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      Evaluation of QuantiFERON-TB Gold Plus for Predicting Incident Tuberculosis among Recent Contacts: A Prospective Cohort Study

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          Abstract

          To the Editor: Screening for latent tuberculosis infection (LTBI) among recent tuberculosis (TB) contacts is an important component of TB control, particularly in settings with low TB incidence aiming toward pre-elimination (1). However, currently available LTBI diagnostics lack sensitivity and have poor predictive value for incident TB (2–8). Consequently, prevention of one incident TB case requires treatment of many individuals for LTBI. This is true for both interferon-γ release assays (IGRAs) and the tuberculin skin test (TST). A recent evaluation found that QuantiFERON Gold-In-Tube (QFT-GIT; Qiagen) and T-SPOT.TB (Oxford Immunotec) performed similarly to the TST when a Bacillus Calmette–Guerin vaccination-stratified TST cutoff was used (8).  A new-generation QuantiFERON (QuantiFERON-TB Gold Plus; QFT-Plus) was recently launched, adding a second TB antigen tube (TB2) that incorporates short peptides designed to stimulate a CD8+ T-cell response, in addition to the CD4+-response tube (TB1) included in previous versions. The proposed rationale for this is that CD8+ responses have been associated with mycobacterial load and recent TB exposure (9, 10). Initial independent evaluations have suggested that QFT-Plus may have improved test sensitivity in active TB compared with QFT-GIT (11), and that the CD8+-targeted antigen tube response may be associated with proxy measures of the degree of TB exposure among contacts (12). However, no studies have examined the prognostic value of QFT-Plus for predicting incident TB. We aimed to address this key knowledge gap in a prospective cohort of TB contacts in the United Kingdom. Methods We recruited adult (≥16 yr old) contacts of pulmonary and extrapulmonary TB index cases from 10 London TB clinics while attending for routine contact screening (July 7, 2015 to November 22, 2016). Participants completed a questionnaire and underwent blood sampling for QFT-Plus (at least 6 weeks from the last known TB exposure). Contacts with evidence of prevalent TB disease (defined as TB diagnosed within 21 days of enrollment, as per previous work [8]) and those who accepted preventive therapy (offered in accordance with contemporary national guidance [13, 14]) were excluded from the analysis. The study was approved by the UK National Research Ethics Service (ref: 14/EM/1208). Participants were linked to national TB surveillance records held by Public Health England, including all statutory TB notifications, to identify those notified with TB (until December 31, 2017). TB notifications were validated by local record review and included those with culture-confirmed TB or a clinical diagnosis with radiological or histological evidence of TB, for which a clinician had prescribed a full course of anti-TB treatment. The QFT-Plus results were interpreted according to the manufacturer’s guidance, with TB antigen responses calculated as TB antigen interferon-γ minus unstimulated control interferon-γ. We calculated incidence rates and rate ratios (IRRs) relative to the negative test category, along with sensitivity, specificity, and predictive values, including the full duration of follow-up. To assess the incremental value of adding the CD8+-stimulating tube in predicting incident TB cases, we compared receiver operating characteristic (ROC) curves and area under the curve (AUC) values obtained using TB1 only, TB2 only, and the maximal TB antigen tube (higher of TB1 and TB2). We also plotted a ROC curve for the calculated difference between the TB1 and TB2 tubes (TB2 − TB1) as a surrogate for the CD8+-specific response, as it has been hypothesized that this may identify contacts with recently acquired Mycobacterium tuberculosis infection, who are at the highest risk of TB disease (12). Results We recruited a total of 623 contacts, 532 (85.4%) of whom had QFT-Plus results (89 missing and 2 indeterminate) and were followed for a median 1.93 years (interquartile range [IQR] 1.65–2.21 yr). QFT-Plus results were positive in 180 of the 532 contacts (33.8%) (Table 1), and 39 (21.7%) of these participants commenced preventive therapy. One patient was notified with prevalent TB (3 days after recruitment). A total of 492 participants were therefore included in the analysis. The included and excluded participants had similar baseline characteristics, except that those who commenced preventive therapy were younger than those who did not (Table 1). Table 1. Baseline characteristics of the study cohort, stratified by Quantiferon-TB Gold Plus results and provision of preventive therapy   QFT-Plus Negative* QFT-Plus Positive QFT-Plus Missing † All No PT* PT Age            Median (IQR) 31 (25–43) 43 (32–54) 30 (26–35) 31.5 (23.7–49) 33 (25–46)  Missing 3 (0.9) 2 (1.4) 0 (0) 1 (1.1) 6 (1)             Sex            Male 165 (46.9) 76 (53.9) 24 (61.5) 37 (40.7) 302 (48.5)  Female 180 (51.1) 62 (44) 15 (38.5) 51 (56) 308 (49.4)  Missing 7 (2) 3 (2.1) 0 (0) 3 (3.3) 13 (2.1)             Ethnicity            White 95 (27) 27 (19.1) 9 (23.1) 31 (34.1) 162 (26)  South Asian 117 (33.2) 55 (39) 13 (33.3) 33 (36.3) 218 (35)  Black African or Caribbean 67 (19) 30 (21.3) 7 (17.9) 15 (16.5) 119 (19.1)  Other 63 (17.9) 24 (17) 10 (25.6) 9 (9.9) 106 (17)  Missing 10 (2.8) 5 (3.5) 0 (0) 3 (3.3) 18 (2.9)             UK born            No 235 (66.8) 126 (89.4) 33 (84.6) 66 (72.5) 460 (73.8)  Yes 111 (31.5) 11 (7.8) 6 (15.4) 24 (26.4) 152 (24.4)  Missing 6 (1.7) 4 (2.8) 0 (0) 1 (1.1) 11 (1.8)             Contact type            Household 210 (59.7) 96 (68.1) 30 (76.9) 49 (53.8) 385 (61.8)  Family nonhousehold 19 (5.4) 7 (5) 2 (5.1) 3 (3.3) 31 (5)  Work or social 62 (17.6) 19 (13.5) 4 (10.3) 14 (15.4) 99 (15.9)  Other 13 (3.7) 3 (2.1) 2 (5.1) 2 (2.2) 20 (3.2)  Missing 48 (13.6) 16 (11.3) 1 (2.6) 23 (25.3) 88 (14.1)             Diabetes            No 318 (90.3) 120 (85.1) 38 (97.4) 83 (91.2) 559 (89.7)  Yes 20 (5.7) 18 (12.8) 0 (0) 6 (6.6) 44 (7.1)  Missing 14 (4) 3 (2.1) 1 (2.6) 2 (2.2) 20 (3.2)             HIV            No 331 (94) 137 (97.2) 37 (94.9) 84 (92.3) 589 (94.5)  Yes 4 (1.1) 0 (0) 1 (2.6) 2 (2.2) 7 (1.1)  Missing 17 (4.8) 4 (2.8) 1 (2.6) 5 (5.5) 27 (4.3)             Follow-up, yr            Median (IQR) 1.94 (1.64–2.21) 1.92 (1.66–2.21) 1.85 (1.67–2.25) 1.56 (1.25– 2.06) 1.88 (1.58–2.20)             Total 352 141 39 91 623 Definition of abbreviations: HIV = human immunodeficiency virus; IQR = interquartile range; PT = preventive therapy; QFT-Plus = QuantiFERON-TB Gold Plus. Data are presented as n (%) unless stated otherwise. * Included in the primary analysis. † Includes two patients with indeterminate QFT-Plus results. Ten patients with incident TB were notified during follow-up (median 222 days after recruitment; range 90–688). Among these patients, the median age was 27 (IQR 21–33), three (30%) were female, the majority (7/10; 70%) were of black African or South Asian ethnicity, and all were non-UK born. All 10 patients completed at least 6 months of TB therapy. Two of these cases (20.0%) were pulmonary in site (both were culture confirmed), and eight were exclusively extrapulmonary (two of which were culture confirmed). One participant with TB was diabetic; the remaining patients with TB were not immunocompromised, and none were infected with human immunodeficiency virus. The TB incidence rates (per 1,000 person-years) were 30.6 (95% confidence interval [CI], 15.3–61.1) and 3.0 (95% CI, 0.8–12.1) in the QFT-Plus–positive and –negative groups, respectively (IRR, 10.1 [95% CI, 2.2–47.7]). The sensitivity of QFT-Plus for incident TB was 80.0% (95% CI, 44.4–97.5). The positive predictive value (PPV) and negative predictive value were 5.7% (95% CI, 2.5–10.9) and 99.4% (95% CI, 98.0–99.9), respectively. The characteristics of QFT-Plus for predicting microbiologically confirmed TB cases are reported in Table 2. Table 2. Incidence rates, rate ratios, and predictive values for incident tuberculosis during follow-up, stratified by Quantiferon-TB Gold Plus results   QFT-Plus Positive QFT-Plus Negative No. of TB cases (microbiologically confirmed and/or clinically diagnosed) 8 2 Participants 140 352 Person-years 261.6 663.0 Incidence rate per 1,000 person-years 30.6 (15.3–61.1) 3.0 (0.8–12.1) Incidence rate ratio 10.1 (2.2–47.7) Positive predictive value 5.7 (2.5–10.9) Negative predictive value 99.4 (98–99.9) Sensitivity 80.0 (44.4–97.5) Specificity 72.6 (68.4–76.5)     No. of TB cases (microbiologically confirmed only) 3 1 Incidence rate per 1,000 person-years 11.5 (3.7–35.6) 1.5 (0.2–10.7) Incidence rate ratio 7.6 (0.8–73.1) Positive predictive value 2.1 (0.4–6.1) Negative predictive value 99.7 (98.4–100) Sensitivity 75.0 (19.4–99.4) Specificity 71.9 (67.7–75.9) Definition of abbreviations: QFT-Plus = QuantiFERON-TB Gold Plus; TB = tuberculosis. ROC curves for prediction of incident TB during all follow-up were similar for the TB1, TB2, and maximal TB antigen responses (AUC 0.80–0.82; Figure 1A). TB2 minus TB1, however, did not discriminate TB progressors from nonprogressors (AUC 0.44 [95% CI, 0.20–0.68]). There was a very strong correlation between the TB1 and TB2 interferon-γ responses (r = 0.993; P < 0.001; Figure 1B). Figure 1. (A) Receiver operating characteristic curves showing the performance of QuantiFERON-TB Gold Plus for predicting incident tuberculosis during the duration of follow-up, stratified by antigen tube interferon-γ responses. TB max = higher of the CD4+-response tube (TB1) and CD8+-response tube (TB2). AUC = area under the curve (95% confidence interval). (B) Scatterplot showing association of interferon-γ responses in the TB1 and TB2 tubes. Discussion We found that the performance of QFT-Plus appeared to be comparable to that previously reported in evaluations of QFT-GIT and T-SPOT.TB, with an IRR of 10.1, 80% sensitivity for detection of incident TB, and an overall PPV for incident TB of 5.7% (8). Interferon-γ responses in the TB1 and TB2 tubes were strongly correlated, and ROC curves showed a minimal difference between them for predicting incident TB. As a result, the calculated difference between TB1 and TB2 responses, as a proxy for the CD8-specific response, did not predict incident TB. However, despite our sample size of 492 recent TB contacts, the number of TB progressors was small, reflecting a low progression risk even among contacts. Thus, a larger-scale study is indicated to investigate subtle differences in the relative prognostic contributions of the TB1 and TB2 antigen tubes. This is the first evaluation of the prognostic value of the QFT-Plus test. The prospective design allowed the collection of detailed clinical, demographic, and laboratory data. We recruited participants while they were receiving routine contact-tracing services, to ensure that the study population would be representative of TB contacts. Therefore, our findings are likely generalizable to other low-incidence settings globally. Moreover, follow-up was robust through linkage to national surveillance records using a validated matching algorithm (15), minimizing the risk of missing incident TB cases. A limitation of this study is that the provision of preventive therapy to a subset of the QFT-Plus–positive patients could have led to selection bias. However, although the patients who received preventive therapy were younger than those who did not (reflecting national policy at the time of the study [13, 14]), other characteristics were similar between the two groups, suggesting that the impact of this bias was likely small. Second, the TB contacts included both pulmonary and extrapulmonary index cases, reflecting national contact screening policy during the study period (13). The PPV of QFT-Plus may be higher among populations that include only pulmonary TB contacts, owing to a higher pretest probability of incident TB. However, previous evaluations of QFT-GIT and T-SPOT.TB also included extrapulmonary contacts, which allows the current findings to be put into this context (8). Third, we did not perform serial testing (before and after exposure), so we were unable to assess QFT-Plus conversions over time, which may provide a more reliable measure of recent M. tuberculosis infection. This reflects the reality of contact screening practices—the ability of assays to accurately stratify TB risk from a single baseline test is therefore a key attribute. The absence of serial testing also means that participants who developed incident TB may have been reexposed to M. tuberculosis during the interval between testing and disease onset, although the overall risk of exposure in the United Kingdom (a low-TB-incidence setting) is likely small. Fourth, QFT-Plus results were missing or indeterminate for 91 of 623 patients (14.6%), in keeping with the proportion of missing results for other IGRAs in our recent evaluation (8). However, these patients’ characteristics were similar to those of the overall study population, suggesting that the risk of subsequent selection bias was likely small. Finally, we included both microbiologically confirmed and clinically diagnosed TB cases in our outcome definition, in keeping with previous IGRA evaluations (3–8). The rationale for this is that extrapulmonary TB, which accounts for a large proportion of TB cases in foreign-born people living in the United Kingdom (16), is often challenging to prove microbiologically. However, all patients who received a diagnosis of TB during the study received a full course of TB therapy, and none were denotified. It is therefore likely that these represented true TB cases, with a low risk of outcome misclassification. In summary, in this first evaluation of the predictive value of QFT-Plus for incident TB, we found that its performance was comparable to that of other commercial IGRAs. Better biomarkers are required to transform management of TB contacts. Supplementary Material Supplements Author disclosures

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          Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.

          Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.
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            Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load.

            High Ag load in chronic viral infections has been associated with impairment of Ag-specific T cell responses; however, the relationship between Ag load in chronic Mycobacterium tuberculosis infection and functional capacity of M. tuberculosis-specific T cells in humans is not clear. We compared M. tuberculosis-specific T cell-associated cytokine production and proliferative capacity in peripheral blood from adults with progressively higher mycobacterial loads-that is, persons with latent M. tuberculosis infection (LTBI), with smear-negative pulmonary tuberculosis (TB), and smear-positive TB. Patients with smear-positive TB had decreased polyfunctional IFN-γ(+)IL-2(+)TNF-α(+) and IL-2-producing specific CD4 T cells and increased TNF-α single-positive cells, when compared with smear-negative TB and LTBI. TB patients also had increased frequencies of M. tuberculosis-specific CD8 T cells, compared with LTBI. M. tuberculosis-specific CD4 and CD8 T cell proliferative capacity was profoundly impaired in individuals with smear-positive TB, and correlated positively with ex vivo IFN-γ(+)IL-2(+)TNF-α(+) CD4 T cells, and inversely with TNF-α single-positive CD4 T cells. During 6 mo of anti-TB treatment, specific IFN-γ(+)IL-2(+)TNF-α(+) CD4 and CD8 T cells increased, whereas TNF-α and IFN-γ single-positive T cells decreased. These results suggest progressive impairment of M. tuberculosis-specific T cell responses with increasing mycobacterial load and recovery of responses during therapy. Furthermore, these data provide a link between specific cytokine-producing subsets and functional capacity of M. tuberculosis-specific T cells, and between the presence of specific CD8 T cells ex vivo and active TB disease. These data have potentially significant applications for the diagnosis of TB and for the identification of T cell correlates of TB disease progression.
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              Negative and positive predictive value of a whole-blood interferon-γ release assay for developing active tuberculosis: an update.

              only limited data are available on the predictive value of interferon-γ release assays for progression from latent tuberculosis infection to active tuberculosis (TB). to build on our initial study comparing the QuantiFERON-TB Gold in-tube assay (QFT) with the tuberculin skin test (TST) in close contacts of patients with TB and evaluating progression to active TB for up to 4 years. a cohort of close contacts of smear-positive index cases established between May 2005 and April 2008 was tested with QFT and TST. Through April 2010, progressors to active TB were consecutively recorded. of the 1,414 contacts (141 children), 1,033 were still resident in Hamburg at the end of the study period, and results of both tests were available for 954. QFT, but not TST, results were associated with exposure time (P < 0.0001). For QFT, 198 of 954 (20.8%) were positive; 63.3% (604) were TST positive at greater than 5 mm and 25.4% at greater than 10 mm. Nine hundred and three contacts refused chemoprevention and 19 developed active TB. All 19 (100%) had been QFT positive with a progression rate of 12.9% (19 of 147) over the observation period. Corresponding values for the TST were significantly lower: 89.5% (17 of 19) and 3.1% (17 of 555) at greater than 5 mm, and 52.6% (10 of 19) and 4.8% (10 of 207) at greater than 10 mm, respectively. The progression rate of 28.6% (6 of 21) for QFT-positive children was significantly higher than 10.3% (13 of 126) for adults (P = 0.03). results suggest that QFT is more reliable than the TST for identifying those who will soon progress to active TB, especially in children.
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                Author and article information

                Journal
                Ann Am Thorac Soc
                Ann Am Thorac Soc
                AnnalsATS
                Annals of the American Thoracic Society
                American Thoracic Society
                2329-6933
                2325-6621
                May 2020
                May 2020
                May 2020
                : 17
                : 5
                : 646-650
                Affiliations
                [ 1 ]University College London

                London, United Kingdom
                [ 2 ]Queen Mary University of London

                London, United Kingdom
                [ 3 ]Royal Free London NHS Foundation Trust

                London, United Kingdom
                [ 4 ]Public Health England Colindale

                London, United Kingdom

                and
                [ 5 ]North Middlesex University Hospital NHS Trust

                London, United Kingdom
                Author notes
                [* ]Corresponding author (e-mail: r.gupta@ 123456ucl.ac.uk ).
                Author information
                http://orcid.org/0000-0002-6257-1285
                http://orcid.org/0000-0002-0380-1116
                http://orcid.org/0000-0001-7501-4448
                http://orcid.org/0000-0002-4774-0853
                http://orcid.org/0000-0001-8544-7685
                http://orcid.org/0000-0002-0370-1430
                Article
                201905-407RL
                10.1513/AnnalsATS.201905-407RL
                7193805
                32083944
                2be7a9b8-f2c3-4e32-9f46-a5f5428257a1
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution License 4.0 ( http://creativecommons.org/licenses/by/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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