Risk factors for interstitial lung disease: a 9-year Nationwide population-based study

Risk factors for interstitial lung disease: a 9-year Nationwide population-based study Background: Understanding the risk factors that are associated with the development of interstitial lung disease might have an important role in understanding the pathogenetic mechanism of interstitial lung disease as well as prevention. We aimed to determine independent risk factors of interstitial lung disease development. Methods: This was a retrospective cohort study with nationwide population-based 9-year longitudinal data. We selected subjects who were aged > 40 years at cohort entry and with a self-reported history of cigarette smoking. Cases were selected based on International Classification of Diseases codes. A cohort of 312,519 subjects were followed until December 2013. We used Cox regression analysis to calculate the hazard ratios (HRs) for interstitial lung disease development. Results: Interstitial lung disease developed in 1972 of the 312,519 subjects during the 9-year period. Smoking (HR: 1.2; 95% confidence interval [CI]: 1.1–1.4), hepatitis C (HR: 1.6; 95% CI: 1.1–2.3), history of tuberculosis (HR: 1.5; 95% CI: 1.1–1.9), history of pneumonia (HR: 1.6; 95% CI: 1.3–2.0), and chronic obstructive pulmonary disease (HR: 1.8; 95% CI: 1.6–2.1), men (HR: 1.9; 95% CI: 1.7–2.1) were significantly associated with the development of interstitial lung disease. The risk of interstitial lung disease development increases with age, and the risk was 6.9 times higher (95% CI: 5.9–8.0) in those aged over 70 than in their forties. Conclusions: Smoking, hepatitis C, history of tuberculosis, history of pneumonia, chronic obstructive pulmonary disease, male sex, and older age were significantly associated with interstitial lung disease development. Keywords: Interstitial lung disease, Epidemiology, Risk factor Background chronic obstructive pulmonary disease (COPD) [5]. ILD If bilateral reticular or reticulonodular opacities are found could have significant impact on health. on chest radiography, interstitial lung disease (ILD) is sus- Three different population-based studies determined pected. ILD is not an uncommon disease [1]. In 2012, that cigarette smoking is a risk factor for lung parenchy- prevalence estimates of ILD with fibrosis ranged from mal as well as interstitial abnormalities in addition to 42.7–63 per 100.000 population in USA, and 1.25–23.4 airway abnormalities [6–8]. However, previous studies per 100.000 population in Europe [2]. examined risk factors from a limited sample size, and Patients with ILD are often asymptomatic until the le- most of them used case-control methodology and did sion progresses significantly. Interstitial pulmonary abnor- not consider many of the potential confounding vari- mality (ILA), which is considered to be an early lesion of ables as risk factors for ILD. interstitial lung disease, has a higher mortality rate than Determining the risk factors that are associated with patients without ILA [3]aswell asILD[4]. Furthermore, the development of ILD might have an important role in in patients with ILD, a study using health insurance claim understanding the pathogenetic mechanism of ILD, early data found that lung cancer incidence is higher than diagnosis, adequate treatment and prevention. The purpose of this study was to identify the inde- * Correspondence: wichoi@dsmc.or.kr pendent risk factors for the development of ILD in a Won-Il Choi and Sonila Dauti contributed equally to this work. 9-year follow-up longitudinal population-based study. Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu 41931, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 2 of 7 Methods identified using ICD-10, including COPD, hepatitis C, gas- Database troesophageal reflux disorder (GERD), and diabetes [10– The National Health Insurance Service (NHI) covers 13]. more than 99% of all Korean residents and includes all health claim data, including diagnostic codes, proce- Statistical analysis dures, prescription drugs, patient personal information, Baseline characteristics (including age, sex, and comor- and hospital information. There is one health insurance bidities) for cases and controls are summarized using de- system with a unique resident registration number for scriptive statistics such as proportion. A chi-squared test each citizen; therefore, duplication of subjects can be was used to compare frequencies of risk factors between avoided. This study used data from the National Health ILD and the control group. Cox proportional hazards re- Insurance Service-National Sample Cohort(NHIS-NSC) gression models were used to evaluate the risk factors 2002–2013 [9], which was released by the KNHIS in for ILD and analyze the associations between ILD and 2015. It includes all medical claims filed from January different variables and comorbidities. The final multi- 2002 to December 2013 for 1,099,094 nationally repre- variate models included age, sex, smoking status (former sentative randomly selected subjects, accounting for ap- or current smoker vs. never smoker), household income, proximately 2.2% of the entire population in the KNHIS and comorbidities such as hepatitis C, herpes, tubercu- in 2002. The data were produced by the KNHIS using a losis, pneumonia, GERD, COPD, diabetes, and hepatitis systematic sampling method to generate a representative B. Risk factor models for ILD were selected according to sample of all 46,605,433 Korean residents in 2002. The sex and smoking as sensitivity analysis. Model selection cohort population underwent biennial medical evalua- method was forward stepwise procedure using likelihood tions through the NHI Corporation between January 1, ratio test with p-value < 0.05 as entry criterion, and 2002, and December 31, 2013. p-value ≥0.10 as removal criterion. A P value < 0.05 considered to be statistically signifi- Study population cant. All statistical analyses were performed using SAS This was a nationwide population-based 9-year longitu- V.9.2 (SAS Institute, Cary, North Carolina, USA). dinal study. We included subjects with a self-reported smoking history, who were ≥ 40 years old, and with Results co-morbidities diagnosed before the index date. Health Incidence and baseline characteristics examination data confirmed self-reported cigarette The final sample included 312,519 subjects, of which smoking history. The health examination data every 1972 developed ILD during the 9-year study period 2 years was linked with the cohort data. (Fig. 1). ILD incidence was 70.1 cases per 100,000 We did not include patients with ILD from 2002 to person-year. 2004 to exclude preexisting cases of ILD during the two All subjects were tracked by December 31, 2013, Follow medical evaluations and 1 year of follow-up. We also ex- up duration was median 65.6 months (interquartile range: cluded patients with ILD who did not visit the clinic 35.5, 89.0) in the ILD group and median 107.5 months 30 days after the index date. The final sample included (interquartile range; 100.2, 109.5) in the non-ILD group. 312,519 subjects. Then, we identified patients with newly The ILD group had a higher percentage of men than diagnosed ILD between January 2005 and December the control. Compared with the control, subjects with 2013. Among the 312,519 subjects, the control group ILD were older, and more likely to be smokers. The ILD was selected by excluding those who had ILD between group was more likely to have comorbidities such as re- 2005 and 2013. spiratory diseases (tuberculosis and pneumonia), dia- betes, chronic renal failure, malignancy, GERD, hepatitis Definition of interstitial lung disease C, and COPD than the control (Table 1). Cases of ILD were selected based on International Clas- sification of Disease-10 (ICD-10) code J84 for other interstitial lung diseases, excluding drug-induced inter- Risk factors for developing ILD stitial lung disorders, interstitial emphysema, and lung Based on a multivariate Cox regression analysis of all vari- diseases caused by external agents. Connective tissue ables (Table 2), smoking was significantly associated with disease-associated ILD, hypersensitivity pneumonitis, the development of ILD (HR: 1.2; 95% CI: 1.1–1.4). and sarcoidosis were excluded. Co-morbidities such as hepatitis C (HR: 1.6; 95% CI: 1.1–2.3), history of tuberculosis (HR: 1.5; 95% CI: 1.1–1.9), Comorbidities history of pneumonia (HR: 1.6; 95% CI: 1.3–2.0), and Comorbidities diagnosed before the index date that could COPD (HR: 1.8; 95% CI: 1.6–2.1) were significantly associ- be associated with an increased risk of lung fibrosis were ated with the development of ILD. Men were almost twice Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 3 of 7 Fig. 1 Flow chart of the study for selection of patients with interstitial lung disease (ILD). ICD: International Classification of Disease as likely to associated with the development of ILD as Discussion women. In the present study, the development of ILD was associ- The risk of ILD development was 1.9 times in the 50s, ated with older age, male sex, cigarette smoking, hepa- 4.1 times in the 60s, and 6.9 times in the 70s, which in- titis C, history of tuberculosis, history of pneumonia, creased sharply with age. In multivariate analysis, age was and COPD. found to be most associated to ILD development showing Smokers were at greater risk of developing ILD than dose response. All the risk factors included in the model non-smokers (HR: 1.2). Similarly, a previous study showed showed relatively narrow confidence intervals. that smoking might contribute to the development of ILD There were no variables that changed the direction of by fibrosis (Odds Ratio: 1.6) [14]. The findings of three dif- the hazard ratio in the univariate and multivariate analyses ferent studies also support a strong association between except hepatitis B, which was statistically not significant. ILA and exposure to tobacco smoke and smoking status The hazard ratios of COPD and history of tuberculosis [6–8]. In this study, the risk of developing ILD was 1.4 in were reduced by almost half after multivariate analysis. His- smokers compared to non-smokers in the univariate ana- tory of pneumonia, hepatitis C and diabetes showed also re- lysis, but decreased 1.2-fold in multivariate analysis. The duced hazard ratios in multivariate analysis. Smoking was lowest risk among the variables associated with ILD oc- associated with the occurrence of ILD, but its magnitude currence is low, indicating that smoking is less involved in was relatively small compared to other variables. ILD development. Multivariate analysis stratified by smoking showed same COPD was associated with the development of ILD in direction and similar magnitude of hazard ratios in all var- the present study. A 2012 review of the pathogenesis of IPF iables. However, hazard ratios stratified by sex were some- and COPD showed similarities between the basic patho- what different in several variables. As a result of stratified genic mechanisms involved in the development of either analysis on the basis of gender, the hazard ratios of COPD emphysema or fibrosis [13]. Coexisting pulmonary fibro- according to man and woman were similar 1.8 and 1.9, re- sis and emphysema is now a distinct entity [15], and spectively. In the case of GERD, multivariate analysis of studies show that the pathologic changes associated male subjects showed that GERD was not a significant risk with these coexisting entities are mostly found in factor, but the hazard ratio for women was 1.3, which was smokers [16–19]. In this study, the risk of developing consistent with the 1.3 observed in the univariate analysis ILDin COPDwas 3.7inunivariateanalysisbut de- (Table 3). GERD, Hepatitis C are significant risk factors in creased 1.8-fold in multivariate analysis. This is pre- females, in contrast malignancy and diabetes are signifi- sumably due to the control of cigarette smoking cant risk factors in males. variables. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 4 of 7 Table 1 Baseline characteristics of patients with interstitial lung disease (n = 1972) and controls (n = 310,547) Variable Interstitial lung disease No. (%) Control No. (%) P value Sex Male 1265 (64.1) 151,124 (48.7) < 0.001 Female 707 (35.9) 159,423 (51.3) Age group (years) 40–49 354 (18.0) 136,576 (44.0) < 0.001 50–59 474 (24.0) 89,952 (29.0) 60–69 662 (33.6) 57,189 (18.4) ≥ 70 482 (24.4) 26,830 (8.6) Baseline comorbidity Malignancy 357 (18.1) 43,007 (13.8) < 0.001 Diabetes 479 (24.3) 48,507 (15.6) < 0.001 Chronic renal failure 27 (1.4) 2187 (0.7) < 0.001 COPD 242 (12.3) 11,204 (3.6) < 0.001 Past history Herpes (B00, B02) 65 (3.3) 9997 (3.2) 0.85 Tuberculosis (A15, A16, B90) 102 (5.2) 5467 (1.8) < 0.001 Pneumonia (J12-J18) 98 (5.0) 6709 (2.2) < 0.001 Hepatitis C (B18.2) 28 (1.4) 2068 (0.7) < 0.001 Hepatitis B (B18.0, B18.1) 66 (3.3) 9859 (3.2) 0.66 GERD (K21) 227 (11.5) 26,643 (8.6) < 0.001 Smoker (ex-smoker or current smoker) 748 (37.9) 93,573 (30.1) < 0.001 Household income (Quartiles), % 81–100 870 (44.1) 131,363 (42.3) 0.11 41–80 635 (32.2) 107,310 (34.6) 11–40 437 (22.2) 66,372 (21.4) 0–10 30 (1.5) 5502 (1.8) a b COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder Hepatitis C was another risk factor associated with the However, the occurrence of organization in cases of pneu- development of ILD in the present study. There have been monia is more common than expected. In 1952, Auerbach conflicting results regarding theprevalenceof anti-hepatitis et al. studied the material from 307 necropsies and found C virus (HCV) antibody in patients with IPF [10, 20, 21]. organization in 38 cases [27]. In 1989, Shachor et al. found However, a 2008 study with HCV-infected patients and that the incidence of tuberculosis in subjects with ILD was HBV-infected controls showed that ILD with fibrosis devel- 4.5 times higher than that of the general population [28]. oped at a significantly greater rate in the HCV group than Dheda et al. studied lung remodeling and fibrosis associated in the HBV group [22]. In 2002, Idilman et al. reported an with lung injury from tuberculosis infection. Lung remodel- increased bronchoalveolar lavage neutrophil count in indi- ing can result in extensive fibrosis and may be interstitial viduals with hepatitis C, suggesting an inflammatory reac- [29]. Therefore, ILD may develop due to tuberculosis or tion in the lungs leading to fibrotic changes [23]. The other lung infections. findings of these studies suggest that systemic factors GERD is a well-known risk factor for IPF [11, 30–32]. stimulating fibrosis, such as HCV infection, may affect the However, our data did not show a significant association development of lung fibrosis. between GERD and ILD. In patients with esophagitis, the Local factors such as history of pneumonia or tubercu- associated odds ratio of pulmonary fibrosis was 1.3–1.6 losis may be associated with lung fibrosis. Nonresolving [30, 33], but there was no significant association between pneumonia may result in organizing pneumonia com- reflux esophagitis and pulmonary fibrosis in this study monly in bacterial infections [24]. Pneumonia due to (Table 2). However, GERD were observed only in women mycoplasma and Legionnaires’ disease has been mostly im- as a significant risk factor for the development of ILD plicated with development of pulmonary fibrosis [25, 26]. (Table 3). In the present study, ICD-10 code defined a Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 5 of 7 Table 2 Univariate and multivariate Cox regression analyses for development of interstitial lung disease during the 9-year follow-up period Risk factor Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Men (reference: women) 1.9 (1.7–2.1) < 0.001 1.9 (1.7–2.1) < 0.001 Age group (years) (reference: 40–49) 50–59 1.9 (1.7–2.2) < 0.001 1.9 (1.7–2.2) < 0.001 60–69 4.3 (3.8–4.9) < 0.001 4.1 (3.6–4.7) < 0.001 ≥70 7.1 (6.2–8.2) < 0.001 6.9 (5.9–8.0) < 0.001 Diabetes (reference: no) 1.6 (1.5–1.8) < 0.001 1.1 (0.9–1.2) 0.06 COPD (reference: no) 3.7 (3.2–4.2) < 0.001 1.8 (1.6–2.1) < 0.001 GERD (reference: no) 1.3 (1.1–1.5) < 0.001 1.0 (0.9–1.3) 0.31 History of herpes (reference: no) 0.97 (0.7–1.2) 0.85 0.9 (0.7–1.2) 0.92 History of tuberculosis (reference: no) 3.0 (2.4–3.7) < 0.001 1.5 (1.1–1.9) 0.003 History of pneumonia (reference: no) 2.2 (1.8–2.7) < 0.001 1.6 (1.3–2.0) < 0.001 Hepatitis C (reference: no) 2.1 (1.4–3.0) < 0.001 1.6 (1.1–2.3) 0.01 Hepatitis B (reference: no) 1.0 (0.8–1.3) 0.84 0.8 (0.7–1.1) 0.39 Smoker (reference: never smoker) 1.4 (1.3–1.6) < 0.001 1.2 (1.1–1.4) < 0.001 Household income, % (reference: 81–100) 41–80 0.8 (0.8–0.9) 0.04 0.9 (0.8–1.0) 0.35 11–40 1.0 (0.9–1.1) 0.85 0.9 (0.8–1.1) 0.87 0–10 1.1 (0.8–1.6) 0.39 1.1 (0.7–1.5) 0.59 HR hazard ratio, CI confidence interval, COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder wider range of ILD. Therefore, in this study, it is esti- in the univariate analysis, the significance reduced to mated that mild cases of pulmonary fibrosis are more borderline in the multivariate analysis (HR 1.1, P = 0.06). involved than previous studies, and that there was no Our study shows that men and older individuals have significant association between reflux esophagitis and a higher risk of developing ILD. Two other studies con- ILD in men. ducted with subjects with interstitial abnormalities found Diabetes is also prevalent with IPF [12, 33]. Although that they were significantly older [7, 8]. Several studies diabetes was an important risk factor for developing ILD have shown that the incidence of ILD with fibrosis is Table 3 Multivariate Cox regression analyses with forward stepwise variable selection method for development of interstitial lung disease during the 9-year follow-up period Risk factor Males Females HR (95% CI) P value HR (95% CI) P value Age group (years) (reference: 40–49) 50–59 2.3 (1.9–2.7) < 0.001 1.4 (1.1–1.7) 0.004 60–69 4.6 (3.9–5.5) < 0.001 3.3 (2.6–4.1) < 0.001 ≥70 8.1 (6.7–9.7) < 0.001 5.4 (4.3–6.7) < 0.001 Malignancy 1.1 (1.0–1.3) 0.045 1.0 (0.8–1.2) 0.68 Diabetes (reference: no) 1.2 (1.0–1.3) 0.006 0.9 (0.7–1.1) 0.38 COPD (reference: no) 1.8 (1.5–2.2) < 0.001 1.9 (1.5–2.4) < 0.001 History of tuberculosis (reference: no) 1.5 (1.2–2.0) < 0.001 1.8 (1.2–2.6) 0.001 History of pneumonia (reference: no) 1.5 (1.1–2.0) 0.002 1.7 (1.2–2.3) 0.001 Hepatitis C (reference: no) 1.3 (0.8–2.1) 0.26 2.1 (1.1–3.8) 0.014 GERD (reference: no) 1.0 (0.9–1.3) 0.38 1.3 (1.0–1.6) 0.013 Smoker (reference: never smoker) 1.2 (1.1–1.4) < 0.001 1.5 (1.1–2.0) 0.005 HR hazard ratio, CI confidence interval, COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 6 of 7 higher in men and increases with advanced age [34–37]. claims. Thus, the controls were more likely to have co- In our study, the HR for developing ILD in those aged morbidities than controls selected from the general popu- ≥70 years was almost 7 times higher than for those aged lation. Although we excluded patients with a diagnosis of 40–49 years. We suggest that ILD would be a result of ILD between January 2002 and December 2004 to exclude the aging process. pre-existing ILD diagnosed before the first year of our We found reduction of risk estimates from the univari- study (2005), patients with ILD could be miscounted as ate to the multivariate analysis of some variables such as new cases if the patient did not require medical care be- COPD and GERD. We did sensitivity analysis based on tween 2002 and 2004, which may have caused inaccur- gender. Both males and females have similar risk esti- acies. In addition, other risk factors, such as pulmonary mates for ILD development in relation to COPD. How- function and high-resolution computed tomography find- ever, GERD is significant risk factor in females but not ings for ILD, could not be evaluated because of the in males. NHIS-NSC 2002–2013 primarily included medical claims. ILD is known as non-homogeneous diseases. Although assessing risk factors for developing specific forms of Conclusions ILD would be ideal, it might be difficult performing such The population is aging, and the incidence of ILD in- kinds of study because surgical lung biopsy was rarely creases with advancing age. Aged men with the history of performed. In addition, assessing risk factors for the ILD previous lung infection or COPD could be a clinical development, the control group should be a general marker of suspect ILD. The demonstration of the associ- population. Therefore, we assess risk factors for develop- ation of these clinical attributes with ILD may encourage ing ILD by population-based cohort database, though it the search for these factors in health examination and does not provide information on specific forms of ILD. stimulate the translational research on ILD development. The incidence of ILD was 70.1 cases per 100,000 per Abbreviation year, which is higher than previously reported [38]. CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; However, the present incidence was calculated for indi- GERD: Gastroesophageal reflux disorder; HR: Hazard ratio; ICD: International classification of disease; ILD: Interstitial lung disease; IPF: Idiopathic viduals > 40 years old. pulmonary fibrosis; NHI: National health insurance Limitations of the present study Acknowledgements We would like to thanks to Ms. Byeong Ju Park for the preparing data sets. The most important limitation of the present study is that the diagnoses of ILD and other comorbidities were Funding defined based on ICD codes, which may be inaccurate This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (No. compared to the diagnoses obtained from a medical 2014R1A5A2010008). chart. Underreporting of asymptomatic ILD or misclassi- fication was also possible. Availability of data and materials The datasets supporting the conclusion of this article is not available. The The validity of the medical insurance claims data for dataset comes from whole national population. National Health Insurance ILD has not been determined in Korea. This database con- (NHI) service strictly controlled the database. NHI completely restricted the sists of random samples of national insurance claim data data sets used in this article open to the public. without identification numbers. Therefore, it was impos- Authors’ contributions sible to validate individual cases through a chart review. All authors have contributed either to the conception, original hypothesis, We may have underestimated ILD incidence because of and design of the cohort. All authors have contributed to the writing and revisions of this article. Data acquisition was performed by CWL and W-IC, inaccurate ILD data. However, previous studies of ILD in- and analysis was performed by DS, HJK, JSP, SHP, W-IC, and CWL All authors cidence using data from the Health Insurance Review and had full access to all the data in the study. W-IC had final responsibility for Assessment Service of Korea [38] reported similar results the integrity of the data and the accuracy of the data analysis and the deci- sion to submit for publication. All authors read and approved the final to those of previous studies [35, 36, 39]. The incidence manuscript. rate of ILD was reportedly 48.5 per 100,000 person-years in Korea based on all claims data from 2008 to 2012 [38]. Ethics approval and consent to participate The current study was approved by the institutional review board at In the present study, the incidence rate was 70.1 per Dongsan Hospital, Keimyung University School of Medicine. The need for 100,000 patients from 2005 to 2013, which appears rea- written informed consent was waived. This study was conducted in sonable because we excluded subjects aged < 40 years. compliance with the Declaration of Helsinki. The present study did not take into consideration of Competing interests relevant risk factor such as occupational and environ- The authors state that they have no competing interests. mental exposure. However, annual income could be a weak proxy of the occupational exposure [40]. Publisher’sNote The present study may be affected by selection bias be- Springer Nature remains neutral with regard to jurisdictional claims in cause the controls were identified based on medical published maps and institutional affiliations. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 7 of 7 Author details 20. Irving WL, Day S, Johnston ID. Idiopathic pulmonary fibrosis and hepatitis C Department of Internal Medicine, Keimyung University Dongsan Hospital, virus infection. Am Rev Respir Dis. 1993;148(6 Pt 1):1683–4. Daegu 41931, Republic of Korea. Department of Allergology, Hospital Serive 21. Meliconi R, Andreone P, Fasano L, Galli S, Pacilli A, Miniero R, Fabbri M, of Kavaje, Kavaje, Albania. Department of Occupational & Environmental Solforosi L, Bernardi M. Incidence of hepatitis C virus infection in Italian Medicine, Sungso Hospital, Andong, Republic of Korea. patients with idiopathic pulmonary fibrosis. Thorax. 1996;51(3):315–7. 22. Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Received: 25 January 2018 Accepted: 24 May 2018 Sezaki H, Hosaka T, Hirakawa M, et al. Hepatitis C virus enhances incidence of idiopathic pulmonary fibrosis. World J Gastroenterol. 2008;14(38):5880–6. 23. Idilman R, Cetinkaya H, Savas I, Aslan N, Sak SD, Bastemir M, Sarioglu M, Soykan I, Bozdayi M, Colantoni A, et al. Bronchoalveolar lavage fluid analysis References in individuals with chronic hepatitis C. J Med Virol. 2002;66(1):34–9. 1. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of 24. Cordier JF, Cottin V, Lazor R, Thivolet-Bejui F. Many faces of bronchiolitis interstitial lung diseases. Am J Respir Crit Care Med. 1994;150(4):967–72. and organizing pneumonia. Semin Respir Crit Care Med. 2016;37(3):421–40. 2. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of 25. Kaufman JM, Cuvelier CA, Van der Straeten M. Mycoplasma pneumonia with idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012; fulminant evolution into diffuse interstitial fibrosis. Thorax. 1980;35(2):140–4. 21(126):355–61. 26. Chastre J, Raghu G, Soler P, Brun P, Basset F, Gibert C. Pulmonary fibrosis 3. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, Okajima following pneumonia due to acute Legionnaires' disease. Clinical, Y, Dupuis J, Latourelle JC, Cho MH, et al. Association between interstitial ultrastructural, and immunofluorescent study. Chest. 1987;91(1):57–62. lung abnormalities and all-cause mortality. Jama. 2016;315(7):672–81. 27. Auerbach SH, Mims OM, Goodpasture EW. Pulmonary fibrosis secondary to 4. Choi WI, Park SH, Dauti S, Park BJ, Lee CW. Interstitial lung disease and risk pneumonia. Am J Pathol. 1952;28(1):69–87. of mortality: 11-year nationwide population-based study. Int J Tuberc Lung 28. Shachor Y, Schindler D, Siegal A, Lieberman D, Mikulski Y, Bruderman I. Dis. 2018;22(1):100–5. Increased incidence of pulmonary tuberculosis in chronic interstitial lung 5. Choi WI, Park SH, Park BJ, Lee CW. Interstitial lung disease and lung Cancer disease. Thorax. 1989;44(2):151–3. development: a 5-year Nationwide population-based study. Cancer Res 29. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung Treat. 2017;50(2):374–81. remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201–9. 6. Lederer DJ, Enright PL, Kawut SM, Hoffman EA, Hunninghake G, van 30. el-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or Beek EJ, Austin JH, Jiang R, Lovasi GS, Barr RG. Cigarette smoking is pulmonary disease with esophagitis in United States military veterans. associated with subclinical parenchymal lung disease: the multi-ethnic Gastroenterology. 1997;113(3):755–60. study of atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 31. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, 2009;180(5):407–14. Raghu G, Investigators IP. Anti-acid treatment and disease progression in 7. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, idiopathic pulmonary fibrosis: an analysis of data from three randomised Yamashiro T, Ross JC, Estepar RS, Lynch DA, Brehm JM, et al. Lung volumes controlled trials. Lancet Respir Med. 2013;1(5):369–76. and emphysema in smokers with interstitial lung abnormalities. N Engl J 32. Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE Jr, Med. 2011;364(10):897–906. Collard HR. Gastroesophageal reflux therapy is associated with longer 8. Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Nishino M, Araki T, Zazueta OE, Kurugol S, et al. MUC5B promoter Med. 2011;184(12):1390–4. polymorphism and interstitial lung abnormalities. N Engl J Med. 2013; 33. Gribbin J, Hubbard R, Smith C. Role of diabetes mellitus and gastro- 368(23):2192–200. oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis. Respir 9. Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Med. 2009;103(6):927–31. Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J 34. Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A, Epidemiol. 2017;46(2):e15. Hubbard RB. The rising incidence of idiopathic pulmonary fibrosis in the UK. 10. Ueda T, Ohta K, Suzuki N, Yamaguchi M, Hirai K, Horiuchi T, Watanabe J, Thorax. 2011;66(6):462–7. Miyamoto T, Ito K. Idiopathic pulmonary fibrosis and high prevalence of 35. Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, Nathan serum antibodies to hepatitis C virus. Am Rev Respir Dis. 1992;146(1):266–8. SD, O'Quinn S, Parker J, Tran TN. Idiopathic pulmonary fibrosis in United 11. Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. States automated claims. Incidence, prevalence, and algorithm validation. Increased prevalence of gastroesophageal reflux in patients with idiopathic Am J Respir Crit Care Med. 2015;192(10):1200–7. pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804–8. 36. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR. Idiopathic 12. Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Diabetes mellitus may pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: increase risk for idiopathic pulmonary fibrosis. Chest. 2003;123(6):2007–11. incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2(7):566–72. 13. Chilosi M, Poletti V, Rossi A. The pathogenesis of COPD and IPF: distinct 37. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of horns of the same devil? Respir Res. 2012;13:3. idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 14. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette 2016;48(1):179–86. smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit 38. Gjonbrataj J, Choi WI, Bahn YE, Rho BH, Lee JJ, Lee CW. Incidence of Care Med. 1997;155(1):242–8. idiopathic pulmonary fibrosis in Korea based on the 2011 ATS/ERS/JRS/ALAT 15. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, statement. Int J Tuberc Lung Dis. 2015;19(6):742–6. Ryerson CJ, Ryu JH, Selman M, Wells AU, et al. An official American Thoracic 39. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and Society/European Respiratory Society statement: update of the international mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. multidisciplinary classification of the idiopathic interstitial pneumonias. Am J 2015;46(3):795–806. Respir Crit Care Med. 2013;188(6):733–48. 40. Evans GW, Kantrowitz E. Socioeconomic status and health: the potential role 16. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to of environmental risk exposure. Annu Rev Public Health. 2002;23:303–31. findings in lung parenchyma: a microscopic study. Chest. 1974;65(1):29–35. 17. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. 2010;41(3):316–25. 18. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, Israel-Biet D, Court-Fortune I, Valeyre D, Cordier JF, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26(4):586–93. 19. Inomata M, Ikushima S, Awano N, Kondoh K, Satake K, Masuo M, Kusunoki Y, Moriya A, Kamiya H, Ando T, et al. An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulm Med. 2014;14:104. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pulmonary Medicine Springer Journals

Risk factors for interstitial lung disease: a 9-year Nationwide population-based study

Free
7 pages
Loading next page...
 
/lp/springer_journal/risk-factors-for-interstitial-lung-disease-a-9-year-nationwide-0hQPFGixmy
Publisher
BioMed Central
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Pneumology/Respiratory System; Internal Medicine; Intensive / Critical Care Medicine
eISSN
1471-2466
D.O.I.
10.1186/s12890-018-0660-2
Publisher site
See Article on Publisher Site

Abstract

Background: Understanding the risk factors that are associated with the development of interstitial lung disease might have an important role in understanding the pathogenetic mechanism of interstitial lung disease as well as prevention. We aimed to determine independent risk factors of interstitial lung disease development. Methods: This was a retrospective cohort study with nationwide population-based 9-year longitudinal data. We selected subjects who were aged > 40 years at cohort entry and with a self-reported history of cigarette smoking. Cases were selected based on International Classification of Diseases codes. A cohort of 312,519 subjects were followed until December 2013. We used Cox regression analysis to calculate the hazard ratios (HRs) for interstitial lung disease development. Results: Interstitial lung disease developed in 1972 of the 312,519 subjects during the 9-year period. Smoking (HR: 1.2; 95% confidence interval [CI]: 1.1–1.4), hepatitis C (HR: 1.6; 95% CI: 1.1–2.3), history of tuberculosis (HR: 1.5; 95% CI: 1.1–1.9), history of pneumonia (HR: 1.6; 95% CI: 1.3–2.0), and chronic obstructive pulmonary disease (HR: 1.8; 95% CI: 1.6–2.1), men (HR: 1.9; 95% CI: 1.7–2.1) were significantly associated with the development of interstitial lung disease. The risk of interstitial lung disease development increases with age, and the risk was 6.9 times higher (95% CI: 5.9–8.0) in those aged over 70 than in their forties. Conclusions: Smoking, hepatitis C, history of tuberculosis, history of pneumonia, chronic obstructive pulmonary disease, male sex, and older age were significantly associated with interstitial lung disease development. Keywords: Interstitial lung disease, Epidemiology, Risk factor Background chronic obstructive pulmonary disease (COPD) [5]. ILD If bilateral reticular or reticulonodular opacities are found could have significant impact on health. on chest radiography, interstitial lung disease (ILD) is sus- Three different population-based studies determined pected. ILD is not an uncommon disease [1]. In 2012, that cigarette smoking is a risk factor for lung parenchy- prevalence estimates of ILD with fibrosis ranged from mal as well as interstitial abnormalities in addition to 42.7–63 per 100.000 population in USA, and 1.25–23.4 airway abnormalities [6–8]. However, previous studies per 100.000 population in Europe [2]. examined risk factors from a limited sample size, and Patients with ILD are often asymptomatic until the le- most of them used case-control methodology and did sion progresses significantly. Interstitial pulmonary abnor- not consider many of the potential confounding vari- mality (ILA), which is considered to be an early lesion of ables as risk factors for ILD. interstitial lung disease, has a higher mortality rate than Determining the risk factors that are associated with patients without ILA [3]aswell asILD[4]. Furthermore, the development of ILD might have an important role in in patients with ILD, a study using health insurance claim understanding the pathogenetic mechanism of ILD, early data found that lung cancer incidence is higher than diagnosis, adequate treatment and prevention. The purpose of this study was to identify the inde- * Correspondence: wichoi@dsmc.or.kr pendent risk factors for the development of ILD in a Won-Il Choi and Sonila Dauti contributed equally to this work. 9-year follow-up longitudinal population-based study. Department of Internal Medicine, Keimyung University Dongsan Hospital, Daegu 41931, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 2 of 7 Methods identified using ICD-10, including COPD, hepatitis C, gas- Database troesophageal reflux disorder (GERD), and diabetes [10– The National Health Insurance Service (NHI) covers 13]. more than 99% of all Korean residents and includes all health claim data, including diagnostic codes, proce- Statistical analysis dures, prescription drugs, patient personal information, Baseline characteristics (including age, sex, and comor- and hospital information. There is one health insurance bidities) for cases and controls are summarized using de- system with a unique resident registration number for scriptive statistics such as proportion. A chi-squared test each citizen; therefore, duplication of subjects can be was used to compare frequencies of risk factors between avoided. This study used data from the National Health ILD and the control group. Cox proportional hazards re- Insurance Service-National Sample Cohort(NHIS-NSC) gression models were used to evaluate the risk factors 2002–2013 [9], which was released by the KNHIS in for ILD and analyze the associations between ILD and 2015. It includes all medical claims filed from January different variables and comorbidities. The final multi- 2002 to December 2013 for 1,099,094 nationally repre- variate models included age, sex, smoking status (former sentative randomly selected subjects, accounting for ap- or current smoker vs. never smoker), household income, proximately 2.2% of the entire population in the KNHIS and comorbidities such as hepatitis C, herpes, tubercu- in 2002. The data were produced by the KNHIS using a losis, pneumonia, GERD, COPD, diabetes, and hepatitis systematic sampling method to generate a representative B. Risk factor models for ILD were selected according to sample of all 46,605,433 Korean residents in 2002. The sex and smoking as sensitivity analysis. Model selection cohort population underwent biennial medical evalua- method was forward stepwise procedure using likelihood tions through the NHI Corporation between January 1, ratio test with p-value < 0.05 as entry criterion, and 2002, and December 31, 2013. p-value ≥0.10 as removal criterion. A P value < 0.05 considered to be statistically signifi- Study population cant. All statistical analyses were performed using SAS This was a nationwide population-based 9-year longitu- V.9.2 (SAS Institute, Cary, North Carolina, USA). dinal study. We included subjects with a self-reported smoking history, who were ≥ 40 years old, and with Results co-morbidities diagnosed before the index date. Health Incidence and baseline characteristics examination data confirmed self-reported cigarette The final sample included 312,519 subjects, of which smoking history. The health examination data every 1972 developed ILD during the 9-year study period 2 years was linked with the cohort data. (Fig. 1). ILD incidence was 70.1 cases per 100,000 We did not include patients with ILD from 2002 to person-year. 2004 to exclude preexisting cases of ILD during the two All subjects were tracked by December 31, 2013, Follow medical evaluations and 1 year of follow-up. We also ex- up duration was median 65.6 months (interquartile range: cluded patients with ILD who did not visit the clinic 35.5, 89.0) in the ILD group and median 107.5 months 30 days after the index date. The final sample included (interquartile range; 100.2, 109.5) in the non-ILD group. 312,519 subjects. Then, we identified patients with newly The ILD group had a higher percentage of men than diagnosed ILD between January 2005 and December the control. Compared with the control, subjects with 2013. Among the 312,519 subjects, the control group ILD were older, and more likely to be smokers. The ILD was selected by excluding those who had ILD between group was more likely to have comorbidities such as re- 2005 and 2013. spiratory diseases (tuberculosis and pneumonia), dia- betes, chronic renal failure, malignancy, GERD, hepatitis Definition of interstitial lung disease C, and COPD than the control (Table 1). Cases of ILD were selected based on International Clas- sification of Disease-10 (ICD-10) code J84 for other interstitial lung diseases, excluding drug-induced inter- Risk factors for developing ILD stitial lung disorders, interstitial emphysema, and lung Based on a multivariate Cox regression analysis of all vari- diseases caused by external agents. Connective tissue ables (Table 2), smoking was significantly associated with disease-associated ILD, hypersensitivity pneumonitis, the development of ILD (HR: 1.2; 95% CI: 1.1–1.4). and sarcoidosis were excluded. Co-morbidities such as hepatitis C (HR: 1.6; 95% CI: 1.1–2.3), history of tuberculosis (HR: 1.5; 95% CI: 1.1–1.9), Comorbidities history of pneumonia (HR: 1.6; 95% CI: 1.3–2.0), and Comorbidities diagnosed before the index date that could COPD (HR: 1.8; 95% CI: 1.6–2.1) were significantly associ- be associated with an increased risk of lung fibrosis were ated with the development of ILD. Men were almost twice Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 3 of 7 Fig. 1 Flow chart of the study for selection of patients with interstitial lung disease (ILD). ICD: International Classification of Disease as likely to associated with the development of ILD as Discussion women. In the present study, the development of ILD was associ- The risk of ILD development was 1.9 times in the 50s, ated with older age, male sex, cigarette smoking, hepa- 4.1 times in the 60s, and 6.9 times in the 70s, which in- titis C, history of tuberculosis, history of pneumonia, creased sharply with age. In multivariate analysis, age was and COPD. found to be most associated to ILD development showing Smokers were at greater risk of developing ILD than dose response. All the risk factors included in the model non-smokers (HR: 1.2). Similarly, a previous study showed showed relatively narrow confidence intervals. that smoking might contribute to the development of ILD There were no variables that changed the direction of by fibrosis (Odds Ratio: 1.6) [14]. The findings of three dif- the hazard ratio in the univariate and multivariate analyses ferent studies also support a strong association between except hepatitis B, which was statistically not significant. ILA and exposure to tobacco smoke and smoking status The hazard ratios of COPD and history of tuberculosis [6–8]. In this study, the risk of developing ILD was 1.4 in were reduced by almost half after multivariate analysis. His- smokers compared to non-smokers in the univariate ana- tory of pneumonia, hepatitis C and diabetes showed also re- lysis, but decreased 1.2-fold in multivariate analysis. The duced hazard ratios in multivariate analysis. Smoking was lowest risk among the variables associated with ILD oc- associated with the occurrence of ILD, but its magnitude currence is low, indicating that smoking is less involved in was relatively small compared to other variables. ILD development. Multivariate analysis stratified by smoking showed same COPD was associated with the development of ILD in direction and similar magnitude of hazard ratios in all var- the present study. A 2012 review of the pathogenesis of IPF iables. However, hazard ratios stratified by sex were some- and COPD showed similarities between the basic patho- what different in several variables. As a result of stratified genic mechanisms involved in the development of either analysis on the basis of gender, the hazard ratios of COPD emphysema or fibrosis [13]. Coexisting pulmonary fibro- according to man and woman were similar 1.8 and 1.9, re- sis and emphysema is now a distinct entity [15], and spectively. In the case of GERD, multivariate analysis of studies show that the pathologic changes associated male subjects showed that GERD was not a significant risk with these coexisting entities are mostly found in factor, but the hazard ratio for women was 1.3, which was smokers [16–19]. In this study, the risk of developing consistent with the 1.3 observed in the univariate analysis ILDin COPDwas 3.7inunivariateanalysisbut de- (Table 3). GERD, Hepatitis C are significant risk factors in creased 1.8-fold in multivariate analysis. This is pre- females, in contrast malignancy and diabetes are signifi- sumably due to the control of cigarette smoking cant risk factors in males. variables. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 4 of 7 Table 1 Baseline characteristics of patients with interstitial lung disease (n = 1972) and controls (n = 310,547) Variable Interstitial lung disease No. (%) Control No. (%) P value Sex Male 1265 (64.1) 151,124 (48.7) < 0.001 Female 707 (35.9) 159,423 (51.3) Age group (years) 40–49 354 (18.0) 136,576 (44.0) < 0.001 50–59 474 (24.0) 89,952 (29.0) 60–69 662 (33.6) 57,189 (18.4) ≥ 70 482 (24.4) 26,830 (8.6) Baseline comorbidity Malignancy 357 (18.1) 43,007 (13.8) < 0.001 Diabetes 479 (24.3) 48,507 (15.6) < 0.001 Chronic renal failure 27 (1.4) 2187 (0.7) < 0.001 COPD 242 (12.3) 11,204 (3.6) < 0.001 Past history Herpes (B00, B02) 65 (3.3) 9997 (3.2) 0.85 Tuberculosis (A15, A16, B90) 102 (5.2) 5467 (1.8) < 0.001 Pneumonia (J12-J18) 98 (5.0) 6709 (2.2) < 0.001 Hepatitis C (B18.2) 28 (1.4) 2068 (0.7) < 0.001 Hepatitis B (B18.0, B18.1) 66 (3.3) 9859 (3.2) 0.66 GERD (K21) 227 (11.5) 26,643 (8.6) < 0.001 Smoker (ex-smoker or current smoker) 748 (37.9) 93,573 (30.1) < 0.001 Household income (Quartiles), % 81–100 870 (44.1) 131,363 (42.3) 0.11 41–80 635 (32.2) 107,310 (34.6) 11–40 437 (22.2) 66,372 (21.4) 0–10 30 (1.5) 5502 (1.8) a b COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder Hepatitis C was another risk factor associated with the However, the occurrence of organization in cases of pneu- development of ILD in the present study. There have been monia is more common than expected. In 1952, Auerbach conflicting results regarding theprevalenceof anti-hepatitis et al. studied the material from 307 necropsies and found C virus (HCV) antibody in patients with IPF [10, 20, 21]. organization in 38 cases [27]. In 1989, Shachor et al. found However, a 2008 study with HCV-infected patients and that the incidence of tuberculosis in subjects with ILD was HBV-infected controls showed that ILD with fibrosis devel- 4.5 times higher than that of the general population [28]. oped at a significantly greater rate in the HCV group than Dheda et al. studied lung remodeling and fibrosis associated in the HBV group [22]. In 2002, Idilman et al. reported an with lung injury from tuberculosis infection. Lung remodel- increased bronchoalveolar lavage neutrophil count in indi- ing can result in extensive fibrosis and may be interstitial viduals with hepatitis C, suggesting an inflammatory reac- [29]. Therefore, ILD may develop due to tuberculosis or tion in the lungs leading to fibrotic changes [23]. The other lung infections. findings of these studies suggest that systemic factors GERD is a well-known risk factor for IPF [11, 30–32]. stimulating fibrosis, such as HCV infection, may affect the However, our data did not show a significant association development of lung fibrosis. between GERD and ILD. In patients with esophagitis, the Local factors such as history of pneumonia or tubercu- associated odds ratio of pulmonary fibrosis was 1.3–1.6 losis may be associated with lung fibrosis. Nonresolving [30, 33], but there was no significant association between pneumonia may result in organizing pneumonia com- reflux esophagitis and pulmonary fibrosis in this study monly in bacterial infections [24]. Pneumonia due to (Table 2). However, GERD were observed only in women mycoplasma and Legionnaires’ disease has been mostly im- as a significant risk factor for the development of ILD plicated with development of pulmonary fibrosis [25, 26]. (Table 3). In the present study, ICD-10 code defined a Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 5 of 7 Table 2 Univariate and multivariate Cox regression analyses for development of interstitial lung disease during the 9-year follow-up period Risk factor Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Men (reference: women) 1.9 (1.7–2.1) < 0.001 1.9 (1.7–2.1) < 0.001 Age group (years) (reference: 40–49) 50–59 1.9 (1.7–2.2) < 0.001 1.9 (1.7–2.2) < 0.001 60–69 4.3 (3.8–4.9) < 0.001 4.1 (3.6–4.7) < 0.001 ≥70 7.1 (6.2–8.2) < 0.001 6.9 (5.9–8.0) < 0.001 Diabetes (reference: no) 1.6 (1.5–1.8) < 0.001 1.1 (0.9–1.2) 0.06 COPD (reference: no) 3.7 (3.2–4.2) < 0.001 1.8 (1.6–2.1) < 0.001 GERD (reference: no) 1.3 (1.1–1.5) < 0.001 1.0 (0.9–1.3) 0.31 History of herpes (reference: no) 0.97 (0.7–1.2) 0.85 0.9 (0.7–1.2) 0.92 History of tuberculosis (reference: no) 3.0 (2.4–3.7) < 0.001 1.5 (1.1–1.9) 0.003 History of pneumonia (reference: no) 2.2 (1.8–2.7) < 0.001 1.6 (1.3–2.0) < 0.001 Hepatitis C (reference: no) 2.1 (1.4–3.0) < 0.001 1.6 (1.1–2.3) 0.01 Hepatitis B (reference: no) 1.0 (0.8–1.3) 0.84 0.8 (0.7–1.1) 0.39 Smoker (reference: never smoker) 1.4 (1.3–1.6) < 0.001 1.2 (1.1–1.4) < 0.001 Household income, % (reference: 81–100) 41–80 0.8 (0.8–0.9) 0.04 0.9 (0.8–1.0) 0.35 11–40 1.0 (0.9–1.1) 0.85 0.9 (0.8–1.1) 0.87 0–10 1.1 (0.8–1.6) 0.39 1.1 (0.7–1.5) 0.59 HR hazard ratio, CI confidence interval, COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder wider range of ILD. Therefore, in this study, it is esti- in the univariate analysis, the significance reduced to mated that mild cases of pulmonary fibrosis are more borderline in the multivariate analysis (HR 1.1, P = 0.06). involved than previous studies, and that there was no Our study shows that men and older individuals have significant association between reflux esophagitis and a higher risk of developing ILD. Two other studies con- ILD in men. ducted with subjects with interstitial abnormalities found Diabetes is also prevalent with IPF [12, 33]. Although that they were significantly older [7, 8]. Several studies diabetes was an important risk factor for developing ILD have shown that the incidence of ILD with fibrosis is Table 3 Multivariate Cox regression analyses with forward stepwise variable selection method for development of interstitial lung disease during the 9-year follow-up period Risk factor Males Females HR (95% CI) P value HR (95% CI) P value Age group (years) (reference: 40–49) 50–59 2.3 (1.9–2.7) < 0.001 1.4 (1.1–1.7) 0.004 60–69 4.6 (3.9–5.5) < 0.001 3.3 (2.6–4.1) < 0.001 ≥70 8.1 (6.7–9.7) < 0.001 5.4 (4.3–6.7) < 0.001 Malignancy 1.1 (1.0–1.3) 0.045 1.0 (0.8–1.2) 0.68 Diabetes (reference: no) 1.2 (1.0–1.3) 0.006 0.9 (0.7–1.1) 0.38 COPD (reference: no) 1.8 (1.5–2.2) < 0.001 1.9 (1.5–2.4) < 0.001 History of tuberculosis (reference: no) 1.5 (1.2–2.0) < 0.001 1.8 (1.2–2.6) 0.001 History of pneumonia (reference: no) 1.5 (1.1–2.0) 0.002 1.7 (1.2–2.3) 0.001 Hepatitis C (reference: no) 1.3 (0.8–2.1) 0.26 2.1 (1.1–3.8) 0.014 GERD (reference: no) 1.0 (0.9–1.3) 0.38 1.3 (1.0–1.6) 0.013 Smoker (reference: never smoker) 1.2 (1.1–1.4) < 0.001 1.5 (1.1–2.0) 0.005 HR hazard ratio, CI confidence interval, COPD chronic obstructive pulmonary disease, GERD gastroesophageal reflux disorder Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 6 of 7 higher in men and increases with advanced age [34–37]. claims. Thus, the controls were more likely to have co- In our study, the HR for developing ILD in those aged morbidities than controls selected from the general popu- ≥70 years was almost 7 times higher than for those aged lation. Although we excluded patients with a diagnosis of 40–49 years. We suggest that ILD would be a result of ILD between January 2002 and December 2004 to exclude the aging process. pre-existing ILD diagnosed before the first year of our We found reduction of risk estimates from the univari- study (2005), patients with ILD could be miscounted as ate to the multivariate analysis of some variables such as new cases if the patient did not require medical care be- COPD and GERD. We did sensitivity analysis based on tween 2002 and 2004, which may have caused inaccur- gender. Both males and females have similar risk esti- acies. In addition, other risk factors, such as pulmonary mates for ILD development in relation to COPD. How- function and high-resolution computed tomography find- ever, GERD is significant risk factor in females but not ings for ILD, could not be evaluated because of the in males. NHIS-NSC 2002–2013 primarily included medical claims. ILD is known as non-homogeneous diseases. Although assessing risk factors for developing specific forms of Conclusions ILD would be ideal, it might be difficult performing such The population is aging, and the incidence of ILD in- kinds of study because surgical lung biopsy was rarely creases with advancing age. Aged men with the history of performed. In addition, assessing risk factors for the ILD previous lung infection or COPD could be a clinical development, the control group should be a general marker of suspect ILD. The demonstration of the associ- population. Therefore, we assess risk factors for develop- ation of these clinical attributes with ILD may encourage ing ILD by population-based cohort database, though it the search for these factors in health examination and does not provide information on specific forms of ILD. stimulate the translational research on ILD development. The incidence of ILD was 70.1 cases per 100,000 per Abbreviation year, which is higher than previously reported [38]. CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; However, the present incidence was calculated for indi- GERD: Gastroesophageal reflux disorder; HR: Hazard ratio; ICD: International classification of disease; ILD: Interstitial lung disease; IPF: Idiopathic viduals > 40 years old. pulmonary fibrosis; NHI: National health insurance Limitations of the present study Acknowledgements We would like to thanks to Ms. Byeong Ju Park for the preparing data sets. The most important limitation of the present study is that the diagnoses of ILD and other comorbidities were Funding defined based on ICD codes, which may be inaccurate This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (No. compared to the diagnoses obtained from a medical 2014R1A5A2010008). chart. Underreporting of asymptomatic ILD or misclassi- fication was also possible. Availability of data and materials The datasets supporting the conclusion of this article is not available. The The validity of the medical insurance claims data for dataset comes from whole national population. National Health Insurance ILD has not been determined in Korea. This database con- (NHI) service strictly controlled the database. NHI completely restricted the sists of random samples of national insurance claim data data sets used in this article open to the public. without identification numbers. Therefore, it was impos- Authors’ contributions sible to validate individual cases through a chart review. All authors have contributed either to the conception, original hypothesis, We may have underestimated ILD incidence because of and design of the cohort. All authors have contributed to the writing and revisions of this article. Data acquisition was performed by CWL and W-IC, inaccurate ILD data. However, previous studies of ILD in- and analysis was performed by DS, HJK, JSP, SHP, W-IC, and CWL All authors cidence using data from the Health Insurance Review and had full access to all the data in the study. W-IC had final responsibility for Assessment Service of Korea [38] reported similar results the integrity of the data and the accuracy of the data analysis and the deci- sion to submit for publication. All authors read and approved the final to those of previous studies [35, 36, 39]. The incidence manuscript. rate of ILD was reportedly 48.5 per 100,000 person-years in Korea based on all claims data from 2008 to 2012 [38]. Ethics approval and consent to participate The current study was approved by the institutional review board at In the present study, the incidence rate was 70.1 per Dongsan Hospital, Keimyung University School of Medicine. The need for 100,000 patients from 2005 to 2013, which appears rea- written informed consent was waived. This study was conducted in sonable because we excluded subjects aged < 40 years. compliance with the Declaration of Helsinki. The present study did not take into consideration of Competing interests relevant risk factor such as occupational and environ- The authors state that they have no competing interests. mental exposure. However, annual income could be a weak proxy of the occupational exposure [40]. Publisher’sNote The present study may be affected by selection bias be- Springer Nature remains neutral with regard to jurisdictional claims in cause the controls were identified based on medical published maps and institutional affiliations. Choi et al. BMC Pulmonary Medicine (2018) 18:96 Page 7 of 7 Author details 20. Irving WL, Day S, Johnston ID. Idiopathic pulmonary fibrosis and hepatitis C Department of Internal Medicine, Keimyung University Dongsan Hospital, virus infection. Am Rev Respir Dis. 1993;148(6 Pt 1):1683–4. Daegu 41931, Republic of Korea. Department of Allergology, Hospital Serive 21. Meliconi R, Andreone P, Fasano L, Galli S, Pacilli A, Miniero R, Fabbri M, of Kavaje, Kavaje, Albania. Department of Occupational & Environmental Solforosi L, Bernardi M. Incidence of hepatitis C virus infection in Italian Medicine, Sungso Hospital, Andong, Republic of Korea. patients with idiopathic pulmonary fibrosis. Thorax. 1996;51(3):315–7. 22. Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Received: 25 January 2018 Accepted: 24 May 2018 Sezaki H, Hosaka T, Hirakawa M, et al. Hepatitis C virus enhances incidence of idiopathic pulmonary fibrosis. World J Gastroenterol. 2008;14(38):5880–6. 23. Idilman R, Cetinkaya H, Savas I, Aslan N, Sak SD, Bastemir M, Sarioglu M, Soykan I, Bozdayi M, Colantoni A, et al. Bronchoalveolar lavage fluid analysis References in individuals with chronic hepatitis C. J Med Virol. 2002;66(1):34–9. 1. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of 24. Cordier JF, Cottin V, Lazor R, Thivolet-Bejui F. Many faces of bronchiolitis interstitial lung diseases. Am J Respir Crit Care Med. 1994;150(4):967–72. and organizing pneumonia. Semin Respir Crit Care Med. 2016;37(3):421–40. 2. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of 25. Kaufman JM, Cuvelier CA, Van der Straeten M. Mycoplasma pneumonia with idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012; fulminant evolution into diffuse interstitial fibrosis. Thorax. 1980;35(2):140–4. 21(126):355–61. 26. Chastre J, Raghu G, Soler P, Brun P, Basset F, Gibert C. Pulmonary fibrosis 3. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, Okajima following pneumonia due to acute Legionnaires' disease. Clinical, Y, Dupuis J, Latourelle JC, Cho MH, et al. Association between interstitial ultrastructural, and immunofluorescent study. Chest. 1987;91(1):57–62. lung abnormalities and all-cause mortality. Jama. 2016;315(7):672–81. 27. Auerbach SH, Mims OM, Goodpasture EW. Pulmonary fibrosis secondary to 4. Choi WI, Park SH, Dauti S, Park BJ, Lee CW. Interstitial lung disease and risk pneumonia. Am J Pathol. 1952;28(1):69–87. of mortality: 11-year nationwide population-based study. Int J Tuberc Lung 28. Shachor Y, Schindler D, Siegal A, Lieberman D, Mikulski Y, Bruderman I. Dis. 2018;22(1):100–5. Increased incidence of pulmonary tuberculosis in chronic interstitial lung 5. Choi WI, Park SH, Park BJ, Lee CW. Interstitial lung disease and lung Cancer disease. Thorax. 1989;44(2):151–3. development: a 5-year Nationwide population-based study. Cancer Res 29. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung Treat. 2017;50(2):374–81. remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201–9. 6. Lederer DJ, Enright PL, Kawut SM, Hoffman EA, Hunninghake G, van 30. el-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or Beek EJ, Austin JH, Jiang R, Lovasi GS, Barr RG. Cigarette smoking is pulmonary disease with esophagitis in United States military veterans. associated with subclinical parenchymal lung disease: the multi-ethnic Gastroenterology. 1997;113(3):755–60. study of atherosclerosis (MESA)-lung study. Am J Respir Crit Care Med. 31. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, 2009;180(5):407–14. Raghu G, Investigators IP. Anti-acid treatment and disease progression in 7. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, idiopathic pulmonary fibrosis: an analysis of data from three randomised Yamashiro T, Ross JC, Estepar RS, Lynch DA, Brehm JM, et al. Lung volumes controlled trials. Lancet Respir Med. 2013;1(5):369–76. and emphysema in smokers with interstitial lung abnormalities. N Engl J 32. Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE Jr, Med. 2011;364(10):897–906. Collard HR. Gastroesophageal reflux therapy is associated with longer 8. Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Nishino M, Araki T, Zazueta OE, Kurugol S, et al. MUC5B promoter Med. 2011;184(12):1390–4. polymorphism and interstitial lung abnormalities. N Engl J Med. 2013; 33. Gribbin J, Hubbard R, Smith C. Role of diabetes mellitus and gastro- 368(23):2192–200. oesophageal reflux in the aetiology of idiopathic pulmonary fibrosis. Respir 9. Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Med. 2009;103(6):927–31. Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J 34. Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A, Epidemiol. 2017;46(2):e15. Hubbard RB. The rising incidence of idiopathic pulmonary fibrosis in the UK. 10. Ueda T, Ohta K, Suzuki N, Yamaguchi M, Hirai K, Horiuchi T, Watanabe J, Thorax. 2011;66(6):462–7. Miyamoto T, Ito K. Idiopathic pulmonary fibrosis and high prevalence of 35. Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, Nathan serum antibodies to hepatitis C virus. Am Rev Respir Dis. 1992;146(1):266–8. SD, O'Quinn S, Parker J, Tran TN. Idiopathic pulmonary fibrosis in United 11. Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. States automated claims. Incidence, prevalence, and algorithm validation. Increased prevalence of gastroesophageal reflux in patients with idiopathic Am J Respir Crit Care Med. 2015;192(10):1200–7. pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804–8. 36. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR. Idiopathic 12. Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Diabetes mellitus may pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: increase risk for idiopathic pulmonary fibrosis. Chest. 2003;123(6):2007–11. incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2(7):566–72. 13. Chilosi M, Poletti V, Rossi A. The pathogenesis of COPD and IPF: distinct 37. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of horns of the same devil? Respir Res. 2012;13:3. idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 14. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette 2016;48(1):179–86. smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit 38. Gjonbrataj J, Choi WI, Bahn YE, Rho BH, Lee JJ, Lee CW. Incidence of Care Med. 1997;155(1):242–8. idiopathic pulmonary fibrosis in Korea based on the 2011 ATS/ERS/JRS/ALAT 15. Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, statement. Int J Tuberc Lung Dis. 2015;19(6):742–6. Ryerson CJ, Ryu JH, Selman M, Wells AU, et al. An official American Thoracic 39. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and Society/European Respiratory Society statement: update of the international mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. multidisciplinary classification of the idiopathic interstitial pneumonias. Am J 2015;46(3):795–806. Respir Crit Care Med. 2013;188(6):733–48. 40. Evans GW, Kantrowitz E. Socioeconomic status and health: the potential role 16. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to of environmental risk exposure. Annu Rev Public Health. 2002;23:303–31. findings in lung parenchyma: a microscopic study. Chest. 1974;65(1):29–35. 17. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol. 2010;41(3):316–25. 18. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, Israel-Biet D, Court-Fortune I, Valeyre D, Cordier JF, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26(4):586–93. 19. Inomata M, Ikushima S, Awano N, Kondoh K, Satake K, Masuo M, Kusunoki Y, Moriya A, Kamiya H, Ando T, et al. An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features. BMC Pulm Med. 2014;14:104.

Journal

BMC Pulmonary MedicineSpringer Journals

Published: Jun 4, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off