Summary Box Plasma 1‐methylnicotinamide is elevated in dupilumab responders, outperforming conventional type‐2 biomarkers. Combining 1‐methylnicotinamide with FeNO achieves the highest predictive accuracy for dupilumab treatment response.

BACKGROUND:Type 2 (T2)-low asthma is often less responsive to inhaled corticosteroids (ICS); however, optimal controller strategies for this phenotype remain inadequately defined. OBJECTIVE:To evaluate whether long-acting muscarinic antagonists (LAMA) are non-inferior to ICS in patients with T2-low mild asthma. METHODS:In this multicenter, pragmatic, randomized, open-label, crossover trial, adults with T2-low mild asthma (blood eosinophils <300/μL, and either FeNO <25 ppb or sputum eosinophils <3%) were randomized 1:1 to 6 months of ICS followed by 6 months of LAMA, or vice versa. The primary outcome was a composite treatment-success endpoint. Non-inferiority was established if the lower bound of the 95% confidence interval (CI) for the success rate difference was greater than -10 percentage points. RESULTS:Among 150 randomized patients, 89 completed both phases (per-protocol population). Treatment success was 7.9 percentage points higher with LAMA (95% CI, -2.9 to 18.8; P<0.001), consistent with two intention-to-treat analyses (risk differences, 4.1-4.2 percentage points). In another intention-to-treat analysis where all uncompleted phases were considered as failures, non-inferiority was not established (-3.3 percentage points; 95% CI, -11.3 to 4.5), though it was supported under a non-responder imputation approach for missing data (one-sided P = 0.020). The favorable effect was more pronounced in patients aged <65 years. Exacerbation rates did not differ significantly, and symptom control and lung function remained stable across both phases. CONCLUSION:In patients with T2-low mild asthma, LAMA monotherapy may be non-inferior to ICS and may be considered an alternative controller option for selected patients.

BACKGROUND:Phenotype-based asthma classification has limitations that have motivated endotype-based approaches grounded in pathophysiology. However, existing biomarkers offer limited specificity and clinical accessibility. Plasma metabolomics, which reflects disease-specific metabolic states, offers a promising strategy for asthma classification. This study aimed to identify metabolic subgroups (metabotypes) of adult asthma using plasma metabolomics, with potential implications for personalized treatment. METHODS:Plasma samples from 407 patients with asthma in the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) were analyzed using Biocrates AbsoluteIDQ p400 HR kit with liquid chromatography-mass spectrometry. After preprocessing, 281 metabolites were natural-log-transformed, standardized, and partitioned by k-means clustering. The number of clusters was determined by a multi-criteria assessment combining cluster validity indices, consensus clustering, stability analysis, and cross-algorithm agreement. RESULTS:Four metabotypes with distinct lipid-class signatures were identified. Group 1 (n = 123) was characterized by elevated ether-linked phosphatidylcholines, comprising younger patients with the earliest symptom onset and female predominance. Group 2 (n = 53) showed elevated lyso-phosphatidylcholines and altered amino acid metabolism (elevated glutamate, reduced glutamine), representing a metabolically intermediate, non-T2-high subgroup. Group 3 (n = 158) exhibited globally reduced sphingomyelins and broadly lower phosphatidylcholines in middle-aged, non-obese patients. Group 4 (n = 73) showed markedly elevated triacylglycerols (TG) and diacylglycerols (DG) with the highest body mass index (BMI), consistent with a non-T2, obesity-related metabotype. The TG/DG signature of Group 4 remained robust after adjustment for BMI, age, and sex. CONCLUSION:Plasma metabolomics identifies clinically meaningful asthma metabotypes, supporting integration of metabolomic profiling into personalized asthma management.

BACKGROUND:The combination of pretreatment peripheral blood eosinophil count (BEC) and FeNO levels for optimizing the therapeutic response of T2-biologics in patients with severe eosinophilic asthma (SEA) remains unclear. OBJECTIVE:To compare longitudinal clinical outcome changes across subgroups stratified by the combination of high and low levels of BEC and FeNO. METHODS:Overall, 278 patients with SEA (anti-IL-5/IL-5Rα users: n = 82; and anti-IL-4Rα users: n = 196) were stratified based on pretreatment BEC and FeNO levels and observed for 6 to 12 months. Group differences in exacerbation rate, lung function, Asthma Control Test, BEC, FeNO, and clinical remission over time were compared. RESULTS:Approximately 75% and 63% of patients presented with concurrent high BEC (≥300 cells/μL) and high FeNO (≥25 ppb) in the anti-IL-5/IL-5Rα and anti-IL-4Rα groups, respectively. Among anti-IL-5/IL-5Rα users, we observed no significant differences among BEC-FeNO groups regarding exacerbation rates or clinical remission. Patients with concurrent high BEC and FeNO levels demonstrated more pronounced reductions in both markers and greater FEV1 and Asthma Control Test score improvements compared with those with high FeNO but low BEC. In the anti-IL-4Rα group, patients with low BEC and FeNO, and those with high BEC but low FeNO, exhibited a significantly lower likelihood of achieving clinical remission (odds ratio [95% CI]: 0.08 [0.00-0.46] and 0.11 [0.01-0.63], respectively) and a slower rate of FEV1 improvement (all P for slope < .05) compared with those with concurrent high BEC and FeNO. CONCLUSION:Concurrently elevated BEC and FeNO levels ensure optimal therapeutic response in patients with SEA who are treated with T2 biologics.

Background:The relationship between pre-treatment levels of blood eosinophil count (BEC), fractional exhaled nitric oxide (F ENO) and sputum eosinophils (Sp-EOS) and treatment response to monoclonal antibodies (mAbs) in severe eosinophilic asthma (SEA) remains unclear. We evaluated pre-treatment levels of BEC, F ENO, Sp-EOS and their combinations as predictors of treatment responses in patients with SEA undergoing anti-interleukin (IL)-5/IL-5Rα or anti-IL-4Rα antibody therapies. Methods:The study included 153 adult patients with SEA (59 anti-IL-5/IL-5Rα and 94 anti-IL-4Rα users). Logistic regression models were used to evaluate the association between predictors and 12-month treatment responses and clinical remission across four domains: exacerbation rate, maintenance of oral corticosteroid dose, forced expiratory volume in 1 s (FEV1) and asthma control test (ACT) improvement. Results:Pre-treatment BEC and Sp-EOS were not associated with treatment responses in either mAb group. For combined data from anti-IL-5/IL-5Rα and anti-IL-4Rα users, the adjusted odds ratios (95% confidence intervals) for a 1-unit increase in log-transformed F ENO were 1.8 (1.21-2.74) for FEV1 response and 2.15 (1.29-3.75) for ACT response. For anti-IL-4Rα users, these values were 2.34 (1.39-4.17) and 3.6 (1.73-8.84), respectively. No significant association between F ENO and treatment response was found among anti-IL-5/IL-5Rα users. Additionally, no associations were observed between BEC, Sp-EOS or F ENO and clinical remission across mAb categories. Combining biomarkers did not significantly enhance predictive ability. Conclusion:In patients with SEA treated with anti-IL-4Rα antibodies, pre-treatment F ENO may be a good predictor for certain treatment response domains.

Background Despite treatment advances, managing asthma remains challenging owing to variability in response across different type 2 inflammation phenotypes. We aimed to compare the differences in pre-treatment profiles related to 12-month asthma exacerbation in patients with baseline high and low blood eosinophil count (BEC) levels. Methods This study included 438 and 231 patients with asthma with pre-treatment BEC levels >300 cells·μL −1 (high BEC) and <150 cells·μL −1 (low BEC), respectively, and no history of systemic corticosteroid use. 40 pre-treatment variables were collected and exacerbation occurrences were tracked over 12 months. The least absolute shrink and selection operator (LASSO) regression was applied to identify key variables for predicting exacerbation occurrences in the two BEC groups. Results Baseline characteristics, including impaired lung function, female sex and sensitivity to stress as an asthma trigger were important predictors of exacerbation in both BEC groups. Significant characteristics related to exacerbation in the high-BEC group included high pre-treatment BEC levels, history of smoking, sensitivity to tobacco smoke and allergic-related conditions. In contrast, key characteristics associated with exacerbation in the low-BEC group included high baseline peripheral neutrophil counts, current smokers, history of tuberculosis and the use of long-acting β2 agonists plus long-acting muscarinic agonists. The prediction model for 12-month exacerbation using baseline characteristics had stronger predictive power in the low-BEC group than the high-BEC group. Conclusion The exacerbation profiles of patients with asthma with high and low pretreatment BEC levels share some common characteristics despite substantial differences.

Background:Asthma is a heterogenous disease having varied phenotypes. The comorbidities associated with asthma vary with age and disease severity. The well-known asthma related comorbid conditions include rhinitis, gastroesophageal reflux disease (GERD), hypertension, obstructive sleep apnea, hormonal disorders, and psychiatric disorders. However, comprehensive analyses of how asthma severity correlates with the prevalence and type of comorbidities remain limited. Understanding these relationships is essential for developing targeted management strategies. This study aims to analyze the comorbid conditions associated with adult asthma based on severity, using data from the National Health Insurance Sharing Service. By comparing non-severe asthma (NSA) and severe asthma (SA) groups, the study seeks to identify key differences in the prevalence and risks of comorbid diseases, thereby providing valuable insights for clinicians managing asthma patients. Methods:National Health Insurance claim records from July 1, 2014 to June 31, 2016 were analyzed in a retrospective population-based study. We analyzed the frequent comorbidities in adult patients with asthma. Patients were divided into the following groups according to severity of asthma: NSA and SA. Risk of the developing major comorbid diseases conditions were analyzed according to the morbidity and severity of asthma. Results:Vasomotor and allergic rhinitis, bronchitis, upper respiratory infection, and GERD were common comorbid conditions in all patients with asthma. chronic obstructive pulmonary disease was more common in SA than in NSA. In major comorbid diseases, patients with asthma had more risk in chronic diseases such as diabetes mellitus [odds ratio (OR) =1.13; 95% confidence interval (CI): 1.13, 1,14] and various types of psychiatric disorder (OR =1.49; 95% CI: 1.48, 1.49), as well as rhinitis (OR =1.94; 95% CI: 1.94, 1.95), GERD (OR =1.66; 95% CI: 1.66, 1.67), and osteoporosis (OR =1.40; 95% CI: 1.39, 1.41). Patients with SA experienced more comorbidities and higher incidence of cardiovascular disease, cerebrovascular disease, dementia, and several psychiatric disorders than patients with NSA. Conclusions:Patients with asthma had a higher risk of chronic diseases than patients without asthma, and there was a tendency of higher risk of major comorbidities in SA. Clinicians should consider the impact of comorbid diseases in the asthma patient care.

Background:Airway remodeling in asthma is induced by the production of vascular endothelial growth factor, and this process is mediated by neuropilin-1 (NRP-1). Objective:To investigate the association between the serum level of NRP-1 and clinical characteristics in asthma. Methods:We measured the serum level of NRP-1 and performed subgroup analysis of NRP-1 according to the clinical characteristics of 421 asthma patients registered in the Cohort for Reality and Evolution of Adult Asthma in Korea. Results:The serum level of NRP-1 was significantly higher in the group under 65 years of age than in the group over 65 years of age (1628.36 ± 589.51 vs 1416.75 ± 671.42; P < 0.001). Current smokers and ex-smokers had a significantly higher serum NRP-1 level compared with that of never smokers (1647.16 ± 572.34 vs 1528.5 ± 579.37; P = 0.041). Medium- and high-inhaled corticosteroid users had a higher serum NRP-1 level compared with that of low-inhaled corticosteroid users (1589.87 ± 591.7 vs 1436.12 ± 419.21; P = 0.049). The serum NRP-1 level was significantly higher in the group with a forced vital capacity (FVC) of 70% or higher than in the group with an FVC of 70% or lower. In univariate analysis, age was a factor influencing serum NRP-1 with a negative correlation (coefficient=-260.90; P < 0.001). Ex-smokers and current smokers were factors influencing serum NRP-1 with a positive correlation (coefficient = 118.66; P = 0.0412). An FVC of 70% or higher was a factor affecting serum NRP-1 with a positive correlation (coefficient = 173.86; P = 0.0224). Multivariable analysis revealed that age (coefficient = -233.53; P < 0.001) and smoking history (coefficient = -122.4; P = 0.0358) were significant variables affecting serum NRP-1. Conclusion:Serum NRP-1 level was high in asthma patients with a younger age and smoking history, suggesting its potential as a clinical marker for predicting early-stage airway remodeling based on the age and smoking status.

Background: In previous studies, several asthma phenotypes were identified using clinical and demographic parameters. Transcriptional phenotypes were mainly identified using sputum and bronchial cells. Objective: We aimed to investigate asthma phenotypes via clustering analysis using clinical variables and compare the transcription levels among clusters using gene expression profiling of the blood. Methods: Clustering analysis was performed using 6 parameters: age of asthma onset, body mass index, pack-years of smoking, forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, and blood eosinophil counts. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and RNA was extracted from selected PBMCs. Transcriptional profiles were generated (Illumina NovaSeq 6000) and analyzed using the reference genome and gene annotation files (hg19.refGene.gft). Pathway enrichment analysis was conducted using GO, KEGG, and REACTOME databases. Results: In total, 355 patients with asthma were included in the analysis, of whom 72 (20.3%) had severe asthma. Clustering of the 6 parameters revealed 4 distinct subtypes. Cluster 1 (n = 63) had lower predicted FEV1 % and higher pack-years of smoking and neutrophils in sputum. Cluster 2 (n = 43) had a higher proportion and number of eosinophils in sputum and blood, and severe airflow limitation. Cluster 3 (n = 110) consisted of younger subjects with atopic features. Cluster 4 (n = 139) included features of late-onset mild asthma. Differentially expressed genes between clusters 1 and 2 were related to inflammatory responses and cell activation. Th17 cell differentiation and interferon gamma-mediated signaling pathways were related to neutrophilic inflammation in asthma. Conclusion: Four clinical clusters were differentiated based on clinical parameters and blood eosinophils in adult patients with asthma form the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort. Gene expression profiling and molecular pathways are novel means of classifying asthma phenotypes.

BACKGROUND:Leukotriene receptor antagonists are recommended to treat asthma and allergic rhinitis. Although they had been used for a long time, recent studies have reported neuropsychiatric adverse drug reactions are associated with montelukast. OBJECTIVE:This study analyzed the adverse drug reactions of montelukast and pranlukast, which are the two most frequently prescribed leukotriene receptor antagonists, respectively in Korea. METHODS:This study retrospectively reviewed ADRs of 5,426 montelukast and 1,146 pranlukast reported in the Korea Adverse Event Reporting System between January 2014 and December 2018. RESULTS:When both drugs are classified by system organ class, the most adverse drug reactions were related to the gastro-intestinal system, followed by psychiatric events. The reported adverse drug reactions for both drugs were more common in women, and the ratio of adverse drug reactions to prescriptions was highest in the elderly. Women aged 19 to 64 years reported more than twice as many adverse drug reactions than men of the same age, and more than 5 times in insomnia. CONCLUSIONS:When prescribing montelukast and pranlukast, attention would need to digestive and sleep disorders, especially women aged 19 to 64. After prescribing montelukast, physicians would need to pay more attention to agitation (5/396378 vs 0/82475), bad or vivid dreams (6/396378 vs 0/82475), anxiety (11/396378 vs 0/82475), depression (14/396378 vs 1/82475), tremor (53/396378 vs 7/82475), irritability (5/396378 vs 1/82475), insomnia (159/396378 vs 25/82475), and headache (68/396378 vs 10/82475), compared to when prescribing pranlukast. Further prospective research needs to elucidate the relationship between neuropsychiatric events and montelukast.

Eosinophils are normally circulating granulocytes that could induce a wide range of diseases when aberrantly activated and damaging specific organs. Although the increased level of blood eosinophils suggests a higher risk of co-existing eosinophilic diseases, it does not always correlate with the magnitude of tissue inflammation or activity of eosinophilic diseases. Therefore, we sought to identify the difference in characteristics of circulating eosinophils according to the presence of eosinophilic diseases using Raman spectroscopy.

Background Limited understanding exists regarding the progression trajectory of severe eosinophilic asthma (SEA) patients on type 2 biologics therapies. Objective We aim to explore distinct longitudinal phenotypes of these patients based on crucial asthma biomarkers. Methods We enrolled 101 adult patients with SEA. Of these, 51 were treated with anti-IL5/IL5Rα or anti-IL5/IL5RαR antibody, and 50 with anti-IL-4Rα antibody. Multi-trajectory analysis, an extension of univariate group-based trajectory modeling, was used to categorize patients based on their trajectories of forced expiratory volume in 1 s (FEV1), blood eosinophil counts (BEC), and fractional exhaled nitric oxide (FeNO) levels at baseline, and after 1, 6, and 12 months of treatment. Associations between trajectory-based clusters and clinical parameters were examined. Results Among anti-IL5/IL5Rα antibody-treated patients, 2 clusters were identified. The cluster characterized by higher baseline BEC and lower FEV1 showed a better response, with improvements in FEV1 and reductions in BEC over time. Among anti-IL-4Rα antibody-treated, 3 clusters were identified. Clusters with moderate BEC and FeNO at baseline demonstrated better improvements in FEV1 and reductions in FeNO, despite increased BEC during follow-up. Conversely, individuals with extremely low FeNO and high BEC at baseline were more likely to experience poorer progression, demonstrating an increase in FeNO and a reduction in FEV1. Conclusion To optimally monitor treatment response in SEA patients on type 2 biologics, integrating longitudinal biomarker features is essential.

AbstractPatients with severe eosinophilic asthma often require systemic medication, including corticosteroids and anti-type 2 (T2) cytokine biologics, to control the disease. While anti-IL5 and anti-IL4Rα antibodies suppress the effects of IL-4, IL-5 and IL-13, the molecular pathways modified by these biologics that are associated with clinical improvement remain unclear. Therefore, we aimed to describe the effects of T2-targeting biologics on the gene expression of blood immune cells. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from eight patients with severe eosinophilic asthma treated with mepolizumab, reslizumab, or dupilumab. PBMCs were obtained before the initiation of biologics and at 1- and 6-month timepoints after the initiation of treatment to elucidate treatment-induced changes. During treatment, the proportions of T cells/natural killer (NK) cells, myeloid cells, and B cells did not change. However, the composition of classical monocytes (CMs) changed: IL1B+ CMs were reduced, and S100A+ CMs were increased. The subsets of T cells also changed, and significant downregulation of the NF-κB pathway was observed. The genes related to the NF-κB pathway were suppressed across T/NK, myeloid, and B cells. The transcriptional landscape did not significantly change after the first month of treatment, but marked changes occurred at six-month intervals. In conclusion, regardless of the type of biologics used, suppression of T2-mediated pathways ultimately reduces the expression of genes related to NF-κB signaling in circulating immune cells. Further studies are warranted to identify potential biomarkers related to treatment response and long-term outcomes.Clinical trial registration number: NCT05164939

BACKGROUND:Epidemiological studies of neuropsychiatric events (NPEs) associated with leukotriene receptor antagonists (LTRAs) have yielded inconsistent results. Recent studies have demonstrated strong temporal relationships between LTRA prescription and NPE occurrence, indicating a need for further investigation. OBJECTIVE:To investigate potential LTRA-related NPEs and associated risk factors. METHODS:Adults with asthma or rhinitis were enrolled from the Korean claims database. The temporal relationship between the first NPE diagnosis and the last LTRA prescription before NPE was evaluated. Nested case-control studies for NPEs and suicide were conducted. Cases (those with NPEs) were matched to controls for age and sex to compare the frequency of LTRA prescription in the lag time before NPE diagnosis. The risk factors for LTRA-related NPEs (developed within 6 months of LTRA prescription) were assessed in people on LTRAs by comparing those with LTRA-related NPEs to those on LTRAs who did not have NPEs. RESULTS:Montelukast and pranlukast were more frequently prescribed within 6 months before NPEs (odds ratio, 1.31, 95% CI, 1.21-1.41, and odds ratio, 1.25, 95% CI, 1.15-1.35). Older adults, low income, high comorbidity burden, and asthma exhibited stronger associations with LTRA-related NPEs than with general NPEs. Sleep disturbances appeared more prevalent in LTRA-related NPEs than in other NPEs. An LTRA prescription within 6 months was associated with suicide in univariate but not in multivariate analysis. CONCLUSIONS:Increased neuropsychiatric risk was observed within 6 months after LTRA prescription. LTRA may lower the threshold for NPEs in those at risk for NPEs, irrespective of sex.

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. We sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT. 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. 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