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Sex differences in the impact of diabetes mellitus on tuberculosis recurrence: a retrospective national cohort study

  • Author Footnotes
    † These authors contributed equally to this article as first authors.
    Dararat Eksombatchai
    Footnotes
    † These authors contributed equally to this article as first authors.
    Affiliations
    Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of Korea

    Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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  • Author Footnotes
    † These authors contributed equally to this article as first authors.
    Dawoon Jeong
    Footnotes
    † These authors contributed equally to this article as first authors.
    Affiliations
    Research and Development Center, The Korean Institute of Tuberculosis, Korean National Tuberculosis Association, Cheongju, Republic of Korea
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  • Jeongha Mok
    Affiliations
    Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea
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  • Doosoo Jeon
    Affiliations
    Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
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  • Hee-Yeon Kang
    Affiliations
    Department of Health Policy and Management, Seoul National University College of Medicine, Seoul, Republic of Korea
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  • Hee Jin Kim
    Affiliations
    Central Training Institute, Korean National Tuberculosis Association, Seoul, Republic of Korea
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  • Hee-Sun Kim
    Affiliations
    Department of Health Policy Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Republic of Korea
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  • Hongjo Choi
    Correspondence
    Co-Corresponding author. Hongjo Choi, Department of Preventive Medicine, Konyang University College of Medicine, 705 Ho, Myeongkok Medical Building, 158 Gwanjeodong-ro, Seo-gu, Daejeon 35365, Republic of Korea, Tel: +82-42-600-8671, Fax: +82-42-600-8629
    Affiliations
    Department of Preventive Medicine, Konyang University College of Medicine, Daejeon, Republic of Korea
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  • Young Ae Kang
    Correspondence
    Corresponding author. Young Ae Kang, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea, Tel: +82-2228-1954, Fax: +82-393-6884
    Affiliations
    Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of Korea

    Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    † These authors contributed equally to this article as first authors.
Open AccessPublished:November 30, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.037

      Highlights

      • Diabetes mellitus was associated with a higher risk of tuberculosis (TB) recurrence.
      • Diabetes mellitus is associated with TB recurrence, especially in men.
      • TB recurrence was at its highest 2 years after successful treatment.
      • The time to TB recurrence was shorter in patients with diabetes mellitus.

      Abstract

      Objectives

      Whether diabetes mellitus (DM) increases tuberculosis (TB) recurrence risk is debatable. We determined the effect of DM on TB recurrence.

      Methods

      This retrospective nationwide cohort study included patients with TB who successfully completed TB treatment during 2011-2017 and were followed up for TB recurrence until August 2020. We performed subdistribution hazard model analyses stratified by sex to assess DM risk related to TB recurrence after successful treatment.

      Results

      Of 199,571 participants who had received successful TB treatment, 47,952 (24%) had DM. There were more men (64.4%), positive acid-fast bacilli smears (35.9%), and positive cultures (49.5%) in the DM group. There were 6208 (3.1%) TB recurrences during 5.1 years of follow-up: 38.9% and 26.6% occurred 1 and 1-2 years after treatment completion, respectively. The recurrence rate was higher in the DM group (3.8%) than in the non-DM group (2.9%, P <0.0001). DM was associated with a higher TB recurrence risk, especially in men (adjusted hazard ratio 1.23, 95% confidence interval 1.15-1.32) but not in women (adjusted hazard ratio 0.96, 95% confidence interval 0.85-1.09).

      Conclusion

      The TB recurrence rate after successful treatment was higher in patients with DM than in patients without DM. DM is associated with TB recurrence in men.

      Keywords

      Introduction

      Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. According to a World Health Organization [

      World Health Organization. Global tuberculosis report 2021, https://apps.who.int/iris/handle/10665/346387; 2021 [accessed 01 July 2022].

      ] report, there were 5.8 million new patients with TB, with an estimated 1.5 million fatalities in 2020. Diabetes mellitus (DM) affects approximately 537 million adults worldwide, with the majority living in low- and middle-income countries. DM was directly responsible for 6.7 million deaths in 2021 [

      International Diabetes Federation, IDF diabetes Atlas. 10th ed., https://www.diabetesatlas.org; 2021 [accessed 01 July 2022].

      ]. The total number of diabetics is projected to increase to 783 million by 2045 [
      • Sun H
      • Saeedi P
      • Karuranga S
      • Pinkepank M
      • Ogurtsova K
      • Duncan BB
      • Stein C
      • Basit A
      • Chan JCN
      • Mbanya JC
      • Pavkov ME
      • Ramachandaran A
      • Wild SH
      • James S
      • Herman WH
      • Zhang P
      • Bommer C
      • Kuo S
      • Boyko EJ
      • Magliano DJ.
      IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045.
      ]. Over the last 3 decades, type 2 DM has increased dramatically across countries with varying income levels [

      World Health Organization. Diabetes, https://www.who.int/health-topics/diabetes#tab=tab_1; 2021 [accessed 01 July 2022].

      ]. The prevalence of DM among patients with pulmonary TB was estimated to be 13.73% worldwide, 13.59% in the western Pacific, and 14.62% in Southeast Asia [
      • Li M
      • Chen T
      • Hua Z
      • Yan H
      • Wang D
      • Li Z
      • Kang Y
      • Zhu N
      • Li C.
      Global, regional, and national prevalence of diabetes mellitus in patients with pulmonary tuberculosis: a systematic review and meta-analysis.
      ].
      DM is well known to be an unfavorable companion for TB. Prospective cohort studies and systematic reviews revealed an increased risk of TB in individuals with DM [
      • Baker MA
      • Lin HH
      • Chang HY
      • Murray MB.
      The risk of tuberculosis disease among persons with diabetes mellitus: a prospective cohort study.
      ,
      • Jeon CY
      • Murray MB.
      Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies.
      ]. Immune cell function is compromised in individuals with type 2 DM, and they have a lower capacity to phagocytose Mycobacterium tuberculosis [
      • Restrepo BI
      • Twahirwa M
      • Rahbar MH
      • Schlesinger LS.
      Phagocytosis via complement or Fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia.
      ]. The clinical presentation of TB in patients with DM is also more severe, with more cavitary patterns on chest X-rays and a greater need for hospitalization at the time of diagnosis [
      • Moreno-Martínez A
      • Casals M
      • À Orcau
      • Gorrindo P
      • Masdeu E
      • Caylà JA
      TB
      Factors associated with diabetes mellitus among adults with tuberculosis in a large European city, 2000–2013.
      ]. In addition, unfavorable treatment outcomes were more likely linked to patients with TB-DM comorbidity. A previous study demonstrated that DM is associated with higher TB mortality, treatment failure, and positive culture after 2 months of treatment [
      • Baker MA
      • Harries AD
      • Jeon CY
      • Hart JE
      • Kapur A
      • Lönnroth K
      • Ottmani SE
      • Goonesekera SD
      • Murray MB.
      The impact of diabetes on tuberculosis treatment outcomes: a systematic review.
      ,
      • Degner NR
      • Wang JY
      • Golub JE
      • Karakousis PC.
      Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment.
      ,
      • Golub JE
      • Mok Y
      • Hong S
      • Jung KJ
      • Jee SH
      • Samet JM.
      Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality.
      ,
      • Huangfu P
      • Ugarte-Gil C
      • Golub J
      • Pearson F
      • Critchley J.
      The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis.
      ].
      However, studies identifying the association between DM and TB relapse or recurrence are limited and controversial. A systematic review and meta-analysis revealed that individuals with DM have an increased risk of recurrent TB [
      • Baker MA
      • Harries AD
      • Jeon CY
      • Hart JE
      • Kapur A
      • Lönnroth K
      • Ottmani SE
      • Goonesekera SD
      • Murray MB.
      The impact of diabetes on tuberculosis treatment outcomes: a systematic review.
      ,
      • Huangfu P
      • Ugarte-Gil C
      • Golub J
      • Pearson F
      • Critchley J.
      The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis.
      ]. Nevertheless, the majority of the included studies did not assess the significant confounding variables and had a small number of recurrent TB populations. In contrast, a systematic review and meta-analysis showed that DM was not associated with recurrent TB [
      • Qiu B
      • Wu Z
      • Tao B
      • Li Z
      • Song H
      • Tian D
      • Wu J
      • Zhan M
      • Wang J.
      Risk factors for types of recurrent tuberculosis (reactivation versus reinfection): A global systematic review and meta-analysis.
      ].
      The increased burden of DM can be a challenge to achieve the goal of TB elimination, and the association between DM and TB outcomes is an important public health issue. Furthermore, patients with recurrent TB were more likely to have poor treatment outcomes, especially treatment failure [
      • Ndambuki J
      • Nzomo J
      • Muregi L
      • Mutuku C
      • Makokha F
      • Nthusi J
      • Ambale C
      • Lynen L
      • Decroo T.
      Comparison of first-line tuberculosis treatment outcomes between previously treated and new patients: a retrospective study in Machakos subcounty.
      ]. We, therefore, conducted a retrospective cohort study using a large nationwide database to determine the impact of DM on TB recurrence.

      Methods

      Sources of data and collection

      The Korean Tuberculosis and Post-Tuberculosis cohort was constructed by linking the following three databases: (i) the Korean National Tuberculosis Surveillance System data regarding individuals with TB notified between 2011 and 2018, (ii) the National Health Information Database of individuals with a history of TB and related diseases between 2006 and 2018, and (iii) Statistics Korea data on the causes of death between 2011 and 2018 [
      • Jeong D
      • Kang HY
      • Kim J
      • Lee H
      • Yoo BN
      • Kim HS
      • Choi H.
      Cohort profile: Korean tuberculosis and post-tuberculosis cohort constructed by linking the Korean national tuberculosis surveillance system and National Health Information database.
      ].

      Study design and population

      This was a retrospective, nationwide cohort study of patients with TB. Initially, 305,260 patients with TB were linked through a combination of the Korean National Tuberculosis Surveillance System and the National Health Information Database, registered between 2011 to 2018. After excluding 65,412 individuals, 239,848 registered individuals with TB and treated between 2011 and 2017 were identified. We excluded patients with TB who registered in 2018 because the follow-up period for TB recurrence was insufficient. Among them, 199,571 patients with successful treatment were included in the final analysis to assess TB recurrence (Figure 1).
      Fig 1
      Fig. 1Flow diagram of the study population.
      DM, diabetes mellitus; TB, tuberculosis.

      Definition and measurement

      Exposure: DM

      DM was defined by any one of the following criteria 1 year before and after TB diagnosis: (i) at least two claims of the International Classification of Diseases coding for DM (E11-E14), and (ii) at least one claim of International Classification of Diseases code for DM and prescription of antidiabetic drugs for more than 4 weeks.

      Outcome: recurrence after successful treatment

      The treatment outcomes of TB were defined according to the criteria suggested by the World Health Organization [
      World Health Organization
      Definitions and reporting framework for tuberculosis.
      ] and reported to the National TB Surveillance System. The sum of the cured and treatment completed was designated as treatment success. The primary outcome of this study was TB recurrence, which can be either reactivated with the same strain (i.e., relapse) or reinfected with a new strain. We defined TB recurrence as reregistered patients with TB after treatment success of the initial TB treatment until August 31, 2020.

      Covariates

      Household income was classified into the fifth quintile (1 = the lowest, 5 = the highest) among health insurance beneficiaries, according to the national health insurance premium, and medical aid beneficiaries were classified into group 0. Variables that may influence the final treatment outcome, including age, sex, nationality, residential region, previous TB treatment history, lesion site, sputum smear results, sputum culture results, comorbidities (end-stage renal disease, cancer, and HIV status), and Charlson comorbidity index (CCI) [

      Canadian Institute for Health Information. Indicator. Library: General Methodology [notes]- Clinical Indictor. Ottawa: Canadian Institute for Health Information, 2021.

      ] were measured as covariates.

      Statistical analyses

      Continuous variables are presented as mean (SD) if the variables were normally distributed, otherwise described as median (interquartile range), and categorical variables are expressed as numbers (percentages). The Student's t-test was used if the variable was normally distributed and the Mann-Whitney test was used to compare continuous variables, and the chi-square test was used to compare categorical variables, as appropriate. The cumulative incidence function was used to estimate the recurrence rate, and the subdistribution hazard model was used to assess the risk of DM related to TB recurrence after successful treatment, considering competing risks. Model 1 was adjusted for age, region, household income, and nationality. Model 2 was adjusted for TB lesions, previous TB history, hospital joining public-private mix collaboration, acid-fast bacilli (AFB) smear, and culture in addition to model 1. Model 3 was adjusted for disability and comorbidity, in addition to model 2. Model 4 was adjusted for disability and CCI scores, in addition to model 2.
      All P-values were two-tailed, and a P-value of <0.05 was deemed statistically significant. All statistical analyses were performed using SAS Enterprise Guide (SAS Institute Inc., Cary, NC, USA) and STATA/MP version 17 (Stata Corp LLC, College Station, TX, USA).

      Results

      General characteristics

      Of 199,571 participants who had received successful treatment, 47,952 (24%) had DM (Figure 1). During the 5.1-year follow-up period, there were 6208 (3.1%) patients with TB recurrence, and the cumulative recurrence rate was 614.8/100,000 person-years (PY). The baseline characteristics of the study participants in the DM and the non-DM groups are shown in Table 1. In DM group, there were more men (64.4%) and older individuals (aged ≥65 years, 53.1%; Table 1). In addition, the proportion of patients with a positive AFB smear (35.9% vs 26.5%), a positive culture (49.5% vs 42.3%), and recurrent TB (3.8% vs 2.9%) was higher in the DM group than in the non-DM group (all P <0.0001). The general characteristics of the DM and non-DM groups stratified by sex were compared (Tables 2 and 3). There were 114,916 (57.6%) men and 84,655 (42.4%) women. Among the men and women, there were 4312 (3.8%) and 1896 (2.2%) patients with TB recurrence, respectively. The recurrence of TB occurred more commonly in the DM group than in the non-DM group in men (4.8% vs 3.4%, P <0.0001; Table 2) but not in women (2.0% vs 2.3%, P-value = 0.06; Table 3).
      Table 1General characteristics of the study population.
      VariablesTotalDiabetes mellitusNon-diabetes mellitusP-value
      199,57147,952151,619
      n (%)n (%)n (%)
      Gender<0.0001
      Men114,916 (57.6)30,874 (64.4)84,042 (55.4)
      Women84,655 (42.4)17,078 (35.6)67,577 (44.6)
      Age-group (year)<0.0001
      18-2414,157 (7.1)204 (0.4)13,953 (9.2)
      25-3426,389 (13.2)757 (1.6)25,632 (16.9)
      35-4426,988 (13.5)2858 (6.0)24,130 (15.9)
      45-5433,270 (16.7)7980 (16.6)25,290 (16.7)
      55-6432,474 (16.3)10,703 (22.3)21,771 (14.4)
      65-7430,244 (15.2)11,820 (24.7)18,424 (12.2)
      75+36,049 (18.1)13,630 (28.4)22,419 (14.8)
      Age; year, median (interquartile range)54 (38-70)66 (55-76)50 (34-66)<0.0001
      Region<0.0001
      Metropolitan88,844 (44.5)20,440 (42.6)68,404 (45.1)
      Others110,727 (55.5)27,512 (57.4)83,215 (54.9)
      Nationality<0.0001
      Korean194,852 (97.6)47,583 (99.2)147,269 (97.1)
      Others4719 (2.4)369 (0.8)4350 (2.9)
      Disability<0.0001
      No175,941 (88.2)38,577 (80.5)137,364 (90.6)
      Physical disability21,208 (10.6)7854 (16.4)13,354 (8.8)
      Internal disability2422 (1.2)1521 (3.2)901 (0.6)
      Household income<0.0001
      0 (Lowest)13,796 (6.9)5265 (11.0)8531 (5.6)
      131,989 (16.0)7596 (15.8)24,393 (16.1)
      232,790 (16.4)6721 (14.0)26,069 (17.2)
      335,512 (17.8)7435 (15.5)28,077 (18.5)
      438,884 (19.5)8948 (18.7)29,936 (19.7)
      5 (Highest)46,600 (23.4)11,987 (25.0)34,613 (22.8)
      Lesion of TB<0.0001
      Pulmonary170,906 (85.6)41,800 (87.2)129,106 (85.2)
      Extra-pulmonary28,665 (14.4)6152 (12.8)22,513 (14.8)
      TB history<0.0001
      New case174,967 (87.7)41,688 (86.9)133,279 (87.9)
      Previous treated case24,604 (12.3)6264 (13.1)18,340 (12.1)
      PPM hospitals<0.0001
      Non-PPM57,750 (28.9)13,181 (27.5)44,569 (29.4)
      PPM/Mix141,821 (71.1)34,771 (72.5)107,050 (70.6)
      Acid-fast bacilli smear<0.0001
      Positive57,469 (28.8)17,236 (35.9)40,233 (26.5)
      Negative107,467 (53.8)23,963 (50.0)83,504 (55.1)
      Unknown34,635 (17.4)6753 (14.1)27,882 (18.4)
      Culture<0.0001
      Positive87,794 (44.0)23,727 (49.5)64,067 (42.3)
      Negative56,826 (28.5)12,335 (25.7)44,491 (29.3)
      UNK54,951 (27.5)11,890 (24.8)43,061 (28.4)
      Charlson comorbidity index score<0.0001
      087,383 (43.8)14,987 (31.3)72,396 (47.8)
      184,634 (42.4)20,967 (43.7)63,667 (42.0)
      28616 (4.3)3381 (7.1)5235 (3.5)
      3 or above18,938 (9.5)8617 (18.0)10,321 (6.8)
      Comorbidity
      Transplantation532 (0.3)326 (0.7)206 (0.1)<0.0001
      HIV221 (0.1)54 (0.1)167 (0.1)0.89
      Cancer4063 (2.0)1515 (3.2)2548 (1.7)<0.0001
      End-stage renal disease2393 (1.2)1841 (3.8)552 (0.4)<0.0001
      Notification year<0.0001
      201132,713 (16.4)6690 (14.0)26,023 (17.2)
      201232,944 (16.5)7280 (15.2)25,664 (16.9)
      201329,564 (14.8)6827 (14.2)22,737 (15.0)
      201428,691 (14.4)6910 (14.4)21,781 (14.4)
      201526,513 (13.3)6806 (14.2)19,707 (13.0)
      201625,561 (12.8)6841 (14.3)18,720 (12.4)
      201723,585 (11.8)6598 (13.8)16,987 (11.2)
      Recurrence TB6208 (3.1)1825 (3.8)4383 (2.9)<0.0001
      PPM, public private mix; TB, tuberculosis.
      Table 2General characteristics of the study population in men.
      VariablesMen
      Diabetes mellitusNon-diabetes mellitusP-value
      30,87484,042
      n (%)n (%)
      Age-group (year)<0.0001
      18-24121 (0.4)7649 (9.1)
      25-34464 (1.5)13,199 (15.7)
      35-442240 (7.3)13,493 (16.1)
      45-546555 (21.2)15,625 (18.6)
      55-648260 (26.8)13,650 (16.2)
      65-747227 (23.4)10,677 (12.7)
      75+6007 (19.5)9749 (11.6)
      Age; year, median (interquartile range)62 (53-72)50 (35-64)<0.0001
      Region<0.0001
      Metropolitan13,577 (44.0)37,988 (45.2)
      Others17,297 (56.0)46,054 (54.8)
      Nationality<0.0001
      Korean30,648 (99.3)81,712 (97.2)
      Others226 (0.7)2330 (2.8)
      Disability<0.0001
      No24,832 (80.4)74,882 (89.1)
      Physical disability5062 (16.4)8542 (10.2)
      Internal disability980 (3.2)618 (0.7)
      Household income<0.0001
      0 (Lowest)3179 (10.3)4835 (5.8)
      14969 (16.1)13,262 (15.8)
      24744 (15.4)14,749 (17.6)
      35023 (16.3)15,834 (18.8)
      45862 (19.0)16,868 (20.1)
      5 (Highest)7097 (23.0)18,494 (22.0)
      Lesion of TB<0.0001
      Pulmonary27,701 (89.7)73,678 (87.7)
      Extra-pulmonary3173 (10.3)10,364 (12.3)
      TB history<0.0001
      New case26,055 (84.4)72,121 (85.8)
      Previously treated case4819 (15.6)11,921 (14.2)
      PPM hospitals<0.0001
      Non-PPM8998 (29.1)26,905 (32.0)
      PPM/Mix21,876 (70.9)57,137 (68.0)
      Acid-fast bacilli smear<0.0001
      Positive11,689 (37.9)23,108 (27.5)
      Negative15,681 (50.8)48,679 (57.9)
      Unknown3504 (11.4)12,255 (14.6)
      Culture<0.0001
      Positive15,932 (51.6)37,227 (44.3)
      Negative8048 (26.1)25,733 (30.6)
      Unknown6894 (22.3)21,082 (25.1)
      Charlson comorbidity index score<0.0001
      010,974 (35.5)42,464 (50.5)
      113,161 (42.6)33,576 (40.0)
      22036 (6.6)2853 (3.4)
      3 or above4703 (15.2)5149 (6.1)
      Comorbidity
      Transplantation231 (0.8)144 (0.2)<0.0001
      HIV47 (0.2)155 (0.2)0.25
      Cancer1136 (3.7)1625 (1.9)<0.0001
      End-stage renal disease1135 (3.7)298 (0.4)<0.0001
      Notification year<0.0001
      20114396 (14.2)14,410 (17.2)
      20124753 (15.4)14,187 (16.9)
      20134480 (14.5)12,531 (14.9)
      20144344 (14.1)11,999 (14.3)
      20154349 (14.1)10,991 (13.1)
      20164387 (14.2)10,477 (12.5)
      20174165 (13.5)9447 (11.2)
      Recurrence TB1475 (4.8)2837 (3.4)<0.0001
      PPM, public private mix; TB, tuberculosis.
      Table 3General characteristics of the study population in women.
      VariablesWomen
      Diabetes mellitusNon-diabetes mellitusP-value
      17,07867,577
      n (%)n (%)
      Age-group (year)<0.0001
      18-2483 (0.5)6304 (9.3)
      25-34293 (1.7)12,433 (18.4)
      35-44618 (3.6)10,637 (15.7)
      45-541425 (8.3)9665 (14.3)
      55-642443 (14.3)8121 (12.0)
      65-744593 (26.9)7747 (11.5)
      75+7623 (44.6)12,670 (18.8)
      Age; year, median (interquartile range)73 (62-79)49 (33-70)<0.0001
      Region<0.0001
      Metropolitan6863 (40.2)30,416 (45.0)
      Others10,215 (59.8)37,161 (55.0)
      Nationality<0.0001
      Korean16,935 (99.2)65,557 (97.0)
      Others143 (0.8)2020 (3.0)
      Disability<0.0001
      No13,745 (80.5)62,482 (92.5)
      Physical disability2792 (16.4)4812 (7.1)
      Internal disability541 (3.2)283 (0.4)
      Household income<0.0001
      0 (Lowest)2086 (12.2)3696 (5.5)
      12627 (15.4)11,131 (16.5)
      21977 (11.6)11,320 (16.8)
      32412 (14.1)12,243 (18.1)
      43086 (18.1)13,068 (19.3)
      5 (Highest)4890 (28.6)16,119 (23.9)
      Lesion of TB0.10
      Pulmonary14,099 (82.6)55,428 (82.0)
      Extra-pulmonary2979 (17.4)12,149 (18.0)
      TB history<0.0001
      New case15,633 (91.5)61,158 (90.5)
      Previously treated case1445 (8.5)6419 (9.5)
      PPM hospitals<0.0001
      Non-PPM4183 (24.5)17,664 (26.1)
      PPM/Mix12,895 (75.5)49,913 (73.9)
      Acid-fast bacilli smear<0.0001
      Positive5547 (32.5)17,125 (25.3)
      Negative8282 (48.5)34,825 (51.5)
      Unknown3249 (19.0)15,627 (23.1)
      Culture<0.0001
      Positive7795 (45.6)26,840 (39.7)
      Negative4287 (25.1)18,758 (27.8)
      Unknown4996 (29.3)21,979 (32.5)
      Charlson comorbidity index score<0.0001
      04013 (23.5)29,932 (44.3)
      17806 (45.7)30,091 (44.5)
      21345 (7.9)2382 (3.5)
      3 or above3914 (22.9)5172 (7.7)
      Comorbidity
      Transplantation95 (0.6)62 (0.1)<0.0001
      HIV7 (0)12 (0)0.07
      Cancer379 (2.2)923 (1.4)<0.0001
      End-stage renal disease706 (4.1)254 (0.4)<0.0001
      Notification year<0.0001
      20112294 (13.4)11,613 (17.2)
      20122527 (14.8)11,477 (17.0)
      20132347 (13.7)10,206 (15.1)
      20142566 (15.0)9782 (14.5)
      20152457 (14.4)8716 (12.9)
      20162454 (14.4)8243 (12.2)
      20172433 (14.3)7540 (11.2)
      Recurrence TB350 (2.0)1546 (2.3)0.06
      PPM, public private mix; TB, tuberculosis.

      Time table of recurrence after successful treatment

      The median time to TB recurrence was 497 (interquartile range, 238-943) days, which was significantly shorter in the DM group (462 days) than in the non-DM group (516 days, P <0.0001).
      Figure 2 shows the percentage of TB recurrence by follow-up years after successful treatment in patients with DM and without DM. Among 6208 TB recurrences, 38.9% were within 1 year (40.9% in DM, 38% in non-DM) and 26.6% were 1-2 years after the completion of the treatment (27.9% in DM and 26% in non-DM). Early recurrence within 2 years after the treatment completion was higher in patients with DM than those without DM (68.9% vs 64%, P-value = 0.007).
      Fig 2
      Fig. 2The percentage of TB recurrence by follow-up years after successful treatment in DM and non-DM groups.
      DM, diabetes mellitus; TB, tuberculosis.
      The cumulative recurrence rate in patients with DM (856.3/100,000 PY) was significantly higher than that in patients without DM (550.2/100,000 PY, P <0.0001). However, when analyzed by sex, it was only significant in men, as demonstrated in Figure 3.
      Fig 3
      Fig. 3The cumulative recurrence rate after treatment success in DM and non-DM groups by sex (a) Cumulative recurrence rate (Total). (b) Cumulative recurrence rate (Men). (c) Cumulative recurrence rate (Women).
      DM, diabetes mellitus.

      Different impact of DM on TB recurrence by sex

      To identify the impact of DM on TB recurrence, we analyzed the data stratified by sex using a subdistribution hazard model in survival analysis (Table 4).
      Table 4Impact of diabetes mellitus on TB recurrence after successful treatment stratified by sex.
      CrudeModel 1
      Model 1 was adjusted for age, region, household income, and nationality.
      Model 2
      Model 2 was adjusted for TB lesions, previous TB history, public private mix hospital, acid-fast bacilli smear, and culture, in addition to model 1.
      Model 3
      Model 3 was adjusted for disability and comorbidity, in addition to model 2.
      Model 4
      Model 4 was adjusted for disability and Charlson comorbidity index scores, in addition to model 2.
      HR95% CIaHR95% CIaHR95% CIaHR95% CIaHR95% CI
      Total
      DM
      No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
      Yes1.351.28-1.431.261.19-1.341.221.15-1.291.221.15-1.291.221.15-1.29
      Men
      DM
      No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
      Yes1.451.37-1.551.291.20-1.381.231.15-1.321.231.15-1.321.231.15-1.32
      Women
      DM
      No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
      Yes0.910.81-1.030.950.84-1.080.960.85-1.090.960.85-1.090.960.85-1.09
      HR, adjusted HR; CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; TB, tuberculosis.
      a Model 1 was adjusted for age, region, household income, and nationality.
      b Model 2 was adjusted for TB lesions, previous TB history, public private mix hospital, acid-fast bacilli smear, and culture, in addition to model 1.
      c Model 3 was adjusted for disability and comorbidity, in addition to model 2.
      d Model 4 was adjusted for disability and Charlson comorbidity index scores, in addition to model 2.
      DM was associated with a higher risk of TB recurrence in men (crude hazard ratio [HR] = 1.45, 95% confidence interval [CI] 1.37-1.55, P <0.0001). When we adjusted other covariates in model 1 to model 4, DM was still associated with increased risk for recurrence of TB in men (adjusted HR = 1.23, 95% CI 1.15-1.32, P <0.0001 in model 4). However, DM was not linked to an increased risk of TB recurrence in women (crude HR = 0.91, 95% CI 0.81-1.03, P-value = 0.13; and adjusted HR = 0.96, 95% CI 0.85-1.09, P-value = 0.55 in model 4).

      Discussion

      According to our findings from a nationwide cohort analysis, the prevalence of DM in participants who had successfully completed TB treatment was 24%. We discovered a 3.1% TB recurrence during 5.1 years of follow-up, with an incidence of 614.8/100,000 PY. The recurrence of TB was higher in patients with DM than those without DM (3.8 % vs 2.9%), and DM was associated with a higher risk of TB recurrence, especially in men. In addition, we found that TB recurrence was the highest 2 years after successful treatment, and the time to recurrence was shorter in patients with DM.
      In line with previous studies, patients with DM in the current study have a greater risk of TB recurrence [
      • Baker MA
      • Harries AD
      • Jeon CY
      • Hart JE
      • Kapur A
      • Lönnroth K
      • Ottmani SE
      • Goonesekera SD
      • Murray MB.
      The impact of diabetes on tuberculosis treatment outcomes: a systematic review.
      ,
      • Golub JE
      • Mok Y
      • Hong S
      • Jung KJ
      • Jee SH
      • Samet JM.
      Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality.
      ,
      • Huangfu P
      • Ugarte-Gil C
      • Golub J
      • Pearson F
      • Critchley J.
      The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis.
      ]. Patients with TB and DM tend to have more severe clinical manifestations, such as severe lung involvement with cavity, positive AFB smear, and a longer sputum culture conversion time, than those without DM [
      • Degner NR
      • Wang JY
      • Golub JE
      • Karakousis PC.
      Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment.
      ,
      • Chiang CY
      • Lee JJ
      • Chien ST
      • Enarson DA
      • Chang YC
      • Chen YT
      • Hu TY
      • Lin CB
      • Suk CW
      • Tao JM
      • Bai KJ.
      Glycemic control and radiographic manifestations of tuberculosis in diabetic patients.
      ,
      • Mi F
      • Tan S
      • Liang L
      • Harries AD
      • Hinderaker SG
      • Lin Y
      • Yue W
      • Chen X
      • Liang B
      • Gong F
      • Du J.
      Diabetes mellitus and tuberculosis: pattern of tuberculosis, two-month smear conversion and treatment outcomes in Guangzhou, China.
      ,
      • Naidoo K
      • Dookie N.
      Insights into recurrent tuberculosis: relapse versus reinfection and related risk factors.
      ]. Several studies have demonstrated that the immunity of individuals with hyperglycemia is impaired, including reduced polymorphonuclear leukocyte function, neutrophil chemotaxis, and phagocytosis [
      • Restrepo BI
      • Twahirwa M
      • Rahbar MH
      • Schlesinger LS.
      Phagocytosis via complement or Fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia.
      ,
      • Delamaire M
      • Maugendre D
      • Moreno M
      • Le Goff MC
      • Allannic H
      • Genetet B
      Impaired leucocyte functions in diabetic patients.
      ]. Alveolar macrophages were less activated in patients with TB and DM, which may increase vulnerability to mycobacterial infection [
      • Wang CH
      • Yu CT
      • Lin HC
      • Liu CY
      • Kuo HP.
      Hypodense alveolar macrophages in patients with diabetes mellitus and active pulmonary tuberculosis.
      ]. In addition, they are more prone to having delayed immune responses to TB infection [
      • Vallerskog T
      • Martens GW
      • Kornfeld H.
      Diabetic mice display a delayed adaptive immune response to Mycobacterium tuberculosis.
      ]. Therefore, low capacity of mycobacterial control in patients with DM can result in a higher risk of TB development, high bacillary burden, and recurrence of TB.
      Another factor that could explain TB recurrence in patients with DM might be the pharmacokinetic and pharmacodynamic effects of anti-TB drugs. A previous study showed that rifampicin concentrations were anticipated to be lower in patients with DM [
      • Chang MJ
      • Chae JW
      • Yun HY
      • Lee JI
      • Choi HD
      • Kim J
      • Park JS
      • Cho YJ
      • Yoon HI
      • Lee CT
      • Shin WG
      • Lee JH.
      Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampin in tuberculosis patients.
      ]. The absorption rate constant and the volume of distribution of rifampicin were found to be affected by DM [
      • Chang MJ
      • Chae JW
      • Yun HY
      • Lee JI
      • Choi HD
      • Kim J
      • Park JS
      • Cho YJ
      • Yoon HI
      • Lee CT
      • Shin WG
      • Lee JH.
      Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampin in tuberculosis patients.
      ]. Another study showed that patients with DM had lower pyrazinamide concentrations than those without DM [
      • Alfarisi O
      • Mave V
      • Gaikwad S
      • Sahasrabudhe T
      • Ramachandran G
      • Kumar H
      • Gupte N
      • Kulkarni V
      • Deshmukh S
      • Atre S
      • Raskar S
      • Lokhande R
      • Barthwal M
      • Kakrani A
      • Chon S
      • Gupta A
      • Golub JE
      • Dooley KE.
      Effect of diabetes mellitus on the pharmacokinetics and pharmacodynamics of tuberculosis treatment.
      ]. As a result, reduced anti-TB drug exposure may increase the risk of recurrence of TB. However, this issue remains contentious. Therefore, further research on anti-TB drug concentrations in DM and their impact on TB recurrence should be conducted.
      By analyzing the data stratified by sex, we found that DM was significantly associated with a higher risk of recurrent TB in men but not in women. We could not fully explain the reason for this difference in the effect of DM on TB recurrence according to sex in our study.
      Men had a higher rate of TB recurrence in some previous studies [
      • Hung CL
      • Chien JY
      • Ou CY.
      Associated factors for tuberculosis recurrence in Taiwan: a nationwide nested case-control study from 1998 to 2010.
      ,
      • Lee H
      • Kim J.
      A study on the relapse rate of tuberculosis and related factors in Korea using nationwide tuberculosis notification data.
      ]. Our findings support the notion that men have a greater rate of TB recurrence. On the other hand, the female sex was not a predictor of TB recurrence, implying that other variables, such as smoking, alcohol consumption, and chronic obstructive pulmonary disease (COPD), could be confounding factors.
      Previous research has revealed that smoking, drinking, and being underweight are risk factors for TB recurrence [
      • Khan A
      • Sterling TR
      • Reves R
      • Vernon A
      • Horsburgh CR.
      Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
      ,
      • Leung CC
      • Yew WW
      • Chan CK
      • Chang KC
      • Law WS
      • Lee SN
      • Tai LB
      • Leung EC
      • Au RK
      • Huang SS
      • Tam CM.
      Smoking adversely affects treatment response, outcome and relapse in tuberculosis.
      ,
      • Lin Y
      • Lin H
      • Xiao L
      • Chen Y
      • Meng X
      • Zeng X
      • Chang C
      • Brigden G
      Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.
      ,
      • Thomas BE
      • Thiruvengadam K
      • Rani S
      • Kadam D
      • Ovung S
      • Sivakumar S
      • Bala Yogendra Shivakumar SV
      • Paradkar M
      • Gupte N
      • Suryavanshi N
      • Dolla CK
      • et al.
      Smoking, alcohol use disorder and tuberculosis treatment outcomes: A dual co-morbidity burden that cannot be ignored.
      ]. However, we lacked information on these variables. As a result, confounding factors may explain the sex difference in the effect of DM on TB recurrence. Smoking statistics in the Republic of Korea showed that men smoke more than women [
      • Gunter R
      • Szeto E
      • Jeong SH
      • Suh SA
      • Waters AJ.
      Cigarette smoking in South Korea: a narrative review.
      ]. Nicotine inhibits macrophage production of tumor necrosis factor-α, which is considered to worsen the severity of the disease, and increase the risk of recurrence [
      • Lin Y
      • Lin H
      • Xiao L
      • Chen Y
      • Meng X
      • Zeng X
      • Chang C
      • Brigden G
      Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.
      ]. Sputum smears and cultures were more likely to remain positive after 2 months of treatment in smokers [
      • Leung CC
      • Yew WW
      • Chan CK
      • Chang KC
      • Law WS
      • Lee SN
      • Tai LB
      • Leung EC
      • Au RK
      • Huang SS
      • Tam CM.
      Smoking adversely affects treatment response, outcome and relapse in tuberculosis.
      ]. We could hypothesize that impaired host immunity in patients with DM, when combined with smoking in men, was associated with increased TB severity and slower microbiological responses. Therefore, men with DM may have a higher rate of TB recurrence.
      A study in Taiwan found that COPD was a risk factor for TB recurrence [
      • Hung CL
      • Chien JY
      • Ou CY.
      Associated factors for tuberculosis recurrence in Taiwan: a nationwide nested case-control study from 1998 to 2010.
      ]. In the Republic of Korea, the men had more COPD comorbidity than the women [
      • Lee EG
      • Rhee CK.
      Epidemiology, burden, and policy of chronic obstructive pulmonary disease in South Korea: a narrative review.
      ]. As a result, COPD could be another confounder. Further prospective research is required to determine whether smoking, alcohol consumption, and COPD are confounding factors in men with DM.
      For DM control status in men and women, we could not find a plausible explanation for the different effects of DM on TB recurrence by sex. In the Republic of Korea, lifestyle modifications, including regular exercise and diet control, are the basic nonpharmacological interventions and recommended to all adults with DM [
      • Hur KY
      • Moon MK
      • Park JS
      • Kim SK
      • Lee SH
      • Yun JS
      • Baek JH
      • Noh J
      • Lee BW
      • Oh TJ
      • Chon S
      • Yang YS
      • Son JW
      • Choi JH
      • Song KH
      • Kim NH
      • Kim SY
      • Kim JW
      • Rhee SY
      • Lee YB
      • Jin SM
      • Kim JH
      • Kim CH
      • Kim DJ
      • Chun S
      • Rhee EJ
      • Kim HM
      • Kim HJ
      • Jee D
      • Kim JH
      • Choi WS
      • Lee EY
      • Yoon KH
      • Ko SH
      Committee of Clinical Practice Guidelines, Korean Diabetes Association
      2021 clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association.
      ]. However, those who regularly walked for exercise (a minimum of 30 minutes per day, for ≥5 days per week) accounted for 38.1% of the adults with DM (37.2% in men and 39.4% in women) based on a Korea National Health and Nutrition Examination Survey [
      • Bae JH
      • Han KD
      • Ko SH
      • Yang YS
      • Choi JH
      • Choi KM
      • Won KC.
      Diabetes fact sheet in Korea 2021.
      ]. Among adults with DM, 61.4% were receiving oral glucose-lowering medications or insulin; however, only 24.5% of the adults with DM achieved a hemoglobin A1c target of <6.5% [
      • Bae JH
      • Han KD
      • Ko SH
      • Yang YS
      • Choi JH
      • Choi KM
      • Won KC.
      Diabetes fact sheet in Korea 2021.
      ]. According to a previous study in the Republic of Korea [
      • Choe SA
      • Kim JY
      • Ro YS
      • Cho SI.
      Women are less likely than men to achieve optimal glycemic control after 1 year of treatment: A multi-level analysis of a Korean primary care cohort.
      ], women are less likely than men to reach glycemic control targets without significant differences in DM treatment. Of our patients with TB-DM in 2013-2018, 79.6% received anti-DM medications. The proportion of metformin prescriptions was 38%; sulfonylurea, 24%; and insulin, 20%. We did not have information on DM control status in our cohort. We cannot conclude whether or not DM severity and treatment have an impact on sex differences in TB recurrence; therefore, these covariates should be investigated in future research.
      In addition to sex, a positive AFB smear, pulmonary TB, previous TB history, and lower household income were also associated with TB recurrence in our study (Supplementary Tables 1 and 2). These findings were consistent with those of previous studies [
      • Lee H
      • Kim J.
      A study on the relapse rate of tuberculosis and related factors in Korea using nationwide tuberculosis notification data.
      ,
      • Bestrashniy JRBM
      • Nguyen VN
      • Nguyen TL
      • Pham TL
      • Nguyen TA
      • Pham DC
      • Fox GJ.
      Recurrence of tuberculosis among patients following treatment completion in eight provinces of Vietnam: a nested case-control study.
      ,
      • Youn HM
      • Shin MK
      • Jeong D
      • Kim HJ
      • Choi H
      • Kang YA.
      Risk factors associated with tuberculosis recurrence in South Korea determined using a nationwide cohort study.
      ]. In particular, low socioeconomic status is associated with multiple biosocial determinants of TB, such as malnutrition, risk behaviors, and low access to health services [
      • Ortblad KF
      • Salomon JA
      • Bärnighausen T
      • Atun R.
      Stopping tuberculosis: a biosocial model for sustainable development.
      ]. Lower household income in our study may contribute to TB recurrence as an association with these multiple biosocial determinants of TB [
      • Hargreaves JR
      • Boccia D
      • Evans CA
      • Adato M
      • Petticrew M
      • Porter JD.
      The social determinants of tuberculosis: from evidence to action.
      ].
      This study has several strengths. First, this was a nationwide cohort study that investigated the impact of DM on TB recurrence. This cohort covered all patients with TB and had a long follow-up period. Second, we used an integrated dataset by linking three national databases; thus, we could analyze more relevant covariates, such as socioeconomic status and comorbidities. Despite these strengths, this study had some limitations. We could not access some of the information because we used data from a retrospective cohort. We lacked details on DM severity (hemoglobin A1c) and DM treatment. This information may have an impact on our findings because poorly controlled DM may influence the severity of TB and TB recurrence. To overcome this limitation, we used the CCI and household income level as covariates for the adjustment because these factors were also known as contributing factors for poor glycemic control in patients with DM [
      • Cottrell EK
      • O'Malley JP
      • Dambrun K
      • Park B
      • Hendricks MA
      • Xu H
      • DeVoe JE.
      The impact of social and clinical complexity on diabetes control measures.
      ,
      • Wilke T
      • Groth A
      • Fuchs A
      • Seitz L
      • Kienhöfer J
      • Lundershausen R
      • Maywald U.
      Real life treatment of diabetes mellitus type 2 patients: an analysis based on a large sample of 394,828 German patients.
      ]. However, in a future study, DM severity and DM treatment indicators should be included. Second, although we collected covariates, such as age, household income, previous TB history, AFB smear, and culture, we were unable to account for potential confounding factors that could have been linked to TB recurrence, including smoking, drinking, body mass index, and occupation. Moreover, factors affecting the severity of TB, particularly smear and culture status after 2 months of treatment, were not collected. Third, because TB genotyping could not be performed, we were unable to distinguish between relapse and reinfection.
      In conclusion, our study demonstrated that DM is associated with TB recurrence, especially in men. These findings support the notion that patients with DM, particularly men, should be prioritized for follow-up after successful TB treatment. Further research should be conducted to determine why TB recurrence predominantly occurs in men with DM, as well as whether it is related to smoking, alcohol consumption, COPD, and other sex-specific risk factors.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This study used the National Health Information Database (NHIS-2019-1-662) of the National Health Insurance Service. This study was supported by grants from the National Evidence-based Healthcare Collaborating Agency funded by the Ministry of Health and Welfare (grant nos. NC19-002, NC20- 003, and NC21-001), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C1235), and an intramural research grant from the Korean National Tuberculosis Association. The funding organizations played no role in the design of the study, choice of enrolled patients, review and interpretation of data, preparation of the manuscript, or final approval of the manuscript.

      Ethical approval

      The study protocol was reviewed and approved by the institutional review board of the National Evidence-Based Healthcare Collaborating Agency (NECAIRB19-008-1). The requirement for written informed consent was waived due to the retrospective nature of the study using public deidentified data.

      Author contributions

      DE contributed to interpretation, initial drafting of the manuscript, manuscript review and revision, and final approval of the version to be submitted. DJ participated in the design of the study, performed the data analysis and interpretation, and revised the manuscript. JM, DJ, HYK, HJK, and HSK contributed to interpretation and critically reviewed the manuscript for important intellectual content. HC and YAK conceptualized and designed the study, acquired and interpreted the data, reviewed and revised the manuscript, funding acquisition, and final approval of the version to be submitted.

      Appendix. Supplementary materials

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