Therapeutic Effect of Omalizumab in Severe Asthma: A Real-World Study in Korea

Lee, Ji-Ho,Lee, Hyun Young,Jung, Chang-Gyu,Ban, Ga-Young,Shin, Yoo Seob,Ye, Young-Min,Nahm, Dong-Ho,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2018 Allergy, Asthma & Immunology Research Vol.10 No.2

<P><B>Purpose</B></P><P>Omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, has proved to be effective for the treatment of severe asthma. However, there is no direct evidence of effectiveness of omalizumab in Korean patients with severe asthma. We sought to evaluate the real-world effectiveness of omalizumab in Korean adult patients suffering from severe asthma and to identify predictors of favorable response.</P><P><B>Methods</B></P><P>A retrospective analysis of electrical medical records was performed on severe allergic asthmatic patients with omalizumab treatment group (OT group) for more than 6 months between March 2008 and February 2016. Propensity score matching was applied to define the standardized treatment control group (STC group) treated without omalizumab. Asthma-related outcomes were compared between the 2 groups, and analyzed before and after omalizumab use in the OT group. Responders to treatment were defined as patients showing >50% reduction in asthma exacerbations and/or systemic steroid requirement during the outcome period.</P><P><B>Results</B></P><P>One hundred twenty-four patients with severe asthma (62 in the OT group; 62 in the STC group) were enrolled in the study. Proportion of patients having the reduction of asthma exacerbation (53.2% vs 35.5%, <I>P</I>=0.015) and the rate of responders (67.7% vs 41.9%, <I>P</I>=0.007) were significantly higher in the OT group than in the STC group. Significant reductions were noted in asthma exacerbation (<I>P</I>=0.006), hospitalization (<I>P</I>=0.009), hospitalization days (<I>P</I>=0.006), systemic corticosteroid requirements (<I>P</I>=0.027), and sputum eosinophil count (<I>P</I>=0.031) in OT group compared with STC group. There were no significant differences in changes of forced expiratory volume in the 1 second (FEV1) levels between the 2 groups. No predictors of responders were found for omalizumab treatment.</P><P><B>Conclusions</B></P><P>Omalizumab can reduce exacerbations/hospitalization/systemic steroid burst in Korean adult patients with severe asthma.</P>

Prescription Patterns and Burden of Pediatric Asthma in Korea

Sol, In Suk,Kim, Yoon Hee,Kim, Soo Yeon,Choi, Sun Ha,Kim, Jong Deok,Kim, Bo Ok,Moon, Ji Eun,Kim, Kyung Won,Sohn, Myung Hyun The Korean Academy of Asthma, Allergy and Clinical 2019 Allergy, Asthma & Immunology Research Vol.11 No.2

<P><B>Purpose</B></P><P>This study aimed to estimate the prevalence, prescription pattern and burden of pediatric asthma in Korea by analyzing the National Health Insurance (NHI) claims data.</P><P><B>Methods</B></P><P>We retrospectively analyzed the insurance claim records from the Korean NHI claims database from January 2010 to December 2014. Asthmatic patients were defined as children younger than 18 years, with appropriate 10th Revision of the International Classification of Diseases codes (J45 or J46) and a prescription for 1 or more asthma maintenance medications at the same date. Hospitalization and emergency department visits for asthma were defined as use of short-acting beta<SUB>2</SUB>-agonists during hospital visits among asthmatic patients.</P><P><B>Results</B></P><P>There were 1,172,807 asthmatic children in 2010, which increased steadily to 1,590,228 in 2014 in Korea. The prevalence showed an increasing trend annually for all ages. The mean prevalence by age in those older than 2 years decreased during the study period (from 39.4% in the 2–3 year age group to 2.6% in the 15–18 year age group). In an outpatient prescription, leukotriene receptor antagonists were the most commonly prescribed medication for all ages. Patients older than 6 years for whom inhaled corticosteroids were prescribed comprised less than 15% of asthmatic patients. The total direct medical cost for asthma between 2010 and 2014 ranged from $376 to $483 million. Asthma-related medical cost per person reached its peak in $366 in 2011 and decreased to $275 in 2014.</P><P><B>Conclusions</B></P><P>The prevalence of pediatric asthma increased annually and decreased with age. Individual cost of asthma showed a decreasing trend in Korean children.</P>

Association Between Epithelial Cytokines and Clinical Phenotypes of Elderly Asthma

Ulambayar, Bastsetseg,Lee, So-Hee,Yang, Eun-Mi,Ye, Young-Min,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2019 Allergy, Asthma & Immunology Research Vol.11 No.1

<P><B>Purpose</B></P><P>Asthma in the elderly has different clinical features including more severe phenotypes with higher comorbidities. Epithelial cells are known to initiate innate/adaptive immune responses in asthmatic airways. We investigated clinical features and epithelial derived cytokine levels in elderly asthmatics compared to non-elderly asthmatics in a cross-sectional cohort of adult asthmatics in order to further understand its pathogenic mechanisms.</P><P><B>Methods</B></P><P>A total of 1,452 adult asthmatics were enrolled from a single tertiary hospital and were classified into 2 groups: 234 elderly (≥ 60 years at initial diagnosis) and 1,218 non-elderly (< 60 years at initial diagnosis) asthmatics. Asthma-related clinical parameters were compared between the 2 groups. Serum levels of epithelial cell-derived cytokines including interleukin (IL)-31, IL-33, IL-8, eotaxin-2, transforming growth factor beta 1 (TGF-β1) and periostin were measured by enzyme-linked immunosorbent assay.</P><P><B>Results</B></P><P>Significantly higher prevalence rates of late-onset asthma (onset age ≥ 40 years) and severe asthma, as well as the lower rate of atopy, blood/sputum eosinophil counts, total immunoglobulin E and eosinophil cationic protein levels were noted in elderly asthmatics compared to non-elderly asthmatics (<I>P</I> < 0.05, respectively). The forced expiratory volume in 1 second (FEV1, % predicted) level tended to be lower in elderly asthmatics (<I>P</I> = 0.07). In addition, serum IL-33 and IL-31 levels were significantly lower in elderly asthmatics, while no differences were found in the serum level of IL-8, eotaxin-2, TGF-β1 or periostin. Among elderly asthmatics, subjects with severe asthma had lower FEV1 (% predicted) value, but showed significantly higher serum levels of eotaxin-2 and TGF-β1, than those with non-severe asthma (<I>P</I> < 0.05 for each).</P><P><B>Conclusions</B></P><P>These findings suggest that age-related changes of epithelial cell-derived cytokines may affect clinical phenotypes and severity of elderly asthma: decreased levels of IL-33 and IL-31 may contribute to less Th2 phenotype, while increased levels of eotaxin-2 and TGF-β1 may contribute to severity.</P>

Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization?

Jeong, Jae Seok,Kim, So Ri,Lee, Yong Chul The Korean Academy of Asthma, Allergy and Clinical 2018 Allergy, Asthma & Immunology Research Vol.10 No.2

<P>Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-δ and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future.</P>

Reference Ranges and Determinant Factors for Exhaled Nitric Oxide in a Healthy Korean Elderly Population

Jo, Eun-Jung,Song, Woo-Jung,Kim, Tae-Wan,Park, Heung-Woo,Chang, Yoon-Seok,Kim, Tae-Bum,Kim, Sang-Heon,Hur, Gyu-Young,Lee, Jae-Hyung,Yoon, Ho-Joo,Park, Hae-Sim,Cho, Nam-Ho,Moon, Hee-Bom,Min, Kyung-Up,C The Korean Academy of Asthma, Allergy and Clinical 2014 Allergy, Asthma & Immunology Research Vol.6 No.6

<P><B>Purpose</B></P><P>Exhaled nitric oxide (NO) is a useful non-invasive biomarker for asthma diagnosis; however, the literature suggests that exhaled NO levels may be affected by demographic factors. The present analysis investigated determinant factors that present exhaled NO reference levels for Korean elderly adults.</P><P><B>Methods</B></P><P>For reference levels, we analyzed the baseline data of healthy adult participants in the Ansung cohort. The fraction of exhaled NO (FeNO) was measured by NIOX MINO®. The characterization of the subjects was performed through structured questionnaires, spirometry, and methacholine challenge tests. To validate the diagnostic utility of the determined reference levels, asthma patients were recruited from medical institutions for FeNO measurement.</P><P><B>Results</B></P><P>A total of 570 healthy subjects were analyzed (mean age, 59.9±12.3; male, 37.0%) for reference levels. FeNO levels significantly correlated with weight, height, body mass index, atopy, or forced expiratory volume in 1 second % predicted by simple linear regression analysis. Multiple linear regression analysis identified gender as an independent determinant for FeNO levels; subsequently, the reference values for FeNO were 18.2±10.6 ppb (5th to 95th percentile, 6.0 to 37.4 ppb) for males and 12.1±6.9 ppb (5th to 95th percentile, 2.5 to 27.0 ppb) for females. The diagnostic utility of FeNO reference levels was validated by receiver operating curve analysis (area under curve, 0.900 for males and 0.885 for females) for diagnosing asthma. The optimal cutoff values for the prediction of asthma were 30.5 ppb for males and 20.5 ppb for females.</P><P><B>Conclusions</B></P><P>The current analysis presented reference ranges and the diagnostic utility of FeNO levels for asthma in Korean elderly adults.</P>

Prevalence, Risk Factors and Cutoff Values for Bronchial Hyperresponsiveness to Provocholine in 7-Year-Old Children

Jung, Sungsu,Suh, Dong In,Lee, So-Yeon,Yoon, Jisun,Cho, Hyun-Ju,Kim, Young-Ho,Yang, Song-I,Kwon, Ji-Won,Jang, Gwang Cheon,Sun, Yong Han,Woo, Sung-Il,Youn, You-Sook,Park, Kang Seo,Cho, Hwa Jin,Kook, My The Korean Academy of Asthma, Allergy and Clinical 2018 Allergy, Asthma & Immunology Research Vol.10 No.5

<P><B>Background</B></P><P>A US Food and Drug Administration (FDA)-approved drug methacholine chloride (Provocholine<SUP>®</SUP>) was recently introduced to Korea where it is now widely used in clinical practice. We aimed to evaluate the prevalence, risk factors and cutoff value of bronchial hyperresponsiveness (BHR) to Provocholine in 7-year-old children.</P><P><B>Methods</B></P><P>Six hundred and thirty-three children from the Panel Study on Korean Children who visited 16 regional hospitals were evaluated. Skin prick tests, spirometry and bronchial provocation tests for Provocholine as well as a detailed history and physical examinations were performed. The bronchial provocation test was reliably performed on 559 of these children.</P><P><B>Results</B></P><P>The prevalence of ever-diagnosed asthma via medical records was 7.7%, and that of current asthma (wheezy episode in the last 12 months + diagnosed asthma by physicians) was 3.2%. The prevalence of BHR to Provocholine was 17.2% and 25.8%, respectively, for a PC20 < 8 and < 16 mg/mL. The risk factors for BHR (PC20 < 16 mg/mL) were atopic dermatitis diagnosis and current dog ownership, whereas those for current asthma were allergy rhinitis diagnosis, a history of bronchiolitis before the age of 3, recent use of analgesics/antipyretics and maternal history of asthma. The BHR prevalence trend showed an increase along with the increased immunoglobulin E (IgE) quartile. The cutoff value of PC20 for the diagnosis of current asthma in children at age 7 was 5.8 mg/mL (sensitivity: 47.1%, specificity: 87.4%).</P><P><B>Conclusions</B></P><P>BHR to Provocholine (PC20 < 8 mg/mL) was observed in 17.2% of 7-year-olds children from the general population and the cutoff value of PC20 for the diagnosis of current asthma was 5.8 mg/mL in this age group. The risk factors for BHR and current asthma showed discrepancies suggesting different underlying mechanisms. Bronchial provocation testing with Provocholine will be a useful clinical tool in the future.</P>

Alteration in Claudin-4 Contributes to Airway Inflammation and Responsiveness in Asthma

Lee, Pureun-Haneul,Kim, Byeong-Gon,Lee, Sun-Hye,Lee, June-Hyuck,Park, Sung-Woo,Kim, Do-Jin,Park, Choon-Sik,Leikauf, George D.,Jang, An-Soo The Korean Academy of Asthma, Allergy and Clinical 2018 Allergy, Asthma & Immunology Research Vol.10 No.1

<P><B>Purpose</B></P><P>Claudin-4 has been reported to function as a paracellular sodium barrier and is one of the 3 major claudins expressed in lung alveolar epithelial cells. However, the possible role of claudin-4 in bronchial asthma has not yet been fully studied. In this study, we aimed to elucidate the role of claudin-4 in the pathogenesis of bronchial asthma.</P><P><B>Methods</B></P><P>We determined claudin-4 levels in blood from asthmatic patients. Moreover, using mice sensitized and challenged with OVA, as well as sensitized and challenged with saline, we investigated whether claudin-4 is involved in the pathogenesis of bronchial asthma. Der p1 induced the inflammatory cytokines in NHBE cells.</P><P><B>Results</B></P><P>We found that claudin-4 in blood from asthmatic patients was increased compared with that from healthy control subjects. Plasma claudin-4 levels were significantly higher in exacerbated patients than in control patients with bronchial asthma. The plasma claudin-4 level was correlated with eosinophils, total IgE, FEV1% pred, and FEV1/FVC. Moreover, lung tissues from the OVA-OVA mice showed significant increases in transcripts and proteins of claudin-4 as well as in TJ breaks and the densities of claudin-4 staining. When claudin-4 was knocked down by transfecting its siRNA, inflammatory cytokine expressions, which were induced by Der p1 treatment, were significantly increased.</P><P><B>Conclusions</B></P><P>These findings thus raise the possibility that regulation of lung epithelial barrier proteins may constitute a therapeutic approach for asthma.</P>

New Sensitization to House Dust Mites in Cefteram-Induced Occupational Asthma: A Case Report

Jin, Hyun Jung,Kim, Jeong-Eun,Kim, Joo-Hee,Ye, Young-Min,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2011 Allergy, Asthma & Immunology Research Vol.3 No.2

<P>Occupational asthma (OA) can improve after cessation of exposure; however, some patients suffer from persistence or aggravation of their asthmatic symptoms. Here we report a case of a new sensitization to house dust mites during the follow-up period in a 37-year-old female patient with OA induced by cefteram pivoxil powder (cefteram powder). She was previously diagnosed with OA caused by inhalation of cefteram powder. Consequently, she left her job and had been well for 9 subsequent years. She began to experience aggravation of her rhinitis and asthmatic symptoms again several months prior to presentation. Her skin-prick test results had converted to strongly positive responses to two types of house dust mites. The serum levels of eosinophil cationic protein (ECP) and the total and specific immunoglobulin (Ig)E levels against the two types of house dust mites were elevated. An inhalation challenge test with <I>Dermatophagoides farinae</I> was performed, and significant bronchoconstriction (21.1% reduction in the forced expiratory volume in the first second) with asthma symptoms was observed at 10 minutes. To our knowledge, this is the first case demonstrating a new sensitization to house dust mites in a patient with OA caused by cefteram powder. Regular monitoring, including skin-prick tests and measurement of specific serum IgE/ECP levels, may help to screen potential cases.</P>

Evaluation of Neutrophil Activation Status According to the Phenotypes of Adult Asthma

Kim, Seung-Hyun,Uuganbayar, Udval,Trinh, Hoang Kim Tu,Pham, Duy Le,Kim, Namhyo,Kim, Minji,Sohn, Hyeukjun,Park, Hae-Sim The Korean Academy of Asthma, Allergy and Clinical 2019 Allergy, Asthma & Immunology Research Vol.11 No.3

<P><B>Purpose</B></P><P>Neutrophils are considered key effector cells in the pathogenic mechanisms of airway inflammation in asthma. This study assessed the activation status of neutrophils in adult asthmatics, and the therapeutic potential of FTY720, a synthetic sphingosine-1-phosphate analog, on activated neutrophils using an <I>in vitro</I> stimulation model.</P><P><B>Methods</B></P><P>We isolated peripheral blood neutrophils (PBNs) from 59 asthmatic patients (including 20 aspirin-exacerbated respiratory disease [AERD] and 39 aspirin-tolerant asthma [ATA] groups). PBNs were stimulated with <I>N</I>-formyl-methionyl-leucyl-phenylalanine (fMLP) or lipopolysaccharide (LPS) and their activation status was determined based on reactive oxygen species (ROS) production, cell surface expression of CD11b, interleukin (IL)-8 and matrix metallopeptidase (MMP)-9 release. PBNs were primed with FTY720 to evaluate its anti-inflammatory action.</P><P><B>Results</B></P><P><I>In vitro</I> PBN stimulation with fMLP or LPS induced a significant increase in ROS/CD11b/IL-8/MMP-9 levels (<I>P</I> < 0.05 for all). In asthmatics, fMLP-induced ROS level was significantly correlated with values of forced expiratory volume in 1 second/forced vital capacity (r = −0.278; <I>P</I> = 0.036), maximal mid-expiratory flow (r = −0.309; <I>P</I> = 0.019) and PC20 methacholine (r = −0.302; <I>P</I> = 0.029). In addition, ROS levels were significantly higher in patients with AERD and in those with severe asthma than in those with ATA or non-severe asthma (<I>P</I> < 0.05 for all). FTY720 treatment could suppress ROS/CD11b levels, and LPS-induced IL-8 and MMP-9 levels (<I>P</I> < 0.05 for all). Responders to FTY720 treatment had significantly higher neutrophil counts in sputum (<I>P</I> = 0.004).</P><P><B>Conclusions</B></P><P>Our findings suggest a useful <I>in vitro</I> PBN stimulation model for evaluating the neutrophil functional status and the therapeutic potentials of neutrophil-targeting candidates in asthmatics.</P>

Endoplasmic Reticulum Stress and the Related Signaling Networks in Severe Asthma

Kim, So Ri,Lee, Yong Chul The Korean Academy of Asthma, Allergy and Clinical 2015 Allergy, Asthma & Immunology Research Vol.7 No.2

<P>The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders. More interestingly, ER stress and the related signaling networks are emerging as important modulators of inflammatory and immune responses in the development of allergen-induced bronchial asthma, especially severe asthma.</P>