Real-World Effectiveness of Biologics in Patients With Severe Asthma: Analysis of the KoSAR.

PURPOSE: Severe asthma is associated with high morbidity and healthcare utilization; however, treatment options for these patients are limited. This study aimed to determine the therapeutic effects of biologics in clinical practice. METHODS: This multicenter, retrospective cohort study included 136 patients who received biologics for at least 4 months between September 2017 and July 2022 at 25 medical centers affiliated with the Korean Severe Asthma Registry (KoSAR). The study evaluated the treatment effects, including acute exacerbation rates, maintenance of oral corticosteroid dosages, lung function, quality of life, blood eosinophil count, and fractional exhaled nitric oxide (FeNO) levels, by comparing measurements before and after 4 months of biologic treatment. Responses for each medication was evaluated based on the Global Evaluation of Treatment Effectiveness score, and any adverse reactions were summarized. RESULTS: With the administration of biologics over the course of 4 months, there was a reduction in asthma acute exacerbations, a significant improvement in lung function, and a significant decrease in daily maintenance dose of oral steroid. Blood eosinophil counts decreased in the mepolizumab and reslizumab groups, while FeNO levels decreased only in the dupilumab group. The Asthma Control Test, Quality of Life Questionnaire for Adult Korean Asthmatics, and the EuroQol-visual analogue scale scores showed a significant improvement. Most patients (80.15%) responded to the biologic treatment. Meanwhile, non-responders often had chronic rhinosinusitis as a comorbidity, exhibited lower lung function, and required higher doses of oral steroids. No severe adverse events were reported. CONCLUSIONS: Biologics are highly effective in Korean patients with Type 2 severe asthma, significantly reducing acute exacerbation rates and doses of oral corticosteroids, while also improving lung function. Therefore, it seems beneficial to administer biologics without any restrictions to patients exhibiting Type 2 severe asthma.

Characteristics of Severe Asthma in the Elderly: Observations From the Korean Severe Asthma Registry (KoSAR).

PURPOSE: Few studies have compared the clinical characteristics of severe asthma (SA) in elderly patients compared to that in nonelderly patients. METHODS: We analyzed data from the Korean SA Registry, a nationwide, real-world observational study of SA in Korea. The baseline clinical characteristics, disease control status, and medication use of the patients were compared between elderly (≥ 65 years) and nonelderly groups. RESULTS: Of the 864 patients with SA, 260 (30.1%) were in the elderly group. The elderly group had lower atopy rate, but had higher prevalence of chronic obstructive pulmonary disease (COPD), hypertension, and osteoporosis than did the nonelderly group. The elderly group had a lower rate of type 2 inflammation and lower levels of forced expiratory volume in 1 second (FEV1) (% predicted) and FEV1/forced vital capacity ratio than did the nonelderly group (P < 0.05 for all). However, asthma symptom scores and the frequency of asthma exacerbation were not significantly different between the 2 groups. Of controller medications, biologics were less frequently used in the elderly group (P < 0.05 for all). CONCLUSIONS: SA in the elderly is characterized by lower lung function, less type 2-low airway inflammation, and comorbidity with COPD. These findings are being taken into consideration in the management of elderly patients with SA in real-world clinical practice.

Work-related asthma in adults with severe asthma from the Korean Severe Asthma Registry (KoSAR).

Background: Exposure to allergens or irritants in the workplace may affect asthma control and the quality of life (QoL) of patients with asthma. Objective: To examine the prevalence and characteristics of work-related asthma (WRA) in adult patients with severe asthma. Methods: We analyzed data from the Korean Severe Asthma Registry (KoSAR), which is a nationwide multicenter observational study on severe asthma in Korea. Severe asthma was defined according to the American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines. WRA was identified on the basis of asthma symptom aggravation at the workplace, as indicated by responses to a structured questionnaire. We compared the demographic and clinical characteristics and QoL between adult patients with severe asthma and WRA and those without WRA. Results: Among 364 patients with severe asthma who were employed at the time of enrollment, 65 (17.9%) had WRA. There were no significant differences in age, sex, obesity, or smoking history between the WRA and non-WRA groups. However, individuals with WRA exhibited a higher prevalence of anxiety (7.7% vs 2.4%, P = 0.046) and depression (12.3% vs 3.7%, P = 0.010) than those without. The levels of asthma control, lung function, and frequency of asthma exacerbations were similar between the two groups, but patients with WRA reported lower QoL, as determined by the Quality of Life Questionnaire for Adult Korean Asthmatics (56.6 ± 14.6 vs. 63.5 ± 13.9, P < 0.001). Conclusion: Patients with severe asthma and WRA are more likely to experience anxiety and depression and have lower QoL than those without WRA.

Relationship of computed tomography-based measurements with symptom perception and quality of life in patients with severe asthma.

BACKGROUND: Symptom perception and quality of life (QOL) are important domains for properly managing severe asthma. This study aimed to assess the relationship between airway structural and parenchymal variables measured using chest computed tomography (CT) and subjective symptom perception and QOL in patients with severe asthma enrolled in the Korean Severe Asthma Registry. METHODS: This study used CT-based objective measurements, including airway wall thickness (WT), hydraulic diameter, functional small airway disease (fSAD), and emphysematous lung (Emph), to assess their association with subjective symptom (cough, dyspnea, wheezing, and sputum) perception measured using the visual analog scale, and QOL measured by the Severe Asthma Questionnaire (SAQ). RESULTS: A total of 94 patients with severe asthma were enrolled in this study. The WT and fSAD% were significantly positively associated with cough and dyspnea, respectively. For QOL, WT and Emph% showed significant negative associations with the SAQ. However, there was no significant association between lung function and symptom perception or between lung function and QOL. CONCLUSION: Overall, WT, fSAD%, and Emph% measured using chest CT were associated with subjective symptom perception and QOL in patients with severe asthma. This study provides a basis for clarifying the clinical correlates of imaging-derived metrics and for understanding the mechanisms of respiratory symptom perception.

Role of diesel exhaust particle-induced cellular senescence in the development of asthma in young and old mice.

BACKGROUND: Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced cellular senescence on the development of asthma according to age have not been thoroughly studied. METHODS: We first confirmed that DEP induced cellular senescence in mouse lungs, and then that DEP-induced cellular senescence followed by intranasal instillation of a low-dose house dust mite (HDM) allergen resulted in murine asthma. Second, we examined age-dependent differential effects using 6-week-old (young) and 18-month-old mice (old), and tested whether the mammalian target of the rapamycin (mTOR) pathway plays an important role in this process. Finally, we performed in vitro experiments using human bronchial epithelial cells (HBEC) originating from young and elderly adults to identify the underlying mechanisms. RESULTS: DEP induced cellular senescence in the airway epithelial cells of young and old mice characterized by increased senescence-associated beta-galactosidase, S100A8/9, and high mobility group box 1 (HMGB1) expressions. DEP-induced cellular senescence with subsequent exposure to a low-dose HDM allergen resulted in asthma in young and old mice. Rapamycin (mTOR pathway inhibitor) administration before DEP instillation significantly attenuated these asthmatic features. In addition, after treatment with a low-dose HDM allergen, S100A9 and HMGB1 over-expressed HBEC originating from young and elderly adults greatly activated co-cultured monocyte-derived dendritic cells (DCs). CONCLUSIONS: This study showed that DEP-induced senescence made both young and old mice susceptible to allergic sensitization and resultant asthma development by enhancing DC activation. Public health efforts to reduce DEP exposure are warranted.

Short-acting ß2-agonist prescriptions in patients with asthma: findings from the South Korean cohort of SABINA III.

BACKGROUND/AIMS: Despite short-acting ß2-agonist (SABA) overuse being associated with poor asthma outcomes, data on SABA use in South Korea is scarce. Herein, we describe prescription patterns of SABA and other asthma medications in patients from the South Korean cohort of the SABA use IN Asthma (SABINA) III study. METHODS: This study included patients with asthma aged ≥ 12 years, who had ≥ 3 consultations with the same healthcare provider, and medical records containing data for ≥ 12 months prior to the study visit. Patients were classified by investigator-defined asthma severity (per 2017 Global Initiative for Asthma recommendations) and practice type (primary or specialist care). Data on disease characteristics, asthma treatments, and clinical outcomes in the 12 months before the study visit were collected using electronic case report forms. RESULTS: Data from 476 patients (mean age, 55.4 years; female, 63.0%) were analyzed. Most patients were treated by specialists (83.7%) and had moderate-to-severe asthma (91.0%). Overall, 7.6% of patients were prescribed ≥ 3 SABA canisters (defined as over-prescription). In patients prescribed SABA in addition to maintenance therapy, 47.4% were over-prescribed SABA. Most patients (95.4%) were prescribed a fixed-dose combination of an inhaled corticosteroid and a long-acting ß2-agonist as maintenance therapy. Although asthma was well-controlled/partly-controlled in 91.6% of patients, 29.6% experienced ≥ 1 severe asthma exacerbation. CONCLUSION: SABA over-prescription was reported in nearly 50% of patients prescribed SABA in addition to maintenance therapy, underscoring the need to align clinical practices with the latest evidence-based recommendations and educate physicians and patients on appropriate SABA use.

IL-23 contributes to Particulate Matter induced allergic asthma in the early life of mice and promotes asthma susceptibility.

Air pollutant exposure leads to and exacerbates respiratory diseases. Particulate Matter (PM) is a major deleterious factor in the pathophysiology of asthma. Nonetheless, studies on the effects and mechanisms of exposure in the early life of mice remain unresolved. This study aimed to investigate changes in allergic phenotypes and effects on allergen-specific memory T cells resulting from co-exposure of mice in the early life to PM and house dust mites (HDM) and to explore the role of interleukin-23 (IL-23) in this process. PM and low-dose HDM were administered intranasally in 4-day-old C57BL/6 mice. After confirming an increase in IL-23 expression in mouse lung tissues, changes in the asthma phenotype and lung effector/memory Th2 or Th17 cells were evaluated after intranasal administration of anti-IL-23 antibody (Ab) during co-exposure to PM and HDM. Evaluation was performed up to 7 weeks after the last administration. Co-exposure to PM and low-dose HDM resulted in increases in airway hyperresponsiveness (AHR), eosinophils, neutrophils, and persistent Th2/Th17 effector/memory cells, which were all inhibited by anti-IL-23 Ab administration. When low-dose HDM was administered twice after a 7-week rest, mice exposed to PM and HDM during the previous early life period exhibited re-increases AHR, eosinophil count, HDM-specific IgG1, and effector/memory Th2 and Th17 cell populations. However, anti-IL-23 Ab administration during the early life period resulted in inhibition. Co-exposure to PM and low-dose HDM reinforced the allergic phenotypes and allergen-specific memory responses in early life of mice. During this process, IL-23 contributes to the enhancement of effector/memory Th2/Th17 cells and allergic phenotypes. KEY MESSAGES: PM-induced IL-23 expression, allergic responses in HDMinstilled mice of early life period. PM-induced effector/memory Th2/Th17 cells in HDMinstilled mice of early life period. Inhibition of IL-23 reduced the increase in allergic responses. Inhibition of IL-23 reduced the increase in allergic responses. After the resting period, HDM administration showed re-increase in allergic responses. Inhibition of IL-23 reduced the HDM-recall allergic responses.

A smartphone-based application for cough counting in patients with acute asthma exacerbation.

Background: While tools exist for objective cough counting in clinical studies, there is no available tool for objective cough measurement in clinical practice. An artificial intelligence (AI)-based cough count system was recently developed that quantifies cough sounds collected through a smartphone application. In this prospective study, this AI-based cough algorithm was applied among real-world patients with an acute exacerbation of asthma. Methods: Patients with an acute asthma exacerbation recorded their cough sounds for 7 days (2 consecutive hours during awake time and 5 consecutive hours during sleep) using CoughyTM smartphone application. During the study period, subjects received systemic corticosteroids and bronchodilator to control asthma. Coughs collected by application were counted by both the AI algorithm and two human experts. Subjects also provided self-measured peak expiratory flow rate (PEFR) and completed other outcome assessments [e.g., cough symptom visual analogue scale (CS-VAS), awake frequency, salbutamol use] to investigate the correlation between cough and other parameters. Results: A total of 1,417.6 h of cough recordings were obtained from 24 asthmatics (median age =39 years). Cough counts by AI were strongly correlated with manual cough counts during sleep time (rho =0.908, P<0.001) and awake time (rho =0.847, P<0.001). Sleep time cough counts were moderately to strongly correlated with CS-VAS (rho =0.339, P<0.001), the frequency of waking up (rho =0.462, P<0.001), and salbutamol use at night (rho =0.243, P<0.001). Weak-to-moderate correlations were found between awake time cough counts and CS-VAS (rho =0.313, P<0.001), the degree of activity limitation (rho =0.169, P=0.005), and salbutamol use at awake time (rho =0.276, P<0.001). Neither awake time nor sleep time cough counts were significantly correlated with PEFR. Conclusions: The strong correlation between cough counts using the AI-based algorithm and human experts, and other indicators of patient health status provides evidence of the validity of this AI algorithm for use in asthma patients experiencing an acute exacerbation. Study findings suggest that CoughyTM could be a novel solution for objectively monitoring cough in a clinical setting.

Rapamycin Restores Different Patterns of Cytokine Expression to Dexamethasone Treatment on CD14++CD16+ Monocytes from Steroid-Resistant Asthma Patients.

OBJECTIVE: We aimed to investigate the differences in interleukin (IL)-10, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated CD14++CD16+ monocytes obtained from asthmatics after dexamethasone or dexamethasone plus rapamycin treatments between clinical steroid responders (R) and non-responders (NR). METHODS: Cytokine expressions in LPS-stimulated CD14++CD16+ p-mammalian target of rapamycin (mTOR) monocytes from R and NR were determined using flow cytometry. RESULTS: IL-10high CD14++CD16+ p-mTOR population following LPS stimulation increased in the R group although decreased in the NR group with dexamethasone treatment. IL-1ßhigh population decreased in the R group although increased in the NR group. Rapamycin treatment after LPS and dexamethasone resulted in a significant increase in the IL-10high population and a significant decrease in the IL-1ßhigh population in the NR group. CONCLUSION: Dexamethasone treatment resulted in different patterns of change in cytokine expressions in LPS-stimulated CD14++CD16+ p-mTOR monocytes between the R and NR. mTOR inhibition can restore steroid responsiveness involving IL-10 and IL-1ß in CD14++CD16+ p-mTOR monocytes.

Staphylococcal Enterotoxin-Specific IgE Sensitization: A Potential Predictor of Fixed Airflow Obstruction in Elderly Asthma.

PURPOSE: Staphylococcus aureus enterotoxin-specific immunoglobulin E (SE-sIgE) sensitization tends to increase with age and is known to be associated with asthma and severity in older adults. However, the long-term impact of SE-sIgE in the elderly remains unknown. This study aimed to examine the relationships between SE-sIgE and fixed airflow obstruction (FAO) in a cohort of elderly asthmatics. METHODS: A total of 223 elderly asthmatics and 89 controls were analyzed. Patients were assessed for demographics, history of chronic rhinosinusitis (CRS), asthma duration, acute exacerbation frequency, and lung function at baseline and then were prospectively followed up for 2 years. Serum total IgE and SE-sIgE levels were measured at baseline. Airflow obstruction was defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7 at baseline and FAO was defined as FEV1/FVC ratio < 0.7 over the 2-year follow-up. RESULTS: At baseline, the prevalence of airflow obstruction was 29.1%. Patients with airflow obstruction were significantly more likely to be male, and have a positive smoking history, comorbid CRS, and higher levels of SE-sIgE than those without airflow obstruction. Multivariate logistic regression analysis showed that airflow obstruction was significantly associated with current smoking and SE-sIgE sensitization at baseline. After the 2-year follow-up, baseline SE-sIgE sensitization was consistently related to FAO. Meanwhile, the number of exacerbations per year was significantly correlated with SE-sIgE levels. CONCLUSIONS: Baseline SE-sIgE sensitization was significantly associated with the number of asthma exacerbations and FAO after the 2-year follow-up in elderly asthmatics. These findings warrant further investigation of the direct and mediating roles of SE-sIgE sensitization on airway remodeling.

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.

Increased Risk of Anemia in Patients with Asthma.

Purpose: Asthma can cause a systemic inflammatory response, and anemia of chronic disease (ACD) is known to be caused by other disorders with a chronic inflammatory state. However, it is unclear whether the incidence of anemia is increased in patients with asthma. The objective of this study was to compare the incidence of anemia in patients with asthma and healthy adults. Patients and Methods: This retrospective cohort study included patients newly diagnosed with asthma at Seoul National University Hospital from 2010 to 2017. Patients with comorbidities before the first visit (index date) that may increase anemia risk were excluded. Cox regression models adjusting for patient age, sex, and obesity were used to compare anemia hazard ratios (HRs) between asthma patients (n=1354) and healthy adults (n=1731). Results: This study included 3085 patients. During 5-y follow-up, anemia occurred in 203 (15.0%) patients with asthma and 79 (4.6%) healthy adults. Compared with healthy adults, the HR for anemia after adjusting for age, sex, and obesity was 4.06 (95% CI: 2.70-6.09) in patients with asthma. In patients aged 18-64.9 y, the adjusted HR of anemia was 3.27 (95% CI: 2.12-5.04) in patients with asthma, compared to healthy patients. In patients >65 y, this adjusted HR was 5.56 (95% CI: 1.31-23.67). Conclusion: The risk of anemia was increased in patients with asthma after adjusting for sex, age, and obesity and excluding comorbidities that can cause anemia. These results suggest the need for regular monitoring for anemia in patients with asthma.

Management of Elderly Asthma: Key Questions and Tentative Answers.

The aging lung undergoes structural changes, immunosenescence, and inflammation, rendering the elderly more susceptible to developing obstructive airway disease. Thus, asthma in those of chronological age ≥ 65 years is not rare. Elderly asthma (EA) imposes considerable burdens in terms of mortality and morbidity, and expenditure. However, clinicians lack knowledge of EA and thus often prescribe inappropriate management. In this review, we ask 3 key questions frequently encountered during EA diagnosis and treatment: 1) Is EA different?; 2) How can we appropriately diagnose EA?; 3) Are there management strategies specific to EA? Based on recent studies, we provide tentative answers as follows: 1) late-onset EA differs in clinical features and pathogenetic mechanisms from non-EA, and thus further phenotypic and endotypic characterization of EA is needed; 2) both over- and under-diagnosis of asthma in the elderly can be reduced if the objective diagnostic tests are appropriately performed; 3) cautious prescription of ICS to selected EA patients should be encouraged, and a multifaceted approach which involves increasing medical awareness and inhaler use proficiency and adherence, seeking the assistance of caregivers, and correcting micronutrient deficiencies is required to reduce acute exacerbations in EA patients.

Chronic viral hepatitis accelerates lung function decline in smokers.

Although hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotrophic viruses, they may affect pulmonary diseases. The purpose of this study was to assess whether chronic viral hepatitis (CVH) infection was associated with a rapid decline in lung function. Repeated measurements of lung function were obtained from a well-curated health check-up database. A case was defined as an individual positive for HBsAg or anti-HCV antibody. A control was randomly selected (from the same dataset) after 1:1 matching in terms of age, sex, height, the body mass index, and smoking status. Separate analyses of non-smokers and smokers were performed. A total of 701 cases were enrolled (586 with HBV and 115 with HCV). In cross-sectional analysis, both forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decreased significantly only in smokers (smoking cases vs. smoking controls) (adjusted p = 6.6 × 10-5 and adjusted p = 2.2 × 10-3, respectively). In longitudinal analysis, smoking cases showed significantly greater FEV1 and FVC decline rates than did smoking controls (adjusted p = 8.5 × 10-3 and adjusted p = 1.2 × 10-5, respectively). Such associations were particularly high in smoking cases at intermediate-to-high risk of hepatic fibrosis, as evaluated by the non-invasive Fibrosis-4 index. In summary, CVH was associated with both decreased lung function and accelerated lung function decline in smokers. A non-invasive measurement of hepatic fibrosis may be useful in predicting rapid lung function decline in smokers with CVH.

Transcriptome analysis of sputum cells reveals two distinct molecular phenotypes of "asthma and chronic obstructive pulmonary disease overlap" in the elderly.

BACKGROUND: Little is known about the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO). This study examined the molecular phenotypes of ACO in the elderly. METHODS: A genome-wide investigation of gene expression in sputum cells from the elderly with asthma, ACO, or COPD was performed using gene set variation analysis (GSVA) with predefined asthma- or COPD-specific gene signatures. We then performed a subsequent cluster analysis using enrichment scores (ESs) to identify molecular clusters in the elderly with ACO. Finally, a second GSVA was conducted with curated gene signatures to gain insight into the pathogenesis of ACO associated with the identified molecular clusters. RESULTS: Seventy elderly individuals were enrolled (17 with asthma, 41 with ACO, and 12 with COPD). Two distinct molecular clusters of ACO were identified. Clinically, ACO cluster 1 (N = 23) was characterized by male and smoker dominance, more obstructive lung function, and higher proportions of both neutrophil and eosinophil in induced sputum compared to ACO cluster 2 (N = 18). ACO cluster 1 had molecular features similar to both asthma and COPD, with mitochondria and peroxisome dysfunction as important mechanisms in the pathogenesis of these diseases. The molecular features of ACO cluster 2 differed from those of asthma and COPD, with enhanced innate immune reactions to microorganisms identified as being important in the pathogenesis of this form of ACO. CONCLUSION: Recognition of the unique biological pathways associated with the two distinct molecular phenotypes of ACO will deepen our understanding of ACO in the elderly.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

IL-23 plays a significant role in the augmentation of particulate matter-mediated allergic airway inflammation.

It has been recently that particulate matter (PM) exposure increases the risk and exacerbation of allergic asthma. However, the underlying mechanisms and factors associated with increased allergic responses remain elusive. We evaluated IL-23 and IL-23R (receptor) expression, as well as changes in the asthmatic phenotype in mice administered PM and a low dose of house dust mite (HDM). Next, changes in the phenotype and immune responses were evaluated after intranasal administration of anti-IL-23 antibody during co-exposure to PM and low-dose HDM. We also performed in vitro experiments to investigate the effect of IL-23. IL-23 expression was significantly increased in Epcam+CD45- and CD11c+ cells, while that of IL-23R was increased in Epcam+CD45- cells only in mice administered PM and low-dose HDM. Administration of anti-IL-23 antibody led to decreased airway hyperresponsiveness, eosinophils, and activation of dendritic cells, reduced populations of Th2 Th17, ILC2, the level of IL-33 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Inhibition of IL-23 in PM and low-dose HDM stimulated airway epithelial cell line resulted in decreased IL-33, GM-CSF and affected ILC2 and the activation of BMDCs. PM augmented the phenotypes and immunologic responses of asthma even at low doses of HDM. Interestingly, IL-23 affected immunological changes in airway epithelial cells.

Effect of Dupilumab in Korean Patients With Uncontrolled Moderate-to-Severe Asthma: A LIBERTY ASTHMA QUEST Sub-analysis.

PURPOSE: To assess the effect of dupilumab on the annualized severe exacerbation rates, change in forced expiratory volume at first second (FEV1), overall asthma control and health-related quality of life in Korean patients from the LIBERTY ASTHMA QUEST study. METHODS: Of the 1,902 patients enrolled in the LIBERTY ASTHMA QUEST study, a phase-3, randomized, double-blind, placebo-controlled, parallel-group study on dupilumab, 74 (4%) were Korean. The patients were randomly assigned to 4 treatment groups (2:2:1:1). The sub-analysis reported herewith was performed with the pooled groups of dupilumab and placebo from the 4 original treatment groups in the LIBERTY ASTHMA QUEST study. The efficacy endpoints were annualized rate of severe exacerbation events during the 52-week study period and changes from baseline in pre-bronchodilator FEV1 in week 12. Asthma control, asthma quality of life and the effect of treatment on the levels of type 2 inflammatory biomarkers were assessed. The safety profile was also evaluated. RESULTS: In Korean patients, annualized severe exacerbation rates were reduced with dupilumab (n = 49) compared to placebo (n = 25) (0.259 vs 1.942) during the 52-week treatment period. The relative risk reduction with dupilumab was 87% (P < 0.001). Improvements in pre-bronchodilator FEV1 (mean difference of 0.24 L, P = 0.021) were observed in week 12 in dupilumab-treated patients. Additionally, improvements in asthma control and asthma-related quality of life were observed; the FeNO and serum immunoglobulin E levels were reduced. The incidence of adverse events and serious adverse events was comparable between the dupilumab and placebo group. A total of 11 patients from the dupilumab group reported 63 injection site reactions. CONCLUSIONS: Dupilumab, as an add-on therapy in severe asthma, is efficacious and has an acceptable safety profile in Korean patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02414854.