Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

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.

Predictors of Early and Late Lung Function Improvement in Severe Eosinophilic Asthma on Type2-Biologics in the PRISM Study.

BACKGROUND: The determinants linked to the short- and long-term improvement in lung function in patients with severe eosinophilic asthma (SEA) on biological treatment (BioT) remain elusive. OBJECTIVE: We sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT. METHODS: 140 adult patients with SEA who received mepolizumab, dupilumab, or reslizumab were followed up for 6 months to evaluate improvement in forced expiratory volume in one second (FEV1). Logistic regression was used to determine the association between potential prognostic factors and improved lung function at 1 and 6 months of treatment. RESULTS: More than a third of patients with SEA using BioT showed early and sustained improvements in FEV1 after 1 month. A significant association was found between low baseline FEV1 and high blood eosinophil count and sustained FEV1 improvement after 1 month (0.54 [0.37-0.79] and 1.88 [1.28-2.97] odds ratios and 95% confidence interval, respectively). Meanwhile, among patients who did not experience FEV1 improvement after 1 month, 39% exhibited improvement at 6 months follow-up. A high ACT score measured at this visit was the most reliable predictor of late response after 6 months of treatment (OR and 95% CI 1.75 [1.09-2.98]). CONCLUSION: Factors predicting the efficacy of biological agents that improve lung function in SEA vary according to the stage of response.

Transporting randomized trial results to estimate counterfactual survival functions in target populations.

When the distributions of treatment effect modifiers differ between a randomized trial and an external target population, the sample average treatment effect in the trial may be substantially different from the target population average treatment, and accurate estimation of the latter requires adjusting for the differential distribution of effect modifiers. Despite the increasingly rich literature on transportability, little attention has been devoted to methods for transporting trial results to estimate counterfactual survival functions in target populations, when the primary outcome is time to event and subject to right censoring. In this article, we study inverse probability weighting and doubly robust estimators to estimate counterfactual survival functions and the target average survival treatment effect in the target population, and provide their respective approximate variance estimators. We focus on a common scenario where the target population information is observed only through a complex survey, and elucidate how the survey weights can be incorporated into each estimator we considered. Simulation studies are conducted to examine the finite-sample performances of the proposed estimators in terms of bias, efficiency and coverage, under both correct and incorrect model specifications. Finally, we apply the proposed method to assess transportability of the results in the Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) trial to all adults with Diabetes in the United States.

Prospective direct comparison of biologic treatments for severe eosinophilic asthma: Findings from the PRISM study.

BACKGROUND: Although various monoclonal antibodies have been used as add-on therapy for severe eosinophilic asthma (SEA), to the best of our knowledge, no direct head-to-head comparative study has evaluated their efficacy. OBJECTIVE: To compare the efficacy of reslizumab, mepolizumab, and dupilumab in patients with SEA. METHODS: This was a multicenter, prospective observational study in patients with SEA who had received 1 of these biologic agents for at least 6 months. Cox proportional hazard models were used to compare the risk of the first exacerbation event, adjusting for sputum or blood eosinophils and common asthma-related covariates. The annual exacerbation rate was analyzed using a negative binomial model, and a mixed-effect model was used to analyze changes in forced expiratory volume in 1 second and asthma control test score over time. RESULTS: A total of 141 patients with SEA were included in the analysis; 71 (50%) received dupilumab; 40 (28%) received reslizumab, and 30 (21%) received mepolizumab. During the 12-month follow-up, 27.5%, 43.3%, and 38.0% of patients in the reslizumab, mepolizumab, and dupilumab groups, respectively, experienced at least 1 exacerbation. However, after adjusting for confounding factors, the dupilumab and mepolizumab groups showed similar outcomes in time-to-first exacerbation, exacerbation rate, forced expiratory volume in 1 second, and asthma control test score to those of the reslizumab group. CONCLUSION: In patients with SEA, treatment with reslizumab, mepolizumab, and dupilumab resulted in comparable clinical outcomes within a 12-month period. TRIAL REGISTRATION: The cohort protocol was sanctioned by the Institutional Review Board of each study center (clinicaltrial.gov identifier NCT05164939).

Risk of asthma and/or wheezing in obese individuals with or without metabolic syndrome: From the Korea National Health and Nutrition Examination Survey data.

Introduction: Obesity increases the risk of asthma; however, whether metabolic syndrome (MS), with obesity being one of its five components, is also associated with increased asthma risk remains unclear. Objective: To investigate the association between the risk of asthma and obesity, MS, and each component of MS. Methods: We performed a cross-sectional study of 41,480 Korean adults by using data from the 2007-2016 Korean National Health and Nutrition Examination Survey. Asthma was defined as a history of physician-diagnosed asthma or wheezing sound within the past 12 months. Results: The adjusted odds ratio (OR) for asthma was significantly increased in participants with obesity (OR 1.30 [95% confidence interval {CI}, 1.27-1.33]; p < 0.0001) and MS (OR 1.23 [95% CI, 1.20-1.25]; p < 0.0001). Obesity and MS showed an additive effect (OR 1.38 [95% CI, 1.34-1.41]; p < 0.001), followed by obesity(+)MS(-) (OR 1.28 [95% CI, 1.25-1.31]; p < 0.001) and obesity(-)MS(+) (OR 1.14 [95% CI, 1.10-1.18]; p < 0.001). Among each metabolic component, only abdominal obesity (OR 1.28 [95% CI, 1.24-1.32]; p < 0.001) and hypertension (OR 1.16 [95% CI, 1.12-1.20]; p < 0.001) significantly increased the risk of asthma. Unlike the female patients (OR 1.39 [95% CI, 1.35-1.43]; p < 0.001), having MS showed a lower risk of asthma in the male patients (OR 0.79 [95% CI, 0.75-0.82]; p < 0.001). Conclusion: The risk of asthma was highest when both obesity and MS were present, followed by obesity alone and MS alone. Abdominal obesity and hypertension were associated with an increased asthma risk, and there was a sex difference that MS lowered the risk of asthma in Korean male patients.

A comparison of treatment response to biologics in asthma-COPD overlap and pure asthma: Findings from the PRISM study.

Background: Despite the increasing use of biologics in severe asthma, there is limited research on their use in asthma-chronic obstructive pulmonary disease overlap (ACO). We compared real-world treatment responses to biologics in ACO and asthma. Methods: We conducted a multicenter, retrospective, cohort study using data from the Precision Medicine Intervention in Severe Asthma (PRISM). ACO was defined as post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and a smoking history of >10 pack-years. Physicians selected biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) based on each United States Food & Drug Administration (FDA) approval criteria. Results: After six-month treatment with biologics, both patients with ACO (N = 13) and asthma (N = 81) showed positive responses in FEV1 (10.69 ± 17.17 vs. 11.25 ± 12.87 %, P = 0.652), Asthma Control Test score (3.33 ± 5.47 vs. 5.39 ± 5.42, P = 0.290), oral corticosteroid use (-117.50 ± 94.38 vs. -115.06 ± 456.85 mg, P = 0.688), fractional exhaled nitric oxide levels (-18.62 ± 24.68 vs. -14.66 ± 45.35 ppb, P = 0.415), sputum eosinophils (-3.40 ± 10.60 vs. -14.48 ± 24.01 %, P = 0.065), blood eosinophils (-36.47 ± 517.02 vs. -363.22 ± 1294.59, P = 0.013), and exacerbation frequency (-3.07 ± 4.42 vs. -3.19 ± 5.11, P = 0.943). The odds ratio for exacerbation and time-to-first exacerbation showed no significant difference after full adjustments, and subgroup analysis according to biologic type was also showed similar results. Conclusions: Biologics treatment response patterns in patients with ACO and asthma were comparable, suggesting that biologics should be actively considered for ACO patients as well.

WITHDRAWN: Prospective direct comparison of biological treatments on severe eosinophilic asthma: Findings from the PRISM study.

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Associations Between Hospital Volume and Overall Survival After Surgery in Older Patients with Breast Cancer.

BACKGROUND: High-volume hospitals (HVHs) are associated with improved overall survival (OS) following surgery for breast cancer compared with low-volume hospitals (LVHs). We examined this association in patients age ≥ 80 years and described patient and treatment characteristics associated with HVHs. PATIENTS AND METHODS: The National Cancer Database was queried for women age ≥ 80 years who underwent surgery for stage I-III breast cancer between 2005 and 2014. Hospital volume was defined as the average number of cases during the year of the patient's index operation and the year prior. Hospitals were categorized into HVHs and LVHs using penalized cubic spline analysis of OS. A cutoff of ≥ 270 cases/year defined HVHs. RESULTS: Among 59,043 patients, 9110 (15%) were treated at HVHs and 49,933 (85%) at LVHs. HVHs were associated with more non-Hispanic Black and Hispanic patients, earlier stage disease (stage I 54.9% vs. 52.6%, p < 0.001), higher rates of breast-conserving surgery (BCS) (68.3% vs. 61.4%, p < 0.001), and adjuvant radiation (37.5% vs. 36.1%, p = 0.004). Improved OS was associated with surgery at a HVH (HR 0.85, CI 0.81-0.88), along with receipt of adjuvant chemotherapy (HR 0.73, CI 0.69-0.77), endocrine therapy (HR 0.70, CI 0.68-0.72), and radiation (HR 0.66, CI 0.64-0.68). CONCLUSIONS: Among patients with breast cancer age ≥ 80 years, undergoing surgery at a HVH was associated with improved OS. Patients who completed surgery at HVHs had earlier stage disease and more commonly received adjuvant radiation when appropriate. Processes of care at HVHs should be identified to improve outcomes in all settings.

Epidemiology of patients with asthma in Korea: Analysis of the NHISS database 2006-2015.

Background: There has been a concerning increase in the prevalence and socioeconomic burden of asthma in Korea. Korea's National Health Insurance System (NHIS) covers insurance payment and claims management for all Koreans. Using National Health Insurance Sharing Service (NHISS) claims data. This study aimed to investigate patterns of healthcare utilization and direct cost in patients with asthma over a 10-year period. Methods: In this retrospective population-based study, we examined NHISS claims records between July 2005 and June 2016 and investigated healthcare utilization among patients with asthma based on age group and severity of disease (non-severe asthma [NSA] and severe asthma [SA]). Results: From 2006 to 2015, the total number of patients with asthma in Korea steadily increased from 743 968 to 2 286 309, with a corresponding increase in prevalence from 1.62% to 4.74%. The proportion of patients with SA decreased from 3.16% in 2006 to 1.56% in 2015; the proportion was consistently higher in men than in women. In addition, patients with SA had a higher cost per outpatient visit than patients with NSA, and the number of outpatient visits per year increased. The inhaled corticosteroid (ICS) prescription rate among patients with asthma decreased from 22.9% in 2006 to 15.7% in 2015. Furthermore, for a period of 10 years, more than 40% of patients with SA have been prescribed short-acting ß-2 agonists (SABAs). Conclusions: Although patients with SA comprised a small proportion of patients with asthma, they incurred greater medical costs per person. The pharmaceutical prescription pattern indicated a lack of ICS-based prescriptions and frequent SABA prescriptions.

Fat mass index and airway hyperresponsiveness in Korean adults.

OBJECTIVE: Airway hyperresponsiveness (AHR) is associated with asthma and obesity, which is defined as a high body mass index. Body mass mainly comprises fat mass (FM) and muscle mass (MM), which are independent of each other. We investigated the effect of changes in FM over time on the development of asymptomatic AHR in adults. METHODS: This long-term longitudinal study included adults who were underwent health checkups at the Seoul National University Hospital Gangnam Center. The participants underwent two methacholine bronchial provocation tests with a follow-up period (between the first and second tests) of more than 3 years and bioelectrical impedance analysis (BIA) at all visits. FM index (FMI; FM normalized for height) and MM index (MMI; MM normalized for height) were calculated using BIA. RESULTS: The study included 328 adult participants (61 women and 267 men). The mean number of BIA measurements was 6.96 and the follow-up duration was 6.69 years. In total, 13 participants showed a positive conversion of AHR. Multivariate analysis indicated that a high rate of change in FMI ([g/m2]/year), not MMI, was significantly associated with the risk of AHR development (P = 0.037) after adjustment for age, sex, smoking status, and FEV1 predicted. CONCLUSION: A rapid gain of FM over time may be a risk factor for developing AHR in adults. Prospective studies are needed to confirm our results and evaluate the role of FM reduction in preventing AHR development in obese adults.

Inhibition of glutaminase 1 activity reverses airway hyperresponsiveness and decreases IL-1ß+ M1s and IL-17 producing ILC3s in high-fat diet-fed obese mice.

In obesity, disturbed glutamine metabolism contributes to enhanced inflammation by inducing alterations in immune cells. As macrophages and innate lymphoid cells (ILCs) are known to be involved in the pathogenesis of obesity-related asthma, we tested our hypothesis that altered glutamine metabolism may link obesity to airway hyperresponsivenss (AHR), a cardinal feature of asthma, focusing on these innate immune cells. Four-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 13 wk in the presence or absence of BPTES [Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide, a selective inhibitor of glutaminase 1 which converts glutamine to glutamate] and their blood, lung, and adipose tissues were analyzed. We then conducted in vitro experiments using bone marrow-derived macrophages (BMDMs) and mouse alveolar macrophage cell line. Furthermore, we investigated plasma glutamine and glutamate levels in obese and nonobese asthmatics. BPTES treatment prevented HFD-induced AHR and significantly decreased IL-1ß+ classically activated macrophages (M1s) and type 3 ILCs (ILC3s) which increased in the lungs of HFD-fed obese mice. In in vitro experiments, BPTES treatment or glutamine supplement significantly reduced the proportion of IL-1ß+NLRP3+ M1s in lipopolysaccharide-stimulated BMDMs and mouse alveolar macrophage cell line. BPTES treatment also significantly reduced the IL-17 producing ILC3s differentiated from ILCs in naïve mouse lung. In addition, plasma glutamate/glutamine ratios were significantly higher in obese asthmatics compared to nonobese asthmatics. Inhibition of glutaminolysis reverses AHR in HFD-induced obese mice and decreases IL-1ß + NLRP3+ M1s and IL-17 producing ILC3s, which suggests altered glutamine metabolism may have a role in the pathogenesis of obesity-related AHR.

Refined moderation analysis with categorical outcomes in precision medicine.

Moderation analysis is an integral part of precision medicine research. Concerning moderation analysis with categorical outcomes, we start with an interesting observation, which shows that heterogeneous treatment effects could be equivalently estimated via a role exchange between the outcome and the treatment variable in logistic regression models. Hence two estimators of moderating effects can be obtained. We then established the joint asymptotic normality for the two estimators, on which basis refined inference can be made for moderation analysis. The improved precision is helpful in addressing the lack-of-power problem that is common in search of moderators. The above-mentioned results hold for both experimental and observational data. We investigate the proposed method by simulation and provide an illustration with data from a randomized trial on wart treatment.

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.

Diagnostic accuracy of dermoscopy for onychomycosis: A systematic review.

Background: Dermoscopy is a non-invasive adjuvant diagnostic tool that allows clinicians to visualize microscopic features of cutaneous disorders. Recent studies have demonstrated that dermoscopy can be used to diagnose onychomycosis. We performed this systematic review to identify the characteristic dermoscopic features of onychomycosis and understand their diagnostic utility. Methods: We searched the Medline, Embase, Scopus, and Cochrane databases from conception until May 2021. Studies on the dermoscopic features of onychomycosis were screened. The exclusion criteria were as follows: fewer than 5 cases of onychomycosis, review articles, and studies including onychomycosis cases that were not mycologically verified. Studies on fungal melanonychia were analyzed separately. We adhered to the MOOSE guidelines. Independent data extraction was performed. Data were pooled using a random effects model to account for study heterogeneity. The primary outcome was the diagnostic accuracy of the dermoscopic features of onychomycosis. This was determined by pooling the sensitivity and specificity values of the dermoscopic features identified during the systematic review using the DerSimonian-Laird method. Meta-DiSc version 1.4 and Review Manager 5.4.1 were used to calculate these values. Results: We analyzed 19 articles on 1693 cases of onychomycosis and 5 articles on 148 cases of fungal melanonychia. Commonly reported dermoscopic features of onychomycosis were spikes or spiked pattern (509, 30.1%), jagged or spiked edges or jagged edge with spikes (188, 11.1%), jagged proximal edge (175, 10.3%), subungual hyperkeratosis (131, 7.7%), ruins appearance, aspect or pattern (573, 33.8%), and longitudinal striae (929, 54.9%). Commonly reported features of fungal melanonychia included multicolor (101, 68.2%), non-longitudinal homogenous pigmentation (75, 50.7%) and longitudinal white or yellow streaks (52, 31.5%). Conclusion: This study highlights the commonly identified dermoscopic features of onychomycosis. Recognizing such characteristic dermoscopic features of onychomycosis can assist clinicians diagnose onychomycosis by the bedside.

Multicenter Prospective Observational Study to Evaluate the Therapeutic Effect and Safety of a Combination of Montelukast and Levocetirizine for Allergic Rhinitis when Administered to Patients with Allergic Rhinitis and Asthma.

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.

Regression trees and ensembles for cumulative incidence functions.

The use of cumulative incidence functions for characterizing the risk of one type of event in the presence of others has become increasingly popular over the past two decades. The problems of modeling, estimation and inference have been treated using parametric, nonparametric and semi-parametric methods. Efforts to develop suitable extensions of machine learning methods, such as regression trees and ensemble methods, have begun comparatively recently. In this paper, we propose a novel approach to estimating cumulative incidence curves in a competing risks setting using regression trees and associated ensemble estimators. The proposed methods use augmented estimators of the Brier score risk as the primary basis for building and pruning trees, and lead to methods that are easily implemented using existing R packages. Data from the Radiation Therapy Oncology Group (trial 9410) is used to illustrate these new methods.

Association Between Clinical Burden and Blood Eosinophil Counts in Asthma: Findings From a Korean Adult Asthma Cohort.

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.

Association of genetic variants of oxidative stress responsive kinase 1 (OXSR1) with asthma exacerbations in non-smoking asthmatics.

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.

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.