GOAT: Gene-level biomarker discovery from multi-Omics data using graph ATtention neural network for eosinophilic asthma subtype.

MOTIVATION: Asthma is a heterogeneous disease where various subtypes are established and molecular biomarkers of the subtypes are yet to be discovered. Recent availability of multi-omics data paved a way to discover molecular biomarkers for the subtypes. However, multi-omics biomarker discovery is challenging because of the complex interplay between different omics layers. RESULTS: We propose a deep attention model named Gene-level biomarker discovery from multi-Omics data using graph ATtention neural network (GOAT) for identifying molecular biomarkers for eosinophilic asthma subtypes with multi-omics data. GOAT identifies genes that discriminate subtypes using a graph neural network by modeling complex interactions among genes as the attention mechanism in the deep learning model. In experiments with multi-omics profiles of the COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) asthma cohort of 300 patients, GOAT outperforms existing models and suggests interpretable biological mechanisms underlying asthma subtypes. Importantly, GOAT identified genes that are distinct only in terms of relationship with other genes through attention. To better understand the role of biomarkers, we further investigated two transcription factors, CTNNB1 and JUN, captured by GOAT. We were successful in showing the role of the transcription factors in eosinophilic asthma pathophysiology in a network propagation and transcriptional network analysis, which were not distinct in terms of gene expression level differences. AVAILABILITY AND IMPLEMENTATION: Source code is available https://github.com/DabinJeong/Multi-omics_biomarker. The preprocessed data underlying this article is accessible in data folder of the github repository. Raw data are available in Multi-Omics Platform at http://203.252.206.90:5566/, and it can be accessible when requested.

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

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

Transcriptomic Expression of T2-Inflammation Genes in Peripheral Blood Mononuclear Cells and Longitudinal Clinical Outcomes in Asthma: Insights from the COREA Study.

BACKGROUND: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients. OBJECTIVE: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use. METHODS: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines. RESULTS: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients. CONCLUSION: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma.

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

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

Higher sclerostin is associated with pulmonary hypertension in pre-dialysis end-stage kidney disease patients: a cross-sectional prospective observational cohort study.

BACKGROUND: Pulmonary hypertension (PH) is a complication of chronic kidney disease (CKD) that contributes to mortality. Sclerostin, a SOST gene product that reduces osteoblastic bone formation by inhibiting Wnt/ß-catenin signaling, is involved in arterial stiffness and CKD-bone mineral disease, but scanty evidence to PH. This study explored the relationship between sclerostin and PH in CKD 5, pre-dialysis end-stage kidney disease (ESKD) patients. METHODS: This cross-sectional prospective observational cohort study included 44 pre-dialysis ESKD patients between May 2011 and May 2015. Circulating sclerostin levels were measured using an enzyme-linked immunosorbent assay. PH was defined as an estimated pulmonary artery systolic pressure > 35 mmHg on echocardiography. RESULTS: Patients with higher sclerostin levels ≥ 218.18pmol/L had echocardiographic structural cardiac abnormalities, especially PH (P < 0.01). On multivariate logistic analysis, sclerostin over 218.19pmol/L was significantly associated with PH (odds ratio [OR], 41.14; 95% confidence interval [CI], 4.53-373.89, P < 0.01), but multivariate Cox regression analysis showed the systemic vascular calcification score over 1 point (Hazard ratio [HR] 11.49 95% CI 2.48-53.14, P = 0.002) and PH ([HR] 5.47, 95% CI 1.30-23.06, P = 0.02) were risk factors for all-cause mortality in pre-dialysis ESKD patients. CONCLUSIONS: Serum sclerostin and PH have a positive correlation in predialysis ESKD patients. The higher systemic vascular calcification score and PH have an association to increase all-cause mortality in pre-dialysis ESKD patients.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

Safety and outcomes of "at-home self-provocation tests" in patients with mild nonsteroidal anti-inflammatory drug-induced urticaria/angioedema.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is common; however, many patients do not receive an accurate diagnosis and are using unnecessary alternative drugs or have medication restrictions. OBJECTIVE: To establish a protocol for provocation tests that can be performed safely and effectively at home to give patients an accurate diagnosis, whereas also delabeling NSAID hypersensitivity. METHODS: We retrospectively analyzed the medical records of 147 patients with NSAID hypersensitivity. All patients had NSAID-induced urticaria/angioedema with less than 10% body surface area skin involvement. One specialist developed the protocol through history taking and chart review. If NSAID hypersensitivity was confirmed, an oral provocation test was performed to confirm the safe alternative medications (group A). If it was undetermined, an oral provocation test was performed to confirm the diagnosis and alternative medications (group B). All oral provocation tests were performed by patients in their homes according to the protocol. RESULTS: Approximately 26% of group A patients had urticaria or angioedema symptoms with alternative drugs, whereas the remaining 74% was safe. In group B, 34% of the patients were diagnosed with having NSAID hypersensitivity. However, 61% did not respond to the culprit drug; therefore, NSAID hypersensitivity had been misdiagnosed. During this at-home self-provocation test, no severe hypersensitivity reactions occurred. CONCLUSION: Many patients originally suspected of having NSAID hypersensitivity were confirmed to have been misdiagnosed. We successfully conducted an effective and safe at-home self-provocation test.

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

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Relationship between asthma and sarcopenia in the elderly: a nationwide study from the KNHANES.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical Relevance of Staphylococcus aureus Nasal Colonization and Staphylococcal Enterotoxin-Specific IgE Sensitization in Late-Onset Asthma.

This prospective observational study examined whether Staphylococcus aureus (SA) nasal colonization and staphylococcal enterotoxin (SE)-specific IgE sensitization synergistically affect clinical outcomes of adults with late-onset asthma (onset age ≥ 40 years). Nasal swabs were taken to evaluate SA colonization. Serum SE-IgE level was measured. Subjects were classified into 4 groups according to SA colonization and SE-IgE sensitization positivity. Among 181 patients with late-onset asthma recruited, the proportions of SA/SE (‒/‒), SA/SE (+ /‒), SA/SE (‒/ +), and SA/SE (+ / +) were 33.7%, 15.5%, 28.2%, and 22.6%, respectively. Severe asthma was more frequent in the SA/SE (+ / +) group than in the SA/SE (‒/‒) group (41.5% vs. 13.1%). The relationship of SA/SE (+ / +) with severe asthma was significant in multivariate logistic regression (vs. SA/SE (‒/‒); adjusted odds ratio: 4.36; 95% confidence intervals: 1.50‒12.73; p = 0.007), whereas SA/SE (+ /‒) or SA/SE (‒/ +) was not. In conclusion, SA nasal colonization and SE-IgE sensitization may synergistically affect disease severity in late-onset asthmatics.

Incidence and Economic Burden of Adverse Drug Reactions in Hospitalization: A Prospective Study in Korea.

BACKGROUND: Adverse drug reactions (ADRs) are escalating, and their socioeconomic burden is increasing. However, large-scale prospective studies investigating ADRs during hospitalization are rare in Korea. We prospectively investigated the incidence, characteristics, and economic burden of ADRs in hospitalized patients based on electronic medical records (EMRs). METHODS: Among patients admitted to three hospitals from October 2016 to October 2017, 5,000 patients were randomly selected and prospectively observed during hospitalization. Research nurses monitored and detected patients who had symptoms, signs, or laboratory findings suspicious for ADRs using an EMR-based detection protocol. Next, allergy and ADR specialists reviewed the medical records to determine the relationship between adverse reactions and drugs. Cases in which a causal relationship was certain, probable/likely, or possible were included in the ADR cases. Clinically meaningful ADR cases or those leading to prolonged hospitalization were defined as significant ADRs. RESULTS: ADRs occurred in 510 (10.2%) patients. The mean length of hospital stay was approximately 5 days longer in patients with ADRs. Opioids accounted for the highest percentage of total ADRs. Significant ADRs were observed in 148 (3.0%) patients. Antibiotics accounted for the highest percentage of significant ADRs. Drug hypersensitivity reactions (DHRs) occurred in 88 (1.8%) patients. Antibiotics accounted for the highest percentage of DHRs. The average medical expenses for one day of hospitalization per patient were highest in significant ADRs, followed by non-significant ADRs, and non-ADRs. CONCLUSION: ADRs in hospitalized patients are an important clinical issue, resulting in a substantial socioeconomic burden. EMR-based strategy could be a useful tool for ADR monitoring and early detection.

Association between obesity and lung function changes by sex and age in adults with asthma.

OBJECTIVE: The lung function changes presenting before and after asthma treatment in obese people remain largely unknown. This study aimed to investigate the association between obesity and lung function changes before and after treatment in adults with asthma. METHODS: We enrolled 937 newly diagnosed asthma patients from Cohort for Reality and Evolution of Adult Asthma in Korea cohort in 2015-2017, who performed follow-up spirometry after three months of asthma treatment. The percentage changes (Δ) between the spirometry results before and after treatment were calculated. Patients were categorized into four body mass index (BMI) groups; underweight (<18.5), normal (18.5-22.9), overweight (23.0-24.9), and obese (≥25.0). Association between percent change of pulmonary function and BMI was analyzed according to sex and/or age (< 45 yrs, 45-65 yrs, ≥ 65 yrs), which were statistically corrected for age, sex, smoking status, and medication history. RESULTS: There was no consistent correlation between BMI and each lung function parameter. However, there were significant differences between BMI and ΔFEV1/FVC before and after 3 months of controller treatment. The obese asthmatics showed significantly lower ΔFEV1/FVC (6.0 ± 13.5%) than the underweight (12.6 ± 21.4%, P = 0.044) or normal weight (9.1 ± 14.6%, P = 0.031). Middle-aged women had higher BMI (24.11 ± 3.60 vs. 22.39 ± 3.52) and lower ΔFEV1/FVC (5.7 ± 11.9% vs. 8.9 ± 14.3%, P = 0.012) than young women. CONCLUSIONS: Obesity is negatively correlated with the ΔFEV1/FVC before and after controller treatment. Sex and age differentially contribute to lung function changes in response to asthma medications in adult asthmatics, showing a significant decrease in the ΔFEV1/FVC in middle-aged women.

Clusters of Severe Eosinophilic Asthma in a Korean Asthma Cohort.

BACKGROUND: Targeted therapies have broadened the available treatment options for patients with severe eosinophilic asthma (SEA). However, differences in the magnitude of treatment responses among patients indicate the presence of various underlying pathophysiological processes and patient subgroups. OBJECTIVES: We aimed to describe the characteristics of SEA and identify its patient subgroups. METHODS: Clinical data from the Cohort for Reality and Evolution of Adult Asthma in Korea were analyzed. Cluster analysis was performed among those with SEA using 5 variables, namely, prebronchodilator forced expiratory volume in 1 s, body mass index, age at symptom onset, smoking amount, and blood eosinophil counts. RESULTS: Patients with SEA showed prevalent sensitization to aeroallergens, decreased lung function, and poor asthma control status. Cluster analysis revealed 3 distinctive subgroups among patients with SEA. Cluster 1 (n = 177) consisted of patients reporting the lowest blood eosinophils (median, 346.8 cells/µL) and modest severe asthma with preserved lung function during the 12-month treatment period. Cluster 2 (n = 42) predominantly included smoking males with severe persistent airway obstruction and moderate eosinophilia (median, 451.8 cells/µL). Lastly, cluster 3 (n = 95) included patients with the most severe asthma, the highest eosinophil levels (median, 817.5 cells/µL), and good treatment response in terms of improved lung function and control status. CONCLUSIONS: Three subgroups were identified in SEA through the cluster analysis. The distinctive features of each cluster may help physicians predict patients who will respond to biologics with greater magnitude of clinical improvement. Further research regarding the underlying pathophysiology and clinical importance of each subgroup is warranted.

Different Impacts of Blood and Sputum Eosinophil Counts on Lung Function and Clinical Outcomes in Asthma: Findings from the COREA Cohort.

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. METHODS: Asthma 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. RESULTS: High 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 twofold 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. CONCLUSION: EOS-S and EOS-B contribute differently to the clinical outcomes and should be taken into account independently to improve asthma care.

Cough Presentation and Cough-Related Healthcare Utilization in Tertiary Care: Analysis of Routinely Collected Academic Institutional Database.

PURPOSE: Routinely collected data (RCD) from electronic health records (EHR) are useful for studying disease epidemiology in the real world. We examined cough presentation and cough-related healthcare utilization using an academic institutional EHR database in Korea. METHODS: In this retrospective cohort study, patients with subacute (3-8 weeks) or chronic cough (> 8 weeks in duration) referred to allergy and asthma clinics were studied. Cases were identified using the search term "cough" or "coughing," which is the chief complaint, in the data fields. Structured data, including demographics, medical history, symptoms, and diagnostic tests, were analyzed. Healthcare utilization was assessed for drug prescriptions, additional tests, or outpatient visits for 1 year. RESULTS: Cough was the chief complaint in 13,223 cases (46.7%) among 28,312 new referrals for 8 years. A total of 3810 subacute and 7150 chronic cough patients were analyzed. The common demographic profile was middle-aged woman (mean age 52.1 years), reported in 63% of the cases. Cough was frequently accompanied by anterior nasal (about 50%), lower airway (30%), or acid reflux disease symptoms (20%), and by test abnormalities in chest X-rays (14%), spirometry (23%), or T2 inflammation markers (40%). Chronic cough patients frequently required additional tests (chest CT scan: 24%), drug prescriptions (codeine: 21.5% and oral steroids: 9.9%), and long-term healthcare utilization (16.0%) for 1 year. CONCLUSIONS: Cough is a common chief complaint at allergy and asthma clinics, but the clinical presentation may be heterogeneous. Further studies are needed to understand long-term outcomes and reduce the disease burden.

A Case Report of Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination and Heparin Use During Hemodialysis.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but life-threatening complication. VITT strongly mimics heparin-induced thrombocytopenia (HIT) and shares clinical features. Heparin is commonly used to prevent coagulation during hemodialysis. Therefore, nephrologists might encounter patients needing dialysis with a history of heparin exposure who developed thrombotic thrombocytopenia after vaccination. A 70-year-old male presented with acute kidney injury and altered mental status due to lithium intoxication. He needed consecutive hemodialysis using heparin. Deep vein thrombosis of left lower extremity and accompanying severe thrombocytopenia of 15,000/µL on 24 days after vaccination and at the same time, nine days after heparin use. Anti-platelet factor 4 antibody test was positive. Anticoagulation with apixaban and intravenous immunoglobulin (IVIG) infusion resolved swelling of his left calf and thrombocytopenia. There were no definitive diagnostic tools capable of differentiating between VITT and HIT in this patient. Although VITT and HIT share treatment with IVIG and non-heparin anticoagulation, distinguishing between VITT and HIT will make it possible to establish a follow-up vaccination plan in a person who has had a thrombocytopenic thrombotic event. Further research is needed to develop the tools to make a clear distinction between the clinical syndromes.

Soluble ACE2 and TMPRSS2 Levels in the Serum of Asthmatic Patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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

BACKGROUND: Some reports have suggested that the clinical and economic burdens of asthma are associated with blood eosinophil levels. The association between clinical burden and blood eosinophil counts were evaluated in a Korean adult asthma cohort. METHODS: Clinical information including blood eosinophil counts that were not affected by systemic corticosteroids were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea database. Clinical burden was defined as 1) asthma control status, 2) medication demand and 3) acute exacerbation (AE) events during 1 consecutive year after enrollment. All patients were divided into atopic and non-atopic asthmatics. The associations between asthma outcomes and the blood eosinophil count were evaluated. RESULTS: In total, 302 patients (124 atopic and 178 non-atopic asthmatics) were enrolled. In all asthmatics, the risk of severe AE was higher in patients with blood eosinophil levels < 100 cells/µL than in patients with levels ≥ 100 cells/µL (odds ratio [OR], 5.406; 95% confidence interval [CI], 1.266-23.078; adjusted P = 0.023). Among atopic asthmatics, the risk of moderate AE was higher in patients with blood eosinophil levels ≥ 300 cells/µL than in patients with levels < 300 cells/µL (OR, 3.558; 95% CI, 1.083-11.686; adjusted P = 0.036). Among non-atopic asthmatics, the risk of medication of Global Initiative for Asthma (GINA) steps 4 or 5 was higher in patients with high blood eosinophil levels than in patients with low blood eosinophil levels at cutoffs of 100, 200, 300, 400, and 500 cells/µL. CONCLUSION: The baseline blood eosinophil count may predict the future clinical burden of asthma.

Adverse drug reactions of montelukast and pranlukast: Analysis of the Korea database.

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.

Discontinuation of inhaled corticosteroids in patients with controlled asthma: The DISCO (Discontinuation of Inhaled Steroid in Controlled asthmatics Over 6 months) study.

BACKGROUND: 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. OBJECTIVE: To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma. METHODS: 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). RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: KCT0002234.