2021年04月, 日本呼吸器学会, 第2回日本呼吸器学会女性研究者奨励賞　　　　　　　　　　　　　　　

A protocol for a Japanese prospective cohort evaluating the features of patients with uncontrolled asthma achieving clinical remission: J-CIRCLE.
Naoya Tanabe, Yu Hara, Kaoruko Shimizu, Satoshi Marumo, Jun Miyata, Kyohei Morita, Tetsuya Watanabe, Keiji Oishi, Masafumi Yamaguchi, Kazuhisa Asai, Yasutaka Nakano, Tsunahiko Hirano, Kazuto Matsunaga, Toshiyuki Koya, Hisako Matsumoto, Koichi Fukunaga, Satoshi Konno, Takeshi Kaneko, Toyohiro Hirai
Respiratory investigation, 62, 6, 1209, 1214, 2024年11月04日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Increasing expectations that biologics can be used as disease-modifying agents have introduced the concept of clinical remission (CR) in managements of severe asthma. Given the clinical relevance of computed tomography (CT) and blood biomarkers, we hypothesized that further refinement of CR criteria as well as incorporation of CT and blood biomarkers as indicators for structural and biological remission (SR, BR) would enable predicting long-term disease stability in patients with severe asthma treated with biologics. METHODS: This Japanese multicenter prospective observational cohort will enroll patients with severe asthma who will start a new biologic (including a change from another biologic). The enrolled patients will be longitudinally followed up for 3 years. At enrollment, patients will undergo postbronchodilator spirometry, blood tests, fractional exhaled nitric oxide, chest and sinus CT, and patient-reported outcome questionnaires. Follow-up examinations will be performed at 1, 3, 6, 12, 24, and 36 months. The rates of CR resulting from different criteria after 1 year of treatment with biologics will be compared, and factors associated with long-term disease stability after 3 years of biologic treatments will be identified. DISCUSSION: This multicenter study in Japan will provide data that will help establish more appropriate criteria for CR, structural remission, and biological remission to predict long-term disease stability in patients with severe asthma who receive biologic therapy. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Kyoto University (No. R4419, approval date June 11th, 2024). TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN000053771).

Lung imaging in COPD and asthma.
Naoya Tanabe, Hiroaki Nakagawa, Seiichiro Sakao, Yoshiharu Ohno, Kaoruko Shimizu, Hidetoshi Nakamura, Masayuki Hanaoka, Yasutaka Nakano, Toyohiro Hirai
Respiratory investigation, 62, 6, 995, 1005, 2024年08月29日, ［国際誌］
英語, 研究論文（学術雑誌）, Chronic obstructive pulmonary disease (COPD) and asthma are common lung diseases with heterogeneous clinical presentations. Lung imaging allows evaluations of underlying pathophysiological changes and provides additional personalized approaches for disease management. This narrative review provides an overview of recent advances in chest imaging analysis using various modalities, such as computed tomography (CT), dynamic chest radiography, and magnetic resonance imaging (MRI). Visual CT assessment localizes emphysema subtypes and mucus plugging in the airways. Dedicated software quantifies the severity and spatial distribution of emphysema and the airway tree structure, including the central airway wall thickness, branch count and fractal dimension of the tree, and airway-to-lung size ratio. Nonrigid registration of inspiratory and expiratory CT scans quantifies small airway dysfunction, local volume changes and shape deformations in specific regions. Lung ventilation and diaphragm movement are also evaluated on dynamic chest radiography. Functional MRI detects regional oxygen transfer across the alveolus using inhaled oxygen and ventilation defects and gas diffusion into the alveolar-capillary barrier tissue and red blood cells using inhaled hyperpolarized 129Xe gas. These methods have the potential to determine local functional properties in the lungs that cannot be detected by lung function tests in patients with COPD and asthma. Further studies are needed to apply these technologies in clinical practice, particularly for early disease detection and tailor-made interventions, such as the efficient selection of patients likely to respond to biologics. Moreover, research should focus on the extension of healthy life expectancy in patients at higher risk and with established diseases.

Lower skeletal muscle density and airway structure on computed tomography in asthma.
Yusuke Hayashi, Naoya Tanabe, Kaoruko Shimizu, Tomoki Maetani, Yusuke Shiraishi, Tsuyoshi Oguma, Hironobu Sunadome, Ryo Sakamoto, Atsuyasu Sato, Susumu Sato, Hiroshi Date, Hisako Matsumoto, Toyohiro Hirai
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2024年08月22日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Lower skeletal muscle density may reflect muscle adiposity and metabolic dysregulation that potentially impair disease control and lung function independent of high body mass index (BMI) in patients with asthma. OBJECTIVE: To investigate whether the lower density of pectoralis muscles (PMs) and erector spinae muscles (ESMs) on chest computed tomography was associated with airway structural changes in patients with asthma. METHODS: Consecutive patients with asthma and healthy controls undergoing chest computed tomography were retrospectively analyzed. The ESM and PM density, areas of subcutaneous adipose tissue near the PM and epicardial adipose tissue, wall area percent of the airways, and airway fractal dimension (AFD) were quantified on computed tomography. RESULTS: The study included 179 patients with asthma (52% women) and 88 controls (47% women). All the controls were 60 years old or younger. The PM and ESM density in female patients with asthma who were 60 years old or younger were significantly lower than those in controls after adjustment for BMI. In female patients with asthma at all ages, lower PM and ESM density (but not subcutaneous or epicardial adipose tissue area) was associated with greater wall area percent of the airways and lower AFD after adjusting for age, height, BMI, smoking status, blood eosinophil count, and oral corticosteroid use. The only association between ESM density and AFD was found in male patients with asthma. CONCLUSION: Lower skeletal muscle density may be associated with airway wall thickening and less complexity of the airway luminal tree in female patients with asthma.

Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: Associations with airflow limitation, health-related independence and mortality.
Naoya Tanabe, Kaoruko Shimizu, Hiroshi Shima, Nobuyasu Wakazono, Yusuke Shiraishi, Kunihiko Terada, Satoru Terada, Tsuyoshi Oguma, Ryo Sakamoto, Masaru Suzuki, Hironi Makita, Atsuyasu Sato, Susumu Sato, Masaharu Nishimura, Satoshi Konno, Toyohiro Hirai
Respirology (Carlton, Vic.), 2024年06月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND OBJECTIVE: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema. METHODS: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT. RESULTS: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality. CONCLUSION: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD.

Increased adiposity to muscle ratio and severity of sinusitis affect quality of life in asthma—Computed tomographic analysis—
Kaoruko Shimizu, Hirokazu Kimura, Naoya Tanabe, Kazuya Tanimura, Shotaro Chubachi, Hiroaki Iijima, Susumu Sato, Nobuyasu Wakazono, Yuji Nakamaru, Kazufumi Okada, Hironi Makita, Houman Goudarzi, Masaru Suzuki, Masaharu Nishimura, Satoshi Konno
Journal of Allergy and Clinical Immunology: Global, 100277, 100277, Elsevier BV, 2024年05月
研究論文（学術雑誌）

Associations of fractional exhaled nitric oxide with airway dimension and mucus plugs on ultra-high-resolution computed tomography in former smokers and nonsmokers with asthma.
Yusuke Hayashi, Naoya Tanabe, Hisako Matsumoto, Kaoruko Shimizu, Ryo Sakamoto, Tsuyoshi Oguma, Hironobu Sunadome, Atsuyasu Sato, Susumu Sato, Toyohiro Hirai
Allergology international : official journal of the Japanese Society of Allergology, 2024年02月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Associations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma. METHODS: The retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored. RESULTS: Ninety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20-35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence. CONCLUSIONS: Higher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.
Naoya Tanabe, Susumu Sato, Takafumi Shimada, Shizuo Kaji, Yusuke Shiraishi, Satoru Terada, Tomoki Maetani, Fumi Mochizuki, Kaoruko Shimizu, Masaru Suzuki, Shotaro Chubachi, Kunihiko Terada, Kazuya Tanimura, Ryo Sakamoto, Tsuyoshi Oguma, Atsuyasu Sato, Megumi Kanasaki, Shigeo Muro, Izuru Masuda, Hiroaki Iijima, Toyohiro Hirai
Respiratory investigation, 62, 1, 121, 127, 2023年12月14日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Nine-Year Trend in the Prevalence of Allergic Diseases and Their Associated Factors in Young Adults.
Munehiro Matsumoto, Hirokazu Kimura, Kaoruko Shimizu, Masaru Suzuki, Satoshi Asakura, Satoshi Hashino, Satoshi Konno
International archives of allergy and immunology, 1, 10, 2023年12月05日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Notably, few studies have evaluated the recent changes in the prevalence of allergic diseases in young adults. Studies examining the risk of allergy in two populations with similar social backgrounds, other than the region in which they live, are rare. METHODS: First-year students from Hokkaido University were enrolled in this study between 2011 and 2019. A questionnaire survey was conducted to determine the annual prevalence of current wheeze, seasonal allergic rhinitis (SAR), and perennial allergic rhinitis (PAR) in nonsmoking young adults. Trends in the presence of these disease conditions were evaluated based on their hometowns (Hokkaido and outside Hokkaido separately) due to the low prevalence of cedar pollen allergies in Hokkaido. The association between these disease conditions and body mass index (BMI) was also assessed. RESULTS: The prevalence of current wheeze and PAR food allergies did not change in both regions. SAR showed a significantly increasing trend; however, the prevalence of SAR was higher among those whose place of origin was not Hokkaido. Current wheeze was positively associated with obesity (p < 0.05), whereas the high prevalence of SAR was not associated with body weight. In contrast, a lean body type was significantly associated with a higher prevalence of PAR (p < 0.05). DISCUSSION/CONCLUSION: The prevalence of current wheeze was stable and that of PAR has decreased over the past 9 years. However, the prevalence of SAR in Hokkaido has been increasing in Japanese young adults. A differential association between current wheeze and BMI was observed when comparing PAR and SAR.

Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation.
Yichi Yang, Hirokazu Kimura, Isao Yokota, Hironi Makita, Michiko Takimoto-Sato, Machiko Matsumoto-Sasaki, Munehiro Matsumoto, Akira Oguma, Yuki Abe, Nozomu Takei, Houman Goudarzi, Kaoruko Shimizu, Masaru Suzuki, Masaharu Nishimura, Satoshi Konno
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2023年11月23日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Real-time asthma exacerbation prediction and acute asthma attack detection are essential for patients with severe asthma. Peak expiratory flow (PEF) exhibits a potential for use in long-term asthma self-monitoring. However, the method for processing PEF calculations remains to be clarified. OBJECTIVE: Present research was conducted to develop clinically applicable novel exacerbation predictors calculated using PEF records. METHODS: Previously proposed exacerbation predictors, including the slope of PEF, percentage predicted PEF, percentage best PEF, the highest PEF over the lowest PEF within specific periods, and PEF coefficient of variation, as well as a novel indicator delta PEF moving average (ΔMA), defined as the difference between 14-day and 3-day average PEF values along with MA adjusted for PEF reference (%ΔMA), were verified using the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma data of 127 patients with severe asthma from whom 73,503 PEF observations were obtained. Receiver operating characteristic curves for all predictors were drawn and the corresponding areas under the curve (AUCs) were computed. Regression analysis for MA and % MA were conducted. RESULTS: The most outstanding performance was demonstrated by ΔMA and %ΔMA, with AUC values of 0.659 and 0.665 in the univariate model, respectively. When multivariate models incorporated with random intercepts for individual participants, the AUC for ΔMA and %ΔMA soared to 0.907 and 0.919, respectively. CONCLUSION: The MA and % MA are valuable indicators that should be considered when deriving predictors from the PEF trajectory for monitoring exacerbations in patients with severe asthma.

Differential impacts between fat mass index and fat-free mass index on patients with COPD.
Takashi Shimada, Shotaro Chubachi, Shiro Otake, Kaori Sakurai, Mamoru Sasaki, Hiroaki Iijima, Naoya Tanabe, Kazuya Tanimura, Kaoruko Shimizu, Toru Shirahata, Masaru Suzuki, Susumu Sato, Hidetoshi Nakamura, Koichiro Asano, Koichi Fukunaga
Respiratory medicine, 217, 107346, 107346, 2023年06月28日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients. METHODS: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared. RESULTS: The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (KCO). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores. CONCLUSION: FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.

脂肪量指数(FMI)と除脂肪量指数(FFMI)のCOPDに与える影響の差異の検討
島田 嵩, 中鉢 正太郎, 大竹 史朗, 中山 真吾, 櫻井 香, 白畑 亨, 仲村 秀俊, 浅野 浩一郎, 清水 薫子, 鈴木 雅, 谷村 和哉, 田辺 直也, 佐藤 晋, 福永 興壱
日本呼吸器学会誌, 12, 増刊, 149, 149, (一社)日本呼吸器学会, 2023年03月
日本語

気管支喘息患者における新旧基準による気管支拡張薬反応性に影響する因子の検討
山本 雅史, 清水 薫子, 木村 孔一, 牧田 比呂仁, 三谷 麻子, 中出 江美, 大沼 有美, 渡邊 千秋, 鈴木 雅, 後藤 秀樹, 豊嶋 崇徳, 西村 正治, 今野 哲
日本呼吸器学会誌, 12, 増刊, 336, 336, (一社)日本呼吸器学会, 2023年03月
日本語

脂肪量指数(FMI)と除脂肪量指数(FFMI)のCOPDに与える影響の差異の検討
島田 嵩, 中鉢 正太郎, 大竹 史朗, 中山 真吾, 櫻井 香, 白畑 亨, 仲村 秀俊, 浅野 浩一郎, 清水 薫子, 鈴木 雅, 谷村 和哉, 田辺 直也, 佐藤 晋, 福永 興壱
日本呼吸器学会誌, 12, 増刊, 149, 149, (一社)日本呼吸器学会, 2023年03月
日本語

Stronger Associations of Centrilobular Than Paraseptal Emphysema With Longitudinal Changes in Diffusing Capacity and Mortality in COPD.
Yusuke Shiraishi, Naoya Tanabe, Kaoruko Shimizu, Akira Oguma, Hiroshi Shima, Ryo Sakamoto, Hajime Yamazaki, Tsuyoshi Oguma, Atsuyasu Sato, Masaru Suzuki, Hironi Makita, Shigeo Muro, Masaharu Nishimura, Susumu Sato, Satoshi Konno, Toyohiro Hirai
Chest, 164, 2, 327, 338, 2023年01月31日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The factors associated with longitudinal changes in diffusing capacity remain unclear among patients with COPD. Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are major emphysema subtypes that may have distinct clinical-physiological impacts in these patients. RESEARCH QUESTION: Are CLE and PSE differently associated with longitudinal changes in diffusing capacity and mortality in patients with COPD? STUDY DESIGN AND METHODS: This pooled analysis included 399 patients with COPD from two prospective observational COPD cohorts. CLE and PSE were visually assessed on CT scan according to the Fleischner Society statement. The diffusing capacity and transfer coefficient of the lung for carbon monoxide (Dlco and KCO) and FEV1 were evaluated at least annually over a 5-year period. Mortality was recorded over 10 years. Longitudinal changes in FEV1, Dlco, and KCO and mortality were compared between mild or less severe and moderate or more severe CLE and between present and absent PSE in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. RESULTS: The Dlco and KCO decline was weakly associated with FEV1 and greater in GOLD stage 3 or above than in GOLD stages 1 and 2. Furthermore, moderate or more severe CLE, but not present PSE, was associated with steeper declines in Dlco for GOLD stages 1 and 3 or higher and KCO for all GOLD stages independent of age, sex, height, and smoking history. The moderate or more severe CLE, but not present PSE, was associated with additional FEV1 decline and higher 10-year mortality among patients with GOLD stage 3 or higher . INTERPRETATION: A CT scan finding of moderate or more severe CLE, but not PSE, was associated with a subsequent accelerated impairment in diffusing capacity and higher long-term mortality in severe GOLD stage among patients with COPD.

Relationships of computed tomography-based small vessel indices of the lungs with ventilation heterogeneity and high transfer coefficients in non-smokers with asthma.
Kaoruko Shimizu, Hirokazu Kimura, Naoya Tanabe, Shotaro Chubachi, Susumu Sato, Masaru Suzuki, Kazuya Tanimura, Hiroaki Iijima, Akira Oguma, Yoichi M Ito, Nobuyasu Wakazono, Michiko Takimoto-Sato, Machiko Matsumoto-Sasaki, Yuki Abe, Nozomu Takei, Hironi Makita, Masaharu Nishimura, Satoshi Konno
Frontiers in physiology, 14, 1137603, 1137603, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: The mechanism of high transfer coefficients of the lungs for carbon monoxide (Kco) in non-smokers with asthma is explained by the redistribution of blood flow to the area with preserved ventilation, to match the ventilation perfusion. Objectives: To examine whether ventilation heterogeneity, assessed by pulmonary function tests, is associated with computed tomography (CT)-based vascular indices and Kco in patients with asthma. Methods: Participants were enrolled from the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) study that included a prospective asthmatic cohort. Pulmonary function tests including Kco, using single breath methods; total lung capacity (TLC), using multiple breath methods; and CT, were performed on the same day. The ratio of the lung volume assessed using single breath methods (alveolar volume; VA) to that using multiple breath methods (TLC) was calculated as an index of ventilation heterogeneity. The volume of the pulmonary small vessels <5 mm2 in the whole lung (BV5 volume), and number of BV5 at a theoretical surface area of the lungs from the plural surface (BV5 number) were evaluated using chest CT images. Results: The low VA/TLC group (the lowest quartile) had significantly lower BV5 number, BV5 volume, higher BV5 volume/BV5 number, and higher Kco compared to the high VA/TLC group (the highest quartile) in 117 non-smokers, but not in 67 smokers. Multivariable analysis showed that low VA/TLC was associated with low BV5 number, after adjusting for age, sex, weight, lung volume on CT, and CT emphysema index in non-smokers (not in smokers). Conclusion: Ventilation heterogeneity may be associated with low BV5 number and high Kco in non-smokers (not in smokers). Future studies need to determine the dynamic regional system in ventilation, perfusion, and diffusion in asthma.

Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma.
Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Michiko Takimoto-Sato, Yuki Abe, Akira Oguma, Munehiro Matsumoto, Nozomu Takei, Machiko Matsumoto-Sasaki, Kaoruko Shimizu, Masaru Suzuki, Noriharu Shijubo, Shau-Ku Huang, Nobuyuki Hizawa, Masaharu Nishimura, Satoshi Konno
Respiratory medicine, 206, 107089, 107089, 2023年01月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There are knowledge gaps in the potential role of Club cell 16-kDa secretory protein (CC16) in severe asthma phenotypes and type 2 inflammation, as well as the longitudinal effect of CC16 on pulmonary function tests and exacerbation risk in epidemiological studies. OBJECTIVE AND METHODS: To assess whether serum CC16 is associated with eosinophilic inflammation in patients with severe asthma. We also examined the effect of this protein on the annual decline in forced expiratory volume in the first second (FEV1) and the risk of exacerbation using a longitudinal approach. We recruited 127 patients with severe asthma from 30 hospitals/pulmonary clinics in Hokkaido, Japan. The least square means and standard error were calculated for T-helper 2 (Th2) biomarkers and pulmonary function test across CC16 tertiles at baseline. We did the same for asthma exacerbation and annual decline in FEV1 with 3 and 5 years' follow-up, respectively. RESULTS: We found that serum CC16 was inversely associated with sputum eosinophils and blood periostin in a dose-response manner. Baseline CC16 and FEV1/forced vital capacity ratio were positively associated in adjusted models (p for trend = 0.008). Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over 5 years of follow-up (p for trend = 0.031, fully adjusted model). We did not find any association of CC16 with exacerbation risk. CONCLUSION: Patients with severe asthma with lower circulatory CC16 had enhanced eosinophilic inflammation with rapid FEV1 decline over time.

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma.
Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Nozomu Takei, Akira Oguma, Machiko Matsumoto-Sasaki, Houman Goudarzi, Hironi Makita, Masaharu Nishimura, Satoshi Konno
Allergology international : official journal of the Japanese Society of Allergology, 2022年12月29日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. METHODS: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150-299, ≥300 cells/μL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. RESULTS: Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/μL in COPD and ≥300 cells/μL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. CONCLUSIONS: We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.
Akira Oguma, Kaoruko Shimizu, Hirokazu Kimura, Naoya Tanabe, Susumu Sato, Isao Yokota, Michiko Takimoto-Sato, Machiko Matsumoto-Sasaki, Yuki Abe, Nozomu Takei, Houman Goudarzi, Masaru Suzuki, Hironi Makita, Toyohiro Hirai, Masaharu Nishimura, Satoshi Konno
Allergology international : official journal of the Japanese Society of Allergology, 72, 2, 262, 270, 2022年11月16日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

むずむず脚症候群を合併したサルコイドーシスの2例　　　　　　　　　　　　　　　
鈴木 孝敏, 木村 孔一, 清水 薫子, 鈴木 雅, 白井 慎一, 堀之内 徹, 藤田 雅彦, 今野 哲
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 42, サプリメント号, 66, 66, 日本サルコイドーシス, 2022年10月
日本語

オマリズマブの長期投与後、投与間隔延長による不応を呈した重症喘息の1例
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 木村 孔一, 中丸 裕爾, 今野 哲
アレルギー, 71, 8, 944, 948, (一社)日本アレルギー学会, 2022年09月
日本語, 現在,重症喘息に対する生物学的製剤の長期使用の報告がなされている.しかし,効果が認められる症例における必要治療継続期間,中止基準については明確な基準はない.今回,オマリズマブによる長期的なコントロール維持の後,投与間隔の延長に伴い,喘息病態が悪化を来たし,その後通常間隔投与に戻したものの,当初の効果を認めなかった重症喘息の1例を経験した.投与間隔を延長したことが,効果減弱に関与した可能性もあり,今後のオマリズマブの長期使用に関する診療の一助となると考え,報告する.(著者抄録)

Effects of obesity on CC16 and their potential role in overweight/obese asthma.
Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Munehiro Matsumoto, Nozomu Takei, Kaoruko Shimizu, Masaru Suzuki, Taku Watanabe, Eiki Kikuchi, Hiroshi Ohira, Ichizo Tsujino, Jun Sakakibara-Konishi, Naofumi Shinagawa, Noriharu Shijubo, Hirokazu Sato, Katsunori Shigehara, Kichizo Kaga, Yasuhiro Hida, Soichi Murakami, Yuma Ebihara, Akinobu Nakamura, Hideaki Miyoshi, Satoshi Hirano, Nobuyuki Hizawa, Tatsuya Atsumi, Shau-Ku Huang, Yoichi M Ito, Masaharu Nishimura, Satoshi Konno
Respiratory research, 23, 1, 174, 174, 2022年06月29日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Subtyping emphysematous COPD by respiratory volume change distributions on CT.
Hiroshi Shima, Naoya Tanabe, Akira Oguma, Kaoruko Shimizu, Shizuo Kaji, Kunihiko Terada, Tsuyoshi Oguma, Takeshi Kubo, Masaru Suzuki, Hironi Makita, Atsuyasu Sato, Masaharu Nishimura, Susumu Sato, Satoshi Konno, Toyohiro Hirai
Thorax, 78, 4, 344, 353, 2022年06月29日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients. OBJECTIVE: To evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts. METHODS: Emphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions. RESULTS: Patients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT. CONCLUSION: Lower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

Association of longitudinal changes in quality of life with comorbidities and exacerbations in patients with severe asthma.
Machiko Matsumoto-Sasaki, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Satoshi Konno
Allergology international : official journal of the Japanese Society of Allergology, 71, 4, 481, 489, 2022年06月16日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Quality of life (QoL) assessment is important in the management of severe asthma, and comorbidities and/or exacerbations may affect longitudinal QoL. However, there are few reports on the longitudinal assessment of QoL in patients with asthma over multiple years and its related factors. This study aimed to clarify the relationship of longitudinal changes in QoL with comorbidities and/or exacerbations during a prolonged observation period in patients with severe asthma. METHODS: A total of 105 subjects who participated in the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) with a six-year follow-up were analyzed. QoL was assessed annually, using the Standardized Asthma Quality of Life Questionnaire, and the subjects were divided into three groups: (1) persistently good QoL, (2) persistently poor QoL, and (3) fluctuating QoL. Assessed comorbidities comprised depression, gastroesophageal reflux disease, and excessive daytime sleepiness (EDS), a key symptom of obstructive sleep apnea. RESULTS: Of 105 subjects with severe asthma, 53 (50%) were classified in the persistently good QoL group, 10 (10%) in the persistently poor QoL group, and 42 (40%) in the fluctuating QoL group. The persistently poor QoL group was associated with shorter time to hospitalization due to exacerbation and the presence of multiple comorbidities. In addition, the presence of EDS was an independent contributor to the fluctuating QoL group compared to the persistently good QoL group. CONCLUSIONS: The presence of multiple comorbidities and hospitalization due to exacerbation contribute to longitudinal changes in QoL in patients with severe asthma.

Associations of pulmonary and extrapulmonary computed tomographic manifestations with impaired physical activity in symptomatic patients with chronic obstructive pulmonary disease.
Yoko Hamakawa, Naoya Tanabe, Hiroshi Shima, Kunihiko Terada, Yusuke Shiraishi, Tomoki Maetani, Takeshi Kubo, Satoshi Kozawa, Koji Koizumi, Masashi Kanezaki, Kaoruko Shimizu, Tsuyoshi Oguma, Atsuyasu Sato, Susumu Sato, Toyohiro Hirai
Scientific reports, 12, 1, 5608, 5608, 2022年04月04日, ［国際誌］
英語, 研究論文（学術雑誌）, In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD.

難治性喘息 重症喘息における生物学的製剤の変更に影響する因子の検討
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 松本 宗大, 木村 孔一, 中丸 裕爾, 伊藤 陽一, 今野 哲
日本呼吸器学会誌, 11, 増刊, 143, 143, (一社)日本呼吸器学会, 2022年04月
日本語

呼吸器病学の若手研究最前線 喘息-COPDオーバーラップの多様性 PIRICA研究解析より　　　　　　　　　　　　　　　
武井 望, 鈴木 雅, 佐々木 真知子, 小熊 昴, 阿部 結希, 清水 薫子, 木村 孔一, 牧田 比呂仁, 西村 正治, 今野 哲
日本呼吸器学会誌, 11, 増刊, 43, 43, (一社)日本呼吸器学会, 2022年04月
日本語

難治性喘息 重症喘息における生物学的製剤の変更に影響する因子の検討　　　　　　　　　　　　　　　
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 松本 宗大, 木村 孔一, 中丸 裕爾, 伊藤 陽一, 今野 哲
日本呼吸器学会誌, 11, 増刊, 143, 143, (一社)日本呼吸器学会, 2022年04月
日本語

The prevalence and physiological impacts of centrilobular and paraseptal emphysema on computed tomography in smokers with preserved ratio impaired spirometry.
Yusuke Shiraishi, Takafumi Shimada, Naoya Tanabe, Kunihiko Terada, Ryo Sakamoto, Tomoki Maetani, Hiroshi Shima, Fumi Mochizuki, Tsuyoshi Oguma, Kaoruko Shimizu, Susumu Sato, Shigeo Muro, Nobuyuki Hizawa, Motonari Fukui, Hiroaki Iijima, Izuru Masuda, Toyohiro Hirai
ERJ open research, 8, 2, 2022年04月, ［国際誌］
英語, 研究論文（学術雑誌）, Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are observed in smokers with preserved ratio impaired spirometry (PRISm, defined as the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ≥0.7 and FEV1 <80%), but their prevalence and physiological impacts remain unestablished. This multicentre study aimed to investigate its prevalence and to test whether emphysema subtypes are differently associated with physiological impairments in smokers with PRISm. Both never- and ever-smokers aged ≥40 years who underwent computed tomography (CT) for lung cancer screening and spirometry were retrospectively and consecutively enrolled at three hospitals and a clinic. Emphysema subtypes were visually classified according to the Fleischner system. Air-trapping was assessed as the ratio of FVC to total lung capacity on CT (TLCCT). In 1046 never-smokers and 772 smokers with ≥10 pack-years, the prevalence of PRISm was 8.2% and 11.3%, respectively. The prevalence of PSE and CLE in smokers with PRISm was comparable to that in smokers with normal spirometry (PSE 43.7% versus 36.2%, p=1.00; CLE 46.0% versus 31.8%, p=0.21), but higher than that in never-smokers with PRISm (PSE 43.7% versus 1.2%, p<0.01; CLE 46% versus 4.7%, p<0.01) and lower than that in smokers with airflow limitation (PSE 43.7% versus 71.0%, p<0.01; CLE 46% versus 79.3%, p<0.01). The presence of CLE, but not PSE, was independently associated with reduced FVC/TLCCT in smokers with PRISm. Both PSE and CLE were common, but only CLE was associated with air-trapping in smokers with PRISm, suggesting different physiological roles of these emphysema subtypes.

Further evidence for association of YKL-40 with severe asthma airway remodeling
Hirokazu Kimura, Kaoruko Shimizu, Naoya Tanabe, Hironi Makita, Natsuko Taniguchi, Hiroki Kimura, Masaru Suzuki, Yuki Abe, Machiko Matsumoto-Sasaki, Akira Oguma, Michiko Takimoto-Sato, Nozomu Takei, Munehiro Matsumoto, Houman Goudarzi, Susumu Sato, Junya Ono, Kenji Izuhara, Toyohiro Hirai, Masaharu Nishimura, Satoshi Konno
Annals of Allergy, Asthma & Immunology, Elsevier BV, 2022年03月
研究論文（学術雑誌）

Early chronic obstructive pulmonary disease: Associations of two spirometry criteria with clinical features.
Fumi Mochizuki, Naoya Tanabe, Hiroaki Iijima, Takafumi Shimada, Yusuke Shiraishi, Tomoki Maetani, Hajime Yamazaki, Kaoruko Shimizu, Masaru Suzuki, Shotaro Chubachi, Hiroichi Ishikawa, Takashi Naito, Hironori Masuko, Tohru Sakamoto, Izuru Masuda, Susumu Sato, Nobuyuki Hizawa, Toyohiro Hirai
Respiratory medicine, 204, 107011, 107011, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Two spirometry criteria have been proposed for early chronic obstructive pulmonary disease (COPD) in young smokers: 1) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < the lower limit of normal (LLN), and 2) FEV1 decline ≥60 ml/year. These criteria have yet to be validated. This study explored clinical factors associated with these two spirometry criteria. METHODS: This retrospective study analysed medical check-up data from 13,010 consecutive subjects aged <50 years who underwent current and 3 previous spirometry tests in Japan. Current ≥10 pack-year smokers were the main focus of analysis; those meeting one or more spirometry criteria were diagnosed with early COPD. Early COPD was categorized into three subtypes: FEV1/FVC < LLN and FEV1 decline <60 ml/year (type 1), FEV1/FVC ≥ LLN and FEV1 decline ≥60 ml/year (type 2), and FEV1/FVC < LLN and FEV1 decline ≥60 ml/year (type 3). RESULTS: Of the 1579 current ≥ 10 pack-year smokers, 488 (30.9%) met the early COPD criteria. Multivariate multinomial logistic models adjusted for age, sex, height, body mass index (BMI) and smoking history indicated that past BMI increase and low exercise were associated with higher type 2 early COPD incidence (odds ratio (OR) [95% confidence interval (CI)] = 4.30 [3.10, 6.04], and 0.80 [0.69, 0.93], respectively) but not with higher type 1 incidence. A history of asthma was associated with higher type 3 incidence (OR [95% CI] = 1.98 [1.18, 3.07]). CONCLUSIONS: The 3 types of spirometry-based early COPD have different clinical factors. Their trajectories should be explored in longitudinal studies.

[A CASE OF SEVERE ASTHMA RESULTING IN DISEASE EXACERBATION AFTER PROLONGATION OF THE DOSING INTERVAL AFTER LONG-TERM OMALIZUMAB ADMINISTRATION].
Machiko Matsumoto-Sasaki, Kaoruko Shimizu, Masanobu Suzuki, Masaru Suzuki, Hirokazu Kimura, Yuji Nakamaru, Satoshi Konno
Arerugi = [Allergy], 71, 8, 944, 948, 2022年, ［国内誌］
日本語, 研究論文（学術雑誌）, At the time of writing of this manuscript, four biologics were clinically available for the treatment of severe asthma, and there were no established recommendations for the period of administration or timing of discontinuation of each biologic. We present a case of severe asthma that was well controlled with long-term omalizumab treatment; however, prolongation of the dosing intervals resulted in disease exacerbation that was refractory to omalizumab treatment despite the restoration of the recommended interval of administration. We suspect that the prolonged dosing intervals might have reduced the efficacy of omalizumab. We report this case because dosing intervals should be considered in clinical practice in cases of long-term omalizumab treatment.

Association of abdominal visceral adiposity with sputum IL-5 levels in asthma.
Houman Goudarzi, Hirokazu Kimura, Hironi Makita, Yuki Abe, Akira Oguma, Michiko Sato, Munehiro Matsumoto, Nozomu Takei, Hiroki Kimura, Kaoruko Shimizu, Masaru Suzuki, Yoichi M Ito, Masaharu Nishimura, Satoshi Konno
Allergology international : official journal of the Japanese Society of Allergology, 71, 1, 137, 139, 2021年09月14日, ［国際誌］
英語

Parenchymal destruction in asthma: Fixed airflow obstruction and lung function trajectory.
Kaoruko Shimizu, Naoya Tanabe, Akira Oguma, Hirokazu Kimura, Masaru Suzuki, Isao Yokota, Hironi Makita, Susumu Sato, Toyohiro Hirai, Masaharu Nishimura, Satoshi Konno
The Journal of allergy and clinical immunology, 149, 3, 934, 942, 2021年08月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Fixed airflow obstruction (FAO) in asthma, particularly in nonsmokers, is generally believed to be caused by airway remodeling. However, parenchymal destruction may also contribute to FAO and longitudinal decline in forced expiratory volume in 1 second (FEV1). OBJECTIVES: To evaluate parenchymal destruction, we used emphysema indices, exponent D, and low-attenuation area percentage (LAA%) on computed tomography (CT), and test whether the parenchymal destruction and airway disease are independently associated with FAO and FEV1 decline in both smoking and nonsmoking asthma. METHODS: Exponent D, LAA%, wall area percentage at segmental airways, and airway fractal dimension (AFD) in those with asthma were measured on inspiratory CT and compared to those in patients with chronic obstructive pulmonary disease (COPD). RESULTS: Exponent D was lower and LAA% was higher in COPD (n = 42) and asthma with FAO (n = 101) than in asthma without FAO (n = 88). The decreased exponent D and increased LAA% were associated with FAO regardless of smoking status or asthma severity. In multivariable analysis, decreased exponent D and increased LAA% were associated with an increased odds ratio of FAO and decreased FEV1, irrespective of wall area percentage and airway fractal dimension. Moreover, decreased exponent D affected the longitudinal decline in FEV1 in those with severe asthma, independent of smoking status. CONCLUSIONS: Patients with asthma with FAO showed parenchymal destruction regardless of smoking status and asthma severity. Parenchymal destruction was associated with an accelerated FEV1 decline, suggesting the involvements of both airway and parenchyma in the pathophysiology of a subgroup of asthma.

Expiratory central airway collapse and symptoms in smokers.
Naoya Tanabe, Kunihiko Terada, Hiroshi Shima, Yoko Hamakawa, Yusuke Shiraishi, Kaoruko Shimizu, Atsuyasu Sato, Tsuyoshi Oguma, Susumu Sato, Toyohiro Hirai
Respiratory investigation, 59, 4, 522, 529, 2021年07月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prevalence and clinical impacts of expiratory central airway collapse (ECAC) in smokers remain controversial. Although studies have shown associations of ECAC with airflow limitation and symptoms, others have shown that higher tracheal collapsibility is associated with lower expiratory-to-inspiratory ratio of lung volume (E/I-LV), but not airflow limitation. This study tested whether ECAC of the trachea and main bronchi could occur exclusively in smokers with lower E/I-LV and affect their symptoms independent of emphysema and intrapulmonary airway disease. METHODS: ECAC was defined as the expiratory-to-inspiratory ratio of cross-sectional lumen area <0.5 for at least one of the three locations, including the trachea, right and left main bronchi on static full-inspiratory, and end-tidal expiratory CT. Symptoms were assessed using the chronic obstructive pulmonary disease (COPD) assessment test (CAT) and modified MRC scale (mMRC). RESULTS: Out of 241 smokers with and without COPD (n = 189 and 52, respectively), ECAC was found in 21 (9%) smokers. No ECAC was found in smokers with E/I-LV ≥0.75. CAT and mMRC in smokers with ECAC were higher than in non-ECAC smokers with E/I-LV <0.75, but comparable to those in non-ECAC smokers with E/I-LV ≥0.75. In the multivariable analysis of smokers with E/I-LV <0.75, ECAC was associated with increased mMRC and CAT independent of CT-emphysema severity, wall area percent of segmental airways, and forced expiratory volume in 1 s CONCLUSIONS: ECAC is associated with worsening of symptoms independent of emphysema and segmental airway disease in smokers with a lower expiratory-to-inspiratory lung volume ratio.

Combined assessment of pulmonary arterial enlargement and coronary calcification predicts the prognosis of patients with chronic obstructive pulmonary disease.
Nozomu Takei, Masaru Suzuki, Naoya Tanabe, Akira Oguma, Kaoruko Shimizu, Hirokazu Kimura, Hironi Makita, Susumu Sato, Toyohiro Hirai, Isao Yokota, Satoshi Konno, Masaharu Nishimura
Respiratory medicine, 185, 106520, 106520, 2021年06月23日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: In chronic obstructive pulmonary disease (COPD), chest computed tomography (CT) provides clinically important cardiovascular findings, which include diameter of pulmonary artery (PA), its ratio to the diameter of the aorta (PA:A ratio), and coronary artery calcium score (CACS). The clinical importance of these cardiovascular findings has not been fully assessed in Japan, where cardiovascular morbidity and/or mortality is reported to be much less compared with Western counterparts. METHODS: PA diameter and PA:A ratio were measured in 172 and 130 patients with COPD who enrolled in the Hokkaido COPD cohort study and the Kyoto University cohort, respectively. CACS was measured in 131 and 128 patients in each cohort. RESULTS: While the highest quartile group in PA diameter was associated with higher all-cause mortality compared to the lowest quartile group in both cohorts, individual assessments of PA:A ratio and CACS were not associated with the long-term clinical outcomes. When PA diameter and CACS were combined, patients with PA enlargement (diameter >29.5 mm) and/or coronary calcification (score >440.8) were associated with higher all-cause mortality in both cohorts. CONCLUSION: Combined assessment of PA enlargement and CACS was associated with poor prognosis, which provides a clinical advantage in management of patients with COPD even in geographical regions with lower risk of cardiovascular diseases.

4剤の生物学的製剤を使用し上下気道の反応性の違いを観察し得た重症喘息の1例
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 中丸 裕爾, 今野 哲
アレルギー, 70, 4, 315, 320, (一社)日本アレルギー学会, 2021年06月
日本語, 現在,重症喘息の治療には4種類の生物学的製剤が使用可能である.その薬剤選択においては,各種2型炎症関連バイオマーカーの測定値,及び好酸球性副鼻腔炎,アレルギー性鼻炎,アトピー性皮膚炎などの併存疾患の有無を考慮すべきと言われている.今回,好酸球性副鼻腔炎,好酸球性中耳炎を合併し,結果的に4種類の生物学的製剤を使用し,上・下気道それぞれの反応性の違いを観察しえた重症喘息の1症例を経験した.4剤の使い分けに関する明確なアルゴリズムは確立されていない現状を鑑み,生物学的製剤による総合的な治療戦略を考える上で意義が大きいと考え,報告する.(著者抄録)

4剤の生物学的製剤を使用し上下気道の反応性の違いを観察し得た重症喘息の1例
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 中丸 裕爾, 今野 哲
アレルギー, 70, 4, 315, 320, (一社)日本アレルギー学会, 2021年06月
日本語

A Comparative Evaluation of Computed Tomography Images for the Classification of Spirometric Severity of the Chronic Obstructive Pulmonary Disease with Deep Learning.
Hiroyuki Sugimori, Kaoruko Shimizu, Hironi Makita, Masaru Suzuki, Satoshi Konno
Diagnostics (Basel, Switzerland), 11, 6, 2021年05月21日, ［国際誌］
英語, 研究論文（学術雑誌）, Recently, deep learning applications in medical imaging have been widely applied. However, whether it is sufficient to simply input the entire image or whether it is necessary to preprocess the setting of the supervised image has not been sufficiently studied. This study aimed to create a classifier trained with and without preprocessing for the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification using CT images and to evaluate the classification accuracy of the GOLD classification by confusion matrix. According to former GOLD 0, GOLD 1, GOLD 2, and GOLD 3 or 4, eighty patients were divided into four groups (n = 20). The classification models were created by the transfer learning of the ResNet50 network architecture. The created models were evaluated by confusion matrix and AUC. Moreover, the rearranged confusion matrix for former stages 0 and ≥1 was evaluated by the same procedure. The AUCs of original and threshold images for the four-class analysis were 0.61 ± 0.13 and 0.64 ± 0.10, respectively, and the AUCs for the two classifications of former GOLD 0 and GOLD ≥ 1 were 0.64 ± 0.06 and 0.68 ± 0.12, respectively. In the two-class classification by threshold image, recall and precision were over 0.8 in GOLD ≥ 1, and in the McNemar-Bowker test, there was some symmetry. The results suggest that the preprocessed threshold image can be possibly used as a screening tool for GOLD classification without pulmonary function tests, rather than inputting the normal image into the convolutional neural network (CNN) for CT image learning.

One-year clinically important deterioration and long-term clinical course in Japanese patients with COPD: a multicenter observational cohort study.
Yuki Abe, Masaru Suzuki, Hironi Makita, Hirokazu Kimura, Kaoruko Shimizu, Satoshi Konno, Masaharu Nishimura
BMC pulmonary medicine, 21, 1, 159, 159, 2021年05月12日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex progression of many clinical presentations, and clinically important deterioration (CID) has been proposed in the Western studies as a composite endpoint of disease progression. The aim of this study was to investigate the relationships between 1-year CID and the following long-term clinical outcomes in Japanese patients with COPD who have been reported to have different characteristics compared to the Westerners. METHODS: Among Japanese patients with COPD enrolled in the Hokkaido COPD cohort study, 259 patients who did not drop out within the first year were analyzed in this study. Two definitions of CID were used. Definition 1 comprised ≥ 100 mL decrease in forced expiratory volume in 1 s (FEV1), ≥ 4-unit increase in St George's Respiratory Questionnaire (SGRQ) score from baseline, or moderate or severe exacerbation. For Definition 2, the thresholds for the FEV1 and SGRQ score components were doubled. The presence of CID was evaluated within the first year from enrollment, and analyzed the association of the presence of CID with following 4-year risk of exacerbations and 9-year mortality. RESULTS: Patients with CID using Definition 1, but not any single CID component, during the first year had a significantly worse mortality compared with those without CID. Patients with CID using Definition 2 showed a similar trend on mortality, and had a shorter exacerbation-free survival compared with those without CID. CONCLUSIONS: Adoption of CID is a beneficial and useful way for the assessment of long-term disease progression and clinical outcomes even in Japanese population with COPD. The definition of CID might be optimized according to the characteristics of COPD population and the observation period for CID.

COPD患者における,気腫・非気腫領域別の呼吸による体積変化率の分布一致度と呼吸機能との関連
島 寛, 田辺 直也, 張 怡, 白石 祐介, 小澤 聡, 小熊 毅, 佐藤 篤靖, 鍛冶 静雄, 清水 薫子, 牧田 比呂仁, 西村 正治, 佐藤 晋, 今野 哲, 平井 豊博
日本呼吸器学会誌, 10, 増刊, 216, 216, (一社)日本呼吸器学会, 2021年04月
日本語

日本人COPD患者の短期clinically important deteriorationと長期臨床経過に関する検討
阿部 結希, 鈴木 雅, 木村 孔一, 清水 薫子, 牧田 比呂仁, 今野 哲, 西村 正治
日本呼吸器学会誌, 10, 増刊, 190, 190, (一社)日本呼吸器学会, 2021年04月
日本語

重症喘息におけるQoLの経年的変化と併存症および増悪との関連
佐々木 真知子, 鈴木 雅, 木村 孔一, 清水 薫子, 牧田 比呂仁, 西村 正治, 今野 哲
日本呼吸器学会誌, 10, 増刊, 235, 235, (一社)日本呼吸器学会, 2021年04月
日本語

日本人の肺気腫サブタイプ別の頻度と臨床的意義に関する検討 多施設共同研究
白石 祐介, 小熊 昂, 嶋田 貴文, 田辺 直也, 寺田 邦彦, 清水 薫子, 望月 芙美, 飯島 弘晃, 室 繁郎, 牧田 比呂仁, 西村 正治, 佐藤 晋, 今野 哲, 平井 豊博
日本呼吸器学会誌, 10, 増刊, 155, 155, (一社)日本呼吸器学会, 2021年04月
日本語

COPD患者における,気腫・非気腫領域別の呼吸による体積変化率の分布一致度と呼吸機能との関連
島 寛, 田辺 直也, 張 怡, 白石 祐介, 小澤 聡, 小熊 毅, 佐藤 篤靖, 鍛冶 静雄, 清水 薫子, 牧田 比呂仁, 西村 正治, 佐藤 晋, 今野 哲, 平井 豊博
日本呼吸器学会誌, 10, 増刊, 216, 216, (一社)日本呼吸器学会, 2021年04月
日本語

気管支喘息における粘液栓と喀痰中炎症プロファイルの関係
小熊 昂, 清水 薫子, 木村 孔一, 鈴木 雅, 牧田 比呂仁, 西村 正治, 今野 哲
日本呼吸器学会誌, 10, 増刊, 175, 175, (一社)日本呼吸器学会, 2021年04月
日本語

日本人COPD患者の短期clinically important deteriorationと長期臨床経過に関する検討
阿部 結希, 鈴木 雅, 木村 孔一, 清水 薫子, 牧田 比呂仁, 今野 哲, 西村 正治
日本呼吸器学会誌, 10, 増刊, 190, 190, (一社)日本呼吸器学会, 2021年04月
日本語

重症喘息におけるQoLの経年的変化と併存症および増悪との関連
佐々木 真知子, 鈴木 雅, 木村 孔一, 清水 薫子, 牧田 比呂仁, 西村 正治, 今野 哲
日本呼吸器学会誌, 10, 増刊, 235, 235, (一社)日本呼吸器学会, 2021年04月
日本語

北海道大学病院における新型コロナウイルス感染症の流行に伴う職務上の影響にかかわる調査結果
阿部 結希, 清水 薫子, 中司 展人, 船木 典子, 長堀 紀子, 菅原 満, 澁谷 斉, 高橋 久美子, 北川 善政, 今野 哲, 渥美 達也
日本医師会雑誌, 150, 1, 95, 100, (公社)日本医師会, 2021年04月
日本語, 新型コロナウイルス感染症(COVID-19)流行による業務への影響を把握し、今後の方策を提案することを目的とし、北海道大学病院に勤務する職員を対象に、2020年2月28日〜5月31日の業務についてアンケート調査を実施した。医育機関という観点から、診療・研究・教育という多面的な評価を行い、欠勤とその理由についても調査した。いずれの業務においても、多様な影響が見られた。欠勤はすべての職種に認められ、主な理由は、家族の一斉休校、休園や自粛要請であった。職場の雰囲気や理解、体制の構築を望む回答者が多く見られ、オンライン化や在宅・分散勤務、感染対策の徹底など、継続が有効と思われる変化も見られた。特に感染対策として、本人あるいは家族の体調不良時の欠勤、復職基準の徹底は重要であり、同時に職員がスムーズに出欠勤できる支援体制が必要と思われた。(著者抄録)

北海道大学病院における新型コロナウイルス感染症の流行に伴う職務上の影響にかかわる調査結果　　　　　　　　　　　　　　　
阿部 結希, 清水 薫子, 中司 展人, 船木 典子, 長堀 紀子, 菅原 満, 澁谷 斉, 高橋 久美子, 北川 善政, 今野 哲, 渥美 達也
日本医師会雑誌, 150, 1, 95, 100, (公社)日本医師会, 2021年04月
日本語, 新型コロナウイルス感染症(COVID-19)流行による業務への影響を把握し、今後の方策を提案することを目的とし、北海道大学病院に勤務する職員を対象に、2020年2月28日〜5月31日の業務についてアンケート調査を実施した。医育機関という観点から、診療・研究・教育という多面的な評価を行い、欠勤とその理由についても調査した。いずれの業務においても、多様な影響が見られた。欠勤はすべての職種に認められ、主な理由は、家族の一斉休校、休園や自粛要請であった。職場の雰囲気や理解、体制の構築を望む回答者が多く見られ、オンライン化や在宅・分散勤務、感染対策の徹底など、継続が有効と思われる変化も見られた。特に感染対策として、本人あるいは家族の体調不良時の欠勤、復職基準の徹底は重要であり、同時に職員がスムーズに出欠勤できる支援体制が必要と思われた。(著者抄録)

Annual Body Weight Change and Prognosis in Chronic Obstructive Pulmonary Disease.
Yuki Abe, Masaru Suzuki, Hiroshi Shima, Yusuke Shiraishi, Naoya Tanabe, Susumu Sato, Kaoruko Shimizu, Hirokazu Kimura, Hironi Makita, Toyohiro Hirai, Satoshi Konno, Masaharu Nishimura
International journal of chronic obstructive pulmonary disease, 16, 3243, 3253, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts. Patients and Methods: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group (<-0.17 kg/year), no change group (-0.17 to ≤0.20 kg/year), and weight gain group (>0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247). Results: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort. Conclusion: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.

[A CASE OF SEVERE ASTHMA WHO REQUIRED A SWITCH OF FOUR BIOLOGICS: DIFFERENTIAL RESPONSES ON UPPER AND LOWER AIRWAYS].
Machiko Matsumoto Sasaki, Kaoruko Shimizu, Masanobu Suzuki, Masaru Suzuki, Yuji Nakamaru, Satoshi Konno
Arerugi = [Allergy], 70, 4, 315, 320, 2021年, ［国内誌］
日本語, 研究論文（学術雑誌）, At the time of writing of this manuscript, four biologics were clinically available for treatment against severe asthma. The choice of four biologics has been taking into account of the results of several type 2 inflammationrelated biomarkers, and the comorbidities of asthma, such as eosinophilic chronic rhinosinusitis, allergic rhinitis, and atopic dermatitis.In this study, we have experienced a case of severe asthma complicated by eosinophilic chronic rhinosinusitis and eosinophilic otitis media, resulting in the use of four biologics, and we observed differential response of upper and lower airways. As a clear algorithm has not been established for the use of four biologics, our experience of this case would provide important lesson for considering the therapeutic strategies against severe asthma.

Central airway and peripheral lung structures in airway disease-dominant COPD.
Naoya Tanabe, Kaoruko Shimizu, Kunihiko Terada, Susumu Sato, Masaru Suzuki, Hiroshi Shima, Akira Oguma, Tsuyoshi Oguma, Satoshi Konno, Masaharu Nishimura, Toyohiro Hirai
ERJ open research, 7, 1, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）, The concept that the small airway is a primary pathological site for all COPD phenotypes has been challenged by recent findings that the disease starts from the central airways in COPD subgroups and that a smaller central airway tree increases COPD risk. This study aimed to examine whether the computed tomography (CT)-based airway disease-dominant (AD) subtype, defined using the central airway dimension, was less associated with small airway dysfunction (SAD) on CT, compared to the emphysema-dominant (ED) subtype. COPD patients were categorised into mild, AD, ED and mixed groups based on wall area per cent (WA%) of the segmental airways and low attenuation volume per cent in the Kyoto-Himeji (n=189) and Hokkaido COPD cohorts (n=93). The volume per cent of SAD regions (SAD%) was obtained by nonrigidly registering inspiratory and expiratory CT. The AD group had a lower SAD% than the ED group and similar SAD% to the mild group. The AD group had a smaller lumen size of airways proximal to the segmental airways and more frequent asthma history before age 40 years than the ED group. In multivariable analyses, while the AD and ED groups were similarly associated with greater airflow limitation, the ED, but not the AD, group was associated with greater SAD%, whereas the AD, but not the ED, group was associated with a smaller central airway size. The CT-based AD COPD subtype might be associated with a smaller central airway tree and asthma history, but not with peripheral lung pathologies including small airway disease, unlike the ED subtype.

Two cases of chronic obstructive pulmonary disease with undetectable diffusing capacity for carbon monoxide.
Ayumi Ohara, Satoshi Konno, Kaoruko Shimizu, Masaru Suzuki, Masafumi Yamamoto, Asako Mitani, Mutsumi Nishida, Takanori Teshima, Masaharu Nishimura
Respiratory investigation, 59, 1, 145, 148, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）, Pulmonary diffusing capacity for carbon monoxide (DLCO) is a valuable pulmonary function test to evaluate the gas exchange capacity of the lungs. Generally, DLCO values are significantly lower in patients with chronic obstructive pulmonary disease (COPD), particularly in those with a predominantly emphysema phenotype. However, it is extremely rare that DLCO values cannot be obtained for reasons other than technical errors. Herein, we report two patients with COPD in whom DLCO values were undetectable without prolonging the breath-holding time for the test. We discuss possible mechanisms for these peculiar findings.

Factors for the Variability of Three Acceptable Maximal Expiratory Flow-Volume Curves in Chronic Obstructive Pulmonary Disease.
Masafumi Yamamoto, Satoshi Konno, Hironi Makita, Katsuaki Nitta, Kaoruko Shimizu, Masaru Suzuki, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Masaharu Nishimura
International journal of chronic obstructive pulmonary disease, 16, 415, 422, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Generally, the maximal expiratory flow-volume (MEFV) curve must be measured for the diagnosis and staging of chronic obstructive pulmonary disease (COPD). As this test is effort dependent, international guidelines recommend that three acceptable trials are required for each test. However, no study has examined the magnitude and factors for the variability in parameters among three acceptable trials. Methods: We evaluated the intra-individual variations in several parameters among three acceptable MEFV curves obtained at one-time point in patients with COPD (n = 28, stage 1; n = 36, stage 2; n = 21, stages 3-4). Next, the factors for such variations were examined using forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Results: The averages of coefficient of variation (CV) for FEV1 and FVC were 2.0% (range: 1.0-3.0%) and 1.6% (0.9-2.2%), respectively. Both parameters were significantly better than peak expiratory flow rate, forced expiratory flow at 50% of expired FVC, and forced expiratory flow at 75% of expired FVC (CVs: 5.0-6.9%). A higher spirometric stage was significantly associated with higher CVs for FVC and FEV1, and older age was significantly correlated with a higher variation in FEV1 alone. Furthermore, a significantly inverse association was observed between emphysema severity, and the CVs for FEV1, but not that for FVC, regardless of spirometric stage. Conclusion: Both FVC and FEV1 are highly reproducible; nevertheless, older age, lower FEV1 at baseline, and non-emphysema phenotype are factors for a higher variability in FEV1 in patients with COPD.

ベンラリズマブ中途不応後、メポリズマブに変更した難治性喘息の1例　　　　　　　　　　　　　　　
佐々木 真知子, 清水 薫子, 松本 宗大, 武井 望, 木村 孔一, 木村 裕樹, 鈴木 雅, 今野 哲
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 40, 1-2, 57, 57, 日本サルコイドーシス, 2020年10月
日本語

Determination of the cutoff values of Th2 markers for the prediction of future exacerbation in severe asthma: An analysis from the Hokkaido Severe Asthma Cohort Study.
Hirokazu Kimura, Hironi Makita, Natsuko Taniguchi, Nozomu Takei, Munehiro Matsumoto, Hiroki Kimura, Houman Goudarzi, Kaoruko Shimizu, Masaru Suzuki, Masaharu Nishimura, Satoshi Konno
Allergology international : official journal of the Japanese Society of Allergology, 2020年09月17日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We recently reported that severe asthma patients with frequent exacerbations showed high blood eosinophil counts (Eo) and fractions of exhaled nitric oxide (FeNO) compared with non-exacerbators. However, we did not determine exact cutoff values related to exacerbation. The aim of this study was to determine the cutoff values of Eo and FeNO that could be related to the exacerbation of severe asthma. We also aimed to confirm the clinical utility of Th2 markers related to exacerbation. METHODS: This study included 105 severe asthma patients who completed a three-year follow-up of a severe asthma cohort study, including smokers. Three Th2 markers were selected, viz., Eo, FeNO, and positive atopic status. Regarding Eo and FeNO, we determined the cutoff values for the definition of "positive" Th2 features using receiver operating characteristic curve analyses, based on the comparisons between frequent exacerbators and other patients. RESULTS: The cutoff values for positive Th2 features were Eo ≥ 250 cells/μL and FeNO ≥31 ppb. Sixteen patients (15.2%) had no Th2 features, 40 (38.1%) had one, 25 (23.8%) had two, and 24 (22.9%) had three. A high number of positive Th2 features was significantly associated with exacerbation frequencies over three years (p < 0.05). Similarly, compared to patients with one or no Th2 features, those with three Th2 features had a significantly higher probability of having more than one exacerbation (p < 0.05). CONCLUSIONS: The cutoff values determined in the current analysis were good predictors of future exacerbations in severe asthma patients.

ベンラリズマブ不応後にメポリズマブへ変更した難治性喘息の1例
佐々木 真知子, 清水 薫子, 鈴木 正宣, 鈴木 雅, 中丸 裕爾, 今野 哲
アレルギー, 69, 8, 678, 682, (一社)日本アレルギー学会, 2020年09月
日本語, 症例は66歳の好酸球性副鼻腔炎を合併した難治性喘息患者.ベンラリズマブ開始後,喘息症状は著明に改善し,末梢血好酸球数は0/μlとなり,月に数回程度使用していた頓用の経口ステロイドも不要となった.しかし,投与開始後7ヵ月目で喘息症状は再燃し,好酸球数は813/μlと増加したため,メポリズマブへ変更したところ,喘息症状に加え鼻症状も改善した.以上の経過からベンラリズマブに対する中和抗体が産生された可能性が考えられた.中和抗体は日常臨床において測定できないため,中和抗体産生に関する症例報告は認めない.本症例においても疑いにとどまるが,臨床経過からはその可能性は高い.また本症例の鼻症状はベンラリズマブへは反応が乏しく,メポリズマブで改善した.生物学的製剤の臓器における治療反応性の違いも重要な観点である.以上から,本症例は生物学的製剤の特色を多面的に反映した経過を示し,報告の価値は高い.(著者抄録)

当科における重症気管支喘息患者に対する生物学的製剤の使用状況
佐々木 真知子, 清水 薫子, 松本 宗大, 武井 望, 山下 優, 鎌田 啓佑, 中久保 祥, 木村 孔一, 木村 裕樹, 長岡 健太郎, 鈴木 雅, 今野 哲
日本呼吸器学会誌, 9, 増刊, 279, 279, (一社)日本呼吸器学会, 2020年08月
日本語

北海道支部3大学共同ワーキンググループの取り組み
長井 桂, 清水 薫子, 宮島 さつき, 橋本 みどり, 佐々木 高明, 高村 圭, 岡本 佳裕, 千葉 弘文, 長内 忍, 日本呼吸器学会北海道支部将来計画委員会/男女共同参画委員会
日本呼吸器学会誌, 9, 増刊, 78, 78, (一社)日本呼吸器学会, 2020年08月
日本語

COPD 疫学・病因・病態 胸部単純CTの心血管指標を用いたCOPD患者の長期臨床経過についての検討
武井 望, 鈴木 雅, 牧田 比呂仁, 清水 薫子, 木村 孔一, 今野 哲, 西村 正治
日本呼吸器学会誌, 9, 増刊, 125, 125, (一社)日本呼吸器学会, 2020年08月
日本語

喘息に関する臨床研究 重症喘息患者における呼気一酸化窒素濃度の経年変化と臨床経過に関する検討
阿部 結希, 鈴木 雅, 木村 孔一, 清水 薫子, 牧田 比呂仁, 西村 正治, 今野 哲
日本呼吸器学会誌, 9, 増刊, 136, 136, (一社)日本呼吸器学会, 2020年08月
日本語

重症喘息患者における呼吸機能の経年変化とその関連因子について
木村 孔一, 牧田 比呂仁, 谷口 菜津子, 木村 裕樹, 清水 薫子, 鈴木 雅, 武井 望, 松本 宗大, Goudarzi Houman, 西村 正治, 今野 哲
日本呼吸器学会誌, 9, 増刊, 223, 223, (一社)日本呼吸器学会, 2020年08月
日本語

当科における重症気管支喘息患者に対する生物学的製剤の使用状況
佐々木 真知子, 清水 薫子, 松本 宗大, 武井 望, 山下 優, 鎌田 啓佑, 中久保 祥, 木村 孔一, 木村 裕樹, 長岡 健太郎, 鈴木 雅, 今野 哲
日本呼吸器学会誌, 9, 増刊, 279, 279, (一社)日本呼吸器学会, 2020年08月
日本語

Per cent low attenuation volume and fractal dimension of low attenuation clusters on CT predict different long-term outcomes in COPD.
Kaoruko Shimizu, Naoya Tanabe, Nguyen Van Tho, Masaru Suzuki, Hironi Makita, Susumu Sato, Shigeo Muro, Michiaki Mishima, Toyohiro Hirai, Emiko Ogawa, Yasutaka Nakano, Satoshi Konno, Masaharu Nishimura
Thorax, 75, 2, 116, 122, 2020年02月, ［査読有り］, ［国際誌］
英語, BACKGROUND: Fractal dimension (D) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. METHODS: Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). RESULTS: In the Hokkaido COPD cohort, higher %LAV, but not D, was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D, but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. CONCLUSION: These well-established cohorts clarify the different prognostic roles of %LAV and D, whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

Annual Fractional Exhaled Nitric Oxide Measurements and Exacerbations in Severe Asthma.
Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Satoshi Konno
Journal of asthma and allergy, 13, 731, 741, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: Fractional exhaled nitric oxide (FENO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FENO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FENO and the development of exacerbations in severe asthma. Patients and Methods: Among the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FENO was measured annually were included. According to the FENO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥50 ppb at all three visits), the sustained low group (<25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FENO during the 3 years (high CV and low CV intermediate groups). Results: The sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FENO was an independent contributing factor to the development of exacerbations. Conclusion: Persistence of FENO above 50 ppb over the years as well as the presence of large variations in FENO levels was associated with the development of exacerbations in patients with severe asthma.

Unique Mortality Profile in Japanese Patients with COPD: An Analysis from the Hokkaido COPD Cohort Study.
Hironi Makita, Masaru Suzuki, Satoshi Konno, Kaoruko Shimizu, Yasuyuki Nasuhara, Katsura Nagai, Yasushi Akiyama, Satoshi Fuke, Hiroshi Saito, Takeshi Igarashi, Kimihiro Takeyabu, Masaharu Nishimura
International journal of chronic obstructive pulmonary disease, 15, 2081, 2090, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate. Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed. Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7-7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (<64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality. Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.

[A CASE OF SEVERE ASTHMA SWITCHED TO MEPOLIZUMAB DUE TO LATE-OCCURRING UNRESPONSIVENESS TO BENRALIZUMAB].
Machiko Matsumoto-Sasaki, Kaoruko Shimizu, Masanobu Suzuki, Masaru Suzuki, Yuji Nakamaru, Satoshi Konno
Arerugi = [Allergy], 69, 8, 678, 682, 2020年, ［国内誌］
日本語, 研究論文（学術雑誌）, We report the case of a 66-year-old patient with severe asthma complicated by eosinophilic chronic rhinosinusitis (ECRS). The patient was initially treated with benralizumab, which resulted in marked improvement of asthma symptoms and reduced the peripheral blood eosinophil count to 0/μL. Additionally, oral steroids were discontinued. After 7 months of benralizumab administration, the asthma symptoms worsened and peripheral blood eosinophil count increased to 813/μL. The neutralizing antibodies to benralizumab may have resulted in the recurrence of symptoms due to eosinophilic inflammation. The nasal symptoms, on which benralizumab had an unremarkable effect, improved when treatment was switched to mepolizumab. However, the difference in effects of biologics on ECRS has not been elucidated and warrants further investigation. To the best of our knowledge, this is the first report of a case of severe asthma in which mepolizumab administration reversed the clinical deterioration of asthma, which was possibly caused by neutralizing antibodies to benralizumab.

A prospective phase II study of carboplatin and nab-paclitaxel in patients with advanced non-small cell lung cancer and concomitant interstitial lung disease (HOT1302).
Hajime Asahina, Satoshi Oizumi, Kei Takamura, Toshiyuki Harada, Masao Harada, Hiroshi Yokouchi, Kenya Kanazawa, Yuka Fujita, Tetsuya Kojima, Fumiko Sugaya, Hisashi Tanaka, Ryoichi Honda, Eiki Kikuchi, Tomoo Ikari, Takahiro Ogi, Kaoruko Shimizu, Masaru Suzuki, Satoshi Konno, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
Lung cancer (Amsterdam, Netherlands), 138, 65, 71, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. PATIENTS AND METHODS: The enrolled patients had treatment-naïve, advanced NSCLC with ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4-6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7-84.8) vs. 47.6% (95% CI: 28.3-67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0-10.2) vs. 4.1 months (95% CI: 3.3-5.4) (HR, 0.60 [95% CI, 0.30-1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8-not reached) vs. 11.9 months (95% CI: 7.3-17.4) (HR, 0.56 [95% CI, 0.24-1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. CONCLUSION: Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.

間質性肺炎合併進行非小細胞肺癌に対するカルボプラチン+ナブパクリタキセル併用療法の第II相試験
高村 圭, 朝比奈 肇, 大泉 聡史, 原田 敏之, 原田 眞雄, 横内 浩, 金沢 賢也, 藤田 結花, 小島 哲弥, 菅谷 文子, 田中 寿志, 本田 亮一, 猪狩 智生, 荻 喬博, 清水 薫子, 鈴木 雅, 今野 哲, 秋田 弘俊, 磯部 宏, 西村 正治, 北海道肺癌臨床研究会
肺癌, 59, 6, 687, 687, (NPO)日本肺癌学会, 2019年11月
日本語

当科におけるリンパ管脈管筋腫症33症例のまとめ
瀧本 理子, 鈴木 雅, 松本 宗大, 武井 望, 山下 優, 木村 孔一, 木村 裕樹, 長岡 健太郎, 清水 薫子, 今野 哲
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 39, 1-2, 115, 115, 日本サルコイドーシス, 2019年10月, ［査読有り］
日本語

気道炎症・バイオマーカー 重症喘息患者における増悪状況とTh2マーカー陽性数の検討
木村 孔一, 牧田 比呂仁, 谷口 菜津子, 木村 裕樹, 清水 薫子, 鈴木 雅, 武井 望, 松本 宗大, Goudarzi Houman, 西村 正治, 今野 哲
アレルギー, 68, 4-5, 491, 491, (一社)日本アレルギー学会, 2019年05月
日本語

喘息患者における全身と痰の炎症バイオマーカーに対する肥満度指数の異なる影響(Differential impact of obesity indices on systemic and sputum inflammatory biomarkers among asthma patients)
Goudarzi Houman, Konno Satoshi, Makita Hironi, Kimura Hirokazu, Matsumoto Munehiro, Takei Nozomu, Kimura Hiroki, Shimizu Kaoruko, Suzuki Masaru, Nishimura Masaharu
日本呼吸器学会誌, 8, 増刊, 365, 365, (一社)日本呼吸器学会, 2019年03月
英語

Annual change in FEV₁ in elderly 10-year survivors with established chronic obstructive pulmonary disease.
Suzuki M, Makita H, Konno S, Shimizu K, Nasuhara Y, Nagai K, Akiyama Y, Fuke S, Saito H, Igarashi T, Takeyabu K, Nishimura M
Scientific reports, 9, 1, 2073, 2073, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Long-term decline in lung function is generally considered to be progressive in individuals with established chronic obstructive pulmonary disease (COPD), despite the presence of intersubject variation. We hypothesized that the annualized rate of decline in forced expiratory volume in 1 second (FEV1) would not be constant among different time periods in the natural history of established COPD. We compared the annual change rates in FEV1 during the first 5 years and the last 5 years, estimated separately using a linear mixed-effects model in 10-year survivors (n = 110). The subjects were classified into three FEV1 decline groups, based on the 25th and 75th percentile values in each time period. The rates of FEV1 changes, calculated from the first 5 years and the last 5 years, did not correlate with each other among 10-year survivors; the subjects of each FEV1 decline group during the first 5 years did not consistently remain in the same FEV1 decline group during the last 5 years. Smoking status and exacerbation frequency were not associated with decline in FEV1. In conclusion, the disease activity, which is often expressed as annualized change in FEV1, might be changeable either way over years in patients with established COPD.

Serum Alpha-1 Antitrypsin Levels and the Clinical Course of Chronic Obstructive Pulmonary Disease.
Nozomu Takei, Masaru Suzuki, Hironi Makita, Satoshi Konno, Kaoruko Shimizu, Hiroki Kimura, Hirokazu Kimura, Masaharu Nishimura
International journal of chronic obstructive pulmonary disease, 14, 2885, 2893, 2019年, ［査読有り］, ［国際誌］
英語, Purpose: Alpha-1 antitrypsin deficiency is associated with the development of chronic obstructive pulmonary disease (COPD), whereas increased levels of serum alpha-1antitrypsin occur in response to inflammation. The effects of alpha-1 antitrypsin levels on the clinical course of COPD had been unclear. We investigated the association of serum alpha-1 antitrypsin levels with the clinical course of COPD patients based on data from a 10-year prospective cohort study. Patients and methods: We analyzed 278 COPD patients who participated in the Hokkaido COPD cohort study and who did not meet the criteria for alpha-1 antitrypsin deficiency. We divided the subjects into 3 groups according to quartiles of serum alpha-1 antitrypsin levels at baseline: lower group (<116 mg/dL, n = 66); middle group (116 to ≤141 mg/dL, n = 145); and higher group (>141 mg/dL, n = 67). The annual change in forced expiratory volume in 1 s (FEV1) and events of COPD exacerbation were monitored during the first 5 years, and mortality was followed-up during the entire 10 years. Results: At baseline, the higher group showed lower body mass index; higher computed tomography emphysema score; lower diffusing capacity; higher levels of acute-phase proteins; and higher blood neutrophil counts. Longitudinal analyses revealed that in the higher group, the annual decline in FEV1 was rapid and the 10-year mortality was higher, but there was no association between serum alpha-1 antitrypsin levels and time to first exacerbation. Conclusion: COPD subjects with higher serum alpha-1 antitrypsin levels were associated with a worse systemic inflammation status and higher 10-year mortality.

Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family.
Shoji T, Konno S, Niida Y, Ogi T, Suzuki M, Shimizu K, Hida Y, Kaga K, Seyama K, Naka T, Matsuno Y, Nishimura M
PloS one, 14, 2, e0212370, 2019年, ［査読有り］

リンパ脈管筋腫症(LAM)を合併した乳癌に対し乳房温存術後に術後照射を施行した2例
木下 留美子, 長江 伸樹, 西岡 健太郎, 橋本 孝之, 清水 伸一, 白土 博樹, 加藤 扶美, 石田 直子, 山下 啓子, 清水 薫子, 鈴木 雅, 今野 哲
北海道外科雑誌, 63, 2, 150, 151, 北海道外科学会, 2018年12月
日本語

Impact of Abdominal Visceral Adiposity on Adult Asthma Symptoms.
Goudarzi H, Konno S, Kimura H, Makita H, Matsumoto M, Takei N, Kimura H, Shimizu K, Suzuki M, Ito YM, Nishimura M, Hi-CARAT investigators
The journal of allergy and clinical immunology. In practice, 7, 4, 1222, 1229, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous studies have shown the association of anthropometric measures with poor asthma symptoms, especially among women. However, the potential influence of visceral adiposity on asthma symptoms has not been investigated well. OBJECTIVE: In this study, we have evaluated whether visceral adiposity is related to poor adult asthma symptoms independent of anthropometric measures and sex. If this relationship presented, we investigated whether it is explained by influence on pulmonary functions and/or obesity-related comorbidities. METHODS: We analyzed data from 206 subjects with asthma from Japan. In addition to anthropometric measures (body mass index and waist circumference), abdominal visceral and subcutaneous fat were assessed by computed tomography scan. Quality of life was assessed using the Japanese version of the Asthma Quality of Life Questionnaire. RESULTS: All obesity indices had inverse association with reduced asthma quality of life among females. However, only the visceral fat area showed a statistical inverse association with Asthma Quality of Life Questionnaire in males. Only abdominal visceral fat was associated with higher gastroesophageal reflux disease and depression scores. Although all obesity indices showed inverse association with functional residual capacity, only visceral fat area had a significant inverse association with FEV1 % predicted, independent of other obesity indices. CONCLUSIONS: Regardless of sex, abdominal visceral fat was associated with reduced asthma quality of life independent of other obesity indices, and this may be explained by the impact of abdominal visceral fat on reduced FEV1 % predicted and higher risk for gastroesophageal reflux disease and depression. Therefore, visceral adiposity may have more clinical influence than any other obesity indices on asthma symptoms.

Contrasting associations of maternal smoking and pre-pregnancy BMI with wheeze and eczema in children
Houman Goudarzi, Satoshi Konno, Hirokazu Kimura, Atsuko Araki, Chihiro Miyashita, Sachiko Itoh, Yu Ait Bamai, Hiroki Kimura, Kaoruko Shimizu, Masaru Suzuki, Yoichi M. Ito, Masaharu Nishimura, Reiko Kishi
Science of the Total Environment, 639, 1601, 1609, Elsevier B.V., 2018年10月15日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Childhood allergies are dynamic and associated with environmental factors. The influence of prenatal maternal smoking and obesity on childhood allergies and their comorbidities remains unclear, especially in prospective cohorts with serial longitudinal observations. Objective: We examined time trends in the prevalence and comorbidity of childhood allergies, including wheeze, eczema, and rhinoconjunctivitis, using a large-scale, population-based birth cohort in Japan, and assessed the effects of prenatal maternal smoking and BMI on the risk of childhood allergies. Methods: Parents completed the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires about symptoms of allergies and their risk factors at age 1, 2, 4, and 7 years. Complete data from all pre- and postnatal questionnaires at age 1, 2, 4, and 7 were available for 3296 mother–child pairs. Results: We observed significant overlap of childhood allergies at 1, 2, 4, and 7 years. Maternal serum cotinine during pregnancy was associated with increased risk of wheezing in the children at age 1, 2, and 4 but disappeared at age 7. In contrast, maternal cotinine levels were inversely associated with the prevalence of eczema in children at age 7. We additionally observed that maternal pre-pregnancy BMI, not children's BMI, had a positive association with wheeze and an inverse association with eczema in 7-year-old children, respectively. We did not find any association of examined maternal factors and rhinoconjunctivitis. Conclusions: We demonstrated contrasting association of prenatal maternal smoking and high BMI with postnatal wheeze and eczema. For precise assessment of allergy-associated risk factors, we need to contrast risk factors for different allergic diseases since focusing solely on one allergic disease may result in misleading information on the role of different risk factors.

呼吸器診療に関する次世代への啓発活動の試み
清水 薫子, 長井 桂, 西村 正治, 橋本 みどり, 宮島 さつき, 佐々木 高明, 高村 圭, 岡本 佳裕, 千葉 弘文, 長内 忍, 日本呼吸器学会北海道支部将来計画委員会
日本サルコイドーシス/肉芽腫性疾患学会雑誌, 38, 1-2, 103, 103, 日本サルコイドーシス, 2018年10月
日本語

【COPD 最新の知見に基づく実地診療の進め方】治療 実地医家はどのように有効な治療を実践すべきか COPDの薬物療法 気管支拡張薬による安定期の管理
清水 薫子, 今野 哲
Medical Practice, 35, 8, 1263, 1267, (株)文光堂, 2018年08月
日本語

Transfer coefficients better reflect emphysematous changes than carbon monoxide diffusing capacity in obstructive lung diseases.
Shimizu K, Konno S, Makita H, Kimura H, Kimura H, Suzuki M, Nishimura M
Journal of applied physiology (Bethesda, Md. : 1985), 125, 1, 183, 189, 2018年07月, ［査読有り］

母親の喫煙およびBMIと小児の喘鳴および湿疹との対照的な関連性(Contrasting associations of maternal smoking and BMI with wheeze and eczema in children)
Goudarzi Houman, Konno Satoshi, Kimura Hirokazu, Araki Atsuko, Miyashita Chihiro, Itou Sachiko, Bamai Yu Ait, Kimura Hiroki, Shimizu Kaoruko, Suzuki Masaru, Ito Yoichi, Nishimura Masaharu, Kishi Reiko
アレルギー, 67, 4-5, 509, 509, (一社)日本アレルギー学会, 2018年05月
英語

Associations of Current Wheeze and Body Mass Index with Perennial and Seasonal Allergic Rhinitis in Young Adults
Munehiro Matsumoto, Satoshi Konno, Hirokazu Kimura, Nozomu Takei, Hiroki Kimura, Kaoruko Shimizu, Houman Goudarzi, Masaru Suzuki, Satoshi Hashino, Masaharu Nishimura
International Archives of Allergy and Immunology, 176, 2, 143, 149, S. Karger AG, 2018年05月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: The coexistence of asthma and allergic rhinitis (AR) and its distinct association with obesity have been reported. However, few studies have differentiated the two types of AR, i.e., perennial (PAR) and seasonal AR (SAR), with regard to their associations with asthma and obesity. The aim of this study was to evaluate the coexistence of current wheeze and two types of AR and the impact of body mass index (BMI) on these two conditions in Japanese young adults. Methods: First-year students from Hokkaido University were enrolled into this study from 2011 to 2016. A questionnaire survey including the prevalence of current wheeze, PAR, and SAR every year for 11,917 nonsmoking young adults was conducted. The difference in the impact of current wheeze and BMI on these two types of AR was separately evaluated. Results: Although both PAR and SAR were significantly associated with current wheeze, the impact of these two AR types on current wheeze was different (OR for PAR = 2.46 vs. OR for SAR = 1.29). When we classified all of the subjects into 4 groups with or/and without the two types of AR, the prevalence of current wheeze was significantly higher in subjects with PAR than in those without PAR (p <
0.001). However, the prevalence of current wheeze did not differ between subjects with or without SAR. Multinomial regression analyses showed that the association of wheeze with PAR and/or SAR was stronger compared to that of wheeze with SAR without PAR. The prevalence of PAR was not associated with BMI. Contrarily, a low BMI was significantly associated with a high SAR prevalence (p <
0.05). Conclusion: Comparisons between PAR and SAR showed that the conditions are differentially associated with current wheeze and BMI.

Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up.
Kimura H, Konno S, Makita H, Taniguchi N, Shimizu K, Suzuki M, Kimura H, Goudarzi H, Nakamaru Y, Ono J, Ohta S, Izuhara K, Ito YM, Wenzel SE, Nishimura M, Hi-CARAT investigators
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2018年05月, ［査読有り］

COPDにおけるCTパラメーターの検討 フラクタル値、Low attenuation volumeの変動に着目して
清水 薫子, Nguyen Van Tho, 鈴木 雅, 牧田 比呂仁, 木村 孔一, 木村 裕樹, 今野 哲, 小川 惠美子, 中野 恭幸, 西村 正治
日本呼吸器学会誌, 7, 増刊, 129, 129, (一社)日本呼吸器学会, 2018年03月, ［査読有り］
日本語

Relationship of annual change in bone mineral density with extent of emphysematous lesions and pulmonary function in patients with COPD
Kenichi Goto, Emiko Ogawa, Kaoruko Shimizu, Hironi Makita, Hidenobu Suzuki, Yoshiki Kawata, Noboru Niki, Masaharu Nishimura, Yasutaka Nakano
International Journal of COPD, 13, 639, 644, Dove Medical Press Ltd., 2018年02月20日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Osteoporosis is a well-known comorbidity in COPD. It is associated with poor health status and prognosis. Although the exact pathomechanisms are unclear, osteoporosis is suggested to be either a comorbidity due to shared risk factors with COPD or a systematic effect of COPD with a cause–effect relationship. This study aimed to evaluate whether progression of osteoporosis is synchronized with that of COPD. Materials and methods: Data from 103 patients with COPD included in the Hokkaido COPD cohort study were analyzed. Computed tomography (CT) attenuation values of thoracic vertebrae 4, 7, and 10 were measured using custom software, and the average value (average bone density
ABD4,7,10) was calculated. The percentage of low attenuation volume (LAV%) for each patient was also calculated for evaluation of emphysematous lesions. Annual change in thoracic vertebral CT attenuation, which is strongly correlated with dual-energy X-ray absorptiometry-measured bone mineral density, was compared with that in FEV1.0 or emphysematous lesions. Results: In the first CT data set, ABD4,7,10 was significantly correlated with age (ρ=-0.331
p=0.0006), body mass index (BMI
ρ=0.246
p=0.0136), St George’s Respiratory Questionnaire (SGRQ) activity score (ρ=-0.248
p=0.0115), eosinophil count (ρ=0.229
p=0.0198), and LAV% (ρ=-0.372
p=0.0001). However, ABD4,7,10 was not associated with FEV1.0. After adjustment for age, BMI, SGRQ activity score, and eosinophil count, no significant relationship was found between ABD4,7,10 and LAV%. Annual change in ABD4,7,10 was not associated with annual change in LAV% or FEV1.0. Conclusion: Progression of osteoporosis and that of COPD are not directly related or synchronized with each other.

Relationship of annual change in bone mineral density with extent of emphysematous lesions and pulmonary function in patients with COPD
Kenichi Goto, Emiko Ogawa, Kaoruko Shimizu, Hironi Makita, Hidenobu Suzuki, Yoshiki Kawata, Noboru Niki, Masaharu Nishimura, Yasutaka Nakano
International Journal of Chronic Obstructive Pulmonary Disease, Vol.13, 639, 644, 2018年02月20日, ［査読有り］
英語, 研究論文（学術雑誌）, Osteoporosis is a well-known comorbidity in COPD. It is associated with poor health status and prognosis. Although the exact pathomechanisms are unclear, osteoporosis is suggested to be either a comorbidity due to shared risk factors with COPD or a systematic effect of COPD with a cause-effect relationship. This study aimed to evaluate whether progression of osteoporosis is synchronized with that of COPD. Data from 103 patients with COPD included in the Hokkaido COPD cohort study were analyzed. Computed tomography (CT) attenuation values of thoracic vertebrae 4, 7, and 10 were measured using custom software, and the average value (average bone density; ABD) was calculated. The percentage of low attenuation volume (LAV%) for each patient was also calculated for evaluation of emphysematous lesions. Annual change in thoracic vertebral CT attenuation, which is strongly correlated with dual-energy X-ray absorptiometry-measured bone mineral density, was compared with that in FEV or emphysematous lesions. In the first CT data set, ABD was significantly correlated with age (=-0.331; =0.0006), body mass index (BMI; =0.246; =0.0136), St George's Respiratory Questionnaire (SGRQ) activity score (=-0.248; =0.0115), eosinophil count (=0.229; =0.0198), and LAV% (=-0.372; =0.0001). However, ABD was not associated with FEV. After adjustment for age, BMI, SGRQ activity score, and eosinophil count, no significant relationship was found between ABD and LAV%. Annual change in ABD was not associated with annual change in LAV% or FEV. Progression of osteoporosis and that of COPD are not directly related or synchronized with each other.

Distinct phenotypes of smokers with fixed airflow limitation identified by cluster analysis of severe asthma
Satoshi Konno, for the HiCARAT Investigators, Natsuko Taniguchi, Hironi Makita, Yuji Nakamaru, Kaoruko Shimizu, Noriharu Shijubo, Satoshi Fuke, Kimihiro Takeyabu, Mitsuru Oguri, Hirokazu Kimura, Yukiko Maeda, Masaru Suzuki, Katsura Nagai, Yoichi M. Ito, Sally E. Wenzel, Masaharu Nishimura, Akira Isada, Takeshi Hattori, Kenichi Shimizu, Takayuki Yoshida, Kentaro Nagaoka, Shinji Nakane, Yoshiyuki Saito, Tsukasa Sasaki, Hideko Honda, Miho Deai, Ayako Muramoto, Natsumi Kudo, Nozomi Sato, Masanobu Suzuki, Hiroshi Saito, Tetsuya Kojima, Shiho Ichimura, Takashi Choji, Motoko Kobayashi, Akihiko Ishikuro, Yoshihiro Ohtsuka, Fumihiro Honmura, Yasushi Akiyama, Toshiyuki Harada, Akira Kamimura, Norio Tashiro, Hiroshi Mikami, Mistuhide Ohmichi, Yoshitaka Sugawara, Toshiki Takahashi, Makoto Yamamoto, Kei Takamura, Yoshio Tokuchi, Yuji Inoue, Katsunori Shigehara, Hideaki Ukita, Kouki Kikuchi, Hiroyuki Koba, Kyuichirou Sekine, Tsuyoshi Nakano, Yoshihiro Ohata, Noritomo Ohnuma, Fumihiko Sato, Hiroyuki Taguchi, Hiroyuki Sugawara, Osamu Honjo, Seiya Togashi, Hirotaka Nishikiori, Junya Kitada, Masaru Fujii, Eiji Shibuya, Hiroshi Tanaka, Yoshihiro Okamoto, Hiromitu Hiroumi, Kazuhiko Watanabe
Annals of the American Thoracic Society, 15, 1, 33, 41, American Thoracic Society, 2018年01月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Rationale: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. Objectives: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. Methods: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics.Clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Results: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. Conclusions: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma.
Konno S, Taniguchi N, Makita H, Nakamaru Y, Shimizu K, Shijubo N, Fuke S, Takeyabu K, Oguri M, Kimura H, Maeda Y, Suzuki M, Nagai K, Ito YM, Wenzel SE, Nishimura M, HiCARAT Investigators ‡, HiCARAT Investigators
Annals of the American Thoracic Society, 15, 1, 33, 41, American Thoracic Society, 2018年01月, ［査読有り］

Serum periostin is associated with body mass index and allergic rhinitis in healthy and asthmatic subjects
Hirokazu Kimura, Satoshi Konno, Hironi Makita, Natsuko Taniguchi, Hiroki Kimura, Houman Goudarzi, Kaoruko Shimizu, Masaru Suzuki, Noriharu Shijubo, Katsunori Shigehara, Junya Ono, Kenji Izuhara, Yoichi Minagawa Ito, Masaharu Nishimura
Allergology International, 67, 3, 357, 363, Japanese Society of Allergology, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Many studies have attempted to clarify the factors associated with serum periostin levels in asthmatic patients. However, these results were based on studies of subjects mainly characterized by high eosinophil counts, which may present as an obstacle for clarification in the identification of other factors associated with serum periostin levels. The aim of this study was to determine the factors associated with serum periostin levels in healthy subjects. We also assessed some factors in asthmatic subjects to confirm their extrapolation for management of asthma. Methods: Serum periostin levels were measured in 230 healthy subjects. Clinical factors of interest included body mass index (BMI) and allergic rhinitis (AR). Additionally, we confirmed whether these factors were associated with serum periostin in 206 asthmatic subjects. We further evaluated several obesity-related parameters, such as abdominal fat distribution and adipocytokine levels. Results: Smoking status, blood eosinophil count, total immunoglobulin E, and the presence of AR were associated with serum periostin in healthy subjects. There was a negative association between BMI and serum periostin in both healthy and asthmatic subjects, while there was a tendency of a positive association with AR in asthmatic subjects. There were no differential associations observed for subcutaneous and abdominal fat in relation to serum periostin in asthmatic subjects. Serum periostin was significantly associated with serum levels of adiponectin, but not with leptin. Conclusions: Our results provided clarity as to the factors associated with serum periostin levels, which could be helpful in the interpretation of serum periostin levels in clinical practice.

Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis
Satoshi Konno, Masahiko Shigemura, Takahiro Ogi, Kaoruko Shimizu, Masaru Suzuki, Kichizo Kaga, Yasuhiro Hida, Yoshihiro Matsuno, Masaharu Nishimura
RESPIRATION, 95, 5, 310, 316, KARGER, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease, Objectives: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. Methods: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. Results: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19-56), and all cases were diagnosed following incidental abnormal radiographic findings. During the followup, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). Conclusions: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients With TSC. (C) 2018 S Karger AG, Basel

Performance of computed tomography-derived pulmonary vasculature metrics in the diagnosis and haemodynamic assessment of pulmonary arterial hypertension
Kaoruko Shimizu, Ichizo Tsujino, Takahiro Sato, Ayako Sugimoto, Toshitaka Nakaya, Taku Watanabe, Hiroshi Ohira, Yoichi M. Ito, Masaharu Nishimura
EUROPEAN JOURNAL OF RADIOLOGY, 96, 31, 38, ELSEVIER IRELAND LTD, 2017年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Few studies have addressed the value of combining computed tomography-derived pulmonary vasculature metrics for the diagnosis and haemodynamic evaluation of pulmonary arterial hypertension (PAH).
Materials and methods: We measured three computed tomography parameters for the pulmonary artery, peripheral vessels, and pulmonary veins: the ratio of the diameter of the pulmonary artery to the aorta (PA/Ao), the cross-sectional area of small pulmonary vessels < 5 mm(2) as a percentage of total lung area (%CSA(<5)), and the diameter of the right inferior pulmonary vein (PVD). The measured quantities were compared between patients with PAH (n = 45) and control subjects (n = 56), and their diagnostic performance and associations with PAH-related clinical indices, including right heart catheterization measurements, were examined.
Results: PA/Ao and %CSA(< 5) were significantly higher in patients with PAH than in controls. Receiver-operating characteristic curve analysis for ability to diagnose PAH showed a high area under the curve (AUC) for PA/Ao (0.95) and modest AUC5 for %CSA(< 5) (0.75) and PVD (0.56). PA/Ao correlated positively with mean pulmonary arterial pressure and PVD correlated negatively with pulmonary vascular resistance. The %CSA(<5) correlated negatively with mean pulmonary arterial pressure and pulmonary vascular resistance and positively with cardiac index. Notably, the PA/Ao and PVD values divided by %CSA(< 5) correlated better with right heart catheterization indices than the non-divided values.
Conclusion: PA/Ao, %CSA(< 5), and PVD are useful non-invasive pulmonary vasculature metrics, both alone and in combination, for diagnosis and haemodynamic assessment of PAH.

Acute bronchodilator responses to β2-agonist and anticholinergic agent in COPD: Their different associations with exacerbation.
Konno S, Makita H, Suzuki M, Shimizu K, Kimura H, Kimura H, Nishimura M, Hokkaido COPD Cohort, Study Investigators
Respiratory medicine, 127, 14, 20, W B SAUNDERS CO LTD, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Acute bronchodilator response (BDR) is a potential phenotypic characteristic of COPD. However, the clinical factors associated with BDR in patients with COPD remain unclear, particularly for BDR to anticholinergic agents.
Objectives: We aimed to clarify the clinical factors associated with BDR to beta 2-agonist and/or anticholinergic agent, considering time-associated variations of BDR. We also evaluated the association between BDR and clinical course of COPD.
Methods: We analyzed 152 subjects who participated in the Hokkaido COPD cohort study. We repeatedly measured BDR to salbutamol (400 mu g) or oxitropium (400 mu g) three times for each every 6 months alternately over 3 years. Reversibility was defined by >= 12% and >= 200 mL increase in FEV1 over baseline. All subjects were classified into three groups based on the BDR stability; consistently reversible, consistently irreversible, and inconsistent. We compared baseline clinical characteristics and the 5-year clinical course of COPD among the three groups.
Results: For either agent, the mean blood eosinophil count was significantly higher in those with consistently reversible than those with consistently irreversible (p < 0.05). The subjects with consistently reversible to oxitropium (p < 0.05), but not to salbutamol (p = 0.56), showed increased risk of exacerbation compared with the other two groups.
Conclusion: We identified the distinct clinical characteristics of COPD associated with acute BDR status. Increased cholinergic airway tone, which is reflected in the higher BDR only to anticholinergic agent, but not to beta 2-agonist, may be associated with exacerbation in COPD. (C) 2017 Elsevier Ltd. All rights reserved.

肥満の重症喘息患者におけるclub cell 16-kDa分泌タンパク質(CC16)とCCケモカインリガンド18(CCL18)の重要な役割(Potential roles of club cell 16-kDa secretory protein(CC16) and CC chemokine ligand 18(CCL18) in obese severe asthmatic patients)
Goudarzi Houman, Konno Satoshi, Makita Hironi, Kimura Hirokazu, Kimura Hiroki, Shimizu Kaoruko, Suzuki Masaru, Nishimura Masaharu
アレルギー, 66, 4-5, 502, 502, (一社)日本アレルギー学会, 2017年05月
英語

重症喘息患者において次世代シークエンス分析により検出された血中エキソソーム性RNA組成の変化(Altered circulating exosomal RNA profiles detected by next-generation sequencing in patients with severe asthma)
Suzuki Masaru, Konno Satoshi, Makita Hironi, Shimizu Kaoruko, Kimura Hiroki, Kimura Hirokazu, Nishimura Masaharu
日本呼吸器学会誌, 6, 増刊, 339, 339, (一社)日本呼吸器学会, 2017年03月
英語

COPD患者における肺癌の発症率と臨床的特徴 北海道COPD集団研究の結果(Incidence and Clinical Characteristics of Lung Cancer in Patients with COPD: from Hokkaido COPD Cohort Study)　　　　　　　　　　　　　　　
Suzuki Masaru, Makita Hironi, Konno Satoshi, Shimizu Kaoruko, Kimura Hiroki, Kimura Hirokazu, Nishimura Masaharu
日本呼吸器学会誌, 6, 増刊, 349, 349, (一社)日本呼吸器学会, 2017年03月
英語

Sinus Computed Tomographic Findings in Adult Smokers and Nonsmokers with Asthma. Analysis of Clinical Indices and Biomarkers.
Hirokazu Kimura, Satoshi Konno, Yuji Nakamaru, Hironi Makita, Natsuko Taniguchi, Kaoruko Shimizu, Masaru Suzuki, Junya Ono, Shoichiro Ohta, Kenji Izuhara, Masaharu Nishimura
Annals of the American Thoracic Society, 14, 3, 332, 341, 2017年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, RATIONALE: When they occur together, sinusitis and asthma are often thought to represent anatomically separate components of the same chronic inflammatory airway disease. Information about the effect of smoking on the interaction between sinusitis and asthma in patients who have both disorders is limited. OBJECTIVES: To evaluate the effect of cigarette smoking on the relationship between the presence and severity of sinusitis and selected asthma-related indices in adults who have asthma. METHODS: This study included 127 patients with severe asthma and 79 patients with mild to moderate asthma. Clinical data were obtained from all subjects during a 2-day stay at Hokkaido University Hospital (Sapporo, Japan). The Lund-Mackay scoring system was used to assess the anatomic extent and severity of sinusitis as revealed by sinus computed tomographic (CT) images obtained during hospitalization. We examined associations between Lund-Mackay scores and a variety of asthma-related indices and levels of biomarkers in blood and sputum. To clarify the effect of smoking on these associations, we conducted separate analyses for nonsmoking (<10 pack-years; n = 130) and smoking subjects (≥10 pack-years; n = 76). MEASUREMENTS AND MAIN RESULTS: In our cohort of adults with asthma, we found significant positive relationships between the presence and severity of sinusitis as assessed by Lund-Mackay score and the severity of asthma as measured by percent predicted FEV1 or FEV1/FVC for nonsmoking subjects (<10 pack-years) but not for cigarette smokers (>10 pack-years). Lund-Mackay scores correlated with blood and sputum eosinophil counts, serum IgE levels, and fractional exhaled nitric oxide, regardless of smoking status. Lund-Mackay scores also showed significant positive associations with serum periostin and chemokine C-C motif ligand 18 levels, regardless of smoking status, whereas a positive association with plasma osteopontin level was seen only for nonsmoking subjects. CONCLUSIONS: We found an association between the severity of sinusitis on CT imaging and the severity of concomitant asthma on spirometry for nonsmoking adults but not for smokers. In adults with asthma, CT imaging evidence of severe sinusitis indicates intense Th2-related inflammation, regardless of smoking status.

Asthma-like Features and Clinical Course of Chronic Obstructive Pulmonary Disease An Analysis from the Hokkaido COPD Cohort Study
Masaru Suzuki, Hironi Makita, Satoshi Konno, Kaoruko Shimizu, Hiroki Kimura, Hirokazu Kimura, Masaharu Nishimura
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 194, 11, 1358, 1365, AMER THORACIC SOC, 2016年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Rationale: Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features, such as significant bronchodilator reversibility, blood eosinophilia, and/or atopy, even if they are not clinically diagnosed as having asthma. However, the clinical significance of asthma-like features overlapping with COPD remains unclear.
Objectives: The aim of this study was to assess the effect of asthma like features on the clinical course of patients with COPD who were adequately treated and followed-up over 10 years.
Methods: A total of 268 patients with COPD who had been clinically considered as not having asthma by respiratory specialists were included in this study. The asthma-like features included in this study were bronchodilator reversibility (Delta FEV1, >= 12% and >= 200 ml), blood eosinophilia (>= 300 cells/mu l), and atopy (positive specific IgE for any inhaled antigen). The annual changes in post-bronchodilator FEV1 and COPD exacerbations were monitored during the first 5 years, and mortality was followed during the entire 10 years of the study.
Measurements and Main Results: Fifty-seven subjects (21%) had bronchodilator reversibility, 52 (19%) had blood eosinophilia, and 67 (25%) had atopy. Subjects with blood eosinophilia had significantly slower annual post-bronchodilator FEV1 decline; bronchodilator reversibility and atopy did not affect the annual post-bronchodilator FEV1 decline, and none of the asthma-like features was associated with development of COPD exacerbation. Even if subjects had two or more asthma-like features, they displayed annual post-bronchodilator FEV1 declines and exacerbation rates similar to those of subjects with one or zero asthma-like features, as well as a lower 10-year mortality rate (P = 0.02).
Conclusions: The presence of asthma-like features was associated with better clinical course in patients with COPD receiving appropriate treatment.

喘息患者におけるサルメテロールとモンテルカストの有効性の差に影響するロイコトリエン関連遺伝因子の検討
山田 英恵, 増子 裕典, 乾 年秀, 金澤 潤, 谷田貝 洋平, 坂本 透, 飯島 弘晃, 今野 哲, 清水 薫子, 牧田 比呂仁, 西村 正治, 國分 二三男, 斎藤 武文, 遠藤 健夫, 二宮 浩樹, 金子 教宏, 檜澤 伸之
アレルギー, 65, 9, 1201, 1208, (一社)日本アレルギー学会, 2016年11月
日本語, 【背景・目的】我々の過去の検討において,中等症持続型喘息患者を対象に吸入ステロイド(ICS)に長時間作用性吸入β2刺激薬(LABA,サルメテロール)またはロイコトリエン受容体拮抗薬(LTRA,モンテルカスト)を追加投与したところ,LABAと比較してLTRAでより大きな気管支拡張効果が得られる患者群が存在し,LABAとLTRAとの薬剤反応性に大きな個体差が認められた.一方,β2受容体遺伝子(ADRB2)におけるGly16Arg多型とLABAとLTRAとの治療効果の差に関連はなかった.本研究ではロイコトリエン受容体遺伝子(CYSLTR1,CYSLTR2)及びプロスタグランジンE2受容体遺伝子(PTGER2,PTGER4)がLABAとLTRAとの治療効果の差に及ぼす遺伝的影響を検討した.【方法】対象はADRB2 Gly16Arg遺伝子型がArg/ArgまたはGly/Glyの成人喘息患者(76名).ロイコトリエン受容体遺伝子(CYSLTR1,2)及びプロスタグランジンE2受容体遺伝子(PTGER2,4)において,それぞれrs321029,rs912278,rs1254600,rs4133101の遺伝子型を決定.ICSにLABAまたはLTRAを16週間追加投与したことによるピークフロー(PF)の改善の差とこれらの遺伝子型との関連を検討した.さらに各ロイコトリエン関連遺伝子とADRB2 Gly16Argとの交互作用についても検討した.【結果】PTGER4遺伝子はLABAとLTRAとによるPFの改善の差に有意に関連した(p=0.0032,rs4133101).さらに,PTGER4遺伝子とADRB2遺伝子との間に有意な交互作用が認められた(p=0.010).【結語】PTGER4遺伝子は喘息患者において,ICSに追加投与したLABAとLTRAとの治療効果の差やADRB2 Arg16Gly多型の遺伝的効果に影響を与えている可能性がある.(著者抄録)

Computed tomography (CT)-assessed bronchodilation induced by inhaled indacaterol and glycopyrronium/indacaterol in COPD
Kaoruko Shimizu, Ruriko Seto, Hironi Makita, Masaru Suzuki, Satoshi Konno, Yoichi M. Ito, Rie Kanda, Emiko Ogawa, Yasutaka Nakano, Masaharu Nishimura
RESPIRATORY MEDICINE, 119, 70, 77, W B SAUNDERS CO LTD, 2016年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Our previous studies suggested that the site of bronchodilation on CT might differ between inhaled beta 2 agonists and inhaled anticholinergics in COPD.
Aim: To assess and compare the bronchodilation effects of inhaled indacaterol and glycopyrronium/indacaterol by airway generation in large airways using CT.
Methods: CT scans at full inspiration and pulmonary function tests were done in 25 patients with moderate-severe COPD before and 4-5 weeks after daily inhalation of indacaterol and again another 4-5 weeks after inhalation of glycopyrronium/indacaterol. Airway inner luminal area (Ai) at the 3rd (segmental) to 6th generation of 8 selected bronchi, a total of 32 sites, in the right lung was analyzed on 3 occasions. Our proprietary software enables us to select the same airways and the same measurement sites for comparison, with simultaneous confirmation using two screens on the computer.
Results: The overall increase of Ai (Delta Ai, %) averaged at all 32 measurement sites induced by glycopyrronium/indacaterol had a significant correlation with FEV1 improvement (r = 0.7466, p < 0.0001). Both Delta Ai, % with indacaterol and Delta Ai, % with additional glycopyrronium were significant at the 3rd to 6th generations. Remarkable increases in Delta Ai, % were found at the 5th and 6th generations in several subjects with indacaterol or additional glycopyrronium. There were no significant site-differences in the bronchodilation pattern caused by indacaterol and by glycopyrronium/indacaterol at any of the 3rd to 6th generations.
Conclusions: Additional bronchodilation with glycopyrronium was demonstrated by CT at the 3rd to 6th generations, with no site-specific differences in bronchodilation between indacaterol and glycopyrronium/indacaterol. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) system (http://www.umin.ac.jp/. ID. UMIN000012043). (C) 2016 Elsevier Ltd. All rights reserved.

抗コリン作動薬に対する気管支拡張反応はCOPD患者の悪化率と関連している(Bronchodilator response to anticholinergic agents is associated with exacerbation rate in patients with COPD)　　　　　　　　　　　　　　　
Konno Satoshi, Makita Hironi, Suzuki Masaru, Shimizu Kaoruko, Kimura Hiroki, Kimura Hirokazu, Nishimura Masaharu
日本呼吸器学会誌, 5, 増刊, 375, 375, (一社)日本呼吸器学会, 2016年03月
英語

COPDにおける喘息様の特徴と臨床経過 北海道COPD集団研究からのデータの分析(Asthma-like Features and Clinical Course in COPD: an Analysis from the Hokkaido COPD Cohort Study)
Suzuki Masaru, Makita Hironi, Konno Satoshi, Shimizu Kaoruko, Kimura Hiroki, Kimura Hirokazu, Nishimura Masaharu
日本呼吸器学会誌, 5, 増刊, 375, 375, (一社)日本呼吸器学会, 2016年03月
英語

Genetic interactions between ADRB2 and PTGER4 on responses to salmeterol or montelukast in Japanese patients with mild persistent asthma
Hideyasu Yamada, Hironon Masuko, Toshihide Inui, Jun Kanazawa, Yohei Yatagai, Tohru Sakamoto, Hiroaki Iijima, Satoshi Konno, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Fumio Kokubu, Takefumi Saito, Takeo Endo, Hiroki Ninomiya, Norihiro Kaneko, Nobuyuki Hizawa
Japanese Journal of Allergology, 65, 9, 1201, 1208, Japanese Society of Allergology, 2016年, ［査読有り］
日本語, 研究論文（学術雑誌）, Background: Long-acting β2-agomsts (LABA) and leukotnene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the β2-adrenergic receptor (ADRB2) gene did not influence the differential bronchodilator effect of salmeterol versus montelukast as an add-on therapy to ICS within 16 weeks of follow-up (the J-Blossom study). Methods: We examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast usmg the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/mm) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes. Results: Although none of 4 genes were associated with ΔPEFsal - ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Glyl6Arg, was associated with ΔPEFsal - ΔPEFmon (p=0.0032). Conclusion: Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chrome adult asthma.

Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma.
Konno S, Taniguchi N, Makita H, Nakamaru Y, Shimizu K, Shijubo N, Fuke S, Takeyabu K, Oguri M, Kimura H, Maeda Y, Suzuki M, Nagai K, Ito YM, Wenzel SE, Nishimura M, Hi-CARAT Investigators
Annals of the American Thoracic Society, 12, 12, 1771, 1780, 2015年12月, ［査読有り］

【アレルギー疾患の疫学】成人喘息とアレルギー性鼻炎の疫学調査 北海道上士幌町における検討　　　　　　　　　　　　　　　
清水 薫子, 今野 哲
アレルギーの臨床, 35, 11, 1047, 1050, (株)北隆館, 2015年10月
日本語, 北海道上士幌町において2006年(3,096名)と2011年(1,472名)にEuropean Community Respiratory Health Survey日本語版によるアンケート調査を行った。肥満、及び1年以上の喫煙歴と過去12ヵ月の喘鳴の有無(喘息期間有症率)に有意な関連が認められ、上士幌町のような非都市部においては、喘息発症に対する喫煙の影響がより明瞭となる可能性も考えられた。2006年と2011年の結果との比較では、医師の診断がある喘息、アレルギー性鼻炎は増加を認める一方、喘息期間有症率は減少し、ガイドラインの普及に伴う適切な加療による変化が予想された。(著者抄録)

Regional bronchodilator response assessed by computed tomography in chronic obstructive pulmonary disease
Kaoruko Shimizu, Hironi Makita, Masaru Hasegawa, Hirokazu Kimura, Satoshi Fuke, Katsura Nagai, Takayuki Yoshida, Masaru Suzuki, Satoshi Konno, Yoichi M. Ito, Masaharu Nishimura
EUROPEAN JOURNAL OF RADIOLOGY, 84, 6, 1196, 1201, ELSEVIER IRELAND LTD, 2015年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background and objective: The reliability of CT assessment of regional bronchodilation is not universally accepted. In this study, using our proprietary 3D-CT software, we first examined airway inner luminal area (Ai) before and after inhalation of SFC in a group of COPD patients and then evaluated the same parameters for two sets of CT data obtained from clinically stable subjects with no intervention.
Methods: We conducted CT at deep inspiration and pulmonary function tests before and one week after inhalation of SFC in 23 COPD patients. As a non-intervention group, we used two sets of CT data obtained with one-year interval in another group of subjects who demonstrated stable pulmonary function (n=8). We measured Ai at the mid-portions of 3rd to 6th generation in 8 bronchi of the right lung, a total of 32 identical sites before and after intervention.
Results: The average bronchodilation at all sites (Delta Ai%: 28.2 + 4.1 (SE)%) (r= 0.65, p < 0.001) and that of each generation significantly correlated with % improvement of FEV1 (Delta FEV1%), which increased from 1.40 +/- 0.10L to 1.58 +/- 0.10L. When subjects were classified into two groups in terms of mean Delta FEV1%, even the poor responders (Delta FEV1% <14% above baseline, n=13) displayed significantly larger Delta Ai% compared with the non-intervention group (19.1 +/- 4.6% versus 2.1 +/- 3.9%). Inter-observer variability for overall AAi% was within acceptable levels.
Conclusions: CT can reliably detect the regional bronchodilation in 3rd to 6th generation airways when Delta FEV1 is as small as 180 ml on average. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) system (http://www.umin.ac.jp/No. UMIN 000002668). (C) 2015 Elsevier Ireland Ltd. All rights reserved.

各種感染症抗体価の年齢別陽性率、及びアトピー素因、気管支喘息、アレルギー性鼻炎との関連 北海道上士幌住民における検討
伊佐田 朗, 今野 哲, 服部 健史, 清水 薫子, 清水 健一, 谷口 菜津子, 檜澤 伸之, 西村 正治
日本職業・環境アレルギー学会雑誌, 22, 2, 65, 72, 日本職業・環境アレルギー学会, 2015年05月
日本語, [背景・目的]近年の種々のアレルギー疾患の頻度を、衛生環境の改善や少子化にともなう乳幼児期の感染症リスクの低下が原因とする、いわゆる衛生仮説が提唱されている。これまで欧米を中心とした検討が多く報告されているが、本邦においては、ヘリコバクターピロリ抗体価とアレルギー疾患との関連性を示す報告があるものの、他の感染症抗体価との関連を検討した報告はない。[方法]平成18年、19年に、北海道上士幌町住民288人を対象に、アレルギー疾患に対する問診、特異的IgE抗体の測定、及び血清中のA型肝炎ウイルス(HAV)、ヘリコバクターピロリ(HP)、クラミドフィラニューモニア(CP)、単純ヘルペスウイルス1(HSV)、サイトメガロウイルス(CMV)のIgG抗体価を測定した。各種抗体陽性率とアトピー素因、気管支喘息、アレルギー性鼻炎との関連を検討した。[結果]各種感染症抗体陽性率は、高齢になるほどその上昇を認めた(CP;P=0.076 他P<0.05)。いっぽう、アトピー素因及びアレルギー性鼻炎の頻度は高齢になるほど減少していた(P<0.05)。全対象を20-39歳、40-59歳、60-79歳と層別化し、各種抗体価とアトピー素因、気管支喘息、アレルギー性鼻炎との関連を検討したが、一部の年齢層において、HAVと気管支喘息、CPとアレルギー性鼻炎との関連を認めたが、他の年齢層、抗体価においては、明らかな関連性を認めなかった。[結語]北海道上士幌住民における、各年齢層における各種感染症抗体陽性率が示された。本検討では、各種感染症抗体価とアトピー素因、気管支喘息、アレルギー性鼻炎との関連は示されなかった。(著者抄録)

Differential changes in quality of life components over 5 years in chronic obstructive pulmonary disease patients
Katsura Nagai, Hironi Makita, Masaru Suzuki, Kaoruko Shimizu, Satoshi Konno, Yoichi M Ito, Masaharu Nishimura, On behalf of the Hokkaido COPD Cohort Study Investigators, Yoshikazu Kawakami, Youichi Nishiura, Hiroshi Saito, Tetsuya Kojima, Takeshi Igarashi, Kiyonobu Kimura, Ikuo Nakano, Moto Katabami, Kouichi Itabashi, Kiyoshi Morikawa, Seiichi Tagami, Yoshihiro Otsuka, Rika Sato, Junichiro Kojima, Shinji Nigawara, Takashi Morioka, Ichiro Sakai, Hiroshi Yamamoto, Shigeaki Ogura, Kenji Akie, Fumihiro Honmura, Shinichi Kusudou, Hiroshi Izumi, Kensuke Baba, Hiroki Goya, Tsuyoshi Nakano, Kimihiro Takeyabu, Yasushi Akiyama, Fujiya Kishi, Akihide Ito, Michihiro Fujino, Masashi Ohe, Toshiyuki Harada, Akira Kamimura, Nobuyuki Hakuma, Noriaki Sukou, Kazuo Takaoka, Isamu Doi, Atsushi Ishimine, Ryouji Nakano, Yasushi Hasegawa, Yasuyuki Nasuhara, Tomoko Betsuyaku, Kunio Hamada, Yoko Ito, Motoko Kobayashi, Takeshi Hosokawa, Satoshi Fuke, Masaru Hasegawa, Nao Odajima, Chinatsu Moriyama, Takayuki Yoshida, Takashi Inomata, Kanako Maki, Eiji Shibuya, Tsukasa Sasaki, Katsuaki Nitta, Masafumi Yamamoto, Shigetaka Mizuno, Kenji Miyamoto, Nobuyuki Hizawa
International Journal of COPD, 10, 745, 757, Dove Medical Press Ltd., 2015年04月13日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: The aim of the study was to examine the longitudinal change in quality of life components of patients with chronic obstructive pulmonary disease (COPD). Methods: In the Hokkaido COPD Cohort Study, 261 subjects were appropriately treated and followed over 5 years with a 74% follow-up rate at the end. The longitudinal changes in St George’s Respiratory Questionnaire (SGRQ) scores were annually evaluated with forced expiratory volume in 1 second (FEV1). The subjects were classified into the rapid decliners, slow decliners, and sustainers based on ΔFEV1/year. Results: The activity component of SGRQ generally deteriorated over time, and its annual decline was the greatest in the rapid decliners (<
25th percentile). In contrast, the symptom component improved significantly year by year in the sustainers (>
75 percentile), and it did not deteriorate even in the rapid decliners. Of the baseline data, predictors for worsening of the activity component were older age and lower body mass index. Larger reversibility was related to symptom component improvement. Of the follow-up data, ΔFEV1/year was the best predictor for worsening of the components of SGRQ. Continuous smoking was another factor for worsening of the activity component. For the symptom component, a history of exacerbation by admission definition was the determinant of its deterioration, whereas use of beta agonists was related to improvement. Conclusion: The longitudinal changes of quality of life and their determinants are markedly different and independent between its components. The activity component of SGRQ generally deteriorated over years, while the symptom component rather improved in some patients with COPD under appropriate treatment.

Differential changes in quality of life components over 5 years in chronic obstructive pulmonary disease patients
Katsura Nagai, Hironi Makita, Masaru Suzuki, Kaoruko Shimizu, Satoshi Konno, Yoichi M. Ito, Masaharu Nishimura
INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, 10, 745, 757, DOVE MEDICAL PRESS LTD, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: The aim of the study was to examine the longitudinal change in quality of life components of patients with chronic obstructive pulmonary disease (COPD).
Methods: In the Hokkaido COPD Cohort Study, 261 subjects were appropriately treated and followed over 5 years with a 74% follow-up rate at the end. The longitudinal changes in St George's Respiratory Questionnaire (SGRQ) scores were annually evaluated with forced expiratory volume in 1 second (FEV1). The subjects were classified into the rapid decliners, slow decliners, and sustainers based on Delta FEV1/year.
Results: The activity component of SGRQ generally deteriorated over time, and its annual decline was the greatest in the rapid decliners (<25th percentile). In contrast, the symptom component improved significantly year by year in the sustainers (>75 percentile), and it did not deteriorate even in the rapid decliners. Of the baseline data, predictors for worsening of the activity component were older age and lower body mass index. Larger reversibility was related to symptom component improvement. Of the follow-up data, Delta FEV1/year was the best predictor for worsening of the components of SGRQ. Continuous smoking was another factor for worsening of the activity component. For the symptom component, a history of exacerbation by admission definition was the determinant of its deterioration, whereas use of beta agonists was related to improvement.
Conclusion: The longitudinal changes of quality of life and their determinants are markedly different and independent between its components. The activity component of SGRQ generally deteriorated over years, while the symptom component rather improved in some patients with COPD under appropriate treatment.

Lower leptin/adiponectin ratio and risk of rapid lung function decline in chronic obstructive pulmonary disease
Masaru Suzuki, Hironi Makita, Jörgen Östling, Laura H. Thomsen, Satoshi Konno, Katsura Nagai, Kaoruko Shimizu, Jesper H. Pedersen, Haseem Ashraf, Piet L. B. Bruijnzeel, Rose A. Maciewicz, Masaharu Nishimura
Annals of the American Thoracic Society, 11, 10, 1511, 1519, American Thoracic Society, 2014年12月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Methods: Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the results were validated using data of 226 subjects with and 268 subjects without airflow limitation, mainly white, from the 4-year COPD Quantification by Computed Tomography, Biomarkers, and Quality of Life (CBQ) study conducted in Denmark. The plasma samples were measured using Human CardiovascularMAP (Myriad RBM, Austin, TX), which could analyze 50 biomarkers potentially linked with inflammatory, metabolic, and tissue remodeling pathways, and single ELISAs were used to confirm the results.
Measurements and Main Results: Higher plasma adiponectin levels and a lower leptin/adiponectin ratio at enrollment were significantly associated with an annual decline in FEV1 even after controlling for age, sex, height, and body mass index in the Hokkaido COPD cohort study (P = 0.003, P = 0.004, respectively). A lower plasma leptin/adiponectin ratio was also significantly associated with an annual decline in FEV<
inf>
1<
/inf>
in subjects with airflow limitation in the CBQ study (P = 0.014), the patients of which had largely different clinical characteristics compared with the Hokkaido COPD cohort study. There were no significant associations between lung function decline and adipokine levels in subjects without airflow limitation.
Conclusions: A lower leptin/adiponectin ratio was associated with lung function decline in patients with COPD in two independent Japanese and Western cohort studies of populations of different ethnicity. Measure of systemic adipokines may provide utility in predicting patients with COPD at higher risk of lung function decline.
Rationale: The rate of annual change in FEV<
inf>
1<
/inf>
is highly variable among patients with chronic obstructive pulmonary disease (COPD). Reliable blood biomarkers are needed to predict prognosis.
Objectives: To explore plasma biomarkers associated with an annual change in FEV<
inf>
1<
/inf>
in patients with COPD.

Lower leptin/adiponectin ratio and risk of rapid lung function decline in chronic obstructive pulmonary disease.
Suzuki M, Makita H, Östling J, Thomsen LH, Konno S, Nagai K, Shimizu K, Pedersen JH, Ashraf H, Bruijnzeel PL, Maciewicz RA, Nishimura M, Hokkaido COPD Cohort Study, Danish Lung Cancer Screening Trial Investigators
Annals of the American Thoracic Society, 11, 10, 1511, 1519, 2014年12月, ［査読有り］

Association of the CAT-262C > T polymorphism with asthma in smokers and the nonemphysematous phenotype of chronic obstructive pulmonary disease
Natsuko Taniguchi, Satoshi Konno, Akira Isada, Takeshi Hattori, Hirokazu Kimura, Kaoruko Shimizu, Yukiko Maeda, Hironi Makita, Nobuyuki Hizawa, Masaharu Nishimura
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 113, 1, 31, +, ELSEVIER SCIENCE INC, 2014年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Catalase (CAT) is a part of the active antioxidant defense system and has been studied with regard to its association with asthma and chronic obstructive pulmonary disease (COPD), which are heterogeneous obstructive pulmonary diseases characterized by chronic airway inflammation. We hypothesized that the CAT gene might be involved in the common pathogenesis underlying asthma and COPD.
Objective: To evaluate the association of CAT polymorphisms with specific phenotypes of asthma and COPD to identify the common underlying pathophysiologic mechanisms of these 2 diseases.
Methods: The -262C> T and -21A> T polymorphisms in the CAT gene were genotyped in 493 individuals with asthma, 265 with COPD, and 1,076 healthy controls. Asthmatic patients were categorized according to smoking status (smokers and nonsmokers) and age at onset (early onset and adult onset) as part of a casecontrol study. In patients with COPD, visual scoring (computed tomographic score) was assessed to determine emphysema severity, which was used to evaluate associations with CAT gene polymorphisms.
Results: Overall, the -262C> T and -21A> T polymorphisms were not associated with asthma. However, the -262CT+TT genotype was significantly associated with adult-onset asthma in smokers (P = .005), and a significant interaction between smoking status and the effect of -262C> T genotype on asthma were observed (P = .01). In patients with COPD, this genotype was significantly associated with a low computed tomographic score (P = .03), which indicates a nonemphysematous type of COPD.
Conclusion: The present study indicates that the CAT gene is involved in the common pathogenesis underlying adult-onset asthma in smokers and the nonemphysematous type of COPD. (C) 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The effects of a Gly16Arg ADRB2 polymorphism on responses to salmeterol or montelukast in Japanese patients with mild persistent asthma
Satoshi Konno, Nobuyuki Hizawa, Hironi Makita, Kaoruko Shimizu, Tohru Sakamoto, Fumio Kokubu, Takefumi Saito, Takeo Endo, Hiroki Ninomiya, Hiroaki Iijima, Norihiro Kaneko, Yoichi M. Ito, Masaharu Nishimura
PHARMACOGENETICS AND GENOMICS, 24, 5, 246, 255, LIPPINCOTT WILLIAMS & WILKINS, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Background
Long-acting beta 2-agonists and leukotriene receptor antagonists are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. The Gly16Arg genotype of the beta 2-adrenergic receptor (ADRB2) gene may influence the bronchodilator effects of beta 2-agonists. We hypothesized that differential responses to long-acting beta 2-agonists or leukotriene receptor antagonists might be determined partly by the Gly16Arg polymorphism in Japanese asthma patients.
Materials and methods
This randomized, genotype-stratified, two-period crossover study included 80 patients with mild-to-moderate asthma (35 Arg/Arg and 45 Gly/Gly individuals). The primary study outcome was the difference in peak expiratory flow (Delta PEF) (Delta PEF, l/min) by genotype after 16 weeks of treatment with salmeterol (Delta PEFsal) or montelukast (Delta PEFmon). In addition, multivariate analyses were used to identify independent factors that were predictive of responses to each treatment.
Results
The mean Delta PEFsal-Delta PEFmon was 19.3 +/- 46.6 among Arg/Arg individuals and 16.8 +/- 51.5 among Gly/Gly individuals, indicating that the Gly16Arg genotype did not influence the differential bronchodilator effect of the two agents. Multivariate analysis showed that higher peripheral eosinophil counts were associated with better response to salmeterol (P < 0.05).
Conclusion
The Gly16Arg genotype did not influence the differential bronchodilator effect of salmeterol or montelukast as an add-on therapy to ICS within 16 weeks of follow-up. Higher peripheral eosinophil counts may be associated with better responses to salmeterol in combination with ICS.

北海道上士幌町における成人喘息,アレルギー性鼻炎有病率の検討 : 2006年, 2011年の比較(成人喘息 病態,口演20,第26回日本アレルギー学会春季臨床大会)
清水, 薫子, 今野, 哲, 谷口, 菜津子, 西村, 正治, 檜澤, 伸之, 谷口, 正実, 赤澤, 晃
アレルギー, 63, 3, 577, 577, 一般社団法人日本アレルギー学会, 2014年04月
日本語, 研究論文（学術雑誌）

Effect of Lung Volume on Airway Luminal Area Assessed by Computed Tomography in Chronic Obstructive Pulmonary Disease
Kenta Kambara, Kaoruko Shimizu, Hironi Makita, Masaru Hasegawa, Katsura Nagai, Satoshi Konno, Masaharu Nishimura
PLOS ONE, 9, 2, e90040, PUBLIC LIBRARY SCIENCE, 2014年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Although airway luminal area (Ai) is affected by lung volume (LV), how is not precisely understood. We hypothesized that the effect of LV on Ai would differ by airway generation, lung lobe, and chronic obstructive pulmonary disease (COPD) severity.
Methods: Sixty-seven subjects (15 at risk, 18, 20, and 14 for COPD stages 1, 2, and 3) underwent pulmonary function tests and computed tomography scans at full inspiration and expiration (at functional residual capacity). LV and eight selected identical airways were measured in the right lung. Ai was measured at the mid-portion of the 3rd, the segmental bronchus, to 6th generation of the airways, leading to 32 measurements per subject.
Results: The ratio of expiratory to inspiratory LV (LV E/I ratio) and Ai (Ai E/I ratio) was defined for evaluation of changes. The LV E/I ratio increased as COPD severity progressed. As the LV E/I ratio was smaller, the Ai E/I ratio was smaller at any generation among the subjects. Overall, the Ai E/I ratios were significantly smaller at the 5th (61.5%) and 6th generations (63.4%) and than at the 3rd generation (73.6%, p<0.001 for each), and also significantly lower in the lower lobe than in the upper or middle lobe (p<0.001 for each). And, the Ai E/I ratio decreased as COPD severity progressed only when the ratio was corrected by the LV E/I ratio (at risk v.s. stage3 p<0.001, stage1 v.s. stage3 p<0.05).
Conclusions: From full inspiration to expiration, the airway luminal area shrinks more at the distal airways compared with the proximal airways and in the lower lobe compared with the other lobes. Generally, the airways shrink more as COPD severity progresses, but this phenomenon becomes apparent only when lung volume change from inspiration to expiration is taken into account.

MS2-7 クラスター解析による難治性喘息病型分類及び喀痰中サイトカインの検討 : 北海道難治性喘息コホート研究(MS2 成人喘息の病態,ミニシンポジウム,第26回日本アレルギー学会春季臨床大会)
谷口 菜津子, 今野 哲, 清水 薫子, 牧田 比呂仁, 西村 正治, HiCARAT研究グループ
アレルギー, 63, 3, 504, 504, 一般社団法人 日本アレルギー学会, 2014年
日本語

Prevalence of adult asthma and allergic rhinitis in kamishihoro, hokkaido -Trends from 2006 through 2011-
Kaoruko Shimizu, Satoshi Konno, Hirokazu Kimura, Takahiro Ogi, Natsuko Taniguchi, Kenichi Shimizu, Akira Isada, Takeshi Hattori, Nobuyuki Hizawa, Masami Taniguchi, Akira Akazawa, Masaharu Nishimura
Japanese Journal of Allergology, 63, 7, 928, 937, Japanese Society of Allergology, 2014年, ［査読有り］
日本語, 研究論文（学術雑誌）, Purpose: To investigate changes in the prevalence of adult asthma and allergic rhinitis from 2006 to 2011 in Kamishihoro, a town in Hokkaido, Japan.
Methods: The Japanese edition of the European Community Respiratory Health Survey questionnaire was completed by 1472 residents aged from 20 to 81 years old. (718 men, 749 women). The age and gender distribution of respondents matched that of respondents in 2006.
Results: Response rates were 98.1% in 2011 and 95.8% in 2006. Wheezing in the last 12 months was reported by 10.7% of men and 8.3% of women in 2011, compared to 12.9% and 9.8%, respectively, in 2006. The questions "Have you ever had asthma?" followed by "Was this confirmed by a doctor?" both received positive answers from 7.9% of men and 7.5% of women in 2011, compared to 5.7% and 6.3%, respectively, in 2006. The rate of current smoking was 34.8% in men and 14.7% in women in 2011, compared to 42.8% and 17.2%, respectively, in 2006. A "Yes" answer to the questionnaire item, "Do you have any nasal allergies, including hay fever?" (defining allergic rhinitis) was given by 23.2% of men and 25.4% of women in 2011, compared to 17.6% and 23.0%, respectively, in 2006. The prevalence of allergic rhinitis was increased, particularly among younger respondents.
Conclusion: Rates of current asthma and allergic rhinitis increased, whereas the rate of wheezing in the past 12 months decreased from 2006 to 2011. Optimal treatment of asthma might be related to these trends.

Anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion: A case report
Tomoe Abe, Masaru Suzuki, Kaoruko Shimizu, Naofumi Shinagawa, Satoshi Oizumi, Yoshihiro Matsuno, Masaya Miyazaki, Mishie Tanino, Shinya Tanaka, Masaharu Nishimura
Journal of Medical Case Reports, 8, 1, 460, BioMed Central Ltd., 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Anaplastic transformation of well-differentiated papillary thyroid carcinoma at distant metastasis sites is rare. To the best of our knowledge, this is the first report of an autopsy case of anaplastic transformation of papillary thyroid carcinoma in multiple lung metastases presenting with a malignant pleural effusion. Case presentation: We report an autopsy case of a 61-year-old Japanese man with anaplastic transformation of papillary thyroid carcinoma with multiple lung metastases presenting with a malignant pleural effusion, which was difficult to diagnose by cytological examination before the autopsy. He presented with a 1-month history of progressive dyspnea, and examination of the left pleural effusion revealed a bloody exudate with an increase in thyroglobulin
however, malignant cells in the pleural fluid were negative for thyroglobulin. Conclusion: It is important to be aware that anaplastic transformation of differentiated thyroid carcinoma could develop in lung metastases and could be a cause of a malignant pleural effusion.

The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma
Natsuko Taniguchi, Satoshi Konno, Takeshi Hattori, Akira Isada, Kaoruko Shimizu, Kenichi Shimizu, Noriharu Shijubo, Shau-Ku Huang, Nobuyuki Hizawa, Masaharu Nishimura
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 111, 5, 376, +, ELSEVIER SCIENCE INC, 2013年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Clara cell secretory protein (CC16) is expressed primarily in the respiratory tract and is a potent anti-inflammatory agent that protects the airway from inflammation. The associations of the A38G polymorphism in this gene with asymptomatic airway hyper-responsiveness (AHR), which is considered a risk factor for future asthma in adults, and the development of adult-onset asthma are unclear.
Objective: To evaluate the association of the CC16 A38G polymorphism with asymptomatic AHR in healthy young adults and the development of adult-onset asthma and the association between plasma CC16 level according to this genotype and asymptomatic AHR.
Methods: Nonspecific AHR was measured in 154 asymptomatic, young, healthy adults using a continuous methacholine inhalation method. The cumulative dose values of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease (Dmin) were used as an index of AHR. Case-control analysis was performed for the association between this polymorphism and the development of asthma in 1,086 unrelated Japanese subjects (504 subjects with asthma and 582 healthy subjects).
Results: The 38AA + AG genotype was associated with lower Dmin values and lower plasma CC16 levels (P=.012 and .020). There was a significant positive correlation between Dmin values and plasma CC16 levels (P=.012). In the case-control study, the 38AA + AG genotype was significantly associated with late-onset asthma (onset at >40 years; odds ratio, 1.63; P=.016).
Conclusion: These results suggest that the CC16 A38G polymorphism may play a role in asymptomatic AHR and contribute to the development of late-onset asthma. (C) 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

THE EFFECTS OF AN ARG16GLY ADRB2 POLYMORPHISM ON RESPONSES TO SALMETEROL OR MONTELUKAST IN JAPANESE PATIENTS WITH MILD PERSISTENT ASTHMA　　　　　　　　　　　　　　　
Konno,Satoshi, Hizawa,Nobuyuki, Makita,Hironi, Shimizu,Kaoruko, Sakamoto,Tohru, Kokubu,Fumio, Saito,Takefumi, Endo,Takeo, Ninomiya,Hiroki, Iijima,Hiroaki, Kaneko,Norihiro, Ito,Yoichi, Nishimura,Masaharu
RESPIROLOGY, 18, 4:SI, 12, 12, WILEY-BLACKWELL, 2013年11月
英語, 研究論文（学術雑誌）

定量的画像解析 COPD患者における1秒量経年変化と肺CT画像所見の推移
清水 薫子, 牧田 比呂仁, 鈴木 雅, 長井 桂, 今野 哲, Nguyen V. Tho, 小川 惠美子, 中野 恭幸, 西村 正治
日本呼吸器学会誌, 2, 増刊, 130, 130, (一社)日本呼吸器学会, 2013年03月, ［査読有り］
日本語

O33-5 クラスター解析による難治性気管支喘息の病型分類 : 北海道難治性喘息コホート研究:HiCARAT(O33 気管支喘息 病態1,口演,第63回日本アレルギー学会秋季学術大会)
谷口 菜津子, 今野 哲, 清水 薫子, 牧田 比呂仁, 西村 正治
アレルギー, 62, 9, 1363, 1363, 一般社団法人 日本アレルギー学会, 2013年
日本語

カタラーゼ遺伝子(CAT)多型が気管支喘息発症に及ぼす影響
谷口,菜津子, 今野,哲, 木村,孔一, 荻,喬博, 清水,薫子, 清水,健一, 伊佐田,朗, 服部,健史, 前田,由起子, 檜澤,伸之, 西村,正治
アレルギー, 61, 9-10, 1514, 1514, 一般社団法人日本アレルギー学会, 2012年10月
日本語, 研究論文（国際会議プロシーディングス）

北海道上士幌町における成人喘息、アレルギー性鼻炎有病率の検討 2006年、2011年の比較
清水,薫子, 今野,哲, 木村,孔一, 荻,喬博, 谷口,菜津子, 清水,健一, 伊佐田,朗, 服部,健史, 西村,正治, 檜澤,伸之, 谷口,正実, 赤澤,晃
アレルギー, 61, 9-10, 1465, 1465, 一般社団法人日本アレルギー学会, 2012年10月
日本語, 研究論文（国際会議プロシーディングス）

Annual Change in Pulmonary Function and Clinical Phenotype in Chronic Obstructive Pulmonary Disease
Masaharu Nishimura, Hironi Makita, Katsura Nagai, Satoshi Konno, Yasuyuki Nasuhara, Masaru Hasegawa, Kaoruko Shimizu, Tomoko Betsuyaku, Yoichi M. Ito, Satoshi Fuke, Takeshi Igarashi, Yasushi Akiyama, Shigeaki Ogura
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 185, 1, 44, 52, AMER THORACIC SOC, 2012年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Rationale: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes.
Objectives: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity.
Methods: A total of 279 eligible patients with COPD(stages I-IV: 26,45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient.
Measurements and Main Results: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32 +/- 24 (SD) ml/yr (n = 261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63 +/- 2, -31 +/- 1, and -2 +/- 1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils.
Conclusions: Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

[Evidence of pharmacotherapy in COPD--key findings from recently-conducted randomized clinical studies].
Shimizu K, Nishimura M
Nihon rinsho. Japanese journal of clinical medicine, 69, 10, 1815, 1820, 日本臨床社, 2011年10月, ［査読有り］
日本語

Comparison of airway remodelling assessed by computed tomography in asthma and COPD
Kaoruko Shimizu, Masaru Hasegawa, Hironi Makita, Yasuyuki Nasuhara, Satoshi Konno, Masaharu Nishimura
RESPIRATORY MEDICINE, 105, 9, 1275, 1283, W B SAUNDERS CO LTD, 2011年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Few studies have directly compared airway remodelling assessed by computed tomography (CT) between asthma and chronic obstructive pulmonary disease (COPD). The present study was conducted to determine whether there are any differences between the two diseases with similar levels of airflow limitation under clinically stable conditions.
Methods: Subjects included older male asthmatic patients (n = 19) showing FEV(1)/FVC <70% with smoking history less than 5-pack/year. Age- and sex-matched COPD patients (n = 28) who demonstrated similar airflow limitation as asthmatic patients and age-matched healthy non-smokers (n = 13) were recruited. Using proprietary software, eight airways were selected in the right lung, and wall area percent (WA%) and airway luminal area (Ai) were measured at the mid-portion of the 3rd to 6th generation of each airway. For comparison, the average of eight measurements per generation was recorded.
Results: FEV(1)% predicted and FEV(1)/FVC was similar between asthma and COPD (82.3 +/- 3.3% vs. 77.6 +/- 1.8% and 57.7 +/- 1.6% vs. 57.9 +/- 1.4%). At any generation, WA% was larger and Ai was smaller in asthma, both followed by COPD and then controls. Significant differences were observed between asthma and controls in WA% of the 3rd to 5th generation and Ai of any generation, while no differences were seen between COPD and controls. There were significant differences in Ai of any generation between asthma and COPD.

Airflow limitation and airway dimensions assessed per bronchial generation in older asthmatics
Kaoruko Shimizu, Masaru Hasegawa, Hironi Makita, Yasuyuki Nasuhara, Satoshi Konno, Masaharu Nishimura
RESPIRATORY MEDICINE, 104, 12, 1809, 1816, W B SAUNDERS CO LTD, 2010年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Background Computed tomography (CT) has been used for non invasive quantitative assessment of airway dimensions, potentially showing airway remodeling, in asthma However, most studies have examined either only one airway or only airways in anatomically unidentified cross sections Using software capable of precisely identifying the generation of airways and measuring airway dimensions perpendicular to the long axis of airways, we examined, in older patients with stable asthma, how inter subject variation in airway dimensions correlated among the 3rd to 6th generation of airways, and then examined relationships between airway dimensions of each generation and indices of airflow limitation
Methods Subjects aged >= 55 years old comprised 59 asthmatic patients who underwent CT and pulmonary function tests on the same day We measured airway wall area (WA%) and innerluminal area (Ai) from the 3rd to the 6th generation of eight bronchi in the right lung
Results Excellent correlations were identified for both WA% and Ai among the generations (r = 0 744-0 930 for WA%) when we took the average of all measured bronchi per generation as a personal representative value Significant correlations of airflow limitation indices with both WA% and Ai/BSA were found at each of the 3rd to 6th generations with similar correlation coefficients (WA% for FEV(1) %predicted, r = -0 410 to -0 556)
Conclusions In older patients with stable asthma, airway wall thickening and narrowing might occur in a parallel manner through 3rd to 6th generation airways Airway dimensions at these areas of airways may thus have significant and similar correlations with indices of airflow limitation (C) 2010 Elsevier Ltd All rights reserved

A Case of Follicular Bronchiolitis Associated with Asthma, Eosinophilia, and Increased Immunoglobulin E
Kaoruko Shimizu, Satoshi Konno, Yasuyuki Nasuhara, Mishie Tanino, Yoshihiro Matsuno, Masaharu Nishimura
JOURNAL OF ASTHMA, 47, 10, 1161, 1164, INFORMA HEALTHCARE, 2010年12月, ［査読有り］
英語, 研究論文（学術雑誌）, A 49-year-old woman, who had been diagnosed with asthma, showed a bilateral diffuse pattern of small centrilobular nodules on CT. Laboratory data revealed peripheral eosinophilia and a marked increase in total serum IgE levels. The nodules detected on CT were initially considered to be associated with bronchiolar infiltration of eosinophils. Pathological findings from thoracoscopy revealed infiltration of eosinophils into the airway lumen and walls, goblet cell hyperplasia, and thickening of the basement membrane in large bronchi, consistent with asthma. However, hyperplastic lymphoid follicles with reactive germinal centers were observed along the bronchioles. The follicles had no evidence of monoclonality suggested by immunohistological analysis, and no remarkable infiltrates of eosinophils, suggesting follicular bronchiolitis (FB). After treatment with prednisolone, the small diffuse nodules improved markedly, and peripheral eosinophilia and total serum IgE levels also decreased. To the best of our knowledge, this is the first documented case report of FB associated with asthma, eosinophilia, and elevated IgE with a definite pathophysiological diagnosis.

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis
Takeshi Hattori, Satoshi Konno, Ayumu Takahashi, Akira Isada, Kaoruko Shimizu, Kenichi Shimizu, Natsuko Taniguchi, Peisong Gao, Etsuro Yamaguchi, Nobuyuki Hizawa, Shau-Ku Huang, Masaharu Nishimura
BMC MEDICAL GENETICS, 11, 151, BIOMED CENTRAL LTD, 2010年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Mannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with sarcoidosis.
Methods: Nine single nucleotide polymorphisms (SNPs), encompassing the MRC1 gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls.
Results: Suggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (P = 0.001).
Conclusions: These results suggest that MRC1 is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in MRC1, a major member of the C-type lectin, contribute to the development of sarcoidosis.

Genetic variants in the mannose receptor gene (MRC1) are associated with asthma in two independent populations
Takeshi Hattori, Satoshi Konno, Nobuyuki Hizawa, Akira Isada, Ayumu Takahashi, Kaoruko Shimizu, Kenichi Shimizu, Peisong Gao, Terri H. Beaty, Kathleen C. Barnes, Shau-Ku Huang, Masaharu Nishimura
IMMUNOGENETICS, 61, 11-12, 731, 738, SPRINGER, 2009年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African-American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African-American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African-American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.

[The Arg16Glybeta2-adrenergic receptor polymorphism influences long term clinical responses to beta2-agonist].
Isada A, Hizawa N, Shimizu K, Shimizu K, Takahashi A, Hattori T, Maeda Y, Takahashi D, Konno S, Nishimura M
Arerugi = [Allergy], 57, 6, 713, 721, 一般社団法人 日本アレルギー学会, 2008年06月, ［査読有り］
日本語, 【背景】β_2アドレナリン受容体(ADRB2)遺伝子の16番アミノ酸におけるグリシン(Gly)からアルギニン(Arg)への変化は受容体の機能的変化をもたらす.長期間のβ_2刺激薬投与により,特にArg/Arg患者では呼吸機能の悪化が報告されている.本研究では日本人喘息患者を対象にArg16Gly多型のβ_2刺激薬長期連用による呼吸機能への影響を検討した.【方法】対象は気管支喘息患者128人(Arg/Arg群64人,Gly/Gly群64人).β_2刺激薬を少なくとも6ヵ月間以上使用した長期連用群と非連用群に分類し,各遺伝子型群におけるβ_2刺激薬連用の有無による1秒量の変化を比較検討した.【結果】Gly/Gly群ではβ_2刺激薬連用によって,より大きな1秒量の改善が認められた(p=0.027-0.041).Arg/Arg群では連用群と非連用群との間に1秒量の改善に差はなかった.【結論】Arg/Arg型の日本人喘息患者においてβ_2刺激薬連用の有用性が小さく,ADRB2遺伝子が治療効果に影響を与えていると考えられた.

Prevalence of adult asthma and allergic rhinitis in Kamishihoro Town, Hokkaido - Associations with smoking habit and obesity
Kaoruko Shimizu, Satoshi Konno, Kenichi Shimizu, Akira Isada, Ayumu Takahashi, Takeshi Hattori, Yukiko Maeda, Daisuke Takahashi, Kiyoshi Takahashi, Takemasa Nakagawa, Masami Taniguchi, Kazuo Akiyama, Akira Akazawa, Nobuyuki Hizawa, Masaharu Nishimura
Japanese Journal of Allergology, 57, 7, 835, 842, 2008年, ［査読有り］
日本語, 研究論文（学術雑誌）, Purpose: To investigate the prevalence of adult asthma and allergic rhinitis, and to analyze associations between smoking habit, obesity and disease in Kamishihoro town, Hokkaido. Methods: The Japanese edition of the European Community Respiratory Health Survey (ECRHS) Questionnaire was completed by 3096 residents (men: 1520, women: 1576) who ranged in age from 18 to 81. Results: Among the respondents, 12.9% of the males and 9.8% of the females responded "Yes" to the questionnaire item, "Wheezing at any time in the last 12 months" (defined as having asthma) and 17.6% of the males and 23.0% of the females responded "Yes" to the question, "Do you have any nasal allergies including hay fever?" (defined as having allergic rhinitis). This prevalence tended to be higher among younger respondents. Smoking habit and obesity were significantly associated with wheezing over the last 12 months, but not with allergic rhinitis. Conclusion: Smoking habit and obesity are significantly associated with asthma in Kamishihoro town, located in a rural area of Hokkaido, Japan. © 2008 Japanese Society of Allergology.

喘息・COPDにおける人工知能を用いた予後予測による疾患マネジメントの向上　　　　　　　　　　　　　　　
清水 薫子, 杉森 博行, 大和証券ヘルス財団研究業績集, 45, 3, 6, 2022年03月
(公財)大和証券ヘルス財団, 日本語

Leading women in respiratory medicine: Letter from Japan
Kaoruko Shimizu, Katsura Nagai, Respirology, 26, 12, 1188, 1189, 2021年12月01日
See related article., John Wiley and Sons Inc, 英語, 速報，短報，研究ノート等（学術雑誌）

COPD患者における,気腫・非気腫領域別の呼吸による体積変化率の分布一致度と呼吸機能との関連
島寛, 田辺直也, 張怡, 白石祐介, 小澤聡, 小熊毅, 佐藤篤靖, 鍛冶静雄, 清水薫子, 牧田比呂仁, 牧田比呂仁, 西村正治, 西村正治, 佐藤晋, 今野哲, 平井豊博, 日本呼吸器学会誌(Web), 10, 2021年

北海道支部3大学共同ワーキンググループの取り組み
長井 桂, 清水 薫子, 宮島 さつき, 橋本 みどり, 佐々木 高明, 高村 圭, 岡本 佳裕, 千葉 弘文, 長内 忍, 日本呼吸器学会北海道支部将来計画委員会/男女共同参画委員会, 日本呼吸器学会誌, 9, 増刊, 78, 78, 2020年08月
(一社)日本呼吸器学会, 日本語

新専門研修における男女共同参画 サブスペシャルティ研修を見据えて 全ての希望者に呼吸専門研修を勧めるために
長井 桂, 清水 薫子, 橋本 みどり, 宮島 さつき, 佐々木 高明, 高村 圭, 岡本 佳裕, 千葉 弘文, 長内 忍, 日本サルコイドーシス/肉芽腫性疾患学会雑誌, 39, 1-2, 113, 113, 2019年10月
日本サルコイドーシス, 日本語

当科におけるリンパ管脈管筋腫症33症例のまとめ　　　　　　　　　　　　　　　
瀧本 理子, 鈴木 雅, 松本 宗大, 武井 望, 山下 優, 木村 孔一, 木村 裕樹, 長岡 健太郎, 清水 薫子, 今野 哲, 日本サルコイドーシス/肉芽腫性疾患学会雑誌, 39, 1-2, 115, 115, 2019年10月
日本サルコイドーシス, 日本語

気道炎症・バイオマーカー 重症喘息患者における増悪状況とTh2マーカー陽性数の検討　　　　　　　　　　　　　　　
木村 孔一, 牧田 比呂仁, 谷口 菜津子, 木村 裕樹, 清水 薫子, 鈴木 雅, 武井 望, 松本 宗大, Goudarzi Houman, 西村 正治, 今野 哲, アレルギー, 68, 4-5, 491, 491, 2019年05月
(一社)日本アレルギー学会, 日本語

COPD患者における呼吸機能と気道内腔体積との関連　　　　　　　　　　　　　　　
小熊 昂, 清水 薫子, 牧田 比呂仁, 阿部 結希, 松本 宗大, 武井 望, 木村 孔一, 木村 裕樹, Goudarzi Houman, 鈴木 雅, 今野 哲, 西村 正治, 日本呼吸器学会誌, 8, 増刊, 246, 246, 2019年03月
(一社)日本呼吸器学会, 日本語

北海道胆振東部地震に伴う大規模停電時の在宅酸素療法患者への対応の後方視的検討　　　　　　　　　　　　　　　
佐藤 峰嘉, 鈴木 雅, 松本 宗大, 武井 望, 山下 優, 木村 孔一, 木村 裕樹, 長岡 健太郎, 清水 薫子, 水柿 秀紀, 大平 洋, 品川 尚文, 辻野 一三, 南須原 康行, 今野 哲, 日本呼吸器学会誌, 8, 増刊, 309, 309, 2019年03月
(一社)日本呼吸器学会, 日本語

β2アドレナリン受容体遺伝子(ADRB2)多型とCOPD患者の長期臨床経過についての検討　　　　　　　　　　　　　　　
武井 望, 鈴木 雅, 牧田 比呂仁, 今野 哲, 清水 薫子, 木村 裕樹, 木村 孔一, 西村 正治, 日本呼吸器学会誌, 8, 増刊, 315, 315, 2019年03月
(一社)日本呼吸器学会, 日本語

重症喘息コホートにおける増悪状況とその関連因子についての検討　　　　　　　　　　　　　　　
木村 孔一, 今野 哲, 牧田 比呂仁, 谷口 菜津子, 木村 裕樹, 清水 薫子, 鈴木 雅, 西村 正治, 日本内科学会雑誌, 108, Suppl., 237, 237, 2019年02月
(一社)日本内科学会, 日本語

気管食道瘻を呈したEGFR遺伝子変異陽性肺腺癌に対してゲフィチニブの胃管投与が有効であった1例
古田 恵, 西村 正治, 榊原 純, 荻 喬博, 阿部 智絵, 北井 秀典, 清水 薫子, 朝比奈 肇, 品川 尚文, 大泉 聡史, 気管支学, 41, 1, 55, 60, 2019年01月25日
<p><b>背景．</b>全身状態不良のepidermal growth factor receptor（EGFR）遺伝子変異陽性非小細胞肺癌患者においても，ゲフィチニブは有用である．今回，我々は気管食道瘻を呈したEGFR遺伝子変異陽性肺腺癌に対してゲフィチニブの胃管投与が有効であった1例を経験したので報告する．<b>症例．</b>69歳女性．呼吸困難が出現したため前医に救急搬送された．画像検査で縦隔リンパ節腫大による気管狭窄所見を認め，低酸素血症が悪化したため人工呼吸管理の上，当院転院となった．転院後は縦隔リンパ節の内部壊死に伴い気管狭窄は改善していたが，気管食道瘻を呈していた．精査の結果，原発性肺腺癌（cT4N2M1a，stage IV），EGFR遺伝子変異陽性Exon 19 deletionと確定した．気管食道瘻により経口内服困難であったためゲフィチニブを胃管より投与開始したところ，約3週間で瘻孔の閉鎖，腫瘍縮小を認めて全身状態も改善した．<b>結論．</b>気管食道瘻を呈した全身状態不良のEGFR遺伝子変異陽性患者において，ゲフィチニブの胃管投与は有用であった．</p>, 特定非営利活動法人 日本呼吸器内視鏡学会, 日本語

呼吸器科医育成を目的とした初期研修医体験型セミナーの取り組み
千葉 弘文, 岡本 佳裕, 佐々木 高明, 清水 薫子, 高村 圭, 長井 桂, 橋本 みどり, 宮島 さつき, 長内 忍, 日本呼吸器学会北海道支部将来計画委員会, 日本サルコイドーシス/肉芽腫性疾患学会雑誌, 38, 1-2, 103, 103, 2018年10月
日本サルコイドーシス, 日本語

原発性免疫不全症(PID)を背景とした、気管支/細気管支炎の成人7症例の検討
小熊 昂, 今野 哲, 鈴木 雅, 清水 薫子, 山田 雅文, 有賀 正, 西村 正治, 日本サルコイドーシス/肉芽腫性疾患学会雑誌, 38, 1-2, 104, 104, 2018年10月
日本サルコイドーシス, 日本語

COPDの診断に至らない喫煙者の長期臨床経過の検討:北海道COPDコホート研究より
武井望, 鈴木雅, 牧田比呂仁, 今野哲, 清水薫子, 木村裕樹, 木村孔一, 西村正治, 日本呼吸器学会誌(Web), 7, 255, 2018年03月10日
日本語

全身性ステロイドによる治療を要した肺サルコイドーシス症の検討
木村孔一, 今野哲, 山口哲生, 四十坊典晴, 服部健史, 山田嘉仁, 清水薫子, 鈴木雅, 西村正治, 日本呼吸器学会誌(Web), 7, 163, 2018年03月10日
日本語

COPD患者の臨床経過に対する体重変化の影響
阿部結希, 鈴木雅, 牧田比呂仁, 今野哲, 清水薫子, 木村裕樹, 木村孔一, 武井望, 松本宗大, 西村正治, 日本呼吸器学会誌(Web), 7, 135, 2018年03月10日
日本語

COPDにおけるCTパラメーターの検討―フラクタル値,Low attenuation volumeの変動に着目して―
清水薫子, THO Nguyen Van, 鈴木雅, 牧田比呂仁, 木村孔一, 木村裕樹, 今野哲, 小川惠美子, 中野恭幸, 西村正治, 日本呼吸器学会誌(Web), 7, 129, 2018年03月10日
日本語

COPDにおけるCTパラメーターの検討 フラクタル値、Low attenuation volumeの変動に着目して　　　　　　　　　　　　　　　
清水 薫子, Nguyen Van Tho, 鈴木 雅, 牧田 比呂仁, 木村 孔一, 木村 裕樹, 今野 哲, 小川 惠美子, 中野 恭幸, 西村 正治, 日本呼吸器学会誌, 7, 増刊, 129, 129, 2018年03月
(一社)日本呼吸器学会, 日本語

COPD患者の臨床経過に対する体重変化の影響　　　　　　　　　　　　　　　
阿部 結希, 鈴木 雅, 牧田 比呂仁, 今野 哲, 清水 薫子, 木村 裕樹, 木村 孔一, 武井 望, 松本 宗大, 西村 正治, 日本呼吸器学会誌, 7, 増刊, 135, 135, 2018年03月
(一社)日本呼吸器学会, 日本語

全身性ステロイドによる治療を要した肺サルコイドーシス症の検討　　　　　　　　　　　　　　　
木村 孔一, 今野 哲, 山口 哲生, 四十坊 典晴, 服部 健史, 山田 嘉仁, 清水 薫子, 鈴木 雅, 西村 正治, 日本呼吸器学会誌, 7, 増刊, 163, 163, 2018年03月
(一社)日本呼吸器学会, 日本語

COPDの診断に至らない喫煙者の長期臨床経過の検討 北海道COPDコホート研究より　　　　　　　　　　　　　　　
武井 望, 鈴木 雅, 牧田 比呂仁, 今野 哲, 清水 薫子, 木村 裕樹, 木村 孔一, 西村 正治, 日本呼吸器学会誌, 7, 増刊, 255, 255, 2018年03月
(一社)日本呼吸器学会, 日本語

原発性免疫不全症(PID)を背景とした、気管支/細気管支炎の成人7症例の検討
小熊 昂, 今野 哲, 鈴木 雅, 清水 薫子, 山田 雅文, 有賀 正, 西村 正治, 日本呼吸器学会誌, 7, 増刊, 261, 261, 2018年03月
(一社)日本呼吸器学会, 日本語

肺病変に対してステロイド内服を要したサルコイドーシス症例の検討
木村孔一, 今野哲, 清水薫子, 鈴木雅, 服部健史, 四十坊典晴, 山口哲生, 西村正治, 日本サルコイドーシス/肉芽腫性疾患学会雑誌, 37, 44, 2017年10月03日
日本語

気管支喘息(成人)管理 増悪 重症喘息患者における3年間の増悪頻度及びその予測因子の検討　　　　　　　　　　　　　　　
木村 孔一, 今野 哲, 牧田 比呂仁, 清水 薫子, 木村 裕樹, 鈴木 雅, 西村 正治, アレルギー, 66, 4-5, 598, 598, 2017年05月
(一社)日本アレルギー学会, 日本語

若年成人における、過去6年間の気管支喘息、アレルギー性鼻炎の有病率の変化　　　　　　　　　　　　　　　
松本 宗大, 今野 哲, 木村 孔一, 清水 薫子, 鈴木 雅, 橋野 聡, 西村 正治, アレルギー, 66, 4-5, 698, 698, 2017年05月
(一社)日本アレルギー学会, 日本語

COPD バイオマーカー COPD患者における血清α1、アンチトリプシン値と臨床経過についての検討　　　　　　　　　　　　　　　
武井 望, 鈴木 雅, 牧田 比呂仁, 今野 哲, 清水 薫子, 木村 裕樹, 木村 孔一, 西村 正治, 日本呼吸器学会誌, 6, 増刊, 131, 131, 2017年03月
(一社)日本呼吸器学会, 日本語

気管支喘息における肺拡散能力指標と画像所見 DLcoとKcoに着目して　　　　　　　　　　　　　　　
清水 薫子, 今野 哲, 牧田 比呂仁, 木村 孔一, 木村 裕樹, 鈴木 雅, 西村 正治, 日本呼吸器学会誌, 6, 増刊, 242, 242, 2017年03月
(一社)日本呼吸器学会, 日本語

呼吸不全に関する調査研究 COPD患者におけるインダカテロールおよびグリコピロニウム/インダカテロールの吸入によるCT画像を用いた気管支拡張効果に関する検討
西村正治, 清水薫子, 瀬戸瑠里子, 牧田比呂仁, 鈴木雅, 今野哲, 伊藤陽一, 神田理恵, 小川惠美子, 中野恭幸, 呼吸不全に関する調査研究 平成28年度 総括研究報告書(Web), 2017年

COPDの重症度は画像所見で判定できるのか? (特集 呼吸器画像診断 : エキスパートの視点) -- (慢性閉塞性肺疾患)
清水 薫子, 西村 正治, 呼吸器ジャーナル, 65, 1, 122, 128, 2017年
医学書院, 日本語

喘息患者における副鼻腔CT所見とバイオマーカーの検討―喫煙が及ぼす影響―
木村孔一, 今野哲, 中丸裕爾, 牧田比呂仁, 谷口菜津子, 清水薫子, 木村裕樹, 鈴木雅, 小野純也, 太田昭一郎, 出原賢治, 西村正治, アレルギー, 65, 4/5, 654, 654, 2016年05月15日
(一社)日本アレルギー学会, 日本語

呼気中一酸化窒素濃度及び末梢血好酸球数による気管支喘息病態の評価　　　　　　　　　　　　　　　
照井 浩也, 今野 哲, 牧田 比呂仁, 谷口 菜津子, 木村 孔一, 清水 薫子, 鈴木 雅, 西村 正治, アレルギー, 64, 3-4, 553, 553, 2015年04月
(一社)日本アレルギー学会, 日本語

成人喘息病態 喘息患者における副鼻腔CT所見とその関連因子　　　　　　　　　　　　　　　
木村 孔一, 今野 哲, 中丸 裕爾, 牧田 比呂仁, 谷口 菜津子, 清水 薫子, 鈴木 雅, 西村 正治, アレルギー, 64, 3-4, 468, 468, 2015年04月
(一社)日本アレルギー学会, 日本語

Relation of plasma osteopontin levels with the clinical course in patients with COPD
Satoshi Konno, Masaru Suzuki, Hironi Makita, Kaoruko Shimizu, Rose Maciewicz, Masaharu Nishimura, EUROPEAN RESPIRATORY JOURNAL, 44, 2014年09月
EUROPEAN RESPIRATORY SOC JOURNALS LTD, 英語, 研究発表ペーパー・要旨（国際会議）

北海道上士幌町における成人喘息、アレルギー性鼻炎有病率の検討 2006年、2011年の比較
清水 薫子, 今野 哲, 木村 孔一, 荻 喬博, 谷口 菜津子, 清水 健一, 伊佐田 朗, 服部 健史, 檜澤 伸之, 谷口 正実, 赤澤 晃, 西村 正治, アレルギー, 63, 7, 928, 937, 2014年08月
【目的】北海道上士幌町の成人喘息,アレルギー性鼻炎有病率の推移を把握する.【方法】2006年(3096名)と2011年(1472名)のEuropean Community Respiratory Health Survey日本語版による調査結果を比較検討した.【結果】回収率は,2006年は95.8%,2011年は98.1%.喘息期間有症率は,2006年は男性12.9%,女性9.8%,2011年は10.7%,8.3%.過去に喘息と言われたことがあり,医師による診断がある群は,2006年は男性5.7%,女性6.3%,2011年は7.9%,7.5%と増加.現喫煙群は,2006年,2011年それぞれ男性42.8%,34.8%,女性17.2%,14.7%と減少.鼻アレルギーのある群は,男性が17.6%から23.2%,女性が23.0%から25.4%と増加.【結論,考察】医師の診断がある喘息,アレルギー性鼻炎は増加した.一方で喘息期間有症率は減少し,適切な加療による変化と予想された.(著者抄録), (一社)日本アレルギー学会, 日本語

難治性喘息患者における血清ペリオスチン濃度と呼吸機能・副鼻腔陰影重症度との関連
木村孔一, 今野哲, 中丸裕爾, 牧田比呂仁, 谷口菜津子, 清水薫子, 前田由起子, 鈴木雅, 長井桂, 小野純也, 太田昭一郎, 出原賢治, 西村正治, アレルギー, 63, 3/4, 568, 568, 2014年04月05日
(一社)日本アレルギー学会, 日本語

北海道上士幌町における成人喘息、アレルギー性鼻炎有病率の検討 2006年、2011年の比較
清水 薫子, 今野 哲, 谷口 菜津子, 西村 正治, 檜澤 伸之, 谷口 正実, 赤澤 晃, アレルギー, 63, 3-4, 577, 577, 2014年04月
(一社)日本アレルギー学会, 日本語

CLINICAL FEATURES OF PATIENTS WITH POSITIVE SPUTUM CULTURE FOR TRICHOSPORON SPECIES
Nozomu Takei, Katsura Nagai, Takashi Inomata, Yasushi Shibue, Natsuko Taniguchi, Kaoruko Shimizu, Masaru Suzuki, Satoshi Konno, Masaharu Nishimura, RESPIROLOGY, 18, 102, 102, 2013年11月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

当院で経験した肺動静脈瘻の臨床的特徴
古田恵, 長井桂, 清水薫子, 鈴木雅, 今野哲, 西村正治, 日本呼吸器学会誌, 2, 307, 2013年03月10日
日本語

気管支喘息患者における血清レプチン濃度の検討
木村 孔一, 今野 哲, 伊佐田 朗, 荻 喬博, 清水 薫子, 清水 健一, 谷口 菜津子, 前田 由起子, 西村 正治, アレルギー, 61, 9-10, 1491, 1491, 2012年10月
(一社)日本アレルギー学会, 日本語

Clinical characteristics and determinants of exacerbation in Japanese patients with COPD: Hokkaido COPD cohort study results
Masaru Suzuki, Hironi Makita, Satoshi Konno, Kaoruko Shimizu, Natsuko Taniguchi, Yoichi M. Ito, Masaharu Nishimura, EUROPEAN RESPIRATORY JOURNAL, 40, 2012年09月
EUROPEAN RESPIRATORY SOC JOURNALS LTD, 英語, 研究発表ペーパー・要旨（国際会議）

O18-1 長時間作用型β2刺激薬/吸入ステロイド薬によるCOPD患者の気管支拡張部位に関する検討(O18 気管支喘息の治療2,口演,第61回日本アレルギー学会秋季学術大会)
清水 薫子, 長谷川 大, 牧田 比呂仁, 南須原 康行, 今野 哲, 西村 正治, アレルギー, 60, 9, 1387, 1387, 2011年10月10日
一般社団法人日本アレルギー学会, 日本語

MW8-3 アレルギー性気道炎症モデルにおけるDHMEQの効果(MW8 動物モデルを用いた喘息病態と治療法開発,ミニワークショップ,第60回日本アレルギー学会秋季学術大会)
清水 健一, 今野 哲, 清水 薫子, 谷口 菜津子, 伊佐田 朗, 高橋 歩, 服部 健史, 梅澤 一夫, 尾崎 倫孝, 藤堂 省, 西村 正治, アレルギー, 59, 9, 1352, 1352, 2010年10月30日
一般社団法人日本アレルギー学会, 日本語

O13-6 A型肝炎ウイルス,ヘリコバクターピロリ抗体とアトピー素因との関連 : 北海道上士幌町住民における検討(O13 統計・疫学,口演,第60回日本アレルギー学会秋季学術大会)
伊佐田 朗, 今野 哲, 高橋 歩, 服部 健史, 清水 健一, 清水 薫子, 谷口 菜津子, 西村 正治, アレルギー, 59, 9, 1383, 1383, 2010年10月30日
一般社団法人日本アレルギー学会, 日本語

O14-3 肺CT3次元気道解析を用いた気管支喘息とCOPDにおける気道病変の比較(O14 喘息画像解析,口演,第60回日本アレルギー学会秋季学術大会)
清水 薫子, 長谷川 大, 牧田 比呂仁, 南須原 康行, 今野 哲, 西村 正治, アレルギー, 59, 9, 1384, 1384, 2010年10月30日
一般社団法人日本アレルギー学会, 日本語

急速に嚢胞性変化をきたした肺サルコイドーシスの1例
清水 薫子, 今野 哲, 福家 聡, 西浦 洋一, 西村 正治, 日本呼吸器学会雑誌 = The journal of the Japanese Respiratory Society, 48, 9, 715, 718, 2010年09月10日
2004年12月感冒様症状を主訴に近医を受診し、胸部CT上両側上葉優位のスリガラス様陰影、小結節影及び軽度の縦隔リンパ節腫脹を認めたが、無治療にて改善した。2005年8月に発熱、咳嗽が出現し、血清ACE活性の上昇、胸部CT上全肺野のスリガラス様陰影、肺門・縦隔リンパ節の増大を認め、経気管支肺生検にて、サルコイドーシスの診断に至った。プレドニゾロン30mg/日の加療にて解熱、血清ACE活性の低下、陰影の改善を認めた。その後プレドニゾロン内服加療下で、自覚症状、血清ACE活性、呼吸機能は不変であったが、2008年1月の胸部CTにて、2007年5月の時点では認めていなかった肺野末梢の著明な嚢胞性変化を認め、2008年10月には更なる増大を認めた。本症例は、肺門・縦隔リンパ節の増大、血清マーカーの上昇を伴わず、ステロイド治療中に明らかな嚢胞性変化の増大をCT画像にて確認できた稀な症例と考えられた。(著者抄録), (一社)日本呼吸器学会, 日本語

気管支喘息及び鼻炎における血清総IgE値及び末梢血好酸球数の検討
高橋 歩, 今野 哲, 伊佐田 朗, 服部 健史, 清水 薫子, 清水 健一, 谷口 菜津子, 高橋 大輔, 谷口 正実, 赤澤 晃, 檜澤 伸之, 西村 正治, アレルギー, 59, 5, 536, 544, 2010年
【背景・目的】血清総IgE値,末梢血好酸球数はアレルギー疾患の診療で広く用いられている.気管支喘息,アレルギー性鼻炎は互いに合併することが知られているが,合併を考慮した上で,これらの指標との関連を詳細に検討した報告はない.本研究では,両疾患の合併を考慮し,血清総IgE値,末梢血好酸球数との関連を検討した.【方法】北海道十勝郡上士幌町住民347人を対象に,問診,血清総IgE値,末梢血好酸球数の測定を行い,両疾患との関連を検討した.【結果】血清総IgE値は,特異的IgE反応の有無に関わらず,喘息単独群,鼻炎喘息合併群で有意に高値であった(p<0.01)が,鼻炎単独群では,上昇を認めなかった.末梢血好酸球数は鼻炎喘息合併群でのみ有意に高値であった(p<0.005).【結語】喘息は,鼻炎と比較し,抗原非特異的な血清総IgE値の上昇がより関与することが示唆された.また,血清総IgE値と末梢血好酸球数の指標としての相違が示唆された., 一般社団法人日本アレルギー学会, 日本語

MS19-#3 気管支喘息患者におけるSiglec-8遺伝子多型の検討(気管支喘息-診断と管理5-疫学と実態調査-,第59回日本アレルギー学会秋季学術大会)
清水 健一, 今野 哲, 前田 由起子, 服部 健史, 伊佐田 朗, 高橋 歩, 清水 薫子, 谷口 奈津子, Gao Peisong, Barnes Kathleen, Bochner Bruce, 西村 正治, アレルギー, 58, 8, 1258, 1258, 2009年09月30日
一般社団法人日本アレルギー学会, 日本語

133 気管支喘息,アレルギー性鼻炎と血中IgE反応,末梢血好酸球数の関連 : 北海道上士幌町における検討(気管支喘息-疫学・統計3,一般演題,第21回日本アレルギー学会春季臨床大会)
高橋 歩, 今野 哲, 檜澤 伸之, 伊佐田 朗, 服部 健史, 清水 薫子, 清水 健一, 谷口 奈津子, 西村 正治, アレルギー, 58, 3, 422, 422, 2009年04月30日
一般社団法人日本アレルギー学会, 日本語

β_2アドレナリン受容体遺伝子(Arg16Gly)多型が気管支喘息患者のβ_2刺激薬長期連用に与える影響
伊佐田 朗, 檜澤 伸之, 清水 健一, 清水 薫子, 高橋 歩, 服部 健史, 前田 由起子, 高橋 大輔, 今野 哲, 西村 正治, アレルギー, 57, 6, 713, 721, 2008年06月20日
【背景】β_2アドレナリン受容体(ADRB2)遺伝子の16番アミノ酸におけるグリシン(Gly)からアルギニン(Arg)への変化は受容体の機能的変化をもたらす.長期間のβ_2刺激薬投与により,特にArg/Arg患者では呼吸機能の悪化が報告されている.本研究では日本人喘息患者を対象にArg16Gly多型のβ_2刺激薬長期連用による呼吸機能への影響を検討した.【方法】対象は気管支喘息患者128人(Arg/Arg群64人,Gly/Gly群64人).β_2刺激薬を少なくとも6ヵ月間以上使用した長期連用群と非連用群に分類し,各遺伝子型群におけるβ_2刺激薬連用の有無による1秒量の変化を比較検討した.【結果】Gly/Gly群ではβ_2刺激薬連用によって,より大きな1秒量の改善が認められた(p=0.027-0.041).Arg/Arg群では連用群と非連用群との間に1秒量の改善に差はなかった.【結論】Arg/Arg型の日本人喘息患者においてβ_2刺激薬連用の有用性が小さく,ADRB2遺伝子が治療効果に影響を与えていると考えられた., 一般社団法人日本アレルギー学会, 日本語

アトピー素因の判定に必要なアレルゲン数の検討
服部 健史, 今野 哲, 清水 薫子, 清水 健一, 伊佐田 朗, 高橋 歩, 前田 由起子, 牧田 比呂仁, 澤崎 健, 檜澤 伸之, 西村 正治, アレルギー, 57, 5, 543, 551, 2008年05月20日
【背景・目的】アトピー素因はダニなどの種々の環境アレルゲンに対し,特異的IgE抗体を過剰に産生する体質と定義され,アトピー素因の判定は皮膚試験や血中抗原特異的IgE抗体の測定によって行われることが多い.本研究の目的は,アトピー素因を少なくとも一つの抗原に対して特異的IgE抗体が陽性と定義した場合に,検討する抗原の数がアトピー素因の判定に与える影響を検討することである.【方法】若年健常者116例,気管支喘息104例,COPD294例,サルコイドーシス64例,さらには北海道上士幌町住民218例(うち気管支喘息33例,COPD5例)を対象に詳細な問診と抗原特異的IgE抗体の測定を行った.少なくとも1つの抗原に対して特異的IgE抗体が陽性の場合をアトピー素因ありと定義し,MAST26[○!R]を用いてアトピー素因の有無を判定した.検討する抗原の数の違いによるアトピー素因の頻度の変化を検討するために,26種類のアレルゲンのうち抗体陽性率が高いアレルゲンから順に抗体陽性者の割合を累積した.上士幌町住民群ではさらにシラカンバを項目に加えて検討した.【結果】検討するアレルゲンの数を増やしていくことで,新たにアトピー素因ありと判定される者はそれ以上増加しなかった.いずれの疾患群においても同様の結果が認められた.対象者全体では,26種類の抗原で判定されたアトピー素因のうち,95%以上は11種類の..., 一般社団法人日本アレルギー学会, 日本語

北海道上士幌町における成人喘息,アレルギー性鼻炎有病率 : 特に喫煙及び肥満との関連について
清水 薫子, 今野 哲, 清水 健一, 伊佐田 朗, 高橋 歩, 服部 健史, 前田 由起子, 高橋 大輔, 高橋 清, 中川 武正, 谷口 正実, 秋山 一男, 赤澤 晃, 檜澤 伸之, 西村 正治, アレルギー, 57, 7, 835, 842, 2008年
【目的】厚生労働科学研究免疫アレルギー疾患予防・治療研究事業の分担研究として,非都市部に位置する北海道上士幌町における成人喘息とアレルギー性鼻炎の有病率を把握し,喫煙,肥満との関連について検討する.【方法】18歳から81歳の上士幌町民,計3096人に対し, European Community Respiratory Health Survey(ECRHS)調査用紙日本語版を用いてアンケート調査を行った.【結果】過去12ヵ月の喘鳴あり(喘息期間有症率)は男性12.9%,女性9.8%であり,男性では60歳以上にやや多い傾向があった.アレルギー性鼻炎有病率は男性17.6%,女性23.0%であり,若い世代で多い傾向があった.過去12ヵ月の喘鳴と1年以上の喫煙歴(p<0.001),および肥満(BMI25以上)(p=0.002)に有意な関連が認められた.一方,アレルギー性鼻炎と喫煙,肥満との関連は認められなかった.【結語】非都市部に位置する上士幌町において,喘息と喫煙,肥満との関連が示された., 一般社団法人日本アレルギー学会, 日本語

69 アレルギー疾患と血清総IgE値および抗原特異的IgE応答との関係 : 北海道上士幌町における検討(疫学2,一般演題(デジタルポスター),第57回日本アレルギー学会秋季学術大会)
高橋 歩, 今野 哲, 檜澤 伸之, 前田 由起子, 服部 健史, 伊佐田 朗, 清水 薫子, 清水 健一, 西村 正治, アレルギー, 56, 8, 1094, 1094, 2007年09月30日
一般社団法人日本アレルギー学会, 日本語

慢性気道疾患のprecision medicine実現に向けたdeep phenotyping
科学研究費助成事業
2023年04月01日 - 2026年03月31日
今野 哲, 村上 正晃, 鈴木 雅, 杉森 博行, 清水 薫子, 木村 孔一
日本学術振興会, 基盤研究(B), 北海道大学, 23H02915

閉塞性肺疾患の多様性の理解と個別化治療に向けた探索的研究
科学研究費助成事業
2016年04月01日 - 2020年03月31日
西村 正治, 鈴木 雅, 今野 哲, 清水 薫子, 牧田 比呂仁
北海道難治性喘息コホート研究：初回登録時のデータを用い、内臓脂肪と喘息症状との関連、肺拡散能と喫煙喘息との関連について報告 をおこなった。現在は、前向き観察研究の結果を用い、呼吸機能の経年変化に影響する因子の解析が進行している。


気管支喘息とCOPDの合併病態に焦点を当てた慢性気道疾患患者の包括的前向きコホート研究 (PIRICA study) ：気管支喘息、COPD、肺気腫、慢性気管支炎のいずれかと医師により診断された55歳以上の患者を対象に広く登録し、前向観察研究が展開中である。約700例の症例登録が完了し、今後目標数は1150例の登録完了を目指す。
日本学術振興会, 基盤研究(A), 北海道大学, 16H02652

CT所見、バイオマーカーから見た気管支喘息における上下気道の連関
科学研究費助成事業
2014年04月01日 - 2017年03月31日
今野 哲, 清水 薫子
喫煙者、COPD患者を含む気管支喘息患者206名において、呼吸機能、好酸球性炎症、副鼻腔炎スコアと関連する血中、喀痰中のバイオマーカーを探索した。特に、非喫煙者と喫煙者に分類し、それぞれの関連を検討した。その中で、血清periostinは、喫煙歴に関わらず、好酸球性炎症と正の相関を認めた。よってperiostinは、喫煙者の多い本邦において、実臨床に応用可能な有用なバイオマーカーであると考えられた。。
日本学術振興会, 基盤研究(C), 北海道大学, 26461151