Although launched in 2015, little is known about the accuracy of QuantiFERON-TB Gold-Plus (QFT-Plus) for diagnosis of latent M. tuberculosis infection (LTBI). Unlike its predecessor, QFT-Plus utilizes two antigen tubes to elicit an immune response from CD4 ϩ and CD8 ϩ T lymphocytes. We conducted a crosssectional study in low-risk health care workers (HCWs) at a single U.S. center to compare QFT-Plus to QuantiFERON-TB Gold in-tube (QFT). A total of 989 HCWs were tested with both QFT and QFT-Plus. Risk factors for LTBI were obtained from a questionnaire. QFT-Plus was considered positive if either antigen tube 1 (TB1) or TB2 tested positive, per the manufacturer's recommendations, or if both TB1 and TB2 tested positive, using a conservative definition. Results were compared using Cohen's kappa and linear regression, respectively. Agreement of QFT with QFT-Plus was high, at 95.6% (95% confidence interval [CI], 94.3 to 96.9; kappa, 0.57). The majority of discordant results between QFT and QFT-Plus TB1 (84.8%) and QFT and QFT-Plus TB2 (88.6%) fell within the range of 0.2 to 0.7 IU/ml. The positivity rate in 626 HCWs with no identifiable risk factors and no self-reported history of positive LTBI tests was 2.1% (CI, 1.0 to 3.2) and 3.0% (CI, 1.7 to 4.3) with QFT and QFT-Plus, respectively. A conservative definition of a QFT-Plus-positive result yielded a positivity rate of 1.0% (CI, 0.2 to 1.7; P value of 0.0002 versus QFT-Plus and 0.07 versus QFT). On follow-up testing, of 11 HCWs with discordant QFT-Plus results, 90.9% (10/11) had a negative QFT result. The QFT-Plus assay showed a high degree of agreement with QFT in U.S. HCWs. A conservative interpretation of QFT-Plus eliminated nearly all nonreproducible positive results in low-risk HCWs. Larger studies are needed to validate the latter finding and to more clearly define conditions under which a conservative interpretation can be used to minimize nonreproducible positive results in low-risk populations.
KEYWORDS latent infection, tuberculosisH ere, we report a significant increase in positivity rate among low-risk health care workers (HCW) undergoing annual tuberculosis (TB) testing in our health system after the fourth-generation QuantiFERON-TB Gold Plus (QFT-Plus) assay replaced the QuantiFERON-TB Gold (QFT) assay. Compared to its predecessor, which stimulates only CD4 ϩ T-lymphocytes in a single TB antigen tube (TB1), the QFT-Plus assay includes a second TB antigen tube (TB2) with a peptide formulation designed to stimulate both CD4 ϩ and CD8 ϩ T-lymphocytes. As recommended by the manufacturer, the QFT-Plus assay is considered positive if either antigen tube (TB1 and/or TB2) result is positive.The QFT-Plus assay replaced the QFT assay in North America on 30 June 2018. After 11 years of use of the QFT assay for occupational testing, our institution switched to the QFT-Plus assay on 16 July 2018. Within weeks, our occupational health staff noticed increases in the number of health visits for medical evaluation and retesting in HCW with positive test results.To investigate this, we conducted a retrospective review of HCW tested with the QFT-Plus assay from 16 July 2018 to 4 September 2018 and compared the rates to those in HCW tested with the QFT assay from the exact same time period in 2017. The HCW QFT-Plus positivity rate was significantly increased compared to that of the QFT assay, with 3.5% (95/2,720) positive in 2018 compared to 2.2% (60/2,748) in 2017 (95% confidence interval [CI] of difference, 0.4 to 2.2%, p ϭ 0.003) ( Fig. 1). Of the 95 positive tests with the QFT-Plus assay, 19 (20.0%) were positive by TB1 only, and 31 (32.6%) were positive by TB2 only. QFT-Plus testing was repeated in 49 patients; of these, only 12 (24.5%) were positive. Using a previously suggested conservative interpretation (positive only if TB1 and TB2 positive) in low-risk HCW (1), the QFT-Plus positivity rate would have been 1.7% (45/2,720), which is more comparable to 2017 QFT positivity rates.Although concerning, this is not the first time we have experienced higher positivity rates for annual TB screening after adoption of a new gamma interferon (IFN-␥) release assay (IGRA). Shortly after QFT was approved by the U.S. Food and Drug Administration (FDA) in 2005 as a replacement for the tuberculin skin test (TST), many North American health systems, including ours ( Fig. 1) (2), started to report unusually high conversion rates with the QFT assay in low-risk HCW, compared with concurrent or historical TST rates (3). Our QFT assay conversion rate has fallen in the recent years (Fig. 1) as a result of preanalytical standardization and manufacturer quality assurance (4).The QFT-Plus assay was introduced on the IGRA market with the touted advantage of better sensitivity than its predecessor in immunocompromised hosts and after recent exposure. However, studies that have compared the QFT-Plus assay to the QFT assay have shown similar sensitivity in patients with active TB and similar test performance in Citation Hogan CA, Tien S, P...
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