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RESEARCH ARTICLE
Increased risk of secondary lung cancer in
patients with tuberculosis: A nationwide,
population-based cohort study
Li-Ju Ho
1
, Hung-Yi Yang
2
, Chi-Hsiang Chung
3
, Wei-Chin Chang
4
, Sung-Sen Yang
5,6
,
Chien-An Sun
7,8
, Wu-Chien ChienID
3,5,9
*, Ruei-Yu SuID
2,10
*
1Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital,
National Defense Medical Center, Taipei, Taiwan, 2Division of Clinical Pathology, Department of Pathology,
Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 3School of Public Health,
National Defense Medical Center, Taipei, Taiwan, 4Department of Oral and Maxillofacial Surgery, Tri-
Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 5Department of Medical
Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 6Graduate
Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, 7Department of Public
Health, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, 8Big Data Research
Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, 9Graduate Institute of Life
Sciences, National Defense Medical Center, Taipei, Taiwan, 10 Department of Pathology and Laboratory
Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
*chienwu@ndmctsgh.edu.tw (WCC); rueiyusu@gmail.com (RYS)
Abstract
Background
Tuberculosis (TB) presents a global threat in the world and the lung is the frequent site of
metastatic focus. A previous study demonstrated that TB might increase primary lung can-
cer risk by two-fold for more than 20 years after the TB diagnosis. However, no large-scale
study has evaluated the risk of TB and secondary lung cancer. Thus, we evaluated the risk
of secondary lung cancer in patients with or without tuberculosis (TB) using a nationwide
population-based dataset.
Methods
In a cohort study of 1,936,512 individuals, we selected 6934 patients among patients with
primary cancer and TB infection, based on the International Classification of Disease (ICD-
p-CM) codes 010–011 from 2000 to 2015. The control cohort comprised 13,868 randomly
selected, propensity-matched patients (by age, gender, and index date) without TB expo-
sure. Using this adjusted date, a possible association between TB and the risk of developing
secondary lung cancer was estimated using a Cox proportional hazards regression model.
Results
During the follow-up period, secondary lung cancer was diagnosed in 761 (10.97%) patients
with TB and 1263 (9.11%) patients without TB. After adjusting for covariates, the risk of sec-
ondary lung cancer was 1.67 times greater among primary cancer in the cohort with TB than
in the cohort without TB. Stratification revealed that every comorbidity (including diabetes,
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OPEN ACCESS
Citation: Ho L-J, Yang H-Y, Chung C-H, Chang W-
C, Yang S-S, Sun C-A, et al. (2021) Increased risk
of secondary lung cancer in patients with
tuberculosis: A nationwide, population-based
cohort study. PLoS ONE 16(5): e0250531. https://
doi.org/10.1371/journal.pone.0250531
Editor: Suresh kumar Subbiah, Universiti Putra
Malaysia, MALAYSIA
Received: December 30, 2020
Accepted: March 8, 2021
Published: May 7, 2021
Copyright: ©2021 Ho et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
any medium, provided the original author and
source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This study was supported by the Tri-
Service General Hospital Research Foundation
(TSGH-B-110012), and the sponsor has no role in
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
hypertension, cirrhosis, congestive heart failure, cardiovascular accident, chronic kidney
disease, chronic obstructive pulmonary disease) significantly increased the risk of second-
ary lung cancer when comparing the TB cohort with the non-TB cohort. Moreover, the pri-
mary cancer types (including head and neck, colorectal cancer, soft tissue sarcoma, breast,
kidney, and thyroid cancer) had a more significant risk of becoming secondary lung cancer.
Conclusion
A significant association exists between TB and the subsequent risk for metastasis among
primary cancers and comorbidities. Therefore, TB patients should be evaluated for the sub-
sequent risk of secondary lung cancer.
Introduction
Tuberculosis (TB) presents a global threat in both developing and developed countries. TB is
caused by bacteria (Mycobacterium tuberculosis) and most often affects the lungs. According
to the World Health Organization, 10 million people become ill with TB annually. Despite
being a preventable and curable disease, 1.5 million people die from TB each year–making it
the world’s top infectious killer [1].
The lung is the frequent site of metastatic focus. About 20% to 54% of malignant tumors
developing elsewhere in our body have pulmonary metastasis [2,3]. This is so-called secondary
lung cancer when cancer cells have spread to the lungs from cancer that started elsewhere in
the body. It is also called metastatic cancer to the lungs and differs from the definition of pri-
mary lung cancer that has originated in the lungs. A previous study demonstrated that TB
might increase primary lung cancer risk by two-fold for more than 20 years after the TB diag-
nosis [4]. However, no large-scale study has evaluated the risk of TB and secondary lung can-
cer. Thus, a nationwide, population-based, matched cohort study is needed to clarify the
association between TB infection and secondary lung cancer. Furthermore, we have conducted
this study to investigate whether comorbidities could attenuate the risk of developing second-
ary lung cancer after TB infection.
Material and methods
Data source and ethics statement
The National Health Insurance (NHI) program began in Taiwan in 1995 and covers more
than 99% of the entire population (or more than 23 million people). The data for this study
were collected from the NHI Research Database (NHIRD) of Taiwan, which uses the Interna-
tional Classification of Diseases, 9
th
Revision, Clinical Modification (ICD-9-CM) codes to
record diagnoses. Therefore, we used the NHIRD inpatient and outpatient databases and the
Registry of Beneficiaries. Patient confidentiality was ensured by double-encrypted identifiers
in the NHIRD. The Institutional Review Board of Tri-Service General Hospital approved this
study (TSGHIRB No.B-109-44), and the committee waived the need for written informed
consent.
Study design and population
The study design and specific patient characteristics, including inclusion and exclusion crite-
ria, are shown in Fig 1. The control cohort (non-TB patients) was randomly matched with TB
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patients according to age, sex, and index date (two controls for each TB patient) using the
same exclusion criteria. The study cohort included 514,889 patients aged �20 years who had
been diagnosed with cancer except for lung origin (ICD-9-CM codes in S1 Table) from 2000
to 2015. The index date was designated as the first clinical visit for primary cancer. The exclu-
sion criteria were: diagnosis with primary cancer before 2000, secondary lung cancer before
tracking, patients without tracking, age <20 years, and unknown gender. The ratio of primary
cancer patients with TB to patients without TB in the study period was maintained at 1:2 to
enhance the power of the statistical tests employed, particularly regarding the stratification
analysis. Using these criteria, 6934 patients with TB infection and 13,868 patients without TB
infection were identified.
Fig 1. Flowchart of study sample selection.
https://doi.org/10.1371/journal.pone.0250531.g001
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Covariates
We examined the sociodemographic factors in the case and control groups, such as age,
monthly income, comorbidity, urbanization level, and hospital level. The patients were divided
into three groups: 20–44 years, 45–69 years, and �70 years. Their monthly income in New Tai-
wan Dollars was divided into three groups: <18,000, 18,000–34,999, and �35,000. Seven
comorbidities (ICD codes as in S1 Table), such as diabetes (DM), hypertension (HTN), cirrho-
sis, congestive heart failure (CHF), cardiovascular accident (CVA), chronic kidney disease
(CKD), and chronic obstructive pulmonary disease (COPD), were also considered into our
study (using ICD9 codes in S1 Table). The patients were categorized into four urbanization
levels. The three hospital levels where patients sought medical attention were also considered:
medical centers, regional hospitals, and local hospitals.
Study outcome
All study participants were followed from the index date until the onset of secondary lung can-
cer (ICD-9-CM codes: 197.0), withdrawal from the NHI program, or the end of 2015. The
covariates included were included those mentioned previously.
Statistical analysis
We performed all analyses using SPSS software version 22 (SPSS Inc., Chicago, Illinois, USA).
χ2 and t-tests were used to evaluate the distribution of categorical and continuous variables,
respectively. Fisher’s exact test was used for categorical variables to examine the statistical dif-
ferences between the two cohorts. The multivariate Cox proportional hazards regression anal-
ysis was used to determine the risk of secondary lung cancer. The results were presented as a
hazard ratio with a 95% confidence interval (CI). The difference in the risk of secondary lung
cancer between TB-infected subjects and control groups was estimated using the Kaplan-
Meier method with the log-rank test. A two-tailed p-value <.05 was considered statistically
significant.
From 2000 to 2015, a total of 558,162 patients with primary cancer were enrolled in this
study in accordance with our inclusion criteria. Secondary lung cancer was observed in 761 of
6934 TB-infected patients, and in 1263 of 13,868 non-TB-infected patients. Table 1 lists demo-
graphic characteristics and comorbidities of the TB (6934) and non-TB cohorts (13,868) dur-
ing this time. In both cohorts, approximately 90% were older than 45 years of age, 72% were
male, and the proportion by age and sex were similar. All comorbidities, except CVA, were sig-
nificantly different in the TB cohort than in the endpoint non-TB cohort: DM (17.41% vs
13.36%; p<.001), HTN (16.33% vs 18.73%; p<.001), cirrhosis (4.12% vs 2.40%; p<.001),
CHF (3.87% vs 2.63%; p<.001), CKD (8.48% vs 5.70%; p<.001), and COPD (11.52% vs
4.25%; p<.001). The TB cohorts had a higher proportion of individuals living at the lowest
urbanization level city (19.12% vs 14.08%; p<.001) and call for treatment in local hospital
(15.10% vs 11.85%; p<.001).
Secondary lung cancer incidence and risk
Table 2 presents factors of secondary lung cancer using Cox regression and Fine & Gray’s
competing risk model. According to our study, the risk of secondary lung cancer was 1.671
times greater in the TB cohort than in the non-TB cohort (aHR = 1.671; 95% CI = 1.525–
1.832; p<.001) after adjusting for gender, age, insurance premium, related comorbidities,
urbanization level, and level of care. All comorbidities were significantly higher in the TB
cohort than in the non-TB cohort: DM (aHR = 1.472; 95% CI = 1.271–1.705; p<.001), HTN
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Table 1. Demographic characteristics and comorbidities of study participants.
TB Total With Without P
Variables n % n % n %
Overall 20,802 6934 33.33 13,868 66.67
Secondary lung cancer <.001
Without 18,778 90.27 6173 89.03 12,605 90.89
With 2024 9.73 761 10.97 1263 9.11
Gender .999
Male 15,069 72.44 5023 72.44 10,046 72.44
Female 5733 27.56 1911 27.56 3,822 27.56
Age (yrs) 67.50 ±14.19 67.05 ±13.63 67.73 ±14.46 <.001
Age groups (yrs) <.001
20–44 1713 8.23 473 6.82 1240 8.94
45–69 9577 46.04 3125 45.07 6452 46.52
≧70 9512 45.73 3336 48.11 6,176 44.53
Insurance premium (NT$) .936
<18,000 20,450 98.31 6818 98.33 13,632 98.30
18,000–34,999 291 1.40 97 1.40 194 1.40
≧35,000 61 0.29 19 0.27 42 0.30
DM <.001
Without 17,742 85.29 5727 82.59 12,015 86.64
With 3060 14.71 1207 17.41 1853 13.36
HTN <.001
Without 17,072 82.07 5802 83.67 11,270 81.27
With 3730 17.93 1132 16.33 2598 18.73
Cirrhosis <.001
Without 20,183 97.02 6648 95.88 13,535 97.60
With 619 2.98 286 4.12 333 2.40
CHF <.001
Without 20,169 96.96 6666 96.13 13,503 97.37
With 633 3.04 268 3.87 365 2.63
CVA .629
Without 19,807 95.22 6608 95.30 13,199 95.18
With 995 4.78 326 4.70 669 4.82
CKD <.001
Without 19,423 93.37 6346 91.52 13,077 94.30
With 1379 6.63 588 8.48 791 5.70
COPD <.001
Without 19,413 93.32 6135 88.48 13,278 95.75
With 1389 6.68 799 11.52 590 4.25
Urbanization level <.001
1 (The highest) 7125 34.25 2183 31.48 4942 35.64
2 9382 45.10 3067 44.23 6315 45.54
3 1017 4.89 358 5.16 659 4.75
4 (The lowest) 3278 15.76 1326 19.12 1952 14.08
Level of care <.001
Hospital center 9793 47.08 2898 41.79 6895 49.72
Regional hospital 8318 39.99 2989 43.11 5329 38.43
Local hospital 2691 12.94 1047 15.10 1,644 11.85
P: Chi-square / Fisher’s exact test for categorical variables and t-test for continuous variables
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Table 2. Factors of secondary lung cancer using Cox regression and Fine & Gray’s competing risk model.
Model Competing risk in the model
Variables Crude HR 95% CI 95% CI PAdjusted HR 95% CI 95% CI P
TB
Without Reference Reference
With 1.478 1.350 1.618 <.001 1.671 1.525 1.832 <.001
Gender
Male 1.083 0.983 1.194 .108 1.088 0.986 1.201 .093
Female Reference Reference
Age groups (yrs)
20–44 Reference Reference
45–69 1.004 0.664 1.124 .074 1.088 0.986 1.201 .093
≧70 1.018 0.865 1.197 .833 1.109 0.942 1.306 .215
Insured premium (NT$)
<18,000 Reference Reference
18,000–34,999 1.096 0.528 1.201 .278 1.073 0.512 1.166 .220
≧35,000 1.512 0.755 3.027 .244 1.352 0.674 2.712 .396
DM
Without Reference Reference
With 1.849 1.601 2.136 <.001 1.472 1.271 1.705 <.001
HTN
Without Reference Reference
With 2.638 2.277 3.057 <.001 2.318 1.993 2.696 <.001
Cirrhosis
Without Reference Reference
With 1.127 0.860 1.478 .385 1.334 1.017 1.750 .038
CHF
Without Reference Reference
With 3.533 2.320 5.380 <.001 3.017 1.979 4.600 <.001
CVA
Without Reference Reference
With 4.848 3.360 6.995 <.001 3.866 2.676 5.584 <.001
CKD
Without Reference Reference
With 2.463 1.915 3.168 <.001 2.562 1.990 3.298 <.001
COPD
Without Reference Reference
With 2.249 1.786 2.833 <.001 2.238 1.770 2.830 <.001
Urbanization level
1 (The highest) 0.779 0.600 1.011 .061 0.797 0.614 1.034 .088
2 0.859 0.702 1.439 .091 0.881 0.749 1.037 .127
3 0.938 0.779 1.474 .300 0.957 0.826 1.109 .559
4 (The lowest) Reference Reference
Level of care
Hospital center 2.465 2.071 2.933 <.001 2.332 1.926 2.823 <.001
Regional hospital 1.814 1.518 2.167 <.001 1.728 1.443 2.070 <.001
Local hospital Reference Reference
HR = Hazard Ratio, CI = Confidence Interval, Adjusted HR: Adjusted variables listed in the Table
P: Chi-square/Fisher’s exact test for categorical variables and t-test for continuous variables
CI: Confidence Interval
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(aHR = 2.318; 95% CI = 1.993–2.696; p<.001), cirrhosis (aHR = 1.334; 95% CI = 1.017–1.750;
p= .038), CHF (aHR = 3.017; 95% CI = 1.979–4.600; p<.001), CVA (aHR = 3.866; 95%
CI = 2.676–5.584; p<.001), CKD (aHR = 2.562; 95% CI = 1.990–3.298; p<.001), and COPD
(aHR = 2.238; 95% CI = 1.770–2.830; p<.001). Compared with the local hospital, the risk of
secondary lung cancer was higher in the medical center (aHR = 2.332; 95% CI = 1.926–2.823;
p<.001) and in the regional hospital (aHR = 1.728; 95% CI = 1.443–2.070; p<.001).
Fig 2 compares the Kaplan-Meier curves for the cumulative incidence of secondary lung
cancer between the TB and non-TB cohorts after 16 years of follow-up. The 1-, 5-, 11-, and
15-year actuarial rates of secondary lung cancer were 6.89%, 10.42%, 10.96%, and 10.97% in
the TB cohort and 4.27%, 8.18%, 9.05%, and 9.10% in the non-TB cohort, respectively. This
geography revealed that TB-infected patients had a significantly higher risk of developing sec-
ondary lung cancer than non-TB patients among primary cancer patients, even in the first
year of tracking.
We found that 761 (10.97%) TB cohort members progressed to secondary lung cancer with
57,340 person-years of follow-up over 16 years, for an incidence rate of 1327 per 100,000 per-
son-years. Conversely, only 1263 (9.10%) of the non-TB cohort members progressed to sec-
ondary lung cancer over the 124,884 person-years of follow-up for 16 years, for an incidence
rate of 1011 per 100,000 person-years. Therefore, the incidence rate of osteoporosis was
1.671-fold higher in the TB cohort than in the non-TB cohort.
Table 3 shows the factors of secondary lung stratified by the variables listed using Cox
regression and Fine & Gray’s competing risk model. All the factors show a significantly higher
risk in TB-infected patients at every stratified level than in non-TB-infected patients.
Table 4 shows the factors of secondary lung cancer among different primary cancer types.
The primary cancer types, including head and neck, colorectal, soft tissue sarcoma, breast, kid-
ney, and thyroid cancer, have a significantly higher risk of developing secondary lung cancer
in TB-infected patients. Nevertheless, bone, melanoma, and testicular cancer show no
difference.
Discussion
Previous studies conducted by the National Cancer Institute found the pulmonary TB was
associated with an increased risk of lung cancer after adjusting for socioeconomic status and
active smoking (odds ratio 2.1, 95% CI = 1.4–3.1) [5]. Epidemiological evidence concerning
the association between pre-existing pulmonary TB and lung cancer has been documented [6–
11]. Similarly, TB was associated with a 1.78-fold increase in lung cancer risk among non-
smokers and adenocarcinoma (relative risk: 1.6; 95% CI = 1.2–2.1) [4]. However, there is no
large-scale study to discuss the association between TB-infected patients with subsequent met-
astatic cancer from other origins.
In our study, TB was associated with a 1.67-fold increase in the risk of secondary lung can-
cer compared with the non-TB cohort after adjusting for numerous potential confounders.
The underlying mechanism of increasing cancer risk after TB infection had been reported. TB
is thought to increase lung cancer risk through chronic pulmonary inflammation and fibrosis.
TB infection may cause a profound and host immune response, with inflammatory cells in the
lung producing extensive cytokine signaling cascades, oxygen species, reactive nitrogen, pros-
taglandins, and tissue-destructive proteases [12,13]. The cell wall component of Mycobacte-
rium tuberculosis can induce the production of nitric oxide and reactive oxygen species, which
have been implicated in DNA damage leading to carcinogenesis [14].
It should be noted that nitrative DNA damage and oxidative DNA damage have been impli-
cated in inflammation-related carcinogenesis [15]. Some data revealed that Mycobacterium
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tuberculosis might also enhance the synthesis of BCL-2, potentially leading to increased anti-
apoptotic activity [16]. Chronic inflammation may also enhance lung fibrosis, which may be
associated with decreased clearance of lymph and lymph-associated particles from the infected
Fig 2. Kaplan-Meier for cumulative risk of secondary lung cancer among primary cancer patients aged 20 and over stratified by TB
with the log-rank test.
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Table 3. Factors of secondary lung cancer stratified by variables listed using Cox regression and Fine & Gray’s competing risk model.
TB With Without (Reference) Competing risk in the model
Stratified Events PYs Rate (per 10
5
PYs) Events PYs Rate (per 10
5
PYs) Adjusted HR 95% CI 95% CI P
Overall 761 57,340.90 1327.15 1263 124,884.91 1011.33 1.671 1.525 1.832 <.001
Gender
Male 537 39,444.69 1361.40 908 89,000.07 1020.22 1.699 1.550 1.863 <.001
Female 224 17,896.21 1251.66 355 35,884.84 989.28 1.611 1.470 1.766 <.001
Age group (yrs)
20–44 57 3026.89 1883.12 134 8816.02 1519.96 1.578 1.439 1.729 <.001
45–69 314 22,904.34 1370.92 559 52,083.65 1073.27 1.627 1.484 1.783 <.001
≧70 390 31,409.67 1241.66 570 63,985.24 890.83 1.775 1.619 1.946 <.001
Insured premium (NT$)
<18,000 746 56,337.98 1324.15 1247 122,847.46 1015.08 1.661 1.516 1.821 <.001
18,000–34,999 11 865.00 1271.67 12 1715.19 699.63 2.315 2.112 2.537 <.001
≧35,000 4 137.92 2900.30 4 322.26 1241.22 2.976 2.715 3.262 <.001
DM
Without 663 45,624.00 1453.18 1,144 104,122.51 1098.71 1.684 1.537 1.846 <.001
With 98 11,716.90 836.40 119 20,762.40 573.15 1.858 1.695 2.037 <.001
HTN
Without 687 44,820.23 1532.79 1,139 96,117.53 1185.01 1.647 1.503 1.806 <.001
With 74 12,520.67 591.02 124 28,767.38 431.04 1.746 1.593 1.914 <.001
Cirrhosis
Without 731 55,081.69 1327.12 1,239 121,468.64 1020.02 1.657 1.512 1.816 <.001
With 30 2259.21 1327.90 24 3416.27 702.52 2.407 2.196 2.638 <.001
CHF
Without 748 54,419.08 1374.52 1,254 119,772.93 1046.98 1.672 1.525 1.833 <.001
With 13 2921.82 444.93 9 5111.98 176.06 3.218 2.936 3.528 <.001
CVA
Without 746 53,561.46 1392.79 1244 115,641.45 1075.74 1.649 1.504 1.807 <.001
With 15 3779.44 396.88 19 9243.46 205.55 2.459 2.243 2.695 <.001
CKD
Without 723 51,376.75 1407.25 1228 115,637.41 1061.94 1.688 1.540 1.850 <.001
With 38 5964.16 637.14 35 9247.50 378.48 2.144 1.956 2.350 <.001
COPD
Without 711 49,078.54 1448.70 1238 117,246.40 1055.90 1.747 1.594 1.915 <.001
With 50 8262.37 605.15 25 7638.51 327.29 2.355 2.148 2.581 <.001
Pneumoconiosis
Without 759 56,747.49 1337.50 1,263 124,776.18 1012.21 1.683 1.535 1.844 <.001
With 2 593.41 337.04 0 108.73 0.00 1- - .970
Sarcoidosis
Without 761 57,340.90 1327.15 1263 124,877.32 1011.39 1.671 1.524 1.832 <.001
With 0 0.00 - 0 7.59 0.00 - - - -
HIV
Without 759 57,233.06 1326.16 1263 124,864.57 1011.50 1.670 1.523 1.830 <.001
With 2 107.85 1854.49 0 20.34 0.00 1- - .990
Urbanization level
1 (The highest) 239 17,642.70 1354.67 460 42,581.05 1080.29 1.597 1.457 1.750 <.001
2 348 24,791.59 1403.70 608 57,101.20 1,064.78 1.679 1.532 1.840 <.001
3 30 3228.48 929.23 41 6408.10 639.82 1.849 1.687 2.027 <.001
(Continued)
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region [17]. Overall, the combination of DNA damage, anti-apoptosis, and the perpetuation of
chronic inflammation may enhance progeny cell mutagenesis. These effects may lead to an
increased risk of primary or secondary lung cancer.
We also found that all comorbidities increased the risk of secondary lung cancer significantly.
This finding may be because more severe comorbidities were associated with the increased toxic-
ity of specific treatments or the use of less aggressive or optimal treatment. These possibilities
would thereby reduce the patient’s remaining life expectancy [18,19]. In recent studies, the pres-
ence of comorbidities was significantly associated with elevated all-cause mortality in patients
diagnosed with lung cancer, even after adjusting for sex, age, and cancer stage [20].
In our study, the study endpoint, the level of care, showed a significant difference. Com-
pared with the non-TB cohort, TB-infected patients went to the local hospital (15.10% vs
Table 3. (Continued)
TB With Without (Reference) Competing risk in the model
Stratified Events PYs Rate (per 10
5
PYs) Events PYs Rate (per 10
5
PYs) Adjusted HR 95% CI 95% CI P
4 (The lowest) 144 11,678.13 1,233.07 154 18,794.56 819.39 1.916 1.748 2.101 <.001
Level of care
Hospital center 379 22,314.91 1698.42 694 55,941.34 1240.59 1.743 1.591 1.911 <.001
Regional hospital 316 25,700.37 1229.55 471 51,400.65 916.33 1.709 1.559 1.873 <.001
Local hospital 66 9325.62 707.73 98 17,542.91 558.63 1.613 1.472 1.768 <.001
HR = Hazard Ratio, CI = Confidence Interval, Adjusted HR: Adjusted variables listed in the table
P: Chi-square/Fisher’s exact test for categoricaly variables and t-test for continuous variables
CI: Confidence Interval
PYs: Person-years
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Table 4. Factors of secondary lung cancer among different primary cancer types using Cox regression and Fine & Gray’s competing risk model.
TB With Without (Reference) Competing risk in the model
Primary cancer
types
Population Events PYs Rate (per 10
5
PYs)
Population Events PYs Rate (per 10
5
PYs)
Adjusted
HR
95% CI 95% CI P
Overall 6934 761 57,340.90 1327.15 13,868 1263 124,884.91 1011.33 1.671 1.525 1.832 <
.001
Head and neck 2563 236 18,422.48 1281.04 5126 356 44,308.93 803.45 1.922 1.623 2.276 <
.001
Colorectal 2560 312 21,330.60 1462.69 5120 571 45,984.63 1241.72 1.521 1.321 1.750 <
.001
Bone 54 4 367.11 1089.59 108 14 1083.85 1291.70 1.366 0.397 4.703 .621
Soft tissue
sarcoma
121 19 970.68 1957.40 242 28 1712.78 1634.77 2.104 1.103 4.013 .024
Melanoma 63 10 462.20 2163.58 126 21 1153.24 1820.96 1.081 0.475 2.464 .852
Breast 705 94 6728.86 1396.97 1410 131 13,787.25 950.15 2.058 1.569 2.700 <
.001
Testicular 18 0 190.42 0.00 36 2 261.48 764.88 0.000 - - .963
Kidney 628 58 6306.78 919.65 1256 106 12,601.34 841.18 1.391 1.001 1.932 .049
Thyroid 222 28 2561.77 1092.99 444 34 3991.41 851.83 1.642 1.007 2.787 .046
HR = Hazard Ratio, CI = Confidence Interval, Adjusted HR: Adjusted variables listed in the Table
P: Chi-square/Fisher’s exact test for categorical variables and t-test for continuous variables
CI: Confidence Interval
PYs: Person-years
https://doi.org/10.1371/journal.pone.0250531.t004
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Increased risk of secondary lung cancer with tuberculosis
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11.85%; p<.001) and regional hospital (43.11% vs 38.43%) for treatments rather than to the
medical center (41.79% vs 49.72%). This is because TB control and elimination relied on the
early detection of active TB cases that prompted anti-TB treatment, identified persons at risk
of exposure, and prevented secondary TB cases [21]. All of this depends on good diagnostic
methods and effective treatments for TB. Thus, apart from medical care, the epidemiology of
TB is increasing [22–24]. Outside of cities, most care is provided at the level of hospitals or
lower at the local and regional levels. In these latter two instances, facilities may not be
equipped to provide acute diagnoses and deliver effective treatment regimens. Thus, these
patients’ characteristics are more at the lower urbanization level and go to their nearby local
and regional hospital in the TB-infected study than non-TB patients. However, after adjusting
for other risks (such as gender, age, insurance premium, related comorbidities, and urbaniza-
tion level), the risk of secondary lung cancer was higher at the medical center (aHR = 2.332;
95% CI = 1.926–2.823; p<.001) and regional hospital (aHR = 1.728; 95% CI = 1.443–2.070; p
<.001). The reason for this is that the NHI in Taiwan is a government-administered insur-
ance-based national healthcare system. It is characterized by good accessibility, comprehensive
population coverage, and relatively low costs [25].
Nevertheless, only the medical center and regional hospital having negative-pressure isola-
tion wards that can isolate TB-infected patients. After they were discharged and developed sec-
ondary lung cancer, they went to their previous and familiar hospitals for help. This makes it a
significantly high risk to “find” secondary lung cancer at medical centers and regional hospitals
by 2.332- and 1.728 times than local hospitals, respectively.
After stratifying by variable factors using Cox regression and Fine & Gray’s competing risk
model, we found that all factors increased the risk in TB-infected patients to develop lung can-
cer compared with non-infected patients. The Kaplan-Meier analysis revealed that TB-infected
patients had a significantly higher risk of developing secondary lung cancer among primary
cancer patients, even during the first year of tracking. The reasons for all the above phenomena
are similar to those mentioned before. Also, these results demonstrated that TB-exposure is a
risk for facilitating primary cancer to metastasize to the lung.
The primary cancer types, including head and neck, colorectal, soft tissue sarcoma, breast,
kidney, and thyroid tumors, have a significantly higher risk of developing secondary lung cancer
in TB-infected patients. Bone, melanoma, and testicular cancer show no difference. These results
are similar to a previous study conducted on 228 cases with lung nodules. Most of the primary
sites are colorectal in 25.8%, head and neck in 19.4%, urological organ in 14.7%, breast cancer in
10.5%, melanoma in 6.5%, and other primary sites (sarcoma, thyroid, squamous cell) in 6.1%
[26]. Because the incidence of melanoma in Taiwan is relatively lower than that of Europe and
America, the metastatic rate may not differ significantly. Also, bone and testicular tumors are
more recurrent tumors and not distal metastases, so both did not show a difference.
Although this was a large-scale population-based nationwide study conducted from 2000 to
2015, it had some limitations. First, the patients’ ethnic background in this study was predomi-
nantly Asian, limiting the generalizability of these results. Second, the health insurance data we
utilized did not include the histological stage and severity of primary cancer that may affect the
metastatic ability. Third, our study also excluded laboratory results, such as sputum culture,
exercise capacity, lifestyle data, nutrition supplements, and family history of systemic disease.
Conclusions
In this study, TB was associated with a 1.67-fold increase in risk of secondary lung cancer com-
pared with non-TB cohorts among the primary cancer. All comorbidities may increase the risk
of developing secondary lung cancer. Therefore, clinicians should consider this in TB-infected
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patients, since TB leads to secondary lung cancer more easily among patients with primary
cancer.
Supporting information
S1 Table. Abbreviation and ICD-9-CM codes.
(DOCX)
Acknowledgments
We would like to thank the Health and Welfare Data Science Center, Ministry of Health and
Welfare (HWDC, MOHW) for their support. This study was supported by the Tri-Service
General Hospital Research Foundation (TSGH-B-110012), and the sponsor has no role in
study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Author Contributions
Conceptualization: Li-Ju Ho, Ruei-Yu Su.
Data curation: Li-Ju Ho, Wei-Chin Chang, Wu-Chien Chien.
Formal analysis: Chi-Hsiang Chung, Wei-Chin Chang.
Methodology: Chi-Hsiang Chung, Chien-An Sun, Wu-Chien Chien.
Project administration: Hung-Yi Yang, Sung-Sen Yang.
Resources: Hung-Yi Yang, Wu-Chien Chien.
Software: Chi-Hsiang Chung, Chien-An Sun.
Supervision: Wu-Chien Chien, Ruei-Yu Su.
Writing – original draft: Li-Ju Ho.
Writing – review & editing: Li-Ju Ho, Wu-Chien Chien, Ruei-Yu Su.
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