The increased risk of healthcare workers (HCWs) for tuberculosis is well established 12. Therefore screening healthcare workers (HCWs) for latent tuberculosis infection (LTBI) and active tuberculosis (TB) is fundamental in infection control programs in hospitals 3. For about a century, the Tuberculin Skin Test (TST) has been used to detect LTBI. However the TST has its known limitations, including cross-reactivity with BCG and non-tubercular mycobacteria (NTM) infections 4. Advances in molecular biology have led to the development of new in-vitro assays that measure interferon (INF)-γ released by sensitized T-cells after stimulation with M. tuberculosis antigens. These tests are more specific than the TST because they use antigens not shared by any of the BCG vaccine strains nor by the more common species of NTM (e.g. M. avium) 5. Besides the higher specificity and at least equal sensitivity as the TST, IGRAs correlate better with surrogate measures of exposure to M. tuberculosis 678 and have a higher predictive value for LTBI progression to active TB in close contacts in low-incidence settings 9.

So far several systematic investigations of LTBI in HCWs using TST and IGRA have been published 101112131415161718 showing a high proportion of TST-positive/IGRA-negative HCWs which is most likely explained by BCG vaccination. In order to reduce the effect of BCG vaccination on TST, the French guidelines for TST interpretation propose high cut points for the TST - increase >10 mm or ≥ 15 mm if no earlier TST is available 19. Alternatively to high cut-offs for TST, a number of European Guidelines on the use of IGRAs suggest use of a two-step strategy - performing an IGRA in those initially positive by the TST and excluding LTBI in those IGRA-negative 202122. In our study we compared the performance of the TST and IGRA in French HCWs when using a high cut-off for the TST.

The study population comprises 148 HCWs. The characteristics of the study population are described in Table 1. Repeated BCG vaccination had 62.2%. For 83.1% the last vaccination was performed more than 20 years before. No undetermined result of the QFT was observed. A positive QFT was observed in 18.9% and a TST ≥ 10 mm in 65.5% (Table 2). The QFT was positive in 9.8% of those with a TST 0-9 mm and in 21.1% of those with a TST ≥ 20 mm. The association between TST diameter and QFT positivity was weak (p for test for trend: 0.081).

In 8 persons an increase >10 mm of the TST was observed but only one out of these 8 HCWs (12.5%) had a positive IGRA (Table 3). Most persons (35.1%) had an increase of the TST ≥ 10 mm. 25.0% of the HCWs pertaining to this category were IGRA-positive. No statistically significant association was found between the different TST results and QFT positivity (p = 0.58). Of the 28 HCWs positive in QFT 10 (35.7%) were considered for X-ray or preventive chemotherapy following French interpretation of the TST. Again, following French Guidelines for TST interpretation a recent LTBI was very probable in 45 (30.4%) HCWs (Table 4). Of these, 20% were positive in the QFT which is a proportion similar to the one of those for whom a recent LTBI was not suspected (18.4%). Compared to the French definition for very probable recent LTBI a cut-off of ≥ 10 mm increased the kappa value for agreement between TST and QFT slightly from 0.02 to 0.11. But in both strategies agreement between TST and QFT was weak or non existent.

Using ≥ 10 mm as cut-off for the TST regardless of an earlier TST, TST+/QFT- discordance was observed in 74 (50%) HCWs and TST-/QFT+ discordance in 5 (3.4%) out of 148 exposed HCWs. In those with TST ≥ 10 mm 23.7% were positive in the QFT.

X-ray was performed in 60 HCWs and no active TB was found. Chemoprevention was proposed to 45 HCWs (Table 3). Logistic regression did not reveal any association between positive QFT or positive TST and age, gender, BCG vaccination, or years spent in healthcare. This was also true when instead of the French definitions the cut-off for TST was reduced to ≥ 10 mm regardless of earlier TST results (data not shown).

In a two-step strategy - performing QFT in HCWs with suspected recent LTBI following TST - 10 (1+8+1) instead of 60 (16.7%) would have been proposed for X-ray. On the other side, using this two-step approach with a high cut-off for the TST would allow to detect 10 out of 28 (35.7%) HCWs positive in the QFT only (Table 3). Using a cut-off of ≥ 10 mm for the TST in a two-step strategy would decrease the number of QFTs needed in this population from 100% to 65.5%, again with the drawback that 5 out of 28 (17.9%) HCWs positive in the QFT would be missed (Table 4).

To our knowledge this is the first study that compared the performance of TST and QFT when screening French HCWs. In those in which recent LTBI was suspected following French guidelines 19, the confirmation rate of the QFT was not higher than in those in whom recent LTBI was not probable. Only about one third (35.7%) of those positive in QFT were also considered positive in TST, which is a rate lower than that reported in other studies 101618. Therefore, our data suggest that the French guidelines for the interpretation of TST in exposed HCWs should be reconsidered. Agreement between TST and QFT was better with ≥ 10 mm as cut-off for TST but still remained weak (kappa = 0.11). Following our data neither increasing the cut-off for TST nor a two-step strategy (IGRA only in TST-positive HCWs) seemed to reduce the influence of BCG vaccination on TST results in a satisfying way.

Positive in QFT were 18.9% of the HCWs with recent contact to an AFB-positive TB case were positive in the QFT. The rate of positive QFT is lower than the one (33%) observed in Portuguese HCWs 25 but lower than the one (10%) observed in German HCWs 1618.

As reported in another study 26 we observed an association between the diameter of the TST and the probability of a positive QFT even though the test for trend was of borderline statistical significance. This might be due to the small sample size (n = 148) of our study. The number of TST-/QFT+ HCWs in our population is much higher than in two meta-analyses 826. But surprisingly, even though the criteria for a positive TST following French guidelines are high compared to other countries, the proportion of TST+/QFT- HCWs was high, too. The risk of progression to active TB in TST+/QFT- HCWs is unknown. A number of publications suggest it is low 9272829. Because of the high sensitivity of the IGRA and the low specificity of the TST, none of the several national guidelines recommend X-ray or chemoprevention in HCWs with a positive TST and a negative IGRA 202122. Therefore it seems reasonable to assume that most TST+/QFT- results do not indicate infection with Mycobacteria tuberculosis.

Introducing IGRA for TB screening in France would reduce the number of X-rays and the preventive chemotherapies by a high proportion (from 65.5% for TST ≥ 10 mm or from 40.5% for TST interpretation following French guidelines to 18.9%). We did not conduct a cost-effectiveness analysis. But nevertheless our analysis corroborates the findings of other cost-benefit analyses. A German cost-effectiveness analysis based on German data on TST and QFT positivity and costs of treatment showed that using the QFT assay, but especially combining the QFT assay following the TST screening of close contacts at a cut-off induration size of 5 mm before LTBI treatment, is highly cost-effective in reducing the disease burden of TB 30. Similar results were observed in an analysis of a hypothetical cohort based on data from Switzerland 31 and Canada 32. There is still an ongoing debate as to whether the introduction of IGRA in TB screening reduces the costs for BCG-vaccinated contacts only 33 or for both vaccinated and non-vaccinated contacts 34. It is still unknown for how long the QFT remains positive after elimination of Mycobacterium tuberculosis from the body either spontaneously or after chemoprevention 3536.

So far the risk of progression towards active tuberculosis for those with TST-/QFT+ combinations is unknown. The well-established high specificity of the QFT and the known limitations of TST sensitivity 8 suggest that this combination indicates infections with Mycobacterium tuberculosis. Following our data a two-step strategy using ≥ 10 mm as cut-off for a positive TST helps to reduce unwarranted X-rays but risks to miss a high proportion (17.9%) of the HCWs positive in QFT and therefore likely infected with Mycobacterium tuberculosis. Further reducing the cut-off for a positive TST to >5 mm would not be useful in our population because already 65% had a TST ≥ 10 mm.

Our data show that the increase criteria (increase >10 mm) for TST interpretation lead to a low sensitivity of the TST without reducing the specificity problems of the TST in a meaningful way. Therefore the use of the increase criteria should be reconsidered. Furthermore it could be shown that a two-step strategy - IGRA if TST ≥ 10 mm - might also lead to a low sensitivity of a TB screening. Therefore our data suggest that IGRA should replace TST when screening HCWs for tuberculosis.

The authors declare that they have no competing interests.

DT designed the study and was involved in data collection and writing of the paper.

BBC was involved in data collection and gave critical comments for manuscript writing.

VN was involved in data collection and gave critical comments for manuscript writing.

MA was involved in data collection and gave critical comments for manuscript writing.

EC was involved in data collection and gave critical comments for manuscript writing.

PG was involved in data collection and gave critical comments for manuscript writing.

FN was involved in data collection and gave critical comments for manuscript writing.

JYM was involved in data collection and gave critical comments for manuscript writing.

MBL was involved in data collection and gave critical comments for manuscript writing.

MHDP was involved in data collection and gave critical comments for manuscript writing.

CG was involved in data collection and gave critical comments for manuscript writing.

GG was involved in data collection and gave critical comments for manuscript writing.

MTH was involved in data collection and gave critical comments for manuscript writing.

FR was involved in data collection and gave critical comments for manuscript writing.

DB was involved in data collection and gave critical comments for manuscript writing.

CB was involved in data collection and gave critical comments for manuscript writing.

GP was involved in data collection and gave critical comments for manuscript writing.

CR was involved in data collection and gave critical comments for manuscript writing.

CG was involved in data collection and gave critical comments for manuscript writing.

AN analysed the data and drafted the manuscript.

All authors read and approved the final manuscript.