Lung (2014) 192:159–165 DOI 10.1007/s00408-013-9523-z
Increased Lung Cancer Risk Among Patients with Pneumococcal Pneumonia: A Nationwide Population-Based Cohort Study Te-Yu Lin • Wen-Yen Huang • Jung-Chung Lin • Cheng-Li Lin • Fung-Chang Sung • Chia-Hung Kao Jun-Jun Yeh
•
Received: 6 August 2013 / Accepted: 4 October 2013 / Published online: 23 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background The possible effects of pneumonia on subsequent lung cancer have been reported, but no relevant publications have focused on the association between pneumococcal pneumonia and lung cancer. The purpose of this study was to perform a nationwide population-based cohort study to investigate the risk of lung cancer after pneumococcus infection. Methods This nationwide population-based cohort study was based on data obtained from the Taiwan National Health Insurance Database. In total, 22,034 pneumococcal pneumonia patients and 88,136 controls, matched for age and sex, were recruited for the study from 1997 to 2010.
Results The incidence rate of lung cancer (28.2 per 1,000 person-years) was significantly higher in pneumococcal pneumonia patients than in controls (8.7 per 1,000 personyears; incidence rate ratio, 3.25; 95 % confidence interval, 3.09–3.42; p \ 0.001). Cox proportional hazards regression analysis showed a hazard ratio of 4.24 (95 % confidence interval, 3.96–4.55) for the pneumococcal pneumonia cohort after adjustment for age, gender, and comorbidities. Conclusions Pneumococcal pneumonia is associated with an increased risk of lung cancer. Thus, physicians should remain aware of this association when assessing patients with pneumococcal pneumonia.
T.-Y. Lin J.-C. Lin Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
C.-H. Kao (&) Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan e-mail: [email protected]
W.-Y. Huang Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan W.-Y. Huang Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan C.-L. Lin F.-C. Sung Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
J.-J. Yeh (&) Department of Internal Medicine and Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Rd., Chiayi 600, Taiwan e-mail: [email protected] J.-J. Yeh Chia Nan University of Pharmacy and Science, Tainan, Taiwan J.-J. Yeh Meiho University, Pingtung, Taiwan
C.-L. Lin F.-C. Sung Department of Public Health, China Medical University, Taichung, Taiwan C.-H. Kao Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan
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Keywords Pneumococcal pneumonia Lung cancer Nationwide population-based Cohort study Taiwan National Health Insurance Database
pneumococcal pneumonia and subsequent risk of lung cancer, as well as the temporal relationship between these two diseases.
Introduction
Materials and Methods
Pneumonia is a common global disease and remains one of the major causes of death among infectious diseases [1]. Among community-acquired pneumonia conditions, approximately 50 % of causative organisms can be found. Among them, Streptococcus pneumonia is a common pathogen [2]. Lung cancer continues to be the leading cause of cancer incidence and mortality worldwide, with more than a million estimated deaths annually [3]. Traditional risk factors of lung cancer are smoking, occupational exposure to arsenates, nitrosamines, and asbestos, or indoor exposure to radon or fumes from fires. Recent evidence suggests that inflammatory processes may play a central role in carcinogenesis [4, 5]. The major sources of inflammation in lung tissue are chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), pneumonia, and tuberculosis. Both pneumonia and lung cancer substantially influence public health; therefore, the association between these two diseases must be clarified. Several studies have examined the association between pneumonia and lung cancer using hospital and communitybased populations [6–18]. A meta-analysis performed by Brenner et al. [19] revealed a positive association between pneumonia and subsequent lung cancer. However, the cited references were mostly case–control studies. Recall bias of exposure assessment, selection bias of the control group, and the validity of the reported pneumonia diagnosis could be considered possible limitations of this type of study. In addition, the temporal relationship between pneumonia and subsequent lung cancer is difficult to assess in case–control studies. Some cohort studies have reported a positive association between pneumonia and lung cancer [20]. However, these studies might not have been able to yield generalizable results, because they have usually focused on high-risk populations, such as heavy smokers and asbestosexposed smokers. Pneumonia can be caused by virus, bacteria, fungi, and parasites, and the relationship between the causative organisms of pneumonia and lung cancer is less clearly understood. Two published reports have shown that Chlamydia pneumonia infection is associated with an increased risk of lung cancer [20, 21]. However, no publications, to the best of our knowledge, focus on the association between pneumococcal pneumonia and lung cancer. Therefore, we conducted a nationwide population-based cohort study that included numerous pneumococcal pneumonia cases to investigate the association between
Data Source
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We established a longitudinal cohort study from the Taiwan National Health Institute Research Database (NHIRD), with whole population admission insured in Taiwan. Taiwan has implemented a compulsory singlepayer National Health Institute (NHI) program since the beginning of 1995, covering more than 99 % of Taiwan’s 23 million residents and prospectively recorded until December 31, 2010. The Bureau of National Health Insurance (BNHI) provided the registration files and medical claims data. All data were confidential and all people were anonymous and de-identified, thus ensuring that the NHI reimbursement data were suitable for public research. Previous studies have addressed information on the NHIRD [22–25]. The accuracy and high validity of diagnoses identified in the NHIRD also has been demonstrated [22]. This study was exempted by the Institutional Review Board of China Medical University (CMU-REC101-012). Patients with Pneumococcal Pneumonia The International Classification of Diseases, Ninth Revision (ICD-9), was used to confirm diagnostic codes. We selected all adult pneumococcal pneumonia (ICD-9 code 481) patients (C20 years old) from the NHIRD. In total, 22,034 patients who had a first-time diagnosis of pneumococcal pneumonia and at least one health care admission from 1997 to 2010 were confirmed; the index date was the date of pneumococcal pneumonia registration. Patients with a history of cancer (ICD-9 codes 140–208) before the index date, or with incomplete age or sex information, were excluded. All patients without a history of pneumonia (ICD-9 codes 480–487) were selected randomly in the NHIRD. To increase the statistical power, four comparison controls (88,136) for each case were frequently matched for age (5 years each), sex, and index year. All of the study patients were monitored until the date on which they were diagnosed with lung cancer. Identification of Lung Cancer Cases Our newly diagnosed patients with lung cancer (ICD-9 code 162) were confirmed by the Registry for Catastrophic Illness Patient Database (RCIPD), and the index date was the date of
Lung (2014) 192:159–165
161 Table 1 Demographic characteristics and co-morbidity in patients with and without pneumococcal pneumonia Variables
p valuea
Pneumococcal pneumonia No (N = 88,136)
Yes (N = 22,034)
n
%
n
%
Male
58,492
66.4
14,623
66.4
Female
29,644
33.6
7,411
33.6
13,320
15.1
3,330
15.1
Sex
1.00
Age (years) 20–45
1.00
46–55
7,968
9
1,992
9
56–65
12,424
14.1
3,106
14.1
66–74
20,956
23.8
5,239
23.8
C75
33,468
38
8,367
38 \0.0001
Hypertension Fig. 1 Cumulative incidence of lung cancer for the pneumococcal pneumonia and the comparison cohorts in Taiwan from 1997 to 2010
lung cancer registration. To apply for a catastrophic illness certificate for reimbursement claims, patients with cancer must provide comprehensive supporting information, such as reports or evidence of cytology and pathology. At least two other oncologists carefully examine their medical and laboratory information. After the rigorous assessments are processed, patients who meet the criteria for the diagnoses are issued certificates.
Yes
12,569
14.3
8,744
39.7
No
75,567
85.7
13,290
60.3
7.4 92.6
5,606 16,428
25.4 74.6
\0.0001
Diabetes mellitus Yes No
6,518 81,618
\0.0001
Hyperlipidemia Yes
2,739
3.1
1,677
7.6
No
85,397
96.9
20,357
92.4 \0.0001
COPD Yes
2,598
3
4,251
19.3
No
85,538
97
17,783
80.7
1
1,899
8.6
87,271
99
20,135
91.4
Yes
2,043
2.3
3,102
14.1
No
86,093
97.7
18,932
85.9
\0.0001
Tuberculosis Yes
Variables of Exposure
No
Potential confounding factors were listed according to established risk factors, and analyses were performed to establish whether these variables were substantially associated with lung cancer. Baseline comorbidities were analyzed as follows: tuberculosis (ICD-9 code 611), asthma (ICD-9 code 493), and chronic obstructive pulmonary disease (COPD, ICD-9 codes 490–496), which is characterized by chronic airway inflammatory process, have been reported as being linked to lung cancers [25–27]. Metabolic syndromes also have been linked to several types of cancer [28, 29]. The relationship between diabetes mellitus (ICD9 code 250) and lung cancers remains controversial [30, 31]. Hyperlipidemia (ICD-9 code 272) and elevated blood pressure (hypertension, ICD-9 codes 401–405) comprise the major components of metabolic syndromes; therefore, they were included in the comorbidity analysis. Statistical Analysis All statistical analyses were performed using the SAS statistical package (Version 9.2 for Windows; SAS Institute, Inc., Cary, NC). Statistical significance was accepted
865
\0.0001
Asthma
COPD chronic obstructive pulmonary disease a
Chi-square test
at a = 0.05. The distributions of categorical characteristics between the pneumococcal pneumonia cohort and the controls were described and compared by conducting v2 tests. The person-years were calculated to assess incidence densities (per 1,000 person-years) until lung cancer diagnosis was identified, loss of follow-up, or censored at the end of 2010. To estimate the age effect, we divided the study patients into categories based on age (20–45, 46–55, 56–65, 66–74, and C75 years) at the index date of pneumococcal pneumonia. To estimate the relative risk (the incidence density rate) and absolute risk (adjusted hazard ratio, aHR) of lung cancer, we proceeded as follows. First, we used the Poisson regression model to assess incidence rate ratios (IRRs), and 95 % confidence intervals (CIs) between the pneumococcal pneumonia cohort and the
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Lung (2014) 192:159–165
Table 2 Incidence rate ratio and adjusted hazard ratio of lung cancer among pneumococcal pneumonia cohort to comparison cohort Variables
Pneumococcal pneumonia No (N = 88,136)
IRR (95 % CI)
aHR (95 % CI)
Yes (N = 22,034)
Event
Person years
Ratea
Event
Person years
Ratea
4,531
522,315
8.7
2,274
80,583
28.2
3.25 (3.09–3.42)***
4.24 (3.96–4.55)***
3,592 939
333,869 188,446
10.8 5
1,757 517
48,227 32,356
36.4 16
3.39 (3.2–3.59)*** 3.21 (2.88–3.57)***
1.85 (1.71–1.99)*** Reference
20–45
14
95,052
0.2
86
21,064
4.1
27.7 (15.8–48.8)***
Reference
46–55
111
53,332
2.1
176
9,568
18.4
8.84 (6.97–11.2)***
4.72 (3.70–6.03)***
Total Sex Male Female Age (years)
56–65
477
84,809
5.6
362
13,472
26.9
4.78 (4.17–5.48)***
9.87 (7.89–12.3)***
66–74
1,702
134,932
12.6
828
18,474
44.8
3.55 (3.27–3.86)***
17.6 (14.2–21.7)***
C75
2,227
154,191
14.4
822
18,005
45.7
3.16 (2.92–3.42)***
18.7 (15.1–23.1)***
Follow-up period B1 year
709
83,774
8.5
1,540
16,382
94
11.1 (10.1–12.1)***
–
[1 year
3,822
438,504
8.8
734
64,202
11.4
1.3 (1.2–1.41)***
–
IRR incidence rate ratio; aHR adjusted hazard ratio: mutually adjusted for age, gender, and comorbidities in Cox proportional hazard regression; CI confidence interval * P \ 0.05; ** P \ 0.01; *** P \ 0.001 a
Rate per 1,000 person-years
controls. Second, we used the Cox proportional hazard regression model to estimate the hazard ratios (HRs) of developing lung cancer. Furthermore, we assessed whether the association of lung cancer varied according to the interval from the index date to the date of lung cancer diagnosis. We divided the time lag into the following two periods: B1 and[1 year. The cumulative incidence of lung cancer between the pneumococcal pneumonia cohort and the controls was assessed using the Kaplan–Meier method, and the differences were assessed with a log-rank test (Fig. 1).
Results Demographic characteristics are shown in Table 1. No statistical difference was found in the distributions of sex and age between the pneumococcal pneumonia cohort and the controls (mean age 63.6 ± 17.7 years). Nearly twothirds of the male patients and more than half of all of the patients in this study were older than age 66 years. The prevalence of comorbidities was greater in the pneumococcal pneumonia cohort. The IRRs (relative risks) and aHRs (absolute risks) between the pneumococcal pneumonia cohort and the controls are shown in Table 2. The overall IRR of lung cancer was 3.25-fold greater in the pneumococcal pneumonia cohort than in the controls (28.2 vs. 8.7 per 1,000 person-years) with an aHR of 4.24 (95 % CI 3.96–4.55) in
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the following 14 years. Analyses stratified by gender showed both genders have significant relative risks of developing lung cancer. For females, the incidence densities were 16.0 and 5.0 per 1,000 person-years between the two cohorts, with a 3.21-fold relative risk of developing lung cancer (95 % CI 2.88–3.57). The aHR of males of lung cancer was 85 % significantly higher than females (95 % CI 1.71–1.99). When stratified by age, the incidence density rates of lung cancer increased as age did and were the highest in the oldest patients of both cohorts (45.7 vs. 14.4 per 1,000 person-years). In the age groups, age 20–45 years had a 27.7-fold higher relative risk of developing lung cancer (95 % CI 15.8–48.8). After adjusting for cofactors, the risk of developing lung cancer increased with age (patients 20–45 years of age were the reference group) with an aHR of 18.7 in the C75 year age group (95 % CI 15.1–23.1). The aHR was calculated according to the interval of the follow-up period from the index date to the date of lung cancer diagnosis. The incidence density rates of lung cancer decreased with the follow-up periods among the pneumococcal pneumonia cohort. We found an 11.1fold significantly higher relative risk of developing lung cancer within 1 year follow-up period (95 % CI 10.1–12.1). Table 3 lists the specific analysis of comorbidities in the IRRs and aHRs between the pneumococcal pneumonia cohort and the controls. Despite excluding all cofactors, the overall IRR of lung cancer was 2.98-fold higher in the pneumococcal pneumonia cohort than in the controls
Lung (2014) 192:159–165
163
Table 3 Incidence rate ratio and adjusted hazard ratio of lung cancer and pneumococcal pneumonia cohort to comparison cohort stratify by comorbidity Variables
Pneumococcal pneumonia No (N = 231,832)
Noneb
IRR (95 % CI)
aHR (95 % CI)
Yes (N = 57,958)
Event
Person years
Rate
3,604
449,768
8.1
3,942
471,100
8.4
51,215
11.5
496,537
8.6
25,778
11.0
a
Person years
Ratea
905
37,708
24
2.98 (2.77–3.21)***
–
1,526
56,692
36.9
3.22 (3.03–3.41)***
Reference
748
23,891
31.3
2.72 (2.44–3.03)***
0.79 (0.73–0.85)***
1,811
65,445
27.7
3.24 (3.06–3.42)***
Reference
463
15,138
30.6
2.78 (2.40–3.22)***
0.98 (0.88–1.08)
Event
Hypertension No Yes
589
Diabetes mellitus No
4,247
Yes
284
Hyperlipidemia No Yes
4,434 97
511,254
8.7
2,107
11,062
8.8
167
75,694
27.8
3.2 (3.05–3.38)***
Reference
4,890
34.2
3.89 (3.03–5)***
0.99 (0.85–1.16)
512,871
8.4
9,445
22.0
1,829
69,758
26.2
3.11 (2.95–3.29)***
Reference
445
10,825
41.1
1.87 (1.58–2.2)***
0.96 (0.86–1.16)
519,113
8.6
2,000
75,076
26.6
3.09 (2.93–3.26)***
Reference
3,203
16.6
5,507
49.8
3.01 (2.24–4.03)***
1.52 (1.32–1.74)***
5,13,783
8.6
8,532
15.5
2,072
69,967
29.6
3.46 (3.28–3.64)***
Reference
202
10,617
19
1.23 (0.99–1.53)
0.66 (0.57–0.76)***
COPD No Yes
4,323 208
Tuberculosis No 4,478 Yes
53
274
Asthma No Yes
4,399 132
IRR incidence rate ratio; aHR adjusted hazard ratio: mutually adjusted for age, gender and comorbidities in Cox proportional hazard regression; CI confidence interval; COPD chronic obstructive pulmonary disease * P \ 0.05; ** P \ 0.01; *** P \ 0.001 a
Rate per 1,000 person-years
b
Patients without any one of comorbidities was classified as the none
(95 % CI 2.77–3.21). Stratified by comorbidities, the pneumococcal pneumonia cohort with hypertension, DM, hyperlipidemia, COPD, TB, and asthma had statistically significantly higher IRR of developing lung cancer than the controls. It showed that the study patients with TB had a 52 % higher risk of lung cancer than did those without (95 % CI 1.32–1.74).
Discussion This is the first nationwide population-based cohort study to investigate the associations between lung cancer and previous pneumococcal pneumonia. Our study showed that the incidence of lung cancer is greater in patients with previous history of pneumococcal pneumonia than in the general population. Most previous studies were hospitalbased research with limited observation cases. The population-based data with age- and sex-matched control groups enabled better external validation than have previous
studies. Moreover, using the NHI data to create a cohort study allowed us to observe the temporal relationship between pneumococcal pneumonia and lung cancer. Pneumococcal pneumonia is diagnosed according to clinical symptoms, physical findings, image findings, and laboratory results (sputum culture or positive urine pneumococcus antigen test). We identified the pneumococcal pneumonia cases based on their ICD-9-CM codes and antibiotics prescriptions. Lung cancer diagnosis entitles patients to qualify for special health care privileges in the ‘‘major critical diseases’’ class in Taiwan’s NHI system. We used both diagnostic codes and the Catastrophic Illness Registry. Histological confirmation is needed under the NHI program to apply for a Catastrophic Illness Card; therefore, the pneumococcal pneumonia and lung cancer data are valid. Reverse causality must be considered in cases of pneumonia, because infections may have been the result of weakening immunity caused by occult lung cancer. For these conditions, ascertainment bias should be considered
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as individuals with pneumonia may have been more likely to be diagnosed with lung cancer because of the use of additional chest X-rays in the infection workup. In the presence of occult lung cancer or the coexistence of pneumococcal pneumonia and lung cancer, the risk of lung cancer during the first year of pneumococcal pneumonia would be magnified. Therefore, lung cancer diagnosis before or within the first year of pneumococcal pneumonia infection was excluded to lessen the possibility of reverse causality and coexistence. After excluding lung cancer occurring during the first year of pneumococcal pneumonia, we still found an increased IRR for lung cancer in the pneumococcal pneumonia cohort. We observed elevated rates of lung cancer among previous pneumococcal pneumonia cases compared with controls, with crude IRR of 1.24 (95 % CI 1.15–1.35; p \ 0.001). These results were consistent with many previous studies, which have reported a positive association between pneumonia and subsequent lung cancer [6–18]. However, the relationship between pneumonia’s causative organisms and lung cancer has been less described. Most of the previous reports revealed a positive association between Chlamydia pneumonia infection and subsequent lung cancer. Streptococcus pneumonia is an important bacterial pathogen of pneumonia; to our knowledge, this study is the first to evaluate the relationship between pneumococcal pneumonia and lung cancer. We observed a higher lung cancer incidence among males in our study (HR, 1.85; 95 % CI 1.71–1.99; p \ 0.001). In a cross-sectional survey by Tsai et al. in 2004, they found a difference in smoking behavior among males and females (45.7 vs. 4.8 %), observing that men smoked significantly more cigarettes per day (18 vs. 11) [32]. Smoking is an important risk factor for lung cancer and could account for the gender discrepancy of lung cancer incidence in our study. The risk of lung cancer is increased in the pneumococcal pneumonia cohort, especially in the older than age 75 years group (HR, 18.7; 95 % CI 15.1–23.1; p \ 0.001). Epidemiology data showed that the age-based risk group of pneumococcal pneumonia is younger than 2 years or older than 75 years. Our data were consistent with previous reports and demonstrated the important role of pneumococcal pneumonia in subsequent lung cancer, especially in the group older than 75 years. Pulmonary infections have been suggested as risk factors for lung cancer. Respiratory tract infections may contribute to lung cancer by promoting airway remodeling and causing inflammation, which could generate reactive oxygen or nitrogen species, increase cellular proliferation, upregulate antiapoptotic pathways, and stimulate angiogenesis [5, 33]. Our data showed increased lung cancer incidence in the pneumococcal pneumonia cohort. Further
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studies should incorporate research that is more experimental and epidemiological to investigate the mechanisms of lung cancer induced by Streptococcus pneumonia infection. There are potential limitations in this study. First, the NHIRD does not contain detailed information regarding smoking habits, alcohol consumption, socioeconomic status, and family history of systemic diseases, all of which may be risk factors for pneumococcal pneumonia or lung cancer. Second, the evidence derived from a retrospective cohort study is generally lower in statistical quality than that from randomized trials because of potential biases related to adjustments for confounding variables. Despite our meticulous study design and control measures for confounding factors, bias resulting from unknown confounders may have affected the results. Third, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology findings, and serum laboratory data, were unavailable regarding our study patient cases. However, the data regarding the diagnoses of pneumococcal pneumonia or lung cancer were, nonetheless, reliable. The major strength of our study is its nationwide population-based settings that included relatively large numbers of pneumococcal pneumonia cases, thus allowing a clear observation of the temporal relationship between pneumonia and lung cancer. Our findings provide epidemiological evidence that pneumococcal pneumonia is a risk factor for subsequent lung cancer and that pneumococcal pneumonia patients should be monitored carefully for lung cancer development. Acknowledgments The study was supported by grants from the study hospital (DMR-101-061 and DMR-100-076); Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TD-B-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). Conflict of interest of interest.
All authors declare that they have no conflicts
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Increased Lung Cancer Risk Among Patients with Pneumococcal Pneumonia: A Nationwide Population-Based Cohort Study Te-Yu Lin • Wen-Yen Huang • Jung-Chung Lin • Cheng-Li Lin • Fung-Chang Sung • Chia-Hung Kao Jun-Jun Yeh
•
Received: 6 August 2013 / Accepted: 4 October 2013 / Published online: 23 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background The possible effects of pneumonia on subsequent lung cancer have been reported, but no relevant publications have focused on the association between pneumococcal pneumonia and lung cancer. The purpose of this study was to perform a nationwide population-based cohort study to investigate the risk of lung cancer after pneumococcus infection. Methods This nationwide population-based cohort study was based on data obtained from the Taiwan National Health Insurance Database. In total, 22,034 pneumococcal pneumonia patients and 88,136 controls, matched for age and sex, were recruited for the study from 1997 to 2010.
Results The incidence rate of lung cancer (28.2 per 1,000 person-years) was significantly higher in pneumococcal pneumonia patients than in controls (8.7 per 1,000 personyears; incidence rate ratio, 3.25; 95 % confidence interval, 3.09–3.42; p \ 0.001). Cox proportional hazards regression analysis showed a hazard ratio of 4.24 (95 % confidence interval, 3.96–4.55) for the pneumococcal pneumonia cohort after adjustment for age, gender, and comorbidities. Conclusions Pneumococcal pneumonia is associated with an increased risk of lung cancer. Thus, physicians should remain aware of this association when assessing patients with pneumococcal pneumonia.
T.-Y. Lin J.-C. Lin Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
C.-H. Kao (&) Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan e-mail: [email protected]
W.-Y. Huang Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan W.-Y. Huang Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan C.-L. Lin F.-C. Sung Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
J.-J. Yeh (&) Department of Internal Medicine and Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Rd., Chiayi 600, Taiwan e-mail: [email protected] J.-J. Yeh Chia Nan University of Pharmacy and Science, Tainan, Taiwan J.-J. Yeh Meiho University, Pingtung, Taiwan
C.-L. Lin F.-C. Sung Department of Public Health, China Medical University, Taichung, Taiwan C.-H. Kao Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan
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Keywords Pneumococcal pneumonia Lung cancer Nationwide population-based Cohort study Taiwan National Health Insurance Database
pneumococcal pneumonia and subsequent risk of lung cancer, as well as the temporal relationship between these two diseases.
Introduction
Materials and Methods
Pneumonia is a common global disease and remains one of the major causes of death among infectious diseases [1]. Among community-acquired pneumonia conditions, approximately 50 % of causative organisms can be found. Among them, Streptococcus pneumonia is a common pathogen [2]. Lung cancer continues to be the leading cause of cancer incidence and mortality worldwide, with more than a million estimated deaths annually [3]. Traditional risk factors of lung cancer are smoking, occupational exposure to arsenates, nitrosamines, and asbestos, or indoor exposure to radon or fumes from fires. Recent evidence suggests that inflammatory processes may play a central role in carcinogenesis [4, 5]. The major sources of inflammation in lung tissue are chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), pneumonia, and tuberculosis. Both pneumonia and lung cancer substantially influence public health; therefore, the association between these two diseases must be clarified. Several studies have examined the association between pneumonia and lung cancer using hospital and communitybased populations [6–18]. A meta-analysis performed by Brenner et al. [19] revealed a positive association between pneumonia and subsequent lung cancer. However, the cited references were mostly case–control studies. Recall bias of exposure assessment, selection bias of the control group, and the validity of the reported pneumonia diagnosis could be considered possible limitations of this type of study. In addition, the temporal relationship between pneumonia and subsequent lung cancer is difficult to assess in case–control studies. Some cohort studies have reported a positive association between pneumonia and lung cancer [20]. However, these studies might not have been able to yield generalizable results, because they have usually focused on high-risk populations, such as heavy smokers and asbestosexposed smokers. Pneumonia can be caused by virus, bacteria, fungi, and parasites, and the relationship between the causative organisms of pneumonia and lung cancer is less clearly understood. Two published reports have shown that Chlamydia pneumonia infection is associated with an increased risk of lung cancer [20, 21]. However, no publications, to the best of our knowledge, focus on the association between pneumococcal pneumonia and lung cancer. Therefore, we conducted a nationwide population-based cohort study that included numerous pneumococcal pneumonia cases to investigate the association between
Data Source
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We established a longitudinal cohort study from the Taiwan National Health Institute Research Database (NHIRD), with whole population admission insured in Taiwan. Taiwan has implemented a compulsory singlepayer National Health Institute (NHI) program since the beginning of 1995, covering more than 99 % of Taiwan’s 23 million residents and prospectively recorded until December 31, 2010. The Bureau of National Health Insurance (BNHI) provided the registration files and medical claims data. All data were confidential and all people were anonymous and de-identified, thus ensuring that the NHI reimbursement data were suitable for public research. Previous studies have addressed information on the NHIRD [22–25]. The accuracy and high validity of diagnoses identified in the NHIRD also has been demonstrated [22]. This study was exempted by the Institutional Review Board of China Medical University (CMU-REC101-012). Patients with Pneumococcal Pneumonia The International Classification of Diseases, Ninth Revision (ICD-9), was used to confirm diagnostic codes. We selected all adult pneumococcal pneumonia (ICD-9 code 481) patients (C20 years old) from the NHIRD. In total, 22,034 patients who had a first-time diagnosis of pneumococcal pneumonia and at least one health care admission from 1997 to 2010 were confirmed; the index date was the date of pneumococcal pneumonia registration. Patients with a history of cancer (ICD-9 codes 140–208) before the index date, or with incomplete age or sex information, were excluded. All patients without a history of pneumonia (ICD-9 codes 480–487) were selected randomly in the NHIRD. To increase the statistical power, four comparison controls (88,136) for each case were frequently matched for age (5 years each), sex, and index year. All of the study patients were monitored until the date on which they were diagnosed with lung cancer. Identification of Lung Cancer Cases Our newly diagnosed patients with lung cancer (ICD-9 code 162) were confirmed by the Registry for Catastrophic Illness Patient Database (RCIPD), and the index date was the date of
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161 Table 1 Demographic characteristics and co-morbidity in patients with and without pneumococcal pneumonia Variables
p valuea
Pneumococcal pneumonia No (N = 88,136)
Yes (N = 22,034)
n
%
n
%
Male
58,492
66.4
14,623
66.4
Female
29,644
33.6
7,411
33.6
13,320
15.1
3,330
15.1
Sex
1.00
Age (years) 20–45
1.00
46–55
7,968
9
1,992
9
56–65
12,424
14.1
3,106
14.1
66–74
20,956
23.8
5,239
23.8
C75
33,468
38
8,367
38 \0.0001
Hypertension Fig. 1 Cumulative incidence of lung cancer for the pneumococcal pneumonia and the comparison cohorts in Taiwan from 1997 to 2010
lung cancer registration. To apply for a catastrophic illness certificate for reimbursement claims, patients with cancer must provide comprehensive supporting information, such as reports or evidence of cytology and pathology. At least two other oncologists carefully examine their medical and laboratory information. After the rigorous assessments are processed, patients who meet the criteria for the diagnoses are issued certificates.
Yes
12,569
14.3
8,744
39.7
No
75,567
85.7
13,290
60.3
7.4 92.6
5,606 16,428
25.4 74.6
\0.0001
Diabetes mellitus Yes No
6,518 81,618
\0.0001
Hyperlipidemia Yes
2,739
3.1
1,677
7.6
No
85,397
96.9
20,357
92.4 \0.0001
COPD Yes
2,598
3
4,251
19.3
No
85,538
97
17,783
80.7
1
1,899
8.6
87,271
99
20,135
91.4
Yes
2,043
2.3
3,102
14.1
No
86,093
97.7
18,932
85.9
\0.0001
Tuberculosis Yes
Variables of Exposure
No
Potential confounding factors were listed according to established risk factors, and analyses were performed to establish whether these variables were substantially associated with lung cancer. Baseline comorbidities were analyzed as follows: tuberculosis (ICD-9 code 611), asthma (ICD-9 code 493), and chronic obstructive pulmonary disease (COPD, ICD-9 codes 490–496), which is characterized by chronic airway inflammatory process, have been reported as being linked to lung cancers [25–27]. Metabolic syndromes also have been linked to several types of cancer [28, 29]. The relationship between diabetes mellitus (ICD9 code 250) and lung cancers remains controversial [30, 31]. Hyperlipidemia (ICD-9 code 272) and elevated blood pressure (hypertension, ICD-9 codes 401–405) comprise the major components of metabolic syndromes; therefore, they were included in the comorbidity analysis. Statistical Analysis All statistical analyses were performed using the SAS statistical package (Version 9.2 for Windows; SAS Institute, Inc., Cary, NC). Statistical significance was accepted
865
\0.0001
Asthma
COPD chronic obstructive pulmonary disease a
Chi-square test
at a = 0.05. The distributions of categorical characteristics between the pneumococcal pneumonia cohort and the controls were described and compared by conducting v2 tests. The person-years were calculated to assess incidence densities (per 1,000 person-years) until lung cancer diagnosis was identified, loss of follow-up, or censored at the end of 2010. To estimate the age effect, we divided the study patients into categories based on age (20–45, 46–55, 56–65, 66–74, and C75 years) at the index date of pneumococcal pneumonia. To estimate the relative risk (the incidence density rate) and absolute risk (adjusted hazard ratio, aHR) of lung cancer, we proceeded as follows. First, we used the Poisson regression model to assess incidence rate ratios (IRRs), and 95 % confidence intervals (CIs) between the pneumococcal pneumonia cohort and the
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Lung (2014) 192:159–165
Table 2 Incidence rate ratio and adjusted hazard ratio of lung cancer among pneumococcal pneumonia cohort to comparison cohort Variables
Pneumococcal pneumonia No (N = 88,136)
IRR (95 % CI)
aHR (95 % CI)
Yes (N = 22,034)
Event
Person years
Ratea
Event
Person years
Ratea
4,531
522,315
8.7
2,274
80,583
28.2
3.25 (3.09–3.42)***
4.24 (3.96–4.55)***
3,592 939
333,869 188,446
10.8 5
1,757 517
48,227 32,356
36.4 16
3.39 (3.2–3.59)*** 3.21 (2.88–3.57)***
1.85 (1.71–1.99)*** Reference
20–45
14
95,052
0.2
86
21,064
4.1
27.7 (15.8–48.8)***
Reference
46–55
111
53,332
2.1
176
9,568
18.4
8.84 (6.97–11.2)***
4.72 (3.70–6.03)***
Total Sex Male Female Age (years)
56–65
477
84,809
5.6
362
13,472
26.9
4.78 (4.17–5.48)***
9.87 (7.89–12.3)***
66–74
1,702
134,932
12.6
828
18,474
44.8
3.55 (3.27–3.86)***
17.6 (14.2–21.7)***
C75
2,227
154,191
14.4
822
18,005
45.7
3.16 (2.92–3.42)***
18.7 (15.1–23.1)***
Follow-up period B1 year
709
83,774
8.5
1,540
16,382
94
11.1 (10.1–12.1)***
–
[1 year
3,822
438,504
8.8
734
64,202
11.4
1.3 (1.2–1.41)***
–
IRR incidence rate ratio; aHR adjusted hazard ratio: mutually adjusted for age, gender, and comorbidities in Cox proportional hazard regression; CI confidence interval * P \ 0.05; ** P \ 0.01; *** P \ 0.001 a
Rate per 1,000 person-years
controls. Second, we used the Cox proportional hazard regression model to estimate the hazard ratios (HRs) of developing lung cancer. Furthermore, we assessed whether the association of lung cancer varied according to the interval from the index date to the date of lung cancer diagnosis. We divided the time lag into the following two periods: B1 and[1 year. The cumulative incidence of lung cancer between the pneumococcal pneumonia cohort and the controls was assessed using the Kaplan–Meier method, and the differences were assessed with a log-rank test (Fig. 1).
Results Demographic characteristics are shown in Table 1. No statistical difference was found in the distributions of sex and age between the pneumococcal pneumonia cohort and the controls (mean age 63.6 ± 17.7 years). Nearly twothirds of the male patients and more than half of all of the patients in this study were older than age 66 years. The prevalence of comorbidities was greater in the pneumococcal pneumonia cohort. The IRRs (relative risks) and aHRs (absolute risks) between the pneumococcal pneumonia cohort and the controls are shown in Table 2. The overall IRR of lung cancer was 3.25-fold greater in the pneumococcal pneumonia cohort than in the controls (28.2 vs. 8.7 per 1,000 person-years) with an aHR of 4.24 (95 % CI 3.96–4.55) in
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the following 14 years. Analyses stratified by gender showed both genders have significant relative risks of developing lung cancer. For females, the incidence densities were 16.0 and 5.0 per 1,000 person-years between the two cohorts, with a 3.21-fold relative risk of developing lung cancer (95 % CI 2.88–3.57). The aHR of males of lung cancer was 85 % significantly higher than females (95 % CI 1.71–1.99). When stratified by age, the incidence density rates of lung cancer increased as age did and were the highest in the oldest patients of both cohorts (45.7 vs. 14.4 per 1,000 person-years). In the age groups, age 20–45 years had a 27.7-fold higher relative risk of developing lung cancer (95 % CI 15.8–48.8). After adjusting for cofactors, the risk of developing lung cancer increased with age (patients 20–45 years of age were the reference group) with an aHR of 18.7 in the C75 year age group (95 % CI 15.1–23.1). The aHR was calculated according to the interval of the follow-up period from the index date to the date of lung cancer diagnosis. The incidence density rates of lung cancer decreased with the follow-up periods among the pneumococcal pneumonia cohort. We found an 11.1fold significantly higher relative risk of developing lung cancer within 1 year follow-up period (95 % CI 10.1–12.1). Table 3 lists the specific analysis of comorbidities in the IRRs and aHRs between the pneumococcal pneumonia cohort and the controls. Despite excluding all cofactors, the overall IRR of lung cancer was 2.98-fold higher in the pneumococcal pneumonia cohort than in the controls
Lung (2014) 192:159–165
163
Table 3 Incidence rate ratio and adjusted hazard ratio of lung cancer and pneumococcal pneumonia cohort to comparison cohort stratify by comorbidity Variables
Pneumococcal pneumonia No (N = 231,832)
Noneb
IRR (95 % CI)
aHR (95 % CI)
Yes (N = 57,958)
Event
Person years
Rate
3,604
449,768
8.1
3,942
471,100
8.4
51,215
11.5
496,537
8.6
25,778
11.0
a
Person years
Ratea
905
37,708
24
2.98 (2.77–3.21)***
–
1,526
56,692
36.9
3.22 (3.03–3.41)***
Reference
748
23,891
31.3
2.72 (2.44–3.03)***
0.79 (0.73–0.85)***
1,811
65,445
27.7
3.24 (3.06–3.42)***
Reference
463
15,138
30.6
2.78 (2.40–3.22)***
0.98 (0.88–1.08)
Event
Hypertension No Yes
589
Diabetes mellitus No
4,247
Yes
284
Hyperlipidemia No Yes
4,434 97
511,254
8.7
2,107
11,062
8.8
167
75,694
27.8
3.2 (3.05–3.38)***
Reference
4,890
34.2
3.89 (3.03–5)***
0.99 (0.85–1.16)
512,871
8.4
9,445
22.0
1,829
69,758
26.2
3.11 (2.95–3.29)***
Reference
445
10,825
41.1
1.87 (1.58–2.2)***
0.96 (0.86–1.16)
519,113
8.6
2,000
75,076
26.6
3.09 (2.93–3.26)***
Reference
3,203
16.6
5,507
49.8
3.01 (2.24–4.03)***
1.52 (1.32–1.74)***
5,13,783
8.6
8,532
15.5
2,072
69,967
29.6
3.46 (3.28–3.64)***
Reference
202
10,617
19
1.23 (0.99–1.53)
0.66 (0.57–0.76)***
COPD No Yes
4,323 208
Tuberculosis No 4,478 Yes
53
274
Asthma No Yes
4,399 132
IRR incidence rate ratio; aHR adjusted hazard ratio: mutually adjusted for age, gender and comorbidities in Cox proportional hazard regression; CI confidence interval; COPD chronic obstructive pulmonary disease * P \ 0.05; ** P \ 0.01; *** P \ 0.001 a
Rate per 1,000 person-years
b
Patients without any one of comorbidities was classified as the none
(95 % CI 2.77–3.21). Stratified by comorbidities, the pneumococcal pneumonia cohort with hypertension, DM, hyperlipidemia, COPD, TB, and asthma had statistically significantly higher IRR of developing lung cancer than the controls. It showed that the study patients with TB had a 52 % higher risk of lung cancer than did those without (95 % CI 1.32–1.74).
Discussion This is the first nationwide population-based cohort study to investigate the associations between lung cancer and previous pneumococcal pneumonia. Our study showed that the incidence of lung cancer is greater in patients with previous history of pneumococcal pneumonia than in the general population. Most previous studies were hospitalbased research with limited observation cases. The population-based data with age- and sex-matched control groups enabled better external validation than have previous
studies. Moreover, using the NHI data to create a cohort study allowed us to observe the temporal relationship between pneumococcal pneumonia and lung cancer. Pneumococcal pneumonia is diagnosed according to clinical symptoms, physical findings, image findings, and laboratory results (sputum culture or positive urine pneumococcus antigen test). We identified the pneumococcal pneumonia cases based on their ICD-9-CM codes and antibiotics prescriptions. Lung cancer diagnosis entitles patients to qualify for special health care privileges in the ‘‘major critical diseases’’ class in Taiwan’s NHI system. We used both diagnostic codes and the Catastrophic Illness Registry. Histological confirmation is needed under the NHI program to apply for a Catastrophic Illness Card; therefore, the pneumococcal pneumonia and lung cancer data are valid. Reverse causality must be considered in cases of pneumonia, because infections may have been the result of weakening immunity caused by occult lung cancer. For these conditions, ascertainment bias should be considered
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164
as individuals with pneumonia may have been more likely to be diagnosed with lung cancer because of the use of additional chest X-rays in the infection workup. In the presence of occult lung cancer or the coexistence of pneumococcal pneumonia and lung cancer, the risk of lung cancer during the first year of pneumococcal pneumonia would be magnified. Therefore, lung cancer diagnosis before or within the first year of pneumococcal pneumonia infection was excluded to lessen the possibility of reverse causality and coexistence. After excluding lung cancer occurring during the first year of pneumococcal pneumonia, we still found an increased IRR for lung cancer in the pneumococcal pneumonia cohort. We observed elevated rates of lung cancer among previous pneumococcal pneumonia cases compared with controls, with crude IRR of 1.24 (95 % CI 1.15–1.35; p \ 0.001). These results were consistent with many previous studies, which have reported a positive association between pneumonia and subsequent lung cancer [6–18]. However, the relationship between pneumonia’s causative organisms and lung cancer has been less described. Most of the previous reports revealed a positive association between Chlamydia pneumonia infection and subsequent lung cancer. Streptococcus pneumonia is an important bacterial pathogen of pneumonia; to our knowledge, this study is the first to evaluate the relationship between pneumococcal pneumonia and lung cancer. We observed a higher lung cancer incidence among males in our study (HR, 1.85; 95 % CI 1.71–1.99; p \ 0.001). In a cross-sectional survey by Tsai et al. in 2004, they found a difference in smoking behavior among males and females (45.7 vs. 4.8 %), observing that men smoked significantly more cigarettes per day (18 vs. 11) [32]. Smoking is an important risk factor for lung cancer and could account for the gender discrepancy of lung cancer incidence in our study. The risk of lung cancer is increased in the pneumococcal pneumonia cohort, especially in the older than age 75 years group (HR, 18.7; 95 % CI 15.1–23.1; p \ 0.001). Epidemiology data showed that the age-based risk group of pneumococcal pneumonia is younger than 2 years or older than 75 years. Our data were consistent with previous reports and demonstrated the important role of pneumococcal pneumonia in subsequent lung cancer, especially in the group older than 75 years. Pulmonary infections have been suggested as risk factors for lung cancer. Respiratory tract infections may contribute to lung cancer by promoting airway remodeling and causing inflammation, which could generate reactive oxygen or nitrogen species, increase cellular proliferation, upregulate antiapoptotic pathways, and stimulate angiogenesis [5, 33]. Our data showed increased lung cancer incidence in the pneumococcal pneumonia cohort. Further
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studies should incorporate research that is more experimental and epidemiological to investigate the mechanisms of lung cancer induced by Streptococcus pneumonia infection. There are potential limitations in this study. First, the NHIRD does not contain detailed information regarding smoking habits, alcohol consumption, socioeconomic status, and family history of systemic diseases, all of which may be risk factors for pneumococcal pneumonia or lung cancer. Second, the evidence derived from a retrospective cohort study is generally lower in statistical quality than that from randomized trials because of potential biases related to adjustments for confounding variables. Despite our meticulous study design and control measures for confounding factors, bias resulting from unknown confounders may have affected the results. Third, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology findings, and serum laboratory data, were unavailable regarding our study patient cases. However, the data regarding the diagnoses of pneumococcal pneumonia or lung cancer were, nonetheless, reliable. The major strength of our study is its nationwide population-based settings that included relatively large numbers of pneumococcal pneumonia cases, thus allowing a clear observation of the temporal relationship between pneumonia and lung cancer. Our findings provide epidemiological evidence that pneumococcal pneumonia is a risk factor for subsequent lung cancer and that pneumococcal pneumonia patients should be monitored carefully for lung cancer development. Acknowledgments The study was supported by grants from the study hospital (DMR-101-061 and DMR-100-076); Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TD-B-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). Conflict of interest of interest.
All authors declare that they have no conflicts
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