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Purpose: Symptoms are important components in determining asthma control and in the adjustment of treatment levels. However, clinical relevance of cough in severe asthma is not well-understood. This study aimed to evaluate the severity and association of cough with patient-reported outcomes (PROs) in patients with severe asthma., Methods: This study analyzed cross-sectional data from the Korean Severe Asthma Registry. The severity of coughing and wheezing symptoms was assessed using a Visual Analog Scale (VAS) ranging from 0 to 100 for each symptom. Additionally, PROs included the Asthma Control Test (ACT), the Severe Asthma Questionnaire (SAQ), and the EuroQoL 5-Dimension (EQ-5D) index. Multivariate linear regression analysis was employed to explore the relationship between cough severity and other PRO scores., Results: A total of 498 patients with severe asthma (age: 57.9 ± 13.1 years, females: 60.2%) were analyzed. The cough VAS score was higher than the wheeze score (median 30, [interquartile range 10-50] vs. 20 [0-50]; P < 0.001). Additionally, 22.5% of patients ranked in a higher tertile for cough severity compared to wheezing, while 18.5% ranked higher for wheezing severity than cough. Significant correlations were observed between cough and wheeze VAS scores (r = 0.61, P < 0.05) and between each symptom's VAS score and the SAQ (cough: r = -0.41, P < 0.001; wheeze: r = -0.52, P < 0.001), ACT scores (cough: r = -0.50, P < 0.001; wheeze: r = -0.63, P < 0.001) and EQ-5D index (cough: r = -0.40, P < 0.001; wheeze: r = -0.45, P < 0.001). In univariate regression analysis, the cough VAS score had weaker descriptive power (R 2 ) values than the wheeze VAS score in relation to the PRO measures. Nevertheless, cough severity remained significantly associated with ACT, SAQ scores and EQ-5D index in multivariate analyses adjusted for wheeze severity and other confounders., Conclusion: Cough frequently presents as a severe symptom in patients with severe asthma and could have distinct impact on asthma control and quality of life., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n  = 6; ATA, n  = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

Although the T helper 2 (Th2) subset is a critical player in the humoral immune response to extracellular parasites and suppression of Th1-mediated inflammation, Th2 cells have been implicated in allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis. GATA binding protein 3 (GATA3) is a primary transcription factor that mediates Th2 differentiation and secretion of Th2 cytokines, including IL-4, IL-5, and IL-13. Here, a nucleus-deliverable form of GATA3-transcription modulation domain (TMD) (ndG3-TMD) was generated using Hph-1 human protein transduction domain (PTD) to modulate the transcriptional function of endogenous GATA3 without genetic manipulation. ndG3-TMD was shown to be efficiently delivered into the cell nucleus quickly without affecting cell viability or intracellular signaling events for T cell activation. ndG3-TMD exhibited a specific inhibitory function for the endogenous GATA3-mediated transcription, such as Th2 cell differentiation and Th2-type cytokine production. Intranasal administration of ndG3-TMD significantly alleviated airway hyperresponsiveness, infiltration of immune cells, and serum IgE level in an OVA-induced mouse model of asthma. Also, Th2 cytokine secretion by the splenocytes isolated from the ndG3-TMD-treated mice substantially decreased. Our results suggest that ndG3-TMD can be a new therapeutic reagent to suppress Th2-mediated allergic diseases through intranasal delivery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Su-Hyeon Lee reports financial support was provided by Good T Cells, Inc. Sang-Kyou Lee reports financial support was provided by Good T Cells, Inc. Jung-Ho Kim reports was provided by Good T Cells, Inc. Sang-Kyou Lee has patent pending to Sang-Kyou Lee., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Exacerbation of asthma is affected by genetic and environmental factors, but little is known about genetic differences according to smoking status. We evaluated genetic factors associated with asthma exacerbations in smokers and non-smokers, and identified the underlying mechanisms via a genome-wide association study (GWAS) and gene-level analyses according to smoking status., Methods: A GWAS on the annual frequency of asthma exacerbations was performed in 420 non-smoking and 188 smoking patients with asthma. Gene-wise associations were analyzed by Multi-marker Analysis of GenoMic Annotation (MAGMA); Gene Ontology analysis was also performed., Results: In the non-smoker group, 189 genes showed significant associations with the annual frequency of exacerbations (permutated P < 0.001). The top 10 genes were F5, KLRC1, TAFA2, AIRE, IER3IP1, CHMP2A, IL31RA, ZNF497, DNMT3L, and MYT1L (permutated P = 1.0 × 10 -4 - 1.7 × 10 -4 ). In smoking asthmatics, 140 genes-including KANK1, ZMYND12, ZNF34, ANXA11, VAV2, CCDC150, CCDC30, CATSPER3, ARMH2, and MPRIP (permutated P = 9.23 × 10 -5 - 5.50 × 10 -4 )-were associated with asthma exacerbations. Genes participating in the innate immune response in non-smokers and the regulation of cell fate (including apoptosis) in smokers were the major causal genes of asthma exacerbation (FDR q < 0.05)., Conclusions: Our findings not only suggest novel genetic candidates for predicting asthma exacerbations, but also that asthma treatment strategies should take into account smoking behavior., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Significant changes in CpG methylation have been identified in nasal polyps, which are the main targets of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD); however, these polyps are composed of various cellular components. In the present study, whole-genome CpG methylation in peripheral blood lymphocytes (PBLs) was analyzed to define the epigenetic changes in lymphocytes, which are the primary immune cells involved in NERD., Materials and Methods: Genomic DNA from peripheral blood mononuclear cells from 27 NERD and 24 aspirin-tolerant asthma (ATA) was subjected to bisulfate conversion and a methylation array. Quantitative CpG methylation, the β-values as a quantitative measure of DNA methylation, in lymphocytes were calculated after adjustments for cellular composition., Results: Fifty-six hypermethylated and three hypomethylated differentially methylated CpGs (DMCs) in PBLs in the NERD compared with ATA. The top 10 CpG loci predicted the methylation risk score, with a positive predictive value of 91.3%, a negative predictive value of 81.5% and an accuracy of 84.3%. As demonstrated in the nasal polyps, 30 DMCs were predicted to bind to the following 10 transcription factors, ranked in descending order: AP-2alphaA, TFII-1, STAT4, FOXP3, GR, c-Est-1, E2F-1, XBP1, ENKTF-1 and NF-1. Gene ontology analysis identified 13 categories such as regulation of T-helper 17 cell differentiation, including SMAD7 and NFKBIZ. PBLs in NERD contained no DMCs in genes associated with the prostaglandin and leukotriene pathways, which were found in ATA., Conclusion: PBLs in NERD form a unique pattern of DNA CpG methylation, and the combined analysis may provide predictive values for NERD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Some reports have suggested that the clinical and economic burdens of asthma are associated with blood eosinophil levels. The association between clinical burden and blood eosinophil counts were evaluated in a Korean adult asthma cohort., Methods: Clinical information including blood eosinophil counts that were not affected by systemic corticosteroids were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea database. Clinical burden was defined as 1) asthma control status, 2) medication demand and 3) acute exacerbation (AE) events during 1 consecutive year after enrollment. All patients were divided into atopic and non-atopic asthmatics. The associations between asthma outcomes and the blood eosinophil count were evaluated., Results: In total, 302 patients (124 atopic and 178 non-atopic asthmatics) were enrolled. In all asthmatics, the risk of severe AE was higher in patients with blood eosinophil levels < 100 cells/µL than in patients with levels ≥ 100 cells/µL (odds ratio [OR], 5.406; 95% confidence interval [CI], 1.266-23.078; adjusted P = 0.023). Among atopic asthmatics, the risk of moderate AE was higher in patients with blood eosinophil levels ≥ 300 cells/µL than in patients with levels < 300 cells/µL (OR, 3.558; 95% CI, 1.083-11.686; adjusted P = 0.036). Among non-atopic asthmatics, the risk of medication of Global Initiative for Asthma (GINA) steps 4 or 5 was higher in patients with high blood eosinophil levels than in patients with low blood eosinophil levels at cutoffs of 100, 200, 300, 400, and 500 cells/µL., Conclusion: The baseline blood eosinophil count may predict the future clinical burden of asthma., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Background: Asthma and nonalcoholic fatty liver disease (NAFLD) are chronic diseases known to be associated with metabolic abnormalities. We aimed to clarify the association between NAFLD and asthma incidence in a large population-based cohort., Methods and Findings: We selected 160,603 individuals without comorbidities from the National Health Insurance Service-National Sample cohort between 2009 and 2014. NAFLD was defined using a surrogate marker, fatty liver index (FLI). During a median of 5.08 years' follow-up, 16,377 subjects (10.2%) were newly diagnosed with asthma and categorized into three groups according to FLI. The cumulative incidence of asthma was higher in subjects with higher vs. lower FLIs (FLI < 30, 10.1%; 30 ≤ FLI < 60, 10.8%; FLI ≥ 60, 10.5%). Higher FLI was associated with an increased incidence of asthma (Hazard ratios (HR)highest vs. lowest FLI, 1.25; 95% CI, 1.15-1.36). The results using another definition of NAFLD, as measured by the hepatic steatosis index (HSI), were similar to the primary results. This association was more pronounced in women than in men (HR 1.46; 95% CI, 1.13-1.64 vs. HR 1.07; 95% CI, 0.94-1.20)., Conclusions: This study demonstrated that NAFLD, as measured by FLI and HSI, may influence the incidence rates of asthma in adults, especially in women., Competing Interests: The authors have declared that no competing interests exist.

Background: Asthma exacerbation threatens patient's life. Several genetic studies have been conducted to determine the risk factors for asthma exacerbation, but this information is still lacking. We aimed to determine whether genetic variants of Oxidative Stress Responsive Kinase 1 (OXSR1), a gene with functions of salt transport, immune response, and oxidative stress, are associated with exacerbation of asthma., Methods: Clinical data were obtained from 1454 asthmatics and single nucleotide polymorphisms (SNPs) of OXSR1 were genotyped. Genetic associations with annual exacerbation rate were analyzed depending on smoking status., Results: Eleven SNPs were selected using Asian data in the International HapMap database. The common allele of rs1384006 C > T of OXSR1 showed a significantly higher annual exacerbation rate than the rare allele in non-smoking asthmatics (CC vs. CT vs. TT: 0.43 ± 0.04 vs. 0.28 ± 0.03 vs. 0.31 ± 0.09, P = 0.004, Pcorr = 0.039). The frequent exacerbators had a significantly higher frequency of the common allele of rs1384006 C > T than did the infrequent exacerbators (74.4% vs. 55.2%, P = 0.004, Pcorr = 0.038)., Conclusion: The common allele of rs1384006 C > T of OXSR1 was associated with the asthma exacerbation rate and a higher risk of being a frequent exacerbator, indicating that non-smoking asthmatics who carry common alleles may be vulnerable to asthma exacerbations., (© 2022. The Author(s).)

Introduction: Allergic rhinitis and asthma share a common inflammatory mechanism and are closely related, recognized as "one airway disease." Thus, the guidelines recommend allergic rhinitis and asthma be treated together, and leukotriene antagonists and antihistamines have been administered simultaneously; however, there are few reports of the use of combination drugs so far., Methods: The aim of the study was to evaluate the treatment effects and adverse events of Monterizine® (a combination of montelukast and levocetirizine); a total of 2,254 patients with perennial allergic rhinitis and asthma were prospectively enrolled from 60 hospitals nationwide in Korea. They were followed up for 3 (Period 1) or 6 months (Period 2). Total nasal symptom score (TNSS), satisfaction, and safety data were collected and compared to baseline., Results: TNSS scores were analyzed for 2,254 subjects. At Period 1 (n = 2,024) and 2 (n = 1,861), the scores decreased significantly from baseline (-1.20 ± 2.49 and -1.63 ± 2.78, p < 0.001). The mean quality of life (QoL) was significantly improved at Period 1 and 2 relative to baseline (-3.75 ± 6.58, -4.83 ± 7.11, both p < 0.0001). There were no serious adverse drug reactions, but there were some minor reactions including nasopharyngitis (2.92%), rhinitis (0.37%), and somnolence (0.34%)., Conclusions: TNSS score and QoL were significantly improved by 3-6 months' treatment with Monterizine without significant adverse reactions. These results indicate that Monterizine, as a combination drug, is effective and safe for improving nasal symptoms and quality of life in patients with allergic rhinitis who also have asthma., (© 2022 S. Karger AG, Basel.)

Background: Current asthma guidelines recommend stepping down controller treatment when the condition is well-controlled for a certain time. However, the optimal step-down strategy for well-controlled patients receiving a low-dose inhaled corticosteroid (ICS) with a long-acting β 2 -agonist (LABA) remains unclear., Objective: This study was a randomized, open-label, three-arm, parallel pragmatic trial comparing two kinds of step-down approaches for maintaining treatment., Methods: Adults with asthma who were aged 18 years or older, and who had been stable with low-dose ICS/LABA for at least 3 months, were enrolled. Subjects (n = 225) were randomly allocated into one of three groups (maintaining low-dose ICS/LABA [G1], discontinuing LABA [G2], and reducing ICS/LABA to once daily [G3]), and were observed for 6 months. The primary end point was a change in Asthma Control Test (ACT) scores between randomization and the final 6-month follow-up., Results: The change in ACT was analyzed in the per-protocol population; noninferiority was not demonstrated in either step-down group compared with the maintenance group (95% confidence interval of the difference, G2 vs G1 = -1.40-0.55; G3 vs G1 = -1.19-0.77). Although over 90% of patients were fine, higher rates of treatment failure were observed in step-down groups (G1: 0%; G2: 9.46%; and G3: 9.09%; P = .027). There were no significant differences between step-down approaches in terms of ACT change or treatment failure., Conclusions: Both step-down methods were not noninferior to maintenance of treatment. Step-down therapy can be attempted when patients are stable, but appropriate monitoring and supervision are necessary with precautions regarding loss of disease control., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background/aims: Omalizumab is the first biologic known to be effective in patients with severe allergic asthma., Methods: This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma., Results: Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001)., Conclusion: Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Background: Quinoline-3-carboxamides have been used to treat autoimmune/inflammatory diseases in humans because they inhibit the functions of S100 calcium-binding protein A9 (S100A9), which participates in the development of neutrophilic inflammation in asthmatics and in an animal model of neutrophilic asthma. However, the therapeutic effects of these chemicals have not been evaluated in asthma. The purpose of this study was to evaluate the effect of paquinimod, one of the quinoline-3-carboxamides, on a murine model of neutrophilic asthma., Methods: Paquinimod was orally administered to 6-week-old C57BL/6 mice sensitized and challenged with ovalbumin (OVA)/complete Freund's adjuvant (CFA) and OVA. Lung inflammation and remodeling were evaluated using bronchoalveolar lavage (BAL) and histologic findings including goblet cell count. S100A9, caspase-1, IL-1 β , MPO, IL-17, IFN- γ , and TNF- α were measured in lung lysates using western blotting., Results: Paquinimod restored the enhancement of airway resistance and the increases in numbers of neutrophils and macrophages of BAL fluids and those of goblet cells in OVA/CFA mice toward the levels of sham-treated mice in a dose-dependent manner (0.1, 1, 10, and 25 mg/kg/day, p.o.). Concomitantly, p20 activated caspase-1, IL-1 β , IL-17, TNF- α , and IFN- γ levels were markedly attenuated., Conclusion: These data indicate that paquinimod effectively inhibits neutrophilic inflammation and remodeling in the murine model of neutrophilic asthma, possibly via downregulation of IL-17, IFN- γ , and IL-1 β ., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Jong-Uk Lee et al.)

Background: Current guidelines for the treatment of asthma and chronic obstructive pulmonary disease overlap (ACO) recommend initial treatment using inhaled corticosteroids (ICSs) plus 1 or more bronchodilators., Objective: To clarify which therapeutic effect is better between the ICS + long-acting β 2 agonist (LABA) and ICS + LABA + long-acting muscarinic antagonist (LAMA) treatment in patients with ACO., Methods: We conducted a multicenter, 48-week, randomized, noninferiority trial. Patients with ACO were enrolled if they were treated with a moderate to high dose of ICS + LABA. In total, 303 patients were involved in the present trial, with 149 receiving ICS + LABA + LAMA. The primary end point was the time to first exacerbation. Secondary outcomes included changes in FEV 1 , forced vital capacity, FEV 1 /forced vital capacity ratio, asthma control, blood eosinophil count, and fractional exhaled nitric oxide., Results: In the ICS + LABA treatment group, 29 of 154 patients (18.83%) experienced exacerbation, whereas 28 of 149 patients (18.79%) experienced exacerbation in the ICS + LABA + LAMA treatment group. The results of this noninferiority study were ultimately inconclusive (hazard ratio, 1.1; 95% CI, 0.66-1.84). However, the patients treated with the addition of LAMA showed significant improvements in FEV 1 and forced vital capacity (P < .001). Asthma control did not improve in either group., Conclusions: Although this study was unable to conclude that ICS + LABA treatment is not inferior to ICS + LABA + LAMA in terms of exacerbation, it is obvious that the ICS + LABA + LAMA treatment group had improved lung function in ACO., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background/aims: The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma has been evaluated in a global clinical trial programme. This post hoc analysis assesses the efficacy and safety of mepolizumab in Korean patients., Methods: Data from Korean patients in the Phase III, placebo-controlled, randomised DREAM (MEA112997/NCT01000506) and MENSA (MEA115588/ NCT01691521) studies were included. Patients ≥ 12 years old with severe eosinophilic asthma received mepolizumab (DREAM: 75, 250 or 750 mg intravenously [IV]; MENSA: 75 mg IV or 100 mg subcutaneously [SC]), or placebo every 4 weeks for 52 weeks (DREAM) or 32 weeks (MENSA). The primary outcome was the rate of clinically significant asthma exacerbations. Secondary outcomes included forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire (ACQ) and St George's Respiratory Questionnaire (SGRQ) scores (MENSA only). Blood eosinophil counts (BEC) and safety were assessed throughout., Results: Reductions in the rate of clinically significant asthma exacerbations were observed with the approved (100 mg SC) and bioequivalent (75 mg IV) doses of mepolizumab in Korean patients who participated in DREAM and MENSA. In MENSA, trends for improvements from baseline at week 32 in pre-bronchodilator FEV1 (75 mg IV group), ACQ-5 and SGRQ scores (in both treatment groups) were seen versus placebo in Korean patients. Incidence of on-treatment adverse events was similar in Korean patients versus non-Korean patients as were observed reductions from baseline in BEC., Conclusion: Mepolizumab treatment provided clinical benefits for Korean patients with severe eosinophilic asthma; the safety profile is consistent with the overall population.

Large-scale data sources, remote sensing technologies, and superior computing power have tremendously benefitted to environmental health study. Recently, various machine-learning algorithms were introduced to provide mechanistic insights about the heterogeneity of clustered data pertaining to the symptoms of each asthma patient and potential environmental risk factors. However, there is limited information on the performance of these machine learning tools. In this study, we compared the performance of ten machine-learning techniques. Using an advanced method of imbalanced sampling (IS), we improved the performance of nine conventional machine learning techniques predicting the association between exposure level to indoor air quality and change in patients' peak expiratory flow rate (PEFR). We then proposed a deep learning method of transfer learning (TL) for further improvement in prediction accuracy. Our selected final prediction techniques (TL1&#95;IS or TL2-IS) achieved a balanced accuracy median (interquartile range) of 66(56~76) % for TL1&#95;IS and 68(63~78) % for TL2&#95;IS. Precision levels for TL1&#95;IS and TL2&#95;IS were 68(62~72) % and 66(62~69) % while sensitivity levels were 58(50~67) % and 59(51~80) % from 25 patients which were approximately 1.08 (accuracy, precision) to 1.28 (sensitivity) times increased in terms of performance outcomes, compared to NN&#95;IS. Our results indicate that the transfer machine learning technique with imbalanced sampling is a powerful tool to predict the change in PEFR due to exposure to indoor air including the concentration of particulate matter of 2.5 μm and carbon dioxide. This modeling technique is even applicable with small-sized or imbalanced dataset, which represents a personalized, real-world setting., Competing Interests: The authors have read the journal’s policy, and the authors of this manuscript have no competing interests.

Background: While the clinical characteristics and outcomes of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have been frequently compared with those of COPD or asthma, the prevalence and features of ACO in patients with severe asthma are unclear., Objectives: Evaluation of the prevalence and clinical features of ACO using the Korean severe asthma registry., Methods: At the time of registration, ACO was determined in patients with severe asthma by attending specialists. Patients were classified into ACO and non-ACO groups, and the demographic and clinical characteristics of these two groups were compared., Results: Of 482 patients with severe asthma, 23.7% had ACO. Patients in the ACO group were more likely to be male (P < .001), older (P < .001), and ex- or current smokers (P < .001) compared with those in the non-ACO group. Patients in the ACO group had lower mean forced expiratory volume in 1 second (P < .001) and blood eosinophil percentage (P = .006), but higher blood neutrophil percentage (P = .027) than those in the non-ACO group. The ACO group used more inhaled long-acting muscarinic antagonist (P < .001), methylxanthine (P = .001), or sustained systemic corticosteroid (P = .002). In addition, unscheduled emergency department visits due to exacerbation were more frequent in the ACO group (P = .006)., Conclusion: Among patients with severe asthma, those with ACO were older, predominantly male, and were more likely to have a smoking history than those with asthma only. Patients with ACO used more systemic corticosteroid and had more frequent exacerbations related to emergency department visits than those with severe asthma only., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Different patterns of bacterial communities have been reported in the airways and gastrointestinal tract of asthmatics when compared to healthy controls. However, the blood microbiome of asthmatics is yet to be investigated. Therefore, we aimed to determine whether a distinct serum microbiome is observed in asthmatics by metagenomic analysis of serum extracellular vesicles (EVs). We obtained serum from 190 adults with asthma and 260 healthy controls, from which EVs were isolated and analyzed. The bacterial composition of asthmatics was significantly different from that of healthy controls. Chao 1 index was significantly higher in the asthma group, while Shannon and Simpson indices were higher in the control group. At the phylum level, Bacteroidetes was more abundant in asthmatics, while Actinobacter, Verrucomicrobia, and Cyanobacteria were more abundant in healthy controls. At the genus level, 24 bacterial genera showed differences in relative abundance between asthmatics and controls, with linear discriminant analysis scores greater than 3. Further, in a diagnostic model based on these differences, a high predictive value with a sensitivity of 0.92 and a specificity of 0.93 was observed. In conclusion, we demonstrated distinct blood microbiome in asthma indicating the role of microbiome as a potential diagnostic marker of asthma.

Background: Few studies have evaluated the impact of air pollution levels on the severity of exacerbations. Thus, we compared the relative risks posed by air pollutant levels on moderate and severe exacerbations. Methods: Exacerbation episodes of 618 from 143 adult asthmatics were retrospectively collected between 2005 and 2015 in a tertiary hospital of Korea. Air pollution GPS data for the location closest to each patient's home were obtained from the national ambient monitoring station. The relative impacts of air pollutants on asthma exacerbations were evaluated via a time-trend controlled symmetrical, bidirectional, case-crossover design using conditional logistic regression models on the day of the exacerbation (T-0) and up to 3 days before the exacerbation (T-1-T-3). Results: Overall asthma exacerbation were associated with O 3 levels in summer and winter (OR: 1.012[1.003-1.02] and 1.009[1.003-1.016]), SO 2 levels in spring and summer (OR: 1.009[1-1.018] and 1.02[1.006-1.035]) and NO 2 levels in winter (OR: 1.007[1.003-1.011]). Analyses of the temporal relationship between O 3 concentrations and exacerbations demonstrated that 63.2% of episodes in the summer occurred when the O 3 concentrations on T-1 were significantly higher than those on control days, while 51% of exacerbation episodes in the winter occurred. Severe and moderate exacerbations were similarly associated with O 3 levels in winter (OR: 1.012 [1.003-1.02] vs. 1.01 [0.999-1.021], p  > 0.05) and in summer (OR: 1.006 [1.002-1.009] vs. 1.009 [1.003-1.016], p  > 0.05). Conclusions: Asthma exacerbations may be associated with the seasonal elevation of O 3 , SO 2 and NO 2 levels in summer and winter with the similar relative risk between moderate and severe exacerbations.

Stratification of asthmatic patients based on relevant biomarkers enables the prediction of responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes; similar approaches in patients with neutrophilic asthma have yet to be developed. We determined whether colony-stimulating factors (CSFs) in the airway reflect the inflammatory phenotypes of asthma and contribute to disease progression of neutrophilic asthma.We analysed three different mouse models of asthma and assessed cytokine profiles in sputum from human patients with asthma stratified according to inflammatory phenotype. In addition, we evaluated the therapeutic efficacy of various cytokine blockades in a mouse model of neutrophilic asthma.Among the CSFs, airway granulocyte CSF (G-CSF) contributes to airway neutrophilia by promoting neutrophil development in bone marrow and thereby distinguishes neutrophilic inflammation from eosinophilic inflammation in mouse models of asthma. G-CSF is produced by concurrent stimulation of the lung epithelium with interleukin (IL)-17A and tumour necrosis factor (TNF)-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17A×TNF-α double-knockout mice reduced the serum level of G-CSF, leading to alleviation of neutrophilic inflammation in the airway. In humans, the sputum level of G-CSF can be used to stratify patients with asthma with neutrophil-dominated inflammation.Our results indicated that myelopoiesis-promoting G-CSF and cytokines as the upstream inducing factors are potential diagnostic and therapeutic targets in patients with neutrophilic asthma., Competing Interests: Conflict of interest: Y-M. Kim has a patent 10-2019-0057637 pending. Conflict of interest: H. Kim has nothing to disclose. Conflict of interest: Seungwon Lee has nothing to disclose. Conflict of interest: S. Kim has a patent 10-2019-0057637 pending. Conflict of interest: J-U. Lee has nothing to disclose. Conflict of interest: Y. Choi has nothing to disclose. Conflict of interest: H.W. Park has nothing to disclose. Conflict of interest: G. You has nothing to disclose. Conflict of interest: H. Kang has nothing to disclose. Conflict of interest: Seyoung Lee has nothing to disclose. Conflict of interest: J-S. Park has nothing to disclose. Conflict of interest: Y. Park has nothing to disclose. Conflict of interest: H-S. Park has nothing to disclose. Conflict of interest: C-S. Park has a patent 10-2019-0057637 pending. Conflict of interest: S-W. Lee has a patent 10-2019-0057637 pending., (Copyright ©ERS 2020.)

Asthma exacerbation is induced by the interaction of genes and environmental factors such as cigarette smoke. NLRP4 counteracts the activity of the inflammasome, which is responsible for asthma exacerbation. In this study, we analyzed the association of single-nucleotide polymorphisms of NLRP4 with the annual rate of exacerbation and evaluated the additive effect of smoking in 1454 asthmatics. Asthmatics possessing the minor allele of rs1696718G > A had more frequent exacerbation episodes than those homozygous for the common allele (0.59 vs. 0.36/year) and the association was present only in current and ex-smokers. There was a significant interaction between the amount smoked and rs16986718 genotypes (p = 0.014) and a positive correlation between the number of annual exacerbation episodes and amount smoked only in rs16986718G > A AA homozygotes. The prevalence of frequent exacerbators (≥2 exacerbation episodes/year) was 2.5 times higher in rs16986718G > A minor allele homozygotes than in common allele homozygotes (12.0% vs. 5.9%). Furthermore, the prevalence was 6 times higher in rs16986718G > A minor allele homozygotes who were current and ex-smokers than in nonsmokers (25.6% vs. 4.1%). The minor allele of rs16986718G > A in NLRP4 may be a genetic marker that predicts asthma exacerbation in adult asthmatics who smoke.

For the past three decades, a large number of genetic studies have been performed to examine genetic variants associated with asthma and its subtypes in hopes of gaining better understanding of the mechanisms underlying disease pathology and to identify genetic biomarkers predictive of disease outcomes. Various methods have been used to achieve these objectives, including linkage analysis, candidate gene polymorphism analysis, and genome-wide association studies (GWAS); however, the degree to which genetic variants contribute to asthma pathogenesis has proven to be much less significant than originally expected. Subsequent application of GWAS to well-defined phenotypes, such as occupational asthma and non-steroidal anti-inflammatory drugexacerbated respiratory diseases, has overcome some of these limitations, although with only partial success. Recently, a combinatorial analysis of single nucleotide polymorphisms (SNPs) identified by GWAS has been used to develop sets of genetic markers able to more accurately stratify asthma subtypes. In this review, we discuss the implications of the identified SNPs in diagnosis of asthma and its subtypes and the progress being made in combinatorial analysis of genetic variants., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2019.)

Using real-world cases, asthma-related clinical data were clustered by patient; 5% of all asthmatics were found to have refractory asthma (RA) with a relatively low lung function (forced expiratory volume in 1 s/forced vital capacity (FEV₁/FVC) less than 80%). Using a multilevel study design for clustered spirometry data observed between 2005 and 2014, we evaluated the association between changes in the ratio of FEV₁ to FVC and variations in acute exposure to air pollution. We analyzed 2310 episodes of RA from 214 neversmoking patients. In spring, a 1 µg/m³ increase in concentration of particles ≤10 μm (PM 10 ) on Lag 1 significantly reduced the ratio by 0.4% (95% confidence interval (CI): 0.1⁻0.7%) after adjusting for sex, age, body mass index (BMI), and total Immunoglobulin E (IgE) level. Unit (ppb) increase in SO₂ concentration on Lag 3 and 4 in fall and on Lag 6 in winter significantly reduced the ratio by 2 to 3% ( p < 0.05). We found that acute exposure to PM 10 in spring or SO₂ in fall or winter were positively associated with lung function drop indicating necessity of control strategies of target air pollutant source by season to protect susceptible population.

Background/aims: The methacholine bronchial provocation test (MBPT) is used to detect and quantify airway hyper-responsiveness (AHR). Since improvements in the severity of asthma are associated with improvements in AHR, clinical studies of asthma therapies routinely use the change of airway responsiveness as an objective outcome. The aim of this study was to assess the relationship between serial MBPT and clinical profiles in patients with asthma., Methods: A total of 323 asthma patients were included in this study. The MBPT was performed on all patients beginning at their initial diagnosis until asthma was considered controlled based on the Global Initiative for Asthma guidelines. A responder was defined by a decrease in AHR while all other patients were considered non-responders., Results: A total of 213 patients (66%) were responders, while 110 patients (34%) were non-responders. The responder group had a lower initial PC20 (provocative concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20%) and longer duration compared to the non-responder group. Members of the responder group also had superior qualities of life, compared to members of the non-responder group. Whole blood cell counts were not related to differences in PC20; however, eosinophil concentration was. No differences in sex, age, body mass index, smoking history, serum immunoglobulin E, or frequency of acute exacerbation were observed between responders and non-responders., Conclusions: The initial PC20, the duration of asthma, eosinophil concentrations, and quality-of-life may be useful variables to identify improvements in AHR in asthma patients.

Purpose: The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone., Methods: This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n = 112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n = 116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, asthma control test score, and the frequency of rescue medication used during the treatment period., Findings: Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, -0.98 [0.06] vs -0.81 [0.06]; P = 0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV 1 , FVC, FEV 1 /FVC, and asthma control test score changes from baseline for the 2 treatment groups. Montelukast/levocetirizine was well tolerated, and the safety profile was similar to that observed in the montelukast group., Implications: The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Annexin-A1 (ANXA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The anti-inflammatory protein ANXA1 and its N-formyl peptide receptor 2 (FPR2) have protective effects on organ fibrosis. However, the exact role of ANXA1 in asthma remains to be determined. The aim of this study was to identify the role of ANXA1 in bronchial asthma., Methods: In mice sensitized and challenged with ovalbumin (OVA-OVA mice) and mice sensitized with saline and challenged with air (control mice), we investigated the potential links between ANXA1 levels and bronchial asthma using ELISA, immunoblotting, and immunohistochemical staining. Moreover, we also determined ANXA1 levels in blood from 50 asthmatic patients (stable and exacerbated states)., Results: ANXA1 protein levels in lung tissue and bronchoalveolar lavage fluid were significantly higher in OVA-OVA mice compared with control mice. FPR2 protein levels in lung tissue were significantly higher in OVA-OVA mice compared with control mice. Plasma ANXA1 levels were increased in asthmatic patients compared with healthy controls. Plasma ANXA1 levels were significantly lower in exacerbated patients compared with stable patients with bronchial asthma (p < 0.05). The plasma ANXA1 levels in controlled asthmatic patients were correlated with forced expiratory volume in 1 s (FEV 1 ) (r = - 0.191, p = 0.033) and FEV 1 /forced vital capacity (FVC) (r = -0.202, p = 0.024)., Conclusion: These results suggest that ANXA1 may be a potential marker and therapeutic target for asthma.

S100A9 is an endogenous danger signal that promotes and exacerbates the neutrophilic inflammatory response. To investigate the role of S100A9 in neutrophilic asthma, S100A9 levels were measured in sputum from 101 steroid-naïve asthmatics using an ELISA kit and the levels were significantly correlated with percentages of neutrophils in sputum. Intranasal administration of recombinant S100A9 markedly increased neutrophil numbers at 8h and 24h later with concomitant elevation of IL-1β, IL-17, and IFN-γ levels. Treatment with an anti-S100A9 antibody restored the increased numbers of neutrophils and the increased airway resistance in OVA/CFA mice toward the levels of sham-treated mice. Concomitantly, the S100A9 and neutrophil elastase double positive cells were markedly reduced with attenuation of IL-1β, IL-17, and IFN-γ levels by the treatment with the anti-S100A9 antibody. Our data support a role of S100A9 to initiate and amplify the neutrophilic inflammation in asthma, possibly via inducing IL-1β, IL-17 and IFN-γ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Interleukin-32(IL-32)γ is a pro-inflammatory cytokine involved in the development and severity of chronic inflammatory diseases, but its role in asthma is unclear., Objective: This study was conducted to evaluate the relationship of IL-32γ levels in sputum with the severity of asthma., Methods: IL-32γ levels in the supernatant of induced sputum obtained from 89 patients with stable asthma were measured using a sandwich enzyme-linked immunosorbent assay (ELISA). The relationships between sputum IL-32γ levels and baseline forced expiratory volume in 1 s (FEV 1 % pred.), inflammatory cell profiles in sputum, and annual frequency of asthma exacerbation were determined., Results: IL-32γ was detected in the sputum of 25 of 89 (28.1%) asthma patients, and the levels of sputum were negatively correlated with FEV 1 % pred. (ρ = -0.312, p = 0.003). The annual exacerbation rate was significantly higher in this group than in the IL-32-negative group (n = 64) (p = 0.03). Sputum IL-32γ levels correlated well with the annual exacerbation rate (ρ = 0.261, p = 0.014), but there were no differences in the inflammatory cell profiles in the induced sputum of IL-32-positive and IL-32-negative patients., Conclusion: The level of IL-32γ in induced sputum may be associated with asthma severity and related with higher risk of asthma exacerbation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Neutrophilic airway inflammation represents a pathologically distinct form of asthma and frequently appears in symptomatic adulthood asthmatics. However, clinical impacts and mechanisms of the neutrophilic inflammation have not been thoroughly evaluated up to date. Areas covered: Currently, distinct clinical manifestations, triggers, and molecular mechanisms of the neutrophilic inflammation (namely Toll-like receptor, Th1, Th17, inflammasome) are under investigation in asthma. Furthermore, possible role of the neutrophilic inflammation is being investigated in respect to the airway remodeling. We searched the related literatures published during the past 10 years on the website of Pub Med under the title of asthma and neutrophilic inflammation in human. Expert commentary: Epidemiologic and experimental studies have revealed that the neutrophilic airway inflammation is induced by a wide variety of stimuli including ozone, particulate matters, cigarette smoke, occupational irritants, endotoxins, microbial infection and colonization, and aeroallergens. These triggers provoke diverse immune and inflammatory responses leading to progressive and sometimes irreversible airway obstruction. Clinically, neutrophilic airway inflammation is frequently associated with severe asthma and poor response to glucocorticoid therapy, indicating the need for other treatment strategies. Accordingly, therapeutics will be targeted against the main mediators behind the underlying molecular mechanisms of the neutrophilic inflammation.

Background: Angiopoietin (Ang)-1 and -2 are involved in the pathogenesis of asthma and have been identified as markers of asthma severity., Objective: To determine the relation between circulating angiopoietins and clinical variables of patients with asthma., Methods: Fifty patients with bronchial asthma and 25 healthy controls were enrolled. Ang1 and Ang2 plasma levels were analyzed in patients with stable and exacerbated asthma., Results: Plasma Ang1 levels were 28.4 ± 4.01 pg/mg in patients with bronchial asthma and 21.2 ± 5.21 pg/mg in healthy controls. Plasma Ang2 levels were 23.96 ± 1.38 pg/mg in patients with bronchial asthma compared with 36.8 ± 4.46 pg/mg in healthy controls (P = .010). The ratio of Ang2 to Ang1 was lower in patients with asthma than in control subjects. Plasma Ang1 concentrations were correlated with the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), and plasma Ang2 levels were correlated with FEV1 percentage of predicted, FEV1/FVC, and total immunoglobulin E values. The ratio of Ang2 to Ang1 was correlated with FEV1 percentage of predicted and FEV1/FVC. Although plasma Ang1 levels tended to be lower in the exacerbated state than in the stable state in patients with asthma, Ang2 levels were higher in the exacerbated state than in the stable state in patients with asthma (P = .001). Plasma Ang2 levels were correlated with initial eosinophil proportions and initial neutrophil proportions. Plasma Ang2 levels and the ratio of Ang2 to Ang1 were correlated with blood eosinophil proportions in the exacerbated state., Conclusion: These results indicate that circulating angiopoietins could be a useful marker of asthma exacerbation., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to evaluate the relation between suicidal ideation, allergic diseases, and excessive Internet use in Korean youth using a national representative dataset., Methods: Data from the Korean Youth Risk Behavior Web-Based Survey (KYRBWS), conducted by the Korean Centers for Disease Control and Prevention, were used in this study. Complex sample logistic regression and structural equation modeling were performed to define the relation between suicidal ideation, allergic disease and excessive Internet use., Results: A total of 73,238 students participated in this survey. In Korea, 19.3% of adolescents had suicidal ideation in the previous year. Asthma (OR=1.23, 95% CI=1.15-1.32, p<0.01) and allergic rhinitis (OR=1.17, 95% CI=1.11-1.22, p<0.01) were identified as risk factors for suicidal ideation after adjusting for school and family factors. Structural equation modeling showed that excessive Internet use interacted with the association between allergic diseases and suicidal ideation., Conclusion: Allergy problems could positively affect suicidal ideation in Korean adolescents. Excessive Internet use could be a mediating factor between allergic disease and suicidal ideation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

Background: Genetic polymorphisms may be responsible for the wide variation in response to inhaled corticosteroids in asthmatic patients. We had previously reported that one polymorphism rs7772821, located on the 3'-UTR of trace amine-associated receptor 6 (TAAR6), is significantly associated with percentile changes in the forced expiratory volume in 1 s (%ΔFEV1) after inhaled corticosteroid treatment in asthmatics using a genome-wide association study. The aim of the present study was to validate the association between 15 single-nucleotide polymorphisms (SNPs) on the TAAR6 and airway responsiveness to inhaled corticosteroids in the asthmatics., Methods: The %ΔFEV1 induced by 4 weeks' treatment with inhaled fluticasone propionate (1000 μg daily) was measured in 246 asthmatics. The 15 SNPs of TAAR6 were genotyped using a TaqMan assay. An association analysis between %ΔFEV1 and TAAR6 polymorphisms was carried out using a linear regression model controlling for age, sex, smoking status, presence of atopy, and baseline FEV1 as covariates., Results: Among the 15 SNPs and seven haplotypes of TAAR6, rs7772821 (T>G) on the 3'-UTR showed the strongest correlation with inhaled corticosteroid-induced %ΔFEV1 (Pcorr=0.002 in the codominant model, Pcorr=0.03 in the dominant model, Pcorr=0.01 in the recessive model). The %ΔFEV1 of the rs7772821T>G minor homozygotes (60.77%) was higher than that of patients harboring either the rs7772821 T/G or T/T genotypes (21.32 and 31.60%, respectively)., Conclusion: The TAAR6 rs7772821 polymorphism may be one of the important genetic factors for predicting the response to treatment with inhaled corticosteroids in asthmatics.

To evaluate the antiallergic effects of oral benzaldehyde in a murine model of allergic asthma and rhinitis, we divided 20 female BALB/c mice aged 8-10 weeks into nonallergic (intraperitoneally sensitized and intranasally challenged to normal saline), allergic (intraperitoneally sensitized and intranasally challenged to ovalbumin), and 200- and 400-mg/kg benzaldehyde (allergic but treated) groups. The number of nose-scratching events in 10 min, levels of total and ovalbumin-specific IgE in serum, differential counts of inflammatory cells in bronchoalveolar lavage (BAL) fluid, titers of Th2 cytokines (IL-4, IL-5, IL-13) in BAL fluid, histopathologic findings of lung and nasal tissues, and expressions of proteins involved in apoptosis (Bcl-2, Bax, caspase-3), inflammation (COX-2), antioxidation (extracellular SOD, HO-1), and hypoxia (HIF-1α, VEGF) in lung tissue were evaluated. The treated mice had significantly fewer nose-scratching events, less inflammatory cell infiltration in lung and nasal tissues, and lower HIF-1α and VEGF expressions in lung tissue than the allergic group. The number of eosinophils and neutrophils and Th2 cytokine titers in BAL fluid significantly decreased after the treatment (P<0.05). These results imply that oral benzaldehyde exerts antiallergic effects in murine allergic asthma and rhinitis, possibly through inhibition of HIF-1α and VEGF., (Copyright © 2014. Published by Elsevier B.V.)

Objectives: Asthma can be suppressed by inhaled corticosteroids (ICS). However, response to ICS shows marked inter-individual variability. This study is aimed to identify the genetic variants associated with the change in the percentage of forced expiratory volume in 1second (%ΔFEV1) following ICS treatment., Methods: A genome-wide association study was performed in a Korean asthmatic cohort. To further investigate these genetic associations, 11 additional single-nucleotide polymorphisms (SNPs) on the allantoicase (ALLC) gene were selected from the HapMap database and genotyped in the same asthmatic patients in the follow-up study., Results: In a genome-wide study, we identified the lowest P-value in ALLC, but none of the SNPs met the genome-wide association criteria (P<1.0×10(-8)). However, among 25 SNPs on ALLC in the follow-up study, 6 variants showed significant associations with the mean %ΔFEV1 in the study subjects (P<3.73×10(-6))., Conclusions: Although the associated signals could not overcome the genome-wide multiple correction due to small sample size (n=189), our results suggest that associated SNPs of ALLC might be genetic predictors of response to ICS, at least with respect to ΔFEV1 in Korean asthmatics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

To better understand the respiratory lipid phenotypes of asthma, we developed a novel method for lipid profiling of bronchoalveolar lavage fluid (BALF) using HPLC-QTOF-MS with an internal spectral library and high-throughput lipid-identifying software. The method was applied to BALF from 38 asthmatic patients (18 patients with nonsteroid treated bronchial asthma [NSBA] and 20 patients with steroid treated bronchial asthma [SBA]) and 13 healthy subjects (NC). We identified 69 lipids, which were categorized into one of six lipid classes: lysophosphatidylcholine (LPC), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), sphingomyelin (SM) and triglyceride (TG). Compared with the NC group, the individual quantity levels of the six classes of lipids were significantly higher in the NSBA subjects. In the SBA subjects, the PC, PG, PS, SM, and TG levels were similar to the levels observed in the NC group. Using differentially expressed lipid species (p value < 0.05, FDR < 0.1 and VIP score of PLS-DA > 1), 34 lipid biomarker candidates with high prediction performance between asthmatics and controls were identified (AUROC > 0.9). These novel findings revealed specific characteristics of lipid phenotypes in asthmatic patients and suggested the importance of future research on the relationship between lipid levels and asthma.

Background: Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis that establishes vascular integrity, and angiopoietin-2 (Ang-2) acts as its natural inhibitor. We considered that angiopoietin might be important in bronchial asthma., Methods: In total, 35 patients with asthma and 20 healthy subjects were studied., Results: The serum Ang-1 levels were significantly elevated in patients with asthma compared to control subjects (293.9 ± 13.8 pg/mL vs. 248.3 ± 16.2 pg/mL, respectively, p = 0.04). The serum Ang-2 levels were not different between the two groups. The areas under the curve (AUC) for serum angiopoietins revealed that the serum level of Ang-1 (0.68) was more sensitive and specific than the serum Ang-2 level (0.55) for differentiating between patients with asthma and control subjects. The serum Ang-1/Ang-2 ratio was correlated with the FEV1/FVC ratio (r = -0.312, p = 0.02), while serum Ang-2 was correlated with body mass index., Conclusions: Our results indicate that the serum Ang-1 levels were higher in asthma patients compared with healthy subjects. As the Ang-1/Ang-2 ratio was related to lung function, the data suggest that serum angiopoietin is associated with lung function in patients with asthma.

Aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with increased asthma severity. To identify plasma biomarkers for the prediction of AERD, the six most abundant plasma proteins (albumin, IgG, antitrypsin, IgA, transferrin, and haptoglobin) in pooled plasma samples were removed using a multiple affinity removal system column. Two-dimensional gel electrophoresis (2DE) was used for differential display proteomic analysis of the pooled plasma. Proteins were identified by matrix assisted laser desorption ionization time-of-flight (MALDI-TOF)/TOF. Enzyme-linked immunosorbent assay (ELISA) was performed to identify and quantify apolipoprotein H (Apo H) in plasma from subjects with AERD and aspirin-tolerant asthma (ATA). Eight protein spots showed differences in relative intensity between pooled plasma from subjects with AERD (n = 8) and those with ATA (n = 8). MALDI-TOF/TOF analysis showed decreases in the levels of alpha-fibrinogen precursor, Apo H, fibrin beta, and proapolipoprotein in AERD as compared with ATA, and increases in chain A human complement component C3, 90-kDa heat shock protein, complement component C4a, and kininogen-1 isoform 2. Apo H concentrations were significantly increased in plasma from subjects with ATA than those with AERD and normal controls, as measured by ELISA (P < 0.01). AERD is characterized by changes in the levels of proteins involved in the coagulation and complement pathways. In addition, Apo H is up-regulated in ATA compared to AERD and normal controls, suggesting that Apo H may be involved in different pathogenesis of ATA from AERD., (Copyright © 2013. Published by Elsevier Ltd.)

Member RAS oncogene family (RAB1A), a member of the RAS oncogene family, cycles between inactive GDP-bound and active GTP-bound forms regulating vesicle transport in exocytosis. Thus, functional alterations of the RAB1A gene may contribute to aspirin intolerance in asthmatic sufferers. To investigate the relationship between single-nucleotide polymorphisms (SNPs) in the RAB1A gene and aspirin-exacerbated respiratory disease (AERD), asthmatics (n=1197) were categorized into AERD and aspirin-tolerant asthma (ATA). All subjects were diagnosed as asthma on the basis of the Global Initiative for Asthma (GINA) guidelines. AERD was defined as asthmatics showing 15% or greater decreases in forced expiratory volume in one second (FEV(1)) or naso-ocular reactions by the oral acetyl salicylic acid (ASA) challenge (OAC) test. In total, eight SNPs were genotyped. Logistic regression analysis identified that the minor allele frequency of +14444 T>G and +41170 C>G was significantly higher in the AERD group (n=181) than in the ATA group (n=1016) (p=0.0003-0.03). Linear regression analysis revealed a strong association between the SNPs and the aspirin-induced decrease in FEV(1) (p=0.0004-0.004). The RAB1A gene may play a role in the development of AERD in asthmatics and the genetic polymorphisms of the gene have the potential to be used as an indicator of this disease.

Air pollutants and obesity are important factors that contribute to asthma. The aim of this study was to assess the airway responsiveness and inflammation in Otsuka-Long Evans Tokushima Fatty (OLETF) obese rats and Long Evans Tokushima-Otsuka (LETO) nonobese rats exposed to diesel exhaust particles (DEPs). Otsuka Long Evans Tokushima fatty rats and LETO rats were exposed intranasally to DEP and then challenged with aerosolized DEP on days 6 to 8. Body plethysmography, bronchoalveolar lavage (BAL), and histology were performed. Enhanced pause (Penh) was measured as an indicator of airway resistance on day 9 and samples were collected on day 10. After exposure to DEP, the OLETF group exhibited a greater increase in Penh compared to that in the LETO group. Moreover, the BAL fluid in mice showed an increase in the total and differential cell counts in the DEP-exposed OLETF group compared to that in the DEP-exposed LETO group. Histological assessment of lung tissue from each group revealed that the DEP-exposed OLETF group tended to have increased inflammatory cell infiltrations in the prebronchial area. Increased peroxisome proliferator-activated receptor γ, coactivator 1β messenger RNA was observed in the lungs of obese rats compared to that in nonobese rats following DEP exposure. These data indicate that the DEP-exposed OLETF group had increased airway responses and inflammation compared to the DEP-exposed LETO group, indicating that diesel particulates and obesity may be co-contributors to asthma.

Background: Neutrophilic airway inflammation is frequently observed in severe uncontrolled asthma (UA) and controlled asthma (CA). However, there is no sputum biomarker to differentiate the 2 conditions., Objective: To identify biomarkers of severe uncontrolled asthma with neutrophilic airway inflammation., Methods: Sputum with a neutrophil content larger than 70% was pooled from 5 patients with severe UA and from 10 patients with CA. Two-dimensional electrophoresis was adopted for differential display proteomics, and candidate proteins were identified using matrix-assisted laser adsorption/ionization-time of flight mass spectrometric analysis. S100 calcium binding protein A9 (S100A9) was identified by western blot and its level was measured in sputum from asthmatics with varying disease severity, patients with chronic obstructive lung disease, and normal controls using enzyme-linked immunosorbent assay., Results: Fourteen protein spots exhibited differences in relative intensity between patients with severe UA and those with CA. Matrix-assisted laser adsorption/ionization-time of flight/time of flight of these spots showed an increase in human neutrophil peptide-2, S100A9, β-amylase, neutrophil gelatinase-associated lipocalin, 4-aminobutyrate transaminase, and cystatin SA in patients with UA compared with patients with CA. There was a decrease in the plunc precursor, complement C3 component, immunoglobulin heavy-chain variable region, glial fibrillary acidic protein isoform-1, IgM κIIIb SON, MLL-AF4 der(11) fusion protein, cytokeratin-8, and recombinant IgG4 heavy chain. S100A9 was detected at a higher level in western blots of neutrophilic sputum from patients with severe UA vs CA. S100A9 levels were significantly increased, as measured by enzyme-linked immunosorbent assay, in neutrophilic UA compared with CA, eosinophilic UA and CA, and chronic obstructive lung disease., Conclusion: S100A9 in sputum may be a biomarker of neutrophilic inflammation in severe UA., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin E (IgE) is one of the central players in asthma and allergic diseases. Although the serum IgE level, a useful endophenotype, is generally increased in patients with asthma, genetic factors influencing IgE regulation in asthma are still not fully understood. To identify the genetic variations associated with total serum and mite-specific IgEs in asthmatics, a genome-wide association study (GWAS) of 657,366 single nucleotide polymorphisms (SNPs) was performed in 877 Korean asthmatics. This study found that several new genes might be associated with total IgE in asthmatics, such as CRIM1 (rs848512, P = 1.18×10(-6); rs711254, P = 6.73×10(-6)), ZNF71 (rs10404342, P = 7.60×10(-6)), TLN1 (rs4879926, P = 7.74×10(-6)), and SYNPO2 (rs1472066, P = 8.36×10(-6); rs1038770, P = 8.66×10(-6)). Regarding the association of specific IgE to house dust mites, it was observed that intergenic SNPs nearby to OPRK1 and LOC730217 might be associated with Dermatophagoides pteronyssinus (D.p.) and Dermatophagoides farinae (D.f.) in asthmatics, respectively. In further pathway analysis, the phosphatidylinositol signaling system and adherens junction pathways were estimated to play a role in the regulation of total IgE levels in asthma. Although functional evaluations and replications of these results in other populations are needed, this GWAS of serum IgE in asthmatics could facilitate improved understanding of the role of the newly identified genetic variants in asthma and its related phenotypes.

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.

Background: In this study, the association of asthma with CD53, a member of the tetraspanin family, was assessed for the first time in a mechanism-based study., Methods: Genetic polymorphisms of CD53 were analyzed in 591 subjects and confirmed in a replication study of 1001 subjects. CD53 mRNA and protein levels were measured in peripheral blood leukocytes, and the effects of the promoter polymorphisms on nuclear factor binding were examined by electrophoretic mobility shift assay. Cellular functional studies were conducted by siRNA transfections., Results: Among tagging SNPs of CD53, the -1560 C>T in the promoter region was significantly associated with asthma risk. Compared with the CC genotype, the CT and TT genotypes were associated with a higher asthma risk, with odd ratios of 1.74 (P=0.009) and 2.03 (P=0.004), respectively. These findings were confirmed in the replication study with odd ratios of 1.355 (P=0.047) and 1.495 (P=0.039), respectively. The -1560 C>T promoter SNP had functional effects on nuclear protein binding as well as mRNA and protein expression levels in peripheral blood leukocytes. When CD53 was knocked down by siRNA in THP-1 human monocytic cells stimulated with house dust mite, the production of inflammatory cytokines as well as NFκB activity was significantly over-activated, suggesting that CD53 suppresses over-activation of inflammatory responses., Conclusions: The -1560 C>T SNP is a functional promoter polymorphism that is significantly associated with population asthma risk, and is thought to act by directly modulating nuclear protein binding, thereby altering the expression of CD53, a suppressor of inflammatory cytokine production., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Asthma is a common respiratory disease that is characterized by bronchial hyperresponsiveness and airway obstruction due to chronic airway inflammation. Atopic asthma is a typical IgE-mediated disease in which the enhanced production of IgE is driven by the activation of Th2 cells, which release a distinct pattern of cytokines, including interleukin 4 (IL4) and IL3, in response to specific antigen presentation. To evaluate the methylation status of the whole genomes of bronchial mucosa tissues from subjects who lacked or had sensitization to Dermatophagoides farina (Df) and Dermatophagoides pteronyssinus (Dp)., Methods: The genome-wide DNA methylation levels in the bronchial mucosa tissues of atopic asthmatics (N=10), non-atopic asthmatics (N=7), and normal controls (N=7) were examined using microarrays., Results: In the bronchial mucosa of atopic asthmatics, hypermethylation was detected at 6 loci in 6 genes, while hypomethylation was detected at 49 loci in 48 genes compared to those of non-atopic asthmatics. Genes that were assigned the ontologies of multicellular organismal process, response to organic substance, hormone metabolic process, and growth factor receptor binding were hypomethylated. The methylation levels in the mucosa of asthmatics and normal controls were similar., Conclusions: The bronchial mucosa of asthmatics who are atopic to Df or Dp have characteristic methylation patterns for 52 genes. The genes and pathways identified in the present study may be associated with the presence of atopy in asthmatics and therefore represent attractive targets for future research.

Nasal polyps are abnormal lesions arising mainly from the nasal mucosa and paranasal sinuses. Since the human class II, major histocompatibility complex, transactivator (CIITA) is a positive regulator of class II, major histocompatibility complex gene transcription, the CIITA gene is thought to be involved in the presence of nasal polyps in asthma and aspirin hypersensitive patients. To investigate the association between CIITA and nasal polyposis, 18 single nucleotide polymorphisms (SNPs) were genotyped in 467 asthmatics who were classified into 158 aspirin-exacerbated respiratory disease (AERD) and 309 aspirin-tolerant asthma (ATA) subgroups. Differences in the frequency distribution of CIITA variations between polyp-positive cases and polyp-negative controls were determined using logistic analyses. Initially, a total of 9 CIITA variants were significantly associated with the presence of nasal polyps in the overall asthma, AERD and ATA groups [P=0.001-0.05, odds ratio (OR)=0.53-2.35 in the overall asthma group; P=0.01-0.02, OR=2.45-2.66 in the AERD group; P=0.001‑0.05, OR=0.45-2.61 in the ATA group using various modes of genetic inheritance]. One the variations (rs12932187) retained this association after multiple testing corrections (Pcorr=0.01) in the overall asthma group. In addition, two variations (rs12932187 and rs11074938) were associated with the presence of nasal polyps following multiple testing corrections (Pcorr=0.02 and 0.04, respectively) in the ATA group. These novel findings suggest that rs12932187 and rs11074938 may constitute susceptibility markers of inflammation of the nasal passages in asthma patients.

Background: Refractory asthma, a subtype of asthma with uncontrolled symptoms despite antiasthma medications, is a heterogeneous syndrome with variable clinical features, presumably different etiologies, and pathophysiological mechanisms. The heterogeneity of refractory asthma, however, is poorly understood. We aimed to characterize refractory asthma and to improve our understanding of the heterogeneity of refractory asthma patients., Methods: We identified refractory asthma patients (n = 96) as defined by the American Thoracic Society's criteria from a cohort of Korean asthma patients (n = 2,187). Then, cluster analysis was conducted to classify subtypes of refractory asthma., Results: Among the study group, 4.4 % (n = 96) of all asthma patients had refractory asthma. Cluster analysis identified four distinct groups of refractory asthma. Age at onset was younger in clusters 1 and 2 than in clusters 3 and 4. Patients in cluster 1 had the most well-preserved pulmonary function; patients in cluster 2 had a female predominance and the most severe airway obstruction; patients in cluster 3 were mostly female and had the most enhanced bronchial hyperresponsiveness; and patients in cluster 4 were most male and tended to be cigarette smokers., Conclusions: The current results suggest that refractory asthma is a heterogeneous syndrome and could be classified into four subtypes. Underlying pathogenesis and therapeutic approaches may differ for the different subtypes and further research is needed.

Background: Aspirin-intolerant asthma is a unique clinical syndrome characterized by acute bronchoconstriction following the administration of aspirin and/or non-steroidal anti-inflammatory drugs., Objective: We assessed the prevalence and investigated the demographic and clinical characteristics of adult patients with aspirin-intolerant asthma in Korea., Methods: Using an adult asthma cohort (COREA) from 11 university hospitals in Korea, we analyzed the prevalence of aspirin-intolerant asthma, defined as a positive response to the question: "Have you ever experienced dyspnea and cough after taking an aspirin or any NSAID (cold medicine)?" Demographic and clinical characteristics were compared between patients with aspirin-intolerant asthma and aspirin-tolerant asthma., Results: Aspirin-intolerant asthma was reported in 68 (5.8%) of 1173 adult asthmatics (age 15-84). Patients with aspirin-intolerant asthma had a lower mean age (43.9 ± 13.4 vs. 49.0 ± 15.6, P = 0.003) and a higher prevalence of rhinosinusitis (77.9% vs. 61.7%, P = 0.012) and atopic dermatitis (16.2% vs. 5.7%, P = 0.001) than aspirin-tolerant asthma patients. There were no significant differences in lung function, asthma severity or the use of asthma controllers. However, aspirin-intolerant asthma was associated with greater use of healthcare services over a lifetime and over the past 12 months. Aspirin-intolerant asthma was significantly associated with emergency room visits over the past 12 months (P = 0.029, OR 2.19, 95% CI 1.08-4.42)., Conclusion: Based on histories, the prevalence of aspirin-intolerant asthma is 5.8% among adult asthma patients in Korea. Aspirin-intolerant asthma is associated with lower age, higher prevalence of rhinosinusitis and atopic dermatitis, and more frequent exacerbations., (Copyright © 2012. Published by Elsevier Ltd.)

Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma., (Copyright © 2012 Elsevier Inc. All rights reserved.)