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.

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.

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.

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.

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.

Prevalence and impact of comorbid laryngeal dysfunction in asthma: A systematic review and meta-analysis.

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.

Macrophage-derived progranulin promotes allergen-induced airway inflammation.

BACKGROUND: Progranulin (PGRN), mainly produced by immune and epithelial cells, has been known to be involved in the development of various inflammatory diseases. However, the function of PGRN in allergic airway inflammation has not been clearly elucidated, and we investigated the role of PGRN in allergic airway inflammation. METHODS: Production of PGRN and various type 2 cytokines was evaluated in mouse airways exposed to house dust mite allergen, and main cellular sources of these molecules were investigated using macrophage, airway epithelial cell, and NKT cell lines. We elucidated the role of PGRN in allergic airway inflammation in mouse models of asthma using macrophage-derived PGRN-deficient mice and NKT cell knockout mice by evaluating cytokine levels in bronchoalveolar lavage fluids and histopathology. We also supplemented recombinant PGRN in the mouse models to confirm the role of PGRN in allergic airway inflammation. RESULTS: PGRN production preceded other cytokines, mainly from macrophages, in the airway exposed to allergen. PGRN induced IL-4 and IL-13 production in NKT cells and IL-33 and TSLP in airway epithelial cells. PGRN-induced Th2 cytokine production was abolished in NKT-deficient mice. Finally, allergic inflammation was significantly attenuated in allergen-exposed PGRN-deficient mice, but inflammation was restored when recombinant PGRN was supplemented during the allergen sensitization period. CONCLUSION: The presence of macrophage-derived PGRN in airways in the early sensitization period may be critical for mounting a Th2 immune response and for following an allergic airway inflammation pathway via induction of type 2 cytokine production in NKT and airway epithelial cells.

Therapeutic Effects of Mesenchymal Stem Cells on a Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Model.

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.

Clinical characteristics of eperisone-induced immediate-type hypersensitivity.

BACKGROUND: Eperisone is a commonly prescribed oral muscle relaxant, but few studies have been conducted of eperisone-induced hypersensitivity reactions. OBJECTIVE: The purpose of this study was to investigate the clinical manifestations of eperisone-induced immediate-type hypersensitivity, and to evaluate the role of an intradermal test (IDT) in eperisone-induced anaphylaxis. METHODS: This study was based on a retrospective review of medical records from 23 patients diagnosed as eperisone-induced immediate-type hypersensitivity with certain or probable causality. Intradermal tests were performed with a sterile 10 mg/mL eperisone solution. RESULTS: Immediate-type hypersensitivity reactions to eperisone occurred within 15 minutes in 8.7%, within 30 minutes in 52.2%, and within 60 minutes in 82.6% of the patients, cumulatively. All patients showed cutaneous symptoms. Gastrointestinal symptoms were the second-most frequent (65.2%), respiratory symptoms (56.5%) followed, and cardiovascular symptoms were the least (39.1%). Nine (39.1%) patients were categorized as severe anaphylaxis. The mean onset time of severe anaphylaxis was 28.89 minutes, which was significantly shorter than non-severe anaphylaxis (p = 0.011). Five patients among the severe anaphylaxis group were evaluated with IDT, and all showed positive results. In contrast, all of the four patients who have done IDT among the moderate anaphylaxis group showed negative results. There was a significant relationship between severe anaphylaxis and positive IDT results (p = 0.008). CONCLUSIONS: Eperisone-induced immediate-type hypersensitivity is not uncommon in Korea, and the IDT could be a useful and safe diagnostic tool, especially in severe anaphylaxis.

Longitudinal analysis to better characterize Asthma-COPD overlap syndrome: Findings from an adult asthma cohort in Korea (COREA).

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), which has received much attention, has not been unanimously defined. OBJECTIVE: In this study, we tried to demonstrate that longitudinally defined ACOS is more useful in the real world than blending patients with asthma and COPD. METHODS: The study patients had undergone two consecutive pulmonary function tests measured at least 3 months apart (n = 1889). We selected the patients who had positive bronchodilator response or methacholine provocation tests (n = 959). Next, we defined ACOS as a patient with a persistent airflow obstruction [forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7] that was identified twice consecutively by an interval of at least 3 months (n = 228). RESULTS: The proportions of patients who were older, male and smokers were significantly higher, and baseline lung function was lower in patients with ACOS. In the longitudinal analysis, the mean change in lung function was high, and a greater decline in FEV1 was observed in patients with ACOS. In addition, we compared ACOS and severe asthma, and we also performed a cluster analysis and compared the results with our definition of ACOS. According to our definition, ACOS is an independent subtype with distinctive characteristics. Finally, a genome-wide association study (GWAS) was performed to identify genetic variations associated with ACOS, but no significant single nucleotide polymorphisms were identified. CONCLUSION: Our findings suggest that ACOS should be defined longitudinally and considered as an independent subgroup distinguished by inherited environmental factors rather than as a genetically distinct independent group.

Breakthrough reactions during rapid drug desensitization: Clinical outcome and risk factors.

BACKGROUND: Severe hypersensitivity reactions (HSRs) interfere with the administration of necessary drugs for patients; drug desensitization can be a good alternative strategy. Although rapid drug desensitization (RDD) has been shown to be safe and effective, some patients still experience breakthrough reactions (BTRs) during desensitization. OBJECTIVE: We aimed to estimate clinical outcomes of RDD and to identify risk factors for BTR. METHODS: From January 2015 to December 2017, retrospective analysis was done in cancer patients with HSRs to chemotherapy and monoclonal antibody who underwent 3-bag, 12-step RDD in Asan Medical Center. RESULTS: A total of 58 patients (42 females; mean age, 54.7 ± 11.0) underwent 234 desensitization procedures. The most common underlying malignancy was gynecologic cancer (n = 26, 44.8%), and platinum-based drugs were common target drugs (135 cases of 36 patients). Twenty-six of 58 patients (44.8%) experienced 56 BTRs, whereas 178 cases (76.1%) of total desensitization did not show any reactions. Among them, 12 patients (20.7%) had moderate BTRs requiring systemic steroids, and 3 (5.1%) experienced severe BTRs requiring epinephrine administration. Logistic regression analysis revealed more severe initial HSRs (OR = 17.94, 95% CI = 1.78-181.68, P = .015), drug allergy history (OR = 7.83, 95% CI = 1.48-41.44, P = .035), and frequency of exposure to the chemotherapeutic agents (OR = 1.14, 95% CI = 1.01-1.28, P = .016) increased the risk of moderate to severe BTR. CONCLUSION: The standardized 12-step protocol for RDD was effective and safe for most patients. Severity of initial HSR, history of drug allergy, and previous high exposure to the chemotherapeutic agent showed a positive correlation with BTR above moderate grade. Studies are needed to propose an individualized protocol according to patient-specific risk assessment.

IL-32γ attenuates airway fibrosis by modulating the integrin-FAK signaling pathway in fibroblasts.

BACKGROUND: Fibrosis in severe asthma often leads to irreversible organ dysfunction. However, the mechanism that regulates fibrosis remains poorly understood. Interleukin (IL)-32 plays a role in several chronic inflammatory diseases, including severe asthma. In this study, we investigated whether IL-32 is involved in fibrosis progression in the lungs. METHODS: Murine models of chronic airway inflammation induced by ovalbumin and Aspergillus melleus protease and bleomycin-induced pulmonary fibrosis were employed. We evaluated the degree of tissue fibrosis after treatment with recombinant IL-32γ (rIL-32γ). Expression of fibronectin and α-smooth muscle actin (α-SMA) was examined and the transforming growth factor (TGF)-ß-related signaling pathways was evaluated in activated human lung fibroblasts (MRC-5 cells) treated with rIL-32γ. RESULTS: rIL-32γ significantly attenuated collagen deposition and α-SMA production in both mouse models. rIL-32γ inhibited the production of fibronectin and α-SMA in MRC-5 cells stimulated with TGF-ß. Additionally, rIL-32γ suppressed activation of the integrin-FAK-paxillin signaling axis but had no effect on the Smad and non-Smad signaling pathways. rIL-32γ localized outside of MRC-5 cells and inhibited the interaction between integrins and the extracellular matrix without directly binding to intracellular FAK and paxillin. CONCLUSIONS: These results demonstrate that IL-32γ has anti-fibrotic effects and is a novel target for preventing fibrosis.

Clusterin Modulates Allergic Airway Inflammation by Attenuating CCL20-Mediated Dendritic Cell Recruitment.

Recruitment and activation of dendritic cells (DCs) in the lungs are critical for Th2 responses in asthma, and CCL20 secreted from bronchial epithelial cells (BECs) is known to influence the recruitment of DCs. Because asthma is a disease that is closely associated with oxidative stress, we hypothesized that clusterin, an oxidative stress regulatory molecule, may have a role in the development of allergic airway inflammation. The aim of this study was to examine whether clusterin regulates CCL20 production from the BECs and the subsequent DC recruitment in the lungs. To verify the idea, clusterin knockout (Clu(-/-)), clusterin heterogeneous (Clu(+/-)), and wild-type mice were exposed intranasally to house dust mite (HDM) extract to induce allergic airway inflammation. We found that the total number of immune cells in bronchoalveolar lavage fluid and the lung was increased in Clu(-/-) and Clu(+/-) mice. Of these immune cells, inflammatory DCs (CD11b(+)CD11c(+)) and Ly6C(high) monocyte populations in the lung were significantly increased, which was accompanied by increased levels of various chemokines, including CCL20 in bronchoalveolar lavage fluid, and increased oxidative stress markers in the lung. Moreover, HDM-stimulated human BECs with either up- or downregulated clusterin expression showed that CCL20 secretion was negatively associated with clusterin expression. Interestingly, clusterin also reduced the level of intracellular reactive oxygen species, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant property of clusterin is suggested to regulate the expression of CCL20 in BECs and the subsequent recruitment of inflammatory DCs in the airway.

Progranulin protects lung epithelial cells from cigarette smoking-induced apoptosis.

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.

Serum progranulin as an indicator of neutrophilic airway inflammation and asthma severity.

BACKGROUND: Progranulin, a protein secreted from the airway epithelium, is known to attenuate the downstream cascade of neutrophilic inflammation in particular. We hypothesized that progranulin may have a role in inflammatory regulation in asthma. OBJECTIVE: To investigate the association between serum progranulin levels and various clinical features in patients with asthma. METHODS: Serum samples and clinical data of 475 patients with asthma and 35 healthy controls at a tertiary referral hospital and its affiliated health promotion center were collected. Serum progranulin levels were compared between patients with asthma and healthy controls and then were compared within the patients with asthma in terms of pulmonary function and measures of inflammatory status. Univariate and multivariate analyses were performed to identify factors associated with severity of asthma. RESULTS: Serum progranulin levels were significantly lower in the asthma group than in healthy group and were positively correlated with prebronchodilator forced expiratory volume in 1 second predicted within patients with asthma. We found a negative correlation between serum progranulin levels and blood neutrophil counts. Multivariate analysis revealed that higher serum progranulin levels were associated with a lower risk of severe asthma (odds ratio, 0.888; 95% confidence interval, 0.846-0.932; P < .001) after adjustment for other variables, such as age, sex, smoking status, blood neutrophil count, and current use of systemic corticosteroids. CONCLUSION: Although the exact mechanism of the anti-inflammatory action of progranulin remains unknown, we suggest that serum progranulin may be an indicator of severe asthma with airflow limitation. Future studies with comprehensive airway sampling strategies are warranted to clarify its role, particularly in neutrophilic asthma.

Association between Polymorphisms in Bitter Taste Receptor Genes and Clinical Features in Korean Asthmatics.

BACKGROUND: Bitter taste receptors (TAS2R) in human airway smooth muscle have recently been shown to have an important role in bronchodilation, together with ß2-adrenergic receptors. OBJECT: To evaluate the association between genetic variations in TAS2R and clinical features, including bronchodilator response and asthma control. METHOD: We analyzed the association between single nucleotide polymorphisms (SNPs) of TAS2R10 and TAS2R14 and variables such as demographic data, atopy, duration of disease, and asthma control status, including variables such as asthma control test (ACT) score, percent predicted value of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio, as well as bronchodilator response (BDR), in 721 asthma patients in Korea. RESULT: Three novel SNPs of 633G>A, 645C>A, and -79G>A in TAS2R10 and 3 known SNPs of -815T>C, -1267G>A, and -1897T>C in TAS2R14 were analyzed. Increased BDR was significantly associated with SNPs of -815T>C [OR (95% CI) = 1.88 (1.01-3.49), p = 0.04 ] [J Gen Physiol 2005;125:535-553; Am J Respir Cell Mol Biol 2010;42:373-3812], -1267A>G [OR (95% CI) = 2.07 (1.03-4.15), p = 0.04] and -1897T>C [OR (95% CI) = 3.05 (1.01-9.23), p = 0.04, in a dominant model, and OR = 1.91 (1.08-3.36), p = 0.02, in a codominant model] of the TAS2R14 gene. There was a significant association between -815T>C and a low mean ACT score [OR (95% CI) = 5.84 (1.94-17.61), p = 0.001]. In haplotype analysis, TAC, CAT, and TGT, or TG and CA haplotypes on TAS2R14 were significantly associated with increased BDR; CAT and CA haplotypes were significantly associated with a low ACT score. CONCLUSION: Genetic variations in TAS2Rs may be valuable genetic markers to predict therapeutic response and outcomes in asthma. Further research in an independent cohort is needed.

Effect of pregnancy in asthma on health care use and perinatal outcomes.

BACKGROUND: It is generally known that pregnancy in asthmatic patients increases the risk of asthma exacerbations and poor perinatal outcomes. However, the effect of pregnancy in asthmatic patients on health care use is not known well. In addition, its effect on perinatal outcomes is still controversial because of study limitations caused by ethical issues. National Health Insurance claim data are an ideal resource for studying real-world health care use patterns of asthma. OBJECTIVE: We sought to evaluate the effect of pregnancy on asthma in terms of asthma-related health care use and prescription patterns in concert with the effect of asthma exacerbations on adverse pregnancy outcomes. METHODS: Among all asthmatic patients in the Korean National Health Insurance claim database from January 2009 to December 2013, pregnant women who delivered in 2011 with pre-existing asthma were enrolled. Analyses included asthma-related health care use and prescription patterns compared between pregnant asthmatic women and nonpregnant female asthmatic control subjects, as well as within the pregnant subjects from before pregnancy throughout postpartum periods. In addition, the association between asthma exacerbation during pregnancy and adverse pregnancy outcomes was assessed. RESULTS: A total of 3,357 pregnant asthmatic patients were compared with 50,355 nonpregnant asthmatic patients, and 10,311 pregnant patients were included to determine the effect of asthma exacerbations on adverse pregnancy outcome in the study. Pregnant asthmatic patients underwent more asthma-related hospitalizations (1.3% vs 0.8%, P = .005) but had significantly fewer outpatient visits and prescriptions for most asthma medications than nonpregnant asthmatic patients. The proportion of patients ever hospitalized gradually increased throughout pregnancy (first trimester, 0.2%; second trimester, 0.5%; and third trimester, 0.7%; P = .018). The prevalence of asthma exacerbation during pregnancy was 5.3%, and the patients who had acute exacerbation during pregnancy had significantly higher asthma-related health care use in terms of hospitalization, intensive care unit admission, and emergency department and outpatient visits within 1 year before delivery than those who had not. However, asthma exacerbation during pregnancy was not significantly related to adverse perinatal outcomes, except for cesarean section (27.1% vs 18.9%, P < .001). All exacerbations were managed with systemic corticosteroids, and the patients who ever experienced acute exacerbations maintained asthma medications, including inhaled corticosteroid-based inhalers, throughout the pregnancy period. CONCLUSION: Pregnancy profoundly affects asthma-related health care use but to a different degree depending on whether the patient experienced an exacerbation. Asthma exacerbation during pregnancy is not associated with adverse pregnancy outcomes while managed appropriately with systemic corticosteroids. However, further studies are needed to clarify the effect of asthma control on perinatal outcome and delivery method.

Classification and implementation of asthma phenotypes in elderly patients.

BACKGROUND: No attempt has yet been made to classify asthma phenotypes in the elderly population. It is essential to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with asthma. OBJECTIVES: To classify elderly patients with asthma by cluster analysis and developed a way to use the resulting cluster in practice. METHODS: We applied k-means cluster to 872 elderly patients with asthma (aged ≥ 65 years) in a prospective, observational, and multicentered cohort. Acute asthma exacerbation data collected during the prospective follow-up of 2 years was used to evaluate clinical trajectories of these clusters. Subsequently, a decision-tree algorithm was developed to facilitate implementation of these classifications. RESULTS: Four clusters of elderly patients with asthma were identified: (1) long symptom duration and marked airway obstruction, (2) female dominance and normal lung function, (3) smoking male dominance and reduced lung function, and (4) high body mass index and borderline lung function. Cluster grouping was strongly predictive of time to first acute asthma exacerbation (log-rank P = .01). The developed decision-tree algorithm included 2 variables (percentage of predicted forced expiratory volume in 1 second and smoking pack-years), and its efficiency in proper classification was confirmed in the secondary cohort of elderly patients with asthma. CONCLUSIONS: We defined 4 elderly asthma phenotypic clusters with distinct probabilities of future acute exacerbation of asthma. Our simplified decision-tree algorithm can be easily administered in practice to better understand elderly asthma and to identify an exacerbation-prone subgroup of elderly patients with asthma.