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Adult atopic dermatitis and exposure to air pollutants—a nationwide population-based study
Ann Allergy Asthma Immunol xxx (2016) 1e5
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Adult atopic dermatitis and exposure to air pollutantsda nationwide population-based study Kuo-Tung Tang, MD *, y; Kai-Chen Ku, MD z; Der-Yuan Chen, MD, PhD *, x, k, {; Ching-Heng Lin, MD, PhD #; Ben-Jei Tsuang, PhD z; Yi-Hsing Chen, MD, PhD *, x * Division
of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan PhD Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan z Department of Environmental Engineering, National Chung-Hsing University, Taichung, Taiwan x School of Medicine, National Yang-Ming University, Taipei, Taiwan k Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan { Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan # Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan y
A R T I C L E
I N F O
Article history: Received for publication October 19, 2016. Received in revised form November 23, 2016. Accepted for publication December 8, 2016.
A B S T R A C T
Background: There is a trend toward an increased worldwide prevalence of allergic diseases. It is speculated that industrialization with resultant air pollution plays a role. However, there are sparse epidemiologic data on the relation between air pollution and atopic dermatitis (AD) in adults. Objective: To investigate the relation between exposure to air pollutants and adult AD in a cross-sectional study based on data from the National Health Insurance Research Database in Taiwan. Methods: We identified 1,023 adult patients with AD and 4,092 age- and sex-matched controls without allergic diseases in 2011. Using data from 71 Environmental Protection Agency monitoring stations across Taiwan, levels of exposure to air pollutants were determined by the location of a subject’s place of residence. Multivariate logistic regression analysis, adjusted for age, sex, levels of urbanization, and family income, was performed. Results: We found an association between particulate matter <2.5 mm in diameter or the Pollutant Standards Index (the highest sub-index of the concentrations of 5 main air pollutants after transformation) and the development of adult AD. The adjusted odds ratios were 1.05 (95% confidence interval 1.02e1.08) and 1.02 (95% confidence interval 1.01e1.03), respectively. Conclusion: These results demonstrated that air pollution, represented by particulate matter <2.5 mm in diameter or the Pollutant Standards Index, was modestly associated with the development of AD in adults. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Reprints: Yi-Hsing Chen, MD, PhD, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Number 1650, Section 4, Taiwan Boulevard, Taichung, Taiwan 40705; E-mail: [email protected]. Professors Ching-Heng Lin, Ben-Jei Tsuang, and Yi-Hsing Chen equally supervised this work. Disclosures: Authors have nothing to disclose. Disclaimer: This study is based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Ministry of Health and Welfare and managed by the National Health Research Institutes (registered numbers 101095 and 102148). The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes. Funding Sources: This study was supported by a grant from the Taichung Veterans General Hospital Research Program (TCVGH-1053802B) and in part by grants from the Taichung Veterans General Hospital, Taiwan (TCVGH-NHRI10405, TCVGH1047324D, TCVGH-1047312C, TCVGH-104G211) and the National Science Council, Taiwan (MOST 103-2314-B-075A-006).
There is a trend toward an increased global prevalence of allergic diseases.1 It has been speculated that industrialization plays a role, based on studies indicating that air pollution contributes to the development of allergic diseases such as asthma and allergic rhinitis.2 Atopic dermatitis (AD) is a pruritic, eczematous, allergic skin disease with a chronic and relapsing course.3 It is a disease mostly of childhood and gradually resolves by adulthood. However, some patients with AD have the disease in adulthood,4 which leads to a compromised quality of life.5 An association between air pollution and childhood AD has been reported in several studies.6,7 However, there are sparse epidemiologic data on the relation between air pollution and AD in adults. Adults are presumed to be more likely to be exposed to air pollutants because of greater participation in outdoor activities. In addition, studies have found higher immunoglobulin E levels and
http://dx.doi.org/10.1016/j.anai.2016.12.005 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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K.-T. Tang et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5
more prevalent sensitization toward environmental allergens in adult than in pediatric patients with AD.8,9 In these patients with “extrinsic AD,” the skin barrier function is impaired compared with patients with intrinsic AD.10 These characteristics imply that adult patients with AD are more likely to be influenced by external factors. Therefore, we hypothesized that adult AD would be associated with air pollution, as is pediatric AD. Thus, we conducted a crosssectional study based on data from a nationwide health insurance database to explore the relation between exposure to air pollutants and the development of adult AD. Methods Patients This cross-sectional study was based on data acquired from the National Health Insurance Research Database (NHIRD),11 which contains comprehensive health care claims data from more than 99% of the entire Taiwanese population of 24 million. Diseases in the NHIRD are coded with International Classifications of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The data in the NHIRD are de-identified before analysis; therefore, the need for informed consent from subjects was waived. We identified 1,023 adult patients (20 years old) who were diagnosed with AD (ICD-9-CM code 691) in 3 consecutive outpatient visits by a dermatologist, an allergist, or a pediatrician or at 1 hospital admission in a random sample population of 1,000,000 patients in Taiwan from January 1 to December 31, 2011. Age- and sex-matched subjects without allergic diseases such as AD, allergic rhinitis (ICD-9-CM code 477), or asthma (ICD-9-CM code 493) were identified as controls at a 1:4 ratio. This study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the Taichung Veterans General Hospital (Taichung, Taiwan; TCVGH CE13152b-3). Levels of Exposure to Air Pollutants Complete data of the air pollutants SO2, NO2, O3, CO, particulate matter <2.5 mm in diameter (PM2.5), and particulate matter 10 mm in diameter (PM10) were available from 71 Environmental Protection Agency monitoring stations across Taiwan since 1994.12 Concentrations of each pollutant were measured continuouslydCO by nondispersive infrared absorption, NO2 by chemiluminescence, O3 by ultraviolet absorption, SO2 by ultraviolet fluorescence, and PM by beta-gauge. A sub-index was computed for each of the 5 pollutants (SO2, NO2, O3, CO, and PM10) based on a conversion of the pollutant’s ambient air concentrations to a scale from 0 through 500. Then, the highest sub-index value was taken as the Pollutant Standards Index (PSI).13 Then, we calculated the average concentrations of these air pollutants and the PSI in 368 townships in Taiwan using the analysis of Cressman.14 Data were absent for 36 (9.8%) townships because of a lack of relevant information. Levels of exposure to each air pollutant were determined by the location of a subject’s place of residence. Socioeconomic Parameters Urbanization of townships in Taiwan has been categorized into 7 levels based on variables such as population density, percentage of the population who had completed college, percentage of the population at least 65 years old, percentage of the population working in agriculture, and the number of physicians per 100,000 people.15 We combined the lowest 4 levels of urbanization into level 4 because of the small numbers of patients in these levels. Thus, level 1 represents the highest degree of urbanization and level 4 represents the lowest. The monthly income of each individual was estimated based on the National Health Insurance payroll brackets on which premiums were charged.
Table 1 Baseline Characteristics of Adults (20 Years Old) With AD and Age- and Sexmatched Controls Without Allergic Diseases in a Random Sample Population of 1,000,000 in Taiwan in 2011a Variable
Adults with AD (n ¼ 1,023)
Adults without allergic diseases (n ¼ 4,092)
Age (y) 20e34 35e49 50e64 65 Sex Women Men Level of urbanization 1 2 3 4 Family income (NTDs) 15,840 15,841e28,800 28,801e45,800 45,801 Level of exposure to air pollutants PM2.5 (mg/m3) PM10 (mg/m3) SO2 (ppb) NO2 (ppb) CO (ppm) O3 (ppb) PSIb
44.3 18.5 412 (40) 264 (26) 174 (17) 173 (17)
44.0 17.8 1,648 (40) 1,056 (26) 696 (17) 692 (17)
580 (57) 443 (43)
2,320 (57) 1,772 (43)
337 317 143 202
(34) (32) (14) (20)
1,220 1,258 726 802
(31) (31) (18) (20)
401 392 150 80
(39) (38) (15) (8)
1,601 1,758 482 251
(39) (43) (12) (6)
33.6 7.9c 56.3 13.9c 4.0 1.5 18.6 5.0 0.5 0.1 27.9 3.4 55.4 7.7c
32.3 7.4 54.5 13.1 3.9 1.4 18.7 5.2 0.5 0.1 27.8 3.3 54.4 7.5
Abbreviations: AD, atopic dermatitis; NTD, New Taiwan dollar (1 NTD ¼ 0.03 V on September 28, 2016); PM10, particulate matter 10 mm in diameter; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a Data are presented as mean SD or number (percentage). b The index considers 5 air pollutants: SO2, NO2, O3, CO, and PM10. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. c P < .005.
Statistics Statistical analysis was conducted using SAS 9.3 (SAS Institute, Cary, North Carolina). Unless specified otherwise, all quantitative data are presented as mean SD. Numerical variables were compared using the Student t test. Categorical variables were compared using the c2 test. Multivariate logistic regression analysis, adjusted for age, sex, levels of urbanization, family income, and levels of exposure to air pollutants, was performed. We also stratified patients according to age, sex, and levels of urbanization and performed multivariate logistic regression analyses for PM2.5 and the PSI. A 2-sided P value less than .005 was considered statistically significant. Results Baseline Characteristics of Adult Patients With AD and Controls Table 1 presents the baseline characteristics of adult patients with AD and matched controls. The mean age of adult patients with AD was 44 years and there was a slight female predominance (57%). Among air pollutants, levels of exposure to PM2.5 and PM10 and the PSI were higher in patients than in matched controls. Multivariate Logistic Regression Analysis of Factors Associated With Development of Adult AD The multivariate logistic regression analysis of factors associated with the development of adult AD is presented in Table 2. In model 1, which included levels of exposure to each air pollutant, level 3 urbanization and PM2.5 were associated with the development of adult AD. In model 2, which included the PSI instead of levels of
K.-T. Tang et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5 Table 2 Multivariate Analysis of Associated Factors of Atopic Dermatitis in Adults in a Random Sample Population of 1,000,000 in Taiwan in 2011 Variable
Adjusted odds ratioa (95% CI) Model 1
Age (y) 20e34 35e49 50e64 65 Sex Female Male Level of urbanization 1 2 3 4 Family income (NTDs) 15,840 15,841e28,800 28,801e45,800 45,801 Level of exposure to air pollutants PM2.5 PM10 SO2 NO2 CO O3 PSIb
Model 2
1.00 0.96 (0.80e1.15) 0.96 (0.78e1.18) 0.98 (0.79e1.20)
1.00 0.97 (0.81e1.16) 0.96 (0.78e1.19) 0.99 (0.80e1.22)
1.00 1.00 (0.87e1.16)
1.00 1.00 (0.87e1.16)
1.00 0.77 (0.62e0.95) 0.58 (0.45e0.75)c 0.73 (0.54e0.99)
1.00 0.90 (0.75e1.08) 0.69 (0.55e0.86)c 0.89 (0.72e1.09)
1.00 0.88 (0.75e1.03) 1.29 (1.03e1.62) 1.31 (0.98e1.76)
1.00 0.88 (0.75e1.03) 1.27 (1.02e1.59) 1.30 (0.97e1.74)
1.05 0.98 1.07 0.98 0.78 1.01 NA
(1.02e1.08)c (0.97e1.00) (1.00e1.16) (0.93e1.02) (0.22e2.73) (0.97e1.05)
NA NA NA NA NA NA 102 (101e103)c
Abbreviations: CI, confidence interval; NA, not available; NTD, New Taiwan dollar (1 NTD ¼ 0.03 V on September 28, 2016); PM10, particulate matter 10 mm in diameter; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a Odds ratios were adjusted for all variables listed in the table. b The index considers 5 air pollutants: SO2, NO2, O3, CO, and PM10. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. c P < .005.
exposure to each air pollutant, the PSI was associated with the development of adult AD. Multivariate Logistic Regression Analysis of Factors Associated With Development of Adult AD After Stratification by Age, Sex, and Urbanization Table 3 presents the multivariate logistic regression analysis of factors associated with the development of adult AD after stratification by age, sex, and urbanization. PM2.5 was significantly associated with the development of AD in patients at least 50 years old, men, and those living in a residence with level 2 urbanization, whereas the PSI was significantly associated with the development of AD in patients 35 to 49 and at least 65 years old, men and those living in a residence with level 1 or 2 urbanization. Discussion This population-based cross-sectional study investigated the association between air pollution and the development of adult AD in Taiwan. There was a modest association between PM2.5 or the PSI and the development of adult AD, which was similar to previous findings in pediatric AD. The mean age of adult patients with AD in Taiwan was 44 years, which was comparable to that found in the US National Health and Wellness Survey in 2013.16 A slight female predominance was noted in adult patients with AD, although it was less pronounced than in previous studies.16,17 There was no difference in levels of urbanization or family income between adult patients with AD and matched controls. Although controversy remains, socioeconomic status has been associated with the development of allergic
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Table 3 Multivariate Analysis of Associated Factors of Atopic Dermatitis in Adults in a Random Sample Population of 1,000,000 in Taiwan in 2011 After Stratification by Age, Sex, and Levels of Urbanization Variable
Stratified by age (y) 20e34 35e49 50e64 65 Stratified by sex Female Male Stratified by level of urbanization 1 2 3 4
Adjusted odds ratio (95% CI) PM2.5
PSIa
1.01 1.06 1.11 1.09
0.99 1.05 1.03 1.04
(0.97e1.05) (1.00e1.12) (1.04e1.18)b (1.03e1.16)b
(0.98e1.01) (1.03e1.07)b (1.01e1.06) (1.01e1.06)b
1.04 (1.01e1.08) 1.06 (1.02e1.11)b
1.02 (1.01e1.03) 1.03 (1.01e1.04)b
0.96 1.11 1.03 1.03
1.05 1.03 0.99 1.01
(0.86e1.08) (1.06e1.16)b (0.96e1.10) (0.99e1.08)
(1.03e1.07)b (1.01e1.04)b (0.96e1.01) (0.99e1.03)
Abbreviations: CI, confidence interval; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a The index considers 5 air pollutants: SO2, NO2, O3, CO, and particulate matter 10 mm in diameter. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. b P < .005.
diseases such as asthma and AD in children.18 Only 1 study investigated the relation between socioeconomic status and the development of AD in adults. The questionnaire study was conducted in southern Sweden and found that the highest prevalence of selfreported eczema was in those with a low socioeconomic status.19 However, the association did not reach statistical significance after controlling for age, sex, and occupational risk. Further study is needed to establish whether socioeconomic status is related to the development of AD in adults. Major air pollutants include particulates, SO2, NO2, O3, and CO, which are of concern for their impact on health and are designated as “criteria” air pollutants by the US Environmental Protection Agency.20 In children, many studies have shown the association between air pollution and the development or aggravation of AD.6,7,12,21,22 In a study of 4,907 French children, lifetime eczema was significantly associated with 3-year average concentrations of PM10, NO2, NOx, and CO in their residences (adjusted odds ratios [ORs] of 1.13, 1.23, 1.06, and 1.08, respectively).6 In 2 prospective birth cohorts in Munich, a total of 2,860 children were followed and the results showed that NO2 exposure was positively associated with physician-diagnosed eczema (OR 1.18).7 The US National Survey of Children’s Health included a representative sample of 91,642 children and moderate to severe eczema was associated with higher levels of NO3 (OR 1.25) and PM2.5 (OR 1.07).22 A nationwide survey of 317,926 middle school students in Taiwan demonstrated that flexural eczema was positively associated with exposure to traffic-related air pollutants, such as CO and NOx, but was negatively associated with PM10.12 Interestingly, exacerbation of AD symptoms was found to be correlated with the ambient concentrations of air pollutants.21 There are scanty data on the relation between air pollution and AD in adults. In a questionnaire study of 10,464 adults 20 to 44 years old in Italy, the prevalence of eczema was significantly associated with living close to industrial plants and with high levels of heavy traffic near the residence.23 Another questionnaire study in southern Sweden demonstrated that living in close proximity to heavy traffic was associated with eczema in 12,071 adults 20 to 59 years old.19 In our study, PM2.5 and the PSI were associated with the development of AD in adults, although the effect sizes were small. Our finding was similar to that reported in previous studies of children.6,7,12
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Particulates are a heterogeneous group of pollutants that are divided into 3 categories: ultrafine (<0.1 mm in diameter), fine (<2.5 mm in diameter; PM2.5), and coarse (2.5e10 mm in diameter; a component of PM10).20 PM2.5, mainly the byproduct of combustion, constitutes most of the total particulate matter in urban areas. Because of its deep penetration into the lower respiratory tract, PM2.5 is most strongly associated with human cardiopulmonary diseases and death.24 The size of the particulate also determines its skin penetration. Studies have found that microspheres smaller than 1.5 to 3 mm can better penetrate the skin through hair follicles or transepidermally.25,26 Therefore, the small size of PM2.5 allows it to easily penetrate the skin. Using a reconstructed human epidermis model, investigators reported that PM2.5 can penetrate the skin and induce an inflammatory response.27 Moreover, the small PM2.5, when inhaled, not only enters the lungs but also translocates across the aireblood barrier to the circulating blood, thereby affecting distant organs including the skin.28,29 These 2 mechanisms are potential explanations for our results in which PM2.5, but not PM10, was associated with the development of adult AD. After stratification, a positive correlation between levels of exposure to PM2.5 or the PSI and adult AD was found in men, older subjects, and subjects living with lower levels of urbanization. It is reasonable to postulate that men participate in outdoor activities more frequently than women; thus, the influence of outdoor air pollution can be presumed to be more prominent in men. The effects of older age and lower levels of urbanization are more difficult to explain within the scope of the present study. Probably the daily activities of older individuals mostly occur near their homes. Therefore, the levels of exposure to air pollutants, calculated based on the location of a subject’s residence, provided a more precise measurement in older individuals than in younger individuals who could spend a large part of their day away from home. Also, the calculation of levels of exposure to air pollutants based on air quality monitoring data was likely to be more accurate for a subject with a lower urbanization level, because there are many other sources of air pollutants in urban areas that were not comprehensively accounted for in our study. Our study had some strengths. First, this is the first study to directly evaluate the impact of exposure to air pollutants on adult AD. Second, the present study is a nationwide and populationbased investigation. Owing to the large scale of the study, it was possible to demonstrate the complex relation between environmental factors and disease. Third, the Environmental Protection Agency in Taiwan provides comprehensive and continuous monitoring data of air pollutants across the island. Because the concentration of air pollutants changes over time, average concentrations based on continuous monitoring provide a more reliable estimation of exposure. There are some limitations to this study. First, some adult patients with AD did not seek medical advice and therefore cases of AD might have been underdiagnosed in the NHIRD. However, those patients who did not seek medical help were presumed to have had milder disease severity. Indeed, patients with moderate to severe disease activity (ie, the cases identified in this study) are of greater clinical concern. In addition, the cases of AD in our study were diagnosed by a physician, so the diagnosis was more reliable compared with that in studies that included self-reported AD symptoms. Second, it was assumed that subjects spent most of their day at their respective residences. However, for some adults who work long hours in an industrial setting, the workplace is the main source of exposure to air pollutants. Furthermore, indoor air pollutants such as tobacco smoke contribute to the total exposure of air pollutants in an individual. These factors were not accounted for in our study and might have biased the results. However, most
individuals are at home for a considerable time every day. In addition, this measurement bias could not be totally eliminated because this was a population-based study. Therefore, our data still provide valuable insights into the relation between air pollutants and adult AD. Third, it was not possible to determine any causal relations in our analyses because of the cross-sectional design of the study. In conclusion, our results demonstrated that air pollution, represented by PM2.5 or the PSI, was modestly associated with the development of AD in adults.
Acknowledgments The authors thank the Healthcare Service Research Center of the Taichung Veterans General Hospital for statistical support.
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Contents lists available at ScienceDirect
Adult atopic dermatitis and exposure to air pollutantsda nationwide population-based study Kuo-Tung Tang, MD *, y; Kai-Chen Ku, MD z; Der-Yuan Chen, MD, PhD *, x, k, {; Ching-Heng Lin, MD, PhD #; Ben-Jei Tsuang, PhD z; Yi-Hsing Chen, MD, PhD *, x * Division
of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan PhD Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan z Department of Environmental Engineering, National Chung-Hsing University, Taichung, Taiwan x School of Medicine, National Yang-Ming University, Taipei, Taiwan k Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan { Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan # Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan y
A R T I C L E
I N F O
Article history: Received for publication October 19, 2016. Received in revised form November 23, 2016. Accepted for publication December 8, 2016.
A B S T R A C T
Background: There is a trend toward an increased worldwide prevalence of allergic diseases. It is speculated that industrialization with resultant air pollution plays a role. However, there are sparse epidemiologic data on the relation between air pollution and atopic dermatitis (AD) in adults. Objective: To investigate the relation between exposure to air pollutants and adult AD in a cross-sectional study based on data from the National Health Insurance Research Database in Taiwan. Methods: We identified 1,023 adult patients with AD and 4,092 age- and sex-matched controls without allergic diseases in 2011. Using data from 71 Environmental Protection Agency monitoring stations across Taiwan, levels of exposure to air pollutants were determined by the location of a subject’s place of residence. Multivariate logistic regression analysis, adjusted for age, sex, levels of urbanization, and family income, was performed. Results: We found an association between particulate matter <2.5 mm in diameter or the Pollutant Standards Index (the highest sub-index of the concentrations of 5 main air pollutants after transformation) and the development of adult AD. The adjusted odds ratios were 1.05 (95% confidence interval 1.02e1.08) and 1.02 (95% confidence interval 1.01e1.03), respectively. Conclusion: These results demonstrated that air pollution, represented by particulate matter <2.5 mm in diameter or the Pollutant Standards Index, was modestly associated with the development of AD in adults. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Reprints: Yi-Hsing Chen, MD, PhD, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Number 1650, Section 4, Taiwan Boulevard, Taichung, Taiwan 40705; E-mail: [email protected]. Professors Ching-Heng Lin, Ben-Jei Tsuang, and Yi-Hsing Chen equally supervised this work. Disclosures: Authors have nothing to disclose. Disclaimer: This study is based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Ministry of Health and Welfare and managed by the National Health Research Institutes (registered numbers 101095 and 102148). The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Ministry of Health and Welfare, or National Health Research Institutes. Funding Sources: This study was supported by a grant from the Taichung Veterans General Hospital Research Program (TCVGH-1053802B) and in part by grants from the Taichung Veterans General Hospital, Taiwan (TCVGH-NHRI10405, TCVGH1047324D, TCVGH-1047312C, TCVGH-104G211) and the National Science Council, Taiwan (MOST 103-2314-B-075A-006).
There is a trend toward an increased global prevalence of allergic diseases.1 It has been speculated that industrialization plays a role, based on studies indicating that air pollution contributes to the development of allergic diseases such as asthma and allergic rhinitis.2 Atopic dermatitis (AD) is a pruritic, eczematous, allergic skin disease with a chronic and relapsing course.3 It is a disease mostly of childhood and gradually resolves by adulthood. However, some patients with AD have the disease in adulthood,4 which leads to a compromised quality of life.5 An association between air pollution and childhood AD has been reported in several studies.6,7 However, there are sparse epidemiologic data on the relation between air pollution and AD in adults. Adults are presumed to be more likely to be exposed to air pollutants because of greater participation in outdoor activities. In addition, studies have found higher immunoglobulin E levels and
http://dx.doi.org/10.1016/j.anai.2016.12.005 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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more prevalent sensitization toward environmental allergens in adult than in pediatric patients with AD.8,9 In these patients with “extrinsic AD,” the skin barrier function is impaired compared with patients with intrinsic AD.10 These characteristics imply that adult patients with AD are more likely to be influenced by external factors. Therefore, we hypothesized that adult AD would be associated with air pollution, as is pediatric AD. Thus, we conducted a crosssectional study based on data from a nationwide health insurance database to explore the relation between exposure to air pollutants and the development of adult AD. Methods Patients This cross-sectional study was based on data acquired from the National Health Insurance Research Database (NHIRD),11 which contains comprehensive health care claims data from more than 99% of the entire Taiwanese population of 24 million. Diseases in the NHIRD are coded with International Classifications of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The data in the NHIRD are de-identified before analysis; therefore, the need for informed consent from subjects was waived. We identified 1,023 adult patients (20 years old) who were diagnosed with AD (ICD-9-CM code 691) in 3 consecutive outpatient visits by a dermatologist, an allergist, or a pediatrician or at 1 hospital admission in a random sample population of 1,000,000 patients in Taiwan from January 1 to December 31, 2011. Age- and sex-matched subjects without allergic diseases such as AD, allergic rhinitis (ICD-9-CM code 477), or asthma (ICD-9-CM code 493) were identified as controls at a 1:4 ratio. This study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the Taichung Veterans General Hospital (Taichung, Taiwan; TCVGH CE13152b-3). Levels of Exposure to Air Pollutants Complete data of the air pollutants SO2, NO2, O3, CO, particulate matter <2.5 mm in diameter (PM2.5), and particulate matter 10 mm in diameter (PM10) were available from 71 Environmental Protection Agency monitoring stations across Taiwan since 1994.12 Concentrations of each pollutant were measured continuouslydCO by nondispersive infrared absorption, NO2 by chemiluminescence, O3 by ultraviolet absorption, SO2 by ultraviolet fluorescence, and PM by beta-gauge. A sub-index was computed for each of the 5 pollutants (SO2, NO2, O3, CO, and PM10) based on a conversion of the pollutant’s ambient air concentrations to a scale from 0 through 500. Then, the highest sub-index value was taken as the Pollutant Standards Index (PSI).13 Then, we calculated the average concentrations of these air pollutants and the PSI in 368 townships in Taiwan using the analysis of Cressman.14 Data were absent for 36 (9.8%) townships because of a lack of relevant information. Levels of exposure to each air pollutant were determined by the location of a subject’s place of residence. Socioeconomic Parameters Urbanization of townships in Taiwan has been categorized into 7 levels based on variables such as population density, percentage of the population who had completed college, percentage of the population at least 65 years old, percentage of the population working in agriculture, and the number of physicians per 100,000 people.15 We combined the lowest 4 levels of urbanization into level 4 because of the small numbers of patients in these levels. Thus, level 1 represents the highest degree of urbanization and level 4 represents the lowest. The monthly income of each individual was estimated based on the National Health Insurance payroll brackets on which premiums were charged.
Table 1 Baseline Characteristics of Adults (20 Years Old) With AD and Age- and Sexmatched Controls Without Allergic Diseases in a Random Sample Population of 1,000,000 in Taiwan in 2011a Variable
Adults with AD (n ¼ 1,023)
Adults without allergic diseases (n ¼ 4,092)
Age (y) 20e34 35e49 50e64 65 Sex Women Men Level of urbanization 1 2 3 4 Family income (NTDs) 15,840 15,841e28,800 28,801e45,800 45,801 Level of exposure to air pollutants PM2.5 (mg/m3) PM10 (mg/m3) SO2 (ppb) NO2 (ppb) CO (ppm) O3 (ppb) PSIb
44.3 18.5 412 (40) 264 (26) 174 (17) 173 (17)
44.0 17.8 1,648 (40) 1,056 (26) 696 (17) 692 (17)
580 (57) 443 (43)
2,320 (57) 1,772 (43)
337 317 143 202
(34) (32) (14) (20)
1,220 1,258 726 802
(31) (31) (18) (20)
401 392 150 80
(39) (38) (15) (8)
1,601 1,758 482 251
(39) (43) (12) (6)
33.6 7.9c 56.3 13.9c 4.0 1.5 18.6 5.0 0.5 0.1 27.9 3.4 55.4 7.7c
32.3 7.4 54.5 13.1 3.9 1.4 18.7 5.2 0.5 0.1 27.8 3.3 54.4 7.5
Abbreviations: AD, atopic dermatitis; NTD, New Taiwan dollar (1 NTD ¼ 0.03 V on September 28, 2016); PM10, particulate matter 10 mm in diameter; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a Data are presented as mean SD or number (percentage). b The index considers 5 air pollutants: SO2, NO2, O3, CO, and PM10. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. c P < .005.
Statistics Statistical analysis was conducted using SAS 9.3 (SAS Institute, Cary, North Carolina). Unless specified otherwise, all quantitative data are presented as mean SD. Numerical variables were compared using the Student t test. Categorical variables were compared using the c2 test. Multivariate logistic regression analysis, adjusted for age, sex, levels of urbanization, family income, and levels of exposure to air pollutants, was performed. We also stratified patients according to age, sex, and levels of urbanization and performed multivariate logistic regression analyses for PM2.5 and the PSI. A 2-sided P value less than .005 was considered statistically significant. Results Baseline Characteristics of Adult Patients With AD and Controls Table 1 presents the baseline characteristics of adult patients with AD and matched controls. The mean age of adult patients with AD was 44 years and there was a slight female predominance (57%). Among air pollutants, levels of exposure to PM2.5 and PM10 and the PSI were higher in patients than in matched controls. Multivariate Logistic Regression Analysis of Factors Associated With Development of Adult AD The multivariate logistic regression analysis of factors associated with the development of adult AD is presented in Table 2. In model 1, which included levels of exposure to each air pollutant, level 3 urbanization and PM2.5 were associated with the development of adult AD. In model 2, which included the PSI instead of levels of
K.-T. Tang et al. / Ann Allergy Asthma Immunol xxx (2016) 1e5 Table 2 Multivariate Analysis of Associated Factors of Atopic Dermatitis in Adults in a Random Sample Population of 1,000,000 in Taiwan in 2011 Variable
Adjusted odds ratioa (95% CI) Model 1
Age (y) 20e34 35e49 50e64 65 Sex Female Male Level of urbanization 1 2 3 4 Family income (NTDs) 15,840 15,841e28,800 28,801e45,800 45,801 Level of exposure to air pollutants PM2.5 PM10 SO2 NO2 CO O3 PSIb
Model 2
1.00 0.96 (0.80e1.15) 0.96 (0.78e1.18) 0.98 (0.79e1.20)
1.00 0.97 (0.81e1.16) 0.96 (0.78e1.19) 0.99 (0.80e1.22)
1.00 1.00 (0.87e1.16)
1.00 1.00 (0.87e1.16)
1.00 0.77 (0.62e0.95) 0.58 (0.45e0.75)c 0.73 (0.54e0.99)
1.00 0.90 (0.75e1.08) 0.69 (0.55e0.86)c 0.89 (0.72e1.09)
1.00 0.88 (0.75e1.03) 1.29 (1.03e1.62) 1.31 (0.98e1.76)
1.00 0.88 (0.75e1.03) 1.27 (1.02e1.59) 1.30 (0.97e1.74)
1.05 0.98 1.07 0.98 0.78 1.01 NA
(1.02e1.08)c (0.97e1.00) (1.00e1.16) (0.93e1.02) (0.22e2.73) (0.97e1.05)
NA NA NA NA NA NA 102 (101e103)c
Abbreviations: CI, confidence interval; NA, not available; NTD, New Taiwan dollar (1 NTD ¼ 0.03 V on September 28, 2016); PM10, particulate matter 10 mm in diameter; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a Odds ratios were adjusted for all variables listed in the table. b The index considers 5 air pollutants: SO2, NO2, O3, CO, and PM10. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. c P < .005.
exposure to each air pollutant, the PSI was associated with the development of adult AD. Multivariate Logistic Regression Analysis of Factors Associated With Development of Adult AD After Stratification by Age, Sex, and Urbanization Table 3 presents the multivariate logistic regression analysis of factors associated with the development of adult AD after stratification by age, sex, and urbanization. PM2.5 was significantly associated with the development of AD in patients at least 50 years old, men, and those living in a residence with level 2 urbanization, whereas the PSI was significantly associated with the development of AD in patients 35 to 49 and at least 65 years old, men and those living in a residence with level 1 or 2 urbanization. Discussion This population-based cross-sectional study investigated the association between air pollution and the development of adult AD in Taiwan. There was a modest association between PM2.5 or the PSI and the development of adult AD, which was similar to previous findings in pediatric AD. The mean age of adult patients with AD in Taiwan was 44 years, which was comparable to that found in the US National Health and Wellness Survey in 2013.16 A slight female predominance was noted in adult patients with AD, although it was less pronounced than in previous studies.16,17 There was no difference in levels of urbanization or family income between adult patients with AD and matched controls. Although controversy remains, socioeconomic status has been associated with the development of allergic
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Table 3 Multivariate Analysis of Associated Factors of Atopic Dermatitis in Adults in a Random Sample Population of 1,000,000 in Taiwan in 2011 After Stratification by Age, Sex, and Levels of Urbanization Variable
Stratified by age (y) 20e34 35e49 50e64 65 Stratified by sex Female Male Stratified by level of urbanization 1 2 3 4
Adjusted odds ratio (95% CI) PM2.5
PSIa
1.01 1.06 1.11 1.09
0.99 1.05 1.03 1.04
(0.97e1.05) (1.00e1.12) (1.04e1.18)b (1.03e1.16)b
(0.98e1.01) (1.03e1.07)b (1.01e1.06) (1.01e1.06)b
1.04 (1.01e1.08) 1.06 (1.02e1.11)b
1.02 (1.01e1.03) 1.03 (1.01e1.04)b
0.96 1.11 1.03 1.03
1.05 1.03 0.99 1.01
(0.86e1.08) (1.06e1.16)b (0.96e1.10) (0.99e1.08)
(1.03e1.07)b (1.01e1.04)b (0.96e1.01) (0.99e1.03)
Abbreviations: CI, confidence interval; PM2.5, particulate matter <2.5 mm in diameter; PSI, Pollutant Standards Index. a The index considers 5 air pollutants: SO2, NO2, O3, CO, and particulate matter 10 mm in diameter. A sub-index value is computed for each pollutant based on the pollutant’s ambient air concentration. The highest sub-index value is taken as the PSI value. b P < .005.
diseases such as asthma and AD in children.18 Only 1 study investigated the relation between socioeconomic status and the development of AD in adults. The questionnaire study was conducted in southern Sweden and found that the highest prevalence of selfreported eczema was in those with a low socioeconomic status.19 However, the association did not reach statistical significance after controlling for age, sex, and occupational risk. Further study is needed to establish whether socioeconomic status is related to the development of AD in adults. Major air pollutants include particulates, SO2, NO2, O3, and CO, which are of concern for their impact on health and are designated as “criteria” air pollutants by the US Environmental Protection Agency.20 In children, many studies have shown the association between air pollution and the development or aggravation of AD.6,7,12,21,22 In a study of 4,907 French children, lifetime eczema was significantly associated with 3-year average concentrations of PM10, NO2, NOx, and CO in their residences (adjusted odds ratios [ORs] of 1.13, 1.23, 1.06, and 1.08, respectively).6 In 2 prospective birth cohorts in Munich, a total of 2,860 children were followed and the results showed that NO2 exposure was positively associated with physician-diagnosed eczema (OR 1.18).7 The US National Survey of Children’s Health included a representative sample of 91,642 children and moderate to severe eczema was associated with higher levels of NO3 (OR 1.25) and PM2.5 (OR 1.07).22 A nationwide survey of 317,926 middle school students in Taiwan demonstrated that flexural eczema was positively associated with exposure to traffic-related air pollutants, such as CO and NOx, but was negatively associated with PM10.12 Interestingly, exacerbation of AD symptoms was found to be correlated with the ambient concentrations of air pollutants.21 There are scanty data on the relation between air pollution and AD in adults. In a questionnaire study of 10,464 adults 20 to 44 years old in Italy, the prevalence of eczema was significantly associated with living close to industrial plants and with high levels of heavy traffic near the residence.23 Another questionnaire study in southern Sweden demonstrated that living in close proximity to heavy traffic was associated with eczema in 12,071 adults 20 to 59 years old.19 In our study, PM2.5 and the PSI were associated with the development of AD in adults, although the effect sizes were small. Our finding was similar to that reported in previous studies of children.6,7,12
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Particulates are a heterogeneous group of pollutants that are divided into 3 categories: ultrafine (<0.1 mm in diameter), fine (<2.5 mm in diameter; PM2.5), and coarse (2.5e10 mm in diameter; a component of PM10).20 PM2.5, mainly the byproduct of combustion, constitutes most of the total particulate matter in urban areas. Because of its deep penetration into the lower respiratory tract, PM2.5 is most strongly associated with human cardiopulmonary diseases and death.24 The size of the particulate also determines its skin penetration. Studies have found that microspheres smaller than 1.5 to 3 mm can better penetrate the skin through hair follicles or transepidermally.25,26 Therefore, the small size of PM2.5 allows it to easily penetrate the skin. Using a reconstructed human epidermis model, investigators reported that PM2.5 can penetrate the skin and induce an inflammatory response.27 Moreover, the small PM2.5, when inhaled, not only enters the lungs but also translocates across the aireblood barrier to the circulating blood, thereby affecting distant organs including the skin.28,29 These 2 mechanisms are potential explanations for our results in which PM2.5, but not PM10, was associated with the development of adult AD. After stratification, a positive correlation between levels of exposure to PM2.5 or the PSI and adult AD was found in men, older subjects, and subjects living with lower levels of urbanization. It is reasonable to postulate that men participate in outdoor activities more frequently than women; thus, the influence of outdoor air pollution can be presumed to be more prominent in men. The effects of older age and lower levels of urbanization are more difficult to explain within the scope of the present study. Probably the daily activities of older individuals mostly occur near their homes. Therefore, the levels of exposure to air pollutants, calculated based on the location of a subject’s residence, provided a more precise measurement in older individuals than in younger individuals who could spend a large part of their day away from home. Also, the calculation of levels of exposure to air pollutants based on air quality monitoring data was likely to be more accurate for a subject with a lower urbanization level, because there are many other sources of air pollutants in urban areas that were not comprehensively accounted for in our study. Our study had some strengths. First, this is the first study to directly evaluate the impact of exposure to air pollutants on adult AD. Second, the present study is a nationwide and populationbased investigation. Owing to the large scale of the study, it was possible to demonstrate the complex relation between environmental factors and disease. Third, the Environmental Protection Agency in Taiwan provides comprehensive and continuous monitoring data of air pollutants across the island. Because the concentration of air pollutants changes over time, average concentrations based on continuous monitoring provide a more reliable estimation of exposure. There are some limitations to this study. First, some adult patients with AD did not seek medical advice and therefore cases of AD might have been underdiagnosed in the NHIRD. However, those patients who did not seek medical help were presumed to have had milder disease severity. Indeed, patients with moderate to severe disease activity (ie, the cases identified in this study) are of greater clinical concern. In addition, the cases of AD in our study were diagnosed by a physician, so the diagnosis was more reliable compared with that in studies that included self-reported AD symptoms. Second, it was assumed that subjects spent most of their day at their respective residences. However, for some adults who work long hours in an industrial setting, the workplace is the main source of exposure to air pollutants. Furthermore, indoor air pollutants such as tobacco smoke contribute to the total exposure of air pollutants in an individual. These factors were not accounted for in our study and might have biased the results. However, most
individuals are at home for a considerable time every day. In addition, this measurement bias could not be totally eliminated because this was a population-based study. Therefore, our data still provide valuable insights into the relation between air pollutants and adult AD. Third, it was not possible to determine any causal relations in our analyses because of the cross-sectional design of the study. In conclusion, our results demonstrated that air pollution, represented by PM2.5 or the PSI, was modestly associated with the development of AD in adults.
Acknowledgments The authors thank the Healthcare Service Research Center of the Taichung Veterans General Hospital for statistical support.
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