamma release assays (QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube [QFT]) are new alternatives to the tuberculin skin test to diagnose latent TB infection (LTBI) that have no cross-reactivity with the BCG vaccine. We evaluated the cost effectiveness of QFT versus CXR versus no screening in BCG-vaccinated elderly populations. METHODS: We constructed a Markov model to evaluate the cost effectiveness of QFT, CXR, and no screening. The target population was a hypothetical cohort of 1000 immunocompetent 65-year-olds, using a societal perspective and a lifetime horizon. All costs and clinical benefits were discounted at a fixed annual rate of 3%. RESULTS: In the base-case analysis, a no-screening strategy resulted in the lowest cost ($US303.51; 14.6475 quality-adjusted life-years [QALYs]) compared with CXR ($US393.22; 14.6477 QALYs) and QFT ($US525.45; 14.6516 QALYs) [year 2008 values]. The sensitivity of QFT, as well as the prevalence of TB and LTBI, influenced the cost effectiveness; when the sensitivity of QFT was higher than 0.89, QFT became more cost effective than providing no screening. As the prevalence of LTBI and TB increased, the QFT strategy became progressively more cost effective. CONCLUSIONS: Providing no routine TB screening is currently the most cost-effective strategy for BCG-vaccinated elderly populations in Japan. There appears to be little role for CXR in TB screening of elderly populations. These findings may be applicable to other countries with intermediate and high TB risks when choosing optimal TB screening of elderly populations.

Cost-effectiveness of QuantiFERON-TB test vs. tuberculin skin test in the diagnosis of latent tuberculosis infection.

OBJECTIVE: To evaluate the cost-effectiveness of the tuberculin skin test (TST), the QuantiFERON-TB Gold test (QFT) and a combination of TST and QFT (TST+QFT) for diagnosing latent tuberculosis infection (LTBI) in France in a bacille Calmette-Guérin (BCG) vaccinated population. METHODS: A decision analysis model evaluated three strategies among simulated adults in close contact with tuberculosis (TB). We calculated direct lifetime medical costs, life expectancies and incremental cost-effectiveness ratios (ICERs). RESULTS: The discounted direct medical costs of care per patient of no testing, TST, QFT and TST+QFT were respectively euro417, euro476, euro443 and euro435, while discounted life expectancies were respectively 25.030, 25.071, 25.073 and 25.062 years. TST had higher costs and lower efficacy than QFT; TST+QFT was associated with an ICER of euro560 per year of life gained (YLG) compared to no testing, and QFT was associated with an ICER of euro730/YLG compared to TST+QFT. The only scenario where QFT was associated with an ICER of >euro75 000/YLG was when the prevalence of LTBI around TB was low (<5%) and TST specificity high (>90%). CONCLUSIONS: In France, for the diagnosis of LTBI after close contact with TB, the TST is more expensive and less effective than QFT. Although it is more expensive, QFT is more effective and cost-effective than TST+QFT under a wide range of realistic test performance scenarios.

Assessment of an Interferon-gamma release assay for the diagnosis of latent tuberculosis infection in haemodialysis patient.

BACKGROUND: The accurate diagnosis of latent tuberculosis infection (LTBI) in haemodialysis patients remains elusive. Impaired immune function associated with chronic kidney failure causes a high number of anergic tuberculin skin tests (TST). Interferon-gamma (INF-gamma) release assays (IGRAs) measuring the INF-gamma secretion of tuberculosis specific T-cells have several advantages over the TST but their significance in dialysis patients is currently uncertain. METHODS: This study examines the test-performances of the QuantiFERON Gold InTube (QFT-GIT) in a cohort of 39 haemodialysis (HD) patients and 52 healthy individuals. RESULTS: INF-gamma secretion in HD patients was significantly lower than in healthy controls, however, mitogen-anergic QFT-GIT results were only found in 2.5% of HD-patients. INF-gamma secretion was independent of duration of HD treatment, dialysis quality and nutritional status. The QFT-GIT showed a closer association with TB risk factors as a proxy for past exposure to TB than the TST. CONCLUSIONS: We conclude that the QFT-GIT is a valid alternative to the TST. Together with the survey of TB risk factors, it may help to diagnose LTBI more accurately in HD-patients.