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† 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 KoreaDepartment of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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
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
Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of KoreaDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
Diabetes mellitus was associated with a higher risk of tuberculosis (TB) recurrence.
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Diabetes mellitus is associated with TB recurrence, especially in men.
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TB recurrence was at its highest 2 years after successful treatment.
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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.
] 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
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 [
]. 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 [
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 [
]. 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 [
Cohort profile: Korean tuberculosis and post-tuberculosis cohort constructed by linking the Korean national tuberculosis surveillance system and National Health Information database.
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).
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 [
] 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.
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.
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. 2The percentage of TB recurrence by follow-up years after successful treatment in DM and non-DM groups.
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. 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).
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.
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 [
]. 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 [
]. Several studies have demonstrated that the immunity of individuals with hyperglycemia is impaired, including reduced polymorphonuclear leukocyte function, neutrophil chemotaxis, and phagocytosis [
]. 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 [
]. 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 [
]. 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 [
Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.
]. 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 [
]. 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 [
Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.
]. 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 [
]. 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 [
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 [
]. 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% [
], 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 [
]. In particular, low socioeconomic status is associated with multiple biosocial determinants of TB, such as malnutrition, risk behaviors, and low access to health services [
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 [
]. 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.
Cohort profile: Korean tuberculosis and post-tuberculosis cohort constructed by linking the Korean national tuberculosis surveillance system and National Health Information database.
Canadian Institute for Health Information. Indicator. Library: General Methodology [notes]- Clinical Indictor. Ottawa: Canadian Institute for Health Information, 2021.
Tuberculosis recurrence over a 7-year follow-up period in successfully treated patients in a routine program setting in China: a prospective longitudinal study.
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