Annals of the American Thoracic Society

Rationale: Although a history of pulmonary tuberculosis (PTB) is a risk factor for developing both chronic obstructive pulmonary disease (COPD) and lung cancer, it remains unclear whether a history of PTB affects lung cancer development in patients with COPD.

Objectives: To investigate whether a history of PTB is associated with an increased risk of lung cancer development in a population with COPD.

Methods: This cohort study included a nationwide representative sample of 13,165 Korean men and women with COPD, aged between 50 and 84 years. In addition, to assess whether the relationship between PTB and lung cancer risk differs between participants with and without COPD, a matched cohort without COPD was included. Participants were matched 1:3 for age, sex, smoking history, and PTB status based on the index health screening examination of corresponding participants with COPD. The two cohorts were followed up for 13 years (January 1, 2003, to December 31, 2015). PTB was diagnosed on the basis of the results of chest radiography, and incident lung cancer was identified from hospitalization and outpatient visit claims (International Classification of Diseases, Tenth Revision diagnosis code C33 or C34).

Results: During 370,617 person-years (PY) of follow-up (median follow-up, 7.7 yr) in the COPD group, we observed 430 incident cases of lung cancer in participants without a history of PTB (incidence rate, 524 per 100,000 PY) and 148 cases in those with a history of PTB (incidence rate, 931 per 100,000 PY). Compared with participants without a PTB history, the fully adjusted subdistribution hazard ratio (95% confidence interval [CI]) for lung cancer in those with a history of PTB was 1.24 (1.03–1.50). The association of PTB history and lung cancer development was more evident in never-smokers with COPD. In contrast, among participants without COPD, the corresponding hazard ratio (95% CI) was 0.98 (0.78–1.22). There was no interaction among PTB, smoking status, and COPD.

Conclusions: A history of PTB was associated with an increased risk of developing lung cancer among patients with COPD in our country with an intermediate tuberculosis burden. Patients with COPD with a history of PTB, particularly never-smokers, might benefit from periodic screening or assessment for lung cancer development.

Chronic obstructive pulmonary disease (COPD) is an established risk factor for lung cancer development (1), and lung cancer is the major cause of death in patients with COPD (2, 3). Smoking is the most commonly encountered risk factor for COPD and lung cancer, and this relationship is explained by the persistent low-grade systemic inflammation caused by smoking (4). However, up to 39% of patients with COPD are never-smokers (5), and a recent large national cohort study showed that COPD was also an independent risk factor for lung cancer development in never-smokers (6). Never-smoker patients with COPD may have an increased lung cancer risk due to occupational exposure, indoor and outdoor air pollution, and a history of other respiratory diseases (710).

A history of pulmonary tuberculosis (PTB) is a risk factor for lung cancer development (1116). Given that a chronic inflammatory process is a potential mechanism of lung cancer development in patients with COPD (17, 18), a history of PTB might add to the risk of lung cancer development in these patients. A history of PTB has been identified as a significant comorbid condition of COPD in countries with an intermediate-to-high burden of tuberculosis (TB) (1923). According to a meta-analysis, adults aged >40 years with a history of PTB would have an approximately three-times-higher risk of developing COPD than those without it (23). South Korea has an intermediate TB burden, and 26.3–33.6% of adults with a history of PTB have COPD (20, 21). Airflow obstruction in subjects with a history of PTB can result from obliteration or distortion of the airway with parenchymal scarring during the chronic inflammatory process of PTB (24). However, it remains unclear whether a history of PTB contributes to lung cancer development, specifically in patients with COPD.

Thus, we investigated the association between a history of PTB and lung cancer development in patients with COPD. In addition, to assess whether the relationship between PTB and lung cancer risk is different in individuals with or without COPD, a matched cohort of participants without COPD was included. We hypothesized that a history of PTB would increase the risk of lung cancer development in patients with COPD.

Study Population and Design

We conducted a population-based cohort study by using the Korean National Health Insurance Service (NHIS)–National Sample Cohort (NSC) 2.0 (NHIS-NSC 2). The NHIS-NSC 2 includes a representative 2.2% sample of the Korean population (25). South Korea has a single-payer universal health system, and the NHIS maintains claims data on all reimbursed inpatient and outpatient visits, procedures, and prescriptions. The sampling procedures and representativeness of the NHIS-NSC cohort have been described elsewhere (25). We used individual participant longitudinal NHIS-NSC 2 registration and claims data collected from January 1, 2002, to December 31, 2015 (25). In addition, the NHIS-NSC 2 includes data from annual or biennial health screening examinations provided free-of-cost by the Ministry of Health and Welfare. Approximately 72% of all eligible persons undergo screening (26).

Participants were included in this study if they 1) had a COPD diagnosis, 2) were aged 50–84 years, and 3) had undergone at least one health screening examination, including chest radiography (CXR) and questionnaires about their smoking status, between January 1, 2003, and December 31, 2015 (n = 14,516). To evaluate whether the relationship between PTB and lung cancer risk differs in participants with and without COPD, we included a matched cohort without COPD. Participants were matched 1:3 for age, sex, smoking history, and PTB status based on the index health screening examination of corresponding participants with COPD (n = 36,744). After excluding 1,351 and 2,277 participants with a history of cancer from each group, the final sample sizes were 13,165 and 34,467 in the COPD and non-COPD groups, respectively (Figure 1). The institutional review board of the Samsung Medical Center approved the study and waived the requirement for informed consent because the NHIS-NSC 2 data were de-identified.

Study Variables

The NHIS-NSC 2 data include modules on insurance eligibility, medical treatment, medical care institutions, and health screening examinations. The insurance eligibility database contains information on age, sex, residential area, and income level. The medical treatment database module contains information on treatments, including disease codes and prescriptions (25). The medical care institution database contains information on the type of institution, location, number of beds, facilities, and physicians. All claims were coded according to the International Classification of Diseases, Tenth Revision (ICD-10) and the Korean Drug and Anatomical Therapeutic Chemical Codes (27). The NHIS routinely audits all claims, and the data are considered reliable (25, 28).

COPD was defined as the presence of the J43 or J44 code (except J43.0; unilateral emphysema) and the prescription of COPD medication at least twice a year, as established at any time before the baseline health screening examination. COPD medications included long-acting muscarinic antagonists, long-acting β2-agonists, the combination of long-acting muscarinic antagonists and β2-agonists, inhaled corticosteroids with long-acting β2-agonists, short-acting muscarinic antagonists, short-acting β2-agonists, the combination of short-acting muscarinic antagonists and β2-agonists, methylxanthines, systemic β-agonists, and phosphodiesterase-4 inhibitors (2, 6, 29).

CXR was conducted as part of health screening examinations, and the findings were classified as normal, inactive TB, active TB (light, moderate, or severe in degree), and suspected PTB by radiologists or TB specialists (30, 31). For this study, a history of PTB was defined as any inactive or active TB on CXR images before the baseline health screening examination or any inactive TB on CXR images at the baseline or follow-up health screening examination.

Lung cancer was defined as the presence of the same C33 or C34 code more than thrice a year or the occurrence of an inpatient hospitalization with the C33 or C34 code (32). Once a person has a cancer diagnosis (C-code), it is included in the medical records and claims are created for that patient. The histologic diagnosis is a major factor in issuing a C33 or C34 code. However, when histologic confirmation is impossible, which mostly occurs in patients not treated for lung cancer, the code is issued under a doctor’s diagnosis that is based on chest computed tomography or positron emission tomography findings. To overcome this limitation, the same C33 or C34 code should be present at least thrice a year or an inpatient hospitalization with the C33 or C34 code should have occurred. In Korea, once a person receives a C-code, he or she is registered to the National Cancer Registry and receives special insurance benefits. Thus, the validity of a cancer diagnosis is strictly reviewed by the health insurance review and assessment service.

Smoking status was determined by self-administered questionnaires during the health screening examinations (occurring on the same date that CXR was performed), and results were categorized into never-smokers, past smokers, and current smokers. The body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared and was categorized according to Asian-specific criteria into underweight (<18.5 kg/m2), normal weight (18.5–22.9 kg/m2), overweight (23–25 kg/m2), and obese (⩾25 kg/m2) (33). Comorbidities during the year before the first health screening examination were obtained from claims data that were defined by using ICD-10 codes and summarized by using the Charlson Comorbidity Index (34, 35). Data on income at the time of the first health screening examination were obtained from the insurance eligibility database. The income level was categorized by using percentile groups (⩽30th, >30th to ⩽70th, and >70th percentiles). At the first health screening examination, the residential area was classified as metropolitan or rural. Metropolitan areas were defined as Seoul, 6 metropolitan cities, and 15 cities with populations >500,000 that have been officially designated as municipal cities (http://www.mois.go.kr/). The NHIS-NSC cohort included mortality data based on death certification collected by the Ministry of Strategy and Finance of South Korea (25).

Statistical Analyses

The study outcome was the incidence of lung cancer. Participants were observed from the time of the initial health screening examination until lung cancer incidence, death, 85 years of age, or December 31, 2015, whichever occurred first.

Cox proportional hazard models were used to evaluate the association of a history of PTB with lung cancer risk. We adjusted for sex (male or female), BMI, smoking status (never-smokers, past smokers, and current smokers), the Charlson Comorbidity Index score, and the income percentile (⩽30th, >30th to ⩽70th, >70th percentile, and unknown). To account for competing risks due to mortality, we fit proportional subdistribution hazard regression models with death as a competing event (36). We examined the assumption of proportional hazards by using plots of the log (−log) survival function and Schoenfeld residuals. We conducted the same analysis separately according to the smoking history and tested whether the effects of a history of PTB on the incidence of lung cancer would differ with the smoking status (never- vs. ever-smokers). To assess the interaction between a history of PTB and smoking, we added the interaction term “TB × smoking status” to the model. To test for an interaction between PTB exposure and COPD and their association with lung cancer, we added the interaction term “COPD × TB” to the model. Age, a strong determinant of cancer, was used as the time scale in the analyses (37).

In addition, to reduce the potential impact of surveillance bias, we excluded participants who developed lung cancer within the first 6–12 months after baseline. A P value of <0.05 was considered to indicate statistical significance. All analyses were performed by using Stata version 15 (StataCorp LP).

Participants in the COPD group (n = 13,165) included 6,841 (52.0%) men and 6,324 (48.0%) women, and the mean age was 66.3 ± 8.4 years. The proportion of participants with a history of PTB was 17.8% (n = 2,339). Participants with a history of PTB were more likely to be men and were more likely to be older and thinner than those without a history of PTB. Regarding the smoking status, participants with a history of PTB were more likely to be ever-smokers (past and current) than those without a history of PTB (31.7% and 44.2%). Participants in the non-COPD group (n = 34,467) included 17,394 (50.5%) men and 17,073 (49.5%) women, and the mean age was 65.3 ± 8.3 years. The proportion of participants with a history of PTB was 15.9% (n = 5,474); with regard to the smoking status, those with a history of PTB were more likely to be ever-smokers (past and current) than those without a history of PTB (30.5% and 41.2%, respectively) (Table 1).

Table 1. Characteristics of study participants at the beginning of follow-up (N = 47,632)

Baseline CharacteristicCOPD (n = 13,165)Non-COPD (n = 34,467)
No TB (n = 10,826)TB (n = 2,339)P ValueNo TB (n = 28,993)TB (n = 5,474)P Value
Sex, n (%)
 Male5,208 (48.1)1,633 (69.8)<0.00113,702 (47.3)3,692 (67.4)<0.001
 Female5,618 (51.9)706 (30.2)15,291 (52.7)1,782 (32.6)
Age, mean (SD), yr66.1 (8.5)67.0 (8.2)<0.00165.3 (8.3)65.4 (7.9)0.25
Body mass index, mean (SD), kg/m224.0 (3.4)22.7 (3.3)<0.00124.1 (3.1)23.2 (2.9)<0.001
Smoking status, n (%)
 Never7,404 (68.3)1,306 (55.8)<0.00120,157 (69.5)3,219 (58.8)<0.001
 Past1,240 (11.5)453 (19.4)3,177 (11.0)961 (17.6)
 Current2,182 (20.2)580 (24.8)5,659 (19.5)1,294 (23.6)
Charlson Comorbidity Index, median (IQR)1 (1–2)1 (1–2)0.450 (0–1)0 (0–1)0.44
Income percentile, n (%)
 ⩽30th2,430 (22.5)575 (24.6)0.046,997 (24.1)1,442 (26.3)0.001
 >30th to ⩽70th2,693 (24.8)569 (24.3)6,635 (22.9)1,232 (22.6)
 >70th5,579 (51.5)1,179 (50.4)15,029 (51.8)2,754 (50.3)
 Unknown124 (1.2)16 (0.7)332 (1.2)46 (0.8)
Residential area, n (%)
 Metropolitan5,149 (47.5)1,204 (51.5)<0.00116,257 (56.1)3,482 (63.6)<0.001
 Rural5,585 (51.6)1,113 (47.6)12,552 (43.3)1,949 (35.6)
 Unknown92 (0.9)22 (0.9)184 (0.6)43 (0.8)

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; IQR = interquartile range; SD = standard deviation; TB = tuberculosis.

During 370,617 person-years (PY) of follow-up (median follow-up, 7.7 yr), we observed 1,113 incident cases of lung cancer in all participants. In the COPD group, there were 430 incident lung cancer cases in participants without a history of PTB (incidence rate, 524 per 100,000 PY) and 148 cases in those with a history of PTB (incidence rate, 931 per 100,000 PY). Likewise, the non-COPD group had 437 and 98 incident lung cancer cases in participants without and with a history of PTB, respectively (incidence rate, 188 vs. 241 per 100,000 PY) (Figure 2). In a model including competing risks due to mortality, the fully adjusted subdistribution hazard ratio (sub-HR) for the incidence of lung cancer was significantly higher in participants with a history of PTB than in participants without a history of PTB (sub-HR, 1.23; 95% confidence interval [CI], 1.01–1.49) in the COPD group. In the non-COPD group, the fully adjusted sub-HR for the incidence of lung cancer in participants with a history of PTB was not different from those without a history of PTB (sub-HR, 0.98; 95% CI, 0.78–1.22) (Table 2). The interaction between PTB exposure and COPD was not significant (P = 0.12).

Table 2. Sub-HRs (95% CIs) for incident lung cancer associated with history of pulmonary TB among participants with and without COPD (N = 47,632)

 Number of Incident Lung CancersIncidence Rate (per 100,000 PY)Crude Sub-HR (95% CI)Adjusted Sub-HR (95% CI)*
COPD
 Overall    
  No TB430524ReferenceReference
  TB1489311.66 (1.38–2.01)1.23 (1.01–1.49)
 Never-smokers
  No TB171296ReferenceReference
  TB555981.90 (1.40–2.58)1.42 (1.04–1.95)
 Ever-smokers
  No TB2591,068ReferenceReference
  TB931,3901.21 (0.95–1.54)1.13 (0.89–1.44)
P for interaction0.020.25
Non-COPD
 Overall
  No TB437188ReferenceReference
  TB982411.25 (1.01–1.56)0.98 (0.78–1.22)
 Never-smokers
  No TB191116ReferenceReference
  TB321291.09 (0.75–1.58)0.91 (0.62–1.33)
 Ever-smokers
  No TB246363ReferenceReference
  TB664121.12 (0.85–1.46)1.01 (0.77–1.33)
P for interaction0.910.68

Definition of abbreviations: CI = confidence interval; COPD = chronic obstructive pulmonary disease; PY = person-years; sub-HR = subdistribution hazard ratio; TB = tuberculosis.

*Sub-HRs for mortality were modeled with mortality as a competing risk, with age being used as the time scale, and were adjusted for sex, body mass index, smoking status, the Charlson Comorbidity Index, and the income percentile (⩽30th, >30th to ⩽70th, and >70th).

In never-smokers with COPD, the fully adjusted sub-HR (95% CI) for lung cancer incidence when comparing participants with a history of PTB with participants without a history of PTB was 1.42 (1.04–1.95). In ever-smokers with COPD, the corresponding sub-HR was 1.13 (0.89–1.44). Although the association of a history of PTB and incident lung cancer was significant in never-smokers alone, the interaction between PTB and smoking history was insignificant in the adjusted model (P = 0.25). Based on subgroup analysis by the smoking status in participants without COPD, the fully adjusted sub-HRs (95% CIs) for the incidence of lung cancer when comparing participants with a history of PTB with those without a history of PTB were 0.91 (0.62–1.33) and 1.01 (0.77–1.33) in never-smokers and ever-smokers, respectively (Table 2 and Figure 2). There was no interaction among PTB exposure, smoking status, and COPD (P = 0.17).

In addition, in the sensitivity analysis after excluding participants who had lung cancer within the first 6 months after baseline, the fully adjusted sub-HRs (95% CIs) for the incidence of lung cancer when comparing participants with a history of PTB with participants without a history of PTB were 1.22 (0.99–1.49) in the COPD group and 0.99 (0.79–1.25) in the non-COPD group (see Table E1 in the online supplement). Among participants with COPD, even after excluding those in whom lung cancer was diagnosed within the first 12 months after baseline, a history of PTB had a similar effect size on lung cancer development. The fully adjusted sub-HRs (95% CIs) were 1.22 (0.99–1.51), 1.44 (1.01–2.05), and 1.12 (0.86–1.45) in the overall study population, in never-smokers, and in ever-smokers, respectively (data not shown).

In this large, nationally representative cohort, a history of PTB identified by using CXR was associated with a 1.23-fold increased risk of lung cancer development among participants with COPD. Although the absolute incidence of lung cancer was higher in ever-smokers than in never-smokers, the association between a history of PTB and lung cancer development was more evident in never-smokers among participants with COPD. On the other hand, a history of PTB was not associated with a risk of lung cancer development among participants without COPD. The results of our study suggest that a history of PTB has an important role in lung cancer development among patients with COPD in a country with an intermediate burden of TB.

Previous population-based studies found a significant association between a history of PTB and lung cancer (11, 15, 16). A study using the national health insurance data of Taiwan found that COPD was more prevalent in those with PTB than in those without PTB and that patients with PTB had a significant increase in lung cancer risk (15). Another population-based study in Taiwan showed that patients with PTB and coexisting COPD had a higher lung cancer risk than the age- and sex-matched control subjects (11). However, these population-based studies did not include information on smoking status, which is the most important risk factor for lung cancer, because of data unavailability. In our study, we included the potential risk factors for lung cancer development, including smoking status. We found that a history of PTB is associated with an increased risk of developing lung cancer, especially in never-smokers with COPD. Although the association was not statistically significant, we were able to observe an increased lung cancer risk among ever-smokers with COPD with a history of PTB. This might have been due to the small sample size. By another interpretation, given the dominant role of smoking in lung cancer development, the effect of a history of PTB in lung cancer development might be overridden in ever-smokers with COPD. Thus, it would be necessary to evaluate and follow-up patients with COPD and a history of PTB, considering their higher risk for lung cancer development, regardless of their smoking status.

The potential mechanism between a history of PTB and incident lung cancer might be associated with a chronic inflammatory process. Host immune responses to Mycobacterium play a major role in lung damage during PTB infection (38). One study found that the host–Mycobacterium interaction may persist even after treatment, which was proved by using positron emission tomography and computerized tomography imaging response patterns consistent with active disease, together with the presence of Mycobacterium tuberculosis messenger RNA in sputum and bronchoalveolar lavage samples (39). Even after microbiologic cure after TB treatment, persistent inflammation might exist (39). This chronic inflammation entails the activation of innate immunity, which in turn leads to the production of cytokines that can promote tumor growth and progression (40). Activated leukocytes participating in the inflammation also produce reactive oxygen and nitrogen species that are associated with cancer development (41, 42).

Another potential mechanism of TB-associated lung cancer risk may be the impact of past TB on the lymphatic system, most notably in the upper lobes, where lung cancers are also most prevalent. A potential mechanism underlying the upper lobe predominance of lung cancer is the relatively poor perfusion of the upper lung regions and the peribronchial system, resulting in slower lymphatic drainage, which might lead to higher particle concentrations and subsequently predispose affected individuals to lung cancer development (43). Considering that PTB is also prevalent in the upper lobes, post-TB destruction of the respiratory system hampers the lymphatic drainage in these regions, which may lead to lung cancer development.

Beyond the immunologic evidence, recent genomic studies provide further evidence on the relationship between TB and lung cancer. Wong and colleagues (44) showed that the TB-related gene set was associated with lung adenocarcinoma among never-smoking Asian women by using genome-wide association study results. In addition, another genomic study demonstrated a link between noncoding RNAs in PTB and host lung tumorigenesis (45). Regarding COPD and lung cancer, repeated airway epithelial injury, with its accompanying high cell-turnover rates and propagation of DNA errors from chronic inflammatory processes, in COPD may lead to amplification of the carcinogenic effects of cigarette smoke or other noxious particles of indoor and/or outdoor air pollution (9, 46). Furthermore, the genetic overlap between COPD and lung cancer has been reported in several studies (47, 48). Taken together, epidemiologic evidence linking COPD and a history of PTB with lung cancer development might be explained by shared biological mechanisms such as chronic inflammatory processes and, in part, genetic and epigenetic mechanisms. However, further studies for how these mechanisms operate and intermingle to develop lung cancer are necessary.

Although a history of PTB was associated with lung cancer development in participants with COPD, this association was not evident in participants without COPD. A possible explanation for this discrepancy is the difference in the severity of previous PTB. In this study, it is difficult to determine the causal relationship between PTB and COPD. However, we consider that when PTB occurs before COPD, participants with COPD would have more severe PTB than those without COPD because PTB could have possibly contributed to airflow obstruction (24). Alternatively, we consider that when COPD occurs before PTB, participants with COPD would experience more severe sequelae from PTB than would participants without COPD. In both cases, chronic inflammatory process would be more severe or more prolonged among participants with COPD than among those without COPD. This in turn would be associated with an increased risk of lung cancer development in the COPD group. Further studies are required to understand the role of PTB history in lung cancer development in people with and without COPD.

Limitations

There are some potential limitations to this study. First, COPD was defined by using ICD-10 codes and medication data, as spirometry data were not available, and there might have been instances of misclassification of the participants with COPD. Nevertheless, this working definition has been validated in multiple publications (2, 6, 49). Second, we defined a history of PTB by using CXR results instead of ICD-10 codes, and some cases may have been misclassified. For this study, we used the health screening exam data collected from January 1, 2002, to December 31, 2015, rather than using ICD-10 codes for defining a history of PTB, because we would have otherwise missed patients who had TB before 2002. In addition, if we had used ICD-10 codes, we could not have identified specific sites of TB because of masking of the site-specific code. Nevertheless, the sensitivity and specificity of the CXR data for detecting PTB were reported as 98% and 75% (50), respectively, so there could have been some misclassification. For example, the use of CXR data alone would have resulted in underestimating the prevalence of a history of TB, as patients who had been treated for TB with a relatively mild disease course would not have persistent imaging abnormalities detectable on CXR images. However, those patients might have been less likely to have a chronic inflammatory lesion that would progress to lung cancer. Moreover, the imaging findings of some patients would have mimicked TB. For example, apical fibrosis could be considered as a history of PTB, resulting in misclassification. Similarly, patients who had lung cancer in the upper lobe might be misclassified as having PTB. Therefore, we did not include active TB after baseline as an exposure and also performed a sensitivity analysis excluding participants in whom lung cancer had been diagnosed within 6–12 months after baseline, and the results were similar. Third, in our study, the proportion of never-smoker patients with COPD (66.2%) was much higher than that in previous reports (51). This could limit the generalizability of this study. The higher proportion of never-smokers could be because this national cohort includes participants with COPD who had been prescribed with COPD medications and had undergone at least one health screening examination, resulting in almost half of the study participants being women. According to the recent survey by the Organization of Economic Cooperation and Development, only 4.4% of women are smokers in South Korea (52, 53), which would have led to a higher proportion of never-smokers with COPD in our study. In addition, although the smoking status might change over time, we only used the one collected at baseline. However, a previous study using the same data set reported that only approximately 2.0% of never-smokers had become smokers at the following health screening examination (6). Fourth, we were not able to include all potential confounders in this study. We were not able to include some factors that might affect lung cancer development, such as emphysema and a family history of malignant disease, because of the limitation of the data. Likewise, we also did not include occupational or environmental exposures, which are well-known risk factors for COPD and lung cancer development among never-smokers (710). However, compared with the data of previous studies (11, 15), our data included information regarding smoking status, which is the most important risk factor in lung cancer development. Sixth, this study was conducted by using Korean national claims data, which were not set up for research purposes. Moreover, as 72% of all eligible individuals underwent a health screening examination, this result may not be generalizable to those who did not. Lastly, there is an intermediate TB burden in Korea, and the results might therefore be different for other populations in other settings. However, our findings would provide useful information for lung cancer screening in patients with COPD in countries with similar burdens of PTB.

Conclusions

In conclusion, a history of PTB was associated with an increased risk of lung cancer development among patients with COPD in our country with an intermediate TB burden. When this association was addressed according to the smoking status of the study population, the association between a history of PTB and lung cancer development was more pronounced in never-smokers. Our study suggests that patients with COPD with a history of PTB who are never-smokers might benefit from periodic screening or assessment for lung cancer development. Further studies with larger sample sizes in other settings are needed to confirm our findings and elucidate the mechanistic link underlying the complex interplay among PTB, COPD, and lung cancer.

The authors thank Jae Joon Yim (Seoul National University College of Medicine, Seoul, South Korea) for his valuable comments and suggestions.

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Correspondence and requests for reprints should be addressed to Juhee Cho, Ph.D., Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea. E-mail: .

*These authors contributed equally to this work.

These authors contributed equally to this work.

Author Contributions: H.Y.P., D.K., S.H.S., H.C., S.H.J., C.-H.L., H.K., O.J.K., C.K.R., and J.C. meet criteria for authorship as recommended by the International Committee of Medical Journal Editors.

This article has a related editorial.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

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