Improving T-cell assays for diagnosis of latent TB infection: Confirmation of the potential role of testing Interleukin-2 release in Iranian patients

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Nabavi, S. Arshi, M.H. Bemanian, A. Aghamohammadi, D. Mansouri, M. Hedayat, A. Nateghian, S. Noorbakhsh, F. Ehsanipour, M. Faranoush, R. Shakeri, M. Mesdaghi, B. Taghvaei, B. Ghalebaghi, D. Babaie, A. Bahrami, M. Fallahpour, H. Esmaeilzadeh, A. Ali Hamidieh, M. Rekabi, J. Ahmadian, N. Eslami, S. Shokri, M. Afshar, F. Jalali, N. Akbarpour, R. Molatefi, N. Rezaei" "autores" => array:28 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Nabavi" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Arshi" ] 2 => array:2 [ "nombre" => "M.H." "apellidos" => "Bemanian" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Aghamohammadi" ] 4 => array:2 [ "nombre" => "D." "apellidos" => "Mansouri" ] 5 => array:2 [ "nombre" => "M." "apellidos" => "Hedayat" ] 6 => array:2 [ "nombre" => "A." "apellidos" => "Nateghian" ] 7 => array:2 [ "nombre" => "S." "apellidos" => "Noorbakhsh" ] 8 => array:2 [ "nombre" => "F." "apellidos" => "Ehsanipour" ] 9 => array:2 [ "nombre" => "M." 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"apellidos" => "Rezaei" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054615001512?idApp=UINPBA00004N" "url" => "/03010546/0000004400000004/v1_201607130013/S0301054615001512/v1_201607130013/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0301054615001251" "issn" => "03010546" "doi" => "10.1016/j.aller.2015.07.003" "estado" => "S300" "fechaPublicacion" => "2016-07-01" "aid" => "714" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2016;44:307-13" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 100 "formatos" => array:3 [ "EPUB" => 5 "HTML" => 64 "PDF" => 31 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Can geodata be used to determine the distribution of fast food outlets in relation to the prevalence and severity of asthma? A novel methodology" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "307" "paginaFinal" => "313" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2991 "Ancho" => 3226 "Tamanyo" => 595719 ] ] "descripcion" => array:1 [ "en" => "Trends of prevalence of current and severe asthma, rhinoconjunctivitis and eczema in relation to outlet density." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A. Sheth, M.I. Asher, P. Ellwood, E. Ellwood" "autores" => array:5 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Sheth" ] 1 => array:2 [ "nombre" => "M.I." "apellidos" => "Asher" ] 2 => array:2 [ "nombre" => "P." "apellidos" => "Ellwood" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "Ellwood" ] 4 => array:1 [ "colaborador" => "the ISAAC Phase Three Study Group" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054615001251?idApp=UINPBA00004N" "url" => "/03010546/0000004400000004/v1_201607130013/S0301054615001251/v1_201607130013/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Improving T-cell assays for diagnosis of latent TB infection: Confirmation of the potential role of testing Interleukin-2 release in Iranian patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "314" "paginaFinal" => "321" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "S. Mamishi, B. Pourakbari, H. Shams, M. Marjani, S. Mahmoudi" "autores" => array:5 [ 0 => array:3 [ "nombre" => "S." "apellidos" => "Mamishi" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "B." "apellidos" => "Pourakbari" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "H." "apellidos" => "Shams" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "M." "apellidos" => "Marjani" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:4 [ "nombre" => "S." "apellidos" => "Mahmoudi" "email" => array:1 [ 0 => "sh-mahmoudi@alumnus.tums.ac.ir" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Pediatric Infectious Disease Research Center, Tehran University of Medical Science, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Infectious Diseases, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Center for Pulmonary and Infectious Disease Control, and Departments of Microbiology and Immunology and Medicine, University of Texas Health Center at Tyler, Tyler, TX, USA" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1259 "Ancho" => 3167 "Tamanyo" => 96035 ] ] "descripcion" => array:1 [ "en" => "The rESAT-6 and rCFP-10 stimulated expression of IL-2 in patients with active tuberculosis and individuals with LTBI. IL-2 release obtained after 72h of incubation with a mixture of rESAT-6 (left panel) and rCFP-10 (right panel) in different groups of subjects: patients with active tuberculosis and subjects with LTBI, respectively. Horizontal bars indicate the medians of the IL-2 values of the respective population." ] ] ] "textoCompleto" => "IntroductionThe cell-mediated immunity-based in vitro gamma interferon release assay (IGRA) of Mycobacterium tuberculosis-specific antigens has potential as a specific and accurate diagnostic means to detect those individuals with M. tuberculosis infection, especially when compared to the skin test.<a class="elsevierStyleCrossRefs" href="#bib0180">1,2</a> According to recent attempts for tuberculosis (TB) eradication, the treatment of latent tuberculosis infection (LTBI) and active TB is urgently required in order to lower and ultimately prevent the further spread of the disease at its present rate.<a class="elsevierStyleCrossRefs" href="#bib0190">3,4</a>Since IGRAs cannot differentiate between active and past TB infections or between LTBI and tuberculosis,<a class="elsevierStyleCrossRefs" href="#bib0200">5,6</a> a rapid and specific diagnosis tool is essential for discrimination of active TB from LTBI. Based on recent reports,<a class="elsevierStyleCrossRefs" href="#bib0200">5,7–10</a> cytokines such Interleukin-2 (IL-2) play a critical role during primary and latent infection; therefore, evaluation of IL-2 could be instrumental in discriminating between active and latent TB infection.Both IGRAs are based on M. tuberculosis-specific antigens, namely, early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10).<a class="elsevierStyleCrossRefs" href="#bib0230">11,12</a> The aim of this study was to evaluate the potential value of IL-2 in stimulated whole blood cells with rESAT-6 and rCFP-10 for the discrimination of active and latent tuberculosis.Material and methodsM. tuberculosis standard strain H37RV DNA was obtained from the National Research Institute of Tuberculosis and Lung Disease (NRITLD), National Mycobacteriologic Reference Laboratory, Tehran, Iran. Coding sequences of each dominant antigen fragment of ESAT-6 and CFP-10 were amplified according to our previous report.<a class="elsevierStyleCrossRef" href="#bib0240">13</a> Each PCR product was ligated into pTZ57R/T cloning vector after purification using QIA quick PCR purification kit (MBI Fermentas, Lithuania). The ESAT-6 and CFP-10 gene were subcloned into pET32a(+) expression vector (Qiagen, USA) using SalI and BamHI for ESAT-6 and BamHI and HindIII enzymes for CFP-10.Protein expression and purification of recombinant ESAT-6 and CFP-10The pET32a(+)-ESAT-6 and pET32a(+)-CFP-10 plasmids were transformed into E. coli BL21 DE3 (Novagen, Germany) expression host as described previously.<a class="elsevierStyleCrossRef" href="#bib0240">13</a> Recombinant ESAT-6 and CFP-10 were purified using nickel–nitrilotriacetic acid (Ni2+–NTA) metal affinity chromatography according to the manufacturer's recommendations for purification of proteins under soluble conditions (Qiagen, USA).PatientsIn this study we included 30 patients with active TB infection, 30 with LTBI, and 30 healthy individuals. Patients were recruited from the infectious diseases ward at the Masih Daneshvari Hospital, affiliated to Shahid Beheshti University of Medical Sciences, Tehran, Iran. All enrolled individuals gave their written informed consent. Individuals were classified as having active TB when the diagnosis was confirmed by positive M. tuberculosis culture from sputum specimens. Individuals who had positive TST were selected and if they had positive QuantiFERON-TB Gold In-Tube test (QFT-G-IT) in the absence of symptomatic, microbiological, or radiological evidence of active tuberculosis were entered into the study and classified as having LTBI. Healthy controls were BCG-vaccinated individuals with no known exposure to M. tuberculosis and a negative response to the QFT-G-IT. We did not include in the study individuals who had positive human immunodeficiency virus screening result.The study received approval from the Ethical Committee of Tehran University of medical sciences (100676).Whole blood stimulationAbout 5ml of whole blood was collected from all study participants into heparinised tubes. The recombinant ESAT-6 and CFP-10 proteins were used at a final concentration of 10μg/mL.<a class="elsevierStyleCrossRef" href="#bib0245">14</a>The diluted antigens (100μL at 20μg/mL) as well as the medium (unstimulated control) and positive control, were then seeded into 96-well plates in triplicate, after which plates were frozen at −80°C until the day of whole blood assay (WBA). The positive control was phytohaemagglutinin (PHA) and was used at a final concentration of 5μg/mL. On the day of WBA, pre-frozen antigen plates were allowed to thaw, and then 100μl of the blood added into each well containing the antigens or controls.The plates were placed at 37°C in a humidified 5% CO2 incubator for three days. Culture supernatants were used for IFN-γ and IL-2 quantification.IFN-γ and IL-2 detectionIFN-γ and IL-2 secretion were measured in the culture supernatants in the whole blood assay stimulated with antigens using IFN-γ ELISA kit and Human IL-2 ELISA kit (Mabtech AB, Sweden).Flat-bottomed 96-well ELISA plates (Nunc Maxisorp, Thermo Fisher Scientific, United Kingdom) were coated with 2μg/mL coating antibody (Mabtech AB, Sweden) and was incubated overnight at 4°C. Wells were washed twice with 200μL/well sterile phosphate buffered saline (PBS) and blocked for 1h at room temperature with 200μL/well PBS with 0.05% Tween 20 containing 0.1% BSA. After incubation with whole blood assay supernatants for 2h plates were developed with 1μg/ml biotin-conjugated Ab (Mabtech) for 1h at room temperature and then streptavidin–HRP (Mabtech) diluted 1:1000 in PBS for 1h at room temperature. Wells were then washed six times and 100μL/well of tetramethylbenzidine (TMB) substrate (Sigma, United Kingdom) was added. Plates were allowed to develop for 20min before adding 100μL/well of 0.5M H2SO4. Plates were read immediately on an ELISA reader at a 450-nm wavelength.Statistical analysisThe differences in levels of biomarkers among groups were analysed using non-parametric analysis of variance with the Kruskal–Wallis test.Receiver operating characteristic (ROC) curve analysis was conducted to determine the best IL-2 and IFN-γ result thresholds in discriminating between cases with active or latent TB, relatively to a specific M. tuberculosis antigen ESAT-6 and CFP-10, and the corresponding sensitivity and specificity were reported. The area under the ROC curve (AUC) and 95% confidence interval (CI) were also calculated. Cut-offs were estimated at various sensitivities and specificities and at the maximum Youden's index (YI), i.e. sensitivity×specificity−1.<a class="elsevierStyleCrossRef" href="#bib0250">15</a> Individual concentrations of IL-2 detected in the plasma from antigen-stimulated culture minus the concentration in the respective control plasma were used for this determination.Statistical analysis was performed using the statistical software STATA 11 (StataCorp, College Station, TX, USA) and p value<0.05 was considered statistically significant.ResultsIn this study, rESAT-6 and rCFP-10 were cloned, expressed successfully and used as M. tuberculosis stimulators. The antigen-specific levels of IFN-γ and IL-2 were evaluated in all 90 subjects included in the study. Thirty individuals were classified as uninfected, 30 as LTBI and 30 as active TB cases (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The interferon-γ release assayOur results revealed a statistical difference between the median IFN-γ levels of the LTBI and control groups after stimulation with rESAT-6 and rCFP-10 antigen (p value=0.05 and 0.028, respectively) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The median level of IFN-γ following stimulation with rESAT-6 in active TB group and LTBI group was 0.61IU/mL (0.2–1.3) and 1.68IU/mL (1.2–4.2), respectively. In addition, the median level of IFN-γ was 0.62IU/mL (0.2–2.5) and 1.84IU/mL (0.43–2.5) following stimulation with rCFP-10 in active TB group and LTBI group, respectively.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>A statistically significant difference was found between the median IFN-γ levels of the both antigens tested: rESAT-6 (p value=0.001) and rCFP-10 (p value=0.002) when compared with the TB disease and control groups (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).The diagnostic ability of the ESAT-6 and CFP-10 demonstrated a good discriminatory power in detecting patients with TB and LTBI infection from those without the infection who were BCG vaccinated. These results demonstrated a good sensitivity and specificity in detecting patients with TB and LTBI infection (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The AUCs for ESAT-6 and CFP-10 were 0.88 and 0.84, respectively (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>The IL-2 release assayDiscrimination between individuals with latent and active tuberculosisObserving the level of IL-2 released after 72h of incubation, we found that the level of IL-2 were significantly higher in LTBI group than in patients with active TB infection following stimulation with rESAT-6 (p value=0.002) and following stimulation with rCFP-10 (p value=0.001), using an unpaired Student's t-test) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>The median level of IL-2 following stimulation with rESAT-6 in the active TB group and LTBI group were 0.3pg/mL (0.2–21.9) and 24.5pg/mL (14.3–40), respectively. In addition, the median levels of IL-2 were 0.3pg/mL (0.2–7.6) and 27.4pg/mL (12.3–38.4) following stimulation with rCFP-10 in active TB group and LTBI group, respectively. No secretion of IL-2 was detected in the control group (median: 0pg/mL (0–0.08) (data not shown)).The discrimination performance (assessed by the area under ROC curve) between LTBI and active TB group were 0.75 and 0.8 for IL-2 following stimulation with rESAT-6 and rCFP-10, respectively (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Maximum discrimination was reached at a cut-off of 11.6pg/mL for IL-2 after stimulation with recombinant rESAT-6 with 72% sensitivity and 79% specificity and 10.7pg/mL for IL-2 following stimulation with rCFP-10 with 75% sensitivity and 79% specificity, respectively (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Seventeen percent and 50% of subjects with active TB and LTBI have IL-2 response of more than two cut-offs following stimulation with rESAT-6. In addition, IL-2 response of more than two cut-offs following stimulation with rCFP-10 was found in 13% of subjects with active TB and 60% of subjects with LTBI.DiscussionTuberculosis control programmes in developing countries are greatly haunted by low case detection rates of LTBI.<a class="elsevierStyleCrossRef" href="#bib0255">16</a> A variety of technologies have been used for the diagnosis of TB, including medical imaging (e.g., chest radiography), microbiology tests (e.g., sputum smear microscopy), histopathology, and immune-based tests (e.g., serologic, antibody detection tests, antigen detection tests, interferon-γ release assays, and skin tests).<a class="elsevierStyleCrossRef" href="#bib0260">17</a> Although detection of acid-fast bacilli or mycobacterial cultures provides indicative values, it cannot serve as a definite diagnostic method due to its complicated procedures. Among these, the skin test is the most widely used screening approach. However, the main drawback of this method is the lack of specificity due to the cross-reactivity with proteins present in other mycobacteria, such as M. bovis BCG.<a class="elsevierStyleCrossRef" href="#bib0265">18</a>The identification of regions of the M. tuberculosis genome that are not present in BCG provides a unique opportunity to develop new highly specific diagnostic reagents. The 10-kDa culture filtrate protein (CFP-10) and 6-kDa early secreted antigen target (ESAT-6) are located in the region of difference-1 (RD-1) of the virulent M. tuberculosis genome but are absent in all BCG strains.<a class="elsevierStyleCrossRef" href="#bib0270">19</a> It has been suggested that polyfunctional T-cells for ESAT-6 or CFP-10 play an important role in control of M. tuberculosis infection.<a class="elsevierStyleCrossRef" href="#bib0275">20</a> Although detection of CFP-10 and ESAT-6 proteins can be used for the early and specific diagnosis of TB and for distinguishing between M. tuberculosis-infected and BCG-vaccinated groups, their value in detection of LTBI remains less clear.<a class="elsevierStyleCrossRefs" href="#bib0280">21–23</a>Several papers using ESAT-6/CFP-10 derivatives in IFN-γ release assays have mostly used three kinds of diagnostic reagents such as recombinant individual proteins or fusion protein, pool of overlapping peptides and selected non-overlapping multi-epitopic peptides;<a class="elsevierStyleCrossRefs" href="#bib0295">24–26</a> although they do not lead to successful differentiation between active TB and LTBI.<a class="elsevierStyleCrossRef" href="#bib0295">24</a>Measurement of multiple cytokines may help identify potential biomarkers for differentiating active TB from LTBI.<a class="elsevierStyleCrossRef" href="#bib0310">27</a>Our study demonstrated the importance of establishing an efficient diagnostic method, based on the IL-2 detection after stimulation of blood with rESAT-6 and rCFP-10 for discrimination of latent TB infection and TB disease. Our data are in agreement with the recent observation by Sargentini et al.<a class="elsevierStyleCrossRef" href="#bib0315">28</a> and Wang et al.<a class="elsevierStyleCrossRef" href="#bib0225">10</a> describing that detection of IL-2 after stimulation with M. tuberculosis antigens may discriminate individuals with latent infection from patients affected by active TB.When there is no definite gold standard for the diagnosis of LTBI, the IL-2 release assay in addition to IGRA can improve the ability of IGRA to identify individuals with recently acquired LTBI.<a class="elsevierStyleCrossRefs" href="#bib0200">5,10,29–31</a>According to the previous meta-analysis, IL-2 is a valid marker for the diagnosis of LTBI.<a class="elsevierStyleCrossRef" href="#bib0200">5</a> IL-2 is promoting T-cell replication and is essential for cellular immunity and granuloma formation. Although IFN-γ is predominantly produced by effector memory T-cells, IL-2 is mostly produced by central memory T-cells.<a class="elsevierStyleCrossRefs" href="#bib0335">32,33</a> The secretion of IL-2 is secreted from cells also secreting IFN-γ in both the early and the later stages of infection and when the antigen load has declined.<a class="elsevierStyleCrossRef" href="#bib0220">9</a> Dual IFN-γ/IL-2-secreting cells in active phase of TB can support their own expansion because IL-2 is a potent T cell growth factor. The presence of these cells in active TB when the antigen load is high may therefore suggest their involvement in the initiation phase of the immune response. IL-2 in LTBI or when the antigen load is reduced or cleared may reflect its function in the termination of T cell responses. This proposed signalling function augments the growth and survival of regulatory T cells that control inflammatory responses.<a class="elsevierStyleCrossRef" href="#bib0220">9</a>The meta-analysis by Menzies et al. reported a pooled sensitivity of 80% and polled specificity of 96% after stimulation with QuantiFERON®-TB Gold In-Tube that used ESAT-6 with CFP-10 for diagnosing LTBI in healthy and immune-suppressed persons.<a class="elsevierStyleCrossRef" href="#bib0230">11</a> Compared with these reports, our estimated sensitivity and specificity for diagnosis of TB was very good (sensitivity 83–84% and specificity 92%). ROC analyses demonstrated sensitivity of 72% and specificity of 79%, in discriminating between latent and active TB, considering response to rESAT-6 by IL-2 release assay for a cut-off of 11.6pg/mL. In addition, sensitivity of 75% and specificity of 79% was demonstrated after stimulation with rCFP-10 protein.We presented both the Positive Likelihood Ratios (PLR) and Negative Likelihood Ratios (NLR) as measures of diagnostic accuracy. Likelihood ratios of >10 or <0.1 indicated high accuracy. A PLR value of >10 for IFN-γ assay after stimulation with both recombinant proteins suggests that patients with TB have an approximately >10-fold higher chance of being positive with this test. This likelihood was 6.5 and 3.6 for IL-2 after stimulation with both recombinant proteins.Since no laboratory tool is currently available to distinguish between individuals in the process of progressing from latent TB infection towards active disease, determination of the interferon-gamma and interleukin-2 T-cell signature might provide rapid tool for clinical management of patient.<a class="elsevierStyleCrossRefs" href="#bib0345">34,35</a> Our study confirmed that IL-2 release assay has the ability to identify individuals with LTBI. However, the relative small sample size may have influenced the result of the analysis due to low numbers of individuals in each category.In conclusion, this study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB. In addition, it was shown that IL-2 could be serving as a marker for discriminating LTBI and active TB. Since the immunology of TB is complex, and understanding LTBI is even more challenging, a large scale study will be needed to establish the usefulness of this biomarker.Ethical disclosuresConfidentiality of dataThe authors declare that no patient data appears in this article.Right to privacy and informed consentThe authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.Protection of human and animal subjectsThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Conflict of interestThe authors have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres688847" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec694634" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Protein expression and purification of recombinant ESAT-6 and CFP-10" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Patients" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Whole blood stimulation" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "IFN-γ and IL-2 detection" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "The interferon-γ release assay" ] 1 => array:3 [ "identificador" => "sec0050" "titulo" => "The IL-2 release assay" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Discrimination between individuals with latent and active tuberculosis" ] ] ] ] ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 6 => array:3 [ "identificador" => "sec0070" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Confidentiality of data" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Right to privacy and informed consent" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Protection of human and animal subjects" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "xack229895" "titulo" => "Acknowledgements" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-27" "fechaAceptado" => "2015-09-30" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec694634" "palabras" => array:4 [ 0 => "IL-2" 1 => "Discrimination" 2 => "Active TB" 3 => "LTBI" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundSince gamma interferon release assays (IGRAs) cannot differentiate between active tuberculosis and latent tuberculosis infection (LTBI), development of rapid and specific diagnosis tools are essential for discriminating between active tuberculosis (TB) from LTBI. Both IGRAs are based on Mycobacterium tuberculosis-specific antigens, namely, early secretory antigenic target 6 (ESAT-6) and 10kDa culture filtrate (CFP-10). The aim of this study was to evaluate the potential value of IL-2 secretion by whole blood cells after stimulation with rESAT-6 and rCFP-10 for discriminating between active and latent tuberculosis. MethodsInterleukin-2 and IFN-γ were measured after blood stimulation of 90 cases (30 with active TB, 30 with LTBI and 30 healthy controls) with recombinant ESAT-6 and CFP-10. Receiver operating characteristic (ROC) curve analysis was conducted to determine the best IL-2 and IFN-γ result thresholds in discriminating between cases with active or latent TB, and the corresponding sensitivity and specificity were recorded. ResultsThe IFN-γ release assay demonstrated a good sensitivity and specificity (sensitivity 83–84% and specificity 92%) for diagnosis of tuberculosis. The discrimination performance of IL-2 assay (assessed by the area under ROC curve) between LTBI and patients with active TB were 0.75 and 0.8 following stimulation with rESAT-6 and rCFP-10, respectively. Maximum discrimination was reached at a cut-off of 11.6pg/mL for IL-2 after stimulation with recombinant rESAT-6 with 72% sensitivity and 79% specificity and 10.7pg/mL for IL-2 following stimulation with rCFP-10 with 75% sensitivity and 79% specificity, respectively. ConclusionThis study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB. In addition, it was shown that IL-2 may be serving as a marker for discriminating LTBI and active TB." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1230 "Ancho" => 3166 "Tamanyo" => 104990 ] ] "descripcion" => array:1 [ "en" => "The rESAT-6 and rCFP-10 stimulated expression of IFN-γ in patients with different groups. IFN-γ release obtained after incubation with a mixture of rESAT-6 (left panel) and rCFP-10 (right panel) in three different groups of subjects: patients with active tuberculosis, subjects with LTBI and healthy non-infected controls, respectively. Horizontal bars indicate the medians of the IFN-γ values of the respective population." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1480 "Ancho" => 3166 "Tamanyo" => 167352 ] ] "descripcion" => array:1 [ "en" => "Receiver operator characteristic (ROC) plot illustrating sensitivity and specificity of IFN-γ in discriminating between the TB (latent infection or disease) and healthy non-infected control groups." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1259 "Ancho" => 3167 "Tamanyo" => 96035 ] ] "descripcion" => array:1 [ "en" => "The rESAT-6 and rCFP-10 stimulated expression of IL-2 in patients with active tuberculosis and individuals with LTBI. IL-2 release obtained after 72h of incubation with a mixture of rESAT-6 (left panel) and rCFP-10 (right panel) in different groups of subjects: patients with active tuberculosis and subjects with LTBI, respectively. Horizontal bars indicate the medians of the IL-2 values of the respective population." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1569 "Ancho" => 3167 "Tamanyo" => 174067 ] ] "descripcion" => array:1 [ "en" => "Receiver operator characteristic (ROC) plot illustrating sensitivity and specificity of IL-2 in discriminating individuals with LTBI and active TB." ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "TB: tuberculosis; LTBI: latent tuberculosis infection; QFT-G-IT: QuantiFERON-TB Gold In Tube." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Active TB</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Subjects with LTBI</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy control</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Age</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">(years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">35.3±18.8</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">40.2±15.8</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">45.3±5.6</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Sex</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Origin</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Iranian \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Afghan immigrant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">TB</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pulmonary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">QFT-G-IT</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Median (IU/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">8.1 (1.1–10.3)</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">6.3 (0.39–8.9)</td><td class="td" title="table-entry " colspan="2" align="center" valign="middle">0.04 (0–0.2)</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1120645.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic characteristics of enrolled individuals." ] ] 5 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "PPV: positive predictive values; NPV: negative predictive values; LR: likelihood ratio; AUC: area under the curve." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cut-off (IU/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sensitivity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Specificity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PPV \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NPV \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR− \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CI 95% \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rESAT-6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">98 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8–0.96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rCFP-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">98 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.74–0.95 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1120647.png" ] ] ] ] "descripcion" => array:1 [ "en" => "The discriminatory power of IFN-γ after stimulation with rESAT-6 and rCFP-10 in detecting patients with TB (both active and latent) and controls." ] ] 6 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "PPV: positive predictive values; NPV: negative predictive values; LR: likelihood ratio; AUC: area under the curve." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cut-off (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sensitivity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Specificity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PPV \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NPV \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR+ \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR− \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CI 95% \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rESAT-6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.61–0.88 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rCFP-10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.67–0.92 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1120646.png" ] ] ] ] "descripcion" => array:1 [ "en" => "The discriminatory power of Il-2 after stimulation with rESAT-6 and rCFP-10 in detecting patients with active TB and LTBI." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:35 [ 0 => array:3 [ "identificador" => "bib0180" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004400000004/v1_201607130013/S0301054615001494/v1_201607130013/en/main.assets" "Apartado" => array:4 [ "identificador" => "6702" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004400000004/v1_201607130013/S0301054615001494/v1_201607130013/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054615001494?idApp=UINPBA00004N"]

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S. Mamishia,b, B. Pourakbaria, H. Shamsc, M. Marjanid, S. Mahmoudia,

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sh-mahmoudi@alumnus.tums.ac.ir

Corresponding author.

a Pediatric Infectious Disease Research Center, Tehran University of Medical Science, Tehran, Iran

b Department of Infectious Diseases, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

c Center for Pulmonary and Infectious Disease Control, and Departments of Microbiology and Immunology and Medicine, University of Texas Health Center at Tyler, Tyler, TX, USA

d Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

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tuberculosis</span> standard strain H37RV DNA was obtained from the National Research Institute of Tuberculosis and Lung Disease &#40;NRITLD&#41;&#44; National Mycobacteriologic Reference Laboratory&#44; Tehran&#44; Iran&#46; Coding sequences of each dominant antigen fragment of <span class="elsevierStyleItalic">ESAT-6</span> and <span class="elsevierStyleItalic">CFP-10</span> were amplified according to our previous report&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">13</span></a> Each PCR product was ligated into pTZ57R&#47;T cloning vector after purification using QIA quick PCR purification kit &#40;MBI Fermentas&#44; Lithuania&#41;&#46; The ESAT-6 and CFP-10 gene were subcloned into pET32a&#40;&#43;&#41; expression vector &#40;Qiagen&#44; USA&#41; using SalI and BamHI for ESAT-6 and BamHI and HindIII enzymes for CFP-10&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protein expression and purification of recombinant ESAT-6 and CFP-10</span><p id="par0025" class="elsevierStylePara elsevierViewall">The pET32a&#40;&#43;&#41;-ESAT-6 and pET32a&#40;&#43;&#41;-CFP-10 plasmids were transformed into <span class="elsevierStyleItalic">E&#46; 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CO<span class="elsevierStyleInf">2</span> incubator for three days&#46; Culture supernatants were used for IFN-&#947; and IL-2 quantification&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">IFN-&#947; and IL-2 detection</span><p id="par0055" class="elsevierStylePara elsevierViewall">IFN-&#947; and IL-2 secretion were measured in the culture supernatants in the whole blood assay stimulated with antigens using IFN-&#947; ELISA kit and Human IL-2 ELISA kit &#40;Mabtech AB&#44; Sweden&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Flat-bottomed 96-well ELISA plates &#40;Nunc Maxisorp&#44; Thermo Fisher Scientific&#44; United Kingdom&#41; were coated with 2<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL coating antibody &#40;Mabtech AB&#44; Sweden&#41; and was incubated overnight at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Wells were washed twice with 200<span class="elsevierStyleHsp" style=""></span>&#956;L&#47;well sterile phosphate buffered saline &#40;PBS&#41; and blocked for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature with 200<span class="elsevierStyleHsp" style=""></span>&#956;L&#47;well PBS with 0&#46;05&#37; Tween 20 containing 0&#46;1&#37; BSA&#46; After incubation with whole blood assay supernatants for 2<span class="elsevierStyleHsp" style=""></span>h plates were developed with 1<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml biotin-conjugated Ab &#40;Mabtech&#41; for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature and then streptavidin&#8211;HRP &#40;Mabtech&#41; diluted 1&#58;1000 in PBS for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature&#46; Wells were then washed six times and 100<span class="elsevierStyleHsp" style=""></span>&#956;L&#47;well of tetramethylbenzidine &#40;TMB&#41; substrate &#40;Sigma&#44; United Kingdom&#41; was added&#46; Plates were allowed to develop for 20<span class="elsevierStyleHsp" style=""></span>min before adding 100<span class="elsevierStyleHsp" style=""></span>&#956;L&#47;well of 0&#46;5<span class="elsevierStyleHsp" style=""></span>M H<span class="elsevierStyleInf">2</span>SO<span class="elsevierStyleInf">4</span>&#46; Plates were read immediately on an ELISA reader at a 450-nm wavelength&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The differences in levels of biomarkers among groups were analysed using non-parametric analysis of variance with the Kruskal&#8211;Wallis test&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Receiver operating characteristic &#40;ROC&#41; curve analysis was conducted to determine the best IL-2 and IFN-&#947; result thresholds in discriminating between cases with active or latent TB&#44; relatively to a specific <span class="elsevierStyleItalic">M&#46; tuberculosis</span> antigen ESAT-6 and CFP-10&#44; and the corresponding sensitivity and specificity were reported&#46; The area under the ROC curve &#40;AUC&#41; and 95&#37; confidence interval &#40;CI&#41; were also calculated&#46; Cut-offs were estimated at various sensitivities and specificities and at the maximum Youden&#39;s index &#40;YI&#41;&#44; i&#46;e&#46; sensitivity<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>specificity<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>1&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> Individual concentrations of IL-2 detected in the plasma from antigen-stimulated culture minus the concentration in the respective control plasma were used for this determination&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using the statistical software STATA 11 &#40;StataCorp&#44; College Station&#44; TX&#44; USA&#41; and <span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Results</span><p id="par0080" class="elsevierStylePara elsevierViewall">In this study&#44; rESAT-6 and rCFP-10 were cloned&#44; expressed successfully and used as <span class="elsevierStyleItalic">M&#46; tuberculosis</span> stimulators&#46; The antigen-specific levels of IFN-&#947; and IL-2 were evaluated in all 90 subjects included in the study&#46; Thirty individuals were classified as uninfected&#44; 30 as LTBI and 30 as active TB cases &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">The interferon-&#947; release assay</span><p id="par0085" class="elsevierStylePara elsevierViewall">Our results revealed a statistical difference between the median IFN-&#947; levels of the LTBI and control groups after stimulation with rESAT-6 and rCFP-10 antigen &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05 and 0&#46;028&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The median level of IFN-&#947; following stimulation with rESAT-6 in active TB group and LTBI group was 0&#46;61<span class="elsevierStyleHsp" style=""></span>IU&#47;mL &#40;0&#46;2&#8211;1&#46;3&#41; and 1&#46;68<span class="elsevierStyleHsp" style=""></span>IU&#47;mL &#40;1&#46;2&#8211;4&#46;2&#41;&#44; respectively&#46; In addition&#44; the median level of IFN-&#947; was 0&#46;62<span class="elsevierStyleHsp" style=""></span>IU&#47;mL &#40;0&#46;2&#8211;2&#46;5&#41; and 1&#46;84<span class="elsevierStyleHsp" style=""></span>IU&#47;mL &#40;0&#46;43&#8211;2&#46;5&#41; following stimulation with rCFP-10 in active TB group and LTBI group&#44; respectively&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">A statistically significant difference was found between the median IFN-&#947; levels of the both antigens tested&#58; rESAT-6 &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and rCFP-10 &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; when compared with the TB disease and control groups &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The diagnostic ability of the ESAT-6 and CFP-10 demonstrated a good discriminatory power in detecting patients with TB and LTBI infection from those without the infection who were BCG vaccinated&#46; These results demonstrated a good sensitivity and specificity in detecting patients with TB and LTBI infection &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The AUCs for ESAT-6 and CFP-10 were 0&#46;88 and 0&#46;84&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">The IL-2 release assay</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discrimination between individuals with latent and active tuberculosis</span><p id="par0100" class="elsevierStylePara elsevierViewall">Observing the level of IL-2 released after 72<span class="elsevierStyleHsp" style=""></span>h of incubation&#44; we found that the level of IL-2 were significantly higher in LTBI group than in patients with active TB infection following stimulation with rESAT-6 &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and following stimulation with rCFP-10 &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; using an unpaired Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The median level of IL-2 following stimulation with rESAT-6 in the active TB group and LTBI group were 0&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;0&#46;2&#8211;21&#46;9&#41; and 24&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;14&#46;3&#8211;40&#41;&#44; respectively&#46; In addition&#44; the median levels of IL-2 were 0&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;0&#46;2&#8211;7&#46;6&#41; and 27&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;12&#46;3&#8211;38&#46;4&#41; following stimulation with rCFP-10 in active TB group and LTBI group&#44; respectively&#46; No secretion of IL-2 was detected in the control group &#40;median&#58; 0<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;0&#8211;0&#46;08&#41; &#40;data not shown&#41;&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The discrimination performance &#40;assessed by the area under ROC curve&#41; between LTBI and active TB group were 0&#46;75 and 0&#46;8 for IL-2 following stimulation with rESAT-6 and rCFP-10&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Maximum discrimination was reached at a cut-off of 11&#46;6<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for IL-2 after stimulation with recombinant rESAT-6 with 72&#37; sensitivity and 79&#37; specificity and 10&#46;7<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for IL-2 following stimulation with rCFP-10 with 75&#37; sensitivity and 79&#37; specificity&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Seventeen percent and 50&#37; of subjects with active TB and LTBI have IL-2 response of more than two cut-offs following stimulation with rESAT-6&#46; In addition&#44; IL-2 response of more than two cut-offs following stimulation with rCFP-10 was found in 13&#37; of subjects with active TB and 60&#37; of subjects with LTBI&#46;</p></span></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Tuberculosis control programmes in developing countries are greatly haunted by low case detection rates of LTBI&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a> A variety of technologies have been used for the diagnosis of TB&#44; including medical imaging &#40;e&#46;g&#46;&#44; chest radiography&#41;&#44; microbiology tests &#40;e&#46;g&#46;&#44; sputum smear microscopy&#41;&#44; histopathology&#44; and immune-based tests &#40;e&#46;g&#46;&#44; serologic&#44; antibody detection tests&#44; antigen detection tests&#44; interferon-&#947; release assays&#44; and skin tests&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">17</span></a> Although detection of acid-fast bacilli or mycobacterial cultures provides indicative values&#44; it cannot serve as a definite diagnostic method due to its complicated procedures&#46; Among these&#44; the skin test is the most widely used screening approach&#46; However&#44; the main drawback of this method is the lack of specificity due to the cross-reactivity with proteins present in other mycobacteria&#44; such as <span class="elsevierStyleItalic">M&#46; bovis</span> BCG&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The identification of regions of the <span class="elsevierStyleItalic">M&#46; tuberculosis</span> genome that are not present in BCG provides a unique opportunity to develop new highly specific diagnostic reagents&#46; The 10-kDa culture filtrate protein &#40;CFP-10&#41; and 6-kDa early secreted antigen target &#40;ESAT-6&#41; are located in the region of difference-1 &#40;RD-1&#41; of the virulent <span class="elsevierStyleItalic">M&#46; tuberculosis</span> genome but are absent in all BCG strains&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">19</span></a> It has been suggested that polyfunctional T-cells for ESAT-6 or CFP-10 play an important role in control of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> infection&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">20</span></a> Although detection of CFP-10 and ESAT-6 proteins can be used for the early and specific diagnosis of TB and for distinguishing between <span class="elsevierStyleItalic">M&#46; tuberculosis-</span>infected and BCG-vaccinated groups&#44; their value in detection of LTBI remains less clear&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">21&#8211;23</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Several papers using ESAT-6&#47;CFP-10 derivatives in IFN-&#947; release assays have mostly used three kinds of diagnostic reagents such as recombinant individual proteins or fusion protein&#44; pool of overlapping peptides and selected non-overlapping multi-epitopic peptides&#59;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">24&#8211;26</span></a> although they do not lead to successful differentiation between active TB and LTBI&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Measurement of multiple cytokines may help identify potential biomarkers for differentiating active TB from LTBI&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">27</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Our study demonstrated the importance of establishing an efficient diagnostic method&#44; based on the IL-2 detection after stimulation of blood with rESAT-6 and rCFP-10 for discrimination of latent TB infection and TB disease&#46; Our data are in agreement with the recent observation by Sargentini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">28</span></a> and Wang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">10</span></a> describing that detection of IL-2 after stimulation with <span class="elsevierStyleItalic">M&#46; tuberculosis</span> antigens may discriminate individuals with latent infection from patients affected by active TB&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">When there is no definite gold standard for the diagnosis of LTBI&#44; the IL-2 release assay in addition to IGRA can improve the ability of IGRA to identify individuals with recently acquired LTBI&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">5&#44;10&#44;29&#8211;31</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">According to the previous meta-analysis&#44; IL-2 is a valid marker for the diagnosis of LTBI&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">5</span></a> IL-2 is promoting T-cell replication and is essential for cellular immunity and granuloma formation&#46; Although IFN-&#947; is predominantly produced by effector memory T-cells&#44; IL-2 is mostly produced by central memory T-cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">32&#44;33</span></a> The secretion of IL-2 is secreted from cells also secreting IFN-&#947; in both the early and the later stages of infection and when the antigen load has declined&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">9</span></a> Dual IFN-&#947;&#47;IL-2-secreting cells in active phase of TB can support their own expansion because IL-2 is a potent T cell growth factor&#46; The presence of these cells in active TB when the antigen load is high may therefore suggest their involvement in the initiation phase of the immune response&#46; IL-2 in LTBI or when the antigen load is reduced or cleared may reflect its function in the termination of T cell responses&#46; This proposed signalling function augments the growth and survival of regulatory T cells that control inflammatory responses&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">9</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The meta-analysis by Menzies et al&#46; reported a pooled sensitivity of 80&#37; and polled specificity of 96&#37; after stimulation with QuantiFERON&#174;-TB Gold In-Tube that used ESAT-6 with CFP-10 for diagnosing LTBI in healthy and immune-suppressed persons&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">11</span></a> Compared with these reports&#44; our estimated sensitivity and specificity for diagnosis of TB was very good &#40;sensitivity 83&#8211;84&#37; and specificity 92&#37;&#41;&#46; ROC analyses demonstrated sensitivity of 72&#37; and specificity of 79&#37;&#44; in discriminating between latent and active TB&#44; considering response to rESAT-6 by IL-2 release assay for a cut-off of 11&#46;6<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#46; In addition&#44; sensitivity of 75&#37; and specificity of 79&#37; was demonstrated after stimulation with rCFP-10 protein&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">We presented both the Positive Likelihood Ratios &#40;PLR&#41; and Negative Likelihood Ratios &#40;NLR&#41; as measures of diagnostic accuracy&#46; Likelihood ratios of &#62;10 or &#60;0&#46;1 indicated high accuracy&#46; A PLR value of &#62;10 for IFN-&#947; assay after stimulation with both recombinant proteins suggests that patients with TB have an approximately &#62;10-fold higher chance of being positive with this test&#46; This likelihood was 6&#46;5 and 3&#46;6 for IL-2 after stimulation with both recombinant proteins&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Since no laboratory tool is currently available to distinguish between individuals in the process of progressing from latent TB infection towards active disease&#44; determination of the interferon-gamma and interleukin-2 T-cell signature might provide rapid tool for clinical management of patient&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">34&#44;35</span></a> Our study confirmed that IL-2 release assay has the ability to identify individuals with LTBI&#46; However&#44; the relative small sample size may have influenced the result of the analysis due to low numbers of individuals in each category&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In conclusion&#44; this study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB&#46; In addition&#44; it was shown that IL-2 could be serving as a marker for discriminating LTBI and active TB&#46; Since the immunology of TB is complex&#44; and understanding LTBI is even more challenging&#44; a large scale study will be needed to establish the usefulness of this biomarker&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ethical disclosures</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Confidentiality of data</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Right to privacy and informed consent</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; The author for correspondence is in possession of this document&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Protection of human and animal subjects</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest&#46;</p></span></span>"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Since gamma interferon release assays &#40;IGRAs&#41; cannot differentiate between active tuberculosis and latent tuberculosis infection &#40;LTBI&#41;&#44; development of rapid and specific diagnosis tools are essential for discriminating between active tuberculosis &#40;TB&#41; from LTBI&#46; Both IGRAs are based on <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>-specific antigens&#44; namely&#44; early secretory antigenic target 6 &#40;ESAT-6&#41; and 10<span class="elsevierStyleHsp" style=""></span>kDa culture filtrate &#40;CFP-10&#41;&#46; The aim of this study was to evaluate the potential value of IL-2 secretion by whole blood cells after stimulation with rESAT-6 and rCFP-10 for discriminating between active and latent tuberculosis&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Interleukin-2 and IFN-&#947; were measured after blood stimulation of 90 cases &#40;30 with active TB&#44; 30 with LTBI and 30 healthy controls&#41; with recombinant ESAT-6 and CFP-10&#46; Receiver operating characteristic &#40;ROC&#41; curve analysis was conducted to determine the best IL-2 and IFN-&#947; result thresholds in discriminating between cases with active or latent TB&#44; and the corresponding sensitivity and specificity were recorded&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The IFN-&#947; release assay demonstrated a good sensitivity and specificity &#40;sensitivity 83&#8211;84&#37; and specificity 92&#37;&#41; for diagnosis of tuberculosis&#46; The discrimination performance of IL-2 assay &#40;assessed by the area under ROC curve&#41; between LTBI and patients with active TB were 0&#46;75 and 0&#46;8 following stimulation with rESAT-6 and rCFP-10&#44; respectively&#46; Maximum discrimination was reached at a cut-off of 11&#46;6<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for IL-2 after stimulation with recombinant rESAT-6 with 72&#37; sensitivity and 79&#37; specificity and 10&#46;7<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for IL-2 following stimulation with rCFP-10 with 75&#37; sensitivity and 79&#37; specificity&#44; respectively&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study demonstrates that rESAT-6 and rCFP-10 can provide a sensitive and specific diagnosis of TB&#46; In addition&#44; it was shown that IL-2 may be serving as a marker for discriminating LTBI and active TB&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
          ]
        ]
      ]
    ]
    "multimedia" => array:7 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1230
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The rESAT-6 and rCFP-10 stimulated expression of IFN-&#947; in patients with different groups&#46; IFN-&#947; release obtained after incubation with a mixture of rESAT-6 &#40;left panel&#41; and rCFP-10 &#40;right panel&#41; in three different groups of subjects&#58; patients with active tuberculosis&#44; subjects with LTBI and healthy non-infected controls&#44; respectively&#46; Horizontal bars indicate the medians of the IFN-&#947; values of the respective population&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1480
            "Ancho" => 3166
            "Tamanyo" => 167352
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Receiver operator characteristic &#40;ROC&#41; plot illustrating sensitivity and specificity of IFN-&#947; in discriminating between the TB &#40;latent infection or disease&#41; and healthy non-infected control groups&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1259
            "Ancho" => 3167
            "Tamanyo" => 96035
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The rESAT-6 and rCFP-10 stimulated expression of IL-2 in patients with active tuberculosis and individuals with LTBI&#46; IL-2 release obtained after 72<span class="elsevierStyleHsp" style=""></span>h of incubation with a mixture of rESAT-6 &#40;left panel&#41; and rCFP-10 &#40;right panel&#41; in different groups of subjects&#58; patients with active tuberculosis and subjects with LTBI&#44; respectively&#46; Horizontal bars indicate the medians of the IL-2 values of the respective population&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1569
            "Ancho" => 3167
            "Tamanyo" => 174067
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Receiver operator characteristic &#40;ROC&#41; plot illustrating sensitivity and specificity of IL-2 in discriminating individuals with LTBI and active TB&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">TB&#58; tuberculosis&#59; LTBI&#58; latent tuberculosis infection&#59; QFT-G-IT&#58; QuantiFERON-TB Gold In Tube&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Active TB</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Subjects with LTBI</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy control</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Age</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">35&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;8</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">40&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;8</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">45&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;6</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Sex</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Origin</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Iranian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Afghan immigrant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">TB</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pulmonary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">QFT-G-IT</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Median &#40;IU&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">8&#46;1 &#40;1&#46;1&#8211;10&#46;3&#41;</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">6&#46;3 &#40;0&#46;39&#8211;8&#46;9&#41;</td><td class="td" title="table-entry  " colspan="2" align="center" valign="middle">0&#46;04 &#40;0&#8211;0&#46;2&#41;</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Demographic characteristics of enrolled individuals&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">PPV&#58; positive predictive values&#59; NPV&#58; negative predictive values&#59; LR&#58; likelihood ratio&#59; AUC&#58; area under the curve&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cut-off &#40;IU&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sensitivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Specificity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PPV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NPV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LR&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AUC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CI 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rESAT-6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;8&#8211;0&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">rCFP-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;74&#8211;0&#46;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">PPV&#58; positive predictive values&#59; NPV&#58; negative predictive values&#59; LR&#58; likelihood ratio&#59; AUC&#58; area under the curve&#46;</p>"
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2015.09.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	6	0	6
2024 October	19	22	41
2024 September	62	16	78
2024 August	67	21	88
2024 July	40	19	59
2024 June	30	12	42
2024 May	35	9	44
2024 April	41	10	51
2024 March	74	17	91
2024 February	51	16	67
2024 January	55	12	67
2023 December	44	16	60
2023 November	36	9	45
2023 October	44	17	61
2023 September	29	9	38
2023 August	49	9	58
2023 July	37	14	51
2023 June	24	15	39
2023 May	45	6	51
2023 April	18	4	22
2023 March	20	2	22
2023 February	20	5	25
2023 January	14	17	31
2022 December	26	9	35
2022 November	19	12	31
2022 October	22	7	29
2022 September	25	37	62
2022 August	19	9	28
2022 July	21	11	32
2022 June	26	14	40
2022 May	39	10	49
2022 April	37	10	47
2022 March	37	16	53
2022 February	36	8	44
2022 January	50	6	56
2021 December	57	10	67
2021 November	27	11	38
2021 October	51	14	65
2021 September	33	13	46
2021 August	7	11	18
2021 July	11	10	21
2021 June	18	11	29
2021 May	12	9	21
2021 April	28	18	46
2021 March	14	17	31
2021 February	18	9	27
2021 January	18	12	30
2020 December	1	0	1
2020 October	1	0	1
2020 July	0	1	1
2018 February	4	3	7
2018 January	3	0	3
2017 December	4	2	6
2017 November	4	3	7
2017 October	4	8	12
2017 September	4	5	9
2017 August	11	5	16
2017 July	8	5	13
2017 June	14	4	18
2017 May	17	1	18
2017 April	6	0	6
2017 March	1	0	1
2016 July	2	0	2

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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