Background
According to the report of World Health Organization (WHO), there are about 8.6 million incident cases of tuberculosis (TB) and about 1.3 million deaths from TB annually [
1]. A Stop TB Partnership has been established to reduce the TB burden to less than 100,000 cases per year by 2050 by focusing on areas of high TB burden [
2]. However, persons in close contacts with TB patients are also at a risk of contracting latent TB infection (LTBI). In 2010, the WHO estimates that nearly 1/3 of the world's population contracted LTBI, and that 10% of these carriers will develop an active TB infection [
3]. The vast majority of these patients will become infectious and perpetuate the cycle of morbidity and mortality. Therefore, it is imperative to diagnose LTBI patients early and efficiently to reduce the global burden of TB.
The traditional method to diagnose TB infection is tuberculin skin test (TST). However, this test does not discriminate LTBI patients. The FDA recently approved the use of interferon gamma release assays (IGRAs) such as the QuantiFERON-TB Gold
® (QFT-G) assay for the diagnosis of LTBI [
4]. In 2011, Korean guidelines stipulate that IGRAs are an alternative method of TST for the diagnosis of LTBI [
5]. IGRAs have some advantages over TST. First, IGRAs lack booster effect. Second, BCG vaccination and infection by non-tuberculosis mycobacterium (NTM) has less effect on the IGRA than on the TST. Third, the patients don't need to revisit for reading the results [
6]. There are several risk factors known to be associated with developing active TB in close contacts, including malnutrition, untreated LTBI, being a household contact, age under 5 years, acid-fast bacilli (AFB) positivity of source case, concomitant human immunodeficiency virus infection, and immunocompromised status [
7],[
8]. However, there is limited data about risk factors for LTBI in close contacts.
The present study was conducted to identify the predominant risk factors of contracting the latent form of the disease and to compare the efficiency of the TST and QFT-G to diagnose LTBI subjects in close contacts of active pulmonary TB patients.
Discussion
This study showed that positive rate of TST and QFT-G is high in those who are in close contact with active pulmonary TB patients. History of TB and household contact were significantly associated with the risk of TST positivity and concordance between TST and QFT-G was 70.4%.
The prevalence of LTBI is expected to be high in close contacts of active TB patients. The prevalence of LTBI in close contacts was reported to be highest among many risk groups for LTBI, including close contacts, foreign-born people, homeless people, injection drug users, and prisoners [
11]. Furthermore, close contact is one of the common risk factor for progression from LTBI to active disease [
11]. In the present study, the positive rates of TST and QFT-G were 38.0% and 28.6% respectively, in South Korean population. Marks et al. reported that a prevalence of LTBI is about 36% in close contacts of persons with infectious TB as assessed by TST in a study conducted in the United States [
12]. Meanwhile, the prevalence of LTBI in household contacts in countries with a high burden of TB is diversely reported from 27% to 93%, again based on TST [
13]. The positive rate of QFT-G in contact investigation for TB was 30.2% in Germany and 19% in Taiwan [
14],[
15]. Given that South Korea has an intermediate burden of TB cases and almost every child receives BCG vaccination at birth, the positive rates of both tests in this study, especially of QFT-G, were considerably high. In a previous multi-center study conducted in South Korea, the positive rate of QFT-G in health care workers was 17.2% and that of TST was 36.7% [
16]. Because QFT-G is not affected by the previous BCG vaccination and most of the NTM infection, high positive rate of QFT-G in this study reconfirms the incidence of LTBI in close contacts of active TB patients is quite high in South Korean population.
Increasing age was significantly associated with TST positivity, but not with QFT-G positivity in the current study. Li et al. reported that prevalence of TST positivity significantly increased with age [
17]. Furthermore, according to the reports of Pareek et al. and Shanaube et al., the result of QFT-G as well as that of TST was associated with increasing age [
18],[
19]. It is uncertain whether increased age is the risk factor of contracting LTBI or whether increased cumulative exposure to
Mycobacterium tuberculosis and/or NTM as people grow older increases positivity of both tests.
Active TB is reported to be more prevalent in men than in women, but reasons for this phenomenon are uncertain due to the lack of studies about gender differences in patients with TB. Gender differences in patients with LTBI were also not studied much. In our study, male gender significantly increased relative risk of TST positivity but not of QFT-G positivity. More data will be needed to clarify the influence of gender in the incidence of LTBI.
The occurrence of LTBI in close contacts with previous pulmonary TB history was significantly high in this study. We aimed to assess the association between previous history of pulmonary TB and the risk of contracting LTBI because the impact of previous history of pulmonary TB on the LTBI had not been well studied. TST and QFT-G are methods to measure lasting adaptive immune responses to
Mycobacterium tuberculosis rather than to identify LTBI directly [
20]. Direct identification of LTBI was impossible until recently. Although IGRA is a officially approved test for the diagnosis of LTBI, Kim et al. reported that IGRA has a limited role in the diagnosis of TB infection in individuals with a history of TB [
21]. Thus, it is uncertain whether positive results of TST and QFT-G depend on the presence of living mycobacteria or persistent immune responses of previous TB infection. Nevertheless, close contacts of active TB patients are at a high risk of infection, and QFT-G is suggested to detect INF-γ released by effector T-cells rather than memory T-cells within a short period of incubation [
22],[
23]. It is therefore mandatory to study the effects of previous TB history on LTBI, including through clinical trials, and to understand the molecular basis of T-cell responses.
Household contact increased the risk of TST- and IGRA-positivity in previous studies [
24],[
25]. Likewise, the result of current study showed that household contact significantly increased relative risk of being TST positive and QFT-G was tend to be more positive in household contacts. It is therefore reasonable to pay particular attention to household contacts during the contact investigation of active TB.
The agreement and kappa values of concordance of TST and IGRA have been reported widely in TB contacts [
9],[
15],[
26]. The common outcome of those studies is that BCG vaccination lowered the agreement between the two tests. In one study performed in Denmark, in which about two-thirds of enrolled subjects were not vaccinated with BCG, the agreement between TST and QFT-G was 94% (κ = 0.866) [
9]. In contrast, most of the people in Korea receive BCG vaccine, and the agreement of two tests in this study was much lower (70.4%, κ = 0.392). In this study, only 11 of 203 subjects who received both tests were not vaccinated with BCG. Thus, subgroup analysis for non-BCG vaccinated people did not show significant results (data not shown). Additionally, high rate of BCG vaccination lowered the statistical power to assess the impact of BCG vaccination on TST or QFT-G. In this study, 11 subjects were QFT-G positive but TST negative. The result of QFT-G might be false positive even though we could not verify the baseline result of QFT-G before contact to active TB patients. Performing QFT-G test repeatedly will be helpful to clarify this issue.
While designing this study, we assumed that smear status and presence of cough in source cases might be important factors influencing the occurrence of LTBI. However, our results show that none of these were risk factors. Therefore, the limitations of this study are as follows. First, the number of enrolled subjects is relatively small because people in Korea are not aware of the concept of LTBI and the importance of screening contacts of TB patients. The knowledge about LTBI needs to be spread among the Korean people. Second, of the 308 enrolled subjects, only 203 subjects were willing to take both TST and QFT-G tests, because we gave them an option of choosing between TST and/or QFT-G according to the Korean guidelines. Both single screening strategy using TST or IGRA and dual screening strategy using TST and subsequent IGRA were recommended in the Korean guidelines. Third, in 65 among 203 subjects who took both tests, QFT-G was conducted later than TST and in 28 among those 65 subjects, the interval between two tests was over 4 days. Van Zyl-Smit et al. have reported that a booster effect of PPD was evident by day 7 post-TST, but not by day 3 [
27]. The booster effect of PPD might have caused false-positive results of QFT-G in some of the subjects in this study. Fourth, the level of contact was not categorized in depth. In particular, in subjects who were a household contact, whether they lived in the same room or not would be an important factor influencing their LTBI risk.
Authors' contributions
HCK and SJL are guarantors of the manuscript. H.C. Kim: contributed as the corresponding author, reviewing all data, and revising the manuscript. SJL: contributed as the primary author, reviewing all data, and writing the manuscript. YEK: contributed to the preparation of the manuscript, and read and approved the final manuscript. YJC: contributed to the preparation of the manuscript, and read and approved the final manuscript. YYJ: contributed to the preparation of the manuscript, and read and approved the final manuscript. JDL: contributed to the preparation of the manuscript, and read and approved the final manuscript. JRK: contributed to the preparation of the manuscript, and read and approved the final manuscript. YSH: contributed to the preparation of the manuscript, and read and approved the final manuscript. HJK: contributed to the preparation of the manuscript, and read and approved the final manuscript. DM: contributed to the preparation of the manuscript, and read and approved the final manuscript. All authors read and approved the final manuscript.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Competing interests
All authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. The research was funded by Canadian Institutes of Health Research, NCT00170209.