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Background: Most knowledge on cough epidemiology was obtained from questionnaire surveys of general populations or small focused studies of patients visiting specialist clinics. Routinely collected data (RCD) from electronic health records (EHR) are useful sources for studying disease epidemiology, but their use was limited in chronic cough. The present study aimed to investigate cough presentation and cough-related healthcare utilization, using the RCD of patients referred with cough.Methods: This is a retrospective cohort study utilizing an academic institutional EHR database. Cough cases were identified using the text search for the chief complaint indicating “cough” in the structured case report form. Using the information, we constructed a retrospective cohort of patients with subacute or chronic cough. Baseline demographics, medical history, concomitant symptoms, and diagnostic tests were analyzed. Healthcare utilization during 1 year since the baseline visit was assessed for drug prescriptions, additional diagnostic tests, outpatient visits, and hospitalization.Results: Among a total of 28,312 new referrals, cough was the chief complaint in 13,223 cases (46.7%). Based on the selection criteria, 3,810 subacute and 7,150 chronic cough patients were finally included. A common demographic profile was middle-aged woman (mean age 52.1 years, and female 63%). Patients had a median three accompanying symptoms (interquartile range: 2–5). Abnormal throat sensation (globus, tickling, or dryness) was the most common (about 70%), but symptoms suggesting nasal diseases, asthma, or acid reflux were also frequent. During the first year, both of subacute and chronic cough patients required multiple drug prescriptions, diagnostic tests, and outpatient visits, but the degree of utilization was higher in patients with chronic cough. Codeine-containing drugs were given to 21.5% of patients with chronic cough, and oral antibiotics to 23.7% and oral steroids to 9.9%.Conclusions: Cough is a common chief complaint among new referrals to tertiary specialist clinics. Cough is accompanied by multiple symptoms and is associated with healthcare utilization, particularly more in patients with chronic cough. Further studies are needed to understand their long-term health outcomes and reduce the disease burden.

Few studies have investigated the relationship between asthma and sarcopenia. We aimed to examine the relationship between asthma and sarcopenia in a community-dwelling geriatric population, especially regarding lung function and asthma control.A cross-sectional dataset from the Korean National Health and Nutrition Examination Survey 2008-2011 was utilized. Data regarding asthma history, age at asthma onset, recent asthma exacerbations, and hospitalization for asthma exacerbations were obtained using structured questionnaires. Appendicular skeletal muscle was calculated as the sum of the skeletal muscle mass, and physical activity was assessed using the International Physical Activity Questionnaire.Asthma presented an estimated incidence of 6.17 ± 0.37% in the elderly. Groups were divided and analyzed according to asthma, muscle mass, and physical activity. Sarcopenia was associated with aging, male sex, smoking history, low body mass index (BMI), and reduced lung function with or without asthma. Sarcopenic asthma had a younger onset and reduced physical activity than non-sarcopenic asthma. Obstructive patterns were more frequent in asthmatics exhibiting low or moderate physical activity levels than in those with high activity, but asthma control was not associated with sarcopenia and physical activity. Multivariate logistic regression analyses showed that compared with control, sarcopenic asthma was associated with FEV1 60%, and airway obstruction, and with aging, male, and lower BMI, compared with non-sarcopenic asthma.Our findings suggest that decreased muscle mass and physical activity levels contribute to reduced lung function in elderly asthmatics. Furthermore, sarcopenic asthma was associated with aging, low BMI, and reduced lung function in the elderly.

Purpose Blood (EOS-B) and sputum (EOS-S) eosinophil counts may contribute differently to asthma pathogenesis. We compared the impact of the baseline EOS-B and EOS-S levels on lung function, asthma control, and exacerbation in Korean asthma patients.MethodsAsthma patients with baseline EOS-B (n=4257) and EOS-S (n=1049) levels from a multicenter cohort (COREA) were included. Pulmonary function test (%FEV1 predicted), asthma control test (ACT), and asthma exacerbation incidence were followed-up every 3 months for one year. Linear mixed effect models and survival analyses were used to examine the association between eosinophilic groups defined by EOS-B or EOS-S and outcomes. ResultsHigh eosinophilic groups were associated with a low baseline value and a high improvement in the %FEV1 predicted and ACT scores over time. The magnitude of group difference in %FEV1 predicted was 2-fold higher in the EOS-S versus EOS-B classification (mean and 95% CI: 4.7 (0.6-8.8) versus 2.0 (0.2-3.7) for the baseline value and -1.5 (-2.3 to -0.8) versus -0.8(-1.1 to -0.4) for the slope of change), whereas it was identical in ACT score. The magnitude of the impact increased linearly with the elevation of the cut-off level for the EOS-B but remained stable for the EOS-S classification. Patients with an elevation of both their EOS-B and EOS-S showed a higher increment in the %FEV1 predicted and ACT over time. Neither the EOS-B nor EOS-S was associated with asthma exacerbation. ConclusionEOS-S and EOS-B contribute differently to the clinical outcomes and should be taken into account independently to improve asthma care.

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 Laryngeal or vocal cord dysfunction has long been regarded as a mimic of asthma; however, recent evidence indicates that it may be a significant comorbid condition in patients with asthma. Objective We aimed to systematically estimate the prevalence of comorbid laryngeal dysfunction (LD) in adults with asthma and characterize its clinical impact on asthma. Methods Electronic databases were searched for relevant studies published until June 2019. Studies were included if LD was objectively defined by direct visualization of laryngeal movement. Outcomes included the prevalence of LD and its association with clinical asthma indicators, such as severity, control, and quality of life. Random effects meta-analyses were performed to calculate the estimates. Results A total of 21 studies involving 1637 patients were identified. Overall, the pooled prevalence of LD in adults with asthma was 25% (95% CI = 15%-37%; I2 = 96%). Prevalence estimates differed according to the diagnostic test utilized, with the lowest overall prevalence (4% [95% CI = 0%-10%; I2 = 90%]) seen when LD was diagnosed by resting laryngoscopy without external stimuli; however, it was much higher when diagnosed by laryngoscopy studies utilizing an external trigger, such as exercise (38% [95% CI = 24%-53%; I2 = 90%]) or in studies using a computed tomography–based diagnostic protocol (36% [95% CI = 24%-49%; I2 = 78%]). Only 7 studies reported the associations between LD and clinical asthma indicators; inconsistencies between studies limited meaningful conclusions. Conclusion LD may be a common comorbidity in asthma, affecting about 25% of adult patients. Further prospective studies are needed to better characterize its clinical impact and the benefits of detecting and managing LD in patients with asthma.

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.This study analyzed the adverse drug reactions of montelukast and pranlukast, which are the two most frequently prescribed leukotriene receptor antagonists, respectively in Korea.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.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.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.

The effects of asthma, chronic obstructive pulmonary disease (COPD), or asthma-COPD overlap (ACO) on coronavirus disease 2019 (COVID-19) remain unclear.We aimed to investigate the effects of chronic obstructive airway diseases such as asthma, COPD, and ACO on COVID-19.In total, 5625 hospitalized patients with COVID-19 were divided into asthma, COPD, ACO, and control groups. A multivariate logistic regression analysis was performed to identify factors affecting the COVID-19 mortality rate. To find out whether chronic obstructive airway diseases such as asthma, COPD, and ACO affect COVID-19 mortality, 1:4 matching was performed, except for the ACO group alone due to a small number of patients.The mortality rates of asthma, COPD, and ACO groups were about 2.3, 4.8, and 5.5 times higher than that of the control group, respectively. Although not statistically significant, the survival probability tended to decrease (asthma, COPD, and combined groups of asthma and ACO, hazard ratio [HR]: 1.84, 1.31, and 1.89, respectively). The survival probability of the combined groups of COPD, ACO, and asthma and the combined groups of COPD and ACO was significantly lower than that of the matched control group (HR: 3.00 and 1.99, respectively).Compared to patients with COVID-19 without chronic obstructive airway disease, patients with these comorbidities are more likely to require oxygen and mechanical ventilators and have a higher mortality rate, which can be considered when classifying and monitoring patients in the era of COVID-19. Therefore, further studies are needed to evaluate the effect of chronic obstructive airway disease, especially ACO, on COVID-19 mortality.

Kyoung-Hee Sohn,1 Myung-Nam Lee,2 Da Woon Sim,3 Sujeong Kim,4 You Sook Cho,5 Hyouk-Soo Kwon,5 Sang-Heon Kim6 1Division of Pulmonology and Allergy, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea; 2Department of Nursing, College of Health Science, Kangwon National University Samcheok, Samcheok-si, Gangwon-do, South Korea; 3Department of Allergy and Clinical Immunology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, South Korea; 4Division of Allergy and Clinical Immunology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea; 5Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 6Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South KoreaCorrespondence: Hyouk-Soo Kwon, Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, Email kwonhs21@naver.com Sang-Heon Kim, Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea, Email sangheonkim@hanyang.ac.kr

Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) are key proteins mediating viral entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although gene expressions of ACE2 and TMPRSS2 have been analyzed in various organs and diseases, their soluble forms have been less studied, particularly in asthma. Therefore, we aimed to measure circulating ACE2 and TMPRSS2 in the serum of asthmatics and examine their relationship with clinical characteristics.Clinical data and serum samples of 400 participants were obtained from an asthma cohort. The soluble ACE2 (sACE2) and soluble TMPRSS2 (sTMPRSS2) level was measured by enzyme-linked immunosorbent assay, and the values underwent a natural log transformation. Associations between sACE2 and TMPRSS2 levels and various clinical variables were analyzed.The patients younger than 70 years old, those with eosinophilic asthma (eosinophils ≥ 200 cells/µL), and inhaled corticosteroids (ICS) non-users were associated with higher levels of sACE2. Blood eosinophils and fractionated exhaled nitric oxide levels were positively correlated with serum ACE2. In contrast, lower levels of sTMPRSS2 were noted in patients below 70 years and those with eosinophilic asthma, while no association was noted between ICS use and sTMPRSS2. The level of sTMPRSS2 also differed according to sex, smoking history, coexisting hypertension, and forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio. The proportion of sputum neutrophils was positively correlated with sTMPRSS2, while the FEV1/FVC ratio reported a negative correlation with sTMPRSS2.The levels of ACE2 and TMPRSS2 were differently expressed according to age, ICS use, and several inflammatory markers. These findings suggest variable susceptibility and prognosis of SARS-CoV-2 infection among asthmatic patients.

Hypersensitivity reactions to cefaclor have increased in accordance with its frequent use. However, only limited data are available on the diagnostic value of skin tests for these conditions, particularly intradermal tests (IDTs).To evaluate the clinical usefulness of IDT compared to the ImmunoCAP test in patients with cefaclor-induced immediate-type hypersensitivity.We conducted a retrospective chart review from January 2010 to June 2020 of adult subjects from 2 tertiary hospitals in Korea with a history of suspected immediate-type hypersensitivity to cefaclor, and who had undergone ImmunoCAP and IDT.Overall, 131 subjects diagnosed with cefaclor hypersensitivity were included in the analysis. Fifty-nine patients (59/131, 45.04%) were positive in both IDT and ImmunoCAP. Fifty-four (54/131, 41.22%) and 6 (6/131, 4.58%) subjects showed positive results only with IDT or the ImmunoCAP test, respectively. Twelve subjects (12/131, 9.16%) were negative by both tests but reacted positively in a drug provocation test. The frequency of IDT positivity was similar regardless of the severity of reactions. However, positivity of ImmunoCAP was lower in subjects with mild reactions compared to those with anaphylaxis. Regarding the diagnosis of cefaclor hypersensitivity, the overall sensitivity of IDT and ImmunoCAP was 0.863 and 0.496, respectively while the specificity was 1. The combination of IDT and ImmunoCAP further increased this sensitivity to 0.908.IDT was more sensitive than ImmunoCAP for the diagnosis of cefaclor allergy, regardless of the severity of the hypersensitivity reaction. Therefore, we recommend a combination of IDT and ImmunoCAP for the diagnosis of cefaclor hypersensitivity.

Background Hypersensitivity reactions to iodinated contrast media (ICM) is a persistent clinical issue with increased use of computed tomography. With the evidence indicating underlying allergic mechanisms, there have been studies regarding the skin tests using ICM. Objective This study aimed to evaluate the intradermal skin test (IDT) as a tool for preventing recurrent hypersensitivity reactions to ICM in patients with prior reactions to a known culprit agent. Methods Sixty-nine patients who had experienced immediate hypersensitivity reactions to ICM were included in the study. All patients underwent IDT with 7 different ICMs, including the causative ICM. We analyzed clinical data from 38 patients who were reexposed to ICMs, grouped by the IDT results to their original culprit ICM. Results Thirty-eight patients showed positive IDT results to the culprit ICM (CULPRIT+), whereas 31 patients showed negative results (CULPRIT−). Sixteen patients from the CULPRIT+ group and 22 from the CULPRIT− group were subsequently exposed to an ICM. In the CULPRIT+ group, 4 of the 5 patients who were subsequently exposed to an IDT-positive ICM reexperienced hypersensitivity reactions. When patients were exposed to IDT-negative ICM as an alternative, hypersensitivity reactions were not observed. In the CULPRIT− group, IDT-positive ICMs did not provoke hypersensitivity reactions whereas 2 patients using IDT-negative ICMs experienced hypersensitivity reactions. Conclusions When the IDT results are positive for the culprit ICM, additional IDTs with other ICMs are needed to select a safe alternative. If the IDT results are negative against the culprit ICM, further IDTs might not play a role in selecting a safe alternative.

Purpose Although genome-wide association studies (GWASs) represent the most powerful approach for identifying genes that influence asthma, to date, no studies have established genetic susceptibility to asthma in the Korean population. This study aimed to identify genetic variants associated with adult Korean asthmatics and compare them with the significant single nucleotide polymorphisms (SNPs) of UK asthmatics from the UK Biobank. Methods Patients were defined as having asthma if they were diagnosed by a doctor or taking medications for asthma. Controls were defined as individuals without asthma or chronic obstructive pulmonary disease. We performed quality control, genotype imputation, GWAS, and PrediXcan analyses. In the GWAS, a P value of < 5 × 10−8 was considered significant. We compared significant SNPs between Korean and UK patients with asthma. Results A total of 1,386 asthmatic patients and 5,205 controls were analyzed. The SNP rs1770, located near the human leukocyte antigen (HLA)-DQB1, was the most significant SNP (P = 4.5 × 10−10). In comparison with 24 SNPs in a GWAS of UK asthmatics, six SNPs were significant with the same odds ratio (OR) direction, including signals related to type 2 inflammation (e.g., IL1RL1, TSLP, and GATA3) and mucus plugging (e.g., MUC5AC). HLA-DQA1 showed an opposite OR direction. The HLA-DQB1 gene demonstrated significantly imputed mRNA expression in the lung tissue and whole blood. Conclusions The SNP rs1770 of HLA-DQB1 was the most significant in Korean asthmatics. Similarities and discrepancies were found in the genetic variants between Korean and UK asthmatics. GWAS of Korean asthmatics should be replicated and compared with those of GWAS of other ethnicities.

We conducted a prospective, mobile-based survey on the self-reported adverse reactions in healthcare workers (HCWs) who received both doses of the BNT162b2 mRNA vaccine. Of the 342 HCWs who completed the two-dose vaccination, 265 (77.5%) responded to the survey at least once. Overall, the rates of adverse reactions were higher after the second dose compared with the first dose (89.1% vs. 80.1%, P = 0.006). The most common systemic reactions were muscle ache (69.1%), fatigue (65.7%), headache (48.7%), chills (44.2%), and fever (32.1%), and were notably more common after the second dose vaccine as well. We also noted a sex difference in which the frequency of adverse reactions after the second dose of the vaccine was significantly higher in females, which was not observed after the first dose. The rates of adverse reactions were lower in older age groups, and the rates and severities of the adverse reactions decreased during the 3-day period following vaccination., Graphical Abstract

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.We aimed to describe the characteristics of SEA and identify its patient subgroups.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.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.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.

Background We performed a prospective survey on the adverse reactions following the first dose of two types of vaccines against coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs) in South Korea. Methods HCWs at a tertiary referral hospital in Seoul, South Korea, received a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) or an mRNA-based vaccine (BNT162b2) between March 5 and March 26, 2021. The HCWs were asked to report adverse reactions through a mobile self-report questionnaire for three days after vaccination. Results A total of 7,625 HCWs received the first dose of ChAdOx1 or BNT162b2 vaccine during the study period. Of them, 5,866 (76.9%) HCWs (ChAdOx1, n = 5,589 [95.3%]; BNT162b2, n = 277 [4.7%]) participated at least once in the survey, of whom 77% were female and 86% were younger than 50 years. The overall adverse reaction rate was 93% in the ChAdOx1 group and 80% in the BNT162b2 group (P < 0.001). Both local and systemic reactions were more commonly reported in the ChAdOx1 group, and the difference was larger in systemic reactions such as fever and fatigue. In the ChAdOx1 group, the incidence of adverse reactions was significantly higher in females and those in the younger age groups, while the BNT162b2 group showed such difference according to age. Conclusion In our prospective survey, vaccine-associated adverse reactions were more commonly reported in the ChAdOx1 group than in the BNT162b2 group. Females and younger age groups experienced vaccine-associated adverse reactions more frequently., Graphical Abstract

Although inhaled corticosteroids (ICSs) are the recommended first-line therapy for asthma, determining whether to continue or discontinue ICS treatment in patients with mild asthma remains challenging for clinicians. Several studies have revealed that patients with mild-persistent asthma maintained a well-controlled state after ICS withdrawal. However, the long-term outcomes of ICS withdrawal have not yet been determined.To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma.We investigated the clinical outcomes of discontinuing ICSs in patients with well-controlled mild asthma and compared the time to loss of control (LOC) between patients who stopped ICS treatment (ICS withdrawal group, IWG) and those who continued treatment for 3 years (continuous ICS group, CIG).A significant difference in the time to LOC was observed between the IWG and CIG (hazard ratio, 2.56; 95% confidence interval, 1.52-4.33; P.001). Increasing fractional exhaled nitric oxide levels (P = 0.008) and sputum eosinophil counts (%) (P = 0.015) revealed a weak but significant association with LOC risk in the CIG. The sputum eosinophil counts (P = 0.039) and serum total immunoglobulin E levels (P = 0.014) were significantly higher in the LOC group than in the non-LOC group of the CIG.Our results suggest that the maintenance of ICS treatment may help keep patients' asthma under control. Furthermore, patients with LOC had significantly higher sputum eosinophil counts in the CIG than those in the non-LOC group. Therefore, continuous ICS use by patients with mild, well-controlled asthma could be associated with good clinical outcomes.ClinicalTrials.gov Identifier: KCT0002234.

Background The occurrence of coronary artery disease (CAD) is unknown to date in patients who have undergone the right ventricular outflow tract (RVOT) reconstruction surgery for congenital heart disease using a bioprosthetic valve or conduit. Purpose We present the incidence and outcomes of CAD in patients who underwent RVOT reconstruction surgery in a single tertiary center. Method From April 1986 to February 2019, 544 patients underwent Rastelli operation or pulmonary valve replacement for conotruncal anomalies at the Seoul National University Children's Hospital in Korea. The patient's medical records and imaging findings were analyzed retrospectively. Results Significant coronary stenosis or occlusion were observed in 19 patients (3.5%) after RVOT reconstruction surgery. Their underlying diseases were pulmonary atresia in 8, tetralogy of Fallot in 3, double outlet right ventricle with pulmonary stenosis in 3, truncus arteriosus in 2, congenitally corrective transposition of great artery in 2, and congenital aortic stenosis in 1. Mechanism of CAD was compression of coronary artery by artificial conduit or valve in 10, intraoperative coronary injury in 7, and intramural course of coronary artery in 2 patients. The median number of RVOT reconstruction surgery before the diagnosis of CAD was 2 times (interquartile range: 2–3 times). The median age at diagnosis of CAD was 15 years (interquartile range: 9.5 - 25 years). The median time to detection of the CAD from the last RVOT reconstruction surgery was 9 years (interquartile range: 3.5–12.5 years). Involved coronary artery was right coronary artery (RCA) in 10, left anterior descending coronary artery (LAD) in 7, and left main coronary artery in 2 patients. Seven (36.8%) patients had underlying congenital coronary anomalies, such as single coronary artery, intramural course of the coronary artery, and anomalous origin of the coronary artery from an abnormal sinus. One patient died due to brain injury on extracorporeal membrane oxygenator after intraoperative coronary injury. Two patients with intramural course of coronary artery and one patient with high take-off of RCA which was compressed by adjacent calcified conduit underwent surgical repair of the CAD. One patient with recurrent ventricular tachycardia needed an implantable cardioverter-defibrillator. Nine patients are on medication for heart failure. Three patients with total occlusion of RCA or LAD showed well-developed collaterals from another normal coronary artery. Conclusion CAD after RVOT reconstruction surgery are not common but can be fatal. Because the clinical significance of CAD and long-term prognosis are not known yet, we need to closely track the patient after RVOT reconstruction surgery. Indications for the management of the CAD should be prepared to prevent sudden cardiac death, arrhythmia, and ventricular dysfunction in these patients. Funding Acknowledgement Type of funding source: None

The human leukocyte antigen (HLA)-B*13:01 was reported as an important risk factor for dapsone hypersensitivity syndrome (DHS) in Chinese and Thai populations.From the Korean nationwide registry, seven subjects with previous DHS were included. Their HLA allele/phenotype frequencies were compared with 8 dapsone-tolerant subjects recruited from a single institution, and general population (n = 485) in Korea. The authors also performed a meta-analysis with these data using previous Chinese and Thai studies.Among the seven DHS subjects, 85.7% presented with the HLA-B*13:01 allele. The HLA-C*03:04, HLA-DRB1*12:02 (both in linkage disequilibrium with HLA-B*13:01), and HLA-A*02:01 alleles were also presented in 85.7%, 71.4%, and 71.4%, respectively. Subjects with HLA-B*13:01 were susceptible to developing DHS compared to dapsone-tolerant controls (odds ratio [OR]: 73.667) and the Korean general population (OR: 139.500). HLA-C*03:04 (OR: 40.935), HLA-DRB*12:02 (OR: 36.613), and HLA-A*02:01 (OR: 5.862) showed similar results. In meta-analysis, HLA-B*13:01 was associated with dapsone-induced hypersensitivity (overall OR: 42.692), and subgroup analyses according to the control types demonstrated similar results (OR:43.694 and 41.866, respectively).Similar to previous Asian population studies, HLA-B*13:01 is significantly associated with the risk of DHS in Korea. These associations may be useful for preventing DHS and improving drug safety.

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 β2 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 FEV1, forced vital capacity, FEV1/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 FEV1 and forced vital capacity (P 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.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are the most severe cutaneous drug hypersensitivity reactions, which are unpredictable adverse drug reactions. SJS/TEN is associated with significant mortality and morbidity; however, effective treatment is difficult. Mesenchymal stem cells (MSCs) are well-known for their anti-inflammatory and tissue regeneration properties. The purpose of the present study was to verify whether MSCs could be applied for the treatment of SJS/TEN. We developed an SJS/TEN mouse model using peripheral blood mononuclear cells from a lamotrigine-induced SJS patient. MSCs were injected into the model to verify the treatment effect. In SJS model mice treated with MSCs, ocular damage rarely occurred, and apoptosis rate was significantly lower. We demonstrated a therapeutic effect of MSCs on SJS/TEN, with these cells presenting a potential novel therapy for the management of this disorder., Graphical Abstract

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 β2-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.

Background and objective Emphysema is characterized by irreversible destruction of alveolar walls with distal air space enlargement. Cigarette smoke (CS) is considered a major risk factor for emphysematous changes in COPD. Progranulin (PGRN), a glycoprotein induced by CS, has been reported to participate in apoptosis. However, the precise role of PGRN in emphysema is currently unknown. This study aimed to evaluate the role of PGRN in human alveolar epithelial cells (AECs) in response to CS. Methods First, PGRN expression was assessed in a mouse model of CS-induced emphysema and in AECs after exposure to CS extract (CSE). Then, the effect of PGRN on CSE-mediated apoptosis was determined under PGRN silencing or overexpressing conditions. To investigate the functional mechanism of PGRN, endoplasmic reticulum (ER) stress markers and the mitogen-activated protein kinase (MAPK) pathway were also evaluated in the CSE-exposed cells. Finally, PGRN expression levels in sera and peripheral blood mononuclear cells (PBMCs) were measured and compared between patients with COPD and healthy subjects. Results Our results revealed that PGRN expression was elevated in CS-exposed mouse lungs and CSE-treated AECs. CSE-induced cellular apoptosis was significantly increased in PGRN-knockdown AECs and decreased in PGRN-overexpression cells. The activation of ER stress-associated molecules correlated with PGRN expression levels. Compared with healthy controls, COPD patients exhibited significantly lower PGRN serum levels and higher PBMC intracellular PGRN levels. Conclusion PGRN in airway epithelial cells may regulate CS-induced AEC apoptosis and may be involved in the development of COPD.