Characteristics of Adult Severe Refractory Asthma in Korea Analyzed From the Severe Asthma Registry

김민혜,김상헌,박소영,반가영,김주희,정재우,문지용,송우정,권혁수,권재우,이재현,강혜련,박종숙,김태범,박흥우,유광하,오연목,고영일,장안수,이병재,조영주,조상헌,박해심,박춘식,윤호주,조유숙 대한천식알레르기학회 2019 Allergy, Asthma & Immunology Research Vol.11 No.1

Purpose: Although mild to moderate asthma is much more common, the morbidity and mortality of severe asthma are much higher. This study was performed to identify and analyze the clinical characteristics of severe asthma in Korea. Methods: We registered patients with severe refractory asthma into the Severe Asthma Registry supported by the Severe Asthma Work Group of the Korean Academy of Asthma, Allergy and Clinical Immunology. Patients were enrolled since 2010 from the 15 university hospitals nationwide in Korea. Severe asthma was defined according to modified European Respiratory Society/American Thoracic Society criteria. Information on demographics, medical history, pulmonary function tests and skin prick tests was collected; the clinical characteristics of severe asthmatics were analyzed from the collected data. Results: A total of 489 patients were enrolled with a mean age of 62.3; 45% are male. Sixty percent of patients received Global Initiative for Asthma step 4 treatment, and 30% received step 5 treatment. The most common comorbidities were allergic rhinitis (58.7%). Aspirin hypersensitivity was observed in 14.0%. Approximately half (53.9%) are non-smokers. Atopy was proven in 38.5% of the patients. Regarding asthma medications, inhaled corticosteroids and long-acting β-agonist combination inhalers were most commonly prescribed (96.5%), followed by leukotriene antagonists (71.0%). A recombinant anti-immunoglobulin E monoclonal antibody (omalizumab) has been used in 1.8% of the patients. The mean forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and FEV1/FVC were 78.7%, 67.5% and 67.9% of predicted values, respectively. The mean Asthma Control Test and quality of life questionnaire scores were 16.5 out of 25 and 59.5 out of 85, respectively. Conclusions: The baseline characteristics of severe asthma patients in the Korea Severe Asthma Registry were analyzed and reported for the first time. With this cohort, further prospective studies should be performed to search for ways to improve management of severe refractory asthma.

Perceptions of Severe Asthma and Asthma-COPD Overlap Syndrome Among Specialists: A Questionnaire Survey

김상헌,문지영,이재현,반가영,김수정,김미애,김주희,김민혜,박찬선,박소영,권혁수,권재우,정재우,강혜련,박종숙,김태범,박흥우,조유숙,유광하,오연목,이병재,장안수,조상헌,박해심,박춘식,윤호주,Severe Asthma Work Group,Korean Academy of Asthma 대한천식알레르기학회 2018 Allergy, Asthma & Immunology Research Vol.10 No.3

Purpose: Severe asthma and asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) are difficult to control and are often associated with poor clinical outcomes. However, much is not understood regarding the diagnosis and treatment of severe asthma and ACOS. To evaluate the current perceptions of severe asthma and COPD among asthma and COPD specialists, we designed an e-mail and internet-based questionnaire survey. Methods: Subjects were selected based on clinical specialty from among the members of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Academy of Tuberculosis and Respiratory Diseases. Of 432 subjects who received an e-mail invitation to the survey, 95 subjects, including 58 allergists and 37 pulmonologists, responded and submitted their answers online. Results: The specialists estimated that the percentage of severe cases among total asthma patients in their practice was 13.9%±11.0%. Asthma aggravation by stepping down treatment was the most common subtype, followed by frequent exacerbation, uncontrolled asthma despite higher treatment steps, and serious exacerbation. ACOS was estimated to account for 20.7% of asthma, 38.0% of severe asthma, and 30.1% of COPD cases. A history of smoking, persistently low forced expiratory volume in 1 second (FEV1), and low FEV1 variation were most frequently classified as the major criteria for the diagnosis of ACOS among asthma patients. Among COPD patients, the highly selected major criteria for ACOS were high FEV1 variation, positive bronchodilator response, a personal history of allergies and positive airway hyperresponsiveness. Allergists and pulmonologists showed different assessments and opinions on asthma phenotyping, percentage, and diagnostic criteria for ACOS. Conclusions: Specialists had diverse perceptions and clinical practices regarding severe asthma and ACOS patients. This heterogeneity must be considered in future studies and strategy development for severe asthma and ACOS.

The Korean Severe Asthma Registry (KoSAR): real world research in severe asthma

( Sang-heon Kim ),( Hyun Lee ),( So-young Park ),( So Young Park ),( Woo-jung Song ),( Joo-hee Kim ),( Heung-woo Park ),( You Sook Cho ),( Ho Joo Yoon ) 대한내과학회 2022 The Korean Journal of Internal Medicine Vol.37 No.2

Severe asthma constitutes a serious health burden with significant morbidity and socioeconomic costs. The development and introduction of new biologics targeting type 2 inflammation changed the paradigm for management of severe asthma and initiated a biological era. These changes impose a challenge to clinicians in managing difficult-to-treat and severe asthma. To understand the characteristics and heterogeneity of severe asthma and to develop a better strategy to manage it, the Korean Academy of Asthma, Allergy and Clinical Immunology, Working Group on Severe Asthma, has organized the Korean Severe Asthma Registry (KoSAR). In this review, we describe the challenges of severe asthma management regarding diagnosis, disease burden, heterogeneity, guidelines, and organization of severe asthma clinics. This review also examines the current global activities of national and regional registries and study groups. In addition, we present the KoSAR vision and organization and describe the findings of KoSAR in comparison with those of other countries.

A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”

Jeong, Jae Seok,Kim, So Ri,Cho, Seong Ho,Lee, Yong Chul MDPI 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.3

<P>Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma.</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>

중증천식의 치료

이태훈 대한내과학회 2018 대한내과학회지 Vol.93 No.2

Severe asthma represents 3-10% of all cases of asthma, but accounts for > 60% of total asthma-related medical costs. Uncontrolled asthma symptoms and frequent asthma exacerbations associated with severe asthma have profound adverse effects on patients’ quality of life. The concepts of difficult-to-treat asthma and severe asthma are different; severe asthma represents one kind of difficult-to-treat asthma. Misdiagnosis, nonadherence, and comorbidities may also be causes of difficult-to-treat asthma. This review discusses important principles in the treatment of difficult-to-treat asthma and severe asthma.

Sex Differences in Severe Asthma: Results From Severe Asthma Network in Italy-SANI

Senna Gianenrico,Latorre Manuela,Bugiani Massimo,Caminati Marco,Heffler Enrico,Morrone Daniela,Paoletti Giovanni,Parronchi Paola,Puggioni Francesca,Blasi Francesco,Canonica Giorgio Walter,Paggiaro Pie 대한천식알레르기학회 2021 Allergy, Asthma & Immunology Research Vol.13 No.2

Purpose: After adolescence, asthma is more frequent in females than in males due to different hormonal, immunologic, and occupational/environmental factors. The higher prevalence and severity of the disease in females have already been reported in international registries. The aim of this study was to explore the difference in terms of clinical, functional, and biological characteristics between male and female patients with severe asthma in a real-life, registry-based setting. Methods: Baseline data from the Severe Asthma Network in Italy registry were analyzed in 1,123 patients with severe asthma, according to sex. Results: Almost 2/3 of severe asthmatics were female. Late-onset asthma, obesity and gastro-esophageal reflux were more frequent in females than in males, while previous smoking habits and nasal polyposis were more frequent in males. Females had poor asthma control and a higher number of severe exacerbations leading to hospitalization, in comparison to males. Biomarkers of type 2 inflammation (blood eosinophil, exhaled nitric oxide, and serum immunoglobulin E levels) were significantly higher in males than in females. The type 2 profile (defined by a combination of these 3 biomarkers) was significantly more frequent in males than in females. In multivariate analysis, late-onset asthma and a normal body mass index were only independent variables associated with the type 2 profile, while male sex and age showed only a trend toward the association with the type 2 profile. Conclusions: Significant differences may be observed between male and female patients with severe asthma, influencing the asthma pheno-endotyping in both sexes.

중증 천식의 임상적, 병태생리적 특징

김상헌 ( Sang Heon Kim ) 대한내과학회 2012 대한내과학회지 Vol.83 No.4

Severe asthma is characterized by poor asthma control and frequent exacerbation despite high degree of medication. Severe asthma leads to not only increased morbidity and mortality but high socioeconomic burden. To date, several research networks have been organized to understand the clinical and pathophysiological characteristics of severe asthma. These groups organized multicenter registries and collected both clinical and biological information. The results of these groups revealed that severe asthma is a very heterogeneous entity, which could not be defined based on a single feature. Various phenotypes of asthma has been identified based on clinical, inflammatory and immune responses. To understand severe asthma more drastically in consideration of many phenotypes, cluster analysis and endotyping severe asthma have been tried. Although uncontrolled inflammation and airway remodeling underlies the development of severe asthma, much is not known about its pathomechanisms. This review discusses the current understanding of the clinical and pathogenic mechanisms of severe asthma based on the recent publications. (Korean J Med 2012;83:424-429)

Development of New Therapies for Severe Asthma

Merritt L. Fajt,Sally E. Wenzel 대한천식알레르기학회 2017 Allergy, Asthma & Immunology Research Vol.9 No.1

Persistent asthma has long been treated with inhaled corticosteroids (CSs), as the mainstay of therapy. However, their efficacy in patients with more severe disease is limited, which led to the incorporation of poor response to ICSs (and thereby use of high doses of ICS) into recent definitions of severe asthma. Several studies have suggested that severe asthma might consist of several different phenotypes, each with ongoing symptoms and health care utilization, despite the use of high doses of ICS, usually in combination with a second or third controller. Several new therapies have been approved for severe asthma. Long-acting muscarinic agents have recently been approved as an additional controller agent and appear to improve lung function, although their effect on symptoms and exacerbations is less. Although bronchial thermoplasty (BT) has emerged as a therapy for severe asthma, little is understood regarding the appropriate selection of these patients. Considerable data have emerged to support the presence of a group of patients with severe asthma who have ongoing Type 2 inflammation. These patients appear to respond to targeted biologic approaches which are at the current time mostly investigational. In contrast, few effective therapies for patients with less or no evidence for Type 2 inflammation have emerged. Many new and exciting therapies are at the forefront for severe asthma therapy and, in conjunction with precision medicine approaches to identify the group of patients likely to respond to these approaches, will change the way we think about treating severe asthma.

Associated Factors for Asthma Severity in Korean Children: A Korean Childhood Asthma Study

Eun Lee,Dae Jin Song,Woo Kyung Kim,Dong In Suh,백혜성,Meeyong Shin,Young Yoo,Jin Tack Kim,Ji-Won Kwon,Gwang Cheon Jang,Dae Hyun Lim,Hyeon-Jong Yang,Hwan Soo Kim,Ju-Hee Seo,Sung-Il Woo,Hyung Young Kim,You 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.1

Purpose: Childhood asthma has a considerable social impact and economic burden, especially in severe asthma. This study aimed to identify the proportion of childhood asthma severity and to evaluate associated factors for greater asthma severity. Methods: This study was performed on 667 children aged 5–15 years with asthma from the nationwide 19 hospitals in the Korean childhood Asthma Study (KAS). Asthma was classified as mild intermittent, mild persistent, and moderate/severe persistent groups according to the National Asthma Education and Prevention Program recommendations. Multinomial logistic regression models were used to identify the associated factors for greater asthma severity. Results: Mild persistent asthma was most prevalent (39.0%), followed by mild intermittent (37.6%), moderate persistent (22.8%), and severe persistent asthma (0.6%). Onset later than 6 years of age (adjusted odds ratio [aOR], 1.69 for mild persistent asthma; aOR, 1.92 for moderate/severe persistent asthma) tended to increase asthma severity. Exposure to environmental tobacco smoke (aOR, 1.53 for mild persistent asthma; aOR, 1.85 for moderate/severe persistent asthma), and current dog ownership with sensitization to dog dander (aOR, 5.86 for mild persistent asthma; aOR, 6.90 for moderate/severe persistent asthma) showed increasing trends with greater asthma severity. Lower maternal education levels (aOR, 2.32) and no usage of an air purifier in exposure to high levels of outdoor air pollution (aOR, 1.76) were associated with moderate/severe persistent asthma. Conclusions: Modification of identified environmental factors associated with greater asthma severity might help better control childhood asthma, thereby reducing the disease burden due to childhood asthma.