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Decreased annual risk of tuberculosis infection in South Korean healthcare workers using interferon-gamma release assay between 1986 and 2005



Tuberculosis (TB) has been a major public health problem in South Korea. Although TB notification rate in Korea is gradually decreasing, still highest among the member countries of the Organization for Economic Cooperation and Development. To effectively control TB, understanding the TB epidemiology such as prevalence of latent tuberculosis infection (LTBI) and annual risk of TB infection (ARI) are important. This study aimed to identify the prevalence of LTBI and ARI among South Korean health care workers (HCWs) based on their interferon-gamma release assays (IGRA).


This was single center, cross-sectional retrospective study in a tertiary hospital in South Korea. We performed IGRA in HCWs between May 2017 and March 2018. We estimated ARI based on IGRA results. Logistic regression model was used to identify factors affecting IGRA positivity.


A total of 3233 HCWs were analyzed. Median age of participants was 38.0 and female was predominant (72.6%). Overall positive rate of IGRA was 24.1% and IGRA positive rates age-group wise were 6.6%, 14.4%, 34.3%, and around 50% in the age groups 20s, 30s, 40s, and 50s and 60s, respectively. The ARIs was 0.26–1.35% between 1986 and 2005; rate of TB infection has gradually decreased in the last two decades. Multivariable analysis indicated that older age, healed TB lesion in x-ray, and male gender were risk factors for IGRA positivity, whereas working in high-risk TB departments was not.


Results showed that ARI in South Korean HCWs gradually decreased over two decades, although LTBI remained prevalent. Our results suggest that the LTBI test result of HCWs might be greatly affected by age, rather than occupational exposure, in intermediate TB burden countries. Thus, careful interpretation considering the age structure is required.

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South Korea is an intermediate tuberculosis (TB) burden country; in 2019, the annual incidence of TB was reported to be 59 per 100,000 [1]. TB is still an important public health concern in South Korea; for effective TB control, understanding its epidemiology, such as the prevalence of latent tuberculosis infection (LTBI) and annual risk of TB infection (ARI) is important. ARI represents the proportion of newly infected or re-infected people over a 1-year period calculated based on the prevalence of LTBI. LTBI prevalence has steadily decreased in South Korea [2, 3]; however, about one third of the general population in South Korea is still thought to have LTBI [4, 5].

To date, LTBI prevalence studies and analysis of ARI have been conducted mainly using the tuberculin skin test (TST) in South Korea [2, 6, 7]. In previous studies, the annual risk of TB infection in South Korea was estimated using TST results in ages 5–9 years, and the ARI was 0.5–5.3% based on a 10-mm induration between 1958 and 1988 [6]. However, studies on ARI using interferon-gamma release assay (IGRA) results in South Korea are lacking.

In this study, we aimed to identify the prevalence of LTBI and estimate ARI in health care settings based on IGRA results of HCWs. We also aimed at identifying the risk factors of LTBI for HCWs with a particular focus on their age in an intermediate TB burden country.


Study population

This study was conducted at Severance Hospital, a 2500-bed tertiary referral hospital in South Korea. A total of 3283 HCWs underwent the LTBI test between May 2017 and March 2018 as part of a national TB elimination program. The LTBI test used was QuantiFERON® TB-Gold In Tube test (QFT-GIT). High-risk departments such as respiratory department and outpatient clinic, medical intensive care unit, emergency department, microbiology laboratory, and radiology department were defined as TB-related departments. We collected data related to participants’ age, sex, occupation, hospital department, and years of employment; other electronic medical records were retrospectively reviewed. Previously healed TB lesions on chest radiographs were defined as calcified nodules or lymph nodes, discrete fibrotic scars with volume loss, or pleural thickening or calcification [8, 9]


The IGRA was performed using a QuantiFERON® TB-Gold In Tube test (QIAGEN, Hilden, Germany) following the manufacturer’s instructions. A positive IGRA result was defined as an interferon-gamma response to the TB antigen minus that of the nil tube of ≥ 0.35 IU/mL. Chest radiographs were evaluated to exclude active TB at the same period. The HCWs were diagnosed with LTBI if the IGRA results were positive.

Annual risk of tuberculosis infection (ARI)

The study subjects were divided into nine age groups (20–24, 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–60, and 60–69 years). ARIs were calculated based on the results of IGRAs using the following math formula [10]

  • ARI (%) = (1 − [1 − IGRA positive rate of each age group/100][1/mean age of each age group]) × 100

  • Midyear of TB infection (y) = 2017-mean age of each age group/2

Statistical analysis

Continuous variables were presented as means ± standard deviation (SD), or median and interquartile range (IQR), and were analyzed using the Student t-test or the Mann–Whitney test. Categorical variables were reported as number and percentage, and were analyzed using the chi-square test or Fisher’s exact test. To determine if IGRA positivity differed according to age in this study, we obtained the probability of a positive result in each subject using logistic regression and expressed it in the form of a figure. Risk factors associated with IGRA positivity were investigated using logistic regression models, and the results were reported as odds ratios (ORs) and 95% confidence intervals (CIs). All tests of significance were 2-tailed, and a p value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS software, version 23.0 (IBM, Armonk, NY, USA) and SAS 9.4 (SAS Institute, Cary NC).


Baseline characteristics of the study population

Overall, 3233 HCWs were analyzed after excluding 50 HCWs who had undergone previous anti-tuberculosis treatment or LTBI treatment (Fig. 1). We also excluded participants with presumptive active TB by chest x-ray and respiratory symptoms. There was no active TB case among our study participants.

Fig. 1
figure 1

Flowchart of the HCWs in the study. HCWs health care workers; IGRA interferon-gamma release assay; LTBI latent tuberculosis infection

Baseline characteristics of HCWs are shown in Table 1. Of the total 3233 HCWs, 2348 (72.6%) were female, and the median age was 38 (IQR 29–46). Occupationally, the proportion of heath aids, physicians, and nurses was similar. The working period was divided into groups ranging from less than 1 year to more than 30 years with the percentage of employees working for 10–20 years being the highest (30.1%). Forty-two HCWs (1.3%) reported healed TB lesion on chest x-ray. Overall, 780 of 3233 HCWs were IGRA positive (24.1%).

Table 1 Baseline characteristics of study population

Prevalence of LTBI and predicted probability for IGRA positivity according to age

Figure 2A shows the IGRA positive rate by age. Based on IGRA results, the prevalence of LTBI were 6.6% in the 20s, 14.4% in the 30s, 34.3% in the 40s, and around 50% in the 50s and 60s, respectively. As age increased, the likelihood of being positive on IGRA also increased, and the slope was 0.0929, which confirmed statistical significance (p < 0.001) (Fig. 2B). At age 40, the predicted probability of IGRA positivity was around 25% (Fig. 2B), and the results were confirmed to be similar to actual IGRA positive rates (Fig. 2A) (AUC = 0.749, diagnostic performance was good) [11] (Additional file 1: Fig. 1).

Fig. 2
figure 2

Prevalence of LTBI and predicted probability for IGRA positivity according to age. A IGRA positive rates according to age group. B Predicted probability for IGRA positivity according to age (p < 0.001)

Annual risk of tuberculosis infection (ARI)

Table 2 and Fig. 3 shows the annual risk of tuberculosis infection between 1986 and 2005. The ARIs were 0.26–1.35% between 1986 and 2005. The risk has gradually decreased over the last two decades.

Table 2 Annual risk of tuberculosis infection
Fig. 3
figure 3

Annual Risk of TB Infection between 1986 and 2005

Risk factors of IGRA positivity

Table 3 shows the risk factors associated with positive IGRA results. According to univariable analysis, older age group, male gender, healed TB on chest x-ray, and longer working duration were risk factors for IGRA positivity. On the other hand, currently working in high-risk (TB related) departments was not a risk factor for IGRA positivity. Even though doctors and nurses face patients directly, IGRA positivity was lower than that among administrative staff, which is explained by the fact that the average age of doctors and nurses was younger than that of administrative staff (Additional file 2: Table 1). In multivariable analysis, older age, healed TB lesion on chest x-ray, and male gender were risk factors for IGRA positivity, whereas currently working in high-risk TB department was not.

Table 3 Factors associated with positive IGRA results


In this study, using 3233 IGRA results of HCWs between 20 and 68 years of age, the overall prevalence of LTBI was 24.1%, and age was the strongest predictor of LTBI, rather than working in TB-related departments. The annual risk of TB infection ranged from 0.26 to 1.35% between 1986 and 2005, and its risk has gradually decreased over the last two decades.

ARI with Mycobacterium tuberculosis is known to be calculated from an observed prevalence of infection, approximating the incidence of infection. ARI for TB is one of the most important indicators for accessing its epidemiology in a population and is potentially informative about the transmission of TB within a community [12]. The main cause for the decline in ARI was a decreased prevalence of active TB in South Korea over 30 years, estimated from 443 to 167 cases per 100,000 population between 1985 and 2005, owing to economic growth and governmental effort to control TB via Bacillus Calmette–Guérin (BCG) vaccination, a TB notification system, and appropriate treatment through public health systems [3, 13]. Additionally, improvement on infection control at medical institutions is believed to have contributed to reducing ARI among HCWs.

To date, trends for TB prevalence and ARI have been documented in several countries, and most research has been based on national TST surveys [14,15,16]. In South Korea, Kim et al. reported that the prevalence of LTBI using TST in persons < 30 years of age decreased from 55.9% in 1965 to 30.8% in 1995. In conjunction with this change, the ARI of TB in persons < 30 years of age decreased from 5.3% in 1965 to 0.5% in 1995 [2]. The use of TST however, has a poor specificity due to its cross-reaction with BCG vaccine strain and nontuberculous mycobacteria. According to a study conducted in South Korea comparing TST and IGRA results according to TB infection risk [4], the agreement between TST and IGRA was not high, and IGRA was a better indicator of the risk of TB infection than TST in a BCG-vaccinated population. There have been attempts to estimate ARI using IGRA [17, 18]. Nishimura et al. used IGRA data from HCWs in a university hospital in Japan and reported estimated ARIs for TB of 0.156% in 1986 and 0.049% in 2004 [19]. In a recent prospective study of a population of 13,580 individuals in China, ARI was estimated by conversion of IGRA and TST [20]. The annual TB infection rate was suggested to be 3.1% based on IGRA conversion and 1.5% based on persistent positive results after IGRA conversion. Meanwhile, however, ARI based on TST conversion was 14.5%, suggesting of limitation of ARI estimation based on TST results. The study concluded that the use of IGRA was more accurate than TST when estimating ARI [20]. However, studies on ARI using IGRA results are lacking in South Korea. Among recent large-scale surveys, a survey of 2051 sample of the 2016 Korea National Health and Nutrition Examination Survey (KNHANES) showed that the overall prevalence of LTBI was 33.2% using TST results [3, 21], which was higher than our study results. Considering the false positivity of TST, we believed that our data using IGRA results would reflect more accurate LTBI prevalence and ARI in South Korea where BCG vaccination is mandatory.

Our study also suggested that LTBI was related to older age, healed TB lesion on chest x-ray, and male gender, and not to current occupation in high-risk TB department. Several previous studies reported that TB-related departments such as respiratory ward or clinic, medical ICU, and emergency department increased the risk of LTBI positivity as compared to other departments [22,23,24]. However, the majority of studies reporting such analyses were conducted in low-incidence settings. Contrarily, in countries with a relatively high TB burden, several studies have reported no significant differences in the LTBI positivity in HCWs working in TB-related department and other departments [25, 26]. The possible reasons for our results include a probability of casual contact with active TB patients in Korea, increased age regardless of working department, and adequate infection control in tertiary hospitals in our study setting.

Although the ARI for TB gradually decreased over 20 years in our study, LTBI prevalence and ARI among HCWs in South Korea were still higher than those in developed countries. This study also showed that the prevalence of LTBI was affected more by age-related risk exposure than working in a TB-related department. It is well known that exposure to TB at a young age and recent infection are major risk factors for the progression to active TB [27, 28]. Therefore, in South Korea, approaches to LTBI treatment among HCWs according to age should be differentiated due to a high likelihood of recent infections at a young age regardless of the department in which one is currently working.

This study has several limitations. First, we conducted this study at a single, tertiary hospital; hence, the findings may not be representative of HCWs in other hospital nor general population in South Korea. Second, in calculating ARI in this study, we used cross-sectional data rather than longitudinal data; hence, the accuracy of findings for old age may decrease given that the IGRA test scores wane as the age increases. Despite these limitations, to our knowledge, this is the first study in South Korea to report the estimation of ARI for TB based on IGRA results, and our study included large HCWs of different ages, working department, and working durations. Considering that age has a great impact on LTBI positivity, long-term follow-up studies are needed to identify how the progression from LTBI to active TB differs by age group.


Our study showed that ARI in HCWs in South Korea has gradually decreased over the last two decades, but LTBI was still considerably prevalent. We also suggest that LTBI among HCWs might be greatly affected by age, rather than occupational exposure in intermediate TB burden countries, hence different LTBI treatment strategies by age group should be considered.

Availability of data and materials

The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.





Latent tuberculosis infection


Annual risk of TB infection


Tuberculin skin test


Bacillus Calmette–Guérin


Healthcare workers


Interferon-gamma release assays


QuantiFERON® TB-Gold In Tube test


Nontuberculous mycobacteria


National Health and Nutrition Examination Survey


  1. WHO. Global tuberculosis report 2020. Geneva: World Health Organization; 2020.

    Google Scholar 

  2. Kim JH, Yim JJ. Achievements in and challenges of tuberculosis control in South Korea. Emerg Infect Dis. 2015;21(11):1913–20.

    Article  Google Scholar 

  3. Song JH, Huh K, Chung DR. Modern history of tuberculosis in Korea. Infect Chemother. 2019;51(4):414–26.

    Article  Google Scholar 

  4. Kang YA, Lee HW, Yoon HI, Cho B, Han SK, Shim YS, Yim JJ. Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA. 2005;293(22):2756–61.

    Article  CAS  Google Scholar 

  5. Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13(10):e1002152.

    Article  Google Scholar 

  6. Hong YP, Kim SJ, Lew WJ, Lee EK, Han YC. The seventh nationwide tuberculosis prevalence survey in Korea, 1995. Int J Tuberc Lung Dis. 1998;2(1):27–36.

    CAS  PubMed  Google Scholar 

  7. Neuenschwander BE, Zwahlen M, Kim SJ, Engel RR, Rieder HL. Trends in the prevalence of infection with mycobacterium tuberculosis in Korea from 1965 to 1995: an analysis of seven surveys by mixture models. Int J Tuberc Lung Dis. 2000;4(8):719–29.

    CAS  PubMed  Google Scholar 

  8. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167(4):603–62.

    Article  Google Scholar 

  9. Joint Committee for the Revision of Korean Guidelines for T, Korean Academy of T, Respiratory D, Korea Centers for Disease C, Prevention. Korean guidelines for tuberculosis. 3rd ed. Seoul: Joint Committee for the Revision of Korean Guidelines for Tuberculosis; 2017.

    Google Scholar 

  10. Cauthen GM, Pio A, ten Dam HG. Annual risk of tuberculous infection. 1988. Bull World Health Organ. 2002;80(6):503–11; discussion 501–2.

  11. Simundic A-M. Diagnostic accuracy, part 1: basic concepts. Point Care J Near-Patient Test Technol. 2012;11:6–8.

    Article  Google Scholar 

  12. Rieder H. Annual risk of infection with Mycobacterium tuberculosis. Eur Respir J. 2005;25(1):181–5.

    Article  CAS  Google Scholar 

  13. Cho KS. Tuberculosis control in the Republic of Korea. Epidemiol Health. 2018;40:e2018036.

    Article  Google Scholar 

  14. Vynnycky E, Fine PE. The annual risk of infection with Mycobacterium tuberculosis in England and Wales since 1901. Int J Tuberc Lung Dis. 1997;1(5):389–96.

    CAS  PubMed  Google Scholar 

  15. Shanaube K, Sismanidis C, Ayles H, Beyers N, Schaap A, Lawrence KA, Barker A, Godfrey-Faussett P. Annual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa. PLoS ONE. 2009;4(11):e7749.

    Article  Google Scholar 

  16. Sutherland I, Bleiker MA, Meijer J, Stýblo K. The risk of tuberculous infection in The Netherlands from 1967 to 1979. Tubercle. 1983;64(4):241–53.

    Article  CAS  Google Scholar 

  17. Díez N, Giner E, Latorre I, Lacoma A, Roig FJ, Mialdea I, Díaz J, Serra-Vidal M, Escribano A, Domínguez J. Use of interferon-gamma release assays to calculate the annual risk of tuberculosis infection. Pediatr Infect Dis J. 2015;34(2):219–21.

    Article  Google Scholar 

  18. Hamaguchi Y, Yamaguchi T, Nishiura H. Estimating the annual risk of tuberculosis infection in Japan from interferon-gamma release assay data. J Theor Biol. 2019;460:125–33.

    Article  Google Scholar 

  19. Nishimura T, Ota M, Mori M, Takano Y, Fujiwara H, Uwamino Y, Uno S, Hasegawa N. The annual risk of tuberculosis infection in newly hired researchers and healthcare workers using interferon-gamma release assay in Japan. J Infect Chemother. 2020;26(8):818–22.

    Article  Google Scholar 

  20. Gao L, Bai L, Liu J, Lu W, Wang X, Li X, Du J, Chen X, Zhang H, Xin H, et al. Annual risk of tuberculosis infection in rural China: a population-based prospective study. Eur Respir J. 2016;48(1):168–78.

    Article  CAS  Google Scholar 

  21. Korea Centers for Disease Control and Prevention. Korean National Tuberculosis Association. 7th Korea National Health and Nutrition Examination Survey, 1st year (2016) tuberculin survey support and quality control. Seoul: Korea Centers for Disease Control and Prevention; 2017.

    Google Scholar 

  22. Zwerling A, van den Hof S, Scholten J, Cobelens F, Menzies D, Pai M. Interferon-gamma release assays for tuberculosis screening of healthcare workers: a systematic review. Thorax. 2012;67(1):62–70.

    Article  Google Scholar 

  23. Vinton P, Mihrshahi S, Johnson P, Jenkin GA, Jolley D, Biggs BA. Comparison of QuantiFERON-TB Gold In-Tube Test and tuberculin skin test for identification of latent Mycobacterium tuberculosis infection in healthcare staff and association between positive test results and known risk factors for infection. Infect Control Hosp Epidemiol. 2009;30(3):215–21.

    Article  Google Scholar 

  24. Whitaker JA, Mirtskhulava V, Kipiani M, Harris DA, Tabagari N, Kempker RR, Blumberg HM. Prevalence and incidence of latent tuberculosis infection in Georgian healthcare workers. PLoS ONE. 2013;8(3):e58202.

    Article  CAS  Google Scholar 

  25. Kim S, Choi H, Jang YJ, Park SH, Lee H. Prevalence of and factors related to latent tuberculous infection among all employees in a referral hospital. Int J Tuberc Lung Dis. 2018;22(11):1329–35.

    Article  CAS  Google Scholar 

  26. Pai M, Gokhale K, Joshi R, Dogra S, Kalantri S, Mendiratta DK, Narang P, Daley CL, Granich RM, Mazurek GH, et al. Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing. JAMA. 2005;293(22):2746–55.

    Article  CAS  Google Scholar 

  27. Radhakrishna S, Frieden TR, Subramani R, Santha T, Narayanan PR. Additional risk of developing TB for household members with a TB case at home at intake: a 15-year study. Int J Tuberc Lung Dis. 2007;11(3):282–8.

    CAS  PubMed  Google Scholar 

  28. WHO. Latent TB infection: updated and consolidated guidelines for programmatic management. Geneva: WHO; 2018.

    Google Scholar 

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We thank Hee-Jin Kim, M.D., M.P.H. (Central Training Institute, Korean National Tuberculosis Association, Seoul, South Korea) for valuable comments and advice in this research.


This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C1235).

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Authors and Affiliations



EHL, NHS, and YAK are responsible for conception and design, development of methodology, analysis and interpretation, writing, reviewing, and revising the manuscript; SHK, JSC, MCK, CHS, SRK, and BHP contributed to the study conceptualization and design, and interpretation of the data; NHS performed the statistical analysis. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Young Ae Kang.

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Ethical approval and consent to participate

The research protocol was approved by the Institutional Review Board (IRB) of Severance Hospital (IRB No. 4-2017-1196). The need for informed consent was waived by the IRB of Severance Hospital due to the retrospective nature of the study. All methods were carried out in accordance with relevant guidelines and regulations.

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1: Figure 1.

Predictive value of Age for IGRA positivity.

Additional file 2: Table 1.

IGRA positivity according to occupation and working department.

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Lee, E.H., Son, NH., Kwak, S.H. et al. Decreased annual risk of tuberculosis infection in South Korean healthcare workers using interferon-gamma release assay between 1986 and 2005. BMC Infect Dis 21, 1161 (2021).

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