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Background Interferon‐gamma (IFN‐γ) release assays (IGRAs) are useful for the assessment of the T‐cell response to severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2). We aimed to assess the performance of the newly developed IGRA ELISA test compared to the pre‐existing assays and to validate the cutoff value in real‐world conditions. Methods We enrolled 219 participants and assessed agreement between STANDARD‐E Covi‐FERON ELISA with Quanti‐FERON SARS‐CoV‐2 (QFN SARS‐CoV‐2), as well as with T SPOT Discovery SARS‐CoV‐2 based on Cohen's kappa‐index. We further determined the optimal cutoff value for the Covi‐FERON ELISA according to the immune response to vaccinations or infections. Results We found a moderate agreement between Covi‐FERON ELISA and QFN SARS‐CoV‐2 before vaccination (kappa‐index = 0.71), whereas a weak agreement after the first (kappa‐index = 0.40) and second vaccinations (kappa‐index = 0.46). However, the analysis between Covi‐FERON ELISA and T SPOT assay demonstrated a strong agreement (kappa‐index >0.7). The cut‐off value of the OS (original spike) marker was 0.759 IU/mL with a sensitivity of 96.3% and specificity of 78.7%, and that of the variant spike (VS) marker was 0.663 IU/mL with a sensitivity and specificity of 77.8% and 80.6%, respectively. Conclusion The newly determined cut‐off value may provide an optimum value to minimize and prevent the occurrence of false‐negative or false‐positive during the assessment of T‐cell immune response using Covi‐FERON ELISA under real‐world conditions. The presence of IFN‐γ in the patient's blood samples can be an indicator of SARS‐CoV‐2 infection or the development of cellular immune response following the COVID‐19 vaccination. An IFN‐γ release assay (IGRA) enables the detection of IFN‐γ in the blood, and, therefore, plays an important role in the detection of SARS‐CoV‐2 or confirmation of the COVID‐19 vaccine's efficacy. Subsequently, an optimum cutoff value of the IGRA's markers is crucial to determine the accuracy of the IGRA test in discriminating the presence or absence of IFN‐γ in the blood samples.

BackgroundGuidelines mandate screening for latent tuberculosis infection (LTBI) prior to anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). However, many are already on immunosuppressive therapy (IST) that may affect the precision of the Tuberculin skin test (TST). Our aim was to assess the performance of the new interferon-gamma release assays (IGRAs) to detect LTBI in patients with IBD.MethodsMEDLINE and EMBASE were searched (up to June 2011) to identify studies evaluating the performance of IGRAs (QuantiFERON-TB Gold [QFT-2G], QuantiFERON-TB Gold In-Tube [QFT-3G] and T-SPOT.TB) in individuals with IBD. Forest plots and pooled estimates using random effects models were created where applicable.ResultsNine unique studies encompassing 1309 patients with IBD were included for analysis. The pooled concordance between the TST and QFT-2G/QFT-3G was 85% (95% confidence interval [CI] 77%–90%). The concordance of the TST and TSPOT.TB was 72% (95% CI 64%–78%). Studies assessing agreement reported more IGRA−/TST+ results versus IGRA+/TST− results. The pooled percentage of indeterminate results was 5% (95% CI 2%–9%) for QFT-2G/QFT-3G. TSPOT.TB showed similar results. Both positive QFT-2G/QFT-3G results (pooled odds ratio [OR] 0.37, 95% CI 0.16–0.87) and positive TST results (pooled OR 0.28, 95% CI 0.10–0.80) were significantly influenced by IST (both P = 0.02).ConclusionsWhile it remains difficult to determine superiority between the IGRAs and the TST, both are negatively affected by IST. Therefore, screening prior to initiation of IST should be considered. Nevertheless, it is imperative that all patients receive screening prior to anti-TNF therapy.

Introduction The association between the risk of latent tuberculosis infection (LTBI) reactivation and immune checkpoint inhibitor (ICI) administration has been reported. Case Presentation A man in his seventies underwent robot‐assisted laparoscopic radical cystectomy with ileal conduit diversion for muscle‐invasive bladder cancer. Three years postoperatively, CT revealed metastases to the para‐aortic lymph nodes and rectum. Four cycles of gemcitabine and carboplatin were administered, with CT showing a partial response (PR). Avelumab maintenance therapy was initiated following radiotherapy for the rectal metastasis. Prior to avelumab administration, LTBI was diagnosed based on a positive interferon‐gamma release assay (IGRA). Isoniazid was administered concurrently with avelumab for 6 months. No active tuberculosis developed, and PR was maintained. Conclusion IGRA screening is advisable prior to ICI initiation. Prompt and appropriate management is warranted in patients with LTBI.

Background: Interferon-gamma release assay (IGRA) has been used in latent tuberculosis (TB) infection and TB diagnosis, but the results from different high TB-endemic countries are different. The aim of this study was to investigate the value of IGRA in the diagnosis of active pulmonary TB (PTB) in China. Methods: We conducted a large-scale retrospective multicenter investigation to further evaluate the role of IGRA in the diagnosis of active PTB in high TB-epidemic populations and the factors affecting the performance of the assay. All patients who underwent valid T-SPOT.TB assays from December 2012 to November 2015 in six large-scale specialized TB hospitals in China and met the study criteria were retrospectively evaluated. Patients were divided into three groups: Group 1, sputum culture-positive PTB patients, confirmed by positive Mycobacterium tuberculosis sputum culture; Group 2, sputum culture-negative PTB patients; and Group 3, non-TB respiratory diseases. The medical records of all patients were collected. Chi-square tests and Fisher's exact test were used to compare categorical data. Multivariable logistic analyses were performed to evaluate the relationship between the results of T-SPOT in TB patients and other factors. Results: A total of 3082 patients for whom complete information was available were included in the investigation, including 905 sputum culture-positive PTB cases, 914 sputum culture-negative PTB cases, and 1263 non-TB respiratory disease cases. The positive rate of T-SPOT.TB was 93.3% in the culture-positive PTB group and 86.1% in the culture-negative PTB group. In the non-PTB group, the positive rate of T-SPOT.TB was 43.6%. The positive rate of T-SPOT.TB in the culture-positive PTB group was significantly higher than that in the culture-negative PTB group (χ2 = 25.118, P < 0.01), which in turn was significantly higher than that in the non-TB group (χ2 = 566.116, P < 0.01). The overall results were as follows: sensitivity, 89.7%; specificity, 56.37%; positive predictive value, 74.75%; negative predictive value, 79.11%; and accuracy, 76.02%. Conclusions: High false-positive rates of T-SPOT.TB assays in the non-TB group limit the usefulness as a single test to diagnose active TB in China. We highly recommend that IGRAs not be used for the diagnosis of active TB in high-burden TB settings.

In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials.gov (NCT 00707317).

SRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13–15 years in Tanzania. Adolescents with a negative T- SPOT.TBR interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA). Among 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03). A three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted. Trial Registration. The trial is registered at ClinicalTrials.gov as NCT02712424.

We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI). On 15 November 2022, we searched the PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), and Cochrane Library databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators independently extracted the study data and assessed their quality using a modified quality assessment of diagnostic accuracy studies (i.e., QUADAS-2) tool. A random-effects model was used to calculate pooled results. We included 403 studies involving 486,886 individuals and found that the pooled indeterminate rate was 3.9% (95% CI 3.5%-4.2%). The pooled indeterminate rate for QuantiFERON®-TB (QFT) was similar to that for T-SPOT®.TB (T-SPOT) [odds ratio (OR) = 0.88, 95% CI 0.59-1.32]; however, the indeterminate rate for a new generation of QFT (QFT-plus) was lower than that of T-SPOT (OR = 0.24, 95% CI 0.16-0.35). The indeterminate rate in the immunocompromised population was significantly higher than that in healthy controls (OR = 3.51, 95% CI 2.11-5.82), and it increased with the reduction of CD4+ cell count in HIV-positive patients. Children's pooled indeterminate rates (OR = 2.56, 95% CI 1.79-3.57) were significantly higher than those of adults, and the rates increased as the children's age decreased. On average, 1 in 26 tests yields indeterminate IGRA results in LTBI screening. The use of advanced versions of the QuantiFERON-TB assay (QFT-plus), may potentially reduce the occurrence of an indeterminate result. Our study emphasizes the high risk of immunosuppression and young age in relation to indeterminate IGRA, which should receive more attention in the management of LTBI. PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020211363, CRD42020211363.

PurposeComparing the performance of commercially available SARS-CoV-2 T-cell immunoassay responses may provide useful information for future observational or intervention studies as well as to their potential customers.MethodWhole blood was collected from a total of 183 subjects fully vaccinated against COVID-19: 55 healthy controls (Group 1), 50 hematological patients (Group 2), 50 chronic kidney disease patients (Group 3), and 28 elderly nursing home residents (Group 4). Samples were tested with the Roche Elecsys® IGRA (Interferon-gamma release assay) SARS-CoV-2 test (Roche Diagnostics, Rotkreuz, Switzerland), the Euroimmun SARS-CoV-2 test (Euroimmun, Lubeck, Germany), the SARS-CoV-2 T Cell Analysis Kit (Miltenyi Biotec, Bergisch Gladbach, Germany), and a flow-cytometry for intracellular cytokine (IFN-γ) staining-based immunoassay (FC-ICS).ResultsOverall, the Roche Elecsys® assay returned the highest number of positive results (151/179; 84.3%), followed by the Euroimmun test (127/183; 69%), and the FC-ICS (135/179; 75%). The Kappa coefficient of agreement was best between IGRAs (0.64). Most discordant results across assays involved patients from Group 2. Overall, IFN-γ concentrations measured by both IGRAs correlated strongly (rho = 0.78; 95% CI 0.71–0.84; P < 0.001) irrespective of the study group. The frequencies of SARS-CoV-2-reactive IFN-γ T cells and IFN-γ concentrations measured by the IGRAs correlated moderately for CD4+ T cells, however, weakly for CD8+ T cells. SARS-CoV-2-experienced participants displayed stronger responses than SARS-CoV-2-naïve when IGRAs, rather than FC-ICS, were used.ConclusionThe SARS-CoV-2 immunoassays evaluated in the present study did not return interchangeable qualitative or quantitative results either in seemingly healthy individuals or in immunosuppressed patients.

Background Interferon-gamma release assays (IGRAs) are widely used for detecting latent tuberculosis infection (LTBI). However, these tests can yield indeterminate results, posing challenges for clinical management. The management of these indeterminate outcomes varies, creating uncertainty in clinical practice. This study systematically evaluates the effectiveness of repeat IGRA testing versus additional tuberculin skin testing (TST) in resolving indeterminate IGRA results during LTBI screening. Methods We conducted a systematic review and meta-analysis, searching PubMed, Embase, Web of Science, and the Cochrane Library databases on May 18, 2024, without start date or language restrictions. Studies were included if they screened for LTBI in healthy or high-risk populations using IGRA, reported indeterminate results, and managed these results with repeat IGRA testing and/or additional TST. A random-effects model was used to calculate pooled results. Results A total of 59 studies were included in this analysis. Among these, 40 studies assessed the use of additional TST in individuals with indeterminate IGRA results, yielding a pooled confirmation rate of 98.6% (95% CI: 96.2–99.8%). Additionally, 27 studies examined repeat IGRA testing, which resulted in a pooled confirmation rate of 68.9% (95% CI: 57.0–79.6%). Furthermore, eight studies evaluated both TST and repeat IGRA testing, with the pooled confirmation rate for the TST being 93.7% (95% CI: 78.7–99.9%), higher than the pooled confirmation rate for repeat testing at 76.5% (95% CI: 44.6–97.1%). However, there was no statistically significant difference in the confirmation rates between the two testing methods (OR = 2.13, 95% CI: 0.47–9.76). Conclusions In managing indeterminate IGRA results during LTBI screening, head-to-head studies show no significant difference in confirmation rates between additional TST and repeat IGRA. Across nearly 60 studies, additional TST tends to have a slightly higher confirmation rate, though the difference is not statistically significant. Clinically, for patients with an initial indeterminate IGRA who are immunocompetent, with convenient sample collection or a need for rapid results, additional TST may help achieve more reliable outcomes. Selection of follow-up testing should consider the cause of indeterminate results, feasibility, and risk of patient loss to follow-up.

The pathogenesis of COVID-19 involves both humoral and cellular immunological responses, with cell-mediated immunity being discussed as the primary and most effective immune response to viral infection. It is supposed that COVID-19 vaccines also elicited effective cell immune response, and specifically IFNγ secreted by SARS-CoV-2-specific T-helper 1 and Tcytotoxic cells. Using an interferon-gamma release assay (IGRA) test, we aimed to monitor cellular post-vaccination immunity in healthy subjects vaccinated with BNT162b2 mRNA COVID-19 vaccine (Comirnaty). We tested 37 healthcare workers (mean age 54.3 years, range 28–72, 22 females, 15 males) following COVID-19 mRNA COVID-19 vaccine and 15 healthy unvaccinated native persons as control subjects using QuantiFERON SARS-CoV-2 RUO test, performed approximately 1 month after vaccination. We also measured virus-neutralizing antibodies. Thirty-one out of 37 tested subjects had significantly raised levels of SARS-CoV-2 specific IFNγ against SARS-CoV-2 Ag1 and Ag2 1 month following COVID-19 vaccination. In addition, we found a significant difference between the IFNγ levels in fully vaccinated subjects and the control group (p < 0.01).We also found a substantial correlation (r = 0.9; p < 0.01) between virus-neutralizing antibodies titers and IFNγ concentrations released by T cells. We believe that IGRA tests are an excellent tool to assess the development of a post-vaccination immune response when immunized against SARS-CoV-2. However, IGRA-based tests should be performed within a few weeks following vaccination. Therefore, we can speculate that the application of these tests to assess long-term immune response is debatable.