8-Iso-prostaglandin F2α as a biomarker of type 2 low airway inflammation and remodeling in adult asthma.

BACKGROUND: Although 8-iso-prostaglandin F2a has been proposed as a potential biomarker for oxidative stress in airway diseases, its specific role in asthma remains poorly understood. OBJECTIVE: To evaluate the diagnostic potential of 8-iso-prostaglandin F2a in assessing airway inflammation, airway remodeling, airway hyperresponsiveness, and oxidative stress in asthma. METHODS: Blood and urine concentrations of 8-iso-prostaglandin F2a were quantified using liquid chromatography-tandem mass spectrometry in 128 adults with asthma who had maintained antiasthma medications. Their correlations with clinical data, sputum cell counts, lung function parameters, and serum markers of epithelial/neutrophil activity and airway remodeling were then analyzed. RESULTS: The urinary 8-iso-prostaglandin F2a concentrations were significantly higher in patients with noneosinophilic asthma than in those with eosinophilic asthma (P < .05). The area under the curve was 0.678, indicating moderate diagnostic accuracy for noneosinophilic asthma. There were significant correlations with neutrophilic inflammation markers and airway remodeling markers (all P < .05). Negative correlations were observed with forced expiratory volume in 1 second (%), forced expiratory volume in 1 second/forced vital capacity, forced expiratory flow at 25% to 75% of forced vital capacity, and serum club cell protein 16 levels (all P < .05). High 8-iso-prostaglandin F2a concentrations were also noted in obese and smoking subgroups (all P < .05). However, the serum 8-iso-prostaglandin F2a concentrations were not correlated with these asthma-related parameters. CONCLUSION: Urinary 8-iso-prostaglandin F2a concentrations are a potential biomarker for phenotyping severe asthma, particularly noneosinophilic asthma, offering oxidative stress-induced epithelial inflammation/remodeling as an additional target in asthma management.

Cannabinoid receptor 2 as a regulator of inflammation induced oleoylethanolamide in eosinophilic asthma.

BACKGROUND: Oleoylethanolamide (OEA), an endogenously generated cannabinoid-like compound, has been reported to be increased in patients with severe asthma and aspirin-exacerbated respiratory disease. Recruitment of activated eosinophils in the airways is a hallmark of bronchial asthma. OBJECTIVE: We explored the direct contribution of cannabinoid receptor 2 (CB2), a cognate receptor of OEA, which induces eosinophil activation in vitro and in vivo. METHODS: We investigated OEA signaling in the eosinophilic cell line dEol-1 in peripheral blood eosinophils from people with asthma. In order to confirm whether eosinophil activation by OEA is CB2 dependent or not, CB2 small interfering RNA and the CB2 antagonist SR144528 were used. The numbers of airway inflammatory cells and the levels of cytokines were measured in bronchoalveolar lavage fluid, and airway hyperresponsiveness was examined in the BALB/c mice. RESULTS: CB2 expression was increased after OEA treatment in both peripheral blood eosinophils and dEol-1 cells. It was also elevated after OEA-induced recruitment of eosinophils to the lungs in vivo. However, SR144528 treatment reduced the activation of peripheral blood eosinophils from asthmatic patients. Furthermore, CB2 knockdown decreased the activation of dEol-1 cells and the levels of inflammatory and type 2 cytokines. SR144528 treatment alleviated airway hyperresponsiveness and eosinophil recruitment to the lungs in vivo. CONCLUSION: CB2 may contribute to the pathogenesis of eosinophilic asthma. Our results provide new insight into the molecular mechanism of signal transduction by OEA in eosinophilic asthma.

Nasal Transcriptome and Epigenome Analysis Identifies the Pathogenic Features of Aspirin-Exacerbated Respiratory Disease.

Dysregulation of the arachidonic acid metabolic pathway is the most widely known pathomechanism of aspirin-exacerbated respiratory disease (AERD). This study aimed to perform integrative analysis of transcriptomic and epigenomic profiling with network analysis to determine the novel pathogenic features of AERD. Ten patients with asthma including 5 patients with AERD and another 5 patients with aspirin tolerant asthma (ATA) were enrolled. Nasal scraping was performed and nasal mucosa was used in omics profiling. Peripheral eosinophil counts, sputum eosinophil counts, fractional exhaled nitric oxide levels, and pulmonary function test results were evaluated. Differentially expressed genes (DEGs), differentially methylated probes (DMPs) and differentially correlated genes (DCGs) between patients with AERD and those with ATA were analyzed. Network analysis using ingenuity pathway analysis (IPA) was performed to determine the gene connection network and signaling pathways. In total, 1,736 DEGs, 1,401 DMPs, and 19 pairs for DCGs were identified. Among DCGs, genes related to vesicle transport (e.g., RAB3B and STX2) and sphingolipid dysregulation (e.g., SMPD3) were found to be hypo-methylated and up-regulated in AERD. Using the canonical pathway analysis of IPA with 78 asthma-related DEGs, signaling pathways of T helper cell differentiation/activation and Fcε receptor I were generated. Up-regulation of RORγt and FcER1A were noted in AERD. Gene expression levels of RAB3B, SYNE1, STX2, SMPD3 and RORγt were significantly associated with sputum eosinophil counts. Quantitative real-time polymerase chain reaction was performed and mRNA expression levels of STX2, SMPD3, RORγt, and FcER1A were significantly higher in AERD compared to ATA. Distinct pathogenic features were identified by using integrative multi-omics data analysis in patients with AERD.

Biomarkers for predicting type 2-high and uncontrolled asthma in real-world practice.

BACKGROUND: Blood eosinophil count (BEC), immunoglobulin (Ig) E, and fractional exhaled nitric oxide (FeNO) are key clinical indicators for identifying type 2 (T2) asthma. OBJECTIVE: To provide optimal cutoff points of T2 markers for assessing T2-high or uncontrolled asthma in real-world practice. METHODS: Various clinical and laboratory parameters were analyzed according to the result of T2 markers (BEC, serum-free IgE, and FeNO) in adults with asthma who had maintained antiasthmatic medications. The cutoff levels for representing uncontrolled asthma were determined using receiver operating characteristic analysis. Blood levels of periostin and eosinophil-derived neurotoxin were measured by enzyme-linked immunosorbent assay. Activation markers of circulating eosinophils (Siglec8+) and neutrophils (CD66+) were analyzed by flow cytometry. RESULTS: Of 133 patients with asthma, 23 (17.3%) had 3 T2 markers (BEC ≥ 300 cells/µL, serum-free IgE ≥ 120 ng/mL, and FeNO ≥ 25 parts per billion) and significantly higher levels of sputum eosinophils, blood eosinophil-derived neurotoxin, and Siglec8+ eosinophils but lower 1-second forced expiratory volume percentage, in addition to a higher rate of uncontrolled status (P < .05 for all). Furthermore, patients with uncontrolled asthma had significantly higher levels of FeNO and BEC with lower 1-second forced expiratory volume percentage (P < .05 for all). The optimal cutoff values for predicting uncontrolled asthma were found to be 22 parts per billion of FeNO levels, 161.4 cells/L of BECs, and 85.9 ng/mL of serum-free IgE levels. CONCLUSION: We suggest the optimal cutoff values of BEC, IgE, and FeNO for classifying T2-high or uncontrolled asthma, which could be applied as candidate biomarkers for targeting patients with asthma who require T2 biologics.

Role of club cell 16-kDa secretory protein in asthmatic airways.

BACKGROUND: Club cell 16-kDa secretory protein (CC16) is a pneumoprotein and functions as an anti-inflammatory or antioxidant protein. However, altered levels of serum CC16 as well as their effect on airways inflammation have not been fully evaluated. METHODS: We recruited 63 adult asthmatics on maintenance medications and 61 healthy controls (HCs). The asthmatic subjects were divided into two groups according to the result of bronchodilator responsiveness (BDR) test: the present BDR (n = 17) and absent BDR (n = 46) groups. Serum CC16 levels were measured by ELISA. As an in vitro study, the effect of Dermatophagoides pteronyssinus antigen 1 (Der p1) on the production of CC16 in airways epithelial cells (AECs) according to a time-dependent manner was assessed; the effects of CC16 protein on oxidative stress system, airways inflammation and remodelling were tested. RESULTS: Serum CC16 levels showed significantly higher in the asthmatics than in the HCs (p < .001) with a positive correlation with FEV1 % (r = .352, p = .005). The present BDR group had significantly lower levels of serum CC16, FEV1 % and MMEF%, but showed higher level of FeNO than the absent BDR group. Serum CC16 levels (below 496.0 ng/mL) could discriminate the present BDR group from the absent BDR group (area under the curve = 0.74, p = .004). In vitro testing demonstrated that Der p1 exposure significantly induced CC16 release from AECs for 1 h, which was progressively decreased after 6 h and followed by MMP-9 and TIMP-1 production. These findings were associated with oxidant/antioxidant disequilibrium and restored by CC16 treatment (but not dexamethasone). CONCLUSION: Decreased CC16 production contributes to persistent airways inflammation and lung function decline. CC16 may be a potential biomarker for asthmatics with BDR.

Association of eosinophil-derived neurotoxin levels with asthma control status in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: The long-term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil-derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin-exacerbated respiratory disease (AERD), and aspirin-tolerant asthma (ATA). METHODS: A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K-EDN ELISA kit. Urinary leukotriene E4 (LTE4 ) level was measured using liquid chromatography-mass spectrometry (LC-MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. RESULTS: In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well-controlled or partly-controlled asthma (ANOVA, p < 0.001); in patients with AERD, the sputum EDN levels showed significant correlations with ACT, ACQ, and AQLQ scores (p = 0.010, r = -0.536, p = 0.001, r = 0.665, and p < 0.001, r = -0.691, respectively), while no differences were noted in patients with ATA. Sputum EDN level was the only significant factor for ACT, ACQ, and AQLQ scores in patients with AERD (p = 0.001, p < 0.001, and p < 0.001, respectively) in the multivariate analysis adjusting for age, sex, peripheral eosinophil count, and urine LTE4 . The ROC curve analysis demonstrated that sputum EDN can predict uncontrolled asthma with 80% sensitivity and 88.2% specificity for ACT ≤ 19 (area under the ROC curve [AUC] = 0.824, p = 0.019); 71.4% sensitivity and 86.7% specificity for ACQ ≥ 1.5 (AUC = 0.752, p = 0.049) only in AERD patients. CONCLUSION: The level of sputum EDN may be a potential biomarker for identifying the asthma control status in patients with AERD.

Incidence and outcomes of adverse drug reactions to first-line anti-tuberculosis drugs and their effects on the quality of life: A multicenter prospective cohort study.

BACKGROUND: In tuberculosis (TB) treatment, adverse drug reactions (ADRs) can interrupt treatment and decrease the quality of life (QoL). We aimed to prospectively investigate the incidence of ADRs to first-line anti-TB drugs and related outcomes and QoL. METHODS: Adult patients with TB who had been treated with first-line anti-TB drugs in five Korean hospitals were enrolled. ADR questionnaire surveys and blood tests were performed four times serially, and QoL was assessed on the fourth TB treatment week (±2 weeks). RESULTS: Of 410 enrolled patients with TB (males, 62%; mean age, 52.1 ± 18.1 years [those aged ≥65 years, 26.6%]), 67.8% experienced any ADRs (≥ grade 2) to TB drugs. The most common ADR was fatigue (53.2%), followed by itching (42.7%) and anorexia (41.7%). Older adult patients experienced relatively more ADRs, including anorexia, dyspepsia, rash, dizziness, anemia, abnormal hepatic/renal function tests, and increased uric acid levels (p < 0.05). Treatment regimens changed for 9.5% of patients owing to ADRs to anti-TB drugs. Patients with any ADRs and older adult patients had significantly lower QoL than their counterparts (p < 0.05). Old age (odds ratio [OR], 1.02) and being male (OR 2.65) were independently associated with ADRs, whereas active smoking (OR 4.73) and a relatively long treatment phase (OR 5.13) were independently associated with hepatotoxicity. CONCLUSION: ADRs to first-line anti-TB drugs were common and related to relatively low QoL, especially among older adults. Although 9.5% of patients had ADR-related regimen changes, most patients with ADRs completed treatments successfully.

Down-regulated surfactant protein B in obese asthmatics.

BACKGROUND: Obesity is a common comorbid condition in adult asthmatics and known as a feature of asthma severity. However, the molecular mechanism under obesity-induced inflammation has not yet been fully understood. OBJECTIVE: Considering the essential role of hydrophobic surfactant protein B (SP-B) in lung function, SP-B was targeted to examine its involvement in the development of obesity-induced airway inflammation in asthmatics. METHODS: The aim was to examine an alteration in circulating SP-B according to obesity in adult asthmatics, 129 asthmatics were enrolled and classified into 3 groups (obese, overweight and normal-weight groups) according to body mass index (BMI). Circulating SP-B levels were determined by enzyme-linked immunosorbent assay. Four single nucleotide polymorphisms of SFTPB gene were genotyped. Serum ceramide levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Significantly lower serum SP-B levels were noted in the obese group than in the overweight or normal-weight group (p = .002). The serum SP-B level was significantly correlated with serum levels of C18:0 ceramide and transforming growth factor beta 1 as well as BMI (r = -0.200; r = -0.215; r = -0.332, p < .050 for all). An inverse correlation was noted between serum SP-B and fractional exhaled nitric oxide levels in female asthmatics (r = -0.287, p = .009). Genetic predisposition of the SFTPB gene at 9306 A>G to the obese and overweight groups was noted. CONCLUSION: Obesity altered ceramide metabolism leading to pulmonary surfactant dysfunction and impaired resolution of airway inflammation, finally contributing to the phenotypes of obese asthmatics.

Role of Thymus and Activation-Regulated Chemokine in Allergic Asthma.

BACKGROUND: Asthma is a chronic inflammatory airway disease characterized by the predominant infiltration of inflammatory cells in the airways. Thymus and activation-regulated chemokine/C-C motif chemokine 17 (TARC/CCL17) is a chemokine responsible for trafficking T helper 2 cells into sites of allergic inflammation. OBJECTIVE: To validate the role of TARC in association with clinical and inflammatory parameters in adult asthmatics. METHODS: We enrolled 128 asthmatic patients and 70 healthy controls (HCs). Asthma-related clinical and laboratory parameters, including lung function and eosinophil counts, were measured. Serum levels of TARC, free immunoglobulin E (IgE), and eosinophil-derived neurotoxin (EDN) were determined by using enzyme-linked immunosorbent assay; serum total IgE level was measured using ImmunoCAP. The levels of inflammatory lipid mediators, such as leukotriene E4 (LTE4), 15-hydroxyeicosatetraenoic acid (15-HETE), thromboxane B2 (TXB2), and prostaglandin F2α (PGF2α), were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Serum TARC levels are significantly higher in asthmatics than in HCs and in allergic asthmatics than in HCs (P < 0.010 for all), with significantly negative correlations between serum TARC levels and FEV1%/MMEF% values (r = -0.314, r = -0.268, P < 0.050 for both). The patients with higher serum TARC levels had higher levels of serum total and free IgE levels (P < 0.050 for both) with positive correlations to serum levels of EDN, TXB2, and 15-HETE (r = 0.233, r = 0.264, and r = 0.223, respectively, P < 0.050 for all). CONCLUSION: We suggest the role of TARC in allergic asthma via contributing to mast cell and eosinophilic inflammation.

Persistent Eosinophilic Inflammation in Adult Asthmatics with High Serum and Urine Levels of Leukotriene E4.

BACKGROUND: Cysteinyl leukotrienes (CysLTs) are key mediators for bronchoconstriction, eosinophil recruitment and mucus production in the airways of asthmatic patients. To better understand the role of CysLTs in different asthma phenotypes, we compared the levels of arachidonic acid metabolites in relation to asthma control status and phenotypes in adult asthmatics on regular anti-asthma medications. METHODS: A total of 137 adult asthmatics (47 with aspirin-exacerbated respiratory disease [AERD] and 90 asthmatics with aspirin-tolerant asthma [ATA]) and 20 healthy controls were enrolled. Arachidonic acid metabolites in serum and urine were analyzed using LC-MS/MS methods, and clinical data, including asthma control status, exhaled NO (FeNO) and lung function tests, were collected. RESULTS: Urine LTE4 levels were significantly higher in AERD patients on inhaled corticosteroid-long-acting ß2- agonist plus leukotriene receptor antagonist (LTRA) treatment than in ATA patients (P=0.001). No differences were found in the serum or urine levels of 15-HETE, TXB2, or PGF2α. High serum LTE4 levels were associated with lower FEV1% and uncontrolled status in AERD patients (P=0.006 and P=0.002, respectively), but not in ATA patients. Multivariate analysis demonstrated that blood eosinophil counts, FeNO levels and aspirin hypersensitivity were significant factors affecting urine LTE4 levels. CONCLUSION: Despite LTRA treatment in AERD, the LTE4 levels remained high and showed close associations with blood eosinophilia, high FeNO levels and impaired disease control. Our real-world evidence indicates that control of asthma is not fully achieved by blocking the CysLT pathway with LTRA. Thus, introduction of treatment modalities targeting eosinophilia could be a better option for patients with high CysLTs.

Effect of TGF-ß1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease.

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-ß1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-ß1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-ß1 and urinary LTE4. The function of TGF-ß1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-ß1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-ß1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-ß1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-ß1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-ß1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

Oleoylethanolamide induces eosinophilic airway inflammation in bronchial asthma.

Asthma is a chronic eosinophilic inflammatory disease with an increasing prevalence worldwide. Endocannabinoids are known to have immunomodulatory biological effects. However, the contribution of oleoylethanolamide (OEA) to airway inflammation remains to be elucidated. To investigate the effect of OEA, the expression of proinflammatory cytokines was measured by RT-qPCR and ELISA in airway epithelial (A549) cells. The numbers of airway inflammatory cells and cytokine levels in bronchoalveolar lavage fluid, airway hyperresponsiveness, and type 2 innate lymphoid cells (ILC2s) were examined in BALB/c mice after 4 days of OEA treatment. Furthermore, eosinophil activation after OEA treatment was evaluated by measuring cellular CD69 levels in eosinophils from human peripheral eosinophils using flow cytometry. OEA induced type 2 inflammatory responses in vitro and in vivo. OEA increased the levels of proinflammatory cytokines, such as IL-6, IL-8, and IL-33, in A549 cells. In addition, it also induced eosinophilic inflammation, the production of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, and airway hyperresponsiveness. OEA increased the numbers of IL-5- or IL-13-producing ILC2s in a mouse model. Finally, we confirmed that OEA increased CD69 expression (an eosinophil activation marker) on purified eosinophils from patients with asthma compared to those from healthy controls. OEA may play a role in the pathogenesis of asthma by activating ILC2s and eosinophils.

Risk Factors Predicting Severe Asthma Exacerbations in Adult Asthmatics: A Real-World Clinical Evidence.

PURPOSE: Minimizing the future risk of asthma exacerbation (AE) is one of the main goals of asthma management. We investigated prognostic factors for risk of severe AE (SAE) in a real-world clinical setting. METHODS: This is an observational study evaluating subjects who were diagnosed with asthma and treated with anti-asthmatic medications from January 1995 to June 2018. Risk factors for SAE were analyzed in 2 treatment periods (during the initial 2 years and the following 3-10 years of treatment) using the big data of electronic medical records. RESULTS: In this study, 5,058 adult asthmatics were enrolled; 1,335 (28.64%) experienced ≥ 1 SAE during the initial 2 years of treatment. Female sex, higher peripheral eosinophil/basophil counts, and lower levels of forced expiratory volume in 1 second (FEV1; %) were factors predicting the risk of SAEs (P < 0.001 for all). Higher serum total immunoglobulin E levels increased the risk of SAEs among the patients having ≤ 2 SAEs (P = 0.025). Patients with more frequent SAEs during the initial 2 years of treatment had significantly higher risks of SAEs during the following years of treatment (P < 0.001, for all) (patients with ≥ 4 SAEs, odds ratio [OR], 29.147; those with 3 SAEs, OR, 14.819; those with 2 SAEs, OR, 9.867; those with 1 SAE, OR, 5.116), had higher maintenance doses of systemic steroids, and showed more gradual decline in FEV1 (%) and FEV1/forced vital capacity levels maintained during the following years of treatment (P < 0.001 for all). CONCLUSIONS: Asthmatics having risk factors for SAEs (female sex, higher peripheral eosinophil/basophil counts, and lower FEV1) should be strictly monitored to prevent future risk and improve clinical outcomes.

Specialist Perception of Severe Asthma in Korea: A Questionnaire Survey.

The Working Group on Severe Asthma of the Korean Academy of Allergy and Clinical Immunology recently published an expert opinion paper on the management of severe asthma in Korea. When developing a consensus, the working group encountered several diagnostic and treatment issues and decided to perform a questionnaire survey of Korean specialists with regard to severe asthma. An e-mail with a uniform resource locator link to the questionnaire was sent to 121 asthma specialists, of whom 44.6% responded. The most commonly accepted definitions of severe asthma were a history of fatal exacerbation or an asthma-triggered need for mechanical ventilation, 3-4 oral corticosteroid (OCS) bursts/year, and maintenance of OCS therapy for 3-6 months per year. Before diagnosing severe asthma, most physicians contemplate chest computed tomography, seek to control chronic rhinosinusitis, and consider poor inhaler compliance. For patients with uncontrolled severe asthma accompanied by type 2 (T2)-high inflammation, most biologics available in Korea were considered appropriate, but gaps were apparent in terms of T2-low asthma treatments. These findings about specialist perception of diagnosis and treatment of severe asthma will inform the use of emerging new drugs and facilitate personalized therapy.

Characteristics of Specialist-Diagnosed Asthma-COPD Overlap in Severe Asthma: Observations from the Korean Severe Asthma Registry (KoSAR).

BACKGROUND: While the clinical characteristics and outcomes of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have been frequently compared with those of COPD or asthma, the prevalence and features of ACO in patients with severe asthma are unclear. OBJECTIVES: Evaluation of the prevalence and clinical features of ACO using the Korean severe asthma registry. METHODS: At the time of registration, ACO was determined in patients with severe asthma by attending specialists. Patients were classified into ACO and non-ACO groups, and the demographic and clinical characteristics of these two groups were compared. RESULTS: Of 482 patients with severe asthma, 23.7% had ACO. Patients in the ACO group were more likely to be male (P < .001), older (P < .001), and ex- or current smokers (P < .001) compared with those in the non-ACO group. Patients in the ACO group had lower mean forced expiratory volume in 1 second (P < .001) and blood eosinophil percentage (P = .006), but higher blood neutrophil percentage (P = .027) than those in the non-ACO group. The ACO group used more inhaled long-acting muscarinic antagonist (P < .001), methylxanthine (P = .001), or sustained systemic corticosteroid (P = .002). In addition, unscheduled emergency department visits due to exacerbation were more frequent in the ACO group (P = .006). CONCLUSION: Among patients with severe asthma, those with ACO were older, predominantly male, and were more likely to have a smoking history than those with asthma only. Patients with ACO used more systemic corticosteroid and had more frequent exacerbations related to emergency department visits than those with severe asthma only.

Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood. OBJECTIVE: We aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA). METHODS: A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of ORMDL3 SNP (rs7216389) was performed. RESULTS: Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTE4 (all P<0.05). The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC (P = 0.033, r = -0.274; P = 0.019, r = -0.299, respectively). Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030). CONCLUSION & CLINICAL RELEVANCE: This is the first study that shows the dysregulated de novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.

Evaluation and Management of Difficult-to-Treat and Severe Asthma: An Expert Opinion From the Korean Academy of Asthma, Allergy and Clinical Immunology, the Working Group on Severe Asthma.

Severe asthma (SA) presents in about 3%-5% of adult asthmatics and is responsible for over 60% of asthma-related medical expenses, posing a heavy socioeconomic burden. However, to date, a precise definition of or clear diagnostic criteria for SA have not been established, and therefore, it has been challenging for clinicians to diagnose and treat this disease. Currently, novel biologics targeting several molecules, such as immunoglobulin E, interleukin (IL)5, and IL4/IL13, have emerged, and many new drugs are under development. These have brought a paradigm shift in understanding the mechanism of SA and have also provided new treatment options. However, we need to agree on a precise definition of and its diagnostic criteria for SA. Additionally, it is necessary to explain the diagnostic criteria and to summarize current standard and additional treatment options. This review is an experts' opinion on SA from the Korean Academy of Asthma, Allergy, and Clinical Immunology, the Working Group on Severe Asthma, and aims to provide a definition of and diagnostic criteria for SA, and propose future direction for SA diagnosis and management in Korea.