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BACKGROUND: TB control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town, South Africa. METHODS: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB burden communities. Prevalent infection was defined as QuantiFERON™-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. RESULTS: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% CI 20.9-24.4), was independently associated with increasing age (aOR 1.24 per additional year, 95% CI 1.15-1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95% CI 1.46-2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI 1.05-7.18). CONCLUSION: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission.

CONTEXTE: La lutte contre la TB nécessite la compréhension et la perturbation de la transmission de la TB. Nous décrivons la prévalence, l'incidence et les facteurs de risque associés à l'infection tuberculeuse infantile au Cap, en Afrique du Sud. MÉTHODES: Nous rapportons des données transversales de référence et d'incidence prospective provenant d'un vaste essai mené auprès d'enfants d'écoles primaires vivant dans des communautés à forte charge de morbidité tuberculeuse. La prévalence de l'infection a été définie comme la positivité au QuantiFERON™-TB Gold Plus (QFT-Plus) telle qu'évaluée au départ. La conversion subséquente en QFT-Plus positif a été mesurée 3 ans plus tard chez les QFT-Plus négatifs au départ. Des modèles de régression logistique multivariée ont examiné les facteurs associés à l'infection tuberculeuse. RÉSULTATS: La positivité QuantiFERON-au départ (prévalence : 22,6%, IC à 95% 20,9­24,4), était indépendamment associée à l'augmentation de l'âge (aOR 1,24 par année supplémentaire, IC à 95% 1,15­1,34) et à l'exposition du ménage à la TB au cours de la vie du participant (aOR 1,87 ; IC à 95% 1,46­2,40). La conversion QFT-Plus à l'année 3 (12,2%, IC à 95% 10,5­14,0 ; taux d'infection annuel : 3,95%) était associée à l'exposition du ménage à un cas de tuberculose index (aOR 2,74 ; IC à 95% 1,05­7,18). CONCLUSION: Les taux d'infection tuberculeuse diagnostiquée par QFT restent élevés dans cette population. La forte association avec l'exposition à la TB dans les ménages renforce l'importance de la recherche des contacts, du traitement préventif et du traitement précoce des maladies infectieuses pour réduire la transmission communautaire.

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BACKGROUND: Recurrence posed an important challenge to pulmonary tuberculosis (PTB) control in China. The prospective study aimed to identify potential risk factors and to explore the value of QuantiFERON-TB Gold Plus (QFT-Plus) in identifying at-risk individuals with treated prior PTB history. METHODS: All eligible individuals aged ≥18 years who had been diagnosed with PTB before 2016 in Zhongmu County, where with an average level of TB prevalence in China, were included and received baseline survey including chest radiography, QuantiFERON-TB Gold In-Tube (QFT-GIT) and QFT-Plus, then PTB recurrence was tracked through a 2-year follow-up. RESULTS: Half of 1068 (52.34%, 559/1068) included eligible participants were QFT-Plus positive at baseline and 21 of them recurred active TB in 2-year follow-up. Individuals aged ≥ 60 years, who had a recent history of TB and smokers were associated with increased risk of TB recurrence with an adjusted odds ratio (aOR) of 3.97 (95% confidence interval (CI): 1.29-12.24), 7.71 (95% CI: 1.74-34.25) and 4.56 (95% CI: 1.62-12.83), respectively. Compared to QFT-Plus negatives, those who were TB2+/TB1- (aOR = 15.34) exhibited stronger association with the risk of TB recurrence than those who were TB1+/TB2+ (aOR = 6.06). A dose response relationship was also found between the risk of TB recurrence with the baseline level of TB2-TB1 (p for trend < 0.001). CONCLUSIONS: High burden of TB infection and high risk of PTB recurrence were observed in the study population. Those with recent onset of prior TB, elderly smokers and QFT-Plus positives especially with TB2 single positive deserved further attention in active TB surveillance.

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BACKGROUND: More efficient and convenient diagnostic method is a desperate need to reduce the burden of tuberculosis (TB). This study explores the multiple cytokines secretion based on QuantiFERON-TB Gold Plus (QFT-Plus), and screens for optimal cytokines with diagnostic potential to differentiate TB infection status. METHODS: Twenty active tuberculosis (ATB) patients, fifteen patients with latent TB infection (LTBI), ten patients with previous TB and ten healthy controls (HC) were enrolled. Whole blood samples were collected and stimulated by QFT-Plus TB1 and TB2 antigens. The levels of IFN-γ, TNF-α, IL-2, IL-6, IL-5, IL-10, IP-10, IL-1Ra, CXCL-1 and MCP-1 in supernatant were measured by Luminex bead-based multiplex assays. The receiver operating characteristic curve was used to evaluate the diagnostic accuracy of cytokine for distinguishing different TB infection status. RESULTS: After stimulation with QFT-Plus TB1 and TB2 antigens, the levels of all cytokines, except IL-5 in TB2 tube, in ATB group were significantly higher than that in HC group. The levels of IL-1Ra concurrently showed the equally highest AUC for distinguishing TB infection from HC, followed by the levels of IP-10 in both TB1 tube and TB2 tube. Moreover, IP-10 levels displayed the largest AUC for distinguishing ATB patients from non-ATB patients. Meanwhile, the levels of IP-10 also demonstrated the largest AUC in both TB1 tube and TB2 tube for distinguishing ATB patients from LTBI. CONCLUSIONS: In addition to conventional detection of IFN-γ, measuring IP-10 and IL-1Ra based on QFT-Plus may have the more tremendous potential to discriminate different TB infection status.

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BACKGROUND: The risk of tuberculosis (TB) disease is higher in individuals with TB infection. In a TB endemic country like India, it is essential to understand the current burden of TB infection at the population level. The objective of the present analysis is to estimate the prevalence of TB infection in India and to explore the factors associated with TB infection. METHODS: Individuals aged > 15 years in the recently completed National TB prevalence survey in India who were tested for TB infection by QuantiFERON-TB Gold Plus (QFT-Plus) assay were considered for this sub-analysis. TB infection was defined as positive by QFT-Plus (value >0.35 IU/ml). The estimates for prevalence, prevalence ratio (PR) and adjusted risk ratio (aRR) estimates with 95% confidence intervals (CIs) were calculated. RESULTS: Of the 16864 individuals analysed, the prevalence of TB infection was 22.6% (95% CI:19.4 -25.8). Factors more likely to be associated with TB infection include age > 30 years (aRR:1.49;95% CI:1.29-1.73), being male (aRR:1.26; 95%CI: 1.18-1.34), residing in urban location (aRR:1.58; 95%CI: 1.03-2.43) and past history of TB (aRR:1.49; 95%CI: 1.26-1.76). CONCLUSION: About one fourth (22.6%) of the individuals were infected with TB in India. Individuals aged > 30 years, males, residing in urban location, and those with past history of TB were more likely to have TB infection. Targeted interventions for prevention of TB and close monitoring are essential to reduce the burden of TB in India.

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BACKGROUND: We implemented the QuantiFERON-TB Gold In-Tube (QFT-GIT) based on peripheral blood mononuclear cells (QFT-PBMCs) and QFT Gold Plus (QFT-Plus) in patients with indeterminate results, and use Mit-Nil value to identify false negatives and impaired cellular immunity. METHODS: One hundred seventy-one out of 2480 patients who had a QFT-GIT test were prospectively recruited and classified as high Nil (n = 35), low Mit (n = 75) and control (n = 61) cohorts. Head-to-head comparisons, i.e., QFT-PBMCs vs. QFT-GIT in high Nil cohort, QFT-Plus vs. QFT-GIT in low Mit cohort, and QFT-PBMCs vs. QFT-GIT in controls, were performed. Lymphocyte subsets counts were conducted in low Mit and control cohorts. RESULTS: A significant reduction of positive rate only occurred in Mit-Nil < 6 IU/ml (p < 0.001). QFT-PBMCs yielded 100 % valid results and had a significant Nil decline in high Nil cohort (0.98 ± 1.06 vs. 9.55 ± 0.64 IU/ml, p < 0.0001), while correlated well with QFT-GIT for qualitative (Cohen's k = 0.93) and quantitative (TB-Ag [R2 = 0.91] and Mit [R2 = 0.94]) analyses. QFT-Plus produced 61.3 % valid results and had a significant Mit increase in low Mit cohort (0.82 ± 0.95 vs. 0.17 ± 0.11 IU/ml, p < 0.0001). Mit-Nil value significantly correlated with lymphocyte subsets counts (R:0.49-0.56, p < 0.0001), separately corresponding to thresholds of 4.26, 5.33, 5.55 and 5.81 IU/ml for predicting decreased total lymphocyte, T lymphocyte, CD4+ and CD8+ cells. CONCLUSIONS: QFT that replacing whole blood with PBMCs should be recommended to handle high Nil samples, and QFT-Plus can declined the frequency of low Mit results. In addition, Mit-Nil < 6 and 5.81 IU/ml are potential thresholds to identify the risk of false negatives and impaired cellular immunity, respectively.

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ABSTRACT Detecting latent tuberculosis infection (LTBI) is important, especially in high-risk populations including healthcare workers (HCWs). QuantiFERON-TB Gold Plus (QFT-Plus) is a new version of the interferon-gamma release assays (IGRAs) to replace the QuantiFERON-TB Gold In-tube (QFT-GIT). However, data on the use of QFT-Plus for LTBI detection in high TB-burden countries are limited. This study was conducted in a TB-endemic setting in Thailand. HCWs were enrolled in the study and underwent both tests during the annual health screening. The testing results were compared and the concordance was determined. Of 102 HCWs, 11 (10.78%) were positive according to both tests, and 15 (14.71%) were positive according to QFT-Plus. The overall agreement between assays was 96.08%, with Cohen's kappa coefficient (k) at 0.82. All four discordant results occurred with QFT-GIT negative and QFT-Plus positive. The comparison between QFT-GIT and QFT-Plus based on each antigen tube (TB1 or TB2) exhibited similar concordance with 99.02% and 95.10% agreement, respectively. The intra-comparison between TB1 and TB2 of QFT-Plus also showed good concordance at 96.08%. Among this group of HCWs, the LTBI prevalence of any positive results in both tests was low. Overall, the study showed good agreement between QFT-Plus and QFT-GIT (k = 0.82) with a minimal difference, suggesting similar assay performance to that mainly carried out in TB-low incidence countries. The results support the use of QFT-Plus for detecting LTBI in a format similar to QFT-GIT.

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Objective: To assess the proportion of indeterminate QuantiFERON-TB Gold Plus (QFT-Plus) results in patients admitted for severe coronavirus disease 2019 (COVID-19) pneumonia and evaluate the factors associated with indeterminate QFT-Plus results. Patients and Methods: Data on COVID-19 admissions at Mayo Clinic in Florida were extracted between October 13, 2020, and September 20, 2021, and data from a prepandemic cohort were extracted between October 13, 2018, and September 20, 2019. A secondary analysis of the COVID-19 cohort was performed using gradient boosting modeling to generate variable importance and SHapley Additive exPlanations plots. Results: Our findings demonstrated more indeterminate QFT-Plus test results in patients hospitalized for severe COVID-19 infection than in patients without COVID-19 (139 of 495, 28.1%). The factors associated with indeterminate QFT-Plus test results included elevated levels of C-reactive protein, ferritin, lactate dehydrogenase and interleukin-6 and included lower levels of leukocyte, lymphocyte, and platelet counts. Conclusion: The patients with severe COVID-19 had a higher likelihood of indeterminate QFT-Plus results, which were associated with elevated levels of inflammatory markers consistent with severe infection. Interferon-gamma release assay screening tests are likely confounded by COVID-19 infection itself, limiting the screening ability for latent tuberculosis infection reactivation. Indeterminate QFT-Plus results may also require follow-up QFT-Plus testing after patient recovery from COVID-19, increasing the cost and complexity of medical decision making and management. Additional risk assessments may be needed in this patient population for screening for latent tuberculosis infection in patients with severe COVID-19.

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OBJECTIVE: This study aimed to compare the accuracy of QuantiFERON-TB Gold Plus (QFT-Plus) and T-SPOT.TB for diagnosing active tuberculosis (ATB) in febrile patients, to explore influencing factors of positive results and to verify the potential value of QFT-Plus in the identification of ATB and latent tuberculosis infection (LTBI). METHODS: A total of 240 febrile patients with ATB (n = 80) and non-ATB (n = 160) were recruited to assess the accuracy of QFT-Plus and T-SPOT.TB for diagnosing ATB. Multivariable logistic regression was used to analyze the influencing factors of positive results. RESULTS: The proportion of indeterminate results (ITRS) in QFT-Plus and T-SPOT.TB were 3.3% and 0%, respectively. The consistency between the results of the QFT-Plus and T-SPOT.TB was substantial. The area under the receiver operating characteristic curve (AUROC) of the QFT-Plus and T-SPOT.TB for diagnosing ATB was 0.792 and 0.849 (p = 0.070), respectively. The sensitivity of differentiating ATB from non-ATB was 92.2% in QFT-Plus versus 95.0% in T-SPOT.TB. The influencing factors of T-SPOT.TB positive result were male (odds ratio (OR) = 2.33, 95% confidence interval (CI) 1.27-4.26, p = 0.006), evidence of previous TB (OR 11.36, 95% CI 4.62-27.94, p < 0.001), while male (OR = 3.17, 95% CI 1.73-5.84, p < 0.001), evidence of previous TB (OR = 7.58, 95% CI 3.60-15.98, p <0.001), and use of immunosuppressant (OR = 0.49, 95% CI 0.260.94, p = 0.030) were influencing factors for QFT-Plus positive result. There was no significant difference in QFT-Plus in differentiating ATB from LTBI in febrile patients. CONCLUSION: There was no significant difference between QFT-Plus and T-SPOT.TB for diagnosing ATB in febrile patients. QFT-Plus is prone to ITRS. The influencing factors including males, evidence of the previous TB, and use of immunosuppressant should be considered when interpreting positive results.

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QuantiFERON-TB Gold Plus (QFT-Plus) is an emerging QuantiFERON test after QuantiFERON-TB Gold In-Tube (QFT-GIT) for tuberculosis infection detection; it is an IFN-γ release assay. We compared QFTPlus, which has an additional TB antigen 2 (TB2) tube to induce cell-mediated (CD8+ T cell) immune responses, with QFT-GIT. We conducted this study to assess the agreement of the QFT-GIT and QFT-Plus assays in immunocompromised patients in a clinical setting. A total of 278 immunocompromised patients and 175 immunocompetent patients from different departments were continuously enrolled from August 2020 to March 2021, and each patient underwent both tests. Correlations between QFT-GIT and QFT-Plus assays showed good agreement (κ value = 0.859). Patients receiving long-term immunosuppressant therapy had the lowest concordance between QFT-GIT and QFT-Plus assays; 9 out of 11 positive latent tuberculosis infection (LTBI) cases were diagnosed by the QFT-Plus assay, implying that QFT-Plus may detect more LTBI than QFT-GIT does in these patients. Indeterminate results were associated with lower lymphocyte, CD4+ T cell, and CD8+ T cell absolute counts, and with lower CD4/CD8 ratios. In conclusion, we found that the QFT-GIT and QFT-Plus assays had high agreement not only in immunocompetent patients but also in immunocompromised patients. QFT-Plus may detect more LTBI than QFT-GIT in patients receiving long-term immunosuppressant therapy. Thresholds were established for lymphocyte absolute counts of >1.15 × 109 cells, and for CD4+ T cell absolute counts of >467.7 × 106 to 478.5 × 106 cells, which may lessen the incidence of indeterminate results. IMPORTANCE This study evaluated the performance of QFT-GIT and QFT-Plus in the diagnosis of M. tuberculosis infection in immunocompromised patients and found that QFT-Plus may detect more LTBI than QFT-GIT does in patients receiving long-term immunosuppressant therapy. We believe that our study makes a significant contribution to the literature because it highlights the different diagnostic accuracies of QFT-GIT and QFT-Plus in different subpopulations of immunocompromised and immunocompetent patients. Selecting a test with better performance, particularly in patients with a high risk of developing active TB, may assist the health sector in better managing TB. Furthermore, we believe that this study will be of significance to the diagnosis of LTBI.

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Background: QuantiFERON-TB-Gold-in-tube (QFT-GIT) is an interferon-gamma release assay (IGRA) used to diagnose latent tuberculosis infection. Limited data exists on performance of QuantiFERON-TB Gold-Plus (QFT-Plus), a next generation of IGRA that includes an additional antigen tube 2 (TB2) while excluding TB7.7 from antigen tube 1 (TB1), to measure TB specific CD4+ and CD8+ T lymphocytes responses. We compared agreement between QFT-Plus and QFT-GIT among highly TB exposed goldminers in South Africa. Methods: We enrolled HIV-negative goldminers in South Africa, aged ≥33 years with no prior history of TB disease or evidence of silicosis. Blood samples were collected for QFT-GIT and QFT-Plus. QFT-GIT was considered positive if TB1 tested positive; while QFT-Plus was positive if both or either TB1 or TB2 tested positive, as per manufacturer's recommendations. We compared the agreement between QFT-Plus and QFT-GIT using Cohen's Kappa. To assess the specific contribution of CD8+ T-cells, we used TB2-TB1 differential values as an indirect estimate. A cut-off value was set at 0.6. Logistic regression was used to identify factors associated with having TB2-TB1>0.6 difference on QFT-Plus. Results: Of 349 enrolled participants, 304 had QFT-Plus and QFT-GIT results: 205 (68%) were positive on both assays; 83 (27%) were negative on both assays while 16 (5%) had discordant results. Overall, there was 94.7% (288/304) agreement between QFT-Plus and QFT-GIT (Kappa = 0.87). 214 had positive QFT-Plus result, of whom 202 [94.4%, median interquartile range (IQR): 3.06 (1.31, 7.00)] were positive on TB1 and 205 [95.8%, median (IQR): 3.25 (1.53, 8.02)] were positive on TB2. A TB2-TB1>0.6 difference was observed in 16.4% (35/214), with some evidence of a difference by BMI; 14.9% (7/47), 9.8% (9/92) and 25.3% (19/75) for BMI of 18.5-24.9, 18.5-25 and >30 kg/m 2, respectively (P=0.03). Conclusion: In a population of HIV-negative goldminers, QFT-Plus showed high agreement with QFT-GIT, suggesting similar performance.

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INTRODUCTION: The new-generation QuantiFERON (QFT)-TB Gold Plus (QFT-Plus) is expected to be useful because it includes a new peptide that is supposed to induce a CD8+ T cell response. There is a need for a new marker with sensitivity higher than that of the conventional IFN-γ release assays owing to false-negative results in the latter. This study aimed to compare cytokines in QFT-plus and QuantiFERON-Gold In-Tube (QFT-GIT) supernatants to discriminate between active tuberculosis and latent tuberculosis infection (LTBI). METHODS: A cross-sectional study was conducted at Tokyo National Hospital, wherein 21 LTBI patients and age and sex-matched active TB patients were randomly selected. The levels of various cytokines were measured and compared using the MAGPIX System, and receiver operating characteristic (ROC) curves were generated. RESULTS: IL-1RA, IFN-γ, CXCL10/IP-10, and CCL4/MIP-1ß levels were higher in the active TB group than in the LTBI group in QFT-GIT antigen (GIT Ag) tubes. In QFT-plus tubes, IL-1RA was higher in TB1 and TB2 tubes, while CCL2/MCP-1 was higher only in TB2 tubes. In Nil tubes, CCL5/RANTES, TNF-α, PDGF-BB, and IL-2 levels were significantly higher in the active TB group. IL-1RA in GIT Ag tubes showed the highest area under the curve of 0.8367. The sensitivity and specificity of IL-1RA were 66.7% (95% confidence interval [CI]: 43.0-85.4) and 90.5% (95% CI: 69.6-98.8), respectively, which were the highest among the cytokines. CONCLUSIONS: IL-1RA level in the QFT-GIT supernatant can be a good marker for discriminating active TB from LTBI.

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OBJECTIVE: QFT-Plus's newly added antigen elicited a specific CD8 T-cell response, which is closely related to active TB (ATB), and the IGRA based on Heparin-binding haemagglutinin (HBHA-IGRA) is a promising tool in latent tuberculosis infection (LTBI) diagnosis. The objective of our study is to evaluate whether the combination of QFT-Plus and HBHA-IGRA can improve the diagnosis accuracy of ATB and LTBI. METHODS: 135 healthcare workers (HCWs) and 57 patients with active pulmonary TB in a Chinese TB Hospital were recruited, HCWs underwent screening for LTBI using the QFT-Plus assay. Flow cytometry was used to analyze the distribution of peripheral blood T lymphocyte subsets in active TB patients with positive culture result. Then, the patients with ATB, individuals with LTBI and healthy TB-uninfected controls (HC) were tested by QFT-Plus and HBHA-IGRA respectively, and the efficiency of distinguishing LTBI from ATB by QFT-Plus and HBHA-IGRA were evaluated by Receiver Operating Characteristic (ROC) curves. RESULTS: QFT-Plus TB2-TB1 which was positively correlated with CD8 T-cell response (r = 0.731, P < 0.001) in peripheral blood was significantly higher in ATB than LTBI and HC (median 0.47 IU/mL versus 0.02 IU/mL and 0.00 IU/mL, respectively; both P < 0.0001). While the HBHA-induced IFN-γ response did not differ between ATB and HC (median 12.12 pg/mL versus 10.95 pg/mL; P = 0.463), but was significantly higher in the LTBI (median 69.67 pg/mL; both P < 0.0001). The ROC area under the curve (AUC) for identifying ATB and LTBI was 0.769 (95% CI: 0.652-0.886; P = 0.0001) for QFT-Plus TB2-TB1, and 0.886 (95% CI:0.791-0.982; P＜0.0001) for HBHA-IGRA. After combining the HBHA-IGRA with QFT-Plus results, the accuracy of identifying ATB and LTBI was improved to 85.7% from 74.3%. CONCLUSIONS: HBHA-based IGRA better differentiates between LTBI and ATB compared to QFT-Plus CD8 T-cell response. In addition, combining HBHA-IGRA and QFT-Plus improves the accuracy of identifying tuberculosis disease status.

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BACKGROUND: The objectives were to estimate the prevalence of latent tuberculosis infection (LTBI) among household contacts (HHCs) with active TB patients, and to identify their risk factors. METHODS: A prospective, cross sectional study was conducted from May to October 2018. All HHCs with active TB cases were included. The subjects underwent two tests: Quantiferon TB-Gold plus assay (QFT-Plus) and tuberculin skin test (TST). Data were analyzed using the Statistical Package for Social Sciences 25. RESULTS: Among 521 HHCs, 101 (24.05%) revealed positive TST and 80 (19.85%) positive QFT-Plus. The significant risk factors associated with positive TST individuals were ≥ 15 years, immunosuppressive therapy, and pulmonary TB (PTB) patients; whereas, those with QFT-Plus positive were ≥ 45 years, alcohol consumption, and immunosuppressive therapy. The concordance rate among 309 individuals who performed both tests was 0.88 %; the kappa value showed good agreement (k = 0.679) and significant correlation (P < 0.001). CONCLUSIONS: The overall rate of LTBI was intermediate. Screening of LTBI should be routine among HHCs, regardless of the site of the disease. Age ≥ 15 years, alcoholics, immunosuppressive therapy, and PTB were potential risk factors. There was a good concordance between TST and QFT-Plus. A QFT-Plus can overcome the limitation of a BCG vaccinated individual, especially in early life.

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OBJECTIVES: A recently released new QuantiFERON (QFT) product, QFT TB Gold plus (QFT-plus), is optimized for both CD4 and CD8 responses and reported to have higher sensitivity compared to the former QFT-3 G. Previously, using supernatants of QFT-3 G, we and others have demonstrated that cytokines other than IFN-γ may be useful in diagnosing tuberculosis. The present study aimed to identify cytokines that are useful for accurately diagnosing active tuberculosis by using QFT-plus and compared the data to those with QFT-3 G. METHODS: Eighty-three active tuberculosis patients and 70 healthy control subjects who were examined by QFT at Tokyo National Hospital from June 2017 to July 2018 were enrolled. QFT-3 G and QFT-plus were performed according to the manufacturer's instructions. At the same time, blood cell culture supernatants were collected and assayed for their cytokine levels using R&D Systems Luminex Assay and MAGPIX System. The levels of cytokines were compared between different antigen-containing tubes (3 G Ag, TB1 and TB2 tubes), as well as between the patients and the control subjects. ROC curves were drawn, and the AUCs were calculated. RESULTS: Five cytokines, i.e., IL-2, IL-6, IL-8, IP-10 and MIP-1ß, produced by human blood cells in three independent tubes containing different tuberculosis antigens were higher in the 3 G Ag tube compared to both the TB1 and TB2 tubes. Further, when the TB1 and TB2 tubes were compared, TB2 showed greater production of only PDGF-BB, and less production of IL-6 and TNF-α. For diagnosing active tuberculosis, the levels of IP-10 were superior to the level of IFN-γ based on showing a larger AUC for ROC curves in our present study setting. Finally, the levels of IFN-γ, IL-1RA, IL-2, IP-10, MCP-1 and MIP-1ß were distinctly different between the active tuberculosis patients and healthy controls. CONCLUSIONS: In summary, there was no cytokine that was higher in the tubes of QFT-plus compared to the tube of QFT-3 G, suggesting inferiority of QFT-plus antigens to 3 G Ag in terms of elicitation of cytokine production. Our results also suggest the usefulness of cytokines that showed a significant difference between the active tuberculosis patients and the healthy controls-namely, IFN-γ, IL-1RA, IL-2, IP-10, MCP-1 and MIP-1ß-for diagnosing tuberculosis, but the roles of these cytokines in the pathogenesis of tuberculosis need to be elucidated (UMIN000035253).

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The QuantiFERON-TB Gold plus (QFT-Plus) assay, an interferon gamma (IFN-γ) release assay (IGRA), was recently introduced as the next version of the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay for diagnosing latent tuberculosis (TB). Whereas the QFT-GIT assay uses only one TB tube that induces a cell-mediated immune (CMI) response of CD4+ T cells, the QFT-Plus has an additional TB antigen 2 tube (TB2) for the CMI response of CD8+ T and CD4+ T cells, in addition to a TB antigen 1 (TB1) tube for the CMI response of CD4+ T cells only. We compared the results of the QFT-Plus and QFT-GIT assays as routine clinical tests for diagnosing TB. Samples from 220 patients referred for routine IGRA in various clinical departments were used. Correlations between IFN-γ levels in the QFT-GIT and QFT-Plus assays were strong and showed good agreement (kappa value = 0.69). Seven cases with positive QFT-GIT assay results and negative QFT-Plus assay results showed IFN-γ values near the cutoff value. However, 10 cases with active TB, recent TB, or immune problems showed discordance with the positive results only in the TB2 tube in QFT-Plus, unlike the negative results in TB1 and TB tubes. In these cases, IFN-γ levels in the TB2 tube were significantly higher than those in other tubes. This is the first study to compare these assays as routine IGRAs in the clinical setting. The QFT-Plus assay showed good agreement with the QFT-GIT assay and is presumably advantageous for patients with active TB, recent TB, and specific immune conditions involving CD8+ T-cell responses.

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Tuberculosis (TB) is one of the leading infectious causes of death worldwide and despite the progress recently made in TB control at a global level, the decline in its incidence is still slow. It is therefore crucial to evaluate the performance of new tools for monitoring of TB treatment. The aim of this study was to evaluate the response to tuberculosis treatment using the QuantiFERON-TB Gold Plus (QFT-Plus) kit. Blood samples of 100 patients with active TB were taken before treatment and after three months, if treatment was successful and sputum culture was negative. Whole blood was incubated in the presence or absence of the TB antigens, TB1 and TB2-specific antigens, and the production of IFN-γ was determined using the QuantiFERON-TB Gold Plus (QFT-Plus) test. The data were analyzed using SPSS 16 software and statistical significance was assessed at a two-tailed P value of 0.05. The median values of IFN-γ released following stimulation with TB1 peptides decreased slightly after treatment (2.5 IU/mL (IQR: 0.9-5.3), compared to the baseline (3.4 IU/mL (IQR: 0.5-6.6)). Also, with respect to the TB1 antigen, 38 out of 45 patients were positive for the QFT test before treatment (84.4%) and 37 cases after treatment (82.2%). On the other hand, the median values of IFN-γ determined with the TB2 test declined marginally after treatment (2.7 IU/mL; IQR: 0.95-5.8), as compared to pretreatment (3.0 IU/mL; IQR: 0.7-8.9). Thirty-nine out of 45 patients (86.7%) before initiation of treatment and 37 cases following a 3-month treatment (82.2%) were had positive values. Moreover, the median values of IFN-γ of TB2 minus TB1 before and after treatment were 0.17 (IQR: 0-1.0) and 0.03 (IQR: 0.0.48), respectively; however, these differences were not significant (p value=0.29). Conclusion: The results of this study show no significant differences between the IFN-γ release in TB patients prior to and after treatment. However, more extensive studies are needed in different populations with higher sample sizes to validate these results.

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The fourth-generation QuantiFERON test for tuberculosis infection, QuantiFERON-TB Gold Plus (QFT-Plus) has replaced the earlier version, QuantiFERON-TB Gold In-Tube (QFT-GIT). A clinical need exists for information about agreement between QFT-Plus and other tests. We conducted this study to assess agreement of test results for QFT-Plus with those of QuantiFERON-TB Gold In-Tube (QFT-GIT), T-SPOT.TB (T-SPOT), and the tuberculin skin test (TST). Persons at high risk of latent tuberculosis infection (LTBI) and/or progression to tuberculosis (TB) disease were enrolled at the 10 sites of the Tuberculosis Epidemiologic Studies Consortium from October 2016 through May 2017; each participant received all four tests. Cohen's kappa (κ) and Wilcoxon signed-rank test compared qualitative and quantitative results of QFT-Plus with the other tests. Test results for 506 participants showed 94% agreement between QFT-Plus and QFT-GIT, with 19% positive and 75% negative results. When the tests disagreed, it was most often in the direction of QFT-GIT negative/QFT-Plus positive. QFT-Plus had similar concordance as QFT-GIT with TST (77% and 77%, respectively) and T-SPOT (92% and 91%, respectively). The study showed high agreement between QFT-GIT and QFT-Plus in a direct comparison. Both tests had similar agreement with TST and T-SPOT.

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

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The new QuantiFERON-TB Gold Plus employs modified peptides optimized to elicit an IFNγ response from CD8+ cytotoxic T lymphocytes in addition to CD4+ T cells. With a view to improve the difficult identification of TB cases, we assessed the combination of two specific immunological markers comprising IFNγ secretion and T cells co-expression of CD25 and CD134 in response to Mycobacterium tuberculosis-specific antigens. A total of 34 subjects with suspected TB and 10 age-matched HD were prospectively enrolled. Assessing the performance of QFT-Plus in terms of the TB1 and TB2 results, we found that in TB patients, the quantitative IFNγ value in TB2 was similar to that in TB1, and we did not find any differences irrespective of the disease (pulmonary or extra-pulmonary). The flow cytometric CD25/CD134 assay, allowed a more accurate differentiation between M. tuberculosis-infected and uninfected patients, with a better combination of sensitivity and specificity, especially by evaluation of CD4+ T-cell subset. All individuals with negative QFT-Plus results displayed a positive CD25/CD134 response. Overall, a positive correlation was found between T cells co-expressing CD25/CD134 and IFNγ levels in response to both QFT-Plus TB antigen tubes, as well as between the QFT-Plus TB1 and TB2 tubes. We demonstrated that both TB1 and TB2 induce a higher expression of CD25+CD134+ markers on CD4+ T cells among infected TB subjects, compared to the lower degree of CD8+ T cells, mainly induced to TB2 stimulation. We suggest that a combined use of classic QFT-Plus and specific CD25/CD134 response may be a useful means in the diagnostic workup for active TB.

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