QJM Advance Access published December 11, 2014 Q J Med doi:10.1093/qjmed/hcu237
Advance Access Publication 30 November 2014
Increased risk of lung cancer among patients with bronchiectasis: a nationwide cohort study W.-S. CHUNG1,2,3, C.-L. LIN4,5, W.-H. HSU6,7 and C.-H. KAO7,8 From the 1Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, 2Department of Health Services Administration, China Medical University, 3Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, 4 Management Office for Health Data, China Medical University Hospital, Taichung, 5College of Medicine, China Medical University, Taichung, 6Department of Respiratory and Critical Care, China Medical University Hospital, Taichung, 7Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung and 8Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan Address correspondence to C.-H. Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. email: [email protected]
Summary Background: We conducted a longitudinal nationwide cohort study in Taiwan to determine whether patients with bronchiectasis are at an increased risk of developing lung cancer. Methods: This study investigated the incidence and risk for lung cancer in 57 576 patients newly hospitalized with bronchiectasis between 1998 and 2010 from the Taiwan National Health Insurance Research Database. The comparison cohort comprised 230 304 individuals from the general population without bronchiectasis. The follow-up period was from the time of the initial hospitalization for bronchiectasis to the date of a lung cancer diagnosis, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of lung cancer by including the variables of sex, age and comorbidities.
Results: The incidence of lung cancer was higher in patients with bronchiectasis than in the comparison cohort (4.58 vs. 2.02 per 1000 person-years). The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the comparison cohort after adjustment for age, sex and comorbidities (adjusted hazard ratio [aHR] = 2.36, 95% confidence interval [CI] = 2.19–2.55). The sex-specific bronchiectasis cohort to comparison cohort revealed that the aHR was 2.41 (95% CI = 2.11–2.76) for the women and 2.33 (95% CI = 2.12–2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts. Conclusion: This nationwide study determined that the patients with bronchiectasis exhibited an increased risk of lung cancer compared with the general population.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected] Page 1 of 9
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Received 8 October 2014 and in revised form 30 October 2014
W.-S. Chung et al.
What is already known on this subject? 1. Lung cancer is a leading cause of cancer death worldwide. 2. Bronchiectasis is a common chronic respiratory disease and similar to chronic obstructive pulmonary disease. 3. Studies on the association between bronchiectasis and lung cancer are few.
What this study adds? 1. The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the control cohort. 2. The incidence rate of lung cancer increased as age increased in both cohorts.
Lung cancer is a leading cause of cancer death worldwide and accounted for 8.2 million deaths in 2012.1 In addition, lung cancer is one of the top five leading cancer incidences and the leading cause of cancer death in Taiwan.2,3 Although cigarette smoking is considered the most critical risk factor for lung cancer, only 10–15% of active smokers develop lung cancer.4 In addition, 25% of all lung cancer cases were estimated to develop in never-smokers, and its incidence is expected to increase because of smoking prevention programs.5 Bronchiectasis is a lung disease characterized by localized destruction and irreversible dilatation of the bronchial tree. The disease is caused by recurrent inflammation or infection of the airway. Bronchiectasis is a common chronic respiratory disease and shares some similarities with chronic obstructive pulmonary disease (COPD) for chronic inflammatory lung diseases.6 Patients with bronchiectasis have been reported to exhibit increased systemic inflammation,7 increased arterial stiffness8 and bone thinning.6,9,10 Inflammatory responses play decisive roles in tumor development and affect immune surveillance.11,12 COPD is recognized as a systemic inflammatory disorder with an increased risk of lung cancer.13,14 In addition, recent studies have indicated an increased risk of lung cancer in individuals with tuberculosis.15,16 Studies on the relationship between bronchiectasis and lung cancer are few. We examined whether bronchiectasis increased
Methods Data source This study used data from the Taiwan National Health Insurance Research Database (NHIRD), which is provided by the Bureau of National Health Insurance (NHI) and managed by the National Health Research Institutes in Taiwan. The universal NHI program has been reformed from 13 insurance-related systems in Taiwan since 1995. Since 2008, the NHI program has enrolled 99% of the residents and has contracted with more than 97% of hospitals and clinics in Taiwan.17 The NHIRD consists of registration files and claims data for reimbursement. We used two registration databases in this study, namely the inpatient claims database and registry for catastrophic illness patients database (RCIPD) of the population in Taiwan (23 million) from 1996 to 2011. The International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) was used for the diagnosis codes. Several Taiwanese studies have indicated a high accuracy and validity of ICD-9-CM diagnosis in the NHIRD.18,19 To protect the privacy of the participants, the data were deidentified and analysed anonymously. The Institutional Review Board of China Medical University approved all of the content of this study (CMUREC-101-012).
Study population The study design was a retrospective populationbased cohort study. We used inpatient claims database to identify patients diagnosed with bronchiectasis (ICD-9-CM 494) at the first hospitalization from 1998 to 2010. A sample of 57 576 patients comprised the bronchiectasis cohort. The diagnosis date of bronchiectasis was defined as the index date. Randomly selected patients from the general population without bronchiectasis frequencymatched according to sex, age (5-year span each), and index year in a ratio of 1:4 comprised the comparison cohort (N = 230 304). Patients who had lung cancer prior to the index year were excluded. The baseline comorbidity history was determined for each participant. The comorbidities were hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), diabetes (ICD-9-CM code 250), pneumoconiosis (ICD-9-CM codes 500–505), pulmonary alveolar pneumonopathy (ICD-9-CM code 516), COPD (ICD-9-CM codes 491, 492 and Page 2 of 9
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Introduction
the risk of developing lung cancer by using a nationwide cohort study.
Lung cancer in bronchiectasis 496), stroke (ICD-9-CM codes 430–438), ischemic heart disease (ICD-9-CM codes 410–414), asthma (ICD-9-CM codes 493) and smoking-related cancers (ICD-9-CM codes 140–150, 157, 160–161 and 189).
Main outcome The primary outcome was newly diagnosed lung cancer (ICD-9-CM code 162). In Taiwan, pulmonologists can apply for a catastrophic illness card for patients with lung cancer. The application of the catastrophic illness card should be scrutinized by peer reviewers. Patients with lung cancer who received a catastrophic illness card can be exempt from paying a copayment and must be registered in the RCIPD. Therefore, we used the RCIPD to confirm the patients with lung cancer in the claims data. The follow-up person-years were determined by calculating the interval between the index date and the date of lung cancer diagnosis, date of withdrawal from the NHI program, date of death, or 31 December 2011, whichever occurred first.
The diagnoses of lung cancer and bronchiectasis were based on the ICD-9 codes, which were judged and determined by related specialists and physicians, according to the pathologic findings for lung cancer and computed tomography (CT)-imaging findings such as increased bronchoarterial ratio (signet-ring sign), contour abnormality (cylindrical, varicose and saccular), lack of bronchial tapering or visibility of peripheral airway within 1 cm of costal pleura for bronchiectasis.
Statistical analysis We used the chi-square test and Student t-test to compare the demographic characteristics (categorical variables and continuous variables) at baseline between the bronchiectasis and comparison cohorts. The incidence rate of lung cancer was calculated for each cohort, and the Kaplan–Meier method was used to estimate proportions of the participants who exhibited lung cancer during the follow-up period. The log–rank test was used to assess the differences in cumulative incidence curves of both cohorts from 1998 to 2011. The incidence rate ratio (IRR) of lung cancer and 95% confidence interval (CI) were estimated using a Poisson regression model. Multivariable Cox proportional hazard regression models were applied to calculate the adjust hazard ratio (HR) and 95% CI of developing lung cancer in the bronchiectasis cohort compared
Results Demographic characteristics and comorbidity between the bronchiectasis patients and non-bronchiectasis controls A total of 57 576 patients comprised the bronchiectasis cohort and 230 304 persons without bronchiectasis comprised the comparison cohort (Table 1). The distributions of age and sex were similar between both cohorts, which predominantly consisted of men (52.9%) and individuals aged 65 years and older (65.3%). The mean age of the bronchiectasis and non-bronchiectasis cohorts were 68.3 (SD = 15.2) and 67.3 (SD = 15.2) years, respectively. The bronchiectasis cohort exhibited a higher prevalence of comorbidities than the comparison cohort at the baseline (P < .001).
Comparison of the incidence and HR of lung cancer stratified by sex, age and comorbidity between the bronchiectasis patients and non-bronchiectasis controls As shown in Table 2, the IRR of lung cancer was 2.27-fold higher in the bronchiectasis cohort compared with the comparison cohort (4.58 vs. 2.02 per 1000 person-years, IRR = 2.27, 95% CI = 2.21– 2.33). After adjustment for age, sex and comorbidities of hypertension, hyperlipidemia, diabetes mellitus, pneumoconiosis, pulmonary alveolar pneumonopathy, COPD, stroke, ischemic heart disease, asthma and smoking-related cancers, the aHR was 2.36 (95% CI = 2.19–2.55) in the bronchiectasis cohort. The sex-specific bronchiectasis cohort to comparison cohort showed that the aHR was 2.41 (95% CI = 2.11–2.76) for the women and 2.33 (95% CI = 2.12–2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts; the Page 3 of 9
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Diagnostic definition of bronchiectasis and lung cancer
with comparison cohort. The multivariable model was adjusted for age, sex and comorbidities, such as hypertension, hyperlipidemia, diabetes mellitus, pneumoconiosis, pulmonary alveolar pneumonopathy and COPD, which yielded a significant difference, as shown in Table 1. A P value of < 0.05 in the two-tailed tests was statistically significant. The entire matching procedure and all of the statistical analyses were performed using the SAS Version 9.3 statistical package (SAS Institute Inc., Cary, NC, USA). To draw the Kaplan–Meier survival curves was conducted using R software (R Foundation for Statistical Computing, Vienna, Austria).
W.-S. Chung et al. Table 1 Demographic characteristics and comorbidity in patients with and without Bronchiectasis Variables
Bronchiectasis
P value
No (N = 230 304)
Sex Female Male Age, years 20–35 36–50 51–65 66–75 >75 Means (SD)a Comorbidity Hypertension Hyperlipidemia Diabetes mellitus Pneumoconiosis Pulmonary alveolar pneumonopathy COPD Stroke Ischemic heart disease Asthma Smoking-related cancers
Yes (N = 57 576)
n
%
n
%
108 388 121 916
47.1 52.9
27 097 30 479
47.1 52.9
8012 22 976 49 092 59 604 90 620 67.3
3.48 9.98 21.3 25.9 39.4 15.2
2003 5744 12 273 14 901 22 655 68.3
3.48 9.98 21.3 25.9 39.4 15.2
Advance Access Publication 30 November 2014
Increased risk of lung cancer among patients with bronchiectasis: a nationwide cohort study W.-S. CHUNG1,2,3, C.-L. LIN4,5, W.-H. HSU6,7 and C.-H. KAO7,8 From the 1Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, 2Department of Health Services Administration, China Medical University, 3Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, 4 Management Office for Health Data, China Medical University Hospital, Taichung, 5College of Medicine, China Medical University, Taichung, 6Department of Respiratory and Critical Care, China Medical University Hospital, Taichung, 7Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung and 8Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan Address correspondence to C.-H. Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. email: [email protected]
Summary Background: We conducted a longitudinal nationwide cohort study in Taiwan to determine whether patients with bronchiectasis are at an increased risk of developing lung cancer. Methods: This study investigated the incidence and risk for lung cancer in 57 576 patients newly hospitalized with bronchiectasis between 1998 and 2010 from the Taiwan National Health Insurance Research Database. The comparison cohort comprised 230 304 individuals from the general population without bronchiectasis. The follow-up period was from the time of the initial hospitalization for bronchiectasis to the date of a lung cancer diagnosis, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of lung cancer by including the variables of sex, age and comorbidities.
Results: The incidence of lung cancer was higher in patients with bronchiectasis than in the comparison cohort (4.58 vs. 2.02 per 1000 person-years). The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the comparison cohort after adjustment for age, sex and comorbidities (adjusted hazard ratio [aHR] = 2.36, 95% confidence interval [CI] = 2.19–2.55). The sex-specific bronchiectasis cohort to comparison cohort revealed that the aHR was 2.41 (95% CI = 2.11–2.76) for the women and 2.33 (95% CI = 2.12–2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts. Conclusion: This nationwide study determined that the patients with bronchiectasis exhibited an increased risk of lung cancer compared with the general population.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected] Page 1 of 9
Downloaded from by guest on December 29, 2015
Received 8 October 2014 and in revised form 30 October 2014
W.-S. Chung et al.
What is already known on this subject? 1. Lung cancer is a leading cause of cancer death worldwide. 2. Bronchiectasis is a common chronic respiratory disease and similar to chronic obstructive pulmonary disease. 3. Studies on the association between bronchiectasis and lung cancer are few.
What this study adds? 1. The bronchiectasis patients exhibited a 2.36-fold increased risk of lung cancer compared with the control cohort. 2. The incidence rate of lung cancer increased as age increased in both cohorts.
Lung cancer is a leading cause of cancer death worldwide and accounted for 8.2 million deaths in 2012.1 In addition, lung cancer is one of the top five leading cancer incidences and the leading cause of cancer death in Taiwan.2,3 Although cigarette smoking is considered the most critical risk factor for lung cancer, only 10–15% of active smokers develop lung cancer.4 In addition, 25% of all lung cancer cases were estimated to develop in never-smokers, and its incidence is expected to increase because of smoking prevention programs.5 Bronchiectasis is a lung disease characterized by localized destruction and irreversible dilatation of the bronchial tree. The disease is caused by recurrent inflammation or infection of the airway. Bronchiectasis is a common chronic respiratory disease and shares some similarities with chronic obstructive pulmonary disease (COPD) for chronic inflammatory lung diseases.6 Patients with bronchiectasis have been reported to exhibit increased systemic inflammation,7 increased arterial stiffness8 and bone thinning.6,9,10 Inflammatory responses play decisive roles in tumor development and affect immune surveillance.11,12 COPD is recognized as a systemic inflammatory disorder with an increased risk of lung cancer.13,14 In addition, recent studies have indicated an increased risk of lung cancer in individuals with tuberculosis.15,16 Studies on the relationship between bronchiectasis and lung cancer are few. We examined whether bronchiectasis increased
Methods Data source This study used data from the Taiwan National Health Insurance Research Database (NHIRD), which is provided by the Bureau of National Health Insurance (NHI) and managed by the National Health Research Institutes in Taiwan. The universal NHI program has been reformed from 13 insurance-related systems in Taiwan since 1995. Since 2008, the NHI program has enrolled 99% of the residents and has contracted with more than 97% of hospitals and clinics in Taiwan.17 The NHIRD consists of registration files and claims data for reimbursement. We used two registration databases in this study, namely the inpatient claims database and registry for catastrophic illness patients database (RCIPD) of the population in Taiwan (23 million) from 1996 to 2011. The International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) was used for the diagnosis codes. Several Taiwanese studies have indicated a high accuracy and validity of ICD-9-CM diagnosis in the NHIRD.18,19 To protect the privacy of the participants, the data were deidentified and analysed anonymously. The Institutional Review Board of China Medical University approved all of the content of this study (CMUREC-101-012).
Study population The study design was a retrospective populationbased cohort study. We used inpatient claims database to identify patients diagnosed with bronchiectasis (ICD-9-CM 494) at the first hospitalization from 1998 to 2010. A sample of 57 576 patients comprised the bronchiectasis cohort. The diagnosis date of bronchiectasis was defined as the index date. Randomly selected patients from the general population without bronchiectasis frequencymatched according to sex, age (5-year span each), and index year in a ratio of 1:4 comprised the comparison cohort (N = 230 304). Patients who had lung cancer prior to the index year were excluded. The baseline comorbidity history was determined for each participant. The comorbidities were hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), diabetes (ICD-9-CM code 250), pneumoconiosis (ICD-9-CM codes 500–505), pulmonary alveolar pneumonopathy (ICD-9-CM code 516), COPD (ICD-9-CM codes 491, 492 and Page 2 of 9
Downloaded from by guest on December 29, 2015
Introduction
the risk of developing lung cancer by using a nationwide cohort study.
Lung cancer in bronchiectasis 496), stroke (ICD-9-CM codes 430–438), ischemic heart disease (ICD-9-CM codes 410–414), asthma (ICD-9-CM codes 493) and smoking-related cancers (ICD-9-CM codes 140–150, 157, 160–161 and 189).
Main outcome The primary outcome was newly diagnosed lung cancer (ICD-9-CM code 162). In Taiwan, pulmonologists can apply for a catastrophic illness card for patients with lung cancer. The application of the catastrophic illness card should be scrutinized by peer reviewers. Patients with lung cancer who received a catastrophic illness card can be exempt from paying a copayment and must be registered in the RCIPD. Therefore, we used the RCIPD to confirm the patients with lung cancer in the claims data. The follow-up person-years were determined by calculating the interval between the index date and the date of lung cancer diagnosis, date of withdrawal from the NHI program, date of death, or 31 December 2011, whichever occurred first.
The diagnoses of lung cancer and bronchiectasis were based on the ICD-9 codes, which were judged and determined by related specialists and physicians, according to the pathologic findings for lung cancer and computed tomography (CT)-imaging findings such as increased bronchoarterial ratio (signet-ring sign), contour abnormality (cylindrical, varicose and saccular), lack of bronchial tapering or visibility of peripheral airway within 1 cm of costal pleura for bronchiectasis.
Statistical analysis We used the chi-square test and Student t-test to compare the demographic characteristics (categorical variables and continuous variables) at baseline between the bronchiectasis and comparison cohorts. The incidence rate of lung cancer was calculated for each cohort, and the Kaplan–Meier method was used to estimate proportions of the participants who exhibited lung cancer during the follow-up period. The log–rank test was used to assess the differences in cumulative incidence curves of both cohorts from 1998 to 2011. The incidence rate ratio (IRR) of lung cancer and 95% confidence interval (CI) were estimated using a Poisson regression model. Multivariable Cox proportional hazard regression models were applied to calculate the adjust hazard ratio (HR) and 95% CI of developing lung cancer in the bronchiectasis cohort compared
Results Demographic characteristics and comorbidity between the bronchiectasis patients and non-bronchiectasis controls A total of 57 576 patients comprised the bronchiectasis cohort and 230 304 persons without bronchiectasis comprised the comparison cohort (Table 1). The distributions of age and sex were similar between both cohorts, which predominantly consisted of men (52.9%) and individuals aged 65 years and older (65.3%). The mean age of the bronchiectasis and non-bronchiectasis cohorts were 68.3 (SD = 15.2) and 67.3 (SD = 15.2) years, respectively. The bronchiectasis cohort exhibited a higher prevalence of comorbidities than the comparison cohort at the baseline (P < .001).
Comparison of the incidence and HR of lung cancer stratified by sex, age and comorbidity between the bronchiectasis patients and non-bronchiectasis controls As shown in Table 2, the IRR of lung cancer was 2.27-fold higher in the bronchiectasis cohort compared with the comparison cohort (4.58 vs. 2.02 per 1000 person-years, IRR = 2.27, 95% CI = 2.21– 2.33). After adjustment for age, sex and comorbidities of hypertension, hyperlipidemia, diabetes mellitus, pneumoconiosis, pulmonary alveolar pneumonopathy, COPD, stroke, ischemic heart disease, asthma and smoking-related cancers, the aHR was 2.36 (95% CI = 2.19–2.55) in the bronchiectasis cohort. The sex-specific bronchiectasis cohort to comparison cohort showed that the aHR was 2.41 (95% CI = 2.11–2.76) for the women and 2.33 (95% CI = 2.12–2.56) for the men. The incidence rate of lung cancer increased as age increased in both cohorts; the Page 3 of 9
Downloaded from by guest on December 29, 2015
Diagnostic definition of bronchiectasis and lung cancer
with comparison cohort. The multivariable model was adjusted for age, sex and comorbidities, such as hypertension, hyperlipidemia, diabetes mellitus, pneumoconiosis, pulmonary alveolar pneumonopathy and COPD, which yielded a significant difference, as shown in Table 1. A P value of < 0.05 in the two-tailed tests was statistically significant. The entire matching procedure and all of the statistical analyses were performed using the SAS Version 9.3 statistical package (SAS Institute Inc., Cary, NC, USA). To draw the Kaplan–Meier survival curves was conducted using R software (R Foundation for Statistical Computing, Vienna, Austria).
W.-S. Chung et al. Table 1 Demographic characteristics and comorbidity in patients with and without Bronchiectasis Variables
Bronchiectasis
P value
No (N = 230 304)
Sex Female Male Age, years 20–35 36–50 51–65 66–75 >75 Means (SD)a Comorbidity Hypertension Hyperlipidemia Diabetes mellitus Pneumoconiosis Pulmonary alveolar pneumonopathy COPD Stroke Ischemic heart disease Asthma Smoking-related cancers
Yes (N = 57 576)
n
%
n
%
108 388 121 916
47.1 52.9
27 097 30 479
47.1 52.9
8012 22 976 49 092 59 604 90 620 67.3
3.48 9.98 21.3 25.9 39.4 15.2
2003 5744 12 273 14 901 22 655 68.3
3.48 9.98 21.3 25.9 39.4 15.2
