BMJ Open. Risk Factors of Asthma Exacerbation Based on Asthma Severity: A Nationwide Population-based Observational Study in South Korea

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1 Risk Factors of Asthma Exacerbation Based on Asthma Severity: A Nationwide Population-based Observational Study in South Korea Journal: Manuscript ID bmjopen-0-00 Article Type: Research Date Submitted by the Author: -Nov-0 Complete List of Authors: Kang, Hye-Rim; Sungkyunkwan University, School of Pharmacy Song, Hyun Jin; University of Florida, College of Pharmacy Nam, Jin Hyun; Medical University of South Carolina Department of Public Health Sciences Hong, Sung-Hyun; Sungkyunkwan University, School of Pharmacy Yang, So-Young; Sungkyunkwan University, School of Pharmacy Ju, SangEun; Sungkyunkwan University, School of Pharmacy Lee, Sang Won; Sungkyunkwan University, School of Pharmacy Kim, Tae-Bum; Asan Medical Center, Department of Allergy and Clinical Immunology Lee, Eui-Kyung; Sungkyunkwan University, School of Pharmacy <b>primary Subject Heading</b>: Respiratory medicine Secondary Subject Heading: Medical management Keywords: Asthma < THORACIC MEDICINE, Exacerbation, Disease severity, Risk factors : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

2 Page of Risk Factors of Asthma Exacerbation Based on Asthma Severity: A Nationwide Population-based Observational Study in South Korea Hye-Rim Kang PharmD, Hyun Jin Song MPharm, PhD, Jin Hyun Nam Senior Research Associate, PhD, Sung-Hyun Hong PharmD, So-Young Yang PharmD, SangEun Ju MBA, Sang Won Lee PhD, Tae-Bum Kim MD, PhD, Eui-Kyung Lee PhD* School of Pharmacy, Sungkyunkwan University, Suwon, Korea College of Pharmacy, University of Florida, Gainesville, Florida, USA Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Corresponding author: Eui-Kyung Lee, PhD Tel.: + -0-, Fax: + --, ekyung@skku.edu Word count, abstract: Word count, text:, - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

3 Page of ABSTRACT Objectives: Asthma exacerbation can reflect management failure, and many risk factors are associated with exacerbation. However, little is known about how each risk factor is associated with exacerbation, based on asthma severity. We identified differences in risk factors according to asthma severity in adult patients. Design: Nationwide population-based observational study. Setting: Korean National Sample Cohort database. Participants: This study included,0 adult asthma patients with at least asthma diagnoses and at least prescription for asthma medication from 00 to 0. Outcome measures: Asthma exacerbation was defined as a prescription for days of oral corticosteroid (CS) or systemic CS injection during asthma-related outpatient visits, hospitalizations, or emergency department visits. Results: In mild and moderate asthma, exacerbation was significantly associated with being female, comorbidities, and history of exacerbations, while the associations of these risk factors were statistically insignificant in severe asthma. However, compared to low medication possession ratio (MPR, < 0%), high MPR ( 0%) showed significant association with exacerbation in moderate and severe asthma, showing adjusted odds ratios of 0. (% confidence interval 0.-0.) and 0. (0.-0.), respectively. In addition, comparing patients experiencing frequent exacerbations to those with only exacerbation in a -year period revealed that old age and comorbidities including atopic dermatitis and anxiety were significant risk factors in mild and moderate asthma, whereas no significant risk factors were identified in severe asthma. Conclusions: Different associations between risk factors and asthma exacerbations based on - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

4 Page of severity suggest that patients with mild asthma require greater attention to comorbidities and exacerbation history, whereas those with severe asthma require greater attention to adherence and management of disease severity. Proper management of relevant risk factors based on severity is required to manage asthma and prevent future exacerbations. Keywords: Asthma, Exacerbation, Risk factors, Disease severity Strengths and limitations of this study This is the first study to identify differences in risk factors of asthma exacerbation according to asthma severity. This is a nationwide population-based observational study that included representative South Korean population of approximately million people between 00 and 0. Our study is subject to potential for inaccuracy of coding and incompleteness of records in claims data - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

5 Page of INTRODUCTION Asthma affects an estimated million people worldwide and contributes to substantial health and economic burdens., As asthma control, being one of the most feasible and effective therapeutic strategies, becomes more important, its evidence base becomes well established, and much of it can be delivered at a primary care level., However, although asthma management has focused on achieving clinical control and reducing the future risk of exacerbations, some countries, including Korea, the United States, and the Slovak Republic, reported hospital admission rates greater than twice the Organization for Economic Cooperation and Development (OECD) average, indicating a failure of preventive care in established asthma cases., To establish and implement an asthma control strategy, it is important to evaluate the risk factors of poor control and frequent exacerbation. Guidelines for the management of asthma recommend that clinicians evaluate patients for a history of asthma exacerbations and the presence of chronic comorbid conditions, as treating those conditions may improve asthma management., Periodic assessments of asthma severity and control are recommended because they include the extent of current impairment and future risk of asthma exacerbations. Previous studies have reported that adherence to medication should be monitored to achieve asthma control. - However, little is known about differences in the risk factors of exacerbation of asthma with different severities, although a cross-sectional study reported that asthma-related health care utilization and direct costs increased depending on the severity. In addition, while mild asthma is predominant in clinical settings and may be accompanied by chronic conditions, previous studies included cases of severe or,, persistent asthma, resulting in limited interpretations of these studies. The purposes of this study were to investigate differences in the risk factors associated with asthma exacerbation in patients with different severities of asthma and to - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

6 Page of evaluate whether the risk factors of patients who developed a single asthma exacerbation differed from those of patients who had frequent exacerbations, providing more comprehensive information that can contribute to evidence-based guidelines to clinicians and professional organizations. SUBJECTS AND METHODS Database This study used the National Sample Cohort data from the National Health Insurance Service (NHIS-NSC) in South Korea. South Korea has a compulsory universal health insurance system that includes medical reimbursement records for the entire Korean population. The NHIS uses a systematic sampling approach to randomly select a representative database of approximately million people from 00 to 0, % of total Korean population. These data are -year cohort data and include age, sex, socioeconomic variables such as the income rank and disability, diagnoses, details of medical treatment, and health examinations. Study design We conducted an observational study to assess the risk factors of asthma exacerbation. For patients satisfying the inclusion criteria, the index date was defined as the date of the first asthma diagnosis between January, 00 and December, 0, which was considered the index period. We defined the first year after the index date as the premeasurement period and the next year as the measurement period (Figure ). The risk factors of the study subjects, with the exception of adherence to medication, were assessed in the premeasurement period. Adherence to medication was assessed in the measurement - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

7 Page of period to account for cases where the time gap between the premeasurement period and the exacerbation was too long for the adherence to be reflected in the exacerbation. This study was approved by the institutional review board of Sungkyunkwan University in South Korea (SKKU-IRB ). All personal identifying information of the included patients was anonymous; therefore, informed consent for this study was waived by the institutional review board. Selection of study subjects Patients were included in this study if they: () received at least diagnoses of asthma as a principal or secondary diagnosis coded according to the International Classification of Disease, Tenth Revision (ICD-0 codes J and J) during the index period; () had at least prescription for of the following asthma medications during the index period: inhaled corticosteroids (ICSs), inhaled long-acting ß-agonists (LABAs), an ICS and a LABA combined in a single inhaler (ICS/LABA), inhaled short-acting ß-agonists (SABAs), oral leukotriene antagonists, xanthine derivatives, mast cell stabilizers, and systemic corticosteroids (CSs); () were 0 years of age. The Global Initiatives for Asthma (GINA) suggests a stepwise approach to asthma management depending on age: children aged years, children aged - years, adolescents, and adults. In NHIS-NSC data, age is presented in the intervals of years; we included only patients aged 0 years. Patients without any claims during the years after the index date were excluded because the risk factors and asthma exacerbation could not be assessed. A study flow chart is presented in Figure. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

8 Page of Assessment of asthma severity level Asthma severity level was assessed on the basis of the patient s medication use as recommended by GINA. According to the guideline, mild asthma is well controlled with lowdose ICS, while moderate asthma is controlled by low-dose ICS/LABA. Severe asthma requires high-dose ICS/LABA, and low-dose OCS can be added as a controller. However, there is a limitation in clearly distinguishing whether the recorded dosage of ICS/LABA is low- or high-dose in NHIS-NSC. As the prescription unit is recorded as a canister or tablet, it is difficult to determine the actual prescribed dose of ICS/LABA. Therefore, in our study, the asthma severity was operationalized on the basis of the definition of severity by the GINA guideline and a previous study that analyzed claims data with its definition of asthma severity. Three mutually exclusive severity levels were defined according to patient s prescribed medication during the premeasurement period. Patient was defined as level (severe) if prescribed with an ICS/LABA single inhaler of various intensity (from low- to high-dose) and received at least one prescription of low-dose oral CSs (OCSs) for at least weeks. A low-dose OCS was defined as a prednisolone equivalent of. mg/day. The patient who was prescribed with a low- or high-dose ICS/LABA single inhaler but was not prescribed with a low-dose OCS was defined as level (moderate). The patient was defined as level (mild) if prescribed with at least one asthma medication, with the exception of an ICS/LABA single inhaler and a low-dose OCS. Risk factor measures In previous studies, age, sex, and the presence of a history of exacerbation were,, reported to be associated with asthma-related healthcare utilization. Various comorbidities including gastroesophageal reflux disease (GERD), rhinitis, sinusitis, chronic - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

9 Page of obstructive pulmonary disease (COPD), atopic dermatitis, and psychiatric disorders, particularly anxiety and depression, were reported in patients with asthma and may affect asthma control and outcomes., - To assess the association between these risk factors and asthma exacerbation, we evaluated each risk factor in the premeasurement period. The comorbidities were identified using ICD-0 codes, as follows: GERD (K), rhinitis (J0 and J), chronic sinusitis (J), COPD (J and J), atopic dermatitis (L0), depression (F and F), and anxiety (F0 and F). Good adherence to medication tended to be associated with a lower risk of asthma exacerbations. 0, We evaluated the medication possession ratio (MPR) as a measure of adherence, which was the number of days of medication supplied divided by the number of days between the first and the last refill. The MPR was calculated for the period from the beginning of the measurement period to the day before the first exacerbation to reflect adherence just before the asthma exacerbation. If the days of supply exceeded, the total number of covered days was considered to be. Based on a previous study, the MPR was divided into low, medium, and high categories; low adherence was defined as < 0% adherent; medium adherence as 0-% adherent; and high adherence as 0% adherent. Outcome measures The primary outcome was asthma exacerbation during the measurement period. Based on previous studies,, an asthma exacerbation was defined as the occurrence of at least of of the following events: outpatient visits, hospitalizations, or emergency department (ED) visits with asthma diagnoses. A CS burst was defined as receiving a prescription for an OCS of at least days or systemic CS injection, and a CS burst through an outpatient visit was considered to be an asthma-related outpatient visit. Similarly, an - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

10 Page of asthma-related ED visit or hospitalization was defined as a claim of the patient s ED visit or hospitalization with a CS burst. Statistical analysis In this analysis, we classified patients into mutually exclusive groups based on the asthma severity level (,, or ) in the premeasurement period. First, we examined and compared the risk factors among asthma severity groups using the chi-square test. Second, to estimate the association between the risk factors and asthma exacerbations, we constructed multivariable logistic regression model and reported adjusted odds ratios (ORs) with % confidence intervals (CIs). Additionally, we performed a subgroup analysis to examine the risk factors of a higher frequency of exacerbation. In each asthma severity group, risk factors for patients with or more exacerbations were evaluated; patients with only exacerbation were used as the reference, and patients with no exacerbations were excluded. All tests were -sided, with a significance level of 0.0. All data transformations and statistical analyses were conducted using SAS version. for Windows (SAS Institute, Cary, NC, USA). RESULTS Patient characteristics according to asthma severity Of the,0 adult patients with asthma included in this study,.% (,),.% (,), and.% () of patients were classified with a severity of level, level, and level, respectively. Patient demographics, comorbidities, history of exacerbation, and MPR differed among the severity groups (Table ). The proportion of patients years of age increased with increasing asthma severity, while the proportion of patients 0- years of age decreased. There was a slight predominance of female patients across all severity levels. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

11 Page 0 of Patients with a higher severity level were more likely to have comorbidities including GERD (p < 0.000), chronic sinusitis (p < 0.000), COPD (p < 0.000), depression (p < 0.000), atopic dermatitis (p = 0.0), and anxiety (p = 0.000). In particular, COPD was times as frequent among level patients compared to level patients (0.00% vs..%), and depression was twice as frequent among level patients as level patients (.% vs..%). Similarly, patients with increased severity were more likely to have a history of each type of exacerbation in the premeasurement period, including outpatient visits, ED visits, and hospitalization (all, p < 0.000). For example,.% (/,) of level patients had a history of hospitalization in the premeasurement period, compared to.% (/,) of level and.% (/) of level patients in the same period. The overall MPR during the measurement period was low:.% of all patients had an MPR of < 0%. More than 0% (,/,) of level patients had a low MPR (< 0%), while > % of level (,/,) and level (/) patients had a high MPR ( 0%). Risk factors associated with asthma exacerbation according to severity In the multivariable logistic regression model, old age remained a significant risk factor of asthma exacerbation across all severity groups (Table ). In particular, when compared to level patients aged 0-, the adjusted OR was. (% CI:.-.) in patients aged - and.0 (% CI:.-.) in patients aged. Female sex was a significant risk factor in patients with a severity of level or, but not level. Asthma exacerbations were associated with comorbidities including GERD, rhinitis, chronic sinusitis, COPD, atopic dermatitis, and anxiety in level patients. However, as the severity increased, the association of asthma exacerbation with comorbidities became insignificant, and no significant association was found between asthma exacerbation and comorbidities in level : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

12 Page of patients. Similarly, a history of asthma exacerbations was not significantly associated with asthma exacerbations in level patients, unlike in level. The MPR was not significantly associated with asthma exacerbation in level patients. However, an MPR of 0% was associated with a decrease in asthma exacerbation, showing adjusted ORs of 0. (% CI: 0.-0.) and 0. (% CI: 0.-0.) in level and level patients, respectively. Risk factors associated with frequent asthma exacerbation according to severity The subgroup analysis of risk factors associated with frequent asthma exacerbation included,,,, and 0 patients of severity levels,, and, respectively, with at least exacerbation in the measurement period (Table ). Old age, atopic dermatitis, anxiety, and a history of outpatient visits were significantly associated with a higher frequency of asthma exacerbation in level and level patients. Similar to the results in Table, an MPR of > 0% was associated with less frequent asthma exacerbation in level patients. However, in level patients, no risk factors showed any significant association with frequent asthma exacerbation. DISCUSSION This study found that the association between each risk factor and asthma exacerbation differed according to severity. The risk of exacerbation was found to be more strongly associated with old age in patients with severe asthma than with mild or moderate asthma. An MPR of > 0% was associated with a decrease in asthma exacerbation in patients with moderate or severe asthma. However, comorbidities including GERD, rhinitis, chronic sinusitis, COPD, atopic dermatitis, and anxiety were associated with asthma exacerbation in patients with mild or moderate asthma, while none showed a significant association with - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

13 Page of exacerbation in patients with severe asthma. Likewise, a history of exacerbation was a risk factor for future asthma exacerbation only in patients with mild or moderate asthma. We also found that frequent exacerbations were associated with these risk factors in patients with mild asthma; in contrast, no risk factors were found to be associated with frequent exacerbations in patients with severe asthma. A previous observational study of the utilization and costs of severe uncontrolled asthma (SUA) reported that age, sex, comorbidities, and a history of exacerbation were associated with asthma utilization in SUA compared to non-sua. However, the research only included patients with persistent asthma, and the definition used for persistent asthma could be inconsistent with persistent asthma in a clinical setting., A descriptive study of asthmarelated health care utilization and direct costs in Korea included patients with varying severities of asthma. However, due to a cross-sectional design with only year of data, the study did not have follow-up period long enough to observe a time-dependent relationship between asthma severity and asthma exacerbation, and could not account for the risk factors of asthma exacerbation. A previous study analyzing the risk factors of asthma-related healthcare use found that old age, being female, chronic asthma, medication compliance, and a history of asthma exacerbation were independent risk factors for increased asthma-related healthcare use. However, the study did not have sufficient statistical power to represent the general adult patient population with asthma. Most previous studies reported an association between each risk factor and asthma exacerbation, 0-, - but no previous observational studies have been performed to comprehensively investigate all of the risk factors included in our study. To our knowledge, this is the first population-based observational study focusing on the difference in association between risk factors and asthma exacerbation according to - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

14 Page of severity. In agreement with previous studies,, we found that a history of exacerbation and comorbidities including GERD, rhinitis, sinusitis, COPD, atopic dermatitis, depression, and anxiety were more prevalent in severe asthma. In addition, the present study showed that being female, having GERD, rhinitis, chronic sinusitis, COPD, atopic dermatitis, anxiety, and a history of exacerbation were independent risk factors of asthma exacerbation in patients with mild or moderate asthma. However, our analysis revealed that patients with severe asthma evidenced statistically less relevant sex, comorbidities, and a history of exacerbation compared to those with mild or moderate asthma, suggesting that patients with severe asthma were more likely to experience exacerbations due to severe asthma alone, while patients with mild or moderate asthma were likely to experience exacerbations due to those risk factors. In addition, high adherence was associated with a decrease in asthma exacerbation in patients with moderate or severe asthma, but not in those with mild asthma, indicating that as severity increased, low adherence became an important risk factor of asthma exacerbation. Considering that more than half of patients with moderate or severe asthma reported an MPR of < 0%, the current management of adherence to asthma medication in Korea was suboptimal. In fact, a previous study reported that the average adherence to asthma medication was 0-0%. Another finding of this study was that risk factors for frequent exacerbation were different according to asthma severity. A previous study reported that severe sinus disease, GERD, and psychological dysfunction were associated with frequent asthma exacerbation in severe asthma, although the interpretation and application of the study results were limited due to the small sample size. Two observational studies reported risk factors associated with frequent emergency department visits, but the effect of each risk factor based on asthma severity was unknown., However, our analysis found that the risk factors were associated with frequent exacerbation in patients with mild or moderate asthma, but not severe asthma. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

15 Page of This supports the importance of managing risk factors in patients with mild or moderate asthma, whereas the asthma severity itself might be an important factor for frequent asthma exacerbation compared to other risk factors in patients with severe asthma. Our study had several strengths. First, use of the national sample cohort database can yield more representative results and overcome the limitations of previous studies that recruited a small number of patients only from tertiary hospitals., Second, we analyzed the risk factors of asthma exacerbation according to asthma severity. Our segmented results suggested that even though a lower proportion of patients with mild or moderate asthma had comorbidities or a history of exacerbation compared to patients with severe asthma, the association between those risk factors and asthma exacerbation should not be overlooked in patients with mild or moderate. Third, the association between adherence to asthma medication and the risk of exacerbation reported in previous studies was inconsistent. Some studies have shown that better adherence was associated with a reduced risk of asthma exacerbation., In contrast, other studies reported that the risk of OCS use, hospitalization, or ED visits increased with better adherence., Our study demonstrated that there were different associations between adherence to asthma medication and reduced risk of asthma exacerbation according to asthma severity, thus providing a basis for the importance of the management of adherence with increasing asthma severity. Some potential limitations should be considered when interpreting our findings. First, as the measurements of comorbidities and exacerbations were based on the diagnoses in claims data, there is the potential for inaccuracies in coding and incompleteness of records. However, a validation study comparing the diagnosis derived from the database with the actual diagnosis in patients medical records in Korea found that the overall positive predictive value of the diagnoses was.%. 0 Second, although the methodology and - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

16 Page of statistical analysis for this study included proxy measures of asthma severity and adherence, residual confounding may still exist due to the observational nature of this study. That is, several variables that could affect the observed outcomes were not fully captured in the database, including spirometry data, education, socioeconomic factors, and the proper use, including adequate inhaler technique, of controller or reliever medication. CONCLUSIONS This study suggests that there were different associations between asthma exacerbation and the individual risk factors of age, sex, comorbidities, history of exacerbation, and adherence according to asthma severity. In patients with mild to moderate asthma, the management of the future risk of exacerbation should consider the history of exacerbation and comorbidities such as GERD, rhinitis, sinusitis, atopic dermatitis, and mood disorders. In contrast, with increasing asthma severity, the risk of exacerbation should be carefully managed by considering adherence to medication. Given the struggle clinicians have had to manage asthma and prevent exacerbations, professional organizations must address the relevant risk factors and intensify evidence-based guidelines. Contributors: HK contributed to the study concept, design, analysis, and interpretation of the data, and the drafting of the manuscript. HS, SH, and TK contributed to the study concept and design. HK and JN contributed to data acquisition and statistical analysis. SY, SJ and SL contributed to the interpretation of the data. EL contributed to the study concept and design, data interpretation, and critical revision of the manuscript for important intellectual content. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

17 Page of Funding: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), which was funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HCC). Competing interests: This study used National Health Insurance Service data (NHIS-0- -) from the NHIS. The authors declare no conflict of interest with the NHIS. Ethical approval: This study was approved by the institutional review board of Sungkyunkwan University in South Korea (SKKU-IRB ). All personal identifying information for patients was anonymous; therefore, informed consent for this study was waived by the institutional review board. Data sharing statement: No additional data available. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

18 Page of Table. Patient demographics, comorbidities, history of exacerbation, and medication possession ratio according to asthma severity Variable* Total (n =,0) Level (n =,) Level (n =,) Level (n = ) Total number of patients,0, (.), (.) (.) Age group Sex 0-,0 (.0),0 (.), (.0) (.) -, (.), (.0), (.0) (.),0 (.),0 (.), (.) (.) P-value < Female, (.), (.), (.) (.) < Comorbidities GERD,0 (.), (.0), (.0) (.) < Rhinitis 0, (.), (.0),0 (.0) (.) 0. Chronic sinusitis, (.), (.) 0 (.) (.) < COPD, (.), (.),0 (.) (0.00) < Atopic dermatitis,0 (.0) (.) (.) (.) 0.00 Depression,00 (.0), (.) 0 (.) (.) < Anxiety,0 (.),0 (.) (.) (.0) History of exacerbation Any exacerbation, (.), (.), (.) (00) < Outpatient visits, (.), (.), (0.0) (.) < ED visits (.) 0 (0.) 0 (.) (.0) < Hospitalizations, (.) (.) (.) (.) < Medication possession ratio (MPR) MPR < 0%, (.), (0.), (.) 0 (.) 0% MPR < 0%, (.) (.) (0.) (.) MPR 0%,0 (.), (.0), (.) (.) < Abbreviations: GERD; gastroesophageal reflux disease, COPD; chronic obstructive pulmonary disease; ED, emergency department *Data are expressed as number (%) unless otherwise specified. The p-value was calculated using the chi-square test for categorical variables. Patients overlapped in each category. The MPR was calculated in the measurement period, whereas age group, sex, comorbidities, and history of exacerbation were evaluated in the premeasurement period. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

19 Page of Table. Multivariable logistic regression model of risk factors associated with asthma exacerbation according to asthma severity Variable Age group Sex Level (n =,) Level (n =,) Level (n = ) Adjusted Odds Ratio % CI P-value Adjusted Odds Ratio % CI P-value Adjusted Odds Ratio 0- reference reference reference % CI P-value < < < Female Comorbidities (presence) GERD..-. < Rhinitis..-. < < Chronic sinusitis COPD Atopic dermatitis Depression Anxiety History of exacerbation (presence) Outpatient visits.0.-. < < ED visits Hospitalizations Medication possession ratio (MPR)* MPR < 0% reference reference reference 0% MPR < 0% < MPR 0% < Abbreviations: CI, confidence interval; GERD; gastroesophageal reflux disease, COPD; chronic obstructive pulmonary disease; ED, emergency department Bold results are statistically significant. *The MPR was calculated in the measurement period, whereas age group, sex, comorbidities, and history of exacerbation were evaluated in the premeasurement period. on March 0 by guest. Protected by copyright. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from

20 Page of Table. Multivariable logistic regression model of risk factors associated with frequent asthma exacerbations ( vs. exacerbation) according to asthma severity Variable Age group Sex Level (n =,) Level (n =,) Level (n = 0) Adjusted Odds Ratio % CI P-value Adjusted Odds Ratio % CI P-value Adjusted Odds Ratio 0- reference reference reference % CI P-value < < < Female Comorbidities (presence) GERD Rhinitis Chronic sinusitis COPD Atopic dermatitis Depression Anxiety History of exacerbation (presence) Outpatient visits..-. < < < 0.00 < 0.00->. 0. ED visits Hospitalizations Medication possession ratio (MPR)* MPR < 0% reference reference reference 0% MPR < 0% < MPR 0% < Abbreviations: CI, confidence interval; GERD; gastroesophageal reflux disease, COPD; chronic obstructive pulmonary disease; ED, emergency department Bold results are statistically significant. *The MPR was calculated in the measurement period, whereas age group, sex, comorbidities, and history of exacerbation were evaluated in the premeasurement period. on March 0 by guest. Protected by copyright. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from

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22 Page of Antó JM, Sunyer J, Basagaña X, et al. Risk factors of new-onset asthma in adults: a population-based international cohort study. Allergy 00;():0 0. doi:0./j x 0. Ahmedani BK, Peterson EL, Wells KE, et al. Examining the relationship between depression and asthma exacerbations in a prospective follow-up study. Psychosom Med 0;():0 0. doi:0.0/psy.0b0eee. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respir Med 00;(0):. doi:0.0/j.rmed Bousquet J, Schunemann HJ, Samolinski B, et al. Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 0 years and future needs. J Allergy Clin Immunol 0;0():0-. doi:0.0/j.jaci Herndon JB, Mattke S, Evans Cuellar A, et al. Anti-inflammatory medication adherence, healthcare utilization and expenditures among Medicaid and children's health insurance program enrollees with asthma. PharmacoEconomics 0;0():. doi:0./ Martin BC, Wiley-Exley EK, Richards S, et al. Contrasting measures of adherence with simple drug use, medication switching, and therapeutic duplication. Ann Pharmacother 00;():. doi:0./aph.k. Reddel HK, Barnes DJ. Pharmacological strategies for self-management of asthma exacerbations. Eur Respir J 00;():. doi:0./ Fuhlbrigge A, Peden D, Apter AJ, et al. Asthma outcomes: Exacerbations. J Allergy Clin Immunol 0;(, Supplement):S-S. doi: Mosen DM, Macy E, Schatz M, et al. How well do the HEDIS asthma inclusion criteria identify persistent asthma? Am J Manag Care 00;(0):0.. Littner MR, Leung FW, Ballard ED, nd, et al. Effects of weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 00;():. doi:0./chest.... Lotvall J, Ekerljung L, Lundback B. Multi-symptom asthma is closely related to nasal blockage, rhinorrhea and symptoms of chronic rhinosinusitis-evidence from the West Sweden Asthma Study. Respir Res 00;:. doi:0./ Lee JH, Haselkorn T, Borish L, et al. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest 00;():-. doi:0./chest.0 0. Watase H, Hagiwara Y, Chiba T, et al. Multicentre observational study of adults with asthma exacerbations: who are the frequent users of the emergency department in Japan? 0;():e00. doi:0./bmjopen Vennera Mdel C, Picado C, Herraez L, et al. Factors associated with severe uncontrolled asthma and the perception of control by physicians and patients. Arch Bronconeumol 0;0():. doi:0.0/j.arbres Bender B, Milgrom H, Rand C. Nonadherence in asthmatic patients: is there a solution to the problem? Ann Allergy Asthma Immunol ;(): ; quiz -. doi:0.0/s0-0(0)00-. ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 00;():. doi:0./ Hasegawa K, Sullivan AF, Tovar Hirashima E, et al. A multicenter observational study of - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

23 Page of US adults with acute asthma: who are the frequent users of the emergency department? J Allergy Clin Immunol 0;(): 0. doi:0.0/j.jaip Williams LK, Peterson EL, Wells K, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol 0;():.e. doi:0.0/j.jaci Stern L, Berman J, Lumry W, et al. Medication compliance and disease exacerbation in patients with asthma: a retrospective study of managed care data. Ann Allergy Asthma Immunol 00;():0. doi:0.0/s0-0(0)00-. Smith K, Warholak T, Armstrong E, et al. Evaluation of risk factors and health outcomes among persons with asthma. J Asthma 00;():. doi:0.00/ McMahon AD, Lipworth BJ, Davey PG, et al. Continuity of prescribing with inhaled corticosteroids and control of asthma. Pharmacoepidemiol Drug Saf 000;(): 0. doi:0.00/0-(0000/0):<::aid-pds0>.0.co;-s 0. Park B, Sung J, Park K, et al. Report of the evaluation for validity of discharged diagnoses in Korean Health Insurance database. Seoul: Seoul National University 00:. - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

24 Page of Figure. Observational study design The index date was defined as the date within the index period when the patient was diagnosed with asthma for the first time. The -year period from the index date was defined as the premeasurement period, in which asthma severity and risk factors except the medication possession ratio (MPR) were measured. The following -year period was defined as the measurement period, in which the MPR and the outcome of this study, asthma exacerbation, were measured. Figure. Study flow chart - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

25 Page of Figure. Observational study design The index date was defined as the date within the index period when the patient was diagnosed with asthma for the first time. The -year period from the index date was defined as the premeasurement period, in which asthma severity and risk factors except the medication possession ratio (MPR) were measured. The following -year period was defined as the measurement period, in which the MPR and the outcome of this study, asthma exacerbation, were measured. x0mm (00 x 00 DPI) - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

26 Page of Figure. Study flow chart 00x00mm (00 x 00 DPI) - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

27 Page of STROBE Statement checklist of items that should be included in reports of observational studies Item No Recommendation Title and abstract (a) Indicate the study s design with a commonly used term in the title or the abstract Introduction [Within the title page and design section of the abstract page ] (b) Provide in the abstract an informative and balanced summary of what was done and what was found [Results section of abstract page ] Background/rationale Explain the scientific background and rationale for the investigation being reported [page ] Objectives State specific objectives, including any prespecified hypotheses [page -] Methods Study design Present key elements of study design early in the paper [page -] Setting Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection [page ] Participants (a) Cohort study Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up [page ] Case-control study Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study For matched studies, give matching criteria and number of exposed and unexposed [N/A] Case-control study For matched studies, give matching criteria and the number of controls per case Variables Clearly define all outcomes, exposures, predictors, potential confounders, and effect Data sources/ measurement modifiers. Give diagnostic criteria, if applicable [page -] * For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group [page -] Bias Describe any efforts to address potential sources of bias [N/A] Study size 0 Explain how the study size was arrived at [page ] Quantitative variables Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why [page -] Statistical methods (a) Describe all statistical methods, including those used to control for confounding Continued on next page [page ] (b) Describe any methods used to examine subgroups and interactions [page ] (c) Explain how missing data were addressed [N/A] (d) Cohort study If applicable, explain how loss to follow-up was addressed [N/A] Case-control study If applicable, explain how matching of cases and controls was addressed Cross-sectional study If applicable, describe analytical methods taking account of sampling strategy (e) Describe any sensitivity analyses [N/A] - : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.

28 Page of Results Participants * (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed [figure ] (b) Give reasons for non-participation at each stage [figure ] (c) Consider use of a flow diagram [figure ] Descriptive data * (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders [page -0 and table ] (b) Indicate number of participants with missing data for each variable of interest [N/A] (c) Cohort study Summarise follow-up time (eg, average and total amount) [N/A] Outcome data * Cohort study Report numbers of outcome events or summary measures over time [N/A] Case-control study Report numbers in each exposure category, or summary measures of exposure Cross-sectional study Report numbers of outcome events or summary measures Main results (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, % confidence interval). Make clear which confounders were adjusted for and why they were included [table and table ] (b) Report category boundaries when continuous variables were categorized [table and table ] (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period [N/A] Other analyses Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses [table ] Discussion Key results Summarise key results with reference to study objectives [page -] Limitations Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias [page -] Interpretation 0 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence [page -] Generalisability Discuss the generalisability (external validity) of the study results [page ] Other information Funding Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based [page ] *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at Annals of Internal Medicine at and Epidemiology at Information on the STROBE Initiative is available at : first published as 0./bmjopen-0-00 on March 0. Downloaded from on March 0 by guest. Protected by copyright.