Scandinavian Journal of Infectious Diseases, 2010; 42: 672678

ORIGINAL ARTICLE

Screening for latent tuberculosis infection in South Korean healthcare workers using a tuberculin skin test and whole blood interferon-g assay

KYUNG JONG LEE1, YOUNG AE KANG1, YOUNG MI KIM2, SANG-NAE CHO2, JIN WOOK MOON1, MOO SUK PARK1, SE KYU KIM1, JOON CHANG1 & YOUNG SAM KIM1
From the 1Department of Internal Medicine, and 2Department of Microbiology,Yonsei University College of Medicine, Seoul, South Korea

Abstract This study compared the results of a tuberculin skin test (TST) and a whole-blood interferon- release assay (IGRA) to screen latent tuberculosis (TB) infection (LTBI) according to risk of TB exposure in South Korea. A cross-sectional comparison of 82 healthcare workers (HCWs) was performed from June 2009 to January 2010. Participants were grouped according to their risk for TB exposure: group 1, frequent and direct contact with active TB patients (n 35); group 2, no known history of direct contact with active TB patients (n 47). For the TST (10-mm induration cut-off), the positive response rate was 42.9% in group 1 and 34.0% in group 2 (p 0.42). For the IGRA, the positive response rate was 40% in group 1 and 10.6% in group 2 (p 0.002). Results obtained from the TST and the IGRA were not in signicant agreement. The working duration of HCWs in TB-related departments was the only signicant risk factor for LTBI (odds ratio 1.03; p 0.031). Further, the IGRA can more accurately discriminate LTBI compared to the TST, based on the risk of TB exposure. These results suggest that the IGRA is diagnostically useful for LTBI in South Korean HCWs.

Introduction It has long been thought that healthcare workers (HCWs) are at an increased risk for Mycobacterium tuberculosis infection as a result of occupational exposure to patients infected with M. tuberculosis [1]. Recent reports have suggested that HCWs in countries with a high prevalence of tuberculosis (TB) have an increased tendency to develop nosocomial TB infections [24]. In South Korea, nurses working in TB-related departments have a 5-fold higher risk for TB development compared to the general population [5]. The US Centers for Disease Control and Prevention (CDC) rst published guidelines for TB prevention in hospitals in 1982 [6], and the International Union Against Tuberculosis and Lung Disease and the World Health Organization (WHO) issued recommendations for infection control within health facilities in 1994 [7]. Extensive efforts to control nosocomial

transmission of TB have become standard practice since the 1990s, when a number of TB outbreaks were reported in hospital settings in low-incidence countries [810]. In addition to environmental control and respiratory protection according to the risk of TB exposure, one of the cornerstones of TB control in healthcare settings in low-incidence countries involves routine screening of HCWs for latent TB infection (LTBI) using a tuberculin skin test (TST), followed by treatment of the LTBI. However, the TST has several limitations, including false-positive results following exposure to nonTB mycobacteria or prior bacille CalmetteGurin (BCG) vaccination. Booster effects from the repeated TST, inter-observer variability and false-negative results due to cutaneous anergy have also been reported [1113]. To overcome the shortcomings of the TST, the CDC has recommended the use of interferon- release assays (IGRA)

Correspondence: Y. S. Kim, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel: 82 2 2228 1971. Fax: 82 2 393 6884. E-mail: [email protected] (Received 2 December 2009; accepted 6 April 2010) ISSN 0036-5548 print/ISSN 1651-1980 online 2010 Informa Healthcare DOI: 10.3109/00365548.2010.485575

LTBI in South Korean healthcare workers for all circumstances in which the TST is currently used [14]. Furthermore, the UK National Institute for Clinical Excellence has recommended a 2-step strategy in which an IGRA is used to conrm TSTpositive cases [15]. In South Korea, the incidence of TB is in the intermediate range (7090/100,000 per y) [16] and TB incidence in HCWs within TB departments is reportedly higher than that of the general population [5,17]. There have been limited reports, however, of LTBI in South Korean HCWs according to TB exposure risk. Recently, the annual risk of infection among newly employed nurses in a private university hospital in South Korea was reported to be at least 3%, based on the TST and QuantiFERON-TB Gold assays [18]. The aim of the present study was to compare the results of the TST and the IGRA as methods for screening LTBI in a private university hospital according to risk of TB exposure. In addition, it was also determined whether the results from the 2 tests were correlated, and thus in agreement.

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of age, pregnancy, allergies to tuberculin, abnormal simple chest radiography ndings suggestive of active TB, and a treatment history of active TB. All participants gave informed written consent and provided a questionnaire that addressed previous BCG vaccination, co-morbidities, and a history of direct contact with active TB patients within their family. Among 101 eligible HCWs, 82 were enrolled (35 in group 1 and 47 in group 2). Four were pregnant and 4 had a history of TB treatment. Another 11 HCWs refused to participate in the study. All participants underwent a TST and a whole-blood IGRA. Tuberculin skin test The TST was performed using a 2 TU dose of puried protein derivative RT23 (Statens Serum Institut, Copenhagen, Denmark), which was introduced intradermally into the forearm using the Mantoux technique [21]. Transverse induration at the TST site was measured by an experienced physician (Dr KJ Lee) in mm after 4872 h. Positive tests were dened as those for which there was an induration of 10 mm. QuantiFERON-TB Gold In-Tube Before performing TST, blood samples were obtained from all participants for a QuantiFERON-TB Gold In-Tube (QFT-IT) assay. The test was performed according to the manufacturers instructions (Cellestis Ltd, Carnegie, VIC, Australia). Briey, blood was drawn directly into 3 evacuated blood collection tubes (1 ml blood each): the rst tube contained heparin alone (Nil tube, negative control), the second tube contained the T cell mitogen, phytohemagglutinin (mitogen tube, positive control), and the third tube contained M. tuberculosis-specic antigens, including ESAT-6, CFP-10, and TB7.7 (TB antigen tube). After mixing, the tubes were incubated upright for 20 h at 37C before plasma was harvested and stored frozen at 20C until further analysis. All analyses were performed within 5 days. The concentration of interferon- in each plasma sample was determined using a QFT enzyme-linked immunosorbent assay. Results were calculated using the QFT-IT software provided by the manufacturer. Statistical analysis Data are expressed as a number (percentage) or median and interquartile range (IQR), because the majority of the data did not follow a normal distribution. Categorical variables were analyzed using a

Methods Study design and setting We conducted a cross-sectional comparison study from June 2009 to January 2010 at Severance Hospital, a tertiary referral hospital in Seoul, South Korea. The study protocol was approved by the Institutional Review Board at Severance Hospital (No.42009-0187). At this hospital, about 400 patients with smear-positive or culture-positive TB are treated each y. About 3035% of the patients were smearpositive TB patients, while the others were smearnegative/culture-positive TB patients. The estimated community prevalence of smear-positive TB is 32 per 100,000 [19], with a 0.19% annual risk of infection in 2007 [20].

Participants The study was designed to recruit HCWs, especially nurses involved in patient care. The nurses were divided into 2 groups according to their risk of exposure to active pulmonary TB. Group 1 consisted of HCWs with frequent direct contact with active TB patients within TB-related departments, and group 2 consisted of HCWs in a hospital setting within paediatric departments with no known history of direct contact with active TB patients. A simple chest radiograph was performed for each HCW to rule out active pulmonary TB and previous TB scarring. HCWs who met any of the following criteria were excluded: younger than 20 y

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K. J. Lee et al. interferon- concentrations were higher in group 1 than in group 2 (0.11 IU/ml for group 1 and 0.00 IU/ml for group 2; p 0.008). The demographic characteristics of the enrolled participants are listed in Table I. Comparison between the TST and QFT-IT assay When a 10-mm induration cut-off was used for the TST, 15 participants (42.9%) had positive test results in group 1 and 16 participants (34%) had positive test results in group 2. There was no signicant difference in the proportion of positive TST results between groups 1 and 2 (p 0.42). For the QFT-IT assay, 14 participants (40%) had positive test results in group 1, whereas only 5 participants (10.6%) had positive test results in group 2. Group 1 showed a signicantly higher proportion of positive QFT-IT assay results compared to group 2 (p0.002; Table II). In group 1, the proportions of positive TST and QFT-IT assay results were not signicantly different (42.9% vs 40%, respectively; p 0.81); however, in group 2 the positive proportion of TST results was higher than that of the QFT-IT assay (34.0% vs 10.6%; p 0.006; Figure 1). Risk factors for positive results in the TST and QFT-IT assay Table III shows the odds ratio for a positive TST or QFT-IT assay result, showing the relative risk factor for LTBI. The duration of time as a healthcare professional in a TB-related department was the only

Pearsons Chi-square test or Fishers exact test; continuous variables were analyzed using a Mann Whitney U-test. Concordance between test results from the TST and QuantiFERON-TB Gold InTube assay were assessed using kappa coefcients ( 0.75, excellent agreement; 0.4, poor agreement; 0.4 0.75, fair-to-good agreement). All tests were 2-tailed and a p-value of 0.05 was deemed to be statistically signicant. SPSS v. 15.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.

Results Participant characteristics In total, 82 HCWs were included in the study, 3 of whom worked in the bronchoscopy suite and the pulmonary function test areas. The other 79 worked in the ward for inpatient care or the outpatient clinic. All participants were female and had a history of BCG vaccination. The median age of the HCWs was 28 y (range 2253 y) and the median working duration within the healthcare profession was 51.5 months (range 0.25276 months). There was no signicant difference in median working duration as a healthcare professional between groups 1 and 2 (51 months vs 52 months, respectively; p 0.45). The median working duration in TB-related departments in group 1 was 36 months (range 0.25192 months). No signicant difference in TST induration size was observed between the 2 groups (8 mm for group 1 and 7 mm for group 2; p 0.49); however, the median
Table I. Baseline characteristics of participants. All participants (n 82) 28 82 20.1 82 2 (2253) (100) (18.821.2) (100) (2)

Characteristics Age, y, median (range) Gender, female, n (%) BMI, median (IQR) Presence of BCG scar, n (%) History of direct contact with TB in family, n (%) Months served as healthcare profession, median (range) Months worked in TB-related department, median (range) TST induration, mm, median (IQR) IFN- concentration, IU/ml TB Ag-nil, median (IQR) Co-morbidity, n (%) None Presenta

Group 1: High risk of exposure (n 35) 29 35 20.5 35 0 (2252) (100) (19.422.3) (100) (0)

Group 2: Low risk of exposure (n 47) 28 47 19.4 47 2 (2353) (100) (18.720.8) (100) (4)

p-Value 0.22 0.009 0.22 0.45 0.001 0.49 0.008

51.5 (0.25276)

51 (0.25276) 36 (0.25192)

52 (3216) 0 (00) 7 (210) 0.00 (0.180.09) 45 (96) 2 (4)

8 (210) 0.03 (0.080.22) 77 (94) 5 (6)

8 (213) 0.11 (0.010.80) 32 (91) 3 (9)

0.65

BMI, body mass index; IQR, interquartile range; BCG, bacille CalmetteGurin; TB, tuberculosis; TST, tuberculin skin test; IFN-, interferon-; TB Ag, tuberculosis antigen; HBsAg, hepatitis B virus surface antigen. aGroup 1: diabetes (1), asthma (1), HBsAg carrier (1). Group 2: Ig A nephropathy (1), ankylosing spondylitis (1).

LTBI in South Korean healthcare workers

Table II. Difference in prevalence of latent TB infection between groups according to TB exposure. All participants (n 82) 31 (37.8) 51 (62.2) 19 (23.2) 63 (76.8) Group 1: High risk of exposure (n 35) 15 (42.9) 20 (57.1) 14 (40) 21 (60) Group 2: Low risk of exposure (n 47) 16 (34.0) 31 (66.0)

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Assay results TST Positive Negative QFT-IT Positive Negative

p-Value 0.42

0.002 5 (10.6) 42 (89.4)

TB, tuberculosis; TST, tuberculin skin test; QFT-IT, QuantiFERON-TB Gold In-Tube.

risk factor for a positive QFT-IT assay (OR 1.03, 95% condence interval (CI) 1.001.05; p 0.031). Age showed an odds ratio of 1.15 (95% CI 0.99 1.33) with marginal signicance for a positive QFTIT assay (p 0.056). Concordance between the TST and QFT-IT assay Table IV shows the concordance between the TST with a 10-mm induration cut-off and the QFT-IT assay among groups. Using the 10-mm induration cut-off, there was no signicant agreement between the 2 tests for all participants ( 0.16 for all participants, 0.24 for group 1, 0.03 for group 2; Table IV). When a 15-mm induration cut-off was used for the TST, there was also no signicant concordance between results of the TST and QFT-IT assay. Figure 2 shows the distribution of interferon- levels by the TST category. TST induration size was associated with a high rate of positivity on the QFTIT (p 0.03). However, there was no signicant difference between interferon- levels by TST category (p 0.55). Figure 3 shows the comparison of interferon- levels according to the TST results among 19 participants with a positive QFT-IT assay. There was no signicant difference in median interferon- levels
50 42.9%

between the TST-negative and TST-positive group (0.80 IU/ml vs 1.17 IU/ml, p 0.25).

Discussion The present study showed a poor correlation between the TST and QFT-IT assay for HCWs. QFT-IT results showed a signicant difference in the prevalence of LTBI according to infection risk. In contrast, the TST could not differentiate the risk of infection among HCWs in a private hospital in South Korea. The QFT-IT assay could accurately reect the risk of TB infection associated with occupational exposure of healthcare workers in a TB-related department; however, the TST failed to accurately reect the risk of TB infection in the healthcare profession. Our results are consistent with previous reports suggesting that the IGRA has a high sensitivity for identifying LTBI without interference due to previous BCG vaccination [2224]. These results suggest that QFT-IT may be an excellent candidate for screening HCWs for nosocomial transmission of TB, especially in HCWs who have been vaccinated with BCG [23]. The reported concordance between the TST and IGRA for diagnosis of LTBI in HCWs is variable. The poor correlation between the TST and QFT-IT assay in the present study is consistent with previous studies on HCWs in Australia, Japan, and South Korea [23 25]; however, a study conducted in India showed good agreement between the TST and QFT-IT assay for HCWs (0.61) [26]. These differences may be explained by differences in the prevalence of LTBI [24], BCG vaccination [27], and in sensitivity of the TST and IGRA for identifying TB infection [28,29]. If both tests have comparable sensitivity, the level of agreement between the tests is likely to increase as TB prevalence in the population increases [24]. Thus, agreement between the 2 tests may be lower in a lowprevalence population. Differences in the methods of BCG vaccination could also be a confounding factor for variable agreement of the 2 tests. In South Korea, BCG vaccination is given at birth and again at 1213 y of age if the child proves to be a TST non-responder

TST
40% 34%

positive proportion (%)

40 30 20 10 0

QFT-IT

10.6%

Group1
High risk of exposure

Group2
Low risk of exposure

Figure 1. Prevalence of latent TB infection among healthcare workers according to exposure risk (TB, tuberculosis; TST, tuberculin skin test; QFT-IT, QuantiFERON-TB Gold In-Tube).

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Table III. Multivariate logistic regression to compare positive results from the TST and QFT-IT assay with risk factors for latent TB infection. Positive TST result Risk factor Older age, per each additional y BMI Duration of healthcare profession, per each additional month Duration of healthcare profession in TB related department, per each additional month OR (95% CI) 0.95 (0.821.10) 0.99 (0.741.31) 1.01 (0.991.03) 1.01 (0.991.03) p-Value 0.46 0.92 0.06 0.41 Positive QFT-IT result OR (95% CI) 1.15 (0.991.33) 0.91 (0.641.30) 0.99 (0.981.01) 1.03 (1.001.05) p-Value 0.056 0.61 0.29 0.031

TB, tuberculosis; TST, tuberculin skin test; QFT-IT, QuantiFERON-TB Gold In-Tube; BMI, body mass index; OR, odds ratio; CI, condence interval.

[27]. In India, however, BCG vaccination is given at birth [26]. The possible underestimation of LTBI by QFT-IT cannot be excluded. Recent studies regarding discordant QuantiFERON-TB Gold (QFT-G) test results among HCWs in the USA have raised concerns over the sensitivity of the QFT-G assay for the detection of LTBI [28]. Extended stimulation assays using ESAT-6 and CFP-10 showed 19% more positive results using overnight assays of HCWs who showed negative results on a conventional QFT-G test [28]. These results may be explained by the possibility that the QFT-G assay identies patients recently infected at a higher risk of reactivation rather than all patients previously infected [29]. A considerable proportion of TST-negative and QFT-IT-positive results in the present study could in part be from the within-subject variability of interferon- concentration in the QFT-IT assay. Interferon- responses close to the cut-off point would likely show positive or negative results in a repeat examination because of within-subject variability [30]. Two of 9 participants with a negative TST
Table IV. Agreement between results from the TST with a 10-mm induration cut-off and the QFT-IT assay. QFT-IT positive All participants TST-positive TST-negative Total Group 1: High risk of exposure TST-positive TST-negative Total Group 2: Low risk of exposure TST-positive TST-negative Total QFT-IT negative

and a positive QFT-IT result showed concentrations close to the cut-off points of 0.40 IU/ml and 0.47 IU/ ml; thus, careful interpretation is needed. In addition, false-negative TST results cannot be fully excluded from the present results. False-negative results could be as a result of cutaneous anergy, recent TB infection, very old TB infection, some viral illnesses, incorrect methods of TST administration, and incorrect interpretation of the reaction [31]. Two of the 9 participants with a negative TST in our study were older than 50 y and another 3 of the 9 participants had less than 6 months of working duration in TB-related departments. False-negative TST results due to waning immunity in old age, recent infection and technical error could be possible in our results. Therefore, the current recommendation of a 2-step strategy for LTBI screening in some countries has the potential of missing several individuals with LTBI. To the best of our

16

11

IFN- level, IU/ml

Total

Kappa 0.16 p 0.13

10 9 19

21 42 63

31 51 82

0.24 8 6 14 7 14 21 15 20 35 p 0.16

-1 0-4 5-9 10-14 15-19 >19

TST induration diameter, mm 0.03 Figure 2. Comparison of the TST and QFT-IT results among healthcare workers. The bar indicates the median value and the horizontal dotted line indicates the interferon- assay cut-off point of 0.35 IU/ml. The TST induration size was associated with a high rate of positivity on the QFT-IT (p 0.03). However, there was no signicant difference between interferon- levels by the TST category (KruskalWallis test, p 0.55) (TST, tuberculin skin test; QFT-IT, QuantiFERON-TB Gold In-Tube; IFN-, interferon-).

2 3 5

14 28 42

16 31 47

p 0.77

TST, tuberculin skin test; QFT-IT, QuantiFERON-TB Gold In-Tube.

LTBI in South Korean healthcare workers

15 1.17 (0.72-5.24)

677

10

0.80 (0.56-1.47)

TST-negative

TST-positive

Figure 3. Comparison of interferon- levels according to the TST results among 19 participants with a positive QFT-IT. There was no signicant difference in interferon- levels between the TSTnegative and TST-positive group (p 0.25). Data are presented as median concentration and interquartile range (TST, tuberculin skin test; IFN-, interferon-).

knowledge, this is the rst study to show different LTBI prevalences using TST and QFT-IT in Korean HCWs according to their risk of exposure. Previous studies have focused only on HCWs in TB-related departments or medical students; thus, comparisons between HCWs according to their working environment are limited [25,27,32] and a recent report about the annual risk of infection among newly employed nurses failed to demonstrate a difference in annual infection according to TB exposure history, because of the short duration of the investigation [18]. In addition to many other factors, the prevalence of LTBI in HCWs may be related to the incidence in the community [33]. In our study, in the participants overall, the prevalence of LTBI in HCWs was 37.8% using the TST and 23.2% using QFT-IT. This is within an intermediate range according to previous reports that have shown a median prevalence of LTBI of 63% in low and middle income countries and 24% in high income countries by TST [33]. Routine infection control interventions at the hospital studied herein include negative-pressure ventilated rooms for isolation of smear-positive patients and the provision of N95 masks. Although these TB control programs are implemented in the hospital, inadvertent exposure occurs in the routine healthcare environment and TB burdens in communities may explain the intermediate prevalence of LTBI in the present study. The true rate of nosocomial transmission of TB, however, cannot be ascertained until serial screening results from HCWs are available and the annual conversion rate to positive QFT-IT results can be measured. In many other developed countries, different strategies have been suggested for LTBI screening of HCWs, including the use of 2-stage testing, in which an initial TST is followed by a QFT-IT test for those with positive TST results [15]. The TB program and

hospital infection control policy in Korea does not recommend routine baseline TST or IGRA screening of HCWs on entry into a hospital setting, or serial screening with TST or IGRA. Regular annual screening using chest X-rays, education, and the provision of respirator protection are recommended to stop the spread of TB in hospitals. However, the higher proportion of positive IGRA results among HCWs with a high risk of exposure compared to those with a low risk of exposure in the present study, suggests the need for improved control measures against TB exposure in occupational settings. To fully appreciate the results of the present study, its limitations should be considered. First, a small number of subjects in 1 hospital may not represent South Korean medical institutions in general. Second, the limited number of job categories included in the present study is not sufcient to represent all HCWs in hospital environments or to identify the risk of infection according to job category. Third, there were no available data regarding the prevalence of LTBI in the community compared to in a healthcare setting or annual risk of infection in the healthcare environment to ascertain nosocomial transmission. Fourth, there was no information on TST and QFTIT status before the HCWs were employed to detect any difference in baseline levels among the groups. In conclusion, the prevalence of LTBI in HCWs with a high risk of exposure in TB-related departments was higher than that of HCWs wit h a low risk of exposure. TST and IGRA results were poorly correlated for the diagnosis of LTBI. Further, only IGRA could accurately reect the risk of TB infection associated with occupational exposure in the healthcare environment of BCG-vaccinated HCWs in an intermediate-burden country. Acknowledgements The authors thank the Korean Institute of Tuberculosis (Seoul, Republic of Korea) for kindly providing the puried protein derivative assay kits at no charge and Woongbee Meditech (Seoul, Republic of Korea) for the donation of the QuantiFERON-TB Gold In-Tube assay kits. Declaration of interest: The authors report no conicts of interest. The authors alone are responsible for the content and writing of the paper. References
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