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Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003–2015: A nationwide population-based study
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Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003–2015: A nationwide population-based study Ji Eun Parka,b, Young Sam Kima, Min Jin Kangc, Cheong Ju Kimd, Chang Hoon Hand, Sun Min Leed, Seon Cheol Parkd,e,∗ a
Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea c Research Institute, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi-do, Republic of Korea d Division of Pulmonology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi-do, Republic of Korea e Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Sarcoidosis Epidemiology Prevalence Incidence Mortality Asia
Background: The prevalence and incidence of sarcoidosis, a granulomatous disorder involving multiple organ systems, varies among geographical regions and ethnicities. This study evaluated the incidence, prevalence, and mortality of sarcoidosis in a large nationwide population-based cohort in Korea. Methods: We used data of the National Health Insurance Service database, which is an extensive health-related database including most Korean residents. Adults with a primary diagnosis of sarcoidosis, as determined by International Classification of Disease-Tenth Revision coding (D86), were identified between 2003 and 2015. The incidence, prevalence, and mortality of sarcoidosis were analysed by sex and age. Results: A total of 6376 individuals had a primary diagnosis of sarcoidosis. Their mean age was 48.8 years, and 58.6% were women. The age-adjusted incidence and prevalence of sarcoidosis were 1.3 and 3.4 per 100,000 population respectively; both tended to increase between 2003 and 2015. The all-cause mortality rate was 13.1 per 1000 sarcoidosis patients. The standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval, 1.5 to 1.8). Conclusions: This is the largest epidemiologic study of sarcoidosis in an Asian population to date. In Korea, the annual incidence and prevalence of sarcoidosis were relatively low but tended to increase over the 13 years of the study period. Importantly, the overall mortality rate of patients with sarcoidosis was higher than that of the general population.
1. Introduction Sarcoidosis is a granulomatous disorder involving multiple organ systems (primarily the lungs and the lymphatic system). The characteristic pathologic findings of sarcoidosis include the presence of noncaseating granulomas in the involved organs; however, the exact cause of the disease remains unknown [1–4]. The prevalence and incidence of sarcoidosis varies by geographical region and ethnicity. The highest incidence has been reported among northern European and African-American individuals (7.2–35.5 per 100,000 population) [5–9]. Studies in Japan and Korea have reported a relatively low incidence of sarcoidosis (0.13–1.01 per 100,000 population) [10,11]. The mortality associated with sarcoidosis also varies by
age, ethnicity, and sex and is highest in women of African-American descent [12–16]. While large-scale epidemiologic studies of sarcoidosis are lacking worldwide, studies among Asian populations are especially scarce. In Korea, no epidemiologic studies on sarcoidosis have been conducted since a small survey-based study in 2001 [11]. The purpose of this study was to estimate the incidence, prevalence, and mortality of sarcoidosis using the National Health Insurance Service (NHIS) database, which is a large health-related database including nearly all residents of Korea.
Abbreviations: CI, confidence interval; ICD-10, International Classification of Disease-Tenth Revision; NHIS, National Health Insurance Service; OECD, Organization for Economic Cooperation and Development ∗ Corresponding author. Ilsan-ro 100, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea. E-mail address: [email protected] (S.C. Park). https://doi.org/10.1016/j.rmed.2018.03.028 Received 18 January 2018; Received in revised form 20 March 2018; Accepted 27 March 2018 0954-6111/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Park, J.E., Respiratory Medicine (2018), https://doi.org/10.1016/j.rmed.2018.03.028
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2. Methods
Table 1 Baseline characteristics of patients with sarcoidosis, 2003–2015.
2.1. Data source and study population
Total Total, n (%) 6376 (100) Age, n (%) Mean 48.9 ± 15.2 20–29 years 582 (9.1) 30–39 years 1276 (20.0) 40–49 years 1380 (21.6) 50–59 years 1617 (25.4) 60–69 years 982 (15.4) 70–79 years 462 (7.3) ≥80 years 77 (1.2) Region of residence, n (%) Urban 2996 (47.0) Rural 3380 (53.0) Household incomea, n (%) 1st quintile 1379 (21.6) 2nd quintile 863 (13.6) 3rd quintile 1053 (16.5) 4th quintile 1344 (21.1) 5th quintile 1737 (27.2)
Since 2000, the NHIS in Korea has provided health insurance services to nearly all residents. All Korean citizens are obliged to register for the health insurance provided by the NHIS. Consequently, a large amount of health-related data has accumulated in the NHIS database, including the insurance eligibility of the participants, medical treatments, medical institutions, and general health examinations. To offer relevant and useful data for health researchers, the NHIS established a population database containing data on personal information and medical treatments in 2002. 2.2. Diagnosis of sarcoidosis Individuals aged ≥20 years visiting medical institutions with a primary diagnosis of sarcoidosis, coded as D86 according to the International Classification of Disease-Tenth Revision (ICD-10) coding system, were identified in the NHIS database between 2002 and 2015. To exclude previously diagnosed cases of sarcoidosis, we did not include sarcoidosis patients in 2002 and analysed only patients who were newly diagnosed with sarcoidosis between 2003 and 2015.
a
Male
Female
2642 (41.4)
3734 (58.6)
45.9 ± 15.2 401 (15.2) 706 (26.7) 492 (18.6) 457 (17.3) 382 (14.5) 177 (6.7) 27 (1.0)
51.1 ± 13.0 181 (4.8) 570 (15.3) 888 (23.8) 1160 (31.0) 600 (16.1) 285 (7.6) 50 (1.4)
1180 (44.7) 1462 (55.3)
1816 (48.6) 1918 (51.4)
523 329 481 606 703
856 (22.9) 534 (14.3) 572 (15.3) 738 (19.8) 1034 (27.7)
(19.8) (12.5) (18.2) (22.9) (26.6)
Household income increases from the 1st to the 5th quintile.
database used.
2.3. Demographics
3. Results
The age, sex, region of residence, and household income of sarcoidosis patients were extracted from the NHIS database between 2003 and 2015. All variables were analysed at the time of the sarcoidosis diagnosis. Household income was categorised into five quintiles, from low to high. The first quintile group represents the 20% of the population with the lowest income, whereas the fifth quintile group represents the 20% of the population with the highest income.
3.1. Baseline characteristics A total of 6376 patients with sarcoidosis were identified. Their mean age was 48.8 ± 14.2 years, and 58.6% were women. Patients aged 50–59 were the most common. Similar proportions of patients were found in urban and rural areas. Most patients had a household income in the fifth quintile (Table 1).
2.4. Outcomes
3.2. Prevalence
Individuals were included at the time of their sarcoidosis diagnosis and followed up until either the end of the study period or death. The prevalence of sarcoidosis was defined as the number of individuals visiting medical institutions who were assigned the ICD-10 code D86 for sarcoidosis as the primary diagnosis. The incidence of sarcoidosis was analysed from 2003 to 2015, after an exclusion period of one year. A new case of sarcoidosis was defined at a patient's first visit with assignment of ICD-10 code D86. The annual mortality in sarcoidosis patients from 2003 to 2015 was also analysed. The standard statistical population was that population during the middle of 2010.
The annual visits for sarcoidosis increased from 578 in 2003 to 2506 in 2015. The average annual age-adjusted prevalence between 2003 and 2015 was 3.4 per 100,000 population (Fig. 1). The prevalence of sarcoidosis was higher in females than in males (4.2 vs. 2.6 per 100,000 population, respectively), and highest between the ages of 50 and 69 years. 3.3. Incidence The average annual age-adjusted incidence of sarcoidosis was 1.3 per 100,000 population. (1.1 and 1.5 per 100,000 population for men and women, respectively). The sarcoidosis incidence in 2015 increased 1.6 times over that in 2003 (Fig. 2). Similar to the prevalence, the ageadjusted incidence was highest between the ages of 50 and 69 years. The incidence of sarcoidosis among men was similar for each age group, whereas the incidence among women was highest between the ages of 50 and 59 years. We found similar incidences in urban and rural areas.
2.5. Statistical analysis Descriptive statistics were performed for all variables. Annual sarcoidosis-related visits and deaths by sex and age were calculated. For the incidence analysis, the first visits with sarcoidosis were calculated. The general population living in Korea aged 20 years or older was used as the denominator for the prevalence and incidence of sarcoidosis, which were calculated by age, sex, and region of residence. The annual mortality rate among sarcoidosis patients was analysed and compared to that of the general Korean population. All statistical analyses were performed with the SAS program, version 9.4 (SAS Institute, Cary, NC, USA).
3.4. Mortality Between 2003 and 2015, a total of 435 patients with sarcoidosis died. The mean annual age-adjusted mortality rate was 13.1 per 1000 sarcoidosis patients; this was similar over the study period (Fig. 3). The mortality rate in males was approximately twice that of females. Moreover, the mortality rate increased with age, and this increase was more pronounced in males. The overall standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval [CI], 1.5 to 1.8) between 2003 and 2015 (Fig. 4).
2.6. Ethics This study was approved by the Institutional Review Board of the National Health Insurance Service of the Ilsan Hospital and adhered to the tenets of the Declaration of Helsinki (2016-12-020-001). Written informed consent was waived as the data were de-identified in the 2
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Fig. 1. Numbers of patient with sarcoidosis and age-adjusted prevalence between 2003 and 2015 (a) and by age groups over all years (b). The rates are per 100,000 population.
4. Discussion
that evaluated 1027 sarcoidosis patients who were newly diagnosed in 2004 [10]. The average incidence rate of sarcoidosis was 1.01 per 100,000 population (0.73 in men and 1.28 in women), and the highest incidence rates by age were seen between 20 and 34 years in males and between 50 and 60 years in women. In Korea, a nationwide surveybased study enrolled 309 sarcoidosis patients between 1992 and 1999 and showed that the incidence rate was 0.027 per 100,000 population in 1993; this increased to 0.125 per 100,000 population in 1998 [11]. The peak age for sarcoidosis was the 30s. In our study, the age-adjusted incidence rate of sarcoidosis was 1.3 per 100,000 population (1.1 and 1.5 per 100,000 population in men and women, respectively); this is similar to the results of the previous Japanese study [10]. The low incidence of sarcoidosis in the previous Korean report was likely due to underdiagnosis as the study was based on a survey from relatively large hospitals.
This is the largest epidemiologic study of sarcoidosis conducted in an Asian population. The annual average age-adjusted prevalence and incidence of sarcoidosis in Korea were 3.4 and 1.3 per 100,000 population, respectively. Both prevalence and incidence were higher in women than in men. The highest prevalence and incidence were between the ages of 50 and 69 years. The annual average age-adjusted mortality rate in sarcoidosis patients was 13.1 per 1000 patients. The mortality rate was higher in men than in women. The overall mortality rate of patients with sarcoidosis was higher than that of the general population. In Asia, the epidemiology of sarcoidosis has been rarely studied, and only few studies have been reported in Japan and Korea. The most recent study was a cross-sectional analysis conducted in Japan in 2008 3
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Fig. 2. Numbers of newly-diagnosed cases of sarcoidosis and age-adjusted incidence between 2003 and 2015 (a) and by age groups over all years (b). Rates are per 100,000 population.
[21]. However, no studies have shown a clear correlation between the incidences of tuberculosis and sarcoidosis. Although the incidence rate of sarcoidosis in our study increased from 2003 to 2015, the incidence rate of tuberculosis in Korea did not change significantly during the same period [22]. Further studies should investigate whether a high incidence rate of tuberculosis is associated with the incidence of sarcoidosis. Differences in sarcoidosis incidence by geographic location, ethnicity, and sex have been reported worldwide. For example, studies in persons of northern European and African-American descent have reported a high incidence of sarcoidosis [5–8,23]. Among these, the incidence in women of African descent in the United States was the highest estimated (between 39.1 and 71 per 100,000 population)
We can only speculate about the cause of the increase in sarcoidosis incidence in this study. Previous studies using autopsy suggested that sarcoidosis may be more common than expected [17,18]. Improved diagnostic techniques and increased disease awareness might have increased the detection rates of sarcoidosis. In Korea, endobronchial ultrasound, a useful diagnostic tool for sarcoidosis, has been used since 2005. The utilisation of computed tomography has also increased continuously during our study period [19]. Previous reports suggested that the increase in the incidence of sarcoidosis might be related to a decrease in that of tuberculosis [20]. South Korea has a relatively high incidence of tuberculosis among the members of the Organization for Economic Co-operation and Development (OECD), and the incidence of tuberculosis in South Korea was 80 per 100,000 population in 2015 4
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Fig. 3. Age-adjusted mortality rates among sarcoidosis patients between 2003 and 2015.
Asian populations have been extremely rare. One study based on a nationwide survey in Japan in 1972 and 1984 found that the age-adjusted mortality rates of sarcoidosis were 0.1–0.2 per million [31]. Several studies have compared the mortality rate of sarcoidosis with that of the general population. The Black Women's Health Study showed that the age-adjusted mortality in sarcoidosis was 94 per 10,000 person-years, which is 2.44 times higher than that of women not diagnosed with the disease [13]. Another study, which was conducted in a British population, also found a significantly higher mortality rate in individuals with sarcoidosis when compared to the general population [26,32]. In our study, the crude mortality rate among patients with sarcoidosis was 14 per 1000 person-years, and the standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% CI, 1.5 to 1.8). However, one study conducted in Minnesota reported that the mortality rate of sarcoidosis was not significantly different from that of the general population [27]. The aetiology of sarcoidosis remains unknown, but environmental factors and genetic susceptibility have been suggested. Multicentre case-control studies have been conducted to identify the predisposing factors of sarcoidosis [33,34]. The ACCESS study of ≥700 patients and nearly 30,000 of their relatives reported that first- and second-degree relatives of sarcoidosis patients were at significantly elevated risk for the disease when compared to matched control subjects [33]. The familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI, 2.3 to 9.7). The same group also studied the association between environmental exposure and sarcoidosis development [34]. The ACCESS study did not find a single predominant risk factor for sarcoidosis; however, it suggested several possible environmental factors, including insecticides, agricultural employment, and microbial bioaerosols. Several studies have also suggested that residence in a rural area is a risk factor for sarcoidosis [6,35–37]. However, it remains unknown whether these factors affect the development of sarcoidosis. Our study found no difference in the incidence of sarcoidosis between urban and rural, and another study in the United States reported a similar sarcoidosis risk between the two areas [23]. In Asia, large-scale epidemiologic studies on sarcoidosis have been extremely rare. Our study is the first large epidemiologic study with a long-term follow-up (> 10 years) in an Asian population. It is a
Fig. 4. Standardised mortality ratios of sarcoidosis in Korea.
[7,23,24]. Studies in populations in northern Europe have also reported a high incidence of sarcoidosis, which is estimated at between 7.2 and 11.5 per 100,000 population [5,6]. The difference in sarcoidosis incidence between the sexes remains unclear. While some studies indicated that sarcoidosis was more common in women [7,25], others have reported no differences [26,27]. One study using a Swedish population-based register reported that men had a higher incidence of the disease than women, regardless of the register case definition [6]. Studies in Korea and Japan found a higher incidence in women than in men, which is similar our findings [10,11]. Sarcoidosis-related mortality rates have also been shown to vary among different geographic and ethnic groups. A population-based study using death certificate data in the United States (1988–2007) reported that mortality was highest women of non-Hispanic AfricanAmerican descent aged ≥55 years [12]. A younger age and AfricanAmerican descent were risk factors for pulmonary fibrosis and cardiac complications, which contributed to the death of the sarcoidosis patients. The age-and sex-adjusted mortality rate due to sarcoidosis was 4.32 per million. Other studies using death certificate data in English and French populations reported similar mortality rates of 3.6–4.2 per million [28–30]. Studies estimating the mortality rates of sarcoidosis in 5
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nationwide population-based study including nearly the entire population of Korea. Despite this strength, our study also has limitations. First, we defined sarcoidosis using only the ICD-10 code assigned by the health care providers, which might have affected the diagnostic accuracy of the data. Data on clinical features, imaging, and pathologic results were not available to us. Therefore, the registration of sarcoidosis codes might not be entirely accurate. Second, we only used one primary diagnostic code for sarcoidosis. Sarcoidosis is a diagnosis of exclusion, and a diagnosis of sarcoidosis may be retracted when new clinical data arise that suggest an alternative diagnosis. Therefore, the diagnostic criteria used in this study might have led to the inclusion of patients who did not have sarcoidosis. Third, the prevalence of sarcoidosis might have been overestimated over the study period. The diagnostic code of sarcoidosis often remains life-long in the patient's medical records because it is rarely clear when the granulomatous inflammation of sarcoidosis completely resolved. Therefore, the prevalence rates in this study may represent lifetime prevalence. Fourth, when we compared the mortality rate of the general Korean population to that of patients with sarcoidosis, we could not exclude sarcoidosis patients from the general Korean population because of limitations of the data analysis. However, we believe that only few individuals with sarcoidosis were included in the total Korean population; therefore, the inclusion of sarcoidosis patients likely did not significantly affect our outcomes.
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5. Conclusions This study showed that the prevalence and incidence of sarcoidosis in Korea were relatively low between 2003 and 2015. This low incidence, which is similar to that in Japan, is approximately one-tenth of that in European or American populations. Importantly, however, the incidence and prevalence of the disease tended to increase over the last 13 years of the study period. The age-adjusted all-cause mortality was 13.1 per 1000 sarcoidosis patients, which was approximately twice that of the general population. Therefore, this trend should be closely monitored to establish optimal healthcare policies and treatment strategies for sarcoidosis. Conflicts of interest None. Author contributions All authors fulfil the criteria of authorship. SCP and JEP conceived and designed the study. SCP and MJK analysed and interpreted the data. JEP, YSK, CJK, CHH and SML reviewed the methodology, analysis and presentation of the results. SCP and JEP wrote the first draft of the manuscript. All authors critically evaluated the data, reviewed the manuscript, and approved the final manuscript. Acknowledgements This work was supported by a National Health Insurance Ilsan Hospital grant (no. NHIS-2017-1-050). This study used data of the National Health Insurance Service database system. The sponsor had no role in the design of the study, the analysis of the data, or the preparation of the manuscript. The authors alone are responsible for the content and writing of the paper. References [1] Statement on sarcoidosis, Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, february 1999, Am. J. Respir. Crit.
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[36] T.T. Nicholson, B.J. Plant, M.T. Henry, C.P. Bredin, Sarcoidosis in Ireland: regional differences in prevalence and mortality from 1996-2005, Sarcoidosis Vasc. Diffuse Lung Dis. 27 (2) (2010) 111–120. [37] D.K. Kajdasz, D.T. Lackland, L.C. Mohr, M.A. Judson, A current assessment of rurally linked exposures as potential risk factors for sarcoidosis, Ann. Epidemiol. 11 (2) (2001) 111–117.
[34] L.S. Newman, C.S. Rose, E.A. Bresnitz, et al., A case control etiologic study of sarcoidosis: environmental and occupational risk factors, Am. J. Respir. Crit. Care Med. 170 (12) (2004) 1324–1330. [35] U. Deubelbeiss, A. Gemperli, C. Schindler, F. Baty, M.H. Brutsche, Prevalence of sarcoidosis in Switzerland is associated with environmental factors, Eur. Respir. J. 35 (5) (2010) 1088–1097.
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Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003–2015: A nationwide population-based study Ji Eun Parka,b, Young Sam Kima, Min Jin Kangc, Cheong Ju Kimd, Chang Hoon Hand, Sun Min Leed, Seon Cheol Parkd,e,∗ a
Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea c Research Institute, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi-do, Republic of Korea d Division of Pulmonology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Gyeonggi-do, Republic of Korea e Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Sarcoidosis Epidemiology Prevalence Incidence Mortality Asia
Background: The prevalence and incidence of sarcoidosis, a granulomatous disorder involving multiple organ systems, varies among geographical regions and ethnicities. This study evaluated the incidence, prevalence, and mortality of sarcoidosis in a large nationwide population-based cohort in Korea. Methods: We used data of the National Health Insurance Service database, which is an extensive health-related database including most Korean residents. Adults with a primary diagnosis of sarcoidosis, as determined by International Classification of Disease-Tenth Revision coding (D86), were identified between 2003 and 2015. The incidence, prevalence, and mortality of sarcoidosis were analysed by sex and age. Results: A total of 6376 individuals had a primary diagnosis of sarcoidosis. Their mean age was 48.8 years, and 58.6% were women. The age-adjusted incidence and prevalence of sarcoidosis were 1.3 and 3.4 per 100,000 population respectively; both tended to increase between 2003 and 2015. The all-cause mortality rate was 13.1 per 1000 sarcoidosis patients. The standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval, 1.5 to 1.8). Conclusions: This is the largest epidemiologic study of sarcoidosis in an Asian population to date. In Korea, the annual incidence and prevalence of sarcoidosis were relatively low but tended to increase over the 13 years of the study period. Importantly, the overall mortality rate of patients with sarcoidosis was higher than that of the general population.
1. Introduction Sarcoidosis is a granulomatous disorder involving multiple organ systems (primarily the lungs and the lymphatic system). The characteristic pathologic findings of sarcoidosis include the presence of noncaseating granulomas in the involved organs; however, the exact cause of the disease remains unknown [1–4]. The prevalence and incidence of sarcoidosis varies by geographical region and ethnicity. The highest incidence has been reported among northern European and African-American individuals (7.2–35.5 per 100,000 population) [5–9]. Studies in Japan and Korea have reported a relatively low incidence of sarcoidosis (0.13–1.01 per 100,000 population) [10,11]. The mortality associated with sarcoidosis also varies by
age, ethnicity, and sex and is highest in women of African-American descent [12–16]. While large-scale epidemiologic studies of sarcoidosis are lacking worldwide, studies among Asian populations are especially scarce. In Korea, no epidemiologic studies on sarcoidosis have been conducted since a small survey-based study in 2001 [11]. The purpose of this study was to estimate the incidence, prevalence, and mortality of sarcoidosis using the National Health Insurance Service (NHIS) database, which is a large health-related database including nearly all residents of Korea.
Abbreviations: CI, confidence interval; ICD-10, International Classification of Disease-Tenth Revision; NHIS, National Health Insurance Service; OECD, Organization for Economic Cooperation and Development ∗ Corresponding author. Ilsan-ro 100, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea. E-mail address: [email protected] (S.C. Park). https://doi.org/10.1016/j.rmed.2018.03.028 Received 18 January 2018; Received in revised form 20 March 2018; Accepted 27 March 2018 0954-6111/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Park, J.E., Respiratory Medicine (2018), https://doi.org/10.1016/j.rmed.2018.03.028
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2. Methods
Table 1 Baseline characteristics of patients with sarcoidosis, 2003–2015.
2.1. Data source and study population
Total Total, n (%) 6376 (100) Age, n (%) Mean 48.9 ± 15.2 20–29 years 582 (9.1) 30–39 years 1276 (20.0) 40–49 years 1380 (21.6) 50–59 years 1617 (25.4) 60–69 years 982 (15.4) 70–79 years 462 (7.3) ≥80 years 77 (1.2) Region of residence, n (%) Urban 2996 (47.0) Rural 3380 (53.0) Household incomea, n (%) 1st quintile 1379 (21.6) 2nd quintile 863 (13.6) 3rd quintile 1053 (16.5) 4th quintile 1344 (21.1) 5th quintile 1737 (27.2)
Since 2000, the NHIS in Korea has provided health insurance services to nearly all residents. All Korean citizens are obliged to register for the health insurance provided by the NHIS. Consequently, a large amount of health-related data has accumulated in the NHIS database, including the insurance eligibility of the participants, medical treatments, medical institutions, and general health examinations. To offer relevant and useful data for health researchers, the NHIS established a population database containing data on personal information and medical treatments in 2002. 2.2. Diagnosis of sarcoidosis Individuals aged ≥20 years visiting medical institutions with a primary diagnosis of sarcoidosis, coded as D86 according to the International Classification of Disease-Tenth Revision (ICD-10) coding system, were identified in the NHIS database between 2002 and 2015. To exclude previously diagnosed cases of sarcoidosis, we did not include sarcoidosis patients in 2002 and analysed only patients who were newly diagnosed with sarcoidosis between 2003 and 2015.
a
Male
Female
2642 (41.4)
3734 (58.6)
45.9 ± 15.2 401 (15.2) 706 (26.7) 492 (18.6) 457 (17.3) 382 (14.5) 177 (6.7) 27 (1.0)
51.1 ± 13.0 181 (4.8) 570 (15.3) 888 (23.8) 1160 (31.0) 600 (16.1) 285 (7.6) 50 (1.4)
1180 (44.7) 1462 (55.3)
1816 (48.6) 1918 (51.4)
523 329 481 606 703
856 (22.9) 534 (14.3) 572 (15.3) 738 (19.8) 1034 (27.7)
(19.8) (12.5) (18.2) (22.9) (26.6)
Household income increases from the 1st to the 5th quintile.
database used.
2.3. Demographics
3. Results
The age, sex, region of residence, and household income of sarcoidosis patients were extracted from the NHIS database between 2003 and 2015. All variables were analysed at the time of the sarcoidosis diagnosis. Household income was categorised into five quintiles, from low to high. The first quintile group represents the 20% of the population with the lowest income, whereas the fifth quintile group represents the 20% of the population with the highest income.
3.1. Baseline characteristics A total of 6376 patients with sarcoidosis were identified. Their mean age was 48.8 ± 14.2 years, and 58.6% were women. Patients aged 50–59 were the most common. Similar proportions of patients were found in urban and rural areas. Most patients had a household income in the fifth quintile (Table 1).
2.4. Outcomes
3.2. Prevalence
Individuals were included at the time of their sarcoidosis diagnosis and followed up until either the end of the study period or death. The prevalence of sarcoidosis was defined as the number of individuals visiting medical institutions who were assigned the ICD-10 code D86 for sarcoidosis as the primary diagnosis. The incidence of sarcoidosis was analysed from 2003 to 2015, after an exclusion period of one year. A new case of sarcoidosis was defined at a patient's first visit with assignment of ICD-10 code D86. The annual mortality in sarcoidosis patients from 2003 to 2015 was also analysed. The standard statistical population was that population during the middle of 2010.
The annual visits for sarcoidosis increased from 578 in 2003 to 2506 in 2015. The average annual age-adjusted prevalence between 2003 and 2015 was 3.4 per 100,000 population (Fig. 1). The prevalence of sarcoidosis was higher in females than in males (4.2 vs. 2.6 per 100,000 population, respectively), and highest between the ages of 50 and 69 years. 3.3. Incidence The average annual age-adjusted incidence of sarcoidosis was 1.3 per 100,000 population. (1.1 and 1.5 per 100,000 population for men and women, respectively). The sarcoidosis incidence in 2015 increased 1.6 times over that in 2003 (Fig. 2). Similar to the prevalence, the ageadjusted incidence was highest between the ages of 50 and 69 years. The incidence of sarcoidosis among men was similar for each age group, whereas the incidence among women was highest between the ages of 50 and 59 years. We found similar incidences in urban and rural areas.
2.5. Statistical analysis Descriptive statistics were performed for all variables. Annual sarcoidosis-related visits and deaths by sex and age were calculated. For the incidence analysis, the first visits with sarcoidosis were calculated. The general population living in Korea aged 20 years or older was used as the denominator for the prevalence and incidence of sarcoidosis, which were calculated by age, sex, and region of residence. The annual mortality rate among sarcoidosis patients was analysed and compared to that of the general Korean population. All statistical analyses were performed with the SAS program, version 9.4 (SAS Institute, Cary, NC, USA).
3.4. Mortality Between 2003 and 2015, a total of 435 patients with sarcoidosis died. The mean annual age-adjusted mortality rate was 13.1 per 1000 sarcoidosis patients; this was similar over the study period (Fig. 3). The mortality rate in males was approximately twice that of females. Moreover, the mortality rate increased with age, and this increase was more pronounced in males. The overall standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval [CI], 1.5 to 1.8) between 2003 and 2015 (Fig. 4).
2.6. Ethics This study was approved by the Institutional Review Board of the National Health Insurance Service of the Ilsan Hospital and adhered to the tenets of the Declaration of Helsinki (2016-12-020-001). Written informed consent was waived as the data were de-identified in the 2
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Fig. 1. Numbers of patient with sarcoidosis and age-adjusted prevalence between 2003 and 2015 (a) and by age groups over all years (b). The rates are per 100,000 population.
4. Discussion
that evaluated 1027 sarcoidosis patients who were newly diagnosed in 2004 [10]. The average incidence rate of sarcoidosis was 1.01 per 100,000 population (0.73 in men and 1.28 in women), and the highest incidence rates by age were seen between 20 and 34 years in males and between 50 and 60 years in women. In Korea, a nationwide surveybased study enrolled 309 sarcoidosis patients between 1992 and 1999 and showed that the incidence rate was 0.027 per 100,000 population in 1993; this increased to 0.125 per 100,000 population in 1998 [11]. The peak age for sarcoidosis was the 30s. In our study, the age-adjusted incidence rate of sarcoidosis was 1.3 per 100,000 population (1.1 and 1.5 per 100,000 population in men and women, respectively); this is similar to the results of the previous Japanese study [10]. The low incidence of sarcoidosis in the previous Korean report was likely due to underdiagnosis as the study was based on a survey from relatively large hospitals.
This is the largest epidemiologic study of sarcoidosis conducted in an Asian population. The annual average age-adjusted prevalence and incidence of sarcoidosis in Korea were 3.4 and 1.3 per 100,000 population, respectively. Both prevalence and incidence were higher in women than in men. The highest prevalence and incidence were between the ages of 50 and 69 years. The annual average age-adjusted mortality rate in sarcoidosis patients was 13.1 per 1000 patients. The mortality rate was higher in men than in women. The overall mortality rate of patients with sarcoidosis was higher than that of the general population. In Asia, the epidemiology of sarcoidosis has been rarely studied, and only few studies have been reported in Japan and Korea. The most recent study was a cross-sectional analysis conducted in Japan in 2008 3
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Fig. 2. Numbers of newly-diagnosed cases of sarcoidosis and age-adjusted incidence between 2003 and 2015 (a) and by age groups over all years (b). Rates are per 100,000 population.
[21]. However, no studies have shown a clear correlation between the incidences of tuberculosis and sarcoidosis. Although the incidence rate of sarcoidosis in our study increased from 2003 to 2015, the incidence rate of tuberculosis in Korea did not change significantly during the same period [22]. Further studies should investigate whether a high incidence rate of tuberculosis is associated with the incidence of sarcoidosis. Differences in sarcoidosis incidence by geographic location, ethnicity, and sex have been reported worldwide. For example, studies in persons of northern European and African-American descent have reported a high incidence of sarcoidosis [5–8,23]. Among these, the incidence in women of African descent in the United States was the highest estimated (between 39.1 and 71 per 100,000 population)
We can only speculate about the cause of the increase in sarcoidosis incidence in this study. Previous studies using autopsy suggested that sarcoidosis may be more common than expected [17,18]. Improved diagnostic techniques and increased disease awareness might have increased the detection rates of sarcoidosis. In Korea, endobronchial ultrasound, a useful diagnostic tool for sarcoidosis, has been used since 2005. The utilisation of computed tomography has also increased continuously during our study period [19]. Previous reports suggested that the increase in the incidence of sarcoidosis might be related to a decrease in that of tuberculosis [20]. South Korea has a relatively high incidence of tuberculosis among the members of the Organization for Economic Co-operation and Development (OECD), and the incidence of tuberculosis in South Korea was 80 per 100,000 population in 2015 4
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Fig. 3. Age-adjusted mortality rates among sarcoidosis patients between 2003 and 2015.
Asian populations have been extremely rare. One study based on a nationwide survey in Japan in 1972 and 1984 found that the age-adjusted mortality rates of sarcoidosis were 0.1–0.2 per million [31]. Several studies have compared the mortality rate of sarcoidosis with that of the general population. The Black Women's Health Study showed that the age-adjusted mortality in sarcoidosis was 94 per 10,000 person-years, which is 2.44 times higher than that of women not diagnosed with the disease [13]. Another study, which was conducted in a British population, also found a significantly higher mortality rate in individuals with sarcoidosis when compared to the general population [26,32]. In our study, the crude mortality rate among patients with sarcoidosis was 14 per 1000 person-years, and the standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% CI, 1.5 to 1.8). However, one study conducted in Minnesota reported that the mortality rate of sarcoidosis was not significantly different from that of the general population [27]. The aetiology of sarcoidosis remains unknown, but environmental factors and genetic susceptibility have been suggested. Multicentre case-control studies have been conducted to identify the predisposing factors of sarcoidosis [33,34]. The ACCESS study of ≥700 patients and nearly 30,000 of their relatives reported that first- and second-degree relatives of sarcoidosis patients were at significantly elevated risk for the disease when compared to matched control subjects [33]. The familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI, 2.3 to 9.7). The same group also studied the association between environmental exposure and sarcoidosis development [34]. The ACCESS study did not find a single predominant risk factor for sarcoidosis; however, it suggested several possible environmental factors, including insecticides, agricultural employment, and microbial bioaerosols. Several studies have also suggested that residence in a rural area is a risk factor for sarcoidosis [6,35–37]. However, it remains unknown whether these factors affect the development of sarcoidosis. Our study found no difference in the incidence of sarcoidosis between urban and rural, and another study in the United States reported a similar sarcoidosis risk between the two areas [23]. In Asia, large-scale epidemiologic studies on sarcoidosis have been extremely rare. Our study is the first large epidemiologic study with a long-term follow-up (> 10 years) in an Asian population. It is a
Fig. 4. Standardised mortality ratios of sarcoidosis in Korea.
[7,23,24]. Studies in populations in northern Europe have also reported a high incidence of sarcoidosis, which is estimated at between 7.2 and 11.5 per 100,000 population [5,6]. The difference in sarcoidosis incidence between the sexes remains unclear. While some studies indicated that sarcoidosis was more common in women [7,25], others have reported no differences [26,27]. One study using a Swedish population-based register reported that men had a higher incidence of the disease than women, regardless of the register case definition [6]. Studies in Korea and Japan found a higher incidence in women than in men, which is similar our findings [10,11]. Sarcoidosis-related mortality rates have also been shown to vary among different geographic and ethnic groups. A population-based study using death certificate data in the United States (1988–2007) reported that mortality was highest women of non-Hispanic AfricanAmerican descent aged ≥55 years [12]. A younger age and AfricanAmerican descent were risk factors for pulmonary fibrosis and cardiac complications, which contributed to the death of the sarcoidosis patients. The age-and sex-adjusted mortality rate due to sarcoidosis was 4.32 per million. Other studies using death certificate data in English and French populations reported similar mortality rates of 3.6–4.2 per million [28–30]. Studies estimating the mortality rates of sarcoidosis in 5
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nationwide population-based study including nearly the entire population of Korea. Despite this strength, our study also has limitations. First, we defined sarcoidosis using only the ICD-10 code assigned by the health care providers, which might have affected the diagnostic accuracy of the data. Data on clinical features, imaging, and pathologic results were not available to us. Therefore, the registration of sarcoidosis codes might not be entirely accurate. Second, we only used one primary diagnostic code for sarcoidosis. Sarcoidosis is a diagnosis of exclusion, and a diagnosis of sarcoidosis may be retracted when new clinical data arise that suggest an alternative diagnosis. Therefore, the diagnostic criteria used in this study might have led to the inclusion of patients who did not have sarcoidosis. Third, the prevalence of sarcoidosis might have been overestimated over the study period. The diagnostic code of sarcoidosis often remains life-long in the patient's medical records because it is rarely clear when the granulomatous inflammation of sarcoidosis completely resolved. Therefore, the prevalence rates in this study may represent lifetime prevalence. Fourth, when we compared the mortality rate of the general Korean population to that of patients with sarcoidosis, we could not exclude sarcoidosis patients from the general Korean population because of limitations of the data analysis. However, we believe that only few individuals with sarcoidosis were included in the total Korean population; therefore, the inclusion of sarcoidosis patients likely did not significantly affect our outcomes.
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5. Conclusions This study showed that the prevalence and incidence of sarcoidosis in Korea were relatively low between 2003 and 2015. This low incidence, which is similar to that in Japan, is approximately one-tenth of that in European or American populations. Importantly, however, the incidence and prevalence of the disease tended to increase over the last 13 years of the study period. The age-adjusted all-cause mortality was 13.1 per 1000 sarcoidosis patients, which was approximately twice that of the general population. Therefore, this trend should be closely monitored to establish optimal healthcare policies and treatment strategies for sarcoidosis. Conflicts of interest None. Author contributions All authors fulfil the criteria of authorship. SCP and JEP conceived and designed the study. SCP and MJK analysed and interpreted the data. JEP, YSK, CJK, CHH and SML reviewed the methodology, analysis and presentation of the results. SCP and JEP wrote the first draft of the manuscript. All authors critically evaluated the data, reviewed the manuscript, and approved the final manuscript. Acknowledgements This work was supported by a National Health Insurance Ilsan Hospital grant (no. NHIS-2017-1-050). This study used data of the National Health Insurance Service database system. The sponsor had no role in the design of the study, the analysis of the data, or the preparation of the manuscript. The authors alone are responsible for the content and writing of the paper. References [1] Statement on sarcoidosis, Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, february 1999, Am. J. Respir. Crit.
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