Clinical predictors of treatment response to tiotropium add-on therapy in adult asthmatic patients: From multicenter real-world cohort data in Korea.

Background: Tiotropium, a long-acting muscarinic antagonist, is recommended for add-on therapy to inhaled corticosteroids (ICS)-long-acting beta 2 agonists (LABA) for severe asthma. However, real-world studies on the predictors of response to tiotropium are limited. We investigated the real-world use of tiotropium in asthmatic adult patients in Korea and we identified predictors of positive response to tiotropium add-on. Methods: We performed a multicenter, retrospective, cohort study using data from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA). We enrolled asthmatic participants who took ICS-LABA with at least 2 consecutive lung function tests at 3-month intervals. We compared tiotropium users and non-users, as well as tiotropium responders and non-responders to predict positive responses to tiotropium, defined as 1) increase in forced expiratory volume in 1 s (FEV1) ≥ 10% or 100 mL; and 2) increase in asthma control test (ACT) score ≥3 after 3 months of treatment. Results: The study included 413 tiotropium users and 1756 tiotropium non-users. Tiotropium users had low baseline lung function and high exacerbation rate, suggesting more severe asthma. Clinical predictors for positive response to tiotropium add-on were 1) positive bronchodilator response (BDR) [odds ratio (OR) = 6.8, 95% confidence interval (CI): 1.6-47.4, P = 0.021] for FEV1 responders; 2) doctor-diagnosed asthma-chronic obstructive pulmonary disease overlap (ACO) [OR = 12.6, 95% CI: 1.8-161.5, P = 0.024], and 3) initial ACT score <20 [OR = 24.1, 95% CI: 5.45-158.8, P < 0.001] for ACT responders. FEV1 responders also showed a longer exacerbation-free period than those with no FEV1 increase (P = 0.014), yielding a hazard ratio for the first asthma exacerbation of 0.5 (95% CI: 0.3-0.9, P = 0.016). Conclusions: The results of this study suggest that tiotropium add-on for uncontrolled asthma with ICS-LABA would be more effective in patients with positive BDR or ACO. Additionally, an increase in FEV1 following tiotropium may predict a lower risk of asthma exacerbation.

Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells.

Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1ß, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.

Acute exacerbation of COPD increases the risk of hip fractures: a nested case-control study from the Korea National Health Insurance Service.

BACKGROUND/AIMS: Hip fracture and acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) could increase mortality in patients with COPD. There are no data on the relationship between AE-COPD and hip fracture, which may significantly affect the prognosis of patients with COPD. Therefore, we conducted this study to determine the effects of AE-COPD on hip fractures in patients with COPD. METHODS: This retrospective, nested, case-control study included 253,471 patients with COPD (≥ 40 years of age) identified from the Korea National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) from 2002 to 2015. Among 176,598 patients with COPD, 1,415 patients with hip fractures were identified. Each case was matched to one control for age (within 10 years), sex, and year of COPD diagnosis. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for hip fractures associated with AE-COPD using conditional logistic regression analysis, adjusting for underlying diseases and smoking history. RESULTS: In patients with AE-COPD, the risk of hip fracture was 2.50 times higher, regardless of systemic corticosteroid use and underlying disease (aOR, 2.50; 95% CI, 1.67 to 3.75). The risk of hip fracture increased if there was one episode of AE in the year before hip fractures (aOR, 2.25; 95% CI, 1.66 to 3.05). Moreover, the risk of hip fracture also increased in patients with more than two episodes of AE the year before hip fractures (aOR, 2.57; 95% CI, 1.61 to 4.10). CONCLUSION: AE-COPD increases the risk of hip fracture regardless of underlying diseases, including osteoporosis, and treatment with systemic corticosteroids.

Association between obesity and lung function changes by sex and age in adults with asthma.

OBJECTIVE: The lung function changes presenting before and after asthma treatment in obese people remain largely unknown. This study aimed to investigate the association between obesity and lung function changes before and after treatment in adults with asthma. METHODS: We enrolled 937 newly diagnosed asthma patients from Cohort for Reality and Evolution of Adult Asthma in Korea cohort in 2015-2017, who performed follow-up spirometry after three months of asthma treatment. The percentage changes (Δ) between the spirometry results before and after treatment were calculated. Patients were categorized into four body mass index (BMI) groups; underweight (<18.5), normal (18.5-22.9), overweight (23.0-24.9), and obese (≥25.0). Association between percent change of pulmonary function and BMI was analyzed according to sex and/or age (< 45 yrs, 45-65 yrs, ≥ 65 yrs), which were statistically corrected for age, sex, smoking status, and medication history. RESULTS: There was no consistent correlation between BMI and each lung function parameter. However, there were significant differences between BMI and ΔFEV1/FVC before and after 3 months of controller treatment. The obese asthmatics showed significantly lower ΔFEV1/FVC (6.0 ± 13.5%) than the underweight (12.6 ± 21.4%, P = 0.044) or normal weight (9.1 ± 14.6%, P = 0.031). Middle-aged women had higher BMI (24.11 ± 3.60 vs. 22.39 ± 3.52) and lower ΔFEV1/FVC (5.7 ± 11.9% vs. 8.9 ± 14.3%, P = 0.012) than young women. CONCLUSIONS: Obesity is negatively correlated with the ΔFEV1/FVC before and after controller treatment. Sex and age differentially contribute to lung function changes in response to asthma medications in adult asthmatics, showing a significant decrease in the ΔFEV1/FVC in middle-aged women.

Clusters of Severe Eosinophilic Asthma in a Korean Asthma Cohort.

BACKGROUND: Targeted therapies have broadened the available treatment options for patients with severe eosinophilic asthma (SEA). However, differences in the magnitude of treatment responses among patients indicate the presence of various underlying pathophysiological processes and patient subgroups. OBJECTIVES: We aimed to describe the characteristics of SEA and identify its patient subgroups. METHODS: Clinical data from the Cohort for Reality and Evolution of Adult Asthma in Korea were analyzed. Cluster analysis was performed among those with SEA using 5 variables, namely, prebronchodilator forced expiratory volume in 1 s, body mass index, age at symptom onset, smoking amount, and blood eosinophil counts. RESULTS: Patients with SEA showed prevalent sensitization to aeroallergens, decreased lung function, and poor asthma control status. Cluster analysis revealed 3 distinctive subgroups among patients with SEA. Cluster 1 (n = 177) consisted of patients reporting the lowest blood eosinophils (median, 346.8 cells/µL) and modest severe asthma with preserved lung function during the 12-month treatment period. Cluster 2 (n = 42) predominantly included smoking males with severe persistent airway obstruction and moderate eosinophilia (median, 451.8 cells/µL). Lastly, cluster 3 (n = 95) included patients with the most severe asthma, the highest eosinophil levels (median, 817.5 cells/µL), and good treatment response in terms of improved lung function and control status. CONCLUSIONS: Three subgroups were identified in SEA through the cluster analysis. The distinctive features of each cluster may help physicians predict patients who will respond to biologics with greater magnitude of clinical improvement. Further research regarding the underlying pathophysiology and clinical importance of each subgroup is warranted.

Natural course of the nodular bronchiectatic form of Mycobacterium Avium complex lung disease: Long-term radiologic change without treatment.

BACKGROUND/PURPOSE: Although the incidence of Mycobacterium avium complex (MAC) lung disease is increasing, the long-term natural course of the nodular bronchiectatic form of MAC lung disease is not well described. The objective of our study is to evaluate long-term radiologic changes in untreated MAC lung disease by analyzing serial chest computed tomography (CT) scan findings. METHODS: Of 104 patients with MAC lung disease, we selected 40 untreated nodular bronchiectatic MAC patients who underwent serial chest CTs without treatment for at least four years (mean = 6.23 years). Majority of patients have minimal symptoms. Two chest radiologists retrospectively reviewed initial and final chest CT scans. Each chest CT scan was scored for presence and extent of bronchiectasis, cellular bronchiolitis, consolidation, cavity, and nodule (maximum score: 30). RESULTS: Of 40 patients, 39 (97.5%) experienced a significant increase in overall CT score (overall difference = 4.89, p<0.001). On repeated measure analysis of variance analysis, cavity yielded the largest increase compared with cellular bronchiolitis (p = 0.013), nodule (p<0.001), and consolidation (p = 0.004). However, there was no significant difference in mean score change between cavity and bronchiectasis (p = 0.073). In analysis between radiologic parameters and the absolute number of involved segments, bronchiectasis showed most significant change compared with nodule (p<0.001) and consolidation (p<0.001). CONCLUSIONS: Most untreated nodular bronchiectatic MAC lung disease cases showed radiologic deterioration over long-term observation periods when we compared serial chest CT scans. Careful monitoring of MAC lung disease with serial chest CT scan can be beneficial in these untreated patients.

Epidemiological trend of pulmonary thromboembolism at a tertiary hospital in Korea.

BACKGROUND/AIMS: Despite increasing interest in pulmonary thromboembolism (PTE), data on recent trends in PTE incidence are limited. This study evaluated the recent incidence rate of PTE. METHODS: We performed a retrospective chart review of patients with PTE admitted to Chung-Ang University Hospital during the 10-year period from 2006 to 2015. Age-standardized incidence and mortality rates were calculated by the direct method per 100,000 populations. To analyze the trend of risk factor, we also calculated the proportions of cancer, major operation, and recent major fracture over that time. RESULTS: Total crude incidence rate of PTE per 100,000 was 229.36 and the age-sex adjusted standardized incidence rate was 151.28 (95% confidence interval [CI], 127.88 to 177.10). The incidence rate have been significantly increased 1.083 times annually from 2006 (105.96 per 100,000) to 2015 (320.02 per 100,000) (95% CI, 1.049 to 1.118; p < 0.001). These incidences also increased annually in age group of 35 to 54, 55 to 74, and ≥ 75 years, and in both males (odds ratio [OR], 1.071; 95% CI, 1.019 to 1.127; p = 0.007) and females (OR, 1.091; 95% CI, 1.047 to 1.136; p < 0.001). Cancer accounted for most of the increase from 20.0% at 2006 to 2007 to 42.8% at 2014 to 2015 (OR, 1.154; 95% CI, 1.074 to 1.240; p < 0.001), while the proportions of recent fracture and major operation remained constant. CONCLUSIONS: The incidence of pulmonary embolism has gradually increased over the 10 years. The increase of PTE incidence was mainly due to increased proportion of cancer patients.

Pulmonary Impairment in Tuberculosis Survivors: The Korean National Health and Nutrition Examination Survey 2008-2012.

OBJECTIVES: Pulmonary tuberculosis (TB) can affect lung function, but studies regarding long-term follow-up in patients with no sequelae on chest X-ray (CXR) have not been performed. We evaluated lung functional impairment and persistent respiratory symptoms in those with prior pulmonary TB and those with prior pulmonary TB with no residual sequelae on CXR, and determined risk factors for airflow obstruction. METHODS: We used data from adults aged ≥ 40 years from the annual Korean National Health and Nutrition Examination Surveys conducted between 2008 and 2012. P values for comparisons were adjusted for age, sex, and smoking status. RESULTS: In total of 14,967 adults, 822 subjects (5.5%) had diagnosed and treated pulmonary TB (mean 29.0 years ago). The FVC% (84.9 vs. 92.6), FEV1% (83.4 vs. 92.4), and FEV1/FVC% (73.4 vs. 77.9) were significantly decreased in subjects with prior pulmonary TB compared to those without (p < 0.001, each). In 12,885 subjects with no sequalae on CXR, those with prior pulmonary TB (296, 2.3%) had significantly lower FEV1% (90.9 vs. 93.4, p = 0.001) and FEV1/FVC% (76.6 vs. 78.4, p < 0.001) than those without. Subjects with prior pulmonary TB as well as subjects with no sequalae on CXR were more likely to experience cough and physical activity limitations due to pulmonary symptoms than those without prior pulmonary TB (p < 0.001, each). In total subjects, prior pulmonary TB (OR, 2.314; 95% CI, 1.922-2.785), along with age, male, asthma, and smoking mount was risk factor for airflow obstruction. In subjects with prior pulmonary tuberculosis, inactive TB lesion on chest x-ray (OR, 2.300; 95% CI, 1.606-3.294) were risk factors of airflow obstruction. CONCLUSION: In addition to subjects with inactive TB lesion on CXR, subjects with no sequelae on CXR can show impaired pulmonary function and respiratory symptoms. Prior TB is a risk factor for airflow obstruction and that the risk is more important when they have inactive lesions on chest X-ray. Hence, the patients with treated TB should need to have regular follow-up of lung function and stop smoking for early detection and prevention of the chronic airway disease.

Seven-day continuous abstinence rate from smoking at 1, 2, or 3 years after the use of varenicline.

BACKGROUND: Varenicline, a selective partial agonist/antagonist of the α4ß2 nicotinic receptor, has proven effectiveness for smoking cessation by several randomized, controlled trials. Because few studies have evaluated the long-term efficacy of varenicline, we tried to evaluate the smoking status of varenicline users up to 3 years after the initial prescription of the drug. METHODS: We interviewed varenicline users who were prescribed the drug from June 2007 to May 2010 by telephone, from June 2010 to May 2011. RESULTS: One-hundred and thirty-three of 250 varenicline users (53.2%) were available for the survey. Seven-day continuous abstinence from smoking was adhered to by 17 of 39 respondents (43.6%) at 1 year, and 11 of 36 (30.6%) and 19 of 58 (32.8%) at 2 and 3 years since the first use of varenicline, respectively. Compared to current smokers, successful quitters were older (55.0 years vs. 49.9 years, p=0.01), had better compliance to the 12-week course (27.7 vs. 9.3%, p=0.01), and had taken varenicline longer (10.1 vs. 5.9 weeks, p=0.01). Fifty-four of 71 current smokers (76.1%) were willing to stop smoking in the near future. The preferred ways to cease smoking were will-power (48.1%), varenicline (25.9%), nicotine replacement therapy (11.1%), and others (14.9%). CONCLUSION: Smokers should be encouraged to stick to the proven way for recommended period of time for successful cessation of smoking.

Classification and implementation of asthma phenotypes in elderly patients.

BACKGROUND: No attempt has yet been made to classify asthma phenotypes in the elderly population. It is essential to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with asthma. OBJECTIVES: To classify elderly patients with asthma by cluster analysis and developed a way to use the resulting cluster in practice. METHODS: We applied k-means cluster to 872 elderly patients with asthma (aged ≥ 65 years) in a prospective, observational, and multicentered cohort. Acute asthma exacerbation data collected during the prospective follow-up of 2 years was used to evaluate clinical trajectories of these clusters. Subsequently, a decision-tree algorithm was developed to facilitate implementation of these classifications. RESULTS: Four clusters of elderly patients with asthma were identified: (1) long symptom duration and marked airway obstruction, (2) female dominance and normal lung function, (3) smoking male dominance and reduced lung function, and (4) high body mass index and borderline lung function. Cluster grouping was strongly predictive of time to first acute asthma exacerbation (log-rank P = .01). The developed decision-tree algorithm included 2 variables (percentage of predicted forced expiratory volume in 1 second and smoking pack-years), and its efficiency in proper classification was confirmed in the secondary cohort of elderly patients with asthma. CONCLUSIONS: We defined 4 elderly asthma phenotypic clusters with distinct probabilities of future acute exacerbation of asthma. Our simplified decision-tree algorithm can be easily administered in practice to better understand elderly asthma and to identify an exacerbation-prone subgroup of elderly patients with asthma.

Risk factors for asthma-related healthcare use: longitudinal analysis using the NHI claims database in a Korean asthma cohort.

BACKGROUND: Though insurance claims data are useful for researching asthma, they have important limitations, such as a diagnostic inaccuracy and a lack of clinical information. To overcome these drawbacks, we used the novel method by merging the clinical data from our asthma cohort with the National Health Insurance (NHI) claims data. METHODS AND RESULTS: Longitudinal analysis of asthma-related healthcare use from the NHI claims database, merged with data of 736 patients registered in a Korean asthma cohort, was conducted for three consecutive years from registration of the cohort. Asthma-related asthma healthcare referred to outpatient and emergency department visits, hospitalizations, and the use of systemic corticosteroids. Univariate and multivariate logistic regression analysis was used to evaluate risk factors for asthma-related healthcare. Over three years after enrollment, many patients changed from tertiary to primary/secondary hospitals with a lack of maintenance of inhaled corticosteroid-based controllers. An independent risk factor for emergency visits was a previous history of asthma exacerbation. In hospitalizations, old age and Asthma Control Test (ACT) score variability were independent risk factors. An independent risk factor for per person cumulative duration of systemic corticosteroids was the FEV1 (Forced expiratory volume in one second)%. The use of systemic corticosteroids was independently associated with being female, the FEV1%, and ACT score variability. CONCLUSION: We found that old age, being female, long-standing asthma, a low FEV1%, asthma brittleness, asthma drug compliance, and a history of asthma exacerbation were independent risk factors for increased asthma-related healthcare use in Korea.

Allergic rhinitis and serum 25-hydroxyvitamin D level in Korean adults.

BACKGROUND: Recently, it has been suggested that airway hyper-responsiveness, asthma, and atopic dermatitis are associated with a low vitamin D level. OBJECTIVE: To evaluate whether the occurrence of allergic rhinitis (AR) is related to serum vitamin D levels in the general Korean adult population. METHODS: Data obtained as part of the fourth annual Korean National Health and Nutrition Examination Survey (2009) of 8,012 adults older than 18 years were analyzed. The correlation between serum 25-hydroxyvitamin D (25[OH]D) level and presence of AR using questionnaires on symptoms, history of diagnosis of AR, and rhinoscopic findings were analyzed. All estimates were calculated based on sampling weight. RESULTS: Mean age was 44.41 years and men constituted 49.8% of the sample. Participants with diagnosed AR constituted 11.1%. The mean 25(OH)D level of the AR group was lower than that of the non-AR group (16.71 ± 0.30 vs 17.75 ± 0.25 ng/mL, P < .001). A comparison of the prevalence of AR in the 3 groups showed that AR steadily decreased in the higher 25(OH)D groups (13.0% in group I [<15 ng/mL], 11.5% in group II [≥15-<25 ng/mL], and 7.2% in group III [≥25 ng/mL], P < .001). After adjusting for body mass index, smoking status, age, sex, sun exposure, income quartile, exercise, and body fat percentage, lower serum 25(OH)D levels remained significantly associated with the presence of AR compared with group III (hazard ratio 1.559 in group I and 1.430 in group II). CONCLUSION: This study suggested a potential association between low vitamin D levels and AR prevalence in Korean adults.

A case of giant, benign schwannoma associated with total lung collapse by bloody effusion.

Benign schwannoma is the most common neurogenic tumor in the mediastinum. Mediastinal benign schwannomas are most often asymptomatic and rarely accompanied by bloody pleural effusion. In the clinical analysis of 7 cases of pulmonary schwannomas, pleural effusion, and blood invasion were evident in 3 patients with malignant schwannoma. Herein, we report a rare case of giant, benign schwannoma presented with total collapse of right lung by massive, bloody pleural effusion.

Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy.

The therapeutic potential of human multipotent mesenchymal stromal cells, especially human adipose tissue-derived stem cells (hASC), is promising. However, there are concerns about the safety of infusion of hASC in human. Recently, we have experienced pulmonary embolism and infarct among family members who have taken multiple infusions of intravenous autologous hASC therapy. A 41-year-old man presented with chest pain for one month. Chest CT showed multiple pulmonary artery embolism and infarct at right lung. Serum D-dimer was 0.8 µg/mL (normal; 0-0.5 µg/mL). He had received intravenous autologous adipose tissue-derived stem cell therapy for cervical herniated intervertebral disc three times (one, two, and three months prior to the visit). His parents also received the same therapy five times and their chest CT also showed multiple pulmonary embolism. These cases represent artificial pulmonary embolisms and infarct after IV injection of hASC. Follow-up chest CT showed spontaneous resolution of lesions in all three patients.

Differences between asthma in young and elderly: results from the COREA study.

BACKGROUND: There has been no large-scale and comprehensive study of the differences between asthma in elderly asthmatics (EA) and non-elderly (i.e. young) asthmatics (NEA). METHODS: We performed principal component analysis (PCA) using 2067 asthmatics (434 EA and 1633 NEA) from the Korean Cohort for Reality and Evolution of adult Asthma (COREA). EA was defined as asthmatics with the chronological age of 65 or more and eleven clinical variables measured at enrollment were used for PCA; symptom score, symptom duration, number of exacerbation during previous one year, smoking pack year, number of controller medications, body mass index, predicted % of FEV1, predicted % FVC, post-bronchodilator FEV1/FVC ratio, atopy index and number of eosinophils in peripheral blood. RESULTS: PCA of all asthmatics showed that EA and NEA were distinctly separated by the first and second principal component on the plot of individual asthmatics according to their scores. For further analysis, we divided all asthmatics into the EA and the NEA group and performed PCA again in each group. The first four principal components with eigenvalues ≥ 1.0 were identified in both groups and they explained 55.5% of the variance in the EA group and 52.4% in the NEA group respectively. Clinical variables showed distinctly different patterns of loading on the first four principal components between the EA and the NEA group. CONCLUSION: EA and NEA have different compositional patterns underlying their clinical variables. These observations helped in understanding the differences between EA and NEA from the integrated view covering various clinical aspects.

Impact of atopy on asthma and allergic rhinitis in the cohort for reality and evolution of adult asthma in Korea.

PURPOSE: Atopy is an important cause of asthma. Few data on the prevalence of atopy or comparisons with clinical characteristics of asthma in Korean patients have been published. We evaluated the effects of atopy on clinical profiles and airway inflammation in Korean asthmatics. METHODS: We retrospectively enrolled 1,492 asthmatics from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort who had undergone skin prick tests for aeroallergens. The patients' clinical characteristics, lung function, PC20, and sputum and blood inflammatory cell counts were compared based on the presence or absence of atopy. Atopy was defined as one or more positive reactions (A/H ratio >1) on a skin prick test. RESULTS: Among 11 aeroallergens, house dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus) were the most prevalent cause of a positive skin prick test. As compared with non-atopic asthmatics, atopic asthmatics showed early onset of the disease. Atopic patients with asthma had a higher FEV1, FVC, and FEV1/FVC as compared with non-atopic patients with asthma. In addition, asthmatics without atopy had more uncontrolled asthma (P=0.001) and severe rhinitis (P<0.05) as compared with atopic asthmatics. Smoking, as measured in pack years, was higher in the non-atopic asthmatics than in the atopic asthmatics. The erythrocyte sedimentation rate was higher in non-atopic asthmatics than in the atopic asthmatics and patients with non-atopic asthma had a higher sputum neutrophil count than did those with atopic asthma. CONCLUSIONS: Our data indicate that atopic asthmatics had an early onset of disease and high IgE levels, while the non-atopic asthmatics had decreased lung function and a high sputum neutrophil count, suggesting that a different approach is needed to treat atopic asthma.

Angiotensin-converting enzyme (ACE) gene polymorphisms are associated with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function. ACE is increased in the bronchoalveolar lavage fluid from patients with IPF, suggesting the role of ACE in the pathogenesis of IPF. We evaluated the role of single-nucleotide polymorphisms (SNPs) in the development risk of IPF. METHODS: Two-hundred twenty patients with IPF and 456 healthy subjects were included in this study. Eleven polymorphisms were selected among those reported previously. Genotype was performed by single base extension. RESULTS: Although absolute LD (|D'|= 1 and r(2 )= 1) was not present, 11 SNPs showed tight LDs. The logistic analysis of the all of 11 SNPs on the ACE genes between patients with IPF and healthy subjects were found to be related with the risk of IPF in recessive type. However, in patients with IPF diagnosed by surgical lung biopsy, only two SNP of -5538T>C and +21288_insdel SNPs were related with the risk of IPF in co-dominant type, and there were no SNPs related with the risk of IPF in dominant type. In patients with IPF diagnosed by clinical criteria or surgical lung biopsy, four SNPs on promoter (-5538T>C, -5508A>C, -3927T>C, -115T>C), one on intron (+15276A>G), one on exon (+21181G>A), and one in three prime region (+21288_insdel) were related with the risk of IPF. CONCLUSIONS: This study showed a newly discovered SNP of ACE associated with the risk of development of IPF. ACE -5538T>C and -5508A>C significantly associated with risk of IPF in Korea.

Identification of asthma clusters in two independent Korean adult asthma cohorts.

Asthma is a heterogeneous airway disease with various clinical phenotypes. It is crucial to clearly identify clinical phenotypes to achieve better asthma management. We used cluster analysis to classify the clinical groups of 724 asthmatic patients from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), and in 1843 subjects from another independent Korean asthma cohort of Soonchunhyang University Asthma Genome Research Centre (SCH) (Bucheon, Republic of Korea). Hierarchical cluster analysis was performed by Ward's method, followed by κ-means cluster analysis. Cluster analysis of the COREA cohort indicated four asthma subtypes: 1) smoking asthma; 2) severe obstructive asthma; 3) early-onset atopic asthma; and 4) late-onset mild asthma. An independent cluster analysis of the SCH cohort also indicated four clusters that were similar to the COREA clusters. Our results indicate that adult Korean asthma patients can be classified into four distinct clusters.

Airway hyperresponsiveness is negatively associated with obesity or overweight status in patients with asthma.

BACKGROUND: Obesity is a risk factor for asthma in the general population, but the effect of obesity on airway hyperresponsiveness (AFHR) or airway inflammation in asthma is not clear. This study evaluated the relationship between obesity and asthma, assessing aspects of symptoms, AHR, and severity. METHODS: In total, 852 patients with asthma diagnosed by asthma specialists based on AHR as confirmed by a methacholine bronchial provocation test, were enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) adult asthma cohort. The intensity of AHR was assessed by the concentration of methacholine needed to cause a 20% decrease in FEV(1) (PC(20)). Patients were classified into four categories based on body mass index (BMI): underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30). RESULTS: BMI was negatively correlated with FEV(1) (l), FVC (l), and FEV(1)/FVC (%) in lung function tests. The prevalence of wheezing increased with higher BMI after adjustment for age, sex, smoking, medication history, and PC(20) (p < 0.0001). logPC(20) was lower in the normal weight group compared with the overweight group (p = 0.003). The risk of moderate or severe AHR (PC(20) ≤ 4 mg/ml) decreased with increased BMI after adjustment for age, sex, smoking, and medication history (p = 0.035). CONCLUSIONS: Obesity is a risk factor for asthma in the general population, but obesity in asthmatic patients is negatively correlated with the intensity of AHR and is not related to asthma severity. Obesity is positively related with the prevalence of wheezing but negatively related to AHR in asthmatic patients.