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A Study on the Relapse Rate of Tuberculosis and Related Factors in Korea Using Nationwide Tuberculosis Notification Data

Objectives From the perspective of public health, tuberculosis (TB) remains an important issue that threatens health. Korea is an intermediate burden country with a TB incidence of 97/100,000 individuals. Among many TB control measures, a relapse rate of TB is one indicator that can be used to indirectly assess the level of TB control in countries and in communities. Relapse TB has an approximately 12% yearly incidence in Korea. This study aims to estimate the relapse rate of TB and to investigate the associated factors by using nationwide TB notification data in Korea. Methods The nationwide TB notification data in 2005 was used with the exclusion criteria of duplicated reporting, foreign-born patients, outcome–died, and outcome–diagnosis changed. The data were double-checked as to whether they were reported again during 2006–2010 and the estimated relapse rate of TB. Associated factors were analyzed by multivariate logistic regression with the variables of age, sex, registration type, results of sputum smear test, medication, and outcome of treatment. Results Among 45,434 TB patients in 2005, 4,371 patients were again reported as TB patients from 2006 to 2010. Five hundred and sixty-four patients were reported more than twice and the cumulative number of relapses was 5,072 cases. The 5-year relapse rate was estimated as 9.62%. The relapse rate decreased yearly: 4.8% in 2006, 2.4% in 2007, 1.6% in 2008, 1.4% in 2009, and 1.0% in 2010. Age, sex, registration type, tuberculosis type, and medication were independently associated with a relapse of TB. In the multivariate logistic regression analysis, the following factors were related: male sex, 40–49 years old; registration type, relapse, treatment after failure, treatment after default, transfer in, and other, the sputum smear-positive pulmonary TB, and medications (including individuals taking 2–5 drugs). Conclusion This study has estimated a 5-year relapse rate of TB in Korea that is slightly lower than the rate of relapse TB in the annual reports. This study could be conducted and cross-checked with data from the National Health Insurance in the future.

. With a decrease of TB patients and low responding rate of the national survey, the national TB status has been identified on a report basis since 2000 [5]. The scale of TB patients has not been decreased, but remains steady [3,4] (Figure 1).
Deaths and the incidence rate caused by TB are also the highest among all infectious diseases. In fact, because of TB infection, Korea has the highest incidence and deaths among the 36 Organisation for Economic Co-operation and Development (OECD) countries and is 70 th e90 th among WHO member states [1]. The patients are mostly distributed in their 20e40s (40%), which is a typical aspect of developing countries. Tuberculosis in Korea was mostly controlled by public health centers, but private hospitals have gradually taken over this role since the mid-1990s, and above 85% of TB patients are treated and controlled in private hospitals since 2010 [3,4,6].
Tuberculosis relapse is divided into two classes: (1) a patient in whom the initial onset has been treated, but the existing M. tuberculosis reactivates into a second onset of TB; and (2) a patient with reinfection with new M. tuberculosis [7,8]. To distinguish between these two classes, genotyping is necessary but unfeasible for every patient. Korea does not identify these two classes [i.e., relapse (reactivated onset) and reinfection] [9]. The relapse rate differs by a country's incidence and control: 0e27% of TB relapses occur within 2 years after treatment completion and most relapses occur within 5

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years; however, some relapses occur 15 years after treatment. In low incidence countries, most relapses occur within 2 years of treatment completion; however, in high incidence countries, relatively high relapse 2 years after treatment completion can be attributed to the relatively high chance of reinfection [10e12]. Among many indicators to control TB, the relapse rate is an indicator that can be used to evaluate a community's level of tuberculosis control [13]. According to the Korea Tuberculosis Annual Report, approximately 12% of annual reported cases are reported as relapse tuberculosis [3,4]. However, no national level study has been conducted with the exception of studies on specific medical institution or TB patients with antimicrobial resistance. This study aims to estimate the relapse rate of TB in Korea by using national data on reported cases and find factors related to the relapse of TB.

Study participants
The data source is the national reported cases of TB patients registered in the TB Integrated Information System (TBnet). The study participants were TB patients registered in TBnet in 2005. The exclusion criteria were patients with duplicate reports, foreigners, chronic TB cases, death after treatment, and changed diagnosis. Among 46,969 patients registered in TBnet in 2005, the following were excluded: 718 duplicate reports, 388 foreigners, 49 changed diagnosis, 262 deaths after treatment, and 118 chronic cases. In this study, 45,434 TB patients were analyzed ( Figure 2).
The data used in this study did not require the submission of informed consent from the patients because the report is mandatory by the tuberculosis prevention law. The author received the data with no personal information and the computer to access the data was not connected with an outside network. This study was approved by the Institutional Review Board of the Korea Centers for Disease Control and Prevention, Cheongju, Korea (No. 2012-05CON-15-P).

Data analysis
Descriptive epidemiological analysis was conducted for the general characteristics of study patients. The Chisquare test was performed for major variables and relapse with 0.05 significance level. Multivariate logistic regression analysis was conducted to analyze factors associated with relapse of TB. SAS 9.2 for Windows (SAS Inc., Cary, NC, USA) was used for data analysis.

General characteristics and variables
The characteristics of TB patients registered in TBnet 2005 were the following. More than one-half (62.1%) of the patients were men. The average age was 47.5 AE 19.8 years. Most patients were above the age of 20 years: 214 patients were aged < 10 years; 2,443 patients were aged 10e19 years; 8134 patients were aged 20e29 years; 7,299 patients were aged 30e39 years; 7338 patients were aged 40e49 years; 5,675 patients were aged 50e59 years; 6,293 patients were aged 60e69 years; and 8,038 patients were aged ! 70 years. The registration types were the following: 34,569 new cases; 5611 relapses; 654 re-registration after cease; 1,812 move-in; and 2,505 others. There were 15,745 sputum smearpositive pulmonary TB cases; 23,437 sputum smearnegative pulmonary TB cases; and 6,216 extrapulmonary TB cases. Group 1 medicines alone were used by 43,276 patients, but 2,158 patients used the other medicine groups. Based on age, location of medical

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H. Lee, J. Kim institution, registration type, and TB type, the number of male patients was statistically significantly greater than the number of women (Table 1).

Factors associated with the relapse rate
Among 45,434 patients in 2005, 4,371 persons were re-reported during the following 5-year period (i.e., 2006e2010). The total number of re-reported cases was 5072 reports with the exclusion of 564 duplicate reports. Therefore, the 5-year relapse rate of TB was 9.62, based on the number of patients. The annual relapse rate  (Figures 3 and 4).
The Chi-square test showed that the relapse rate in public health center patients with treatment results were associated with age, sex, registration type, TB type, and medicine. With these variables, multivariate logistic regression was performed to confirm that most related variables in the Chi-square test were also related.
The relapse rate for all study patients was higher in men than in women with an odds ratio of 1.33 [95% confidence interval (95% CI), 1.24e1.43]. Because of the small size of the < 10-year-old group, the reference was patients in the 10s age group and the odds ratio of relapse in the 40s age group was significant at 1.20 (95% CI, 1.01e1.42); however, the other age groups did not show a significant difference. Compared to users of private medical institutions, public health center users were more likely to relapse with an odds ratio of 1.23    Table 3). For patients in public health centers, all dropout records were input and a multivariate logistic regression was performed. Public health centers rarely used Group 2 medicines (< 1%); therefore, they were excluded in the analysis. In the multivariate analysis among the patients in public health centers, the relapse rate was not associated with age. This finding was different from the analysis

Interpretation of the results
This study aimed to identify factors associated with relapse of TB in Korea by using national reported case data. The relapse rate for a 5-year period in this study was 9.6%, which was lower than the rate reported in the Annual Report on the Notified Tuberculosis Patients in

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H. Lee, J. Kim Korea [3,4]. The relapse rate did not include relapse after the 5-year period. The reported rate of private medical institutions was estimated below 60%. The TB infection of risk groups such as residents in unauthorized facilities and homeless people was not identified. For various reasons, the relapse rate in this study was underestimated in comparison to the annual reported relapse rate. The relapse of TB can be divided into two categories: (1) recurrence by reactivation of same bacteria in the previous infection and (2) reinfection. These two factors can be confirmed with genotyping, but in this study with national reported cases, the patients' clinical data could not be attained; therefore, recurrence and reinfection could not be identified [7,9]. Korea does not conduct TB DNA finger printing tests on TB patients, and a special methodology is necessary to distinguish between these two aspects. A literature review indicates that within 2 years of treatment more cases of recurrences result from reactivation of existing bacteria and more cases of reinfection occur after 2 years of treatment with another person's TB bacteria. A high TB incidence rate is controversially associated with reinfection [10,14]. In this study, 42% of the relapsed TB patients had relapsed within 1 year and 65% of patients had relapsed within 2 years. If we were to extend the follow-up period, the relapse rate within 2 years would be lower. This finding contrasted with the results of existing studies. A study conducted in one private hospital revealed that 80% of TB patients with completion of treatment needed additional treatment [8,9,15]. Compared to the existing study in Korea, the relapse rate in 2 years after treatment was lower and closer to the other country's study results [8,9,15].
The relapse of TB was higher in men, which is the case with TB infection. The relapse rate by sex was higher in some studies, but other studies show no relation [16,17]. This study also confirmed that men relapsed more, based on Chi-square and multivariate regression analyses. Relapse occurred more in patients in the 40s, 50s, and 60s age groups. This may be associated with the increase of TB patients and latent tuberculosis infection. However, there was no relation between age and the relapse rate in this study's multivariate logistic regression with patients registered in the public health centers with treatment results available. This suggests that previous treatment results, rather than age effect, affects the relapse of TB.
To confirm the same results in the all TB patients, it is necessary to secure treatment results in patients treated and controlled by private medical institutions. Among patients using private medical institutions, the relapse rate was higher compared to the rate of public health centers. This finding could be explained in that first infected TB patients treated by Group 1 medicines were mostly treated in public health centers, whereas incurable TB patients with relapsed TB or antimicrobial-resistant TB were treated in private medical institutions. Furthermore, treatment dropout is also relatively higher in private medical institutions [6].
Compared with new cases, relapsed patients, treatment failure patients, and re-registered patients after cease of treatment were more highly relapsed. It may be that patients with second treatment are more relapsed, compared to patients with new cases. In particular, patients with treatment failure could be relapsed again, even with full recovery after long-term treatment. These results corresponded with the results of existing studies that factor in relapse is previous TB infection [14].
The relapse of patients with treatment failures were also far higher (Tables 4 and 5). Treatment failure is mostly attributable to antimicrobial-resistant tuberculosis. The relapse could be high, even after full recovery after long-term treatment.
It could be a good method to lower the relapse by managing the first TB-infected patients to take medicine thoroughly and periodically not to fail treatment [15]. For convenience of intake, the everyday intake of medicines is better for lowering TB relapse, compared to taking medicines two or three times weekly. Directly observed therapy (DOT) in general lowers the relapse rate, but some researchers are suspicious of the effectiveness of DOT [8,18]. The relapse rate with short-term chemical therapy (e.g., rifampin) is < 5%; however, this studys relapse rate of patients with full recovery using public health centers with treatment results was 7.3%. This rate was higher than the rate reported in existing studies [19]. Patients with an irregular medicine intake period, a cavity observed on chest X-ray, and sputumpositive results after a 2 month-intake of medicine have a relapse rate >5%; however, in this study, no clinical data were secure and could not be confirmed [18]. The completion patients' relapse rate was 11.7%, which is higher than the relapse rate of patients with full recovery.
Without confirming negative TB, completion patients, who were in reality treatment failures, could be reported as relapse patients [20]. Move-out patients also showed a higher relapse rate. This may be because the patients were no longer treated without move-in to other medical institutions. However, more study on conformity is needed.

Strength and limitations
Studies outside Korea indicate relapse factors of TB such as irregular intake of medicine, alcoholism, smoking, previous history of TB infection, and diseases accompanied by a decline in immunocompetence [15]. This study could not investigate the associated factors of behavior or clinical situations of patients and did not confirm factors. Furthermore, no questionnaires were conducted to investigate the behaviors and socioeconomic characteristics of patients and this study

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has limited variables [15]. Private medical institution had limited results after dropout of the registry; therefore, no relapse rate was calculated for the dropout patients. Medical doctors and medical institution are required to report TB patients, but it is not mandatory to report treatment and control of TB patients. To overcome this limit, the National Health Insurance data should be utilized for the visit period, TB bacteria test date, medicine intake information, insurance type, and insurance premium. This current study's limitation would also be overcome by surveying a sample representative population to cover health behavior and socioeconomic status. In the disease code after 2008, multidrug-resistant TB and extensively drug-resistant TB were introduced as "U88.0" and "U88.1", respectively. Using reported cases after 2008, a study on the relapse of antimicrobialresistant TB patients could be conducted, which this

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H. Lee, J. Kim study did not investigate. However, this study has a strong point in that it secured representativeness and confidence of data by using national TB reported cases, and calculated the relapse rate of tuberculosis in Korea, and identified factors associated with relapse of TB.

Conflicts of interest
The authors have no conflicts of interest to declare.