Predictors of persistently positive Mycobacterium-tuberculosis-specific interferon-gamma responses in the serial testing of health care workers

Abstract

BackgroundData on the performance of Mycobacterium-tuberculosis-specific interferon-(IFN)-γ release assays (IGRAs) in the serial testing of health care workers (HCWs) is limited. The objective of the present study was to determine the frequency of IGRA conversions and reversions and to identify predictors of persistent IGRA positivity among serially tested German HCWs in the absence of recent extensive tuberculosis (TB) exposure.MethodsIn this observational cohort-study HCWs were prospectively recruited within occupational safety and health measures and underwent a tuberculin skin test (TST) and the IGRA QuantiFERON®-TB Gold In-Tube (QFT-GIT) at baseline. The QFT-GIT was repeated 18 weeks later in the median. QFT-GIT conversions (and reversions) were defined as baseline IFN-γ < 0.35 IU/ml and follow-up IFN-γ ≥ 0.35 IU/ml (and vice versa). Predictors of persistently positive QFT-GIT results were calculated by logistic regression analysis.ResultsIn total, 18 (9.9%) and 15 (8.2%) of 182 analyzed HCWs were QFT-GIT-positive at baseline and at follow-up, respectively. We observed a strong overall agreement between baseline and follow-up QFT-GIT results (κ = 0.70). Reversions (6/18, 33.3%) occurred more frequently than conversions (3/162, 1.9%). Age and positive prior and recent TST results independently predicted persistent QFT-GIT positivity. Furthermore, the chance of having persistently positive QFT-GIT results raised about 3% with each additional 0.1 IU/ml increase in the baseline IFN-γ response (adjusted odds ratio 1.03, 95% confidence interval 1.01-1.04). No active TB cases were detected within an observational period of more than two years.ConclusionsThe QFT-GIT's utility for the application in serial testing was limited by a substantial proportion of reversions. This shortcoming could be overcome by the implementation of a borderline zone for the interpretation of QFT-GIT results. However, further studies are needed to clearly define the within-subject variability of the QFT-GIT and to confirm that increasing age, concordantly positive TST results, and the extend of baseline IFN-γ responses may predict the persistence of QFT-GIT positivity over time in serially tested HCWs with only a low or medium TB screening risk in a TB low-incidence setting.

Within-Subject Variability of Mycobacterium tuberculosis-Specific Gamma Interferon Responses in German Health Care Workers

“…The extent of within-subject variability that we determined approximates the proposed borderline zones. Three recent serial testing studies among German and Portuguese HCWs demonstrated that the implementation of a QFT borderline zone of 0.2 to 0.7 IU/ml may safely reduce the rate of inconsistent results (26,29,31). For the T-SPOT, evidence for the safety of a specific borderline zone is sparse.…”

“…The present study was conducted at the University Hospital Bergmannsheil in Bochum, Germany, between July 2010 and February 2011. All IGRAs were performed at the Pulmonary Research Laboratory by a team with profound experience in IGRA research (26,27). Eligible HCWs were recruited prospectively by an occupational physician.…”

“…Studies on reproducibility and within-subject variability were predominantly from high-incidence settings (India and South Africa) and included only small numbers of subjects (67 in total) (6,32,34). In contrast, serial testing studies were mostly from countries with a low to intermediate TB incidence (5,13,20,(24)(25)(26)36). Across the board, these studies indicate that IGRA conversions and reversions occur at variable rates due to significant variability and that the manufacturers' simplistic dichotomous negative-to-positive cutoffs may not be appropriate for the interpretation of repeat IGRA results.…”

Simultaneous and Longitudinal Comparison of Interferon Gamma Release Assay Data from Health Care Workers in Japan

“…However, use of the more sensitive QFT-GIT test in the present study diagnosed 25% of subjects with LTBI; this proportion is very much higher than that of the general population [22]. A recent systematic review of the utility of IGRA assays used to screen HCW for TB showed that the initial positivity rate was 1.3-31.0%; the analysis included data from countries where the incidence of TB is high [7]. Such variation is attributable to differences in sample sizes and the backgrounds of HCW among the studies; the extent of involvement and contact with TB patients, administration of chemo-prophylaxis, and years of work with TB patients, will have varied significantly among the studies.…”

“…One practical way to control TB is routine screening of HCW for latent tuberculosis infections (LTBIs) and administration of chemoprophylaxis to HCW suspected to have LTBIs. Therefore, evaluation of Mycobacterium tuberculosis (Mtb) infective status is crucial in HCW working in hospitals dedicated to TB patients [2,7,8]. In such contexts, screening of HCW should be routine and data should be evaluated longitudinally [2,9].…”