TB screening in Canadian health care workers using interferon-gamma release assays.
ABSTRACT While many North American healthcare institutions are switching from Tuberculin Skin Test (TST) to Interferon-gamma release assays (IGRAs), there is relatively limited data on association between occupational tuberculosis (TB) risk factors and test positivity and/or patterns of test discordance.
We recruited a cohort of Canadian health care workers (HCWs) in Montreal, and performed both TST and QuantiFERON-TB Gold In Tube (QFT) tests, and assessed risk factors and occupational exposure.
In a cross-sectional analysis of baseline results, the prevalence of TST positivity using the 10 mm cut-off was 5.7% (22/388, 95%CI: 3.6-8.5%), while QFT positivity was 6.2% (24/388, 95%CI: 4-9.1%). Overall agreement between the tests was poor (kappa=0.26), and 8.3% of HCWs had discordant test results, most frequently TST-/QFT+ (17/388, 4.4%). TST positivity was associated with total years worked in health care, non-occupational exposure to TB and BCG vaccination received after infancy or on multiple occasions. QFT positivity was associated with having worked as a HCW in a foreign country.
Our results suggest that LTBI prevalence as measured by either the TST or the QFT is low in this HCW population. Of concern is the high frequency of unexplainable test discordance, namely: TST-/QFT+ subjects, and the lack of any association between QFT positivity and clear-cut recent TB exposure. If these discordant results are indeed false positives, the use of QFT in lieu of TST in low TB incidence settings could result in overtreatment of uninfected individuals.
- [Show abstract] [Hide abstract]
ABSTRACT: Objective To assess the agreement between the tuberculin skin test (TST) and the QuantiFERON-TB Gold test (QFT-G) as pre-employment screening tests for latent tuberculosis infection (LTBI) among healthcare workers. Methods A retrospective cross-sectional study was conducted among 1412 healthcare workers who were screened for LTBI during the period from August 2009 to May 2011 at a tertiary-care hospital in the Kingdom of Saudi Arabia (KSA). The studied population was screened for LTBI using both TST and QFT-G simultaneously. The agreement between both tests was quantified using the Kappa coefficient (κ). Results Comparing the results of QFT-G with TST, the tests had a significant overall agreement of 73.7% (1040/1412; κ = 0.33; p < 0.01). Negative concordance comprised 60.1% of the results, and positive concordance comprised 13.5%. However, positive TST but negative QFT comprised 16.3% of the results, and negative TST but positive QFT-G comprised 10.1%. Concordance was significantly associated with young age, female gender, Saudi-born nationals, and early career but not job type (clinical versus non-clinical) nor status of Bacillus Calmette–Guerin (BCG) vaccination. Conclusions This study demonstrated 73.7% overall agreement between TST and QFT-G results among healthcare workers during pre-employment screening for LTBI. The results need to be confirmed in future studies before recommending QFT-G as a pre-employment screening test for LTBI.Journal of Infection and Public Health 11/2014;
- [Show abstract] [Hide abstract]
ABSTRACT: A systematic review and meta-analysis was conducted to evaluate the agreement between Tuberculin Skin Test (TST) and Quantiferon (QFT) in screening for tuberculosis (TB) infection among healthcare workers (HCWs) and to estimate associations between TST and QFT agreement and variables of interest, such as Bacillus Calmette-Guérin (BCG) vaccination and incidence of TB. Cross-sectional and longitudinal studies on HCWs, published in English until October 2013, comparing TST and QFT results, were selected. For each study Cohen's κ value and a 95% confidence interval were calculated. Summary measures and indexes of heterogeneity between studies were calculated. 29 studies were selected comprising a total of 11,434 HCWs. Cohen's κ for agreement between TST and QFT for 24 of them was 0.28 (95% CI 0.22 to 0.35), with the best value in high TB incidence countries and the lowest rate of BCG vaccination. Currently, there is no gold standard for TB screening and the most-used diagnostic tools show low agreement. For evidence-based health surveillance in HCWs, occupational physicians need to consider a number of factors influencing screening results, such as TB incidence, vaccination status, age and working seniority.Journal of occupational medicine and toxicology (London, England). 01/2015; 10:2.
- [Show abstract] [Hide abstract]
ABSTRACT: The present study was designed to investigate the utility of Quantiferon TB gold (QFT-G) and Tuberculin skin test (TST) for diagnosis of latent TB infection (LTBI) in high crowding TB endemic zone of Nagpur, India and their comparison with associated risk factors. Out of 342 eligible participants, QFT-G and TST were performed in 162 participants. The prevalence of LTBI observed according to QFT-G and TST was 48% and 42% respectively, with an agreement of 52.47%. QFT-G positivity was associated with age while TST positivity was associated with body mass index (BMI). Duration of exposure emerged as a key risk factor significantly associated with both the tests. The prevalence of LTBI was quite high in the studied zone as detected by both the evaluated tests and thus, the combination of both the tests will be best predictive for LTBI in such high TB endemic regions.PLoS ONE 03/2014; 9(3):e89524. · 3.53 Impact Factor
TB Screening in Canadian Health Care Workers Using
Interferon-Gamma Release Assays
Alice Zwerling1,2, Mihaela Cojocariu2,5, Fiona McIntosh5, Filomena Pietrangelo4, Marcel A. Behr1,2,3,
Kevin Schwartzman2,3, Andrea Benedetti1,2, Nandini Dendukuri1, Dick Menzies1,2,3, Madhukar Pai1,2*
1Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada, 2Respiratory Epidemiology & Clinical Research Unit, Montreal
Chest Institute, Montreal, Canada, 3Department of Medicine, McGill University Health Centre, Montreal, Canada, 4Department of Occupational Health & Safety, McGill
University Health Center, Montreal, Canada, 5Research Institute of the McGill University Health Center, Montreal, Canada
Background: While many North American healthcare institutions are switching from Tuberculin Skin Test (TST) to
Interferon-gamma release assays (IGRAs), there is relatively limited data on association between occupational tuberculosis
(TB) risk factors and test positivity and/or patterns of test discordance.
Methods: We recruited a cohort of Canadian health care workers (HCWs) in Montreal, and performed both TST and
QuantiFERON-TB Gold In Tube (QFT) tests, and assessed risk factors and occupational exposure.
Results: In a cross-sectional analysis of baseline results, the prevalence of TST positivity using the 10 mm cut-off was 5.7%
(22/388, 95%CI: 3.6–8.5%), while QFT positivity was 6.2% (24/388, 95%CI: 4–9.1%). Overall agreement between the tests was
poor (kappa=0.26), and 8.3% of HCWs had discordant test results, most frequently TST2/QFT+ (17/388, 4.4%). TST positivity
was associated with total years worked in health care, non-occupational exposure to TB and BCG vaccination received after
infancy or on multiple occasions. QFT positivity was associated with having worked as a HCW in a foreign country.
Conclusions: Our results suggest that LTBI prevalence as measured by either the TST or the QFT is low in this HCW
population. Of concern is the high frequency of unexplainable test discordance, namely: TST2/QFT+ subjects, and the lack
of any association between QFT positivity and clear-cut recent TB exposure. If these discordant results are indeed false
positives, the use of QFT in lieu of TST in low TB incidence settings could result in overtreatment of uninfected individuals.
Citation: Zwerling A, Cojocariu M, McIntosh F, Pietrangelo F, Behr MA, et al. (2012) TB Screening in Canadian Health Care Workers Using Interferon-Gamma
Release Assays. PLoS ONE 7(8): e43014. doi:10.1371/journal.pone.0043014
Editor: Marc Tebruegge, The University of Melbourne & The Murdoch Childrens Research Institute & The Royal Children’s Hospital Melbourne, Australia
Received May 31, 2012; Accepted July 16, 2012; Published August 20, 2012
Copyright: ? 2012 Zwerling et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Canadian Institutes of Health Research (CIHR) grant 81362. AZ received a doctoral fellowship from CIHR, and MP
received a New Investigator Award from CIHR. MP also received a salary award from Fonds de recherche du Que ´bec–Sante ´. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: MP serves on the editorial boards of PLoS One and PLoS Medicine. He is a Section Editor with PLoS One. MB is co-author of a United
States patent on molecular differences between species of the Mycobacterium tuberculosis complex. U.S. patent filed May 25, 1999 Bozicevic, Field and Francis,
LLP, Palo Alto, CA, 94301. Serial number 09/313,191. Issued as U.S. patent 6,291,190 B1 October 2001. This does not alter the authors’ adherence to all the PLoS
ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
Fuelled by the HIV epidemic, the emergence of multi- and
extensively drug resistant tuberculosis (MDR & XDR-TB) and an
increasingly mobile population, tuberculosis (TB) continues to be a
global concern and a serious risk to health care workers (HCW)
worldwide [1,2,3,4,5]. In many high income countries, HCWs are
screened at regular intervals for Latent TB Infection (LTBI) in an
effort to identify new infections that can be targeted for preventive
Traditionally TB screening in HCWs has been conducted using
the Tuberculin Skin Test (TST), a test with known limitations
[9,10,11]. Recently, Interferon gamma release assays (IGRAs) are
being increasingly used for LTBI screening. Several systematic
reviews have suggested that IGRAs are as sensitive, and more
specific than the TST in identifying LTBI, particularly in low TB
incidence settings [12,13,14,15]. However, the use of IGRAs for
routine screening of HCWs remains an area of controversy, and
the Canadian guidelines among others have not endorsed IGRAs
for serial testing in this population [16,17]. Despite this, the use of
IGRAs in routine screening of HCWs is increasing, and with it, a
large number of studies have reported high within subject
variability, high rates of discordant test results and high rates of
conversions and reversions among HCWs screened with these
novel assays [18,19].
We recruited HCWs from a low TB incidence setting into a
prospective longitudinal cohort, in which HCWs are undergoing
annual testing with TST and QFT. At intake into this cohort all
participants underwent baseline testing. Primary objectives of this
analysis were a) to assess the association between test positivity and
occupational TB exposure in a cohort of Canadian HCWs; and b)
to assess the association between patterns of test discordance and
occupational TB exposure and other TB risk factors.
PLOS ONE | www.plosone.org1August 2012 | Volume 7 | Issue 8 | e43014
Materials and Methods
Study Setting & Population
This study was conducted at the McGill University Health
Centre (MUHC), a university affiliated hospital network that
employs over 11,500 health care and other personnel at seven
hospitals in Montreal. TB incidence is low in Quebec with an
annual incidence rate of 2.5 per 100,000 persons. Over the past
decade, approximately 100–150 active TB cases have been
reported annually on the island of Montreal, an incidence rate
of approximately 7.1/100 000 persons per year .
HCWs at the MUHC undergo TB screening both as part of
pre-employment health evaluations and through regular occupa-
tional health and safety monitoring. The majority of employees are
to be screened for LTBI on an annual schedule, while those in
high risk settings such as mycobacteriology laboratories are
screened every 6 months. TB screening of MUHC HCWs has
been traditionally done using the TST and is conducted by the
Department of Occupational Health and Safety (OHS).
Study Design & Ethics approval
HCWs were approached for participation in the study at their
TB screening visit with the OHS. In order to be eligible for the
study, participants must have been due for scheduled TB
screening, and could not have had a positive TST ($10 mm
induration) in the past. Therefore, ‘baseline testing’ refers to the
first measurement for this study; for some participants this was
their first ever TST, while others had been undergoing annual
occupational TB screening, with negative test results in the past.
HCWs who provided written informed consent were recruited to
our prospective longitudinal cohort, and are now being followed
and tested annually with both the TST and QFT.
At the baseline study visit, the blood draw was first performed
for the QFT test, and subsequently the TST was placed. Finally,
HCWs completed an interviewer-facilitated questionnaire cover-
ing occupational and non-occupational TB exposure. The study
was approved by the ethics review board of the MUHC.
Tuberculin Skin Test
The TST was performed using the Mantoux method by a
trained nurse hired by the research study; 5TU (0.1) ml of
Tubersol PPD (Aventis Pasteur) was used, and results read as per
the Canadian TB Standards . In cases where the HCW had not
been tested with the TST within the last 10 years, a 2 step TST
was performed if the initial result was negative (,10 mm). Upon
initial testing, an induration of $10 mm was considered positive
Interferon-gamma release assay testing
The QuantiFERON-TB Gold In-Tube test (QFT) (Cellestis
Ltd/Qiagen, Carnegie, Australia) was performed as per the
manufacturer’s instructions in a research lab at the Montreal
General Hospital. The QFT result was considered positive if the
interferon-gamma response in the TB antigen tube minus the
response in the nil tube was $0.35 IU/ml as per the manufac-
turer’s guidelines. Quantitative values of IFN-gamma were also
recorded; as per manufacturer’s suggestions all values greater than
10 were truncated at 10.
Ascertainment of TB Exposure
HCWs completed a questionnaire covering demographics,
travel history, training and work history in health care, health
care work in foreign countries, potential non-occupational
exposure to TB, and potential exposure to TB in the occupational
environment. Known occupational exposures are charted in the
personnel files maintained by the Department of Occupational
Health and Safety.
While there is no gold standard for LTBI, we hypothesized that
a higher level of exposure to TB correlates with a higher
probability of infection. We identified key occupational exposures
based on a priori risk factors including: a) unprotected exposure to a
smear positive infectious TB patient, b) direct contact with TB
patients, c) type of HCW, and d) years worked in health care .
Management of Positive Results
As per the current MUHC policy, participants with a positive
TST result were referred for chest x-ray plus clinical evaluation by
a pulmonologist. When judged appropriate, LTBI treatment was
recommended by the pulmonologist. The same process applied to
participants with a positive QFT result, regardless of the
accompanying TST result.
All analyses were performed with Stata, version 11 (Stata Corp,
Texas, USA). Percent agreement and kappa statistics, were
calculated to estimate test concordance. To assess the association
between test positivity (separately for TST and QFT) and the
occupational exposure variables of interest, we performed
multivariable logistic regression. Variable selection for the model
was done using a priori clinical knowledge. The association between
risk factors and the joint patterns of TST and QFT results was
assessed by nominal multinomial logistic regression. Four patterns
were assessed: concordant negatives (base or reference outcome),
concordant positives, discordant QFT+/TST2 and discordant
QFT2/TST+. Odds ratios and their accompanying 95%
confidence intervals were estimated from the multivariable
polytomous logistic regression model.
From May 2007 to December 2011, we approached 638 HCWs
who had been referred for TST. Three hundred and ninety seven
HCWs (62%) provided informed consent, completed the ques-
tionnaire, and underwent study testing procedures. Most common
reasons for non-participation were lack of time, dislike of needles
and/or of blood draw. Incomplete and invalid tests were excluded
(including tests which could not be performed due to processing or
laboratory errors. Completed questionnaires, and valid test results
were available for 388 HCWs.
Among the 388 study participants with complete results, 87.9%
(341/388) had had a prior TST planted either through routine TB
screening at the MUHC or at another location prior to
employment at the MUHC (but not within the preceding 3
months), 41/388 (11.3%) had never had TST performed
previously while 6/388 (1.6%) could not recall. A second step
TST was performed on 41 TST naı ¨ve HCWS and 59 HCWs who
had not been tested with TST within the last ten years. Among
those previously tested, 332/341(97.4%) had documented TST
negative while 9/341 (2.6%) had been previously tested with TST
but had never been read.
Participant Demographics & TB Exposure
Participant characteristics are displayed in Table 1. The
majority of HCWs were female (288/388, 74%) and the median
age was 34.4 years (Inter-quartile range, IQR: 26.9–44.7 years).
The majority were Canadian-born non-aboriginal (272/388 70%),
and the majority of foreign born participants (86/114, 75%) had
arrived in Canada more than 5 years prior to study enrolment.
TB Screening in Canadian Health Care Workers
PLOS ONE | www.plosone.org2August 2012 | Volume 7 | Issue 8 | e43014
HCWs had worked a median of 5 years (IQR 2- 12 years) in the
health care services sector. Prior BCG vaccination was reported by
36.1% (140/388) of the cohort.
The median number of years since the last TST prior to study
recruitment was 2.2 years, (IQR: 1.4–3.6 yrs) and the median
number of TST tests performed prior to study enrollment was 2,
(IQR:1–3) with some OHS charts reporting up to 14 TST tests per
Baseline test positivity
The prevalence of TST positivity using the 10 mm cut-off was
estimated to be 5.7% (22/388, 95%CI: 3.6–8.5%), while QFT
positivity was 6.2% (24/388, 95%CI: 4–9.1%), with only one
Table 1. Participant Characteristics (N=388).
Participant CharacteristicsN (%)
Age Median34.4 yrs
IQR 26.9–44.7 yrs
Sex Female 288 (74.2%)
Country of birth Canadian born (non-aboriginal)272 (70.1%)
Canadian born (aboriginal)2 (0.5%)
Foreign born: low TB inc. (#25/100, 000) 63 (16.3%)
Foreign born : moderate TB inc (26–100/100,000)23 (5.9%)
Foreign born: high TB inc (.100/100,000)28 (7.2%)
Educational levelHigh school or less 46 (11.9%)
College or university degree231 (59.5%)
Post graduate degree108 (27.8%)
Did not report 3 (0.8%)
Job category Non- clinical staff120 (30.9%)
Nursing staff 94 (24.2%)
Medical doctors40 (10.3%)
Other clinical staff115 (29.6%)
Laboratory staff19 (4.9%)
BCG vaccination No vaccination248 (63.9%)
At birth or within 1 year 57 (14.7%)
Post infancy36 (9.3%)
Received multiple BCG vaccinations 7 (1.8%)
Unknown timing 40 (10.3%)
Direct contact with a patient with TBYes 145 (37.4%)
No 243 (62.6%)
Non-occupational TB exposure*
TB case in same household9 (2.3%)
TB case at school6 (1.6%)
TB case in same room15 (3.9%)
Friends with TB case10 (2.6%)
No TB exposure in the community361 (93%)
Total years worked in health care Median5 yrs
IQR (IQR: 2–12 yrs)
Worked as a HCW outside of Canada? No343 (88.4%)
Travel outside of Canada (.1 month) No 279 (71.9%)
Yes 109 (28.1%)
Prior TSTYes – negative 332 (85.6%)
Yes - but not read9 (2.3%)
No 41 (10.6%)
Don’t know6 (1.6%)
*Not mutually exclusive categories, therefore will not total to 100.
TB Screening in Canadian Health Care Workers
PLOS ONE | www.plosone.org3August 2012 | Volume 7 | Issue 8 | e43014
indeterminate QFT result. Quantitative TST results ranged from
0 to 25 mm. When appropriate, two step TST was performed,
and in 5/100 (5%) cases HCWs became TST positive upon
second step testing, these HCWs were referred for follow-up but
were not considered positive for subsequent analyses. QFT results
(TB Ag- nil) ranged from 0–10 IU/ml. All HCWs with positive
TST results were referred to see a pulmonologist, however in 7
cases, HCWs did not make a follow-up appointment. Treatment
was recommended in 7/15 (46.7%) HCWs; 5 completed therapy,
while 2 refused treatment. Treatment was not recommended in
the remaining 8 HCWs, either due to concerns with drug
interactions (n=1), age over 35 years (n=2) or because they were
considered false-positives (n=5).
Positivity estimates stratified by prior TST status, test type,
BCG vaccination status, and country of birth are displayed in
Table 2. Among those with no prior TST history, the QFT
positivity rate was 4.9% (2/41, 95%CI: 0.6–16.5%) while the TST
rate was almost twice that at 9.8% (4/41, 95%CI: 2.7–21.9%).
When restricted to those with prior negative TST the test positivity
rates for both tests decreased and the rate for QFT positivity
became almost 2 percentage points higher than that of TST.
Among BCG vaccinated HCWs, test positivity was slightly lower
for QFT than TST.
Concordance between quantitative TST and QFT results is
displayed in Figure 1. Three hundred and forty-eight (89.7%)
HCWs were found to be negative by both tests, while 7 (1.8%)
were concordant positives (lower left and upper right hand
quadrants of Figure 1). TST positive/QFT negative discordant
results were found in 15/388 cases (3.9%) and TST negative/
QFT positive in 17/388 cases (4.4%).
Among those with no history of BCG vaccination, only 3/248
(1.2%) were TST+/QFT2 discordant, while 10/248 (4%) were
TST2/QFT+ discordant. Among the BCG vaccinated, a much
higher rate of TST+/QFT2 discordance was observed (12/140
,8.6%), compared to TST2/QFT+ discordance (7/140 ,5%).
Overall agreement between the tests was 91.7% with a kappa
value of 0.26 which can be interpreted as fair to poor agreement
[21,22]. When the analysis was restricted to only those HCWs
with BCG vaccination, the agreement decreased slightly to 86.3%,
while the kappa value improved slightly to 0.3.
As seen in Figure 1, only 4 points (1 not shown) suggest clearly
concordant positive results, while the remaining points (although
still concordantly positive are close to the QFT positivity cut-off
both among concordant positives and discordant TST+/QFT2.
There was no statistically significant difference between the
median IFN-gamma value among concordant positives (medi-
an:2.6, IQR:0.55–2.97) and among the discordant QFT +/TST
negatives (median: 0.69, IQR:0.47–2.74).
When we considered a more stringent cut-off based on visual
inspection of the scatterplot, we found that by employing a cut-off
of 1.0 IU/ml for the QFT test , 13 HCWs would be reclassified as
QFT negative; among these, 3/13 (23%) were TST positive
leading to a lower QFT positivity rate of 11/388 (2.8%). This
reclassification would lead to a TST+/QFT2 discordance rate of
4.6% while the TST2/QFT+ discordance rate would decrease to
Multivariable logistic regression
The final multivariable model included the following indepen-
dent variables: age, sex, non-occupational TB exposure (yes/no),
birth in a country with high TB incidence, type of health care
work (nurse, doctor, clinical staff, lab staff or nonclinical support
staff), Total years worked and or spent training in health care,
Travel more than one month outside Canada, worked as aHCW
in a foreign country, BCG vaccination at birth or unknown timing,
BCG vaccination post-infancy or multiple BCG vaccinations, self-
reported exposure to active TB patients, documented occupational
exposure to TB, age at immigration, birth outside of Canada, and
finally prior negative TST (Table 3).
Inthe final model,non-occupational
(OR=11.7, 95%CI: 2.5–55.7), total years worked in health care
(OR=1.09 for every additional year, 95%CI: 1.003–1.2), BCG
vaccination after infancy and or multiple BCG vaccinations
(OR=23.05, 95%CI:3.9–135.2) were all statistically significantly
associated with TST positivity. Prior negative TST (OR=0.065,
95%CI: 0.01–0.3) had a strong inverse association with TST
positivity in the present study. The only variable to be statistically
significantly associated with QFT positivity was having worked as
a HCW in a foreign country (OR=6.44, 95%CI: 1.6–25.0),
We performed a stratified analysis of only those HCWs with
previous negative TST. Among this group, we found the same
significant variables associated with TST positivity in the
multivariable regression with the exception of total years worked
in health care was no longer significant in the model. This suggests
that the cumulative risk of years working in health care is not a
Table 2. Test Positivity among HCWs, stratified by test type, prior TST status, BCG vaccination status and country of origin.
Subgroup TST Positive/Tested (%)95%CIQFT Positive/Tested (%) 95%CI
Overall 22/388 (5.7%) 3.6–8.5%24/388 (6.2%)4.0–9.1%
BCG Vaccinated18/140 (12.9%)4.6–1.0% 13/140 (9.3%)5.0–15.4%
No history of BCG 4/248 (1.6%)7.8–19.6%11/248(4.4%)2.2–7.8%
Canadian Born**5/274 (1.8%)0.4–4.1%11/274 (4.0%)2.0–7.1%
Foreign Born 17/114 (14.9%)0.6–4.2% 13/114 (11.4%)6.2–18.7%
Foreign Born (High TB Incidence) 4/28 (14.3%)8.9–22.8% 3/28 (10.7%)2.3–28.2%
Prior TST4/41 (9.8%) 2.7–21.9%2/41 (4.9%) 0.6–16.5%
No prior TST Unknown prior TST5/15 (33.3%) 11.8–61.6% 3/15 (20.0%)4.2–48.1%
Prior Negative TST 13/332 (3.9%) 2.1–6.6%19/332 (5.7%) 3.5–8.8%
**Including Canadian-born aboriginals.
Note: 2 step TST: 5/100, (5.0%).
TB Screening in Canadian Health Care Workers
PLOS ONE | www.plosone.org4August 2012 | Volume 7 | Issue 8 | e43014
significant predictor among those who have been routinely
screened in this context.
Patterns of discordance and their association with TB risk
Using a multinomial logistic regression model we assessed the
potential association between risk factors and 4 patterns of test
concordance/discordance: concordant negatives, concordant pos-
itives, and two types of discordance: QFT+/TST2 and QFT2/
TST+. All outcomes were compared to the base outcome of
concordant negatives (Table 4). In multivariable analysis the only
three variables significantly associated with concordant positive
results were BCG vaccination after birth and/or multiple
vaccinations (OR=36.32, 95%CI: 1.73–761.31), having worked
in a foreign country as a HCW (OR=30, 95%CI: 1.34–669.8),
and prior negative TST, which showed a statistically significant
protective effect (OR=0.02 95%CI: 0.001–0.57)
No variables were statistically significantly associated with
QFT+/TST2 discordance; possibly due to the very small sample
size (n=17). Several variables were associated with QFT2/TST+
(OR=28.14 96%CI: 3.08–257.03), BCG vaccination at birth/
timing unknown (OR=19.24, 95%CI:1.29–287.21) BCG vacci-
nation after birth and/or multiple vaccinations (OR=63.02,
95%CI: 3.71–1069.35), Total years spent working in health care
(OR=1.23, 95%CI: 1.06–1.42), age at immigration (per year
increase among foreign-born), (OR=1.15, 95%CI:1.03–1.3) and
finally inverse protective effect of prior negative TST (OR=0.08,
Results from this cohort of Canadian HCWs suggest that the
prevalence of positivity for LTBI, as measured by either the TST
or the QFT, in this population, is low. Furthermore, many HCWs
had discordant test results, where the prognosis and treatment
recommendations remain unclear.
Infrequent test positivity (using either test) and weak concor-
dance, may suggest that the noise level (or non-specific responses)
from these tests in a low TB incidence setting may be such that the
true signal (ie: immunological responses indicating LTBI) is
difficult to distinguish. Non-specific variation has been shown to
occur in both tests, and despite being health care workers, this
cohort remains a low risk population [11,19]. One alternative but
not mutually exclusive hypothesis suggests these tests may be
measuring independent immunological processes. Unfortunately,
these hypotheses are difficult to test in the absence of a gold
standard for LTBI.
Unlike many IGRA studies in HCWs, QFT did not estimate a
lower positivity rate overall compared with the TST in this cohort
. Comparable positivity rates have been reported from HCW
studies in the United States and Italy, and may be more frequent
in cohorts with low BCG vaccination [23,24]. The nature and
profile of this particular HCW cohort is an important factor;
MUHC HCWs with prior positive TST results do not undergo
routine screening, and were therefore excluded. This leads to an
underestimation of the overall prevalence of positive TST results
among MUHC HCWs undergoing regular screening. When
restricted to those HCWs who were TST naive, we found a
positivity rate two-fold higher using the TST compared with QFT
(9.8% vs. 4.9%). Although this did not reach statistical
significance, it is consistent with earlier studies from low TB
incidence countries . Similar results have been reported in
other North American HCW cohorts, including a conference
abstract by Dorman et al., where they reported on a large multi-
center study including 1,313 HCWs from the United States .
Both IGRAs: the QFT and the TSPOT.TB test were performed,
as well as the TST, and positivity rates were 5.3%, 6.9% and 6.8%
respectively. Highlighting both the low overall positivity and
comparable rates estimated by the IGRAs and the TST among
low risk populations.
TST+/QFT2 discordant results are often attributed to BCG
vaccination. In this cohort, the low level of BCG vaccination
(36.1%) may lead to more comparable positivity rates between the
Figure 1. Scatterplot of quantitative TST and QFT results (n=388)*. *2 points not visible on graph: a)TST=0, IFN-g=10 & b)TST=17, IFN-
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two tests. The effect of BCG was evident when restricted to
vaccinated HCWs, the TST rate increased by two fold to 12.9%
while the QFT rate saw a smaller increase to 9.3%. Rates for both
types of discordance remained high, and while TST+/QFT2
discordance was associated with non-occupational exposure, years
worked in health care, and BCG vaccination, TST2/QFT+
discordance could not be explained by any of the variables we
Results from the multivariable analysis assessing the association
between LTBI risk factors and TST positivity were consistent with
previous studies . Given the non-specific nature of the TST,
and its known cross-reactivity with BCG vaccinated persons, we
are not surprised by the strong association with BCG when
vaccination was performed later in life and/or repeated. Similarly,
‘total years worked in health care’ has been shown in several
studies in HCWs to be consistently associated with TST positivity
The association of positive TST results with self-reported non-
occupational exposure was unexpected in our low TB incidence
setting. However, this effect was strong and consistent across
analyses, indicating non-occupational exposure to TB may
continue to play an important role. Conversely, known occupa-
tional exposure to TB was not significantly associated with positive
results for either test. It may be that most potential hospital source
cases were appropriately diagnosed and isolated, effectively
reducing nosocomial transmission. Non-occupational TB exposure
may also imply longer duration plus lack of proper ventilation and
infection control measures, resulting in a higher likelihood of
transmission. Finally, known occupational exposures may be less
likely to result in transmission than are undetected hospital
exposures, which neither participants nor Occupational Health &
Safety can report. QFT positivity was associated significantly with
just one variable: having worked as a HCW in a foreign country,
which could be a proxy for high risk exposure to TB. This variable
Table 3. Multivariable logistic regression model assessing association between test positivity and risk factors.
Association with TST
positivity Association with QFT positivity
adj. OR 95% CIadj. OR95% CI
Male2 (0.5–7.9) 11.4 (0.5–3.9)
Age (yrs) 0.98 (0.9–1.1)1.03 (0.98–1.1)
Birth in a low/moderate TB incidence country11
Birth in a country with high TB incidence2.31 (0.3–16.7)1.57 (0.3–7.6)
Job Category Non-clinical staff11
Doctors4.18 (0.4–45.6)1.9 (0.4–10.1)
Nurses1.09 (0.2–7.9) 0.7(0.2–3.2)
Clinical staff1.88 (0.3–10.8)0.78(0.2–2.9)
Laboratory staff4.48 (0.45–44.7)--
Non-Occupational TB Exposure
No reported exposure 11
Self-reported TB exposure 11.7(2.5–55.7)0.45(0.05–3.9)
Total years worked in health care (yrs)1.09 (1.003–1.2)0.99(0.9–1.1)
Travel outside Canada .1 month No1
Yes2.31(0.7–8.2) 11.13 (0.4–3.1)
Worked as a HCW in a foreign countryNo11
Yes 1.09(0.2–5.9) 6.44 (1.6–25.0)
Self-reported occupational contact with a patient with active TB No11
Yes0.88 (0.54–1.44) 0.94(0.6–1.4)
Known unprotected occupational exposure No11
Yes1.35 (0.91–2.0)0.95 (0.7–1.3)
Vaccination at birth/timing unknown 4.17(0.81–21.49)0.97 (0.3–3.2)
Vaccination post-infancy or .1 BCG23.05 (3.9–135.2) 2.7(0.8–9.5)
Country of Birth Canada11
Age at immigration to Canada (yrs)1.06 (0.99–1.1)0.96(0.9–1.0)
Prior TSTNo prior TST or not read11
Prior negative TST0.065 (0.01–0.3)0.54(0.1–2.0)
Statistically significant results are presented in bolded text.
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Table 4. Multinomial logistic regression model, assessing the relationship between risk factors and patterns of concordant and discordant test results.
Odds Ratios (95%CI)
Discordant TST+ +/QFT2 2
QFT + +/TST2 2
Birth in a low/moderate TB incidence country
Birth in a country with high TB incidence
Non-Occupational TB Exposure
No reported exposure
Self-reported TB exposure
Total years worked in health care (yrs)
Travel outside Canada .1 month
Worked as a HCW in a foreign country
Self-reported occupational contact with active TB
Known occupational exposure to
unprotected patient with active TB
No BCG vaccination
BCG vaccination at birth/timing unknown
BCG vaccination post-infancy or multiple vaccinations
Age at immigration to Canada (yrs)
No prior TST or not read
Prior negative TST
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was also significantly associated with concordant positive results,
suggesting these cases may be true LTBI and not false positives.
It has been hypothesized that the TST is more likely to remain
positive over time compared with the QFT, which may be a more
dynamic test and has been shown to have high rates of reversions
upon repeat testing . It is therefore possible that TST positivity
tends to be associated with cumulative TB exposure, while QFT
positivity may be more linked to acute exposure, and hence less
likely to persist. While it is not possible to test this hypothesis using
the cross-sectional data presented here, we plan to investigate this
further using future longitudinal data from this cohort.
Many have suggested alternative cut-offs for the QFT might
improve reproducibility,reduce subsequent
improve concordance with the TST [19,28]. We evaluated two
alternative cut-offs for the QFT test. Using the most stringent cut-
off we found lower overall rates of discordance, noticeably a
twofold decrease in TST2/QFT+ discordance compared with
TST+/QFT2 discordance. This result more closely reflects results
from other studies which have consistently identified TST+/
QFT2 as the most frequent type of reported discordance .
Strengths & Limitations
Our study was conducted in a low TB incidence setting, where
TB exposure can be more accurately captured. We attempted to
capture all potential exposures, both in the non-occupational and
in the occupational setting; unprotected exposures to active TB
patients were confirmed through occupational health and safety
records. It is possible that we have not captured all occupational
exposures, while TB exposure is a relatively rare event at the
MUHC, and is well documented in Occupational Health and
Safety charts, we cannot exclude the possibility that there were
unrecognized exposures for which the HCW cannot report nor
would there be any note of such an exposure in their OHS charts.
Recent work has shown that IGRAs have a certain within-
subject (intra-assay) variability that can be caused by a range of
factors, including: variation in sample collection and processing,
improper incubation and storage, as well as laboratory factors or
host biology [19,29]. To address these concerns we attempted to
reduce variability and further standardized sample processing and
incubation times. Periodically, the assay was repeated on the same
blood to assess reproducibility of results. However, we still cannot
eliminate the possibility that some of the QFT results were false
One significant limitation for all studies investigating diagnostic
tests for LTBI is the lack of gold standard. While studies have
looked at rates of disease progression in HCWs, this is not feasible
in our low incidence setting where LTBI treatment is widely used
Upon one time testing of a cohort of Canadian HCWs, we
found test positivity as measured by TST or QFT was low. Of
concern is the high frequency of unexplainable test discordance,
namely: TST2/QFT+ subjects, and the lack of association of
positive tests (especially QFT) with clear-cut recent TB exposure.
In settings with low TB incidence, these dynamic tests may result
in such high levels of non-specific results compared with the true
underlying prevalence of LTBI that more precise tests may be
required to correctly identify TB. Without a clear understanding
of what underlying processes each test is measuring (ie: acute,
dynamic, static), and the long-term prognosis of HCWs with
discordant test results, it remains unclear how to implement QFT
tests into current HCW screening programs, and what additional
value they may offer over the TST.
Many thanks to all the participating MUHC HCWs for their time and
interest in the study. The authors gratefully acknowledge the staff at the
Occupational Health and Safety Department of the MUHC and all TB
research and TB clinic staff of the Montreal Chest Institute for their time,
support and cooperation.
Conceived and designed the experiments: AZ DM MB KS MP. Performed
the experiments: AZ MC FM FP. Analyzed the data: AZ AB ND MP.
Contributed reagents/materials/analysis tools: MB. Wrote the paper: AZ
MP. Revised the manuscript: AB ND MB DM KS.
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