Researcher Profile and Settings

Master

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

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Profile and Settings

Affiliation

• Hokkaido University, School of Medicine

Profile and Settings

• Name (Japanese)

  Konno

• Name (Kana)

  Satoshi

• Name

  200901007391255868

Affiliation

• Hokkaido University, School of Medicine

Achievement

Research Interests

• Respiratory Medicine   

Research Areas

• Life sciences / Respiratory medicine

Research Experience

• 2019/04 - Today 北海道大学大学院医学研究院 呼吸器内科学教室 教授
• 2016/04 - 2019/03 北海道大学大学院医学研究院 呼吸器内科学教室 准教授
• 2011/05 - 2016/03 Hokkaido University Hokkaido University Hospital
• 2005/04 - 2011/04 Hokkaido University Hokkaido University Hospital
• 2005/01 - 2005/03 Hokkaido University Hokkaido University Hospital
• 2002/04 - 2004/12 Johns Hopkins大学 喘息アレルギーセンター ポスドクフェロー
• 1995/04 - 2002/03 Hokkaido University Hokkaido University Hospital

Awards

• 2023 公益財団法人 テルモ生命科学振興財団 2022 年度 Ⅲ研究助成金
   ライフコースアプローチによる喘息/肥満に対するコホート研究 

  受賞者: 今野 哲
• 2019 公益財団法人 寿原記念財団研究助成
   肥満が気管支喘息病態に及ぼす分子生物学的機序の解明 

  受賞者: 今野 哲
• 2019 公益財団法人日本呼吸器財団 公益財団法人 日本呼吸器財団研究助成
   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 

  受賞者: 今野 哲
• 2018 公益財団法人 健康科学財団研究助成
   肥満が気管支喘息病態に及ぼす分子生物学的機序の解明及びその臨床応用 

  受賞者: 今野 哲
• 2017 公益財団法人 秋山記念生命科学振興財団 公益財団法人 秋山記念生命科学振興財団研究助成
   気管支喘息におけるピークフロー値変動の規定因子、及び喘息の自然史に与える影響
• 2017 公益財団法人大和証券ヘルス財団 公益財団法人大和証券ヘルス財団研究助成
   高齢者におけ気管支喘息とCOPDの共通病態の解明 －両疾患の枠を超えたバイオマーカーの探索－
• 2017 日本サルコイドーシス・肉芽腫性疾患学会 千葉保之・本間日臣記念賞
   サルコイドーシスの多様性の理解に向けた包括的アプローチ 

  受賞者: 今野 哲
• 2010 Pneumo Forum賞
   COPD患者の気管支拡張反応に与えるアドレナリン受容体遺伝子(ADRB2)多型の意義 

  受賞者: 今野 哲
• 2010 日本呼吸器学会 English session award
   Association of beta2-adrenoreceptor genotype with bronchodilator responses (BDR) in COPD 

  受賞者: KONNO Satoshi
• 2005 日本アレルギー協会 アボットジャパン学術奨励賞
   気管支喘息、アレルギー反応におけるオステオポンチンの関与 

  受賞者: 今野 哲

Published Papers

• 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.) 2024/06/24 

  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 2772-8293 2024/05
• Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review.

  Naoki Kosaka, Takanori Uchiyama, Masahiro Onozawa, Jun Nagai, Jiro Koya, Suguru Ishizaka, Toshiyuki Nagai, Yohei Ikebe, Kenjiro Kato, Zen-Ichi Tanei, Jun Sakakibara-Konishi, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Hideki Ujiie, Satoshi Hirano, Satoshi Konno, Toshihisa Anzai, Koji Taniguchi, Shinya Tanaka, Takanori Teshima

  Internal medicine (Tokyo, Japan) 2024/04/16 [Refereed]
   

  We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.
• Exploratory analysis of the accuracy of echocardiographic parameters for the assessment of right ventricular function and right ventricular-pulmonary artery coupling.

  Hideki Shima, Ichizo Tsujino, Junichi Nakamura, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Satonori Tsuneta, Yasuyuki Chiba, Michito Murayama, Isao Yokota, Satoshi Konno

  Pulmonary circulation 14 (2) e12368  2024/04 

  Echocardiography is a widely used modality for the assessment of right ventricular (RV) function; however, few studies have comprehensively compared the accuracy of echocardiographic parameters using invasively obtained reference values. Therefore, this exploratory study aimed to compare the accuracy of echocardiographic parameters of RV function and RV-pulmonary artery (PA) coupling. We calculated four indices of RV function (end-systolic elastance [Ees] for systolic function [contractility], τ for relaxation, and β and end-diastolic elastance [Eed] for stiffness), and an index of RV-PA coupling (Ees/arterial elastance [Ea]), using pressure catheterization, cardiac magnetic resonance imaging, and a single-beat method. We then compared the correlations of RV indices with echocardiographic parameters. In 63 participants (54 with pulmonary hypertension (PH) and nine without PH), Ees and τ correlated with several echocardiographic parameters, such as RV diameter and area, but the correlations were moderate (|correlation coefficients (ρ)| < 0.5 for all parameters). The correlations of β and Eed with echocardiographic parameters were weak, with |ρ| < 0.4. In contrast, Ees/Ea closely correlated with RV free wall longitudinal strain (RVFW-LS)/estimated systolic PA pressure (eSPAP) (ρ = -0.72). Ees/Ea also correlated with tricuspid annular plane systolic excursion/eSPAP, RV diameter, and RV end-systolic area, with |ρ | >0.65. In addition, RVFW-LS/eSPAP yielded high sensitivity (0.84) and specificity (0.75) for detecting reduced Ees/Ea. The present study indicated a limited accuracy of echocardiographic parameters in assessing RV systolic and diastolic function. In contrast to RV function, they showed high accuracy for assessing RV-PA coupling, with RVFW-LS/eSPAP exhibiting the highest accuracy.
• Prognostic Value of Combined Assessments of Late Gadolinium Enhancement and Fluorodeoxyglucose Uptake in Cardiac Sarcoidosis.

  Sho Kazui, Sakae Takenaka, Toshiyuki Nagai, Satonori Tsuneta, Kenji Hirata, Yoshiya Kato, Hirokazu Komoriyama, Yuta Kobayashi, Akinori Takahashi, Kiwamu Kamiya, Taro Temma, Takuma Sato, Atsushi Tada, Yutaro Yasui, Michikazu Nakai, Takahiro Sato, Ichizo Tsujino, Kohsuke Kudo, Satoshi Konno, Toshihisa Anzai

  JACC. Cardiovascular imaging 2024/03/11
• Current advances in pulmonary functional imaging.

  Hidetoshi Nakamura, Toyohiro Hirai, Hajime Kurosawa, Kazuki Hamada, Kazuto Matsunaga, Kaoruko Shimizu, Satoshi Konno, Shigeo Muro, Koichi Fukunaga, Yasutaka Nakano, Ichiro Kuwahira, Masayuki Hanaoka

  Respiratory investigation 62 (1) 49 - 65 2024/01 

  Recent advances in imaging analysis have enabled evaluation of ventilation and perfusion in specific regions by chest computed tomography (CT) and magnetic resonance imaging (MRI), in addition to modalities including dynamic chest radiography, scintigraphy, positron emission tomography (PET), ultrasound, and electrical impedance tomography (EIT). In this review, an overview of current functional imaging techniques is provided for each modality. Advances in chest CT have allowed for the analysis of local volume changes and small airway disease in addition to emphysema, using the Jacobian determinant and parametric response mapping with inspiratory and expiratory images. Airway analysis can reveal characteristics of airway lesions in chronic obstructive pulmonary disease (COPD) and bronchial asthma, and the contribution of dysanapsis to obstructive diseases. Chest CT is also employed to measure pulmonary blood vessels, interstitial lung abnormalities, and mediastinal and chest wall components including skeletal muscle and bone. Dynamic CT can visualize lung deformation in respective portions. Pulmonary MRI has been developed for the estimation of lung ventilation and perfusion, mainly using hyperpolarized 129Xe. Oxygen-enhanced and proton-based MRI, without a polarizer, has potential clinical applications. Dynamic chest radiography is gaining traction in Japan for ventilation and perfusion analysis. Single photon emission CT can be used to assess ventilation-perfusion (V˙/Q˙) mismatch in pulmonary vascular diseases and COPD. PET/CT V˙/Q˙ imaging has also been demonstrated using "Galligas". Both ultrasound and EIT can detect pulmonary edema caused by acute respiratory distress syndrome. Familiarity with these functional imaging techniques will enable clinicians to utilize these systems in clinical practice.
• 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 2023/12/05 

  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 2023/11/23 

  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.
• High-precision rapid testing of omicron SARS-CoV-2 variants in clinical samples using AI-nanopore.

  Kaoru Murakami, Shimpei I Kubota, Kumiko Tanaka, Hiroki Tanaka, Keiichiroh Akabane, Rigel Suzuki, Yuta Shinohara, Hiroyasu Takei, Shigeru Hashimoto, Yuki Tanaka, Shintaro Hojyo, Osamu Sakamoto, Norihiko Naono, Takayui Takaai, Kazuki Sato, Yuichi Kojima, Toshiyuki Harada, Takeshi Hattori, Satoshi Fuke, Isao Yokota, Satoshi Konno, Takashi Washio, Takasuke Fukuhara, Takanori Teshima, Masateru Taniguchi, Masaaki Murakami

  Lab on a chip 23 (22) 4909 - 4918 2023/11/07 [Refereed]
   

  A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants.
• Visible Bronchial Obstruction after Hematopoietic Stem Cell Transplantation.

  Takatoshi Suzuki, Sho Nakakubo, Masaru Suzuki, Satoshi Konno

  Internal medicine (Tokyo, Japan) 62 (21) 3255 - 3256 2023/11/01
• 80歳以上の高齢者に対する経気管支生検の安全性と有用性の検討

  畠山 酉季, 高島 雄太, 鈴木 孝敏, 棟方 奈菜, 中村 友彦, 高橋 宏典, 古田 恵, 北井 秀典, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 品川 尚文, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (6) 444 - 444 0287-2137 2023/11
• DirectPathにおけるオブリーク法による気管支鏡ナビゲーション作成の検討

  小熊 昂, 庄司 哲明, 畠山 酉季, 福井 伸明, 松浦 結子, 松永 章宏, 小林 冬美子, 高島 雄太, 品川 尚文, 三宅 浩太郎, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (6) 444 - 444 0287-2137 2023/11
• 次期細径超音波気管支鏡の挿入性及び穿刺性評価

  高島 雄太, 品川 尚文, 嘉島 相裕, 有里 仁希, 森永 大亮, 猪狩 智生, 伊藤 祥太郎, 辻 康介, 高橋 宏典, 庄司 哲明, 七戸 俊明, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (6) 444 - 445 0287-2137 2023/11
• Exposure to organophosphate flame retardants and plasticizers is positively associated with wheeze and FeNO and eosinophil levels among school-aged children: The Hokkaido study.

  Yi Zeng, Houman Goudarzi, Yu Ait Bamai, Rahel Mesfin Ketema, Maarten Roggeman, Fatima den Ouden, Celine Gys, Chihiro Miyashita, Sachiko Ito, Satoshi Konno, Adrian Covaci, Reiko Kishi, Atsuko Ikeda-Araki

  Environment international 181 108278 - 108278 2023/11 

  Exposure to organophosphate flame retardants and plasticizers (PFRs) increases the risk of asthma and allergies. However, little is known about its association with type 2 inflammation (T2) biomarkers used in the management of allergies. The study investigated associations among urinary PFR metabolite concentrations, allergic symptoms, and T2 biomarkers. The data and samples were collected between 2017 and 2020, including school children (n = 427) aged 9-12 years living in Sapporo City, Japan, among the participants of "The Hokkaido Study on Environment and Children's Health." Thirteen urinary PFR metabolites were measured by LC-MS/MS. Allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. For T2 biomarkers, the peripheral blood eosinophil counts, fraction of exhaled nitric oxide level (FeNO), and serum total immunoglobulin E level were measured. Multiple logistic regression analysis, quantile-based g-computation (qg-computation), and Bayesian kernel machine regression (BKMR) were used to examine the associations between the health outcomes of the individual PFRs and the PFR mixtures. The highest concentration of PFR was Σtris(1-chloro-isopropyl) phosphates (ΣTCIPP) (Median:1.20 nmol/L). Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was significantly associated with a high odds ratio (OR, 95%CI:1.36, 1.07-1.72) for wheeze. TDCIPP (OR, 95%CI:1.19, 1.02-1.38), Σtriphenyl phosphate (ΣTPHP) (OR, 95%CI:1.81, 1.40-2.37), and Σtris(2-butoxyethyl) phosphate (ΣTBOEP) (OR, 95%:1.40, 1.13-1.74) were significantly associated with increased odds of FeNO (≥35 ppb). ΣTPHP (OR, 95%CI:1.44, 1.15-1.83) was significantly associated with high eosinophil counts (≥300/μL). For the PFR mixtures, a one-quartile increase in all PFRs (OR, 95%CI:1.48, 1.18-1.86) was significantly associated with high FeNO (≥35 ppb) in the qg-computation model. The PFR mixture was positively associated with high FeNO (≥35 ppb) and eosinophil counts (≥300/μL) in the BKMR models. These results may suggest that exposure to PFRs increases the probability of asthma, allergies, and T2 inflammation.
• Impact of cancer on the prevalence, management, and outcome of patients with chronic thromboembolic pulmonary hypertension.

  Junichi Nakamura, Ichizo Tsujino, Hideki Shima, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Isao Yokota, Satoshi Konno

  Journal of thrombosis and thrombolysis 2023/08/24 

  INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) results from unresolved thrombotic obstruction of the pulmonary vasculature. Cancer is a known risk factor for CTEPH. This study aimed to determine the impact of cancer on the prevalence, management, and outcomes of patients with CTEPH. MATERIALS AND METHODS: In this retrospective study involving 99 patients sequentially diagnosed with CTEPH in our hospital, the prevalence of 10 comorbid conditions including a past history of cancer at the time of CTEPH diagnosis were calculated. RESULTS: Among the 99 patients, 17 (17%) had a history of cancer. Breast cancer (n = 6) was the most common cancer type, followed by gastrointestinal cancer (n = 3), uterine cancer (n = 2), and malignant lymphoma (n = 2). Between patients with and without cancer, there were no differences in the demographics, severity of CTEPH, and management; however, the 5-year survival rate was lower for patients with cancer (65%) than for those without (89%). In addition, patients with cancer had significantly worse survival than those without (p = 0.03 by log-rank test). During follow-up, nine patients developed cancer after the diagnosis of CTEPH. Among the 99 patients, 13 died during follow-up, 6 (46%) of whom died of cancer. CONCLUSIONS: 17% of our patients with CETPH were diagnosed with cancer, with breast and gastrointestinal tract cancers being the most common. Cancer comorbidity was associated with a poor prognosis and contributed to death in 46% of deceased patients. The impact of cancer on CTEPH should be further evaluated in the future.
• Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

  Michiko Takimoto-Sato, Masaru Suzuki, Hiroki Kimura, Haiyan Ge, Munehiro Matsumoto, Hironi Makita, Satoko Arai, Toru Miyazaki, Masaharu Nishimura, Satoshi Konno

  Respiratory research 24 (1) 201 - 201 2023/08/17 

  BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).
• Association of longitudinal cardiac troponin trajectory with adverse events in patients with cardiac sarcoidosis.

  Sho Kazui, Sakae Takenaka, Toshiyuki Nagai, Yoshiya Kato, Hirokazu Komoriyama, Yuta Kobayashi, Akinori Takahashi, Kiwamu Kamiya, Takuma Sato, Atsushi Tada, Yutaro Yasui, Michikazu Nakai, Takahiro Sato, Ichizo Tsujino, Satoshi Konno, Toshihisa Anzai

  International journal of cardiology 389 131268 - 131268 2023/08/15 

  BACKGROUND: Although high-sensitivity cardiac troponins may be sensitive and easily repeatable markers of disease activity in patients with cardiac sarcoidosis (CS), the association between longitudinal cardiac troponin trajectory and adverse events remains unclear. This study aimed to clarify whether longitudinal cardiac troponin levels were associated with adverse events in patients with CS. METHODS: We examined 63 consecutive CS-initiated prednisolone (PSL) patients with available longitudinal high-sensitivity cardiac troponin T (cTnT) data between December 2013 and March 2023. The area under the cTnT trajectory, which reflected cumulative cTnT release, was calculated to assess the association between longitudinal cTnT levels and adverse events. Patients were divided into two groups according to the median area under the cTnT trajectory per month. The primary outcome was a composite of sustained ventricular tachycardia or fibrillation, worsening heart failure, and sudden cardiac death (SCD). RESULTS: In total, 463 cTnT measurements were collected over a median follow-up period of 30.4 (interquartile range [IQR] 15.6-34.2) months. The primary outcome was observed in 12 (19%) patients. A higher area under the cTnT trajectory was significantly associated with an increased incidence of the primary outcome (P = 0.027), while cTnT levels before and one month after initiation of PSL, and these changes were not related to adverse events (P = 0.179, 0.096, and 0.95, respectively). CONCLUSIONS: Longitudinal cTnT trajectory following PSL initiation was associated with adverse cardiac events in patients with CS, suggesting that longitudinal measurement of cTnT would be useful for the early identification of high-risk patients.
• Clinical characteristics and natural course of chronic obstructive pulmonary disease and/or asthma in Japanese patients: a summary report of two Hokkaido-based cohort studies.

  Masaru Suzuki, Hironi Makita, Satoshi Konno, Masaharu Nishimura

  Respiratory investigation 61 (4) 527 - 539 2023/07 

  Chronic obstructive pulmonary disease (COPD) and asthma are the most common chronic airway diseases and are characterized by chronic airway inflammation and airflow limitation. Japanese patients with COPD or asthma have characteristics different from those of Westerners. Therefore, understanding the characteristics and clinical course of Japanese patients with COPD and those with asthma, particularly severe asthma, is critical for their management and appropriate treatment. The Hokkaido COPD cohort and Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) are high-quality cohort studies of COPD and asthma in the Japanese population and provide valuable data. This report summarizes the clinical findings from the two cohort studies and provides data for more appropriate management of Japanese patients with COPD and/or asthma. Overall, 279 patients with COPD were followed up for up to 10 years in the Hokkaido COPD cohort study, and 127 with severe asthma were followed up for up to 6 years in the Hi-CARAT study. Seventy-nine patients with mild-to-moderate asthma provided baseline data for the Hi-CARAT study. In each disease, several distinct factors, including systemic status and non-pulmonary factors, were associated with important clinical outcomes, such as lung function decline, exacerbations, impaired quality of life, and mortality. Therefore, multifaceted evaluation based on the characteristics of the Japanese population is necessary for the management of COPD and asthma.
• Associations of COVID-19 symptoms with omicron subvariants BA.2 and BA.5, host status, and clinical outcomes in Japan: a registry-based observational study.

  Sho Nakakubo, Naoki Kishida, Kenichi Okuda, Keisuke Kamada, Masami Iwama, Masaru Suzuki, Isao Yokota, Yoichi M Ito, Yasuyuki Nasuhara, Richard C Boucher, Satoshi Konno

  The Lancet. Infectious diseases 2023/06/30 

  BACKGROUND: Previous SARS-CoV-2 infection and vaccination, coupled with the rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We aimed to characterise the clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes. METHODS: In this registry-based observational study, individuals registered in Sapporo's web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Eligibility criteria included symptomatic individuals who tested positive for SARS-CoV-2 (PCR or antigen test), and individuals who were not tested for SARS-CoV-2 but developed new symptoms after a household member tested positive for SARS-CoV-2. Symptom prevalence, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed. FINDINGS: Data were collected and analysed between April 25 and Sept 25, 2022. For 157 861 omicron-infected symptomatic individuals, cough was the most common symptom (99 032 [62·7%] patients), followed by sore throat (95 838 [60·7%] patients), nasal discharge (69 968 [44·3%] patients), and fever (61 218 [38·8%] patients). Omicron BA.5 infection was associated with a higher prevalence of systemic symptoms than BA.2 in vaccinated and unvaccinated individuals (adjusted odds ratio [OR] for fever: 2·18 [95% CI 2·12-2·25]). Omicron breakthrough-infected individuals with three or more vaccinations or previous infection were less likely to exhibit systemic symptoms (fever 0·50 [0·49-0·51]), but more likely to exhibit upper respiratory symptoms (sore throat 1·33 [1·29-1·36]; nasal discharge 1·84 [1·80-1·89]). Infected older individuals (≥65 years) had lower odds for all symptoms. However, when symptoms were manifest, systemic symptoms were associated with increased odds for severe disease (dyspnoea 3·01 [1·84-4·91]; fever 2·93 [1·89-4·52]), whereas upper respiratory symptoms were associated with decreased odds (sore throat 0·38 [0·24-0·63]; nasal discharge 0·48 [0·28-0·81]). INTERPRETATION: Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a higher systemic symptom prevalence than BA.2. Vaccination and previous infection reduced systemic symptom prevalence and improved outcomes but increased upper respiratory tract symptom prevalence. Systemic, but not upper respiratory, symptoms in older people heralded severe disease. Our findings could serve as a practical guide to use COVID-19 symptoms to appropriately modify health-care strategies and predict clinical outcomes for older patients with omicron infections. FUNDING: Japan Agency for Medical Research and Development.
• 呼吸器内視鏡の新技術 ガイドシース用新型側方鉗子の開発

  品川 尚文, 高島 雄太, 伊藤 光一郎, 塚越 貴之, 伊藤 遼佑, 管 武志, 吉田 英謙, 永松 龍司, 武山 哲英, 七戸 俊明, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (Suppl.) S171 - S171 0287-2137 2023/06
• 80歳以上の高齢者に対する経気管支生検の安全性と有用性の検討

  畠山 酉季, 高島 雄太, 鈴木 孝敏, 棟方 奈菜, 中村 友彦, 高橋 宏典, 古田 恵, 北井 秀典, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 品川 尚文, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (Suppl.) S217 - S217 0287-2137 2023/06
• DirectPathにおけるオブリーク法による気管支鏡ナビゲーション作成の検討

  小熊 昂, 庄司 哲明, 畠山 酉季, 福井 伸明, 松浦 結子, 松永 章宏, 小林 冬美子, 高島 雄太, 品川 尚文, 三宅 浩太郎, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (Suppl.) S223 - S223 0287-2137 2023/06
• 次期細径超音波気管支鏡の挿入性及び穿刺性評価

  高島 雄太, 品川 尚文, 嘉島 相裕, 有里 仁希, 森永 大亮, 猪狩 智生, 伊藤 祥太郎, 辻 康介, 高橋 宏典, 庄司 哲明, 七戸 俊明, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (Suppl.) S257 - S257 0287-2137 2023/06
• Prevalence of Allergic Diseases across All Ages in Japan: A Nationwide Cross-Sectional Study Employing Designated Allergic Disease Medical Hospital Network.

  Yasunori Ito, Taisuke Kato, Koichi Yoshida, Kyohei Takahashi, Yuma Fukutomi, Mizuho Nagao, Tatsuki Fukuie, Hiroshi Matsuzaki, Minoru Gotoh, Akio Tanaka, Satoshi Konno, Junichiro Tezuka, Yosikazu Nakamura, Yuichi Adachi

  JMA journal 6 (2) 165 - 174 2023/04/14 

  INTRODUCTION: Allergic diseases affect both children and adults, but generation-specific prevalence rates are unclear. METHODS: An online questionnaire was used from December 2021 to January 2022 to survey the prevalence of allergic diseases among staff and their families of designated allergic disease medical hospitals in Japan. In this study, bronchial asthma (BA), atopic dermatitis (AD), food allergies (FAs), allergic rhinitis (AR), allergic conjunctivitis (AC), metal allergies (MAs), and drug allergies (DAs) were the allergic diseases surveyed. RESULTS: In total, 18,706 individuals were surveyed (median age, 36 years; quartile range, 18-50). Allergic disease was reported in 62.2% of respondents. Across all ages, prevalence rates were as follows: BA (14.7%), AD (15.6%), FAs (15.2%), AR (47.4%), AC (19.5%), MAs (1.9%), and DAs (4.6%). The prevalence of BA and AR was higher in male children, whereas that of FAs and AC was higher in adult females. The prevalence of MAs and DAs peaked during adulthood and predominated among females. CONCLUSIONS: Our results suggest that approximately two-thirds of the Japanese population may have an allergic disease, with AR being the most prevalent.
• 当科におけるPD-L1陰性非小細胞肺癌に対する免疫チェックポイント阻害薬治療についての後方視的検討

  田上 敬太, 菊地 英毅, 庄司 哲明, 吉川 修平, 黒木 俊宏, 嘉島 相裕, 高木 統一郎, 三浦 瞬, 猪狩 智生, 小熊 昂, 古田 恵, 高島 雄太, 朝比奈 肇, 菊地 順子, 榊原 純, 品川 尚文, 今野 哲

  肺癌 (NPO)日本肺癌学会 63 (2) 126 - 127 0386-9628 2023/04
• 化学放射線療法+デュルバルマブ療法を施行後に病勢進行となった非小細胞肺癌の次治療の後方視的検討

  嘉島 相裕, 庄司 哲明, 古田 恵, 吉川 修平, 黒木 俊宏, 田上 敬太, 高木 統一郎, 三浦 瞬, 小熊 昂, 猪狩 智生, 高島 雄太, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲

  肺癌 (NPO)日本肺癌学会 63 (2) 127 - 127 0386-9628 2023/04
• RET融合遺伝子陽性肺腺癌に対してセルペルカチニブ投与後に多彩な有害事象を呈した症例

  関 萌花, 猪狩 智生, 榊原 純, 吉川 修平, 黒木 俊宏, 田上 敬太, 嘉島 相裕, 高木 統一郎, 三浦 瞬, 小熊 昂, 高島 雄太, 古田 恵, 庄司 哲明, 朝比奈 肇, 菊地 順子, 菊地 英毅, 品川 尚文, 今野 哲, 伊藤 健一郎

  肺癌 (NPO)日本肺癌学会 63 (2) 128 - 128 0386-9628 2023/04
• Clinical and Hemodynamic Responses to Imatinib in Pulmonary Veno-Occlusive Disease/Pulmonary Capillary Hemangiomatosis: A Retrospective Pilot Study of Five Cases and Review of the Literature

  Junichi Nakamura, Ichizo Tsujino, Hideki Shima, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Satonori Tsuneta, Ryo Hisada, Masaru Kato, Satoshi Konno

  American Journal of Cardiovascular Drugs 23 (3) 329 - 338 1175-3277 2023/03/30
• Serum Lactate Dehydrogenase Level One Week after Admission Is the Strongest Predictor of Prognosis of COVID-19: A Large Observational Study Using the COVID-19 Registry Japan.

  Sho Nakakubo, Yoko Unoki, Koji Kitajima, Mari Terada, Hiroyuki Gatanaga, Norio Ohmagari, Isao Yokota, Satoshi Konno

  Viruses 15 (3) 2023/03/02 

  Clinical features of COVID-19 are diverse, and a useful tool for predicting clinical outcomes based on clinical characteristics of COVID-19 is needed. This study examined the laboratory values and trends that influence mortality in hospitalised COVID-19 patients. Data on hospitalised patients enrolled in a registry study in Japan (COVID-19 Registry Japan) were obtained. Patients with records on basic information, outcomes, and laboratory data on the day of admission (day 1) and day 8 were included. In-hospital mortality was set as the outcome, and associated factors were identified by multivariate analysis using the stepwise method. A total of 8860 hospitalised patients were included. The group with lactate dehydrogenase (LDH) levels >222 IU/L on day 8 had a higher mortality rate compared to the group with LDH levels ≤222 IU/L. Similar results were observed in subgroups formed by age, body mass index (BMI), underlying disease, and mutation type, except for those aged <50 years. When age, sex, BMI, underlying disease, and laboratory values on days 1 and 8 were tested for factors strongly associated with in-hospital mortality, LDH on day 8 was most strongly associated with mortality. LDH level on day 8 was the strongest predictor of in-hospital mortality in hospitalised COVID-19 patients, indicating its potential usefulness in post-treatment decision-making in severe COVID-19 cases.
• 非小細胞肺癌での化学放射線+デュルバルマブ療法後の免疫チェックポイント阻害剤再投与の後方視的検討

  嘉島 相裕, 庄司 哲明, 古田 恵, 猪狩 智生, 高島 雄太, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 今野 哲

  日本呼吸器学会誌 (一社)日本呼吸器学会 12 (増刊) 278 - 278 2186-5876 2023/03
• 抗血小板薬・抗凝固薬内服患者における経気管支生検の有害事象の検討

  庄司 哲明, 品川 尚文, 高島 雄太, 菊池 創, 池澤 靖元, 高階 太一, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 45 (2) 89 - 97 0287-2137 2023/03 

  背景.抗血栓薬内服患者において,休薬して経気管支生検を行った場合の安全性は明らかではない.今回,休薬して経気管支生検を行った場合の有害事象発生率を内服していない患者と比較した.対象と方法.2010年8月から2015年7月までに北海道大学病院内科Iで施行したガイドシース併用気管支腔内超音波断層法下生検,超音波気管支鏡ガイド下針生検,経気管支肺生検,直視下生検について,有害事象と抗血小板薬のみ内服,抗凝固薬のみ内服,両方内服との関連を後ろ向きに検討した.年齢,性別などの因子も含め単変量解析,多変量解析を行った.内服患者では日本呼吸器内視鏡学会手引き書Ver.2.0およびVer.3.0に従って休薬した.結果.経気管支生検の施行件数は1320件で,抗血栓薬なし1145件,抗血小板薬のみ131件,抗凝固薬のみ24件,両方20件だった.有害事象発生率は全体7.0%,抗血栓薬なし7.2%,抗血小板薬のみ4.6%,抗凝固薬のみ0.0%,両方15.0%だった.単変量解析,多変量解析いずれも内服なし群と各内服群に有意差はなかった(多変量解析,抗血小板薬のみ:p=0.463,抗凝固薬のみ:p=0.988,両方:p=0.249).結論.抗血小板薬・抗凝固薬を内服している患者でも適切な休薬期間を設けることで有害事象発生が有意に増加することなく経気管支生検を施行できる可能性が示された.(著者抄録)
• 抗血小板薬・抗凝固薬内服患者における経気管支生検の有害事象の検討

  庄司 哲明, 品川 尚文, 高島 雄太, 菊池 創, 池澤 靖元, 高階 太一, 今野 哲

  気管支学 (NPO)日本呼吸器内視鏡学会 45 (2) 89 - 97 0287-2137 2023/03
• Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy.

  Mineyoshi Sato, Nako Maishi, Yasuhiro Hida, Aya Yanagawa-Matsuda, Mohammad Towfik Alam, Jun Sakakibara-Konishi, Jin-Min Nam, Yasuhito Onodera, Satoshi Konno, Kyoko Hida

  Cancer medicine 2023/02/19 

  In lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre-administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8-positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre-administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T-cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre-administration significantly reduced PD-L1 expression. When combined with an ICI and paclitaxel, only DC101 pre-administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre-administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration.
• 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 2023/01/31 

  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 

  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.
• Risk of bleeding associated with transbronchial biopsy using flexible bronchoscopy in patients with echocardiographic or chest CT evidence of pulmonary hypertension.

  Yuta Takashima, Naofumi Shinagawa, Daisuke Morinaga, Junichi Nakamura, Megumi Furuta, Tetsuaki Shoji, Hajime Asahina, Eiki Kikuchi, Junko Kikuchi, Jun Sakakibara-Konishi, Ichizo Tsujino, Satoshi Konno

  BMC pulmonary medicine 22 (1) 449 - 449 2022/11/28 [Refereed]
   

  BACKGROUND: Endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) facilitates the diagnosis of various respiratory diseases. The safety of performing EBUS-guided TBB in patients with a finding of pulmonary hypertension (PH) is controversial. Little is known about the relationship between the risk of bleeding associated with EBUS-guided TBB in the presence of PH suspected on echocardiography or chest CT. METHODS: To assess the risk of bleeding associated with EBUS-guided TBB in patients with presumed PH per echocardiography or chest CT, we retrospectively reviewed the medical records of 314 consecutive patients who underwent EBUS-guided TBB using a guide sheath (GS), as well as echocardiography and chest CT. Bleeding complication was defined as over one minute of suctioning; repeated wedging of the bronchoscope; instillation of cold saline, diluted vasoactive substances, or thrombin due to persistent bleeding. Findings of suspected PH were defined as peak tricuspid regurgitation velocity (TRV) > 2.8 m/s on echocardiography or pulmonary artery to aorta ratio (PA:A ratio) > 0.9 on chest CT. RESULTS: In total, 35 (11.1%) patients developed bleeding, and all cases were managed safely. Furthermore, 17 (5.4%) and 59 (18.8%) patients were suspected to have PH based on echocardiography and chest CT, respectively. Among the patients suspected to have PH on echocardiography, five (5/17 = 29.4%) patients developed bleeding. Among the patients suspected to have PH on chest CT, 11 (11/59 = 18.6%) patients developed bleeding. Univariate analysis revealed that long diameter (≥ 30 mm) of the lesion, lesion location (the biopsy site was inner than the segmental bronchus), bronchoscopic diagnosis of malignancy, and additional biopsy were potential predictive factors for bleeding. The finding of suspected PH on echocardiography correlated significantly with bleeding (p = 0.03). On multivariate analysis, long diameter (≥ 30 mm) of the lesion (p = .021) and findings of suspected PH on echocardiography (p = .049) were significantly associated with bleeding. CONCLUSION: All cases of bleeding in the present study were managed safely. The risk of bleeding is moderately elevated when PH is suspected by echocardiography in patients undergoing EBUS-guided TBB using a GS.
• Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer.

  Hirofumi Takahashi, Jun Sakakibara-Konishi, Megumi Furuta, Tetsuaki Shoji, Kosuke Tsuji, Daisuke Morinaga, Eiki Kikuchi, Junko Kikuchi, Takuro Noguchi, Kanako C Hatanaka, Yutaka Hatanaka, Naofumi Shinagawa, Satoshi Konno

  Cancer science 2022/11/21 

  Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.
• EGFR変異陽性非小細胞肺癌におけるosimertinib耐性とNotch経路の関わり

  高橋 宏典, 榊原 純, 古田 恵, 庄司 哲明, 辻 康介, 森永 大亮, 菊地 英毅, 菊地 順子, 野口 卓郎, 畑中 佳奈子, 畑中 豊, 品川 尚文, 今野 哲

  肺癌 (NPO)日本肺癌学会 62 (6) 715 - 715 0386-9628 2022/11
• EBUS-GS-TBB検体の腫瘍細胞含有率に関連する臨床因子についての検討

  高島 雄太, 品川 尚文, 有里 仁希, 嘉島 相裕, 庄司 哲明, 古田 恵, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 畑中 佳奈子, 松野 吉宏, 畑中 豊, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 44 (6) 459 - 459 0287-2137 2022/11
• 非小細胞肺癌のmitotic slippageに対するDNA修復阻害の有用性についての基礎的検討

  辻 康介, 菊地 英毅, 高島 雄太, 庄司 哲明, 森永 大亮, 伊藤 祥太郎, 高橋 宏典, 朝比奈 肇, 菊地 順子, 品川 尚文, 榊原 純, 今野 哲

  肺癌 (NPO)日本肺癌学会 62 (6) 754 - 754 0386-9628 2022/11
• Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency.

  Kuniaki Seyama, Masaru Suzuki, Sadatomo Tasaka, Toshihiro Nukiwa, Tadashi Sato, Satoshi Konno, Susan Sorrells, Junliang Chen, Maria Esperança Aragonés, Hitoshi Minamino

  Respiratory investigation 60 (6) 831 - 839 2022/11 

  BACKGROUND: Safety and pharmacokinetics (PK) of alpha1-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha1-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD. METHODS: This was a multi-center, open-label extension (OLE) study that enrolled adult patients with AATD, who had completed the preceding safety and PK clinical trial. Patients were administered with Alpha-1 MP (60 mg/kg) weekly, for 52 weeks, and this could be renewed annually. Alpha1-MP trough levels (Cmin) were evaluated, and safety endpoints include: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs potentially related to Alpha-1 MP, chronic obstructive pulmonary disease (COPD) exacerbations, laboratory parameters, vital signs, and pulmonary function tests (forced expiration volume in 1 s [FEV1] and forced vital capacity [FVC]). RESULTS: Four patients underwent Alpha-1 MP intravenous infusions at a mean (SD) of 210.8 (9.54) for 213 weeks (four years), with a Cmin of 55.73 (4.99) mg/dL. A total of fifty-four TEAEs were reported in four patients, in which most of them were mild (n = 52, 96.3%). Two patients had five SAEs, and all were unrelated to treatment. Three mild TEAEs were potentially related to treatment with Alpha-1 MP. No clinically significant findings in laboratory parameters, COPD exacerbations, or vital signs were observed. There were no identifiable differences in FEV1 and FVC throughout the study period. CONCLUSIONS: Long-term weekly intravenous infusions of 60 mg/kg Alpha-1 MP are generally safe and well-tolerated in Japanese patients with AATD. CLINICALTRIALS: GOV: NCT02870348; JAPIC CTI: JapicCTI-163194.
• SARS-CoV-2 Omicron detection by antigen tests using saliva.

  Kaoru Murakami, Sumio Iwasaki, Satoshi Oguri, Kumiko Tanaka, Rigel Suzuki, Kasumi Hayasaka, Shinichi Fujisawa, Chiaki Watanabe, Satoshi Konno, Isao Yokota, Takasuke Fukuhara, Masaaki Murakami, Takanori Teshima

  Journal of clinical virology plus 2 (4) 100109 - 100109 2022/11 

  The Omicron emerged in November 2021 and became the predominant SARS-CoV-2 variant globally. It spreads more rapidly than ancestral lineages and its rapid detection is critical for the prevention of disease outbreaks. Antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) yield results more quickly than standard polymerase chain reaction (PCR). However, their utility for the detection of the Omicron variant remains unclear. We herein evaluated the performance of ICA and CLEIA in saliva from 51 patients with Omicron and 60 PCR negative individuals. The sensitivity and specificity of CLEIA were 98.0% (95%CI: 89.6-100.0%) and 100.0% (95%CI: 94.0-100.0%), respectively, with fine correlation with cycle threshold (Ct) values. The sensitivity and specificity of ICA were 58.8% (95%CI: 44.2-72.4%) and 100.0% (95%CI: 94.0-100.0%), respectively. The sensitivity of ICA was 100.0% (95%CI: 80.5-100.0%) when PCR Ct was less than 25. The Omicron can be efficiently detected in saliva by CLEIA. ICA also detects high viral load Omicron using saliva.
• Thrombocytopenia and pneumonitis associated with BNT16B2b2 mRNA COVID-19 vaccine: A case report

  Yuichi Kojima, Kimihiro Takeyabu, Miki Satoh, Satoshi Konno

  Clinical Infection in Practice 16 100204 - 100204 2590-1702 2022/11
• Efficacy and safety of oral pulmonary vasodilators in pulmonary veno‐occlusive disease

  Junichi Nakamura, Ichizo Tsujino, Hideki Shima, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Satonori Tsuneta, Ryo Hisada, Masaru Kato, Satoshi Konno

  Pulmonary Circulation 12 (4) 2045-8940 2022/10
• 非小細胞肺癌のmitotic slippageに対するDNA修復阻害の有用性についての基礎的検討(Inhibition of DNA damage repair for mitotic slippage after paclitaxel treatment in non-small cell lung cancer)

  辻 康介, 菊地 英毅, 高島 雄太, 庄司 哲明, 朝比奈 肇, 菊地 順子, 品川 尚文, 榊原 純, 今野 哲

  日本癌学会総会記事 81回 P - 1063 0546-0476 2022/09
• 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 (一社)日本アレルギー学会 71 (8) 944 - 948 0021-4884 2022/09 

  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)
• Various factors contribute to death in patients with different types of pulmonary hypertension: A retrospective pilot study from a single tertiary center.

  Junichi Nakamura, Ichizo Tsujino, Hiroshi Ohira, Toshitaka Nakaya, Ayako Sugimoto, Takahiro Sato, Taku Watanabe, Masaru Suzuki, Masaru Kato, Isao Yokota, Satoshi Konno

  Respiratory investigation 60 (5) 647 - 657 2022/09 

  BACKGROUND: A few studies have focused on the cause of death from different types of pulmonary hypertension (PH). This study aimed to systematically analyze the primary and secondary causes of death and compare the profiles between different PH groups. METHODS: The contribution of PH to death was assessed in precapillary PH (i.e., group 1 [pulmonary arterial hypertension], group 3 [PH associated with lung disease], and group 4 [chronic thromboembolic PH]) using specific criteria; death was classified into three categories: PH death (death due to PH only), PH-related death, and PH-unrelated death. Disorders other than PH that contributed to death were analyzed, and mortality profiles were compared between groups. RESULTS: Eighty deceased patients with PH were examined (group 1, n = 28; group 3, n = 39; and group 4, n = 13). The contribution of PH to death was significantly different between the three groups. "PH death" was most common in group 1 (61%), "PH-related death" in group 3 (56%), and "PH-related death" and "PH-unrelated death" in group 4 (38% for both). The highest contributing factor to death other than PH was respiratory failure in group 3 and malignant disease in group 4. CONCLUSIONS: Significant variations in the causes of death were observed in groups 1, 3, and 4 PH patients. In addition to PH, respiratory failure and malignant disease significantly contributed to death in group 3 and group 4 PH, respectively. Understanding the precise death cause may be important in achieving better outcomes in PH patients.
• Combination therapy with remdesivir and immunomodulators improves respiratory status in COVID-19: A retrospective study.

  Yuichi Kojima, Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Nozomu Takei, Junichi Nakamura, Munehiro Matsumoto, Hiroshi Horii, Kazuki Sato, Hideki Shima, Masaru Suzuki, Satoshi Konno

  Journal of medical virology 94 (12) 5702 - 5712 2022/08/02 

  Immunomodulators (tocilizumab/baricitinib) improve outcomes of coronavirus disease (COVID-19) patients, but the synergistic effect of remdesivir is unknown. The effect of combination therapy with remdesivir, immunomodulators, and standard treatment in COVID-19 patients was investigated. This retrospective, single-center study included COVID-19 patients who were treated with tocilizumab or baricitinib. The severity of respiratory status in the two groups on day 14 and day 28 and the duration to respiratory recovery in both groups were compared, and the effect of remdesivir use on respiratory status was examined in a multivariate analysis. Ninety-eight patients received tocilizumab or baricitinib; among them, 72 used remdesivir (remdesivir group) and 26 did not (control group). The remdesivir group achieved faster respiratory recovery than the control group (median 11 days vs. 21 days, p=0.033), faster weaning from supplemental oxygen (HR 2.54, 95% CI 1.14-5.66, p=0.021). Age, body mass index, diabetes mellitus, and time from onset to oxygen administration were independent prognostic factors. The remdesivir group achieved better severity level at days 14 and 28 (p=0.033 and 0.003, respectively) and greater improvement from baseline severity (p=0.047 and 0.018, respectively). Remdesivir combination therapy did not prolong survival (HR 0.31, 95% CI 0.04-2.16, p=0.23). Among severely ill COVID-19 patients who received immunomodulator, remdesivir contributed to a shorter respiratory recovery time and better respiratory status at days 14 and 28. Concomitant remdesivir with immunomodulators and standard treatment may provide additional benefit in improving respiratory status of COVID-19 patients. This article is protected by copyright. All rights reserved.
• An Adult Case of Unilateral Left Pulmonary Artery Agenesis Presenting with Hemoptysis.

  Yuriko Ishida, Masaru Suzuki, Hiroshi Horii, Junichi Nakamura, Munehiro Matsumoto, Sho Nakakubo, Takahiro Sato, Ichizo Tsujino, Ryo Morita, Daisuke Abo, Satoshi Konno

  Internal medicine (Tokyo, Japan) 62 (5) 763 - 767 2022/07/22 

  Pulmonary artery agenesis (PAA) is a rare congenital vascular anomaly usually diagnosed during infancy. We herein report a 67-year-old man with PAA manifesting as massive hemoptysis. Contrast-enhanced computed tomography of the chest revealed the diagnosis of PAA, which we speculated to have resulted in the present event. Detailed angiography provided more accurate information on the pulmonary vasculature and collateral circulation, which helped us plan tailored treatment. Although very rare, we must consider the possibility of PAA in adults with unexplained hemoptysis.
• 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 2022/06/29 

  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 2022/06/29 

  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 2022/06/16 

  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.
• Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia

  Michiko Takimoto-Sato, Toshinari Miyauchi, Masaru Suzuki, Hideyuki Ujiie, Toshifumi Nomura, Tomoo Ikari, Tomohiko Nakamura, Kei Takahashi, Machiko Matsumoto-Sasaki, Hirokazu Kimura, Hiroki Kimura, Yuichiro Matsui, Takashi Kitagataya, Ren Yamada, Kazuharu Suzuki, Akihisa Nakamura, Masato Nakai, Takuya Sho, Koji Ogawa, Naoya Sakamoto, Naoko Yamaguchi, Noriyuki Otsuka, Utano Tomaru, Satoshi Konno

  Frontiers in Genetics 13 2022/05/05 

  Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids. Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T &gt; G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid. Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.
• Exposure to PM2.5 and Lung Function Growth in Pre- and Early-Adolescent Schoolchildren: A Longitudinal Study Involving Repeated Lung Function Measurements in Japan.

  Toru Takebayashi, Masataka Taguri, Hiroshi Odajima, Shuichi Hasegawa, Keiko Asakura, Ai Milojevic, Ayano Takeuchi, Satoshi Konno, Miki Morikawa, Teruomi Tsukahara, Kayo Ueda, Yasufumi Mukai, Mihoko Minami, Yuuji Nishiwaki, Takesumi Yoshimura, Masaharu Nishimura, Hiroshi Nitta

  Annals of the American Thoracic Society 19 (5) 763 - 772 2022/05 

  Rationale: Epidemiological evidence indicates that ambient exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5) has adverse effects on lung function growth in children, but it is not actually clear whether exposure to low-level PM2.5 results in long-term decrements in lung function growth in pre- to early-adolescent schoolchildren. Objectives: To examine long-term effects of PM2.5 within the 4-year average concentration range of 10-19 μg/m3 on lung function growth with repeated measurements of lung function tests. Methods: Longitudinal analysis of 6,233 lung function measurements in 1,466 participants aged 8-12 years from 16 school communities in 10 cities around Japan, covering a broad area of the country to represent concentration ranges of PM2.5, was done with a multilevel linear regression model. Forced expiratory volume in 1 second, forced vital capacity (FVC), and maximal expiratory flow at 50% of FVC were used as lung function indicators to examine the effects of 10-μg/m3 increases in the PM2.5 concentration on relative growth per each 10-cm increase in height. Results: The overall annual mean PM2.5 level was 13.5 μg/m3 (range, 10.4-19.0 μg/m3). We found no association between any of the lung function growth indicators and increases in PM2.5 levels in children of either sex, even after controlling for potential confounders. Analysis with two-pollutant models with O3 or NO2 did not change the null results. Conclusions: This nationwide longitudinal study suggests that concurrent, long-term exposure to PM2.5 at concentrations ranging from 10.4 to 19.0 μg/m3 has little effect on lung function growth in preadolescent boys or pre- to early-adolescent girls.
• 今月の症例 両側滲出性胸水と全身浮腫で発症し、局所麻酔下胸腔鏡でサルコイドーシスと診断した1例

  篠崎 鮎香[臺], 木村 孔一, 山下 優, 堀井 洋志, 佐藤 一紀, 中村 順一, 中久保 祥, 鎌田 啓佑, 鈴木 雅, 中里 信一, 松野 吉宏, 今野 哲

  日本内科学会雑誌 (一社)日本内科学会 111 (5) 984 - 989 0021-5384 2022/05
• Gargling with povidone iodine has a short-term inhibitory effect on SARS-CoV-2 in patients with COVID-19

  T. Seikai, A. Takada, A. Hasebe, M. Kajihara, K. Okuya, T. Sekiguchi (Yamada), W. Kakuguchi, S. Konno, Y. Ohiro

  Journal of Hospital Infection 123 179 - 181 0195-6701 2022/05 [Refereed][Not invited]
  
• Multiple Routes of Antibody-Dependent Enhancement of SARS-CoV-2 Infection.

  Kosuke Okuya, Takanari Hattori, Takeshi Saito, Yoshihiro Takadate, Michihito Sasaki, Wakako Furuyama, Andrea Marzi, Yoichi Ohiro, Satoshi Konno, Takeshi Hattori, Ayato Takada

  Microbiology spectrum 10 (2) e0155321  2022/04/27 

  Antibody-dependent enhancement (ADE) of infection is generally known for many viruses. A potential risk of ADE in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has also been discussed since the beginning of the coronavirus disease 2019 (COVID-19) pandemic; however, clinical evidence of the presence of antibodies with ADE potential is limited. Here, we show that ADE antibodies are produced by SARS-CoV-2 infection and the ADE process can be mediated by at least two different host factors, Fcγ receptor (FcγR) and complement component C1q. Of 89 serum samples collected from acute or convalescent COVID-19 patients, 62.9% were found to be positive for SARS-CoV-2-specific IgG. FcγR- and/or C1q-mediated ADE were detected in 50% of the IgG-positive sera, whereas most of them showed neutralizing activity in the absence of FcγR and C1q. Importantly, ADE antibodies were found in 41.4% of the acute COVID-19 patients. Neutralizing activity was also detected in most of the IgG-positive sera, but it was counteracted by ADE in subneutralizing conditions in the presence of FcγR or C1q. Although the clinical importance of ADE needs to be further investigated with larger numbers of COVID-19 patient samples, our data suggest that SARS-CoV-2 utilizes multiple mechanisms of ADE. C1q-mediated ADE may particularly have a clinical impact since C1q is present at high concentrations in plasma and its receptors are ubiquitously expressed on the surfaces of many types of cells, including respiratory epithelial cells, which SARS-CoV-2 primarily infects. IMPORTANCE Potential risks of antibody-dependent enhancement (ADE) in the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been discussed and the proposed mechanism mostly depends on the Fc gamma receptor (FcγR). However, since FcγRs are exclusively expressed on immune cells, which are not primary targets of SARS-CoV-2, the clinical importance of ADE of SARS-CoV-2 infection remains controversial. Our study demonstrates that SARS-CoV-2 infection induces antibodies that increase SARS-CoV-2 infection through another ADE mechanism in which complement component C1q mediates the enhancement. Although neutralizing activity was also detected in the serum samples, it was counteracted by ADE in the presence of FcγR or C1q. Considering the ubiquity of C1q and its cellular receptors, C1q-mediated ADE may more likely occur in respiratory epithelial cells, which SARS-CoV-2 primarily infects. Our data highlight the importance of careful monitoring of the antibody properties in COVID-19 convalescent and vaccinated individuals.
• Comparative Efficacy of Tocilizumab and Baricitinib Administration in COVID-19 Treatment: A Retrospective Cohort Study.

  Yuichi Kojima, Sho Nakakubo, Nozomu Takei, Keisuke Kamada, Yu Yamashita, Junichi Nakamura, Munehiro Matsumoto, Hiroshi Horii, Kazuki Sato, Hideki Shima, Masaru Suzuki, Satoshi Konno

  Medicina (Kaunas, Lithuania) 58 (4) 2022/04/04 

  Background and Objectives: Tocilizumab and baricitinib have been observed to improve the outcomes of patients with coronavirus disease 2019 (COVID-19). However, a comparative evaluation of these drugs has not been performed. Materials and Methods: A retrospective, single-center study was conducted using the data of COVID-19 patients admitted to Hokkaido University hospital between April 2020 and September 2021, who were treated with tocilizumab or baricitinib. The clinical characteristics of the patients who received tocilizumab were compared to those of patients who received baricitinib. Univariate and multivariate logistic regression analyses of the outcomes of all-cause mortality and improvement in respiratory status were performed. The development of secondary infection events was analyzed using the Kaplan-Meier method and the log-rank test. Results: Of the 459 patients hospitalized with COVID-19 during the study, 64 received tocilizumab treatment and 34 baricitinib treatment, and those 98 patients were included in the study. Most patients were treated with concomitant steroids and exhibited the same severity level at the initiation of drug treatment. When compared to each other, neither tocilizumab nor baricitinib use were associated with all-cause mortality or improvement in respiratory status within 28 days from drug administration. Conclusions: Age, chronic renal disease and early administration of TCZ or BRT from the onset of COVID-19 were independent prognostic factors for all-cause mortality, whereas anti-viral drug use and the severity of COVID-19 at baseline were associated with an improvement in respiratory status. Secondary infection-free survival rates of patients treated with tocilizumab and those treated with baricitinib did not significantly differ. The results suggest that both tocilizumab and baricitinib could be clinically equivalent agents of choice in treatment of COVID-19.
• 肺病変にステロイドが奏功したPOIKTMPの1例(アンコール演題)

  佐藤 理子, 鈴木 雅, 猪狩 智生, 中村 友彦, 高橋 桂, 佐々木 真知子, 木村 孔一, 木村 裕樹, 宮内 俊成, 乃村 俊史, 氏家 英之, 山口 直子, 大塚 紀幸, 外丸 詩野, 今野 哲

  日本呼吸器学会誌 (一社)日本呼吸器学会 11 (増刊) 272 - 272 2186-5876 2022/04
• オシメルチニブ長期内服中に亜鉛欠乏に伴う壊死性遊走性紅斑様皮疹を生じた一例

  山本 岳, 朝比奈 肇, 岩田 浩明, 高桑 恵美, 伊藤 祥太郎, 國崎 守, 高島 雄太, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲

  日本呼吸器学会誌 (一社)日本呼吸器学会 11 (増刊) 303 - 303 2186-5876 2022/04
• C-reactive protein level predicts need for medical intervention in pregnant women with SARS-CoV2 infection: A retrospective study.

  Ryutaro Yamamoto, Hiroshi Asano, Takeshi Umazume, Masato Takaoka, Kiwamu Noshiro, Yoshihiro Saito, Kinuko Nakagawa, Kentaro Chiba, Sho Nakakubo, Yasuyuki Nasuhara, Satoshi Konno, Hidemichi Watari

  The journal of obstetrics and gynaecology research 48 (4) 938 - 945 2022/04 

  AIM: To make effective use of the limited available hospital space during the Coronavirus disease 2019 (COVID-19) pandemic, we conducted this study to investigate the laboratory indices that identify pregnant women with SARS-CoV2 infection who require medical intervention. METHODS: We carried out a retrospective analysis of pregnant women positive for COVID-19 who were admitted to Hokkaido University Hospital from September 2020 to June 2021. Medical interventions included oxygen supplementation, systemic corticosteroids, or supplemental liquids to treat infection-related symptoms. RESULTS: Forty-two infected pregnant patients were admitted to the hospital, half of whom required medical intervention (n = 21). Fever, C-reactive protein (CRP), and platelet count are all associated with need for medical intervention. Of the 32 patients with a fever of ≥37.5°C on days 0-3 after onset of syndromes, 22 (69%) continued to have a fever on days 4-6, of which 19 (86.4%) required medical intervention. CRP level on days 4-6 predicted the presence or absence of medical intervention (area under the receiver operating characteristic curve = 0.913), with a sensitivity of 81% and specificity of 100% at a CRP cutoff of 1.28 mg/dL. CONCLUSIONS: The need for medical intervention in pregnant patients can be predicted with high accuracy using a CRP cutoff of 1.28 mg/dL on days 4-6 after onset of syndromes. The presence of fever also may be an easy marker for selecting subjects who need or will need therapeutic intervention. These could be an effective triage method to determine appropriate indications for the hospitalization of pregnant women in future outbreaks.
• 小細胞肺癌転化を来したEGFR遺伝子変異陽性肺癌の3例

  森永 大亮, 榊原 純, 古田 恵, 品川 尚文, 合田 智宏, 若林 健人, 高桑 恵美, 高階 太一, 今野 哲

  肺癌 (NPO)日本肺癌学会 62 (2) 107 - 114 0386-9628 2022/04 

  背景.Epidermal growth factor receptor(EGFR)遺伝子変異陽性肺癌はtyrosine kinase inhibitor(EGFR-TKI)が高い奏効率を示すが,その後耐性化を来す.近年その耐性化の機序が解明され,小細胞肺癌(small cell lung cancer:SCLC)転化は耐性化の2〜15%を占めるが転化後の治療,転帰など詳細な報告は少ない.症例1.66歳,女性.6次治療のオシメルチニブ投与中に胸水の増悪を認め,セルブロックでSCLCの形態に変化した腫瘍を認めた.症例2.47歳,男性.6次治療のS-1投与中にNSE,ProGRPの上昇と胸膜播種の悪化を認め,胸膜病変の生検を施行しSCLCの診断となった.症例3.67歳,男性.初回治療のエルロチニブ開始後14ヵ月目に肺原発の増大を認め,再生検でSCLC転化を認めた.3例ともシスプラチン+イリノテカンを投与し病勢制御しえた.結論.EGFR遺伝子変異陽性肺癌の小細胞肺癌転化の症例に対し,シスプラチン+イリノテカン療法が有用な治療選択肢となる可能性がある.しかし同治療の詳細な報告は限られており,さらなる症例集積が必要である.(著者抄録)
• Underdiagnosis of cardiac sarcoidosis by ECG and echocardiography in cases of extracardiac sarcoidosis.

  Hiroshi Ohira, Takahiro Sato, Osamu Manabe, Noriko Oyama-Manabe, Akiko Hayashishita, Toshitaka Nakaya, Junichi Nakamura, Naoko Suzuki, Ayako Sugimoto, Sho Furuya, Satonori Tsuneta, Taku Watanabe, Ichizo Tsujino, Satoshi Konno

  ERJ open research 8 (2) 2022/04 

  Background: Although screening with 12-lead electrocardiography and transthoracic echocardiography for cardiac involvement has been recommended for patients with biopsy-proven extracardiac sarcoidosis, cardiac sarcoidosis has been reported even in patients with normal electrocardiography and echocardiography findings. We investigated the prevalence and characteristics of these patient cohorts. Methods: We studied 112 consecutive patients (age, 55±17 years, 64% females) with biopsy-proven extracardiac sarcoidosis who had undergone 18F-fluorodeoxyglucose positron emission tomography and cardiac magnetic resonance imaging for cardiac sarcoidosis evaluation. The patients were categorised as those showing normal findings both in electrocardiography and transthoracic echocardiography (normal group) and those showing abnormal findings in one or both examinations (abnormal group). Results: 33 (29%) and 79 (71%) patients were categorised into the normal and abnormal groups, respectively, of which 6 (18%) and 43 (54%) patients, respectively, were diagnosed with cardiac sarcoidosis (p<0.01). Of these six patients in the normal group, two with multiple-organ sarcoidosis showed clinical deterioration of cardiac involvement and required steroid therapy; three with small cardiac involvement showed natural remission over follow-up assessments; and one underwent steroid therapy and showed an improvement in the left ventricular ejection fraction to within normal limits. Conclusions: The prevalence of cardiac sarcoidosis in patients with biopsy-proven extracardiac sarcoidosis and normal electrocardiography and transthoracic echocardiography findings was ∼20%. Electrocardiography and transthoracic echocardiography may not detect cardiac sarcoidosis in patients without conduction and morphological abnormalities. However, some of these patients may subsequently show clinically manifested cardiac sarcoidosis. Physicians should be mindful of this population.
• Lymphocytic panhypophysitis and anti-rabphilin-3A antibody with pulmonary sarcoidosis.

  Yuka Takahashi, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Hiroki Nishimura, Hirokazu Kimura, Masaru Suzuki, Satoshi Konno, Ai Shimizu, Yoshihiro Matsuno, Michinari Okamoto, Hiroaki Motegi, Naoko Iwata, Haruki Fujisawa, Atsushi Suzuki, Yoshihisa Sugimura, Hideaki Miyoshi, Tatsuya Atsumi

  Pituitary 25 (2) 321 - 327 2022/04 

  PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.
• Delayed-onset Organizing Pneumonia Emerging after Recovery from Coronavirus Disease 2019: A Report of Three Cases Diagnosed Using Transbronchial Cryobiopsy and a Review of the Literature.

  Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Junichi Nakamura, Munehiro Matsumoto, Hiroshi Horii, Kazuki Sato, Daisuke Morinaga, Masaru Suzuki, Nanase Okazaki, Emi Takakuwa, Yoshihiro Matsuno, Satoshi Konno

  Internal medicine (Tokyo, Japan) 61 (9) 1403 - 1410 2022/03/05 

  We present three cases with an atypical clinical course of organizing pneumonia (OP) secondary to COVID-19. Three patients were discharged with satisfactory improvement after standard steroid therapy for COVID-19. Shortly after the completion of treatment, the patients experienced a flare-up of symptoms. Imaging results showed new lesions in the lungs. Transbronchial lung cryobiopsy showed histological findings consistent with OP in all cases. Steroids were administered, and a good therapeutic response was observed. This report is the first to describe pathologically confirmed OP that developed after recovery from COVID-19. Careful follow-up is advisable for patients who have recovered from COVID-19.
• 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 1081-1206 2022/03
• [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 

  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.
• Clinical Characteristics of Patients and Factors Associated with Switching Biologics in Asthma.

  Machiko Matsumoto-Sasaki, Kaoruko Simizu, Masanobu Suzuki, Masaru Suzuki, Hirokazu Kimura, Yuji Nakamaru, Yoichi M Ito, Akihiro Honma, Satoshi Konno

  Journal of asthma and allergy 15 187 - 195 2022 

  Purpose: Biologics have been used increasingly for the treatment of severe asthma. However, established guidelines for the selection, switching, or discontinuation of biologics do not exist. We aimed to identify the clinical characteristics of patients with asthma who required switching biologics and the factors associated with switching biologics. Patients and Methods: This was a retrospective study of 42 patients with severe asthma treated with biologics at the Hokkaido University Hospital between 23rd June 2016 and 30th April 2021, when two biologics were available in Japan. We compared the characteristics of subjects who continued and switched biologics. The time to switch the biologics was assessed by type 2 inflammatory biomarkers, pulmonary function indices, and the presence of comorbidities, including the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) score and aspirin exacerbated respiratory diseases (AERD), using the Kaplan-Meier method and a multivariate Cox proportional hazards model. Results: Eight and five patients were treated by mepolizumab and benralizumab at baseline, respectively among the 31% (13/42) who switched the biologics. Subjects who required switching biologics were characterized by high blood eosinophil counts, younger age, JESREC scores of 11 points or higher, and AERD. The time taken to switch biologics was significantly shorter in the subgroups with high JESREC scores (≥11) or AERD, compared with their counterparts with low JESREC scores or without AERD (both, P < 0.05). JESREC scores of ≥11, but not the presence of AERD, were associated with time to switch biologics. Conclusion: The presence of eosinophilic chronic rhinosinusitis based on JESREC scores of ≥11 and younger age were factors associated with switching biologics in asthma.
• Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma.

  Masaru Suzuki, John J Cole, Satoshi Konno, Hironi Makita, Hiroki Kimura, Masaharu Nishimura, Rose A Maciewicz

  Clinical and translational allergy 11 (10) e12091  2021/12 

  BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan®), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups.
• Multiple introductions of SARS-CoV-2 B.1.1.214 lineages from mainland Japan preceded the third wave of the COVID-19 epidemic in Hokkaido.

  Takako Shimura, Kodai Abe, Toshiki Takenouchi, Mamiko Yamada, Hisato Suzuki, Makoto Suematsu, Sho Nakakubo, Keisuke Kamada, Satoshi Konno, Takanori Teshima, Kenjiro Kosaki

  Travel medicine and infectious disease 44 102210 - 102210 2021/11/22 

  BACKGROUND: The third wave of the COVID-19 epidemic in the island of Hokkaido, the second largest island in Japan, began abruptly in October 2020. METHODS: We conducted a phylodynamic analysis of the SARS-CoV-2 genome sequences obtained from tertiary medical centers in the Greater Tokyo Area and Sapporo, the largest city in the island of Hokkaido, and genome sequences published by GISAID, an international SARS-CoV-2 genome database. We also analyzed the statistics on the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 versus 2020. RESULTS: At least eight sub-lineages belonging to the B.1.1.214 lineage were introduced to the island of Hokkaido from the island of Honshu, the mainland of Japan from late July to November 2020, during the governmental travel promotion program. Five of the eight sub-lineages originated from the Greater Tokyo Area. Comparison of the monthly ratios of the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 and 2020 revealed that the highest value occurred in October 2020. CONCLUSION: We contend that the Japanese governmental travel promotion program contributed to the introduction of the B.1.1.214 sub-lineages from the main island of Honshu to the island of Hokkaido, and drove the third wave in Hokkaido, even if we are unable to establish the causality.
• 肺動脈圧の上昇が疑われる症例でのEBUS-GS-TBBに伴う出血に関する検討

  高島 雄太, 品川 尚文, 山本 岳, 森永 大亮, 古田 恵, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 中村 順一, 辻野 一三, 今野 哲

  気管支学 (一社)日本呼吸器内視鏡学会 43 (6) 690 - 690 0287-2137 2021/11
• 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 2021/09/14 [Refereed]
  
• Association of high serum soluble interleukin 2 receptor levels with risk of adverse events in cardiac sarcoidosis.

  Yuta Kobayashi, Takuma Sato, Toshiyuki Nagai, Kenji Hirata, Satonori Tsuneta, Yoshiya Kato, Hirokazu Komoriyama, Kiwamu Kamiya, Takao Konishi, Kazunori Omote, Hiroshi Ohira, Kohsuke Kudo, Satoshi Konno, Toshihisa Anzai

  ESC heart failure 8 (6) 5282 - 5292 2021/09/12 [Refereed]
   

  AIMS: Although soluble interleukin 2 receptor (sIL-2R) is a potentially useful biomarker in the diagnosis and evaluation of disease severity in patients with sarcoidosis, its prognostic implication in patients with cardiac sarcoidosis (CS) is unclear. We sought to investigate whether sIL-2R was associated with clinical outcomes and to clarify the relationship between sIL-2R levels and disease activity in patients with CS. METHODS AND RESULTS: We examined 83 consecutive patients with CS in our hospital who had available serum sIL-2R data between May 2003 and February 2020. The primary outcome was a composite of advanced atrioventricular block, ventricular tachycardia or ventricular fibrillation, heart failure hospitalization, and all-cause death. Inflammatory activity in the myocardium and lymph nodes was assessed by 18 F-fluorideoxyglucose positron emission tomography/computed tomography. During a median follow-up period of 2.96 (IQR 2.24-4.27) years, the primary outcome occurred in 24 patients (29%). Higher serum sIL-2R levels (>538 U/mL, the median) were significantly related to increased incidence of primary outcome (P = 0.037). Multivariable Cox regression analysis showed that a higher sIL-2R was independently associated with an increased subsequent risk of adverse events (HR 3.71, 95% CI 1.63-8.44, P = 0.002), even after adjustment for significant covariates. sIL-2R levels were significantly correlated to inflammatory activity in lymph nodes (r = 0.346, P = 0.003) but not the myocardium (r = 0.131, P = 0.27). CONCLUSIONS: Increased sIL-2R is associated with worse long-term clinical outcomes accompanied by increased systemic inflammatory activity in CS patients.
• Performance of Qualitative and Quantitative Antigen Tests for SARS-CoV-2 Using Saliva.

  Isao Yokota, Takayo Sakurazawa, Junichi Sugita, Sumio Iwasaki, Keiko Yasuda, Naoki Yamashita, Shinichi Fujisawa, Mutsumi Nishida, Satoshi Konno, Takanori Teshima

  Infectious disease reports 13 (3) 742 - 747 2021/08/24 [Refereed]
   

  The rapid detection of SARS-CoV-2 is critical for the prevention of disease outbreaks. Antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) can yield results more quickly than PCR. We evaluated the performance of ICA and CLEIA using 34 frozen PCR-positive (17 saliva samples and 17 nasopharyngeal swabs [NPS]) and 309 PCR-negative samples. ICA detected SARS-CoV-2 in only 14 (41%) samples, with positivity rates of 24% in saliva and 59% in NPS. Notably, ICA detected SARS-CoV-2 in 5 of 6 samples collected within 4 days after symptom onset. CLEIA detected SARS-CoV-2 in 31 (91%) samples, with a positivity of 82% in saliva and 100% in NPS. These results suggest that the use of ICA should be limited to an earlier time after symptom onset and CLEIA is more sensitive and can be used in situations where quick results are required.
• 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 2021/08/23 [Refereed]
   

  BACKGROUND: Fixed airflow obstruction (FAO) in asthma, particularly in non-smoking subjects, 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 sec (FEV1). OBJECTIVES: To evaluate parenchymal destruction using emphysema indices, exponent D and low attenuation area percent (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 non-smoking asthma. METHODS: D, LAA%, wall area percent (WA%) at segmental airways, and airway fractal dimension (AFD) in asthmatics were measured on inspiratory CT and compared to those in chronic obstructive pulmonary disease (COPD) patients. RESULTS: 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 D and increased LAA% were associated with FAO regardless of smoking status or asthma severity. In multivariable analysis, decreased D and increased LAA% were associated with an increased odds ratio of FAO and decreased FEV1, irrespective of WA% and AFD. Moreover, decreased D affected the longitudinal decline in FEV1 in severe asthmatics, independent of smoking status . CONCLUSIONS: Asthmatics with FAO showed the parenchymal destruction regardless of smoking status and asthma severity. The 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.
• Paradoxical Formation of a Pleuroparenchymal Fibroelastosis-like Lesion in the Chronic Course of Pulmonary Sarcoidosis.

  Michiru Sawahata, Takeshi Johkoh, Takeshi Kawanobe, Chiyoko Kono, Takuji Suzuki, Masashi Bando, Koichi Hagiwara, Noriharu Shijubo, Satoshi Konno, Tetsuo Yamaguchi

  Internal medicine (Tokyo, Japan) 2021/08/06 [Refereed]
   

  We herein report the long-term changes in chest computed tomography (CT) findings from early sarcoidosis lesions to pleuroparenchymal fibroelastosis (PPFE)-like lesions in a 30-year-old man with granulomas on a transbronchial lung biopsy. Multiple bilateral micronodular and nodular opacities around the bronchovascular bundle in the upper lobes detected by chest CT in 2004 disappeared, but paradoxically, peripheral consolidations continued to grow at the periphery of the original lesions. Chest CT in 2017 confirmed the progression of bilateral shrinkage of the upper lobe, spread of peripheral consolidations and wedge-shaped opacities below the first rib, and bronchiectatic air bronchograms, confirming PPFE-like lesions.
• The effect of the outbreak of COVID-19 on respiratory physicians and healthcare in Japan: Serial nationwide surveys by the Japanese Respiratory Society.

  Keisuke Kamada, Satoshi Konno, Takeshi Kaneko, Koichi Fukunaga, Yoshinori Hasegawa, Akihito Yokoyama

  Respiratory investigation 59 (6) 792 - 798 2021/07/31 [Refereed]
   

  BACKGROUND: The impact of the outbreak of COVID-19 on the work of respiratory physicians in Japan has not yet been evaluated. The study investigates the impact of the outbreak on respiratory physicians' work over time and identifies problems to be addressed in the future. METHODS: We conducted a web-based survey of respiratory physicians in 848 institutions. The survey comprised 32 questions and four sections: Survey 1 (April 20, 2020), Survey 2 (May 27, 2020), Survey 3 (August 31, 2020), and Survey 4 (December 4, 2020). RESULTS: The mean survey response rate was 24.9%, and 502 facilities (59.2%) participated in at least one survey. The proportion of facilities that could perform PCR tests for diagnosis and more than 20 tests per day gradually increased. The percentage capable of managing extracorporeal membrane oxygenation (ECMO) or more than five ventilators did not increase over time. The proportion that reported work overload of 150% or more, stress associated with lack of personal protective equipment (PPE), and harassment or stigma in the surrounding community did not sufficiently improve. CONCLUSION: While there was an improvement in expanding the examination system and medical cooperation in the community, there was no indication of enhancement of the critical care management system. The overwork of respiratory physicians, lack of PPE, and harassment and stigma related to COVID-19 did not sufficiently improve and need to be addressed urgently.
• The prevalence of comorbid respiratory disease among COVID-19 patients, and mortality during the first wave in Japan: A nationwide survey by the Japanese Respiratory Society.

  Hiroyuki Nagase, Yoshihiro Nishimura, Hisako Matsumoto, Naoya Sugimoto, Takashi Iwanaga, Akiko Sano, Satoshi Konno, Nobuyuki Hizawa, Koichiro Asano, Takahiko Horiguchi, Akihito Yokoyama

  Respiratory investigation 59 (5) 679 - 682 2021/07/15 [Refereed]
   

  There is a concern that persons with underlying respiratory disease may have increased susceptibility to COVID-19 and/or increased severity/mortality if infected. However, information regarding such patients during the first wave of the epidemic is lacking in Japan. We surveyed chest physicians nationwide, and collected anonymous data concerning 1444 patients. Among COVID-19 patients, the prevalence of asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILD) was 3.4%, 4.8%, and 1.5%, respectively. Among COVID-19 patients with these 3 comorbidities, exacerbation of the comorbidity occurred in 12.2%, 18.8%, and 36.4%, respectively, and mortality (6.2% overall) was 4.1%, 13.0%, and 31.8%, respectively. The prevalence of asthma among COVID-19 patients was not higher than that for the general population, and mortality in COVID-19 patients with asthma was not higher than mortality in COVID-19 patients without underlying respiratory disease. COVID-19 patients having COPD or ILD had relatively high mortality, especially for ILD.
• The impact of the COVID-19 pandemic on asthma treatment in Japan: Perspectives based on doctors' views.

  Haruna Kitazawa, Nobuyuki Hizawa, Yoshihiro Nishimura, Takao Fujisawa, Takashi Iwanaga, Akiko Sano, Hiroyuki Nagase, Hisako Matsumoto, Takahiko Horiguchi, Satoshi Konno, Koichiro Asano

  Respiratory investigation 59 (5) 670 - 674 2021/07/06 [Refereed]
   

  The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds.
• 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 2021/06/23 [Refereed]
   

  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.
• Nationwide surveillance of antimicrobial susceptibility of 509 rapidly growing mycobacteria strains isolated from clinical specimens in Japan.

  Keisuke Kamada, Atsushi Yoshida, Shigekazu Iguchi, Yuko Arai, Yutaka Uzawa, Satoshi Konno, Masahiro Shimojima, Ken Kikuchi

  Scientific reports 11 (1) 12208 - 12208 2021/06/09 [Refereed]
   

  This study aimed to identify effective treatments against rapidly growing mycobacteria (RGM) infections by investigating the minimum inhibitory concentrations (MIC) of 24 antimicrobial agents and their molecular mechanisms of resistance. In total, 509 clinical RGM isolates were identified by analyzing the sequences of three housekeeping genes (hsp65, rpoB, and sodA), and their susceptibilities to 24 antimicrobial agents were tested. We also performed sequencing analysis of antimicrobial resistance genes (rrl, rrs, gyrA, and gyrB). To identify Mycobacteroides abscessus group subspecies, we performed PCR-based typing and determined the sequevar of erm(41). We identified 15 RGM species, most of which were susceptible to amikacin and linezolid. Among these species, arbekacin and sitafloxacin had the lowest MIC among the same class of antimicrobials. The MIC of rifabutin for M. abscessus subsp. abscessus (MAB) was lower than that for M. abscessus subsp. massiliense (MMA). The proportion of MAB isolates with MIC ≤ 2 mg/L for rifabutin was significantly higher than that of MMA [MAB: 50/178 (28.1%) vs. MMA: 23/130 (17.7%); p = 0.041]. In summary, our study revealed the antimicrobial susceptibility profile of 15 RGM species isolated in Japan and indicated that arbekacin, sitafloxacin, and rifabutin may be possible therapeutic options for RGM infections.
• 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) 2021/05/21 [Refereed]
   

  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 2021/05/12 [Refereed]
   

  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.
• 新型コロナウイルス感染症が北海道内の病院・診療所の診療に与えた影響に関するアンケート調査

  齋藤 充史, 千葉 弘文, 服部 健史, 黒沼 幸治, 中久保 祥, 鎌田 啓佑, 田代 典夫, 田中 裕士, 福家 聡, 今野 哲

  日本呼吸器学会誌 (一社)日本呼吸器学会 10 (3) 245 - 250 2186-5876 2021/05 

  北海道における新型コロナウイルス感染症(coronavirus disease 2019:COVID-19)流行の経験を全国の医療従事者と共有し、大病院と診療所/クリニックとの相違を明らかにすることで、今後の診療に役立てることを目的としてアンケート調査を実施した。診療所ではCOVID-19対策における物理的な制約や、経営的な影響、ストレスに感じる項目など、病院とは異なる影響や考え方があることが明らかとなった。今後それぞれの医療現場の立場・状況に応じてCOVID-19に対する方策を検討することの重要性が示唆された。(著者抄録)
• ORMDL3/GSDMB genotype is associated with distinct phenotypes of adult asthma.

  Haruna Kitazawa, Hironori Masuko, Jun Kanazawa, Rie Shigemasa, Kentaro Hyodo, Hideyasu Yamada, Yohei Yatagai, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Tomomitsu Hirota, Mayumi Tamari, Tohru Sakamoto, Nobuyuki Hizawa

  Allergology international : official journal of the Japanese Society of Allergology 70 (4) 495 - 497 2021/04/30 [Refereed]
  
• Effect of varying storage conditions on diagnostic test outcomes of SARS-CoV-2.

  Satoshi Oguri, Shinichi Fujisawa, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Junichi Nakamura, Hiroshi Horii, Kazuki Sato, Mutsumi Nishida, Takanori Teshima, Yoichi Ohiro, Ayato Takada, Satoshi Konno

  The Journal of infection 83 (1) 119 - 145 2021/04/03 [Refereed]
  
• 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 (公社)日本医師会 150 (1) 95 - 100 0021-4493 2021/04 

  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)
• Characteristics of patients with a diagnosis of sarcoidosis: a comparison of the 2006 and 2015 versions of diagnostic criteria for sarcoidosis in Japan.

  Noritaka Sakamoto, Michiru Sawahata, Yoshitaka Yamanouchi, Satoshi Konno, Noriharu Shijubo, Tetsuo Yamaguchi, Yosikazu Nakamura, Takuji Suzuki, Koichi Hagiwara, Masashi Bando

  Journal of rural medicine : JRM 16 (2) 77 - 82 2021/04 [Refereed]
   

  Objective: Histological verification of epithelioid cell granuloma is important in diagnosing sarcoidosis; tissue sampling is a worldwide requirement. In 2006, to reduce medical expenses and avoid invasive procedures, diagnostic criteria without histological verification were permitted by the Japanese government. In 2015, new diagnostic criteria, allowed clinical diagnoses based on only respiratory, ocular, and cardiac systems with at least a two-system involvement, increasing the need to sample tissue from clinically unevaluable organs in suspected sarcoidosis. This study aimed to compare the characteristics of patients who were diagnosed with sarcoidosis according to the 2006 and 2015 criteria. Materials and Methods: Using the 2015 version, we re-evaluated the characteristics of 264 patients with diagnosed or suspected sarcoidosis according to the 2006 criteria, at Jichi Medical University Hospital between 2004 and 2012 (clinical diagnosis, 84; histological diagnosis, 117; suspected sarcoidosis 63). Results: Thirty-nine patients were diagnosed with suspected sarcoidosis due to the absence of at least a two-system involvement; two patients had insufficient laboratory data suggestive of sarcoidosis. Six patients moved from suspected sarcoidosis to a histological diagnosis because of a greater leniency in the criteria for supportive findings. The 2015 diagnostic criteria excluded patients with organ involvement without a requirement for systemic steroids from the clinical diagnosis group. A case of schwannoma, erroneously placed in the clinical diagnosis group by the 2006 criteria, was reclassified according to the 2015 criteria. Conclusion: The 2015 version is preferable for clinically diagnosing sarcoidosis, even without histological specimens, and provides guidance for indications for systemic treatment.
• Geographical distribution and regional differences in 532 clinical isolates of rapidly growing mycobacterial species in Japan.

  Keisuke Kamada, Atsushi Yoshida, Shigekazu Iguchi, Yuko Arai, Yutaka Uzawa, Satoshi Konno, Masahiro Shimojima, Ken Kikuchi

  Scientific reports 11 (1) 4960 - 4960 2021/03/02 [Refereed]
   

  Infectious diseases caused by nontuberculous mycobacteria (NTM) are increasingly becoming a major global problem. Additionally, Mycobacteroides abscessus subsp. abscessus (MAB) infections are refractory to macrolides. This study was conducted to investigate the epidemiology of rapidly growing mycobacteria (RGM) species isolated from clinical specimens in Japan and assess differences in the regional distribution of lower respiratory specimens (LRS)- and non-lower respiratory specimens (NLRS)-derived species. 532 strains (427 LRS, 92 NLRS and 15 unknown specimens) were isolated in nine areas of Japan. We collected 418 specimens from Bio Medical Laboratories (BML), Inc., and 114 specimens from 45 hospitals in Japan. Their epidemiological differences were examined according to the specimen type, region, and climate. Fifteen species were identified. The proportion of M. abscessus group (MAG) strains was significantly lower in NLRS than in LRS (35.9% vs. 68.4%). The proportion of MAG strains was higher in northern Japan than in other regions (83.7% vs. 60.5%). Variations in strain abundance among RGM species was evident in regions with a mean annual temperature below 15 °C. We conclude that the proportions of MAG strains differed between NLRS and LRS in Japan. In addition, the mean annual temperature likely influenced the distribution of RGM species.
• Characteristics of COVID-19 patients admitted into two hospitals in sapporo, Japan: Analyses and insights from two outbreak waves.

  Takeshi Hattori, Atsushi Saito, Hirofumi Chiba, Koji Kuronuma, Masaru Amishima, Daisuke Morinaga, Yasuo Shichinohe, Yasuyuki Nasuhara, Satoshi Konno

  Respiratory investigation 59 (2) 180 - 186 2021/03 [Refereed]
   

  BACKGROUND: Coronavirus disease (COVID-19) emerged in January 2020 in Sapporo city, and the outbreak has shown two peaks. METHODS: A total of 260 COVID-19 patients were enrolled and categorized into three groups according to the pandemic pattern, jobs and situation, and disease severity. We compared clinical characteristics according to these categories. RESULTS: We found two pandemic peaks, and the proportion of patients and health providers who were infected in other hospitals had increased in the latter two periods (period 2: 49.6%, period 3: 32.7%). Particularly, the proportion of infected health providers was 27% in period 2, and they tended to be younger females with a mild condition. Severity of the disease (requirement of oxygen and/or mechanical ventilation) was associated with advanced age, and all the patients who died during admission were over 60 years old. CONCLUSIONS: We reported the temporal dynamics and characteristics of the COVID-19 pandemic in Sapporo city, Japan. This survey from the viewpoint of the hospital provides a new insight into and a better guide for the further management of the COVID-19 pandemic.
• Equivalent SARS-CoV-2 viral loads by PCR between nasopharyngeal swab and saliva in symptomatic patients.

  Isao Yokota, Takeshi Hattori, Peter Y Shane, Satoshi Konno, Atsushi Nagasaka, Kimihiro Takeyabu, Shinichi Fujisawa, Mutsumi Nishida, Takanori Teshima

  Scientific reports 11 (1) 4500 - 4500 2021/02/24 [Refereed]
   

  Emerging evidences have shown the utility of saliva for the detection of SARS-CoV-2 by PCR as alternative to nasopharyngeal swab (NPS). However, conflicting results have been reported regarding viral loads between NPS and saliva. We conducted a study to compare the viral loads between NPS and saliva in 42 COVID-19 patients. Viral loads were estimated by the cycle threshold (Ct) values. SARS-CoV-2 was detected in 34 (81%) using NPS with median Ct value of 27.4, and 38 (90%) using saliva with median Ct value of 28.9 (P = 0.79). Kendall's W was 0.82, showing a high degree of agreement, indicating equivalent viral loads in NPS and saliva. After symptom onset, the Ct values of both NPS and saliva continued to increase over time, with no substantial difference. Self-collected saliva has a detection sensitivity comparable to that of NPS and is a useful diagnostic tool with mitigating uncomfortable process and the risk of aerosol transmission to healthcare workers.
• Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

  Saori Sakaue, Etsuro Yamaguchi, Yoshikazu Inoue, Meiko Takahashi, Jun Hirata, Ken Suzuki, Satoru Ito, Toru Arai, Masaki Hirose, Yoshinori Tanino, Takefumi Nikaido, Toshio Ichiwata, Shinya Ohkouchi, Taizou Hirano, Toshinori Takada, Satoru Miyawaki, Shogo Dofuku, Yuichi Maeda, Takuro Nii, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Kyuto Sonehara, Ryushi Tazawa, Konosuke Morimoto, Masahiro Takaki, Satoshi Konno, Masaru Suzuki, Keisuke Tomii, Atsushi Nakagawa, Tomohiro Handa, Kiminobu Tanizawa, Haruyuki Ishii, Manabu Ishida, Toshiyuki Kato, Naoya Takeda, Koshi Yokomura, Takashi Matsui, Masaki Watanabe, Hiromasa Inoue, Kazuyoshi Imaizumi, Yasuhiro Goto, Hiroshi Kida, Tomoyuki Fujisawa, Takafumi Suda, Takashi Yamada, Yasuomi Satake, Hidenori Ibata, Nobuyuki Hizawa, Hideki Mochizuki, Atsushi Kumanogoh, Fumihiko Matsuda, Koh Nakata, Tomomitsu Hirota, Mayumi Tamari, Yukinori Okada

  Nature communications 12 (1) 1032 - 1032 2021/02/15 [Refereed]
   

  Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
• SARS-CoV-2 detection by fluorescence loop-mediated isothermal amplification with and without RNA extraction.

  Keisuke Taki, Isao Yokota, Tatsuya Fukumoto, Sumio Iwasaki, Shinichi Fujisawa, Masayoshi Takahashi, Saeki Negishi, Kasumi Hayasaka, Kaori Sato, Satoshi Oguri, Mutsumi Nishida, Junichi Sugita, Satoshi Konno, Tomoya Saito, Takanori Teshima

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 (2) 410 - 412 2021/02 [Refereed]
   

  Rapid and simple point-of-care detection of SARS-CoV-2 is an urgent need to prevent pandemic. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) can detect SARS-CoV-2 more rapidly than RT-PCR. Saliva is non-invasive specimen suitable for mass-screening, but data comparing utility of nasopharyngeal swab (NPS) and saliva in RT-LAMP test are lacking and it remains unclear whether SARS-CoV-2 could be detected by direct processing of samples without the need for prior RNA extraction saliva. In this study, we compared utility of saliva and NPS samples for the detection of SARS-CoV-2 by a novel RT-fluorescence LAMP (RT-fLAMP). The sensitivity and specificity of the RT-fLAMP with RNA extraction were 97% and 100%, respectively, with equivalent utility of NPS and saliva. However, sensitivity was decreased to 71% and 47% in NPS and saliva samples without RNA extraction, respectively, suggesting that RNA extraction process may be critical for the virus detection by RT-fLAMP.
• 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 

  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.
• Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex.

  Tetsuaki Shoji, Yo Niida, Takahiro Osawa, Ryuji Matsumoto, Kotaro Sakurai, Masaru Suzuki, Yoshihiro Matsuno, Satoshi Konno

  Respiratory medicine case reports 34 101526 - 101526 2021 

  A woman with a diagnosis of tuberous sclerosis complex (TSC) presented with TSC2 gene mutation and various manifestations, including epilepsy, renal angiomyolipomas (AML), and pathologically confirmed multifocal micronodular pneumocyte hyperplasia (MMPH). With oral administration of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, MMPH and AML were markedly reduced. Further, after starting treatment with everolimus, serum levels of surfactant protein (SP)-A and SP-D, which reflect type II pneumocyte hyperplasia, decreased to the normal range. At the time of writing of this manuscript, 6 years after starting everolimus, MMPH lesions did not relapse and SP-A/D remained the low levels. This is the first case of everolimus efficacy shown for histologically confirmed MMPH in genetically determined TSC patient, with time course of serum SP-A and SP-D.
• 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) 2021/01 [Refereed]
   

  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 2021/01 [Refereed]
   

  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 [Refereed]
   

  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.
• A case of radio-insensitive SMARCA4-deficient thoracic undifferentiated carcinoma with severe right heart failure.

  Shotaro Ito, Hajime Asahina, Naoko Yamaguchi, Utano Tomaru, Tadashi Hasegawa, Yutaka Hatanaka, Kanako C Hatanaka, Hiroshi Taguchi, Taisuke Harada, Hiroshi Ohira, Daisuke Ikeda, Hidenori Mizugaki, Eiki Kikuchi, Junko Kikuchi, Jun Sakakibara-Konishi, Naofumi Shinagawa, Satoshi Konno

  Respiratory medicine case reports 32 101364 - 101364 2021 [Refereed]
   

  SMARCA4-deficient thoracic sarcomatoid tumors were characterized by inactivating mutations of SMARCA4 and often found in the chest of young and middle-aged males with a smoking history. Recently, SMARCA4-deficient thoracic sarcomatoid tumors were reported to represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. The main complication of this tumor is compression of the respiratory tract and/or blood vessels. A 39-year-old man presented with a 2-month history of fever and dyspnea. Computed tomography revealed a mediastinal tumor invading the right and left pulmonary arteries. Because of severe right heart failure, we considered him ineligible for bronchoscopy. We scheduled palliative irradiation with 40 Gy/20 Fr to improve hemodynamics and perform endobronchial ultrasound transbronchial needle aspiration later. However, irradiation was ineffective, and his general condition deteriorated quickly and he died after a 7-week hospitalization. An autopsy revealed that the diagnosis was SMARCA4-deficient thoracic undifferentiated carcinoma. It has been reported that this tumor is insensitive to radiotherapy and there were some cases which responded to an immune checkpoint inhibitor. Therefore, when caring for patients with mediastinal tumors that invade and compress the trachea and large vessels, it is important to consider this tumor as a differential diagnosis and try to make a pathological diagnosis as soon as possible.
• Successful management of a patient with active Cushing‍'‍s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia.

  Akiko Yuno, Yoshiyuki Kenmotsu, Yuka Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Yu Yamashita, Junichi Nakamura, Sho Nakakubo, Keisuke Kamada, Masaru Suzuki, Hirokazu Sugino, Naoko Inoshita, Satoshi Konno, Hideaki Miyoshi, Tatsuya Atsumi, Yutaka Sawamura, Akira Shimatsu

  Endocrine journal 68 (4) 477 - 484 2020/12/24 [Refereed]
   

  We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.
• Proposal of COVID-19 Clinical Risk Score for the management of suspected COVID-19 cases: a case control study.

  Sho Nakakubo, Masaru Suzuki, Keisuke Kamada, Yu Yamashita, Junichi Nakamura, Hiroshi Horii, Kazuki Sato, Munehiro Matsumoto, Yuki Abe, Kosuke Tsuji, Nobuhisa Ishiguro, Yasuyuki Nasuhara, Satoshi Konno

  BMC infectious diseases 20 (1) 858 - 858 2020/11/18 [Refereed]
   

  BACKGROUND: No clinical scoring system has yet been established to estimate the likelihood of coronavirus disease (COVID-19) and determine the suitability of diagnostic testing in suspected COVID-19 patients. METHODS: This was a single-center, retrospective, observational study of patients with suspected COVID-19 and confirmed COVID-19. Patient background, clinical course, laboratory and computed tomography (CT) findings, and the presence of alternative diagnoses were evaluated. Clinical risk scores were developed based on clinical differences between patients with and without COVID-19. RESULTS: Among 110 patients suspected of having COVID-19, 60.9% underwent polymerase chain reaction (PCR) testing based on the judgment of physicians. Two patients were found to have COVID-19. The clinical characteristics of 108 non-COVID-19 patients were compared with those of 23 confirmed COVID-19 patients. Patients with COVID-19 were more likely to have a history of high-risk exposures and an abnormal sense of taste and smell. The COVID-19 group had significantly higher rates of subnormal white blood cell counts, lower eosinophil counts, and lower procalcitonin levels than the non-COVID-19 group. When blood test results, CT findings, and the presence of alternative diagnoses were scored on an 11-point scale (i.e., "COVID-19 Clinical Risk Score"), the COVID-19 group scored significantly higher than the non-COVID-19 group, more than four points in the COVID-19 group. All non-COVID patients who did not undergo PCR had a score of 4 or less. CONCLUSIONS: The COVID-19 Clinical Risk Score may enable the risk classification of patients suspected of having COVID-19 and can help in decision-making in clinical practice, including appropriateness of diagnostic testing. Further studies and prospective validation with an increased sample size are required.
• Strategic Outlook toward 2030: Japan's research for allergy and immunology - Secondary publication.

  Takeya Adachi, Keigo Kainuma, Koichiro Asano, Masayuki Amagai, Hiroyuki Arai, Ken J Ishii, Komei Ito, Eiichi Uchio, Motohiro Ebisawa, Mitsuhiro Okano, Kenji Kabashima, Kenji Kondo, Satoshi Konno, Hidehisa Saeki, Mariko Sonobe, Mizuho Nagao, Nobuyuki Hizawa, Atsuki Fukushima, Shigeharu Fujieda, Kenji Matsumoto, Hideaki Morita, Kazuhiko Yamamoto, Akemi Yoshimoto, Mayumi Tamari

  Allergology international : official journal of the Japanese Society of Allergology 69 (4) 561 - 570 2020/10 [Refereed][Not invited]
   

  Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030.
• 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 2020/09/17 [Refereed][Not invited]
   

  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.
• New Clinical Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis/Mycosis and its Validation.

  Koichiro Asano, Akira Hebisawa, Takashi Ishiguro, Noboru Takayanagi, Yasuhiko Nakamura, Junko Suzuki, Naoki Okada, Jun Tanaka, Yuma Fukutomi, Shigeharu Ueki, Koichi Fukunaga, Satoshi Konno, Hiroto Matsuse, Katsuhiko Kamei, Masami Taniguchi, Terufumi Shimoda, Tsuyoshi Oguma

  The Journal of allergy and clinical immunology 147 (4) 1261 - 1268 2020/09/10 [Refereed][Not invited]
   

  BACKGROUND: There are several clinical diagnostic criteria for allergic bronchopulmonary aspergillosis (ABPA). However, these criteria have not been validated in detail, and no criteria for allergic bronchopulmonary mycosis (ABPM) is currently available. OBJECTIVE: We propose new diagnostic criteria for ABPA/ABPM, consisting of ten components, and compare its sensitivity and specificity to existing methods. METHODS: Rosenberg-Patterson's criteria proposed in 1977, International Society for Human and Animal Mycology (ISHAM) criteria proposed in 2013, and our new criteria, were applied to 79 cases with pathological ABPM and the control population with allergic mucin in the absence of fungal hyphae (n = 37), chronic eosinophilic pneumonia (n = 64), Aspergillus-sensitized severe asthma (n = 26), or chronic pulmonary aspergillosis (n = 24). These criteria were also applied to the 179 cases with physician-diagnosed ABPA/ABPM in a nation-wide Japanese survey. RESULTS: The sensitivity for pathological ABPM with Rosenberg-Patterson criteria, ISHAM criteria, and our new criteria were 25.3%, 77.2%, and 96.2%, respectively. The sensitivity for physician-diagnosed ABPA/ABPM were 49.2%, 82.7%, and 94.4%, respectively. The area under the curve for the receiver operation characteristic curve was 0.85, 0.90, and 0.98 for Rosenberg-Patterson criteria, ISHAM criteria, and the new criteria, respectively. The sensitivity for ABPM cases that were culture-positive for non-Aspergillus fungi, were 14.3%, 47.6%, and 90.5% with Rosenberg-Patterson criteria, ISHAM criteria, and the new criteria, respectively. CONCLUSION: The new diagnostic criteria showed better sensitivity and specificity for diagnosing ABPA/ABPM, compared with existing criteria.
• 巨大粘液栓を伴った肺粘表皮癌の1例

  高橋 桂, 品川 尚文, 加藤 達哉, 高橋 宏典, 國崎 守, 樋田 泰浩, 加賀 基知三, 土井 和尚, 松野 吉宏, 今野 哲

  気管支学 (NPO)日本呼吸器内視鏡学会 42 (5) 441 - 447 0287-2137 2020/09 

  背景.粘表皮癌は比較的稀な肺腫瘍であり、中でも粘液栓を伴った粘表皮癌は報告例も少ない。症例.症例は27歳、女性。左胸痛、咳嗽、喀痰が出現し、近医を受診。肺炎の診断で抗菌薬を開始されるも改善なく、胸部CTでは左主気管支の完全閉塞を認め、当科入院となった。全身麻酔下で気管支鏡検査を施行するも左主気管支は粘液栓が連なって存在しており、診断に耐えうる検体採取が困難であった。2回目の気管支鏡検査では迅速病理診断を併用し、粘表皮癌cT2aN0M0 stage IBと診断された。腫瘍の存在部位より左肺全摘も考慮されたが、術前に低悪性度な粘表皮癌と診断がついていたことで左下葉切除術+気管支形成術が施行され、腫瘍は完全切除され左肺全摘が回避された。結論.粘液栓を伴った粘表皮癌においては迅速病理診断を併用した気管支鏡検査が有用であり、本症例のように術前に確定診断をつけることで肺機能を温存した治療も検討される。(著者抄録)
• Efficacy of a novel SARS-CoV-2 detection kit without RNA extraction and purification.

  Tatsuya Fukumoto, Sumio Iwasaki, Shinichi Fujisawa, Kasumi Hayasaka, Kaori Sato, Satoshi Oguri, Keisuke Taki, Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Satoshi Konno, Mutsumi Nishida, Junichi Sugita, Takanori Teshima

  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 98 16 - 17 2020/09 [Refereed][Not invited]
   

  Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the diagnosis of coronavirus disease 2019 (COVID-19) and preventing the spread of the virus. A novel detection kit - the 2019 Novel Coronavirus Detection Kit (nCoV-DK) - halves the detection time by eliminating the steps of RNA extraction and purification. We evaluated the concordance between the nCoV-DK and direct PCR. The virus was detected in 53/71 specimens (74.6%) by direct PCR and in 55/71 specimens (77.5%) by nCoV-DK; the overall concordance rate was 94.4%: 95.2% for nasopharyngeal swab, 95.5% for saliva, and 85.7% for sputum. The nCoV-DK test effectively detects SARS-CoV-2 in all types of sample including saliva, while reducing the time required for detection, labor, and the risk of human error.
• Progression of Central-peripheral Band and Traction Bronchiectasis Clusters Leading to Chronic Respiratory Failure in a Patient with Fibrotic Pulmonary Sarcoidosis.

  Michiru Sawahata, Noriharu Shijubo, Takeshi Johkoh, Takeshi Kawanobe, Yasumaro Fujiki, Masashi Bando, Koichi Hagiwara, Tamiko Takemura, Satoshi Konno, Tetsuo Yamaguchi

  Internal medicine (Tokyo, Japan) 2020/08/22 [Refereed][Not invited]
   

  We herein report a rare case of pulmonary sarcoidosis leading to chronic respiratory failure with restrictive ventilatory impairment during a 53-year-long observation period. Nine years after the histological diagnosis of stage I sarcoidosis on chest X-ray in a woman in her 20s, she developed bilateral reticular and granular opacities on chest computed tomography and was started on prednisone for 18 years. Seven years after prednisone withdrawal, these persisting opacities around the bronchovascular bundle, including a central-peripheral band, had progressed, forming traction bronchiectasis clusters and peripheral cysts, some of which developed continuously at the distal side of these clusters, with eventual upper lobe shrinkage.
• 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 (一社)日本呼吸器学会 9 (増刊) 279 - 279 2186-5876 2020/08
• Comparison of SARS-CoV-2 detection in nasopharyngeal swab and saliva.

  Sumio Iwasaki, Shinichi Fujisawa, Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Tatsuya Fukumoto, Kaori Sato, Satoshi Oguri, Keisuke Taki, Hajime Senjo, Junichi Sugita, Kasumi Hayasaka, Satoshi Konno, Mutsumi Nishida, Takanori Teshima

  The Journal of infection 81 (2) e145-e147  2020/08 [Refereed][Not invited]
  
• Preoperative Pulmonary Function Testing to Predict Recurrence of Chronic Rhinosinusitis With Nasal Polyps

  Yuji Nakamaru, Masanobu Suzuki, Aya Honma, Akira Nakazono, Shogo Kimura, Keishi Fujiwara, Shinya Morita, Satoshi Konno, Akihiro Homma

  ALLERGY & RHINOLOGY 11 2152-6567 2020/07 

  Background: Although the close relationship between the upper and lower airways has been highlighted previously, little is known about the association between lung function and the recurrence of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the factors associated with pulmonary function that affect CRSwNP recurrence after surgery.Methods: We performed a series of routine pulmonary function tests for general anesthesia prior to CRSwNP surgery. The values for each parameter were compared in the presence or absence of recurrence.Results: Sixty-nine patients with CRSwNP were included. The percent predicted forced expiratory volume in one second (%FEV1) in the recurrent group was significantly lower than that in the non-recurrent group (P = .005). A multivariable logistic regression model revealed that %FEV1 was a positive predictor of recurrence (odds ratio: 0.96, 95% CI: 0.92-0.99, P = .023). There were no significant differences in the other pulmonary functions between the two groups.Conclusions: We found that %FEV1 may be a predictor of CRSwNP recurrence after surgery. As %FEV1 is a pulmonary function test that is routinely performed before surgery, this parameter is readily applicable. Moreover, as %FEV1 appears to have the potential to reveal concealed asthma, %FEV1 might be a particularly useful tool for the prediction of CRSwNP recurrence after surgery.
• 新型コロナウイルス感染症診療における呼吸器内科医師の活動実態に関するアンケート調査結果

  鎌田 啓佑, 今野 哲, 金子 猛, 福永 興壱, 長谷川 好規, 横山 彰仁

  日本呼吸器学会誌 (一社)日本呼吸器学会 9 (4) 233 - 238 2186-5876 2020/07 

  呼吸器内科医師の「coronavirus infectious disease 2019」(COVID-19)診療に対する役割の実態を把握し、診療環境の問題点を明らかにすることを目的とし、全国アンケート調査を実施した。COVID-19診療により、57%の医療機関が呼吸器内科の通常診療業務を縮小しているにもかかわらず、63%の医療機関で業務量の増加を実感していた。85%の施設が個人防護具の不足について強くストレスを感じていた。またCOVID-19に関連してハラスメントを受けたと回答した施設は29%に及んだ。(著者抄録)
• クライオ生検で診断し得たT細胞性リンパ腫再発の1例

  佐藤 理子, 品川 尚文, 辻 康介, 松本 宗大, 木村 孔一, 鈴木 雅, 米田 和樹, 清水 亜衣, 松野 吉宏, 今野 哲

  気管支学 (NPO)日本呼吸器内視鏡学会 42 (4) 343 - 348 0287-2137 2020/07 

  背景.悪性リンパ腫は時に肺病変を呈するが、経気管支肺生検では診断が困難な場合も多い。症例.40歳代女性。42歳時に非特異型末梢性T細胞性リンパ腫に対して化学療法で加療され、以後寛解を維持していた。2年後に湿性咳嗽が出現、CTで右肺下葉に浸潤影を認め抗菌薬で加療されたが改善に乏しく、当科に精査入院した。診断目的に右B8aからendobronchial ultrasound-guided transbronchial biopsy using guide sheath(EBUS-GS-TBB)及び経気管支クライオ生検を施行した。病理ではクライオ生検の検体のみに壊死組織中に腫瘍細胞を認め、免疫染色でCD3、Epstein-Barr virus-encoded small RNA-in situ hybridization(EBER-ISH)陽性であり、T細胞性リンパ腫再発と診断した。その後化学療法施行のため血液内科に転科した。結論.T細胞性リンパ腫の再発をクライオ生検で診断し得た症例を経験した。(著者抄録)
• Temporal trends and determinants of PFR exposure in the Hokkaido Study.

  Michiel Bastiaensen, Yu Ait Bamai, Atsuko Araki, Houman Goudarzi, Satoshi Konno, Sachiko Ito, Chihiro Miyashita, Yiming Yao, Reiko Kishi, Adrian Covaci

  International journal of hygiene and environmental health 228 113523 - 113523 2020/07 [Refereed][Not invited]
   

  The phase-out of polybrominated diphenyl ethers (PBDE) flame retardants has led to the rapid increase of alternatives such as phosphate flame retardants and plasticizers (PFRs) in many consumer products. Exposure to these additive chemicals is widespread and potentially harmful to humans and the environment. In the present study, we assessed the exposure to PFRs through the analysis of metabolites in urine collected from 7-year old children from Hokkaido, Japan between 2012 and 2017. This allowed us to investigate temporal and seasonal trends for PFR metabolite concentrations and to study determinants of exposure. Thirteen metabolites of seven PFRs were measured in morning spot urine samples (n = 400). Multiple regression models were used to quantify the yearly increase in metabolite concentrations per sampling year. Information on the demographics, indoor environment and dietary habits of the participants were derived from self-administered questionnaires. PFR metabolite concentrations were comparable to our previous study of school children (7-12 years old). Eight PFR metabolites were detected in >50% of the samples. During the study time period, concentrations of three metabolites increased significantly: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 13.3% per year), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP; 12.9% per year), and 2-ethylhexyl phenyl phosphate (EHPHP; 6.7% per year). We also found seasonality as a determinant for several PFR metabolites, with 2-fold higher levels in summer for BCIPHIPP and BDCIPP. Concentrations were also significantly impacted by ventilation habits. More frequent window opening or use of mechanical ventilation was consistently associated with higher levels of PFR metabolites in children's urine. This is the first study to show that human exposure to PFRs has increased in recent years in Japan, which indicates that further research into this class of chemicals is warranted.
• Older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples.

  Takeshi Hattori, Masaru Amishima, Daisuke Morinaga, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Yasuo Shichinohe, Shinichi Fujisawa, Mutsumi Nishida, Yasuyuki Nasuhara, Takanori Teshima, Satoshi Konno

  The Journal of infection 82 (1) 159 - 198 2020/06/21 [Refereed][Not invited]
  
• ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization.

  Haruna Kitazawa, Hironori Masuko, Jun Kanazawa, Rie Shigemasa, Kentaro Hyodo, Hideyasu Yamada, Yohei Yatagai, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Tomomitsu Hirota, Mayumi Tamari, Tohru Sakamoto, Nobuyuki Hizawa

  Allergology international : official journal of the Japanese Society of Allergology 70 (1) 55 - 60 2020/05/19 [Refereed][Not invited]
   

  BACKGROUND: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. METHODS: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. RESULTS: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1). CONCLUSIONS: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.
• Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer.

  Tetsuaki Shoji, Eiki Kikuchi, Junko Kikuchi, Yuta Takashima, Megumi Furuta, Hirofumi Takahashi, Kosuke Tsuji, Makie Maeda, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno

  Cancer chemotherapy and pharmacology 85 (5) 843 - 853 2020/05 [Refereed][Not invited]
   

  PURPOSE: We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells. METHODS: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines. RESULTS: All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins, as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors, and had significantly more proteasomal proteolytic activity than their parental counterparts. CONCLUSIONS: The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.
• A Sickle Cell Crisis in a Blood Culture Bottle.

  Keisuke Kamada, Takeshi Matsuda, Satoshi Konno, Hideaki Oka

  Internal medicine (Tokyo, Japan) 59 (7) 1013 - 1013 2020/04/01 [Refereed][Not invited]
  
• Characteristics of 68 patients with clinically proven sarcoidosis based on the Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 criteria.

  Yoshitaka Yamanouchi, Michiru Sawahata, Noritaka Sakamoto, Shu Hisata, Noriharu Shijubo, Satoshi Konno, Tetsuo Yamaguchi, Meri Watanabe, Hidetoshi Kawashima, Takuji Suzuki, Masashi Bando, Koichi Hagiwara

  Respiratory investigation 58 (2) 102 - 109 2020/03 

  BACKGROUND: The presence of histologically evident epithelioid granuloma is required for the diagnosis of sarcoidosis worldwide. The Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 diagnostic criteria (JSSOG 2015 criteria) includes "clinically proven diagnosis" (involvement of at least 2 of 3 systems confirmed solely by clinical assessment) because of the frequency of sarcoidosis with ocular, cardiac, and respiratory involvement in Japan and the difficulty of obtaining specimens. Here, we describe in detail the clinical presentation of clinically diagnosed sarcoidosis. METHODS: We enrolled 68 consecutive patients with clinically diagnosed sarcoidosis (12 men, 56 women) based on the JSSOG 2015 criteria who were treated at Jichi Medical University between December 2018 and January 2000. We analyzed age at diagnosis, organ involvement, and laboratory findings. RESULTS: Age at diagnosis was unimodal in women. Ocular, splenic, cardiac, and skin involvement, and hypercalcemia were observed in 95.6%, 8.8%, 7.4%, 5.9%, and 35.0% of patients, respectively. High serum lysozyme and soluble interleukin-2 receptor (sIL-2R) levels, bilateral hilar lymphadenopathy on chest radiography, high-grade atrioventricular block or fatal ventricular arrhythmia, and bundle branch block were found in 18.8%, 48.3%, 95.6%, 5.0%, and 10.0% of patients, respectively. CONCLUSIONS: The age-specific distribution of clinically diagnosed sarcoidosis was similar to histologically diagnosed sarcoidosis in women, as previously reported. Rates of elevated serum lysozyme and sIL-2R levels were lower in this study than previously reported in histologically diagnosed patients in Japan.
• Bromodomain and extraterminal domain inhibition synergizes with WEE1-inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer.

  Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Motofumi Suzuki, Hajime Kikuchi, Makie Maeda, Tetsuaki Shoji, Megumi Furuta, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno

  International journal of cancer 146 (4) 1114 - 1124 0020-7136 2020/02/15 [Refereed][Not invited]
   

  Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
• Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.

  Atsuko Araki, Yu Ait Bamai, Michiel Bastiaensen, Nele Van den Eede, Toshio Kawai, Tazuru Tsuboi, Chihiro Miyashita, Sachiko Itoh, Houman Goudarzi, Satoshi Konno, Adrian Covaci, Reiko Kishi

  Environmental research 183 109212 - 109212 2020/02/03 [Refereed][Not invited]
   

  BACKGROUND: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures. OBJECTIVES: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children. METHODS: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income. RESULTS: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group. CONCLUSIONS: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.
• 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 2020/02 [Refereed][Not invited]
   

  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.
• 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

  Japanese Journal of Allergology 69 (8) 678 - 682 1347-7935 2020 

  We report the case of a 66-year-old patient with severe asthma complicated by eosinophilic chronic rhinosinusi-tis (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 biologices 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.
• Nivolumab-induced immune thrombocytopenia in a patient with malignant pleural mesothelioma

  Jun Sakakibara-Konishi, Mineyoshi Sato, Kohei Kasahara, Masahiro Onozawa, Hidenori Mizugaki, Eiki Kikuchi, Hajime Asahina, Naofumi Shinagawa, Satoshi Konno

  Respiratory Medicine Case Reports 31 2213-0071 2020/01/01 

  Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab. Frequency of hematological irAE is low and there are few reports about hematological irAE and association between irAE and outcome of nivolumab in patients with MPM. We present a case of recurrent MPM who responded to nivolumab treatment and experienced nivolumab-induced immune thrombocytopenia (ITP). Although high dose dexamethasone was administered and platelet count increased transiently, re-administration of dexamethasone was required to maintain normal count of platelet. The careful and intensive management of ITP treatment is necessary in cases who show no response or relapse to initial glucocorticoids treatment. This is the first report about nivolumab-induced ITP and association with response to nivolumab in MPM.
• Pathogenic Effect of Prevotella intermedia on a Mouse Pneumonia Model Due to Methicillin-Resistant Staphylococcus aureus With Up-Regulated α-Hemolysin Expression.

  Yu Yamashita, Kentaro Nagaoka, Hiroki Kimura, Masaru Suzuki, Tatsuya Fukumoto, Kasumi Hayasaka, Norihito Kaku, Yoshitomo Morinaga, Katsunori Yanagihara, Satoshi Konno

  Frontiers in microbiology 11 587235 - 587235 2020 [Refereed]
   

  Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a common causative agent of pneumonia; however, the detailed mechanism underlying severe MRSA pneumonia, including association with oral hygiene or periodontitis, remains poorly characterized. In this study, we examined the pathogenic effect of Prevotella intermedia, a major periodontopathic pathogen, on MRSA pneumonia. Methods: The pathogenic effect of the supernatant of P. intermedia (Pi Sup) was investigated in a murine MRSA pneumonia model, using several clinical strains; whereas the bactericidal activity of polymorphonuclear leukocytes (PMNs) was investigated in vitro. The effect of Pi Sup on messenger RNA (mRNA) expression of the toxin/quorum sensing system (rnaIII) was investigated by quantitative reverse transcription PCR both in vitro and in vivo. Results: Mice infected by hospital-acquired MRSA (HA-MRSA) with Pi Sup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, and higher α-hemolysin (hla) expression in the lungs, than those without Pi Sup. A similar effect of Pi Sup was not observed with MRSA strains producing Panton-Valentine leucocidin (PVL) or toxic shock syndrome toxin (TSST). In vitro, Pi Sup suppressed bactericidal activity of PMNs against the HA-MRSA strain. HA-MRSA was the clinical strain with the highest ability to proliferate in the lungs and was accompanied by time-dependent up-regulation of rnaIII and hla. Conclusions: Our results provide novel evidence that the product of P. intermedia exerts a pathogenic effect on MRSA pneumonia, in particular with a strain exhibiting strong proliferation in the lower airway tract. Moreover, our results indicate that P. intermedia affects MRSA toxin expression via quorum sensing in a strain-dependent fashion, which might be important for understanding the pathogenesis of severe MRSA pneumonia.
• Traditional Japanese Herbal Medicine Hochu-Ekki-to Promotes Pneumococcal Colonization Clearance via Macrophage Activation and Interleukin 17A Production in Mice.

  Sho Nakakubo, Soichiro Kimura, Kazuyuki Mimura, Chiaki Kajiwara, Yoshikazu Ishii, Satoshi Konno, Kazuhiro Tateda

  Frontiers in cellular and infection microbiology 10 569158 - 569158 2020 [Refereed]
   

  Streptococcus pneumoniae may colonize the nasopharynx, and as pneumococcal colonization causes invasive diseases and the subsequent transmission, reducing bacterial burden in the nasal cavity is critical. Hochu-ekki-to (TJ-41) is a traditional Japanese herbal medicine that exerts immunomodulatory effects in host cells. In this study, we investigated the potency of TJ-41 in modulating pneumococcal colonization clearance by activating host immunity. Mice, intranasally inoculated with pneumococci, were treated orally with TJ-41. During colonization, TJ-41 treatment significantly reduced pneumococcal burden and increased macrophage population in the nasopharynx. Furthermore, interleukin 17A production was significantly enhanced after TJ-41 treatment. In vitro experiment using nasal-derived cells revealed that pneumococcal antigen exposure upregulated the transcription of interleukin 17A in the TJ-41-treated group compared with that in the control group. Macrophages activated by killed bacteria were significantly increased in the presence of TJ-41 in an interleukin 17A-dependent manner. Moreover, TJ-41 enhanced phagocytosis, inhibited bacterial growth, and improved the antigen-presenting capacity of macrophages. Our results demonstrate that TJ-41 accelerates the clearance of pneumococcal nasopharyngeal colonization via macrophage activation. Subsequent production of interleukin 17A provides an additional benefit to effector cells.
• Rapidly progressive organizing pneumonia associated with COVID-19.

  Hiroshi Horii, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Junichi Nakamura, Yasuyuki Nasuhara, Satoshi Konno

  Respiratory medicine case reports 31 101295 - 101295 2020 [Refereed]
   

  We report a case of clinically diagnosed secondary organizing pneumonia (SOP) associated with coronavirus disease 2019 (COVID-19). A 70-year-old woman who had been diagnosed with COVID-19 was admitted to Hokkaido University Hospital. Although her fever, cough, dyspnea, and serum C-reactive protein levels improved, she developed rapidly progressive respiratory failure and computed tomography revealed the development of bilateral lung consolidation. Her dyspnea was relieved, and her oxygenation levels and radiological findings improved after commencing corticosteroid treatment. Blood biomarkers for interstitial lung disease, Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), showed different responses during the clinical course of her disease. Evaluation of serial changes in levels of KL-6 and SP-D may help diagnose and monitor COVID-19-associated organizing pneumonia (OP). Clinicians should be aware that SOP can develop in response to COVID-19 and that these patients may benefit from the use of steroids.
• 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 [Refereed]
   

  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 [Refereed][Not invited]
   

  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.
• Pulmonary capillary hemangiomatosis-predominant vasculopathy in a patient with rheumatoid arthritis-associated interstitial lung disease: An autopsy report.

  Junichi Nakamura, Ichizo Tsujino, Gaku Yamamoto, Toshitaka Nakaya, Kei Takahashi, Hirokazu Kimura, Takahiro Sato, Taku Watanabe, Shimpei Nakagawa, Noriyuki Otsuka, Hiroshi Ohira, Satoshi Konno

  Respiratory medicine case reports 31 101215 - 101215 2020 [Refereed][Not invited]
   

  Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension (PH) associated with poor prognosis. Clinically, it is characterized by severe hypoxemia, centrilobular ground-glass opacities on computed tomography, and pulmonary congestion triggered by pulmonary vasodilating therapy. In some cases, PCH has been reported to develop with other disorders including connective tissue disease; however, to date, no reports have described PCH in a patient with rheumatoid arthritis. We report a case of a 59-year-old male PCH patient with rheumatoid arthritis and associated pulmonary fibrosis. He was initially diagnosed with severe group 3 PH and received sildenafil, which generated a favorable hemodynamic response. However, 5 years later, his pulmonary hemodynamics deteriorated, and he died at the age of 67. An autopsy was performed, and thickening of alveolar septa and capillary proliferation, pathological features of PCH, were extensively observed in both lungs. We discuss when PCH developed, how sildenafil improved his hemodynamics, and how PCH could be clinically detected by noninvasive evaluations.
• Lung metastasis from gastric cancer presenting as diffuse ground-glass opacities.

  Yuki Abe, Masaru Suzuki, Kosuke Tsuji, Mineyoshi Sato, Hirokazu Kimura, Hiroki Kimura, Kentaro Nagaoka, Emi Takakuwa, Yoshihiro Matsuno, Satoshi Konno

  Respiratory medicine case reports 30 101104 - 101104 2020 [Refereed][Not invited]
   

  Most metastatic lung tumors display well-defined, round, multiple nodular shadows, whereas the presence of diffuse ground-glass opacities on chest computed tomography generally suggests non-malignant conditions. Here, we report an unusual case of pulmonary metastasis from gastric cancer in which diffuse ground-glass opacities were observed in all lung segments. A 59-year-old man with a 3-month history of worsening chest pain and shortness of breath was referred to the pulmonary clinic. Chest computed tomography revealed low attenuation areas, suggesting emphysema, along with diffuse ground-glass opacities and interlobular septal thickening in both lungs. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating the alveolar septa. Immunohistochemical staining of the cancer cells was positive for CDX-2, cytokeratin 7, and cytokeratin 20, and negative for surfactant apoprotein-A, TTF-1, and Napsin A. Gastrointestinal endoscopy revealed an ulcerative tumor in the stomach, and a biopsy from the tumor demonstrated malignant cells with similar morphology and immunophenotypes as those in the lungs. The final diagnosis was diffuse lung metastasis from gastric cancer. Our case shows that although multiple, well-defined nodules are typically considered to be the classic presentation of pulmonary metastasis, clinicians should also be aware of the possibility of pulmonary metastasis presenting as diffuse ground-glass opacities.
• Validation of a new serum granulocyte-macrophage colony-stimulating factor autoantibody testing kit.

  Koh Nakata, Tatsuki Sugi, Keiko Kuroda, Kazutaka Yoshizawa, Toshinori Takada, Ryushi Tazawa, Takahiro Ueda, Ami Aoki, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Miku Oda, Haruyuki Ishii, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Taizou Hirano, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takuro Sakagami, Takahiro Tanaka, Ayako Mikami, Nobutaka Kitamura

  ERJ open research 6 (1) 2020/01 [Refereed][Not invited]
   

  Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.
• 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 0169-5002 2019/12 [Refereed][Not invited]
   

  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.
• Multiple exposures to organophosphate flame retardants alter urinary oxidative stress biomarkers among children: The Hokkaido Study.

  Yu Ait Bamai, Michiel Bastiaensen, Atsuko Araki, Houman Goudarzi, Satoshi Konno, Sachiko Ito, Chihiro Miyashita, Yiming Yao, Adrian Covaci, Reiko Kishi

  Environment international 131 105003 - 105003 0160-4120 2019/10 [Refereed][Not invited]
   

  Organophosphate flame retardants (PFRs) are used as additives in plastics and other applications such as curtains and carpets as a replacement for brominated flame retardants. As such, exposure to PFR mixtures is widespread, with children being more vulnerable than adults to associated health risks such as allergies and inflammation. Oxidative stress is thought to be able to modulate the development of childhood airway inflammation and atopic dermatitis. To evaluate these associations, the present study investigated the relationship between urinary PFR metabolites, their mixtures and urinary oxidative stress biomarkers in children as part of the Hokkaido Study on Environment and Children's Health. The levels of the oxidative stress biomarkers, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL), and 4-hydroxynonenal (HNE), and of 14 PFR metabolites were measured in morning spot urine samples of 7-year-old children (n = 400). Associations between PFR metabolites or PFR metabolite mixtures and oxidative stress biomarkers were examined by multiple regression analysis and weighted quantile sum regression analysis, respectively. We found that the non-chlorinated PFR metabolites, 2-ethylhexyl phenyl phosphate (EHPHP), bis(2-butoxyethyl) phosphate (BBOEP), and diphenyl phosphate (DPHP) were associated with increased levels of oxidative stress biomarkers. Furthermore, the PFR metabolite mixture was associated with increased levels of HEL and HNE, but not 8-OHdG. The combination of elevated top 2 PFR metabolites was not associated with higher urinary oxidative stress marker levels. This is the first study to report associations between urinary PFR metabolites and oxidative stress biomarkers among children.
• Anti-PcrV titers in non-cystic fibrosis patients with Pseudomonas aeruginosa respiratory tract infection.

  Kentaro Nagaoka, Yu Yamashita, Hirokazu Kimura, Hiroki Kimura, Masaru Suzuki, Tatsuya Fukumoto, Kasumi Hayasaka, Mari Yoshida, Takafumi Hara, Hideki Maki, Tomoyuki Ohkawa, Satoshi Konno

  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 87 54 - 59 1201-9712 2019/10 [Refereed][Not invited]
   

  OBJECTIVE: The epidemiology and role of the anti-PcrV titer in non-cystic fibrosis patients with Pseudomonas aeruginosa airway tract infections is not fully understood. This study was performed to compare the anti-PcrV titers of patients with and without P. aeruginosa respiratory tract infections. METHODS: This prospective cohort study was conducted at Hokkaido University Hospital in Japan. Participants had blood and sputum specimens collected on admission. They were divided into two groups based on their sputum culture results. Those with a P. aeruginosa infection were assigned to the P. aeruginosa (PA) group and those without a P. aeruginosa infection were assigned to the non-PA group. Serum anti-PcrV titers were measured using a validated ELISA. RESULTS: Of the 44 participants, 15 were assigned to the PA group and 29 were assigned to the non-PA group. In the PA group, 10/15 participants (66.7%) had an anti-PcrV titer >1000ng/ml compared to 3/29 participants (10.3%) in the non-PA group (p<0.001). In the PA group, two of the five participants with an anti-PcrV titer <1000 ng/ml died of recurrent P. aeruginosa pneumonia; the other three participants did not develop pneumonia. CONCLUSION: The anti-PcrV titers in participants with P. aeruginosa infection varied considerably. Patients with low anti-PcrV titers and refractory P. aeruginosa infections need to be monitored closely.
• Inhaled GM-CSF for Pulmonary Alveolar Proteinosis.

  Ryushi Tazawa, Takahiro Ueda, Mitsuhiro Abe, Koichiro Tatsumi, Ryosuke Eda, Shotaro Kondoh, Konosuke Morimoto, Takeshi Tanaka, Etsuro Yamaguchi, Ayumu Takahashi, Miku Oda, Haruyuki Ishii, Shinyu Izumi, Haruhito Sugiyama, Atsushi Nakagawa, Keisuke Tomii, Masaru Suzuki, Satoshi Konno, Shinya Ohkouchi, Naoki Tode, Tomohiro Handa, Toyohiro Hirai, Yoshikazu Inoue, Toru Arai, Katsuaki Asakawa, Takuro Sakagami, Atsushi Hashimoto, Takahiro Tanaka, Toshinori Takada, Ayako Mikami, Nobutaka Kitamura, Koh Nakata

  The New England journal of medicine 381 (10) 923 - 932 0028-4793 2019/09/05 [Refereed][Not invited]
   

  BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).
• Efficacy of Azithromycin in a Mouse Pneumonia Model against Hospital-Acquired Methicillin-Resistant Staphylococcus aureus.

  Yu Yamashita, Kentaro Nagaoka, Hiroki Kimura, Masaru Suzuki, Satoshi Konno, Tatsuya Fukumoto, Koji Akizawa, Norihito Kaku, Yoshitomo Morinaga, Katsunori Yanagihara

  Antimicrobial agents and chemotherapy 63 (9) 0066-4804 2019/09 [Refereed][Not invited]
   

  The use of macrolides against pneumonia has been reported to improve survival; however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM) and compared it with that of vancomycin (VCM) and daptomycin (DAP) in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection and then treated with AZM, VCM, or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (interleukin-6 [IL-6] and macrophage inflammatory protein-2 [MIP-2]) in bronchoalveolar lavage fluid or toxin expression levels (α-hemolysin [Hla] and staphylococcal protein A [Spa]) was observed following AZM treatment. In vitro, AZM suppressed the growth of MRSA in late log phase but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.
• Management of Severe Asthma: a European Respiratory Society/American Thoracic Society Guideline.

  Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, Gaga M, Kellermeyer L, Khurana S, Knight S, McDonald VM, Morgan RL, Ortega VE, Rigau D, Subbarao P, Tonia T, Adcock IM, Bleecker ER, Brightling C, Boulet LP, Cabana M, Castro M, Chanez P, Custovic A, Djukanovic R, Frey U, Frankemolle B, Gibson P, Hamerlijnck D, Jarjour N, Konno S, Shen H, Vitary C, Bush A

  The European respiratory journal 0903-1936 2019/09 [Refereed][Not invited]
   

  欧州呼吸器学会(ERS)、米国胸部疾患学会(ATS)による重症喘息のガイドライン
• Effects of Anaerobic Culturing on Pathogenicity and Virulence-Related Gene Expression in Pneumococcal Pneumonia.

  Kentaro Nagaoka, Yu Yamashita, Hiroki Kimura, Masaru Suzuki, Satoshi Konno, Tatsuya Fukumoto, Koji Akizawa, Yoshitomo Morinaga, Katsunori Yanagihara, Masaharu Nishimura

  The Journal of infectious diseases 219 (10) 1545 - 1553 0022-1899 2019/04/19 [Refereed][Not invited]
   

  BACKGROUND: The pathogenicity of Streptococcus pneumoniae under anaerobic conditions remains largely unknown. We examined the pathogenicity of S. pneumoniae cultured under anaerobic conditions in a murine model of pneumococcal pneumonia. METHODS: Mice were infected with S. pneumoniae grown under anaerobic or aerobic conditions. The pathogenic effects in vivo in the lower airway tract were then compared. The effect of anaerobic culture on lytA/ply transcript levels in vitro and in vivo were analyzed by quantitative real-time polymerase chain reaction. RESULTS: Mice inoculated with anaerobically cultured S. pneumoniae exhibited significantly lower survival rates and higher bacterial loads in the lungs and blood as compared to those infected with aerobically cultured S. pneumoniae. Aerobically cultured S. pneumoniae in the early log phase of growth was also able to induce severe pneumonia at levels equivalent to those of anaerobic S. pneumoniae. However, ply/gyrB transcript levels were significantly increased in the lungs of mice infected with anaerobically grown S. pneumoniae. In vitro, S. pneumoniae grown under anaerobic culture conditions demonstrated greater proliferation than S. pneumoniae grown under aerobic culture conditions, and bacterial concentrations were maintained for 24 hours without detectable upregulation of lytA messenger RNA. CONCLUSIONS: S. pneumoniae grown under anaerobic conditions had the potential to induce severe invasive bacteremic pneumococcal pneumonia in a manner different from that of S. pneumoniae grown under aerobic conditions.
• A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts.

  Kanazawa J, Kitazawa H, Masuko H, Yatagai Y, Sakamoto T, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Hizawa N

  BMC medical genetics 20 (1) 58 - 58 2019/04 [Refereed][Not invited]
   

  BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.
• A case of primary bacteraemia caused by Salmonella enterica serovar Corvallis in an immunocompetent adult after travel to Southeast Asia

  Sho Nakakubo, Kentaro Nagaoka, Masaru Suzuki, Satoshi Konno, Yasushi Shibue, Tetsuya Ikeda, Masaharu Nishimura

  Access Microbiology 1 (1) 2019/03/01 

  Introduction. Non-typhoidal Salmonella (NTS) that typically causes diarrhoeal disease in humans has a dramatically more severe and more invasive presentation than typhoid fever in immunocompromised adults. However, the incidence and significance of NTS primary bacteraemia in immunocompetent adults have been unclear. Case presentation. A 24-year-old man presented to our hospital with a high fever 14 days after travelling to Vietnam and Cambodia for 14 days. His past medical history, family history and social history were unremarkable, except for his dietary intake history during his stay in Southeast Asia. He did not have any abdominal pain, diarrhoea, enterocolitis, arthritis, or abscesses, as determined by multiple examinations, which included computed tomography. The initial blood cultures identified the presence of Gram-negative bacilli, which were finally identified as the Salmonella enterica subspecies serovar Corvallis. Thus, S. enterica serovar Corvallis was the most likely primary bacteria in this patient. Since domestic outbreaks of NTS infections are extremely rare, our case patient was diagnosed with travel-related bacteraemia. The patient had an uneventful recovery after antibiotic administration. Conclusion. We report a rare case of bacteraemia caused by S. enterica serovar Corvallis in an immunocompetent adult after travelling through Vietnam and Cambodia. From the experience of our case, we suggest that more caution is necessary when diagnosing the unique clinical features of travel-related NTS infections.
• An adult case of severe life-threatening Mycoplasma pneumoniae pneumonia due to a macrolide-resistant strain, Japan: a case report.

  Matsumoto M, Nagaoka K, Suzuki M, Konno S, Takahashi K, Takashina T, Ishiguro N, Nishimura M

  BMC infectious diseases 19 (1) 204 - 204 2019/02 [Refereed][Not invited]
   

  BACKGROUND: Until now, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MP) infection among adult patients has been low, and severe MP pneumonia due to a macrolide-resistant strain has seldom been reported. Here, we describe a rare case of severe life-threatening MP pneumonia due to a macrolide-resistant strain in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid. CASE PRESENTATION: A 39-year-old apparently healthy woman complained of fever and productive cough. Three days after onset, she was admitted to a local general hospital. On admission, her vital signs were stable except for high-grade fever. The patient's chest X-ray and chest computed tomography images revealed subsegmental consolidation in her right lower lobe. Treatment with ampicillin/sulbactam, and azithromycin were initiated under a clinical diagnosis of community-acquired pneumonia. After treatment initiation, her fever had not subsided, and the pulmonary lesion had extended to the entire lower lobe. Thus, treatment with prednisolone as steroid pulse therapy was initiated from clinical day 7. However, neither her symptoms nor her pulmonary lesion improved; therefore, she was transferred to our hospital for further examination and treatment. On admission (clinical day 14), her indirect hemagglutination titer for MP was elevated at 1:2560, and bronchoalveolar fluid examination yielded positive results for the mycoplasma antigen. Based on these clinical findings, we confirmed a case of severe life-threatening MP pneumonia. Since her respiratory condition was extremely severe, we initiated levofloxacin and tetracycline. Two days later (clinical day 16), her fever, malaise, and hypoxia resolved, and her pulmonary lesions had significantly improved. Further molecular identification yielded the DNA of MP from her bronchoalveolar fluid, and mutation of A2063G in the 23S rRNA gene was revealed. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain. CONCLUSION: More awareness is needed on the emergence of macrolide-resistant MP infection in adults, because severe infection could develop despite initial treatment with macrolide and steroid therapy, which are generally considered as standard therapy for MP.
• 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 2019/02 [Refereed][Not invited]
   

  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.
• Complete Genome Sequences of Streptococcus pneumoniae Strains HU-OH (Serotype 3, Sequence Type 183 [ST183]), NU83127 (Serotype 4, ST246), and ATCC 49619 (Serotype 19F, ST1203).

  Kentaro Nagaoka, Satoshi Konno, Kazunori Murase, Taisei Kikuchi, Yoshitomo Morinaga, Katsunori Yanagihara, Ichiro Nakagawa

  Microbiology resource announcements 8 (9) 2019/02 [Refereed][Not invited]
   

  Streptococcus pneumoniae is a pathogenic bacterium frequently found in the respiratory tract of humans and commonly causes pneumonia and bacterial meningitis. Here, the complete circular genome sequences of three S. pneumoniae strains with different serotypes and sequence types have been reported.
• Cathepsin S, a new serum biomarker of sarcoidosis discovered by transcriptome analysis of alveolar macrophages.

  Hiroyuki Tanaka, Etsuro Yamaguchi, Nobuhiro Asai, Toyoharu Yokoi, Masaki Nishimura, Haruhisa Nakao, Masashi Yoneda, Yoshinori Ohtsuka, Satoshi Konno, Noritaka Yamada

  Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 36 (2) 141 - 147 2019 [Refereed][Not invited]
   

  Background: Development of reliable new biomarkers remains crucial to improve diagnosis and assessing disease activity in sarcoidosis. The objective of this study was to seek such markers from the gene expression signature of alveolar macrophages by transcriptome analysis. Methods: Pooled RNA extracted from alveolar macrophages from patients with active sarcoidosis and control patients was subjected to transcriptome analysis using microarrays. Expressed gene intensity in sarcoidosis relative to that in control was calculated. We measured serum cathepsin S (CTSS) concentrations in 89 healthy volunteers, 107 patients with sarcoidosis, 26 with interstitial pneumonia, 150 with pneumoconiosis, and 76 with pulmonary mycobacteriosis by the enzyme-linked immunosorbent assay. Results: Among 12 genes with ratios higher than that of a housekeeping gene, we selected CTSS for scrutinizing protein expression in serum because of the feasibility of the protein assay. CTSS concentrations were significantly increased in sarcoidosis compared with not only controls but also all the other lung diseases. Receiver operating characteristics curve for sarcoidosis and parenchymal lung diseases revealed an area under the curve of 0.800 (95% confidence interval, 0.751-0.850; p=1.4 x 10-18) with 70% sensitivity and 78% specificity at a CTSS concentration of 15.5 ng/ml. A significant trend was identified between CTSS concentrations and the number of affected organs. Serum CTSS concentrations varied in parallel with clinical courses both spontaneously and in response to corticosteroid therapy. Epithelioid cells in granulomas were positive for immunohistochemical staining with CTSS. Conclusions: CTSS has the potential to be a useful biomarker in sarcoidosis.
• 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 [Refereed][Not invited]
   

  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.
• A cis-eQTL Allele Lowering Gene Expression of CHL3L1 Is Associated with Late-Onset Adult Asthma in Japanese

  Shigemasa, R, Kanazawa, J, Kitazawa, H, Masuko, H, Hyodo, K, Yatagai, Y, Sakamoto, T, Kaneko, Y, Iijima, H, Naito, T, Saito, T, Noguchi, E, Konno, S, Nishimura, M, Hirota, T, Tamari, M, Hizawa, N

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE AMER THORACIC SOC 199 1073-449X 2019 [Refereed][Not invited]
  
• Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family.

  Tetsuaki Shoji, Satoshi Konno, Yo Niida, Takahiro Ogi, Masaru Suzuki, Kaoruko Shimizu, Yasuhiro Hida, Kichizo Kaga, Kuniaki Seyama, Tomoaki Naka, Yoshihiro Matsuno, Masaharu Nishimura

  PloS one 14 (2) e0212370  2019 [Refereed][Not invited]
   

  Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary disease, generally manifesting as a tuberous sclerosis complex (TSC), characterised by multiple, small ground-glass nodular shadows on chest computed tomography (CT). Histological examination typically reveals multicentric, well-demarcated, nodular type II pneumocystic growth. Herein, we describe three cases of this rare pulmonary disease occurring within one family. Using reverse transcription polymerase chain reaction (RT-PCR) and direct DNA sequencing, we identified a novel germline mutation, a point mutation in TSC1 intron 5, which yielded a splice variant and loss of function of TSC1. Furthermore, immunohistochemical staining indicated the expression of phospho-p70S6K and phospho-4E-BP1, suggesting that TSC1 function was impaired by the novel gene mutation in MMPH cells.
• Nationwide survey on the organ-specific prevalence and its interaction with sarcoidosis in Japan

  Takeshi Hattori, Satoshi Konno, Noriharu Shijubo, Tetsuo Yamaguchi, Yukihiko Sugiyama, Sakae Honma, Naohiko Inase, Yoichi M. Ito, Masaharu Nishimura

  Scientific Reports 8 (1) 9440  2045-2322 2018/12/01 [Refereed][Not invited]
   

  Previous studies attempted to characterize the subjects with sarcoidosis according to differences in sex, age, and the presence of specific organ involvement. However, significant interactions among these factors precluded a clear conclusion based on simple comparison. This study aimed to clarify the age- and sex-stratified prevalence of specific organ involvement and the heterogenous nature of sarcoidosis. Using the data of 9,965 patients who were newly registered into a database at the Ministry of Health, Labour and Welfare, Japan between 2002 and 2011, we evaluated the age- and sex-specific prevalence of the eye, lung, and skin involvement of sarcoidosis. We also attempted corresponding analysis considering multiple factors. As compared with several decades ago, the monophasic age distribution in men became biphasic, and the biphasic distribution in women, monophasic. The prevalence of pulmonary and cutaneous lesions was significantly associated with age, whereas the prevalence of ocular involvement showed a biphasic pattern. The prevalence of bilateral hilar lymphadenopathy was significantly higher, whereas the prevalence of diffuse lung shadow was significantly lower, in subjects with ocular involvement than those without ocular involvement. Corresponding analysis visually clarified the complex interactions among factors. Our results contribute to a better understanding of the heterogeneous features of sarcoidosis.
• Safety and pharmacokinetics of Alpha-1 MP (Prolastin^®-C) in Japanese patients with alpha₁-antitrypsin (AAT) deficiency.

  Seyama K, Nukiwa T, Sato T, Suzuki M, Konno S, Takahashi K, Nishimura M, Steinmann K, Sorrells S, Chen J, Hayashi KI

  Respiratory investigation 57 (1) 89 - 96 2212-5345 2018/11 [Refereed][Not invited]
   

  BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0-7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).
• 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 2213-2198 2018/11 [Refereed][Not invited]
   

  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.
• Complete Genome Sequence of Streptococcus agalactiae Serotype III, Multilocus Sequence Type 335 Strain HU-GS5823, Isolated from a Human Patient in Japan with Severe Invasive Infection.

  Kentaro Nagaoka, Satoshi Konno, Kazunori Murase, Taisei Kikuchi, Ichiro Nakagawa

  Microbiology resource announcements 7 (20) 2018/11 [Refereed][Not invited]
   

  Streptococcus agalactiae is an important causal pathogen of neonatal and obstetric sepsis, and it may be involved in invasive infection in immunocompromised and elderly individuals. Here, we report the complete genome sequence of Streptococcus agalactiae serotype III strain HU-GS5823, which was isolated from a patient in Japan with an invasive infection.
• 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 1879-1026 2018/10/15 [Refereed][Not invited]
   

  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.
• A Case of Retroperitoneal Fibrosis Diagnosed as IgG4-related Disease After 35 Years.

  Konno S, Matsuno Y, Ichimiya S, Nishimura M, Kawakami Y

  Internal medicine (Tokyo, Japan) 58 (4) 609 - 613 0918-2918 2018/10 [Refereed][Not invited]
   

  In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4+ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.
• 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 8750-7587 2018/07 [Refereed][Not invited]
  
• 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 0954-7894 2018/05 [Refereed][Not invited]
  
• 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 1423-0097 2018/05/01 [Refereed][Not invited]
   

  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.
• Neutrophil predominance in bronchoalveolar lavage fluid is associated with disease severity and progression of HRCT findings in pulmonary Mycobacterium avium infection

  Takashi Inomata, Satoshi Konno, Katsura Nagai, Masaru Suzuki, Masaharu Nishimura

  PLoS ONE 13 (2) e0190189  1932-6203 2018/02/01 [Refereed][Not invited]
   

  Pulmonary Mycobacterium avium complex (MAC) infection is increasing in prevalence worldwide even in immunocompetent individuals. Despite its variable clinical course, the clinical and immunological factors associated with radiographical severity and progression are not largely unknown. We aimed to study the association between the inflammatory cell and cytokine profiles at the local infected site, and the radiological severity and/or progression of pulmonary MAC infection. In this retrospective cohort study, 22 healthy subjects and 37 consecutive patients who were diagnosed as having pulmonary MAC infection by positive cultures of bronchoalveolar lavage (BAL) fluids were enrolled. The 37 patients were divided into 2 groups based on the predominant BAL inflammatory cell type: the lymphocyte-dominant (LD) group and neutrophil-dominant (ND) groups. The high-resolution computed tomography score in both the lavaged segment and whole lung and cytokines profiles were compared between the 2 groups. The clinical course after the BAL procedure was also compared between the 2 groups. Both the segment and whole lung scores in the ND group were significantly higher than the LD group (P < 0.001). Levels of IL-8 in the BAL fluids were significantly higher in the ND group compared to the LD group (P = 0.01). In contrast, levels of IL-22 were significantly lower in the ND group compared to the LD group (P < 0.001). The prevalence of patients who showed deterioration of the disease was significantly higher in the ND group (83.3%) than the LD group (12.5%) (P < 0.01). Neutrophil-predominant inflammatory response at the infected site is associated with the radiographical severity and progression of pulmonary MAC infection.
• Clinical significance of serum anti-GM-CSF autoantibody levels in autoimmune pulmonary alveolar proteinosis

  Masaki Nishimura, Etsuro Yamaguchi, Ayumu Takahashi, Nobuhiro Asai, Eisuke Katsuda, Toyohiro Ohta, Yoshinori Ohtsuka, Kenshi Kosaka, Ayako Matsubara, Hiroyuki Tanaka, Norihito Yokoe, Akihito Kubo, Satoshi Konno, Kenji Baba

  Biomarkers in Medicine 12 (2) 151 - 159 1752-0371 2018/02/01 [Refereed][Not invited]
   

  Aim: Precise clinical significance of antigranulocyte-macrophage colony stimulating factor (GM-CSF) autoantibody levels in autoimmune pulmonary alveolar proteinosis (aPAP) has not been well studied. Methods: We obtained sera from 50 healthy controls, 46 aPAP patients, 50 with sarcoidosis, 52 with idiopathic interstitial pneumonia and 75 with pneumoconiosis. The clinical course of aPAP patients was assessed by scoring computed tomography images in 19 patients. Results: The cut-off level of anti-GM-CSF IgG for discrimination between aPAP and other diffuse lung diseases was 2.8 μg/ml with 100% sensitivity and 98% specificity. Antibody levels at baseline were significantly lower in the improved group than in the unimproved group (p = 0.008). Conclusion: Our results indicate the existence of threshold levels of serum anti-GM-CSF IgG for the development and persistence of aPAP.
• 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 2325-6621 2018/01/01 [Refereed][Not invited]
   

  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.
• 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 0025-7931 2018 [Refereed][Not invited]
   

  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
• Allergic bronchopulmonary aspergillosis in Japan: A nationwide survey.

  Tsuyoshi Oguma, Masami Taniguchi, Terufumi Shimoda, Katsuhiko Kamei, Hiroto Matsuse, Akira Hebisawa, Noboru Takayanagi, Satoshi Konno, Koichi Fukunaga, Kazuki Harada, Jun Tanaka, Katsuyoshi Tomomatsu, Koichiro Asano

  Allergology international : official journal of the Japanese Society of Allergology 67 (1) 79 - 84 1323-8930 2018/01 [Refereed][Not invited]
   

  BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic pulmonary disease characterized by a hypersensitivity reaction to Aspergillus species colonizing the airways. The clinical characteristics of ABPA may differ depending on genetic and environmental background. We performed a nationwide survey to determine the clinical characteristics of ABPA in Japan. METHODS: In 2013, a questionnaire on physician-diagnosed ABPA/allergic bronchopulmonary mycosis was sent to 903 medical centers specializing in respiratory or allergic diseases. Cases fulfilling the following criteria were categorized as possible ABPA-central bronchiectasis (ABPA-CB): 1) presence of specific serum immunoglobulin E (IgE) antibodies or a positive skin reaction to Aspergillus, and 2) bronchiectasis or mucoid impaction in the central bronchi. RESULTS: Of 499 physician-diagnosed cases reported by 132 clinical centers, 358 cases met the criteria for possible ABPA-CB. Median age of ABPA-CB onset was 57 (interquartile range, 44-68) years; later-onset disease, developing ≥50 years of age, accounted for 66% of the cases and was associated with female sex, delayed onset of asthma, and lower levels of serum IgE. A third of the patients (120 patients, 34%) exhibited low levels of serum total IgE (<1000 IU/mL). Aspergillus species were isolated from sputum in 126/213 cases (59%), and Schizophyllum commune was identified in 12 (6%) patients. During the course of the treatment, ABPA recurred in 169 (48%) cases. CONCLUSIONS: This nationwide survey identified several unique clinical characteristics of ABPA in Japan, such as late-onset, relatively lower serum IgE levels, and frequent recurrences/flares.
• 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 1440-1592 2018 [Refereed][Not invited]
   

  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.
• Orchestrating Role of Apoptosis Inhibitor of Macrophage in the Resolution of Acute Lung Injury

  Hiroki Kimura, Masaru Suzuki, Satoshi Konno, Hideo Shindou, Takao Shimizu, Takahide Nagase, Toru Miyazaki, Masaharu Nishimura

  JOURNAL OF IMMUNOLOGY 199 (11) 3870 - 3882 0022-1767 2017/12 [Refereed][Not invited]
   

  Appropriate resolution of inflammation is known to be essential in tissue homeostasis. In this study, we evaluated the significance of a macrophage-derived soluble protein, apoptosis inhibitor of macrophage (AIM), in LPS-induced lung injury in mice. After oropharyngeal administration of LPS, the level of free-form serum AIM increased on days 2-4, accompanied by the resolution of inflammation, which was observed in the cellular profile of bronchoalveolar lavage fluid. In an experiment using wild-type (WT) and AIM(-/-) mice, the resolution of inflammation was accelerated in AIM(-/-) mice when compared with the WT mice, which was reversed when recombinant AIM protein was administered. The changes in the histopathological findings and inflammatory mediators followed similar trends, and the ratio of apoptotic cells was increased in AIM(-/-) mice when compared with the WT mice. In vitro analysis showed that macrophage phagocytosis of apoptotic neutrophils was suppressed in the presence of AIM, indicating that anti-resolution property of AIM involves efferocytosis inhibition. In lipidomic analysis of lung tissues, the levels of several lipid mediators increased markedly when LPS was given to WT mice. However, in AIM(-/-) mice, the concentrations of these lipid mediators were not significantly upregulated by LPS. These data reflect the significant role of AIM in lipid metabolism; it may suppress lipid metabolites at baseline, and then produce an inflammatory/pathologic pattern in the event of LPS-induced lung injury. Taken together, AIM may play an orchestrating role in the resolution process of inflammation by altering the profile of pulmonary lipid mediators in mice.
• Resolution rate of pulmonary sarcoidosis and its related factors in a Japanese population

  Takeshi Hattori, Satoshi Konno, Noriharu Shijubo, Mitsuhide Ohmichi, Tetsuo Yamaguchi, Masaharu Nishimura

  RESPIROLOGY 22 (8) 1604 - 1608 1323-7799 2017/11 [Refereed][Not invited]
   

  Background and objective: A number of previous studies have reported on the rate of resolution of pulmonary sarcoidosis and its associated factors. However, most of the studies were conducted several decades ago and no similar surveys have been conducted in recent years. The aim of this study was to evaluate the rate of resolution of pulmonary sarcoidosis and its related factors in recently diagnosed patients, and to compare the results with those from previous studies. Methods: This study included 306 patients who had been newly diagnosed with pulmonary sarcoidosis between 2000 and 2009 in Sapporo, Japan. Chest radiographical findings were assessed at the initial visit and at the 2- or 5-year observation points. The rates of resolution on chest radiographs and the association with clinical manifestations were evaluated. Results: The resolution rates were 17.9% at the 2-year and 29.9% at the 5-year observation point. These rates were lower than those reported in the earlier surveys. Younger subjects (aged <40 years) showed resolution more often (P < 0.05). The absence of extra-pulmonary organ involvement was associated with resolution at 5 years (P < 0.05). Conclusion: The clinical course of pulmonary sarcoidosis may be changing, showing a tendency not to resolve. At least in part, this may be due to the ageing of the Japanese population.
• Genetic association of the functional CDHR3 genotype with early-onset adult asthma in Japanese populations

  Jun Kanazawa, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Hideyasu Yamada, Yoshiko Kaneko, Haruna Kitazawa, Hiroaki Iijima, Takashi Naito, Takefumi Saito, Emiko Noguchi, Satoshi Konno, Masaharu Nishimura, Tomomitsu Hirota, Mayumi Tamari, Nobuyuki Hizawa

  ALLERGOLOGY INTERNATIONAL 66 (4) 563 - 567 1323-8930 2017/10 [Refereed][Not invited]
   

  Background: Recent studies have demonstrated that a coding SNP (rs6967330, Cys529 -> Tyr) in cadherin-related family member 3 (CDHR3), which was previously associated with wheezing illness and hospitalizations in infancy, could support efficient human rhinovirus C (RV-C) entry and replication. Here, we sought to examine the genetic contribution of this variant to the development of adult asthma. Methods: We performed a candidate gene case-control association study of 2 independent Japanese populations (a total of 3366 adults). The odds ratios (ORs) for association of the A allele at rs6967330 with adult asthma were calculated according to age at onset of asthma. In addition, the effect of the CDHR3 genotype on the development of specific asthma phenotypes was examined. Results: The A allele was associated with asthma (OR = 1.56; Mantel-Haenszel p = 0.0040) when the analysis was limited to patients with early-onset adult asthma. In addition, when the analysis was limited to atopic individuals, a stronger association of the CDHR3 variant with early-onset asthma was found, and interaction of the CDHR3 genotype with atopy was demonstrated. Finally, a significant association of this variant was specifically found with a phenotype of asthma characterized by atopy, early-onset, and lower lung function. Conclusions: Our study supports the concept that the CDHR3 variant is an important susceptibility factor for severe adult asthma in individuals who develop the disease in early life. The interaction between the CDHR3 variant and atopy indicates that genetic predisposition to early respiratory viral infection is combined with atopy in promoting asthma. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.
• Acute bronchodilator responses to beta 2-agonist and anticholinergic agent in COPD: Their different associations with exacerbation

  Satoshi Konno, Hironi Makita, Masaru Suzuki, Kaoruko Shimizu, Hirokazu Kimura, Hiroki Kimura, Masaharu Nishimura

  RESPIRATORY MEDICINE 127 14 - 20 0954-6111 2017/06 [Refereed][Not invited]
   

  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.
• 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 2329-6933 2017/03 [Refereed][Not invited]
   

  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.
• Understanding the complex interactions between obesity and asthma

  Satoshi Konno

  Japanese Journal of Allergology 66 (7) 919 - 922 1347-7935 2017 [Refereed][Not invited]
  
• 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 1073-449X 2016/12 [Refereed][Not invited]
   

  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.
• The effects of pulmonary vasodilating agents on right ventricular parameters in severe group 3 pulmonary hypertension: a pilot study

  Takahiro Sato, Ichizo Tsujino, Ayako Sugimoto, Toshitaka Nakaya, Taku Watanabe, Hiroshi Ohira, Masaru Suzuki, Satoshi Konno, Noriko Oyama-Manabe, Masaharu Nishimura

  Pulmonary Circulation 6 (4) 524 - 531 2045-8932 2016/12 [Refereed][Not invited]
   

  Pulmonary arterial hypertension (PAH)-approved vasodilators improve right ventricular (RV) function in patients with PAH. However, whether PAH-approved drugs ameliorate RV morphology and function in lung disease-associated pulmonary hypertension (lung-PH) remains unclear. We aimed to prospectively evaluate the changes in RV volume and ejection fraction (RVEF) in 14 consecutive severe lung-PH patients treated with PAH-approved vasodilators. Severe lung-PH was defined as a mean pulmonary arterial pressure (MPAP) of >= 35 mmHg or an MPAP of >= 25 mmHg with a cardiac index (L/min/m(2)) of <2. Right heart catheterization and cardiac magnetic resonance (CMR) imaging were performed at baseline and at 3 months after starting sildenafil with or without other PAH-approved drugs. Follow-up was conducted at 3 months in 11 participants; compared with baseline values, MPAP and pulmonary vascular resistance (PVR) decreased by 18% and 37%, respectively. Baseline CMR imaging revealed an elevated RV end-diastolic volume index (RVEDVI; mL/m(2)) of 117.5 +/- 35.9 and a below-average RVEF of 25.2% +/- 7.2%; after 3 months, RVEDVI decreased by 23.7% (P = 0.0061) and RVEF increased by 32.9% (P = 0.0165). Among the 11 patients, 3 were thought to be a stable and homogenous subset in terms of background lung disease and medical management administered. These 3 patients exhibited similar ameliorations in PVR and RVEF, compared with the other 8 patients. PAH-approved drug treatment may improve RV dilatation and systolic function among patients with severe lung-PH.
• 気管支喘息として治療中に発見、診断に至ったIgG4関連肺疾患の2例

  鎌田 啓佑, 今野 哲, 長岡 健太郎, 鈴木 雅, 西村 正治

  日本サルコイドーシス/肉芽腫性疾患学会雑誌 日本サルコイドーシス 36 (1-2) 92 - 92 1883-1273 2016/10
• 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 0954-6111 2016/10 [Refereed][Not invited]
   

  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.
• Variants near the HLA complex group 22 gene (HCG22) confer increased susceptibility to late-onset asthma in Japanese populations

  Yohei Yatagai, Tomomitsu Hirota, Tohru Sakamoto, Hideyasu Yamada, Hironori Masuko, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Emiko Noguchi, Mayumi Tamari, Michiaki Kubo, Atsushi Takahashi, Satoshi Konno, Hironi Makita, Masaharu Nishimura, Minako Hijikata, Naoto Keicho, Sakae Homma, Yoshio Taguchi, Arata Azuma, Shoji Kudoh, Nobuyuki Hizawa

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 138 (1) 281 - 283 0091-6749 2016/07 [Refereed][Not invited]
  
• 気管支喘息として治療中に発見、診断に至ったIgG4関連肺疾患の2例

  鎌田 啓佑, 今野 哲, 長岡 健太郎, 鈴木 雅, 西村 正治

  アレルギー (一社)日本アレルギー学会 65 (4-5) 649 - 649 0021-4884 2016/05
• Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults

  Taku Watanabe, Ichizo Tsujino, Satoshi Konno, Yoichi M. Ito, Chisa Takashina, Takahiro Sato, Akira Isada, Hiroshi Ohira, Yoshinori Ohtsuka, Yuma Fukutomi, Hiroyuki Nakamura, Yukio Kawagishi, Chiharu Okada, Nobuyuki Hizawa, Masami Taniguchi, Akira Akasawa, Masaharu Nishimura

  PLOS ONE 11 (3) e0148926  1932-6203 2016/03 [Refereed][Not invited]
   

  Objective A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population. Methods We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index >= 25kg/m(2)) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation. Results In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72-0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09-1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI: 1.05-2.38) for obesity. Conclusions In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered.
• Role of Lung Function Genes in the Development of Asthma

  Hideyasu Yamada, Hironori Masuko, Yohei Yatagai, Tohru Sakamoto, Yoshiko Kaneko, Hiroaki Iijima, Takashi Naito, Emiko Noguchi, Satoshi Konno, Masaharu Nishimura, Tomomitsu Hirota, Mayumi Tamari, Nobuyuki Hizawa

  PLOS ONE 11 (1) e0145832  1932-6203 2016/01 [Refereed][Not invited]
   

  Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 x 10(-4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.
• 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 1347-7935 2016 [Refereed][Not invited]
   

  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 2329-6933 2015/12 [Refereed][Not invited]
  
• Two cases of hard metal lung disease showing gradual improvement in pulmonary function after avoiding dust exposure

  Hiroya Terui, Satoshi Konno, Kichizo Kaga, Yoshihiro Matsuno, Kanako C. Hatanaka, Hiromi Kanno, Hiroshi Moriyama, Motohiro Uo, Masaharu Nishimura

  JOURNAL OF OCCUPATIONAL MEDICINE AND TOXICOLOGY 10 29  1745-6673 2015/08 [Refereed][Not invited]
   

  We present herein two cases of hard metal lung disease (HMLD) with distinct pathological findings. Both cases showed gradual improvements in pulmonary function over a period of a few years (Case 1: 30 months; Case 2: 12 months) after the avoidance of dust exposure, while improvements on high-resolution computed tomography were modest. The increased lymphocytes and decreased CD4/CD8 ratio in BALF observed at initial diagnosis normalized after the avoidance of dust exposure in one case. To the best of our knowledge, this is the first report demonstrating continual follow-up of pulmonary function and radiographic findings, and a comparison of BALF findings before and after avoidance of hard metal dust exposure.
• Contrasting associations of body mass index and measles with asthma and rhinitis in young adults

  Hirokazu Kimura, Satoshi Konno, Akira Isada, Yukiko Maeda, Manabu Musashi, Masaharu Nishimura

  ALLERGY AND ASTHMA PROCEEDINGS 36 (4) 293 - 299 1088-5412 2015/07 [Refereed][Not invited]
   

  Asthma and allergic rhinitis often coexist and are increasing worldwide, particularly among the younger generation. Although the prevalences of adult asthma and allergic rhinitis and their risk factors have been reported, there have been few studies focusing on young adults. The aim of this study was to evaluate the prevalences of asthma and allergic rhinitis and their associated factors in Japanese young adults. A questionnaire survey of new students at Hokkaido University about the presence of current wheeze and rhinitis and a history of several viral infections during childhood was conducted in 2008 and 2010. The prevalences of wheeze and rhinitis and their associated factors were evaluated. Of 4076 nonsmoking subjects aged 18-25 years, 261 (6.4%) had current wheeze and 1373 (33.7%) had allergic rhinitis. On multivariate analyses, current wheeze was associated with high body mass index (BMI), atopic dermatitis, allergic rhinitis, food allergy, and a history of measles infection. In contrast, allergic rhinitis was associated with low BMI, current wheeze, atopic dermatitis, food allergy, and no history of measles. When subjects were classified into four groups by the presence or absence of wheeze and rhinitis, both high BMI and a history of measles were positively associated with wheeze without rhinitis but negatively associated with rhinitis without wheeze. High BMI and past measles infection showed contrasting associations with asthma and allergic rhinitis in nonsmoking young adults. It is important to not only recognize the common pathophysiological characteristics of asthma and allergic rhinitis but also to understand their differences.
• 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 0720-048X 2015/06 [Refereed][Not invited]
   

  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.
• Genome-Wide Association Study For Late-Onset Asthma Demonstrates Possible Association With A Gene Related To Diffuse Panbronchiolitis

  Yatagai,Y, Sakamoto,T, Yamada,H, Masuko,H, Kaneko,Y, Iijima,H, Naito,T, Noguchi,E, Hirota,T, Tamari,M, Makita,H, Konno,S, Nishimura,M, Hizawa,N

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE AMER THORACIC SOC 191 1073-449X 2015/05 [Not refereed][Not invited]
  
• 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 1178-2005 2015/04/13 [Refereed][Not invited]
   

  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.
• Elemental Analysis of Histopathological Specimens of Tungsten Carbide Lung Disease Using Synchrotron Radiation XRF and XAFS

  Motohiro UO, Takahiro WADA, Tomoko SUGIYAMA, Ikuo NAKANO, Kiyonobu KIMURA, Natsuko TANIGUCHI, Takashi INOMATA, Satoshi KONNO, Masaharu NISHIMURA

  Advances in X-ray Chemical Analysis アグネ技術センター 46 (46) 177 - 186 0911-7806 2015/03 [Refereed][Not invited]
  
• Historical transition of management of sarcoidosis

  Inomata M, Konno S, Azuma A

  W J Respir. 28 4 - 16 2015 [Refereed][Invited]
  
• Smoking and adult asthma, COPD

  Satoshi Konno

  Japanese Journal of Allergology 64 (8) 1127 - 1134 1347-7935 2015 [Refereed][Not invited]
  
• Factors associated with the presence of allergen-specific ige responses in asthma patients who had no ige responses detectable by mast-26

  Hiroaki Iijima, Yoshiko Kaneko, Hironori Masuko, Hideyasu Yamada, Yohei Yatagai, Tohru Sakamoto, Koji Kanemoto, Hiroichi Ishikawa, Takefumi Saito, Takeo Endo, Hiroki Ninomiya, Akihiro Nomura, Takahide Kodama, Norihiro Kaneko, Fumio Kokubu, Hironi Makita, Satoshi Konno, Masaharu Nishimura, Nobuyuki Hizawa

  Japanese Journal of Allergology 64 (9) 1242 - 1253 1347-7935 2015 [Refereed][Not invited]
   

  Aim: To elucidate the characteristics of patients with asthma who have specific IgE responses to inhaled allergens detected by ImmunoCAP, which is not detectable by MAST-26. Methods: A total of 168 patients with adult asthma who reside in the Kanto region were recruited. Levels of total serum IgE and allergen specific IgE antibodies towards 14 common inhaled allergens (MAST-26) were measured. Among these samples, 48 patients with no detectable allergen-specific IgE (group A) and 44 patients with strong sensitization to Dermatophagoides farinae (group B) were selected for further assessment of their sensitization to inhaled allergens such as cockroach and moth using ImmunoCAP. Results: In group A, ImmunoCAP detected specific IgE responses to some inhaled allergens in 27.1% of the patients. The strongest predictive factor for the presence of allergen-specific IgE responses detected by ImmunoCAP was elevated levels of total serum IgE (p = 0.0007). In group B, the presence of IgE responses specific to cockroach or moth by ImmunoCAP were found in 27.8% or 52.3% of the patients, respectively. The predictive factor for the presence of these positive IgE responses was also elevated levels of total serum IgE (p=0.0003). Conclusion: Asthma patients with no detectable specific IgE responses to any inhaled allergens by MAST-26 may be still sensitized to common inhaled allergens, including cockroach and moth. Thus, the presence of allergen-specific IgE responses may be re-assessed by ImmunoCAP in patients with asthma, especially when patients have higher levels of total serum IgE .
• 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 2325-6621 2014/12/01 [Refereed][Not invited]
   

  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.
• Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population

  Y. Yatagai, T. Sakamoto, H. Yamada, H. Masuko, Y. Kaneko, H. Iijima, T. Naito, E. Noguchi, T. Hirota, M. Tamari, S. Konno, M. Nishimura, N. Hizawa

  CLINICAL AND EXPERIMENTAL ALLERGY 44 (11) 1327 - 1334 0954-7894 2014/11 [Refereed][Not invited]
   

  BackgroundIt is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering. ObjectiveTo identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure. MethodsWe performed a GWAS by genotyping a total of 480098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues. ResultsIn the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P=1.43x10(-7)). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P=0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P=7.92x10(-9)). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung. ConclusionsOur study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.
• 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 - + 1081-1206 2014/07 [Refereed][Not invited]
   

  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.
• Clinical features and determinants of COPD exacerbation in the Hokkaido COPD cohort study

  Masaru Suzuki, Hironi Makita, Yoichi M. Ito, Katsura Nagai, Satoshi Konno, Masaharu Nishimura

  EUROPEAN RESPIRATORY JOURNAL 43 (5) 1289 - 1297 0903-1936 2014/05 [Refereed][Not invited]
   

  Exacerbations are among the major factors that may affect the natural history of chronic obstructive pulmonary disease (COPD). The aim was to investigate the clinical characteristics and determinants of COPD exacerbations in our 5-year observational cohort study which had a very low exacerbation frequency. A total of 279 patients with COPD participated in the Hokkaido COPD cohort study, and 268 subjects who had clinical data for multiple visits were analysed. Exacerbation was defined in multiple ways: the patient's subjective complaint, symptom definition, requiring prescription change, requiring antibiotic treatment, or requiring hospital admission. Exacerbation frequency (events per person per year) was 0.78 +/- 1.16, 0.24 +/- 0.47, 0.20 +/- 0.43, 0.13 +/- 0.28 and 0.06 +/- 0.19 for subjective complaint and symptom, prescription, antibiotic and hospital admission definitions, respectively. Exacerbation events did not significantly affect the annual decline in forced expiratory volume in 1 s. A high St George's Respiratory Questionnaire total score, especially activity score, and a low body mass index were strongly associated with exacerbation-free survival, exacerbation frequency and development of recurrent exacerbations. Despite the low exacerbation frequency in our cohort, impaired health-related quality of life and weight loss were found to be independent risk factors for COPD exacerbations.
• 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 1744-6872 2014/05 [Refereed][Not invited]
   

  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.
• 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  1932-6203 2014/02 [Refereed][Not invited]
   

  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.
• Effects of thymic stromal lymphopoietin (TSLP) genotypes on asthma phenotypes defined by the atopy cluster-influence of smoking habits

  Hiroaki Iijima, Hideyasu Yamada, Yohei Yatagai, Yoshiko Kaneko, Takashi Naito, Tohru Sakamoto, Hironori Masuko, Tomomitsu Hirota, Mayumi Tamari, Satoshi Konno, Masaharu Nishimura, Nobuyuki Hizawa

  Japanese Journal of Allergology (一社)日本アレルギー学会 63 (1) 33 - 44 0021-4884 2014/02 [Refereed][Not invited]
   

  Introduction: We have previously reported that a distinct sensitization pattern was associated with thymic stromal lymphopoietin (TSLP) genotype. The aim of this study is to identify the characteristics of asthma phenotypes determined by a cluster analysis of IgE responsiveness and the relationship between these phenotypes and TSLP genotypes. Patients and methods: We studied 297 patients of adult asthma and 1571 non-asthmatic healthy adults from Ibaraki, a prefecture in central Japan and Kamishihoro, a cedar-free, birch-dominant town in northern Japan. Levels of total serum IgE and specific IgE antibodies towards 14 major inhaled allergens were measured. With the use of these measures, cluster analysis was applied to classify the phenotypes of adult asthma. We also examined the genetic effects of 2 TSLP functional single nucleotide polymorphism (SNPs) on the development of each asthma phenotype using multinomial logistic regression analysis. Results: The cluster analysis identified four distinct clinical phenotypes of asthma, including "Dust mite dominant" (A, N = 82), "Multiple pollen" (B, N =14), "Cedar dominant" (C. N = 44), and "Low reactivity" (D, N =154). Asthma phenotype A consisted of younger patients with elevated IgE levels and decreased pulmonary function. Asthma phenotype B was characterized by sensitization by many pollen allergens. Asthma phenotype C was not formed in Kamishihoro. Asthma phenotype D was a group of older women who are less atopic. In current or past smokers, both TSLP SNPs (rs2289276 and rs3860933) were associated with the asthma phenotype D (odds ratio 2.11 [1.36-3.30] and 2.11 [1.34-3.33], respectively). Conclusion: In patients with adult asthma who are less atopic. the genetic polymorphisms of TSLP may have some important roles in the development of the disease in smokers.
• Severe Pulmonary Hypertension in Adult Pulmonary Langerhans Cell Histiocytosis: The Effect of Sildenafil as a Bridge to Lung Transplantation

  Takayuki Yoshida, Satoshi Konno, Ichizo Tsujino, Takahiro Sato, Hiroshi Ohira, Fengshi Chen, Hiroshi Date, Akihiro Ishizu, Hironori Haga, Mishie Tanino, Masaharu Nishimura

  INTERNAL MEDICINE 53 (17) 1985 - 1990 0918-2918 2014 [Refereed][Not invited]
   

  Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.
• 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 1347-7935 2014 [Refereed][Not invited]
   

  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.
• Sensitization to laboratory animal allergens among students and researchers exposed to laboratory rodents in Hokkaido University

  Aya Yoshimura, Manabu Musashi, Takeaki Kaneko, Shunsuke Ohnishi, Chieko Orito, Yukako Kawahara, Satoshi Hashino, Masami Morimatsu, Satoshi Konno, Jiro Arikawa, Tetsuya Ishii, Masaya Sawamura, Ichiro Ueda

  Japanese Journal of Allergology 63 (8) 1132 - 1139 1347-7935 2014 [Refereed][Not invited]
   

  Background: Based on a case who developed anaphylaxis after mouse bite which occurred at Hokkaido University, we studied on allergic sensitization prevalence for laboratory animals among students and researchers who are exposed to laboratory rodents and rabbit, for the purpose of allergy prevention, particularly anaphylaxis. Methods: We carried out the health check-up on laboratory animal allergy (LAA) by questionnaires and specific-IgE antibody test for 555 rodents and/or rabbit handlers from whom informed consent was obtained. Result: Prevalence of positive IgE antibody higher than class 1 to mice, rats, hamsters, guinea pigs, and/or rabbits in the examinees was 14.1% (62/441), 17.9% (50/279), 18.8% (6/32), 17.4% (4/23), and 11.3% (12/106), respectively. Moreover, among users of mouse, those who had allergic symptoms during contact with animals resulted in significantly higher positive rate for anti-mouse IgE antibody test than the other (38.1% vs 8.8%, p< 0.01). Conclusion: Health check-up including measurement of specific-IgE antibody against laboratory animals is useful for understanding allergic sensitization.
• Genome-Wide Association Study for Levels of Total Serum IgE Identifies HLA-C in a Japanese Population

  Yohei Yatagai, Tohru Sakamoto, Hironori Masuko, Yoshiko Kaneko, Hideyasu Yamada, Hiroaki Iijima, Takashi Naito, Emiko Noguchi, Tomomitsu Hirota, Mayumi Tamari, Yoshimasa Imoto, Takahiro Tokunaga, Shigeharu Fujieda, Satoshi Konno, Masaharu Nishimura, Nobuyuki Hizawa

  PLOS ONE 8 (12) e80941  1932-6203 2013/12 [Refereed][Not invited]
   

  Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13: 60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07 x 10(-10)). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.
• FIVE CASES WITH OUT-OF-PROPORTION GROUP 3 PULMONARY HYPERTENSION WITH FAVORABLE HEMODYNAMIC RESPONSE TO VASODILATORS

  Kuroki Akane, Sato Takahiro, Tsujino Ichizo, Igarashi Ayako, Ohira Hiroshi, Yamada Asuka, Watanabe Taku, Suzuki Masaru, Konno Satoshi, Nishimura Masaharu

  RESPIROLOGY 18 172  1323-7799 2013/11 [Refereed][Not invited]
  
• 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 - + 1081-1206 2013/11 [Refereed][Not invited]
   

  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.
• Increased prevalence of cigarette smoking in Japanese patients with sarcoidosis

  Takeshi Hattori, Satoshi Konno, Noriharu Shijubo, Mitsuhide Ohmichi, Masaharu Nishimura

  Respirology 18 (7) 1152 - 1157 1323-7799 2013/10 [Refereed][Not invited]
   

  Background and objective: Several studies have shown that individuals with sarcoidosis in Western populations are less likely to have smoked before diagnosis. Epidemiological characteristics of sarcoidosis are known to differ between Japanese and Westerners. Therefore, the relationship between cigarette smoking and sarcoidosis in a Japanese population was investigated. Methods: Three hundred eighty-eight patients newly diagnosed with sarcoidosis between 2000 and 2008 were retrospectively identified. The results of two large surveys of smoking prevalence in Japan provided reference data. Specific clinical manifestations of sarcoidosis were compared between current smokers and never-smokers, after excluding former smokers. Results: The prevalence of current smokers at the time of the diagnosis of sarcoidosis was 59.6% in men and 27.9% in women. With the exception of men in their 30s, the prevalence was higher in all age groups compared with the general Japanese population. The prevalence of lung parenchymal involvement tended to be higher in current smokers than in never-smokers (odds ratio = 1.33 (0.99-1.77), P = 0.054). Conclusions: This retrospective cohort study suggests that smoking prevalence is higher in Japanese sarcoidosis patients than that reported in Western sarcoidosis patients and that there could be different relationships between smoking and the development of sarcoidosis in these populations. © 2013 Asian Pacific Society of Respirology.
• Incidence, clinical manifestations and prognosis of cardiac sarcoidosis in patients with pulmonary sarcoidosis

  Abe Tomoe, Sato Takahiro, Tsujino Ichizo, Ohira Hiroshi, Yoshinaga Keiichiro, Oyama-Manabe Noriko, Hattori Takeshi, Konno Satoshi, Nishimura Masaharu, Karino Tomoe

  EUROPEAN RESPIRATORY JOURNAL 42 0903-1936 2013/09/01 [Refereed][Not invited]
  
• Serum KL-6 concentrations are associated with molecular sizes and efflux behavior of KL-6/MUC1 in healthy subjects

  Masahiko Shigemura, Satoshi Konno, Yasuyuki Nasuhara, Noriharu Shijubo, Chikara Shimizu, Masaharu Nishimura

  CLINICA CHIMICA ACTA 424 148 - 152 0009-8981 2013/09 [Refereed][Not invited]
   

  Background: Serum KL-6, a sialylated sugar chain on human MUC1, is used as a marker of interstitial lung diseases. We recently reported that efflux behavior of KL-6/MUC1 from the alveoli into the bloodstream assessed by molecular analysis differed according to genetically determined molecular sizes and influenced serum KL-6 concentrations in sarcoidosis. This study was designed to investigate associations between molecular size and efflux behavior of KL-6/MUC1, and factors contributing to serum KL-6 concentrations in healthy subjects. Methods: Western blot analysis using anti-KL-6 antibody was performed on serum obtained from 250 healthy subjects. Results: The efflux behavior of KL-6/MUC1 differed according to the genetically determined molecular sizes in healthy subjects. In subjects having low molecular size, there were significant associations between smoking status, aging, renal function and serum KL-6 concentrations. However, these associations were not significant in the subjects having higher molecular size and the efflux behavior of high molecular size was the only significant determinant of serum KL-6 concentrations. Conclusions: This study showed an association between KL-6/MUC1 efflux based on molecular size and serum KL-6 concentrations in healthy subjects. We propose that the molecular size and efflux behavior of KL-6/MUC1 should be considered when interpreting serum KL-6 concentrations. (c) 2013 Elsevier B.V. All rights reserved.
• Nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan.

  Tsukasa Okamoto, Yasunari Miyazaki, Takashi Ogura, Kingo Chida, Nobuoki Kohno, Shigeru Kohno, Hiroyuki Taniguchi, Shinobu Akagawa, Yoshiro Mochizuki, Kohei Yamauchi, Hiroki Takahashi, Takeshi Johkoh, Sakae Homma, Kazuma Kishi, Soichiro Ikushima, Satoshi Konno, Michiaki Mishima, Ken Ohta, Yasuhiko Nishioka, Nobuyuki Yoshimura, Mitsuru Munakata, Kentaro Watanabe, Yoshihiro Miyashita, Naohiko Inase

  Respiratory investigation 51 (3) 191 - 9 2212-5345 2013/09 [Refereed][Not invited]
   

  BACKGROUND: In 1999, a Japanese epidemiological survey of chronic hypersensitivity pneumonitis (HP) showed that summer-type HP was the most prevalent variant of the disease. The number of reported cases of chronic HP has recently been increasing, and the clinical features of the disease seem to have changed. We conducted another nationwide epidemiological survey of chronic HP in Japan to determine better estimates of the frequency and clinical features of the disease. METHODS: A questionnaire was sent to qualified hospitals throughout Japan, and data on cases of chronic HP diagnosed between 2000 and 2009 were collected. RESULTS: In total, 222 cases of chronic HP from 22 hospitals were studied. Disease subtypes included bird-related HP (n=134), summer-type HP (n=33), home-related HP (n=25), farmer's lung (n=4), isocyanate-induced HP (n=3), and other types (n=23). The median proportion of lymphocytes in bronchoalveolar lavage fluid was high (24.5%). The primary findings of computed tomography of the chest were ground-glass attenuation and interlobular septal thickening. Centrilobular fibrosis was the major pathological finding on examination of surgical lung biopsy specimens from 93 patients. The median survival time was 83 months. CONCLUSIONS: The proportion of bird-related HP was higher than that in the previous epidemiological survey, and the proportions of isocyanate-induced HP and farmer's lung were lower. A crucial step in diagnosing chronic HP is to thoroughly explore the possibility of antigen exposure.
• Asthma Phenotypes in Japanese Adults - Their Associations with the CCL5 and ADRB2 Genotypes

  Yoshiko Kaneko, Hironori Masuko, Tohru Sakamoto, Hiroaki Iijima, Takashi Naito, Yohei Yatagai, Hideyasu Yamada, Satoshi Konno, Masaharu Nishimura, Emiko Noguchi, Nobuyuki Hizawa

  ALLERGOLOGY INTERNATIONAL 62 (1) 113 - 121 1323-8930 2013/03 [Refereed][Not invited]
   

  Background: Cluster analyses were previously performed to identify asthma phenotypes underlying asthma syndrome. Although a large number of patients with asthma develop the disease later in life, these previous cluster analyses focused mainly patients with younger-onset asthma. Methods: Cluster analysis examined the existence of distinct phenotypes of late-onset asthma in Japanese patients with adult asthma. We then associated genotypes at the CCL5, TSLP, IL4, and ADRB2 genes with the clusters of asthma identified. Results: Using the 8 variables of age, sex, age at onset of the disease, smoking status, total serum IgE, %FEV1, FEV1/FVC, and specific IgE responsiveness to common inhaled allergens, two-step cluster analysis of 880 Japanese adult asthma patients identified 6 phenotypes: cluster A (n = 155): older age at onset, no airflow obstruction; cluster B (n = 170): childhood onset, normal-to-mild airflow obstruction; cluster C (n = 119): childhood onset, the longest disease duration, and moderate-to-severe airflow obstruction; cluster D (n = 108): older age at onset, severe airflow obstruction; cluster E (n = 130): middle-age at onset, no airflow obstruction; and cluster F (n = 198): older age at onset, mild-to-moderate airflow obstruction. The CCL5-28C>G genotype was significantly associated with clusters A, B and D (OR 1.65, p = 0.0021; 1.67, 0.018; and 1.74, 0.011, respectively). The ADRB2 Arg16Gly genotype was also associated with clusters B and D (OR 0.47, p = 0.0004; and 0.63, 0.034, respectively). Conclusions: The current cluster analysis identified meaningful adult asthma phenotypes linked to the functional CCL5 and ADRB2 genotypes. Genetic and phenotypic data have the potential to elucidate the phenotypic heterogeneity and pathophysiology of asthma.
• Four cases with group 3 out-of-proportion pulmonary hypertension with a favorable response to vasodilators

  Ayako Igarashi, Takahiro Sato, Ichizo Tsujino, Hiroshi Ohira, Asuka Yamada, Taku Watanabe, Masaru Suzuki, Satoshi Konno, Masaharu Nishimura

  Respiratory Medicine Case Reports 9 (1) 4 - 7 2213-0071 2013 [Refereed][Not invited]
   

  Some patients with group 3 pulmonary hypertension (PH) (PH due to lung disease and/or hypoxia) exhibit disproportionately advanced or " out-of-proportion" PH. In the present case series, we document four consecutive patients with progressive out-of-proportion group 3 PH. All patients exhibited progressive dyspnea or peripheral edema and were treated by pulmonary artery hypertension (PAH)-specific vasodilator(s). At the follow-up assessment 3-4 months later, symptoms/signs and pulmonary hemodynamic measurements improved in all four patients (45 ± 8% decrease in pulmonary vascular resistance). Pulmonary oxygenation deteriorated in one patient but improved or did not significantly change in the remaining three cases. Importantly, the background lung parenchymal disease (early-onset chronic obstructive pulmonary disease, rheumatoid arthritis-associated interstitial pneumonia, and combined pulmonary fibrosis and emphysema) was stable upon progression of the right heart failure symptoms/signs, and also during the 3-4-month follow-up period in all cases. We herein describe the clinical features of the four cases and discuss the potential benefits and risks of PAH-specific treatment in this emerging population. © 2013 Elsevier Ltd.
• A case of sarcoidosis with eosinophilia in peripheral blood and bronchoalveolar lavage fluid

  Ayumu Takahashi, Satoshi Konno, Kanako Hatanaka, Yoshihiro Matsuno, Etsuro Yamaguchi, Masaharu Nishimura

  Respiratory Medicine Case Reports 8 (1) 43 - 46 2213-0071 2013 [Refereed][Not invited]
   

  A 70-year-old woman, who has had a diagnosis of sarcoidosis since she was 38 years old, showed newly appearing diffuse ground-glass opacities in the bilateral lung field, and bilateral enlargement of the hilar and mediastinal lymph nodes. Based on findings from bronchoalveolar lavage fluid (BALF) and pathology analysis, eosinophilic pneumonia accompanied by sarcoidosis was suspected. Both disease conditions (sarcoidosis and BALF eosinophilia) worsened and improved simultaneously, and she showed two similar episodes during the follow-up. This case prompted us to conduct a retrospective investigation of eosinophil percentage in peripheral blood and BALF in 178 patients (excluding our patient) who had received a diagnosis of sarcoidosis between 2000 and 2009 in our department. Among the 178 patients, the highest eosinophil percentage in BALF was 2.6% in contrast, peripheral blood eosinophilia was very common. Thus we concluded that, for subjects with sarcoidosis, marked eosinophilia in BALF, as observed in the case of this 70-year-old woman, was exceptional. © 2013 Elsevier Ltd.
• A distinct sensitization pattern associated with asthma and the thymic stromal lymphopoietin (TSLP) genotype

  Hiroaki Iijima, Yoshiko Kaneko, Hideyasu Yamada, Yohei Yatagai, Hironori Masuko, Tohru Sakamoto, Takashi Naito, Tomomitsu Hirota, Mayumi Tamari, Satoshi Konno, Masaharu Nishimura, Emiko Noguchi, Nobuyuki Hizawa

  Allergology International 62 (1) 123 - 130 1440-1592 2013 [Refereed][Not invited]
   

  Background: Atopy is a phenotypically heterogeneous condition, and the extent to which atopy accounts for asthma is controversial. In this study, we aimed to identify the presence of distinct sensitization patterns to common inhaled allergens and their association with asthma, allergic rhinitis and TSLP genotypes. Methods: We studied 1683 adults from Tsukuba, a city in central Japan and 297 adults from Kamishihoro, a cedar-free, birch-dominant town in northern Japan. Levels of total serum IgE and specific IgE antibodies towards 14 major inhaled allergens were measured. With the use of these measures, cluster analysis was applied to classify the subjects' sensitization patterns. We also examined the genetic effects of 2 TSLP functional SNPs on the development of each sensitization pattern. Results: In the Tsukuba study, cluster analysis identified four clusters, including "Dust mite dominant", "Multiple pollen", "Cedar dominant", and "Low reactivity". In the Kamishihoro study, "Dust mite dominant", "Multiple pollen" and "Low reactivity" clusters were also identified, but a "Cedar dominant" cluster was not formed. The association with asthma was strongest for the "Dust mite dominant" cluster in both the Tsukuba and the Kamishihoro studies. In never smokers, both SNPs were associated with the "Dust mite dominant" cluster (OR > 1.2). In contrast, in current or past smokers, these alleles were inversely associated with the "Multiple pollen" cluster (OR < 0.5). Conclusions: Cluster analysis identified the presence of distinct sensitization patterns to common inhaled allergens. TSLP may cause asthma by promoting innate allergic responses to indoor allergens and this contribution is significantly modified by smoking. © 2013 by Japanese Society of Allergology.
• Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma

  K. Shimizu, S. Konno, M. Ozaki, K. Umezawa, K. Yamashita, S. Todo, M. Nishimura

  CLINICAL AND EXPERIMENTAL ALLERGY 42 (8) 1273 - 1281 0954-7894 2012/08 [Refereed][Not invited]
   

  Background Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor kappa B activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor jB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma. Objective The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma. Methods The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin-1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated. Results Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of alpha-smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin-1 by bronchial epithelial cells were inhibited by DHMEQ. Conclusions and Clinical Relevance These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.
• The prevalence of rhinitis and its association with smoking and obesity in a nationwide survey of Japanese adults

  Satoshi Konno, N. Hizawa, Y. Fukutomi, M. Taniguchi, Y. Kawagishi, C. Okada, Y. Tanimoto, K. Takahashi, A. Akasawa, K. Akiyama, M. Nishimura

  Allergy: European Journal of Allergy and Clinical Immunology 67 (5) 653 - 660 0105-4538 2012/05 [Refereed][Not invited]
   

  Background: Rhinitis is a common disease, and its prevalence is increasing worldwide. Several studies have provided evidence of a strong association between asthma and rhinitis. Although smoking and obesity have been extensively analyzed as risk factors of asthma, associations with rhinitis are less clear. Objective: The aims of our study were (i) to evaluate the prevalence of rhinitis using the European Community Respiratory Health Survey (ECRHS) questionnaire in Japanese adults and (ii) to evaluate the associations of smoking and body mass index (BMI) with rhinitis. Methods: Following our study conducted in 2006-2007 to determine the prevalence of asthma using the ECRHS questionnaire, our present analysis evaluates the prevalence of rhinitis and its association with smoking and BMI in Japanese adults 20-79 years of age (N = 22819). We classified the subjects (20-44 or 45-79 years) into four groups as having (i) neither rhinitis nor asthma (ii) rhinitis without asthma (iii) asthma without rhinitis or (iv) rhinitis with asthma. We then evaluated associations with smoking and BMI in each group. Results The overall age-adjusted prevalence of rhinitis was 35.1% in men and 39.3% in women. A higher prevalence was observed in the younger population than in the older population. Active smoking and obesity were positively associated with asthma without rhinitis. In contrast, particularly in the 20- to 44-year age-group, active smoking and obesity were negatively associated with rhinitis without asthma. Conclusion The results of the present study suggest that smoking and obesity may have different effects on the development of rhinitis and asthma. © 2012 John Wiley & Sons A/S.
• Effects of molecular structural variants on serum Krebs von den Lungen-6 levels in sarcoidosis

  Masahiko Shigemura, Yasuyuki Nasuhara, Satoshi Konno, Chikara Shimizu, Kazuhiko Matsuno, Etsuro Yamguchi, Masaharu Nishimura

  JOURNAL OF TRANSLATIONAL MEDICINE 10 111  1479-5876 2012/05 [Refereed][Not invited]
   

  Background: Serum Krebs von den Lungen-6 (KL-6), which is classified as human mucin-1 (MUC1), is used as a marker of sarcoidosis and other interstitial lung diseases. However, there remain some limitations due to a lack of information on the factors contributing to increased levels of serum KL-6. This study was designed to investigate the factors contributing to increased levels of serum KL-6 by molecular analysis. Methods: Western blot analysis using anti-KL-6 antibody was performed simultaneously on the bronchoalveolar lavage fluid (BALF) and serum obtained from 128 subjects with sarcoidosis. Results: KL-6/MUC1 in BALF showed three bands and five band patterns. These band patterns were associated with the MUC1 genotype and the KL-6 levels. KL-6/MUC1 band patterns in serum were dependent on molecular size class in BALF. Significantly increased levels of serum KL-6, serum/BALF KL-6 ratio and serum soluble interleukin 2 receptor were observed in the subjects with influx of high molecular size KL-6/MUC1 from the alveoli to blood circulation. The multivariate linear regression analysis involving potentially relevant variables such as age, gender, smoking status, lung parenchymal involvement based on radiographical stage and molecular size of KL-6/MUC1 in serum showed that the molecular size of KL-6/MUC1 in serum was significant independent determinant of serum KL-6 levels. Conclusions: The molecular structural variants of KL-6/MUC1 and its leakage behavior affect serum levels of KL-6 in sarcoidosis. This information may assist in the interpretation of serum KL-6 levels in sarcoidosis.
• 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 1073-449X 2012/01 [Refereed][Not invited]
   

  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.
• Association between Body Mass Index and Asthma among Japanese Adults: Risk within the Normal Weight Range

  Yuma Fukutomi, Masami Taniguchi, Hiroyuki Nakamura, Satoshi Konno, Masaharu Nishimura, Yukio Kawagishi, Chiharu Okada, Yasushi Tanimoto, Kiyoshi Takahashi, Akira Akasawa, Kazuo Akiyama

  INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 157 (3) 281 - 287 1018-2438 2012 [Refereed][Not invited]
   

  Background: Increasing amounts of data have shown that some Asian populations are more susceptible to increased weight and development of noncommunicable disease than Western populations. However, little is known about the association between increased weight, particularly within the normal range, and the development of asthma among Asian populations. Methods: To examine the association between increased body mass index (BMI) and asthma among Japanese adults, data from a nationwide population-based cross-sectional survey of asthma prevalence in Japan were analyzed (n = 22,962; age range 20-79 years). BMIs were classified into 7 categories considering WHO recommendations (cutoff points: 17.00, 18.50, 23.00, 25.00, 27.50 and 30.00), and the association between BMI and the prevalences of asthma as well as asthma symptoms were assessed by multivariate logistic regression. Results: The prevalences of obesity (BMI 6 30.00) in this population were relatively low (males 3.0%, females 2.3%). BMI categories of 25.00 or higher in both genders were significantly associated with an increased risk of asthma compared with the reference category (BMI 18.50-22.99). Even in females with a BMI of 23.00-24.99, the prevalence of asthma significantly increased (adjusted odds ratio 1.49, 95% confidence interval 1.16-1.92) compared with that in the reference category. Conclusions: An increase in the prevalence of asthma among Japanese females starts at a BMI of 23.00, which was relatively lower than those reported from Western countries. This finding suggests that the Japanese population is likely to have asthma with a lesser degree of obesity than Western populations. Copyright (C) 2011 S. Karger AG, Basel
• Total serum IgE levels and atopic status in patients with sarcoidosis

  Takeshi Hattori, Satoshi Konno, Masahiko Shigemura, Kazuhiko Matsuno, Chikara Shimizu, Katsunori Shigehara, Noriharu Shijubo, Nobuyuki Hizawa, Etsuro Yamaguchi, Masaharu Nishimura

  ALLERGY AND ASTHMA PROCEEDINGS 33 (1) 90 - 94 1088-5412 2012/01 [Refereed][Not invited]
   

  To date, two studies have reported lower total serum immunoglobulin E (IgE) levels and lower prevalence of atopy in patients with sarcoidosis compared with healthy subjects. However, those reports did not consider age or gender differences between cases and controls. In addition, the association between total serum IgE levels and clinical manifestations of sarcoidosis has not been clarified. This study assessed total serum IgE levels and prevalence of atopy in patients with sarcoidosis after taking age and sex differences into account and evaluated associations between total serum IgE levels and clinical manifestations of sarcoidosis. Total serum IgE levels and prevalence of atopy on initial visits were compared between 189 patients with sarcoidosis and 378 age- and sex-matched controls. Associations between total serum IgE levels and involvement of each affected organ were evaluated. Changes in total serum IgE levels during the clinical course of sarcoidosis were also evaluated. Total serum IgE levels were significantly lower in patients with sarcoidosis than in controls, independent of atopic status (atopic subjects, p = 0.025; nonatopic subjects, p < 0.001). Total serum IgE levels did not differ according to the involvement of different organs. Total serum IgE levels decreased further, albeit only slightly, after disease remission (p < 0.001). Increased susceptibility to sarcoidosis may be attributable to several underlying genetic or environmental factors that result in lower total serum IgE levels. (Allergy Asthma Proc 33:90-94, 2012; doi: 10.2500/aap.2012.33.3491)
• Impact of asthmatic control status on serum cystatin C concentrations

  Masahiko Shigemura, Satoshi Konno, Yasuyuki Nasuhara, Chikara Shimizu, Kazuhiko Matsuno, Masaharu Nishimura

  CLINICAL CHEMISTRY AND LABORATORY MEDICINE 50 (8) 1367 - 1371 1434-6621 2012 [Refereed][Not invited]
   

  Background: To determine whether cystatin C accurately reflects renal function in asthma, we investigated serum cystatin C concentrations in a large number of asthmatic patients by adjusting for several confounding factors that might affect serum cystatin C concentrations. Methods: A total of 126 asthmatic patients and 126 healthy volunteers, matched for age and gender, were studied. Results: Serum cystatin C concentrations in symptomatic subjects with asthma were significantly higher than in healthy controls (p < 0.001) and asymptomatic subjects with asthma (p = 0.007), whereas no significant difference was observed between healthy controls and asymptomatic subjects. In asthmatic subjects, serum cystatin C concentrations were not influenced by inhaled corticosteroid (ICS). However, serum cystatin C concentrations were significantly higher in subjects who were regularly treated by oral corticosteroid (OCS) (p = 0.001). Conclusions: Serum cystatin C concentrations are elevated in asthmatic patients; particularly while symptomatic and/or taking OCS but not ICS. Serum cystatin C concentrations may not accurately reflect renal function in those patients.
• Beta2-adrenergic receptor polymorphisms as a determinant of preferential bronchodilator responses to beta 2-agonist and anticholinergic agents in Japanese patients with chronic obstructive pulmonary disease

  Satoshi Konno, Hironi Makita, Masaru Hasegawa, Yasuyuki Nasuhara, Katsura Nagai, Tomoko Betsuyaku, Nobuyuki Hizawa, Masaharu Nishimura

  PHARMACOGENETICS AND GENOMICS 11 21 (11) 687 - 693 1744-6872 2011/11 [Refereed][Not invited]
   

  Background Previous studies have shown that polymorphisms in the beta 2-adrenergic receptor gene (ADRB2) may influence bronchodilator response (BDR) to both beta 2-agonists and anticholinergics, possibly by intracellular cross-talk, but in opposite ways, in the Japanese population. We hypothesized that the preferential response to either class of bronchodilators might be determined by ADRB2 polymorphisms in patients with chronic obstructive pulmonary disease (COPD). Objective To examine the association of ADRB2 polymorphisms and preferential BDR to beta 2-agonists and anticholinergics in patients with COPD. Design and participants The participants had been enrolled in the Hokkaido COPD cohort study. BDR to either class of bronchodilators (salbutamol or oxytropium, 0.4 mg) was measured every 6 months for 2 years. Considering the variation of BDR within and between days, mean values of postbronchodilator increases in forced expiratory volume in 1 s (Delta FEV1) for the two agents measured at two different visits were initially used for the primary analysis (N = 189). To confirm the results of the primary analysis, Delta FEV1 measured at a single visit was also used for secondary analyses. Results Although a significant correlation between BDRs to salbutamol and to oxytropium was observed (P < 0.001, r = 0.36), there were individuals who responded preferentially to one of the two agents. When the participants were classified into two groups based on the bronchodilator causing the better response (salbutamol-dominant group and oxytropium-dominant group), Arg allele was significantly more common in the oxytropium-dominant group than in the salbutamol-dominant group (0.001 < P < 0.05). Conclusion ADRB2 polymorphism may be a determinant of preferential BDR to either beta 2-agonists or anticholinergics in patients with COPD. Pharmacogenetics and Genomics 21:687-693 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
• Role of osteopontin, a multifunctional protein, in allergy and asthma

  S. Konno, M. Kurokawa, T. Uede, M. Nishimura, S. -K. Huang

  CLINICAL AND EXPERIMENTAL ALLERGY 41 (10) 1360 - 1366 0954-7894 2011/10 [Refereed][Invited]
   

  Osteopontin (OPN) is an extracellular matrix protein and immune modulator with a wide range of functions. OPN is recognized as a key cytokine in Th1 immune responses, yet its potential involvement in allergic/asthmatic responses has been investigated only recently. Current data from molecular and cellular studies and studies of OPN-deficient mice provide evidence that OPN plays multiple roles in the regulation of allergic responses, including regulation of IgE response, inflammatory cell migration, and the development of airway fibrosis and angiogenesis. These results suggest that OPN is a pleiotropic cytokine that functions both systemically and locally in tissue mucosa. Notably, OPN is able to exert its effects through different functional domains, and the secreted and intracellular forms of OPN may have distinct functions. Future research to elucidate all aspects of OPN function is needed to ultimately establish its role in the regulation of immune responses and various disease processes, including those critically involved in the development of allergies and asthma.
• 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 0954-6111 2011/09 [Refereed][Not invited]
   

  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.
• [A case of multifocal micronodular pneumocyte hyperplasia without clinical findings of tuberous sclerosis].

  Taniguchi N, Konno S, Nasuhara Y, Matsuno Y, Oka T, Nishimura M

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 49 (5) 355 - 359 1343-3490 2011/05 [Refereed][Not invited]
   

  A 30-year-old woman was referred because of multiple ground-glass opacities (GGOs) on chest CT examination. Lung biopsy was performed. Histologically, multifocal well-demarcated nodular lesions comprising proliferation of type II pneumocytes with mild fibrous thickening of the alveolar septa were observed in the lung tissue. We made a histopathologic diagnosis of multifocal micronodular pneumocyte hyperplasia (MMPH). Neither the clinical findings nor the family history of the patient suggested tuberous sclerosis (TSC). MMPH is a pulmonary manifestation of tuberous sclerosis, together with lymphangioleiomyomatosis (LAM). MMPH should be considered as a differential diagnosis of multiple GGOs in the lung even when findings of TSC and LAM are not recognized.
• 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 0277-0903 2010/12 [Refereed][Not invited]
   

  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.
• 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 0954-6111 2010/12 [Refereed][Not invited]
   

  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
• Japanese-Specific Filaggrin Gene Mutations in Japanese Patients Suffering from Atopic Eczema and Asthma

  Rinko Osawa, Satoshi Konno, Masashi Akiyama, Ikue Nemoto-Hasebe, Toshifumi Nomura, Yukiko Nomura, Riichiro Abe, Aileen Sandilands, W. H. Irwin McLean, Nobuyuki Hizawa, Masaharu Nishimura, Hiroshi Shimizu

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 130 (12) 2834 - 2836 0022-202X 2010/12 [Refereed][Not invited]
  
• 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  1471-2350 2010/10 [Refereed][Not invited]
   

  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.
• [A case of pulmonary sarcoidosis with rapid progression of multiple cystic lesions].

  Shimizu K, Konno S, Fuke S, Nishiura Y, Nishimura M

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 48 (9) 715 - 718 1343-3490 2010/09 [Refereed][Not invited]
  
• Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

  Pei-Song Gao, Kenichi Shimizu, Audrey V. Grant, Nicholas Rafaels, Lin-Fu Zhou, Sherry A. Hudson, Satoshi Konno, Nives Zimmermann, Maria I. Araujo, Eduardo V. Ponte, Alvaro A. Cruz, Masaharu Nishimura, Song-Nan Su, Nobuyuki Hizawa, Terry H. Beaty, Rasika A. Mathias, Marc E. Rothenberg, Kathleen C. Barnes, Bruce S. Bochner

  EUROPEAN JOURNAL OF HUMAN GENETICS 18 (6) 713 - 719 1018-4813 2010/06 [Refereed][Not invited]
   

  Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits Fc epsilon RI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 x 10(-5)) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6'-sulfo-sLe(x), a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma. European Journal of Human Genetics (2010) 18, 713-719; doi: 10.1038/ejhg.2009.239; published online 20 January 2010
• A Patient Presenting with Side Chest Pain, in which Multiple Cystic Lesions were Detected Throughout the Entire Lung Fields.

  Konno Satoshi, Nishimura Masaharu

  Nihon Naika Gakkai Kaishi The Japanese Society of Internal Medicine 99 (5) 1130 - 1131 0021-5384 2010/05/10
• The role of atopy in the clinical course of pulmonary sarcoidosis in the Japanese population

  Takeshi Hattori, Satoshi Konno, Ayumu Takahashi, Akira Isada, Masahiko Shigemura, Kazuhiko Matsuno, Chikara Shimizu, Nobuyuki Hizawa, Etsuro Yamaguchi, Masaharu Nishimura

  ALLERGY AND ASTHMA PROCEEDINGS 31 (3) 238 - 243 1088-5412 2010/05 [Refereed][Not invited]
   

  Sarcoidosis is a multisystem disorder characterized by a T-helper 1 (Th1)-mediated immune response. Conversely, atopy is characterized by the presence of a specific immunoglobulin E (IgE) E response in association with a Th2-type immune response. Several epidemiological studies have shown that atopic status influences disease activity and clinical course for several Th1-mediated diseases. The aim of this study was to evaluate associations between atopic status and clinical findings of sarcoidosis. We further evaluated the impact of atopic status on the clinical course of pulmonary sarcoidosis. We defined atopy as a positive specific IgE response to at least one common inhaled allergen (multiple antigen simultaneous test scores, lumicount of >1.01). Subjects comprised 134 patients given a diagnosis of sarcoidosis between 2000 and 2006, divided into atopic and nonatopic groups. Several clinical findings were compared between the two groups. Furthermore, 100 subjects observed 2 years after diagnosis were divided into resolving and persistent clinical course groups according to chest radiography and associations with atopic status were evaluated. Atopy was more prevalent among men than women (p = 0.009) and subjects with atopy were younger (p = 0.002) and showed less frequent lung parenchymal lesions (stages II and III; p = 0.018) compared with subjects without atopy. The prevalence of atopy was higher in the resolving clinical course group than in the persistent clinical course group (p = 0.002) and this association was independent of sex, age, presence of lung parenchymal lesions, and presence of extra pulmonary lesions (p = 0.037). Classification of sarcoidosis based on atopic status might be useful for predicting the clinical course of pulmonary sarcoidosis. (Allergy Asthma Proc 31:238-243, 2010; doi: 10.2500/aap.2010.31.3336)
• Levels of Transferrin in Bronchoalveolar Lavage Fluid in Sarcoidosis

  Masahiko Shigemura, Yasuyuki Nasuhara, Satoshi Konno, Takeshi Hattori, Chikara Shimizu, Kazuhiko Matsuno, Masaharu Nishimura

  LUNG 188 (2) 151 - 157 0341-2040 2010/04 [Refereed][Not invited]
   

  There has been only one report showing high levels of transferrin (Tf) in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis. This study was designed to assess the levels of Tf in both BALF and serum and to examine the relationship between the levels of Tf and other disease markers in sarcoidosis. Subjects were 64 sarcoidosis and 10 healthy controls. Tf in BALF and serum was measured by nephelometric assay. Median Tf levels in BALF from sarcoidosis was 0.70 (range, 0.00-3.97) mg/dl, which was significantly higher compared with controls (0.36 (range, 0.00-1.02) mg/dl; p = 0.005). In contrast, median Tf levels in serum from sarcoidosis was 258 (range, 171-383) mg/dl, which was significantly lower compared with controls (322 (range, 234-356) mg/dl; p = 0.003). Tf levels in BALF were significantly correlated with both the percentage of lymphocytes (r = 0.617, p = 0.001) and serum angiotensin-converting enzyme activity (r = 0.363, p = 0.003) and serum soluble interleukin-2 receptor (r = 0.450, p = 0.001) in sarcoidosis. Levels of Tf in BALF from patients with sarcoidosis were not influenced by smoking status. The levels of Tf in sarcoidosis are high in BALF, but low in serum. Increased levels of Tf in BALF may reflect the disease activity.
• A functional polymorphism (-603A -> G) in the tissue factor gene promoter is associated with adult-onset asthma

  Akira Isada, Satoshi Konno, Nobuyuki Hizawa, Mayumi Tamari, Tomomitsu Hirota, Michishige Harada, Yukiko Maeda, Takeshi Hattori, Ayumu Takahashi, Masaharu Nishimura

  JOURNAL OF HUMAN GENETICS 55 (3) 167 - 174 1434-5161 2010/03 [Refereed][Not invited]
   

  Tissue factor (TF) is important for initiation of coagulation and for the increased thrombin activity observed at sites of inflammation. Thrombin activity is induced by allergen challenge in asthmatic airways and is involved in the pathogenesis of asthma. A-603A -> G polymorphism (rs1361600) in the promoter region of the TF gene has been associated with serum TF levels and with the development of cardiovascular diseases. The aim of this study was to determine whether the functional -603A -> G polymorphism has genetic influences on the development of asthma. Case-control analysis was performed of the association between six common single-nucleotide polymorphisms (SNPs), including the -603A -> G polymorphism, at the TF gene, and the development of asthma, using two unrelated Japanese populations. In the primary population (n 826), the GG genotype at the -603A -> G polymorphism was associated with adult-onset asthma (onset at >= 21 years of age) (odds ratio (OR) 2.886, P=0.0231). A second population showed a similar tendency (n=1654, OR 1.602, P=0.064). Transcriptional activity of promoters with -603A -> G genotypes were examined using luciferase promoter assays. The -603G allele was associated with higher promoter activity (P<0.05). The association between the functional polymorphism (-603A -> G) in the TF gene promoter and adult-onset asthma indicates that TF is a candidate gene contributing to asthma susceptibility. Journal of Human Genetics (2010) 55, 167-174; doi: 10.1038/jhg.2010.4; published online 12 February 2010
• Primary Mediastinal Liposarcoma, with 6 Years of Follow-up to Autopsy, Revealed Histopathological Features of Primary and Metastatic Lesions

  Satoshi Konno, Satoshi Oizumi, Naofumi Shinagawa, Eiki Kikuchi, Jun Konishi, Kenichiro Ito, Nobuyuki Hizawa, Akihiro Takiyama, Shinya Tanaka, Masaharu Nishimura

  INTERNAL MEDICINE 49 (8) 771 - 775 0918-2918 2010 [Refereed][Not invited]
   

  Primary mediastinal liposarcoma was observed in a 73-year-old man. Because of tight adhesions to adjacent tissues, neither complete resection nor surgical debulking of the tumor was possible. A T-tube was inserted into the patient's trachea for severe dyspnea, and he was treated with radiotherapy and an oral peroxisome proliferator-activated receptor-gamma agonist. The patient died 6 years after the initial diagnosis. Autopsy revealed liposarcoma composed of 3 subtypes in the primary tumor: well-differentiated, dedifferentiated, and round cell components. Round cell and dedifferentiated liposarcomas were predominantly observed in the metastatic nodules.
• Nationwide Cross-Sectional Population-Based Study on the Prevalences of Asthma and Asthma Symptoms among Japanese Adults

  Yuma Fukutomi, Hiroyuki Nakamura, Fumio Kobayashi, Masami Taniguchi, Satoshi Konno, Masaharu Nishimura, Yukio Kawagishi, Junko Watanabe, Yuko Komase, Yasuhiro Akamatsu, Chiharu Okada, Yasushi Tanimoto, Kiyoshi Takahashi, Tomoaki Kimura, Akira Eboshida, Ryoji Hirota, Junko Ikei, Hiroshi Odajima, Takemasa Nakagawa, Akira Akasawa, Kazuo Akiyama

  INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 153 (3) 280 - 287 1018-2438 2010 [Refereed][Not invited]
   

  Background: Asthma is a common respiratory disease worldwide. However, few reports are available on the prevalences of asthma and asthma symptoms among Asian subjects. Methods: To determine the prevalences of asthma and asthma symptoms among Japanese subjects, we performed a nationwide cross-sectional, population-based study on Japanese adults aged 20-79 years. Ten areas spread throughout the country were randomly selected. Door-to-door or postal surveys were performed using a translated version of the European Community Respiratory Health Survey questionnaire. Results: The survey was completed by 23,483 participants. The overall response rate was 70.6%. The prevalences of wheeze and current asthma among all participants aged 20-79 years were 10.1% (95% CI: 9.7-10.5%) and 4.2% (95% CI: 4.0-4.5%), respectively. The prevalences among young adults aged 20-44 years were 9.3% (95% CI: 8.7-9.9%) and 5.3% (95% CI: 4.8-5.8%), respectively. The prevalence of current asthma was highest in females aged 30-39 years in comparison with the other gender and age groups. Conclusions: This nationwide study determined the prevalences of asthma and asthma symptoms among Japanese adults. The results provide fundamental information on the respiratory health of Japanese adults. Copyright (C) 2010 S. Karger AG, Basel
• Evaluating total serum IgE levels and peripheral eosinophil count in asthma and rhinitis

  Ayumu Takahashi, Satoshi Konno, Akira Isada, Takeshi Hattori, Kaoruko Shimizu, Kenichi Shimizu, Natsuko Taniguchi, Daisuke Takahashi, Masami Taniguchi, Akira Akazawa, Nobuyuki Hizawa, Masaharu Nishimura

  Japanese Journal of Allergology 59 (5) 536 - 544 0021-4884 2010 [Refereed][Not invited]
   

  Background: Total serum immunoglobulin (Ig)E levels and peripheral blood eosinophil counts are widely examined to evaluate patients with various allergic diseases. Asthma and allergic rhinitis often coexist However, the significance of these indices for asthma and rhinitis under consideration of the status of co-existence has not been fully elucidated and was therefore examined in the present study. Methods: Subjects comprised 347 adult residents in Kamishihoro town, Hokkaido. Relationships between two indices and asthma, rhinitis and their coexistence were analyzed. Results: Serum IgE (sIgE) levels were significantly higher in asthma with (p< 0.01) or without (p< 0.01) rhinitis, regardless of atopic status, but not in rhinitis alone. Peripheral eosinophil counts were significantly higher only in asthma with rhinitis (p< 0.005). Conclusion: Compared with rhinitis, non-antigen-specific IgE production may contribute more to elevated levels of sIgE in asthma. In addition, the significance of sIgE and peripheral eosinophil count as indices of evaluating asthma and rhinitis might differ. © 2010 Japanese Society of Allergology.
• Regulatory role of DC-derived osteopontin in systemic allergen sensitization

  Masatsugu Kurokawa, Satoshi Konno, Ayumu Takahashi, Beverly Plunkett, Susan R. Rittling, Yutaka Matsui, Shigeyuki Kon, Junko Morimoto, Toshimitsu Uede, Satoshi Matsukura, Fumio Kokubu, Mitsuru Adachi, Masaharu Nishimura, Shau-Ku Huang

  EUROPEAN JOURNAL OF IMMUNOLOGY 39 (12) 3323 - 3330 0014-2980 2009/12 [Refereed][Not invited]
   

  Osteopontin (OPN) is a secreted phosphoglycoprotein with a wide range of functions, and is involved in various pathophysiological conditions. However, the role of OPN in IgE and Th2-associated allergic responses remains incompletely defined. The aim of this study was to elucidate the role of OPN in systemic allergen sensitization in mice. When compared with OPN(+/+) mice, significantly increased levels of OVA-induced IgE were found in OPN(-/-) mice. OPN(-/-) DC demonstrated an increased capacity to enhance Th2 cytokine production in CD4(+) T cells from sensitized OPN(+/+) mice. Furthermore, significantly reduced levels of IL-12p70 expression were seen in LPS-stimulated OPN(-/-) DC as compared with the WT DC, and the reduction was reversible by the addition of recombinant OPN (rOPN). rOPN was able to suppress OVA-induced IL-13 production in the cultures of CD4 and OPN(-/-) DC, but this inhibitory activity was neutralized by the addition of anti-IL-12 Ab. In addition, administration of rOPN in vivo suppressed OVA-specific IgE production; however, this suppressive effect was abrogated in IL-12-deficient mice. These results indicate that DC-derived OPN plays a regulatory role in the development of systemic allergen sensitization, which is mediated, at least in part, through the production of endogenous IL-12.
• 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 0093-7711 2009/12 [Refereed][Not invited]
   

  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.
• Osteopontin is involved in migration of eosinophils in asthma

  A. Takahashi, M. Kurokawa, S. Konno, K. Ito, S. Kon, S. Ashino, T. Nishimura, T. Uede, N. Hizawa, S-K Huang, M. Nishimura

  CLINICAL AND EXPERIMENTAL ALLERGY 39 (8) 1152 - 1159 0954-7894 2009/08 [Refereed][Not invited]
   

  P>Background Osteopontin (OPN) is an extracellular matrix protein with a wide range of functions, and is involved in various inflammatory diseases. However, the role of OPN in eosinophilic airway inflammation is unclear. Objective To elucidate the role of OPN in eosinophilic airway inflammation. Methods OPN protein levels in induced sputum from asthmatic patients and healthy controls were measured. Eosinophil migration assays were performed in the presence or absence of OPN, a blocking antibody (Ab) recognizing its integrin-binding domain (2K1) and an anti-integrin alpha 4 Ab (P1H4). In the mouse asthma model, the levels of eosinophilia were examined in bronchoalveolar lavage fluids (BALFs) from ovalbumin (OVA)-sensitized and -challenged mice with or without administration of an Ab (M5) corresponding to human 2K1. Results Levels of OPN in induced sputum were significantly higher in asthmatic patients when compared with healthy controls. In addition, levels of OPN were correlated with the percentage of sputum eosinophils. OPN induced significant migration of human eosinophils and this effect was inhibited by 2K1 and P1H4. M5 significantly attenuated OVA-induced eosinophilia in BALFs. Conclusion These results indicate that OPN plays a role in the migration of eosinophils into the airways and may be involved in the pathogenesis of asthma.
• [Usefulness of fluorodeoxyglucose-positron emission tomography in a case of pleural sarcoidosis].

  Hattori T, Konno S, Inomata T, Nasuhara Y, Betsuyaku T, Nishimura M

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 47 (7) 658 - 662 1343-3490 2009/07 [Refereed][Not invited]
   

  BACKGROUND: Pleural sarcoidosis is not a rare disease, and some patients with sarcoidosis experience chest pain, although the cause is often unknown. Various studies have indicated that fluorodeoxyglucose-positron emission tomography (FDG-PET) is useful for diagnosing and monitoring sarcoidosis. CASE: A 62-year-old man noted left-side dominant chest and back pain, although chest computed tomography (CT) revealed no abnormalities. Two months later, chest and back pain rapidly increased in severity and blurred vision appeared. In addition to uveitis, renal dysfunction was observed and chest CT on admission revealed enlargement of bilateral hilar/mediastinal lymph nodes and diffuse small nodular opacities and subpleural nodules, mainly in the segment of the left upper lobe (S1+2). FDG-PET revealed intense FDG uptake in bilateral peripheral lung parenchyma, spread widely along the subpleura and right inguinal lymph nodes with high uptake in the hilar and mediastinal lymph nodes. Sarcoidosis was diagnosed by transbronchial lung biopsy and renal biopsy. Oral corticosteroid treatment was performed due to persistent chest and back pain and rapid progression of renal dysfunction. Chest and back pain immediately disappeared and renal function improved. Follow-up FDG-PET performed 2 months after corticosteroid treatment revealed no areas of intense FDG uptake.
• Genetic impact of a butyrophilin-like 2 (BTNL2) gene variation on specific IgE responsiveness to dermatophagoides farinae (Der f) in Japanese

  Satoshi Konno, Daisuke Takahashi, Nobuyuki Hizawa, Takeshi Hattori, Ayumu Takahashi, Akira Isada, Yukiko Maeda, Shau-Ku Huang, Masaharu Nishimura

  Allergology International 58 (1) 29 - 35 1440-1592 2009 [Refereed][Not invited]
   

  Background: Dermatophagoides farinae (Der f) is one of the most frequently implicated allergens in several allergic diseases. Several genome-wide screens have identified a linkage between chromosome 6p21 and mite-specific IgE responsiveness. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily and, on the basis of its homology to B7-1, has been implicated as a costimulatory molecule involved in T-cell activation. BTNL2 resides in the HLA region on chromosome 6p21, and significant associations between BTNL2 gene polymorphisms and several inflammatory diseases have been reported. Objective: The aim of this study was to examine whether BTNL2 gene polymorphisms are associated with specific IgE responses to Der f. Methods: Three single nucleotide polymorphisms (SNPs), including 2 coding SNPs and 1 intron SNP, were studied. One of the coding SNPs was the rs2076530 A > G, which has a functional consequence. A total of 863 unrelated Japanese subjects (447 positive and 416 negative for IgE to Der f) were recruited for a case-control study. Results: Controlling for gender, age, smoking, and the presence of asthma, multiple logistic regression analyses showed that homozygosity of the rs2076530 A allele, which has been reported to be a risk allele for sarcoidosis, was associated with a risk of sensitization towards Der f (Odds ratio 1.55, p = 0.0060). Conclusions: Although an association which may be due to the linkage disequilibrium with other genes in 6p 21 needs to be ruled out, the present findings suggest that the BTNL2 gene might be one of the candidate genes that is responsible for the pathogenesis of Der f-specific IgE responsiveness. © 2009 Japanese Society of Allergology.
• Effects of Corticosteroids on Osteopontin Expression in a Murine Model of Allergic Asthma

  Masatsugu Kurokawa, Satoshi Konno, Satoshi Matsukura, Mio Kawaguchi, Koushi Ieki, Shintarou Suzuki, Miho Odaka, Shin Watanabe, Tetsuya Homma, Masayuki Sato, Hiroko Takeuchi, Takashi Hirose, Shau-Ku Huang, Mitsuru Adachi

  INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 149 7 - 13 1018-2438 2009 [Refereed][Not invited]
   

  Background: Osteopontin (OPN) contributes to the development of T helper 1 (Th1)-mediated immunity and Th1-associated diseases. However, the role of OPN in bronchial asthma is unclear. Corticosteroids reduce airway inflammation, as reflected by the low eosinophil and T-cell counts, and the low level of cytokine expression. We investigated OPN production and the inhibitory effects of corticosteroids on OPN production in a murine model of allergic asthma. Methods: BALB/c mice were sensitized by intraperitoneal injections of ovalbumin (OVA) with alum. Some mice received daily injections of dexamethasone (DEX) or phosphate-buffered saline for 1 week. All OVA-challenged mice were exposed to aerosolized 1% OVA for 30 min an hour after these injections. After the OVA challenge, the mice were killed, and bronchoalveolar lavage (BAL) fluid and lung tissue were examined. Results: The levels of OPN protein in BAL fluid and OPN mRNA in lung tissue increased after OVA challenge. Most OPN-expressing cells were CD11c+ cells and some were T cells. DEX decreased the levels of OPN protein in the BAL fluid, and those of OPN mRNA and OPN protein in lung tissue. Conclusions: OPN may play an important role in allergic bronchial asthma. Corticosteroids inhibit OPN production in mice with allergic asthma. The beneficial effect of corticosteroids in bronchial asthma is partly due to their inhibitory effects on OPN production. Copyright (c) 2009 S. Karger AG, Basel
• Diversity of protein carbonylation in allergic airway inflammation

  Katsura Nagai, Tomoko Betsuyaku, Satoshi Konno, Yoko Ito, Yasuyuki Nasuhara, Nobuyuki Hizawa, Takahito Kondo, Masaharu Nishimura

  FREE RADICAL RESEARCH 42 (11-12) 921 - 929 1071-5762 2008/11 [Refereed][Not invited]
   

  Oxidative stress is involved in asthma. This study assessed the carbonylation of sputum proteins in 23 uncontrolled adult asthmatic patients and 23 healthy controls. Carbonylated proteins (68 kDa and 53 kDa) were elevated in asthmatics when compared to controls and the 68-kDa carbonylated protein was significantly correlated with sputum eosinophilia. The kinetics of protein carbonylation in bronchoalveolar lavage fluid (BALF) were then examined in a mouse ovalbumin-induced allergic inflammation model. It was found that the carbonylation of various BALF proteins did not uniformly occur after challenge. The appearance of the 53-kDa carbonylated protein was limited within 24 h, while carbonylation of 68-kDa protein peaked at 48 h and was associated with BALF eosinophilia. Thus, it was demonstrated that the 68-kDa and 53-kDa proteins, corresponding to albumin and alpha 1-antitrypsin, respectively, were specifically carbonylated in allergic inflammation in humans and in mice and that eosinophils may play a role in mediating carbonylation of albumin.
• Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysernatous phenotype in COPD patients

  N. Hizawa, H. Makita, Y. Nasuhara, M. Hasegawa, K. Nagai, Y. Ito, T. Betsuyaku, S. Konno, M. Nishimura

  EUROPEAN RESPIRATORY JOURNAL 32 (2) 372 - 378 0903-1936 2008/08 [Refereed][Not invited]
   

  It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C > G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age >= 40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD. Patients with COPD were studied (n=267). All of the patients underwent pulmonary high-resolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G > A, -28C > G and 375T > C. A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of < 15%, even stronger evidence for this association was noted. Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of late-onset asthma and chronic obstructive pulmonary disease with milder emphysema.
• [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] 6 57 (6) 713 - 721 0021-4884 2008/06 [Refereed][Not invited]
   

  Background: The coding region variant ArglGGly at the β_2-adrenoceptor gene (ADRB2) is functionally relevant, and is common in Japanese. Longer term clinical responses to short-acting and longacting β_2 agonists have been influenced by the Arg16Gly polymorphism. The purpose of the present study is to assess the clinical effects of real life usage of β_2-agonist (long-acting β_2-agonist, regular use of short-acting beta2 agonist, or oral β_2-agonist), as an add-on medication to inhaled steroids, in Arg/Arg and Gly/Gly patients with asthma. Methods: In a retrospective analysis of outpatient records, 27 patients with Arg/Arg and 35 patients with Gly/Gly had regular usage of β_2-agonist, whereas 37 patients with Arg/Arg and 29 patients with Gly/Gly had as-needed usage of β_2-agonist. During the follow-up periods at Hokkaido University Hospital, long term bronchodilator responses were assessed using 3 indexes: 1) improvement in FEV1 (ΔFEV1 [ml]), 2) ΔFEV_1/FEV_1 at an initial visit, 3) ΔFEV_1/predicted FEV_1. Results: In patients with Gly/Gly genotype, compared with as-needed usage of β_2-agonist, the regular usage of β_2-agonist was associated with greater improvement in FEV1 in every index (p=0.027-0.041). In contrast, in patients with Arg/Arg genotype, the regular usage of β_2-agonist showed no greater improvement in FEV_1 compared with as-needed β_2-agonist usage. Conclusion: Gly/Gly and Arg/Arg genotype responses to regular usage of β_2-agonists may differ in patients with asthma.
• [Evaluation of atopy by antigen specific IGE antibody].

  Hattori T, Konno S, Shimizu K, Shimizu K, Isada A, Takahashi A, Maeda Y, Makita H, Sawazaki K, Hizawa N, Nishimura M

  Arerugi = [Allergy] 57 (5) 543 - 551 0021-4884 2008/05 [Refereed][Not invited]
  
• the Hokkaido COPD Cohort Study Group Functional SNPs of the CCL5 gene and non-emphysematous phenotype in patients with COPD.

  Hizawa, N, Makita H, Nasuhara Y, Hasegawa M, Nagai K, Ito Y, Betsuyaku T, Konno S, Nishimura M

  Eur Respir J. 32 (2) 372-378  2008/01 [Refereed][Not invited]
  
• 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 0021-4884 2008 [Refereed][Not invited]
   

  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.
• Adult langerhans cell histiocytosis with independently relapsing lung and liver lesions that was successfully treated with etoposide

  Satoshi Konno, Nubuyuki Hizawa, Tomoko Betsuyaku, Masanori Yasuo, Hiroshi Yamamoto, Tomonobu Koizumi, Masaharu Nishimura

  INTERNAL MEDICINE 46 (15) 1231 - 1235 0918-2918 2007 [Refereed][Not invited]
   

  A 35-year-old man initially presented with cough and fever. Computed tomography (CT) revealed diffuse small cysts in the lung, and multiple nodules in the liver. Lung and liver biopsies revealed that pathology was consistent with Langerhans cell histiocytosis. Lung shadows increased despite cessation of smoking, whereas the liver involvement improved. After initiating treatment with prednisolone, the chest CT findings improved. However, the liver nodules started to increase while tapering prednisolone. Intravenous etoposide was started, and the liver nodules decreased markedly. The difference in the clinical course between the lung and liver lesions might have been the result of differences in the clonality of these two organs.
• Genetic impact of functional single nucleotide polymorphisms in the 3 '-UTR region of the chemoattractant receptor expressed on Th2 cells (CRTH2) gene on asthma and atopy in a Japanese population

  Yukiko Maeda, Nobuyuki Hizawa, Daisuke Takahashi, Yoshinobu Fukui, Satoshi Konno, Masaharu Nishimura

  INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 142 (1) 51 - 58 1018-2438 2007 [Refereed][Not invited]
   

  Background: The human chemoattractant receptor expressed on Th2 cells (CRTH2), the receptor for prostaglandin D 2, induces cell migration in eosinophils, basophils, and Th2 cells. The gene encoding CRTH2 is located on chromosome 11q13. Several groups, including ours, have reported significant associations between this region and various traits associated with allergic diseases such as asthma and atopy. Two single nucleotide polymorphisms in the 3'-UTR of the CRTH2 gene (1544G -> C and 1651G -> A) are associated with the mRNA stability of the gene; they have also been associated with asthma in both African American and Chinese populations. Methods: Because CRTH2 is a biologically important candidate gene on chromosome 11q13, we conducted a case-control analysis using 787 Japanese subjects (384 asthmatics and 403 controls) to evaluate the genetic impact of the CRTH2 gene on asthma and asthma-related traits. Four polymorphisms [1544G -> C (rs11571288), 1651G -> A (rs545659), 11336T -> C (rs2074422), and 12375G -> T (rs561285)] were studied. Results: The allele, genotype, or haplotype frequencies for 2 functional polymorphisms in our Japanese population were significantly different from those in the Chinese or African American populations. No association was found between any polymorphisms or haplotypes in the CRTH2 gene and asthma, atopy, or total serum IgE levels in a Japanese population. Conclusions: Our data failed to support previous associations of functional polymorphisms at the 3 mu-UTR of the CRTH2 gene implicated in asthma. We did show a significant difference in the allele and genotype frequencies as well as different haplotype frequencies among African American, Chinese, and Japanese populations, suggesting that the genetic impacts of these functional polymorphisms on asthma and asthma-related phenotypes may vary in different populations. Copyright (c) 2007 S. Karger AG, Basel.
• Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects

  Yukiko Maeda, Nobuyuki Hizawa, Eisei Jinushi, Ayumi Honda, Daisuke Takahashi, Yoshinobu Fukui, Satoshi Konno, Tadamichi Shimizu, Hiroshi Shimizu, Etsuro Yamaguchi, Masaharu Nishimura

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 174 (10) 1119 - 1124 1073-449X 2006/11 [Refereed][Not invited]
   

  Rationale: The human cholinergic receptor muscarinic-1 (CHRM1) is widely distributed in the lungs. In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation. The CHRM1 gene is located on chromosome 11q13, which is one of the candidate loci for asthma and atopy. Objectives: To determine the role of the CHRM1 gene polymorphisms in asthma. Methods: We studied nine single-nucleotide polymorphisms (-18379G > A, -9697C > T, -6965T > C, -4953A > G, +267A > C, +1353C > T, +3970C > G, +5418C > G, and +5455G > T) in a case-control study using 326 patients with asthma and 333 healthy control subjects. We also examined functional consequences of the -9697C > T and -4953A > G polymorphisms at the regulatory region using an mRNA reporter assay. Measurements and Main Results: Two common single-nucleoticle polymorphisms (-9697C > T and -4953A > G) were associated with asthma. The odds ratio for the TT homozygotes at the -9697C > T polymorphism was 0.29 compared with the CC homozygotes (95% confidence interval, 0.12-0.73; p = 0.008), and the odds ratio for the GG homozygotes at the -4953A > G polymorphism was 1.86 compared with the AA homozygotes (95% confidence interval, 1.04-3.34; p = 0.038). Haplotype analysis showed that the -9697T/-6965T/-4953A haplotype was associated with a lower risk of asthma (p = 0.00055) and the -9697C/-6965T/-4953G haplotype was associated with an increased risk of asthma (p = 0.020). The -9697T/-4953A haplotype was also associated with lower luciferase activity in vitro compared with the -9697C/-4953G haplotype. Conclusions: This study, together with an in vitro functional study, suggests that the CHRM1 gene is an important susceptibility locus for asthma on chromosome 11q13.
• Interleukin-10 and Th2 cytokines differentially regulate osteopontin expression in human monocytes and dendritic cells

  Satoshi Konno, John A. Eckman, Beverly Plunkett, Xinfang Li, Jeffery S. Berman, John Schroeder, Shau-Ku Huang

  JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 26 (8) 562 - 567 1079-9907 2006/08 [Refereed][Not invited]
   

  Osteopontin (OPN) is a pleiotrophic phosphoprotein involved in homeostatic and pathophysiologic responses. It is known to be a chemotactic cytokine for dendritic cells (DCs), a critical cell type in both innate and adaptive immune responses. We report herein a contrasting role of interleukin-10 (IL-10) and Th2 cytokines in the regulation of OPN expression in human monocytes and monocyte-derived DCs (Mo-DCs). Our results showed first that the expression of OPN in monocytes and Mo-DCs was induced in a time-dependent and dose-dependent manner by IL-10 but was inhibited by IL-4 or IL-13. Further, the basal level of OPN expression was also inhibited by IL-4. This inhibitory effect of IL-4 was associated with a faster decay of OPN transcripts and a decreased proximal promoter activity of OPN in IL-4-treated cells. These results demonstrate a novel role of IL-10 and Th2 cytokines in the regulation of DC function through their contrasting regulatory activities on the expression of OPN.
• Association between nonspecific airway hyperresponsiveness and Arg16Gly beta(2)-adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects

  Yoshinobu Fukui, Nobuyuki Hizawa, Daisuke Takahashi, Yukiko Maeda, Eisei Jinushi, Satoshi Konno, Masaharu Nishimura

  CHEST 130 (2) 449 - 454 0012-3692 2006/08 [Refereed][Not invited]
   

  Background: Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human beta(2)-adrenergic receptor (beta(2)-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of beta(2)-AR gene polymorphism on AHR in asymptomatic healthy subjects. Objective: To determine whether polymorphism of the beta(2)-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects. Design and participants: A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification. Results: The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 +/- 0.56 (mean +/- SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 +/- 0.56 (p < 0.05). Conclusion: This study indicates that a specific beta(2)-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.
• Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility

  N Hizawa, Y Maeda, S Konno, Y Fukui, D Takahashi, M Nishimura

  CLINICAL AND EXPERIMENTAL ALLERGY 36 (7) 872 - 876 0954-7894 2006/07 [Refereed][Not invited]
   

  Background We previously detected a promoter polymorphism (-109C/T) in the gene for the beta-chain of the high-affinity receptor for IgE (FCER1B), which was associated with total serum IgE levels but not with asthma in a Japanese population. A genetic interaction is biologically plausible between Fc epsilon RI-beta and the plasminogen activator inhibitor 1 (PAI-1), which is highly expressed in mast cells in asthmatics and plays an essential role in airway remodelling. We hypothesized that FCER1B promoter polymorphisms, by modifying the intensity of mast cell activation signals, modulate the genetic effects of a functional 4G/5G polymorphism in the PAI-1 gene on asthma. Objective To examine whether FCER1B promoter polymorphisms (-109C/T and -654C/T) influence the genetic effects of the functional polymorphism (4G/5G) at the PAI-1 promoter region on asthma susceptibility using a case-control analysis. Methods Subjects (374 asthmatic patients and 374 non-asthmatic controls) were divided into combined genotype groups based on the presence of FCER1B-109TT and -654CC genotypes and the PAI-1 4G allele. Logistic regression analysis was used to estimate adjusted odds ratios for asthma associated with the different genotype groups. Results Individuals homozygous for the FCER1B-109T/-654C haplotype and the PAI-1 5G allele had a reduced susceptibility to asthma; the odds ratio for the development of asthma was 0.20 (95% confidence interval, 0.084-0.46; P=0.00015) for them, compared with individuals also homozygous for the -109T/-654C haplotype at FCER1B but carrying the 4G allele at PAI-1. The regression model also showed an interaction of the PAI-1 4G/5G genotype with the FCER1B-109C/T (P for interaction=0.0017) or FCER1B-654C/T (P for interaction=0.031) on asthma. Conclusions The present findings suggest a synergistic interaction between FCER1B and PAI-1 genes in asthma susceptibility.
• IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity

  M Kawaguchi, D Takahashi, N Hizawa, S Suzuki, S Matsukura, F Kokubu, Y Maeda, Y Fukui, S Konno, SK Huang, M Nishimura, M Adachi

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 117 (4) 795 - 801 0091-6749 2006/04 [Refereed][Not invited]
   

  Background: IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. Upregulated IL17F gene expression has been observed at sites of allergen challenge in the airways of patients with asthma, suggesting that IL-17F is involved in the pathophysiology of asthma. Objective: To investigate the role of IL-17F in asthma pathogenesis, we conducted genetic analyses of association of asthma with the common variants of IL17F, using 867 unrelated Japanese subjects. Methods: Five polymorphisms were studied, including the coding-region sequence variant single nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161 (H 161 R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins. Results: Homozygosity of the H 161 R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H 161 R homozygote compared with the wild-type homozygote (P =.0039). This result remains significant (P =.0079) after adjustment for the presence of atopy using the Mantel-Haenszel chi(2) test. In addition, in vitro functional experiments demonstrated that the H161R variant of IL-17F lacks the ability to activate the mitogen-activated protein kinase pathway, cytokine production, and chemokine production in bronchial epithelial cells, unlike wild-type IL-17F. Furthermore, the H161R variant blocked induction of IL-8 expression by wild-type IL-17F. Conclusion: The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma.
• Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population

  Y Tanino, N Hizawa, S Konno, Y Fukui, D Takahashi, Y Maeda, SK Huang, M Nishimura

  CLINICAL AND EXPERIMENTAL ALLERGY 36 (2) 219 - 225 0954-7894 2006/02 [Refereed][Not invited]
   

  Secreted phosphoprotein 1 (SPP1) is a cytokine with pleiotrophic immunological activities, including activation of macrophage chemotaxis and T-helper type 1 (Th1) immune responses. SPP1 gene polymorphisms have been shown to be associated with several immune inflammatory diseases including multiple sclerosis (MS), which is characterized by fewer allergic symptoms and lower numbers of allergen sensitizations. The present study examined whether SPP1 gene polymorphisms are associated with total serum IgE levels, atopy and asthma in a Japanese population. This case-control association analysis examined 611 subjects, including 268 subjects with asthma. We genotyped three promoter and two exon polymorphisms at SPP1: -1687A/G; -381T/C; -94 deletion/G; 5891C/T; and 7052T/C. Association analyses of SPP1 polymorphisms showed that homozygosities for the 5891T allele (P=0.009) and 7052C allele (P=0.001) were significantly associated with increased levels of total IgE in non-asthmatic subjects. However, these variants were not associated with asthma and atopy. Interestingly, individuals carrying the 5891C allele, which is more prevalent in patients with MS in Japanese populations, displayed significantly lower levels of total serum IgE. Individuals homozygous for the 7052C allele, which is associated with development of systemic lupus erythematosus, displayed significantly higher total serum IgE levels. These findings suggest that genetic polymorphisms in SPP1 may play a role in controlling basal levels of total serum IgE, independent of atopy.
• Total serum IgE levels in eosinophilic lung diseases

  Takeshi Hattori, Nobuyuki Hizawa, Daisuke Takahashi, Akira Isada, Ayumu Takahashi, Yukiko Maeda, Yoshinobu Fukui, Satoshi Konno, Masaharu Nishimura

  Japanese Journal of Allergology 55 (6) 647 - 654 0021-4884 2006 [Refereed][Not invited]
   

  Background: We previously reported elevated levels of total serum IgE in patients with asthma, regardless of their atopic status. We hypothesized that certain factors inherent to asthma may contribute to this non-specific elevation of total serum IgE. In the current study, to evaluate the role of eosinophils in the regulation of total serum IgE, we examined whether peripheral blood eosinophil count is associated with total serum IgE level in patients with eosinophilic lung diseases. Methods: Ninety-nine healthy controls, 277 patients with asthma, 15 patients with acute eosinophilic pneumonia, 21 patients with chronic eosinophilic pneumonia were studied for total serum IgE levels and peripheral blood eosinophil counts. Results: Patients with acute or chronic eosibophilic pneumonia had significantly increased total serum IgE levels compared with healthy controls regardless as atopic status (p < 0.001). In non-atopic subjects with eosinophilic lung diseases, total serum IgE level was significantly correlated with peripheral blood eosinophil count (r = 0.42, p < 0.001. n = 57). Conclusion: Our findings suggest that, in addition to antigen-specific IgE production, non-specific IgE production may contribute to elevated levels of total serum IgE in patients with asthma or eosinophilic pneumonia. An increased number of activated eosinophils may underlie an increased total serum IgE level in these conditions.
• Osteopontin: A potential biomarker for successful bee venom immunotherapy and a potential molecule for inhibiting IgE-mediated allergic responses

  Satoshi Konno, Nobuyuki Hizawa, Masaharu Nishimura, Shau-Ku Huang

  Allergology International 55 (4) 355 - 359 1440-1592 2006 [Refereed][Invited]
   

  Venom immunotherapy (VIT) is proven to be curative for insect allergy, but the mechanisms and the biomarkers associated with clinical efficacy remain elusive. We report herein the discovery of a leading candidate biomarker, osteopontin (OPN), for VIT. From cDNA microarray and clustering analyses, an increased expression of OPN was found in patients who completed 5-6 years of VIT and discontinued therapy for 3-6 years as compared with the untreated group. A significantly higher level of serum OPN was found in the completed treatment group as compared with the untreated group. Following VIT, kinetically increased levels of OPN associated with reduced venom specific IgE levels were noted in subjects with large local allergic reactions to venom. These findings together with the fact that OPN is involved in Th1-associated immune response strongly suggest a role of OPN as a functional biomarker for VIT. ©2006 Japanese Society of Allergology.
• Enhanced expression of interleukin-18 receptor alpha chain by CD4+T cells in sarcoidosis

  YQ Zhou, E Yamaguchi, Y Fukui, S Konno, Y Maeda, K Kimata, M Nishimura

  CHEST 128 (4) 2497 - 2503 0012-3692 2005/10 [Refereed][Not invited]
   

  Study objectives: To investigate the expression of interleukin-18 receptor alpha chain (IL-18R alpha) in BAL and peripheral blood (PB) T cells in patients with sarcoidosis compared with control subjects, to evaluate the relationship between the expression and clinical manifestations, and to clarify the mechanisms of altered expression. Subjects and methods: The study subjects consisted of 21 patients with sarcoidosis and 8 normal control subjects. The expression of IL-18R alpha was examined by flow cytometry. Results: The proportions of BAL CD4+ and PB CD4+ T cells expressing IL-18R alpha were significantly increased in patients with sarcoidosis compared to control subjects. BAL CD4+ T cells expressed IL-18R alpha in a higher proportion than did paired CD8+ T cells in patients with sareoidosis but not in control subjects. Greater proportions of BAL CD4+ T cells and BAL CD8+ T cells than of their PB counterparts expressed IL-18R alpha in both patients and control subjects. CD4+ T cells were more sensitive to the induction of IL-18R alpha by cytokines in vitro, such as interleukin (IL)-2, IL-12, and tumor necrosis factor-alpha than were CD8+ T cells. increased expression of IL-18R alpha by BAL T cells commonly observed in patients and control subjects was associated with the expansion of CD45RO+ cells in BAIL T cells. However, there were no significant correlations between the expression of IL-18R alpha by any cell populations and BAL findings, serum angiotensin-converting enzyme activities, radiograph stages, or clinical courses. Conclusion: The overexpression of IL-18Ra predominantly by CD4+ T cells in sareoidosis emphasizes crucial roles played by T-helper type I cells in the IL-18/IL-18R alpha system in sarcoidosis.
• Level of osteopontin is increased after bee venom immunotherapy

  S Konno, DBK Golden, J Schroeder, RG Hamilton, LM Lichtenstein, SK Huang

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 115 (6) 1317 - 1318 0091-6749 2005/06 [Refereed][Not invited]
  
• Increased expression of osteopontin is associated with long-term bee venom immunotherapy

  S Konno, DBK Golden, J Schroeder, RG Hamilton, LM Lichtenstein, SK Huang

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 115 (5) 1063 - 1067 0091-6749 2005/05 [Refereed][Not invited]
   

  Background: Venom allergen immunotherapy (VIT) is proven to be highly effective for insect allergy, but the mechanisms and the biomarkers associated with clinical efficacy remain elusive. Objective: The aim of this study was to identify candidate biomarkers associated with successful VIT. Methods: Gene chip array and clustering analyses of PBMCs from subjects with or without VIT were performed. Results: From gene chip array and clustering analyses, an increased expression of osteopontin was found in patients who completed 5 to 6 years of VIT and discontinued therapy for 3 to 6 years (completed treatment group) compared with the untreated group. A significantly higher level of serum osteopontin was found in the completed treatment group compared with the untreated group (n = 16 in each group; P < .001). Conclusion: The upregulation of osteopontin after VIT suggests a role of osteopontin as a candidate biomarker for VIT.
• Endotoxin contamination contributes to the in vitro cytokine-inducing activity of osteopontin preparations

  S Konno, T Hoshi, T Taira, B Plunkett, SK Huang

  JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 25 (5) 277 - 282 1079-9907 2005/05 [Refereed][Not invited]
   

  Recently, both native and recombinant preparations of human osteopontin (OPN) have been shown to be able to induce the production of several proinflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) or purified monocytes. In the present study, we found that commercially available native and recombinant OPNs contain variable amounts of endotoxin (LPS) and that removal of endotoxin by polymyxin B-agarose column abrogated their cytokine-inducing activity. These results suggest the questionable evidence of the ability of OPN to induce several cytokines in human PBMCs and draw attention to the exquisite sensitivity of PBMCs/monocytes to endotoxin contaminants.
• Studies on airway hyperresponsiveness by the astograph® method in asthmatics and young adult non-asthmatic asymptomatics

  Yoshinobu Fukui, Etsuro Yamaguchi, Nobuyuki Hizawa, Yukiko Maeda, Daisuke Takahashi, Satoshi Konno, Motoko Kobayashi, Takeshi Hosokawa, Eisei Jinushi, Kei Takamura, Yasuyuki Nasuhara, Masaharu Nishimura

  Japanese Journal of Allergology 53 (6) 565 - 574 0021-4884 2004 [Refereed][Not invited]
   

  We investigated airway hyperresponsiveness (AHR) by the continuous inhalation method using an Astograph® in 105 asthmatics and 141 non-asthmatic asymptomatics. The range of Dmin (1 U = one minute inhalation of 1 mg/ml of methacholine) of asthmatics was 0.001 to 28.70 U, and that of adjusted Dmin of non-asthmatic asymptomatics was 0.28 to 190 U thus, an apparent overlap was recognized in the distributions of Dmin. Ninety-five percent of asthmatics had a Dmin lower than 7 U, and 95% of non-asthmatic asymptomatics had a Dmin higher than 0.9 U. Presuming that almost all asthmatics had AHR, it was inferred that nearly half of non-asthmatic asymptomatics had AHR, too. Comparison with previous reports suggests that AHR in healthy people may be increasing generally. When Dmin is determined to be > 7 U by the Astograph® method, it is likely that the patient does not have asthma. When a patient has a Dmin < 0.9 U, it is highly probable that the patient has asthma.
• Autoimmune thyroid disease accompanied by recurring episodes of painful thyroid ameliorated by thyroidectomy

  S Konno, N Konno, M Yokobori, K Kazui, T Hase, T Uematsu, M Nishimura

  JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION 25 (11) 996 - 1000 0391-4097 2002/12 [Refereed][Not invited]
   

  A 71-yr-old female initially presented with clinical and biochemical hyperthyroidism with high TSH binding inhibitory immunoglobulin (TBII) and anti-thyroid peroxidase antibody (TPOAb) titers. Histological findings of the thyroid revealed hyperplasia with a focal germinal center, indicating Graves' disease and mild focal chronic thyroiditis. Four episodes of painful and tender thyroid occurred over the next 2 yr accompanied by acute inflammatory reactions. The first episode that developed while the patient was in a hyperthyroid state was soon followed by hypothyroidism associated with further increases in anti-thyroglobulin antibody (TGAb) and TIPOAb titers. The subsequent 3 episodes occurred during the hypothyroid state, when the TGAb titer progressively increased with each episode. We performed subtotal thyroidectomy to prevent further episodes. Specimens obtained at thyroidectomy showed that extreme fibrosis had replaced the thyroid parenchyma with collapsed follicles and moderate lymphocyte infiltration. No further episodes occurred after thyroidectomy, and during a 3-yr follow-up period, TBII and thyroid-stimulating antibody (TSAb) disappeared and TGAb and TPOAb titers decreased. This case report provides further evidence supporting the notion that thyroid epithelial destruction progresses during relatively short periods of recurrent painful thyroid and that thyroidectomy helps patients affected by this condition that are unresponsive to other treatment strategies.
• A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma

  N Hizawa, E Yamaguchi, S Konno, Y Tanino, E Jinushi, M Nishimura

  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 166 (5) 686 - 690 1073-449X 2002/09 [Refereed][Not invited]
   

  The CC chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) attracts eosinophils, basophils, and T cells during inflammation and immune response, indicating a possible role for this chemokine in asthma. Both the -403A and -28G alleles of the RANTES promoter region exhibit significantly enhanced promoter activity in reporter constructs in vitro. We therefore investigated the genetic influence of these alleles on the development of asthma using case-control analysis in a Japanese population (298 patients with asthma and 311 control subjects). Given the evidence for heterogeneity of asthma according to age at onset, we divided patients with asthma into three subgroups: 117 late-onset patients with asthma (onset at more than 40 years of age) 83 middle-onset patients with asthma (onset at 20 to 40 years of age), and 98 early-onset patients with asthma (onset at less than 20 years of age). The -28G allele was significantly associated with late-onset asthma (odds ratio = 2.033; 95% confidence interval, 1.379-2.998; corrected p < 0.0025) but was not associated with the other two asthma subgroups. The -403A allele was not associated with any of the asthma subgroups. Further evidence of the importance of the -28G allele was a significant increase in the production of RANTES in vitro in individuals who carried this allele. Our findings suggest that, among Japanese, the -28G allele of the RANTES promoter region confers susceptibility to late-onset asthma.
• Cytokines and Th2 cells in AEP of smoking

  Y Tanino, E Yamaguchi, K Takaoka, Y Fukui, S Konno, N Hizawa, M Nishimura

  ALLERGY 57 (5) 463 - 464 0105-4538 2002/05 [Refereed][Not invited]
  
• (CCTTT)(n) repeat polymorphism in the NOS2 gene promoter is associated with atopy

  S Konno, N Hizawa, E Yamaguchi, E Jinushi, M Nishimura

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 108 (5) 810 - 814 0091-6749 2001/11 [Refereed][Not invited]
   

  Background: Several studies have shown that nitric oxide (NO) plays a role in the regulation of the T(H)1/T(H)2 balance, indicating the potential for NO to contribute to the development of atopy and several other allergic diseases, including bronchial asthma. NO synthase 2 (NOS2) is critically involved in the synthesis of NO during several inflammatory states, and the gene encoding NOS2 is located at chromosome 17q11.2-q12, where 2 genome scans have identified a candidate locus for atopy and asthma. Objective: The 14-repeat allele of the (CCTTT)(n) repeat polymorphism in the NOS2 promoter region is a powerful enhancer of promoter activity in reporter constructs in vitro. We tested whether this potentially functional allele in the NOS2 gene influences the development of atopy and asthma. Methods: We studied a total of 497 unrelated Japanese subjects (141 nonatopic healthy controls, 102 atopic healthy controls, 56 nonatopic asthmatic subjects, and 198 atopic asthmatic subjects). The odds ratio (OR) was calculated for atopy and asthma in carriers of the 14-repeat allele through use of logistic regression models. Atopy was defined as a positive specific IgE level to at least 1 of 10 common inhaled allergens. Results: The 14-repeat allele was inversely associated with atopy (OR = 0.42, P < .01). The association remained significant when the model was controlled for asthmatic status (OR = 0.36, P < .01). This allele, however, was associated neither with the development of asthma nor with total serum IgE levels. Conclusion: Our findings suggest that the (CCTTT)(n) repeat polymorphism in the promoter of the NOS2 gene that affects promoter activity is a risk factor for the development of atopy, and this genetic effect seems independent of asthma.
• Increased total serum IgE levels in patients with asthma and promoter polymorphisms at CTLA4 and FCER1B

  N Hizawa, E Yamaguchi, E Jinushi, S Konno, Y Kawakami, M Nishimura

  JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 108 (1) 74 - 79 0091-6749 2001/07 [Refereed][Not invited]
   

  Background: Increasing evidence indicates that total serum IgE levels are largely determined by genetic factors, and we recently established that the -109C/T promoter polymorphism at FCER1B is a genetic factor that affects total serum IgE levels. The gene encoding cytotoxic T lymphocyte antigen 4 (CTLA4) is another candidate factor in high IgE responsiveness, because B7-CD28/CTLA4 interaction can promote the differentiation and development of the T(H)2 lymphocyte subset. Objective: We intended to determine whether CTLA4 is associated with increased levels of total serum IgE or with the development of asthma or atopy. Methods: We performed a case-control study involving 339 patients with asthma and 305 healthy control subjects, of whom 226 of the patients with asthma and 219 of the healthy control subjects had previously been genotyped for the -109C/T promoter polymorphism at FCER1B. In the current study, we genotyped 2 polymorphisms in the CTLA4 gene, one involving the promoter (-318C/T) and the other involving exon I ((+)49A/G), in addition to the FCER1B promoter polymorphism. Results: Patients with asthma who were homozygous for the -318C allele at the CTLA4 promoter region had higher levels of total serum IgE than patients with asthma carrying the -318T allele (P = .00470). The analysis of -318C/T (at CTLA4) and -109C/T (at FCER1B) promoter polymorphisms showed a significant correlation between the combined genotypes and increased levels of total IgE in patients with asthma (P = .000014). In contrast, no correlation between total serum IgE levels and -318C/T or +49A/G genotypes was detected in 305 healthy control subjects. There was no evidence indicating an association between a putative allele for asthma or atopy and alleles at any of the CTLA4 polymorphic loci. Conclusion: Our findings suggest that promoter polymorphisms of both CTLA4 and FCER1B are genetic factors that influence total serum IgE levels in patients with asthma. This supports the theory that variance in total serum IgE levels in patients with asthma is determined by mutations in multiple genes, each of which has a relatively small effect on the phenotype.
• Carcinoid tumor detected in gastric adenoma during long-term follow-up

  T Harada, M Imura, M Masutani, S Konno, H Miyazaki, A Nomura, S Okushiba, H Katoh, T Itoh, M Shimizu, Y Kawakami

  GASTROINTESTINAL ENDOSCOPY 53 (7) 804 - 806 0016-5107 2001/06 [Refereed][Not invited]
  
• [Three adults with mild varicella and bronchial mucosal lesions].

  Konno S, Tsuneta Y, Jinushi E, Ukita H, Harada T, Aida A, Nishiura Y, Takahashi W, Kawai T

  Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 36 (4) 363 - 368 1343-3490 1998/04 [Refereed][Not invited]
  

MISC

• 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  2021/06
• 医学と医療の最前線 薬剤の反応性から見た喘息とCOPD及び両者の合併病態

  今野 哲  日本内科学会雑誌  110-  (5)  1002  -1006  2021/05
• 一目瞭然!目で診る症例

  鎌田 啓佑, 藤田 留美, 西條 大悟, 松田 剛, 小野 大輔, 佐々木 雅一, 今野 哲, 岡 秀昭  日本内科学会雑誌  110-  (5)  1013  -1016  2021/05
• 新型コロナウイルス感染症が北海道内の病院・診療所の診療に与えた影響に関するアンケート調査

  齋藤 充史, 千葉 弘文, 服部 健史, 黒沼 幸治, 中久保 祥, 鎌田 啓佑, 田代 典夫, 田中 裕士, 福家 聡, 今野 哲  日本呼吸器学会誌  10-  (3)  245  -250  2021/05  

  北海道における新型コロナウイルス感染症(coronavirus disease 2019:COVID-19)流行の経験を全国の医療従事者と共有し、大病院と診療所/クリニックとの相違を明らかにすることで、今後の診療に役立てることを目的としてアンケート調査を実施した。診療所ではCOVID-19対策における物理的な制約や、経営的な影響、ストレスに感じる項目など、病院とは異なる影響や考え方があることが明らかとなった。今後それぞれの医療現場の立場・状況に応じてCOVID-19に対する方策を検討することの重要性が示唆された。(著者抄録)
• 【内科疾患の診断基準・病型分類・重症度】(第1章)呼吸器 好酸球性肺炎

  木村 孔一, 今野 哲  内科  127-  (4)  540  -541  2021/04
• 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  2021/04  

  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)
• 【COVID-19の病態・診断・治療 現場の知恵とこれからの羅針盤】(VI章)各施設はどのようにCOVID-19を診断・治療していたのか 各施設の対応 北海道大学病院

  中久保 祥, 今野 哲  呼吸器ジャーナル  別冊-  163  -167  2021/01  

  ＜Point＞●北海道は全国に先駆けてCOVID-19感染拡大の波を経験し,当院では軽症から量重症まで幅広く診療を行った.●ECMO導入症例をはじめ,重症化した症例の予後は厳しく,重い後遺症を残し得ることを実感した.重症化を防ぐ治療戦略が望まれる.●COVID-19疑い症例の診療では,複数の臨床所見を基に総合的に判断しPCR検査の適否を考えるべきであり,その判断材料として臨床スコアが有用かもしれない.(著者抄録)
• 北海道胆振東部地震・大規模停電における、在宅酸素療法患者に関するアンケート調査

  森 勇樹, 千葉 弘文, 福家 聡, 今野 哲, 大崎 能伸, 高橋 弘毅  日本呼吸器学会誌  9-  (6)  397  -403  2020/11  

  北海道胆振東部地震に引き続き発生した大規模停電による在宅酸素療法(home oxygen therapy:HOT)患者への影響を把握するため、日本呼吸器学会北海道支部会員を対象にアンケート調査を実施した。HOT患者は回答施設の87%に通院していた。停電時でも参照可能な連絡先リストは59%の施設で準備されており、安否確認を行った施設は56%であった。HOT患者の臨時入院は43施設でみられ、最大32名を受け入れた施設があった。緊急時のHOT患者受け入れに関して、あらかじめ近隣施設と連携していたのは29%で、そのうちそれを患者に周知していた施設は40%であった。(著者抄録)
• 当科におけるadolescent and young adult世代胸部悪性腫瘍患者に関する検討

  塩泡 亜衣, 榊原 純, 國崎 守, 古田 恵, 高島 雄太, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 品川 尚文, 今野 哲  日本呼吸器学会誌  9-  (5)  319  -324  2020/09  

  思春期・若年成人(adolescent and young adult:AYA)世代胸部悪性腫瘍患者36例を後方視的に検討した。肺癌/胸腺腫瘍/原発不明癌が31/4/1例、performance status(PS)0/1は33例、1例を除いて併存疾患はなかった。肺腺癌18例中EGFR遺伝子変異陽性は6例、ALK融合遺伝子陽性は4例だった。生存期間中央値(median survival time:MST)は全体で69.4ヵ月、肺癌で32.8ヵ月だった。PS良好で併存疾患が少なく遺伝子変異陽性が多いことがAYA世代患者の特徴であり、予後延長に寄与した可能性がある。(著者抄録)
• 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  2020/09  

  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)
• 免疫アレルギー疾患研究10か年戦略2030 「見える化」による安心社会の醸成

  足立 剛也, 貝沼 圭吾, 浅野 浩一郎, 天谷 雅行, 新井 洋由, 石井 健, 伊藤 浩明, 内尾 英一, 海老澤 元宏, 岡野 光博, 椛島 健治, 近藤 健二, 今野 哲, 佐伯 秀久, 園部 まり子, 長尾 みづほ, 檜澤 伸之, 福島 敦樹, 藤枝 重治, 松本 健治, 森田 英明, 山本 一彦, 吉本 明美, 玉利 真由美  アレルギー  69-  (1)  23  -33  2020/02  

  「免疫アレルギー疾患研究10ヵ年戦略2030」の策定経緯、特徴、その戦略について解説した。医療提供体制の構築に基づく医療の均てん化等、研究開発以外に推進されている取り組みと本研究戦略との位置付けを明確にし、2030年までに目指す詳細な戦略を厚生労働省が初めて策定した。戦略1として、先制的医療等を目指す免疫アレルギーの本態解明に関する基盤研究、戦略2として、免疫アレルギー研究の効果的な推進と社会の構築に関する横断研究、戦略3として、ライフステージ等免疫アレルギー疾患の特性に注目した重点研究が定められている。
• ニボルマブ投与継続が可能であった尿細管間質性腎炎を発症した膜性腎症合併肺癌の1例

  佐々木 真知子, 水柿 秀紀, 榊原 純, 近藤 桂一, 深澤 雄一郎, 今野 哲  日本呼吸器学会誌  9-  (1)  71  -75  2020/01  

  症例は65歳女性。半年前より尿蛋白を指摘されネフローゼ症候群の精査目的に当院腎臓内科を受診した。左肺下葉に腫瘤影を指摘され当科を紹介され、肺扁平上皮癌cStage IVと診断した。ネフローゼ症候群の原因は肺癌に伴う膜性腎症と診断された。1次治療後に原発巣の増悪があり、2次治療としてニボルマブ(nivolumab)を開始し、1コースの5日目にGrade 2のクレアチニン増加を認めた。腎生検を施行され、病理組織診断は膜性腎症および尿細管間質性腎炎であった。その後、1.5〜4ヵ月ごとにニボルマブを投与し部分奏効を維持している。(著者抄録)
• 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  2019/10  [Not refereed][Not invited]
  
• 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  2019/05  [Not refereed][Not invited]
  
• 【喘息・COPD-病態の多様性の捉えかたと最適な治療選択】COPD病態の多様性と最適な治療アプローチ 好酸球性気道炎症とCOPD フェノタイプか,喘息合併か

  鈴木 雅, 今野 哲  呼吸器ジャーナル  67-  (2)  270  -275  2019/05  

  ＜文献概要＞Point ・好酸球性気道炎症を有するCOPD=喘息-COPDオーバーラップ(ACO)とは限らない.・好酸球性気道炎症を有するCOPD患者はステロイド薬への治療反応性が良い可能性がある.・喘息と診断されないCOPD患者においても好酸球性気道炎症の有無を検討することは重要である.
• 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  2019/03  [Not refereed][Not invited]
  
• 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  2019/03  [Not refereed][Not invited]
  
• 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  2019/03  [Not refereed][Not invited]
  
• 【喘息診療Update 2019】ライフスタイルが喘息病態に及ぼす影響 喫煙、肥満

  今野 哲  Pharma Medica  37-  (3)  29  -32  2019/03
• 高齢者における、気管支喘息とCOPDの共通病態の解明 両疾患の枠を超えたバイオマーカーの探索

  今野 哲  大和証券ヘルス財団研究業績集  (42)  1  -4  2019/03  

  気管支喘息、慢性閉塞性肺疾患(COPD)の両疾患の共通病態を明らかにし、新たな病型分類に基づいた新規治療データの探索を試みた。127人の喫煙者を含む重症気管支喘息患者に対し、血液、呼吸機能検査、呼気NO濃度(FeNO)測定、副鼻腔CT等を実施し、それらの検査結果を用いて階層的クラスタリング法にて病型分類をおこなった。その結果、気管支喘息とCOPDの共通の要素をきたす患者群は、大きく二つの分子生物学的分類がなされた。その2群における炎症性バイオマーカーは大きくことなり、一つのクラスターでは喀痰中のIL-5が高値であり、好酸球数、FeNO、血清IgE値の上昇を認めていたのに対し、もう一つのクラスターは、IL-6、オステオポンチンの上昇、および末梢血、喀痰好酸球数、FeNO、血清IgE値の上昇は認めていなかった。一方、好酸球性炎症と関連する副鼻腔スコアと、気道炎症バイオマーカー、呼吸機能との関連を、軽症〜重症を含む気管支喘息患者206人において、全対象を喫煙者と非喫煙者に分けて検討した。その結果、各種バイオマーカーは、喫煙歴に関わらず、副鼻腔スコアと正の相関を認めたのに対し、呼吸機能検査は非喫煙者のみで関連を認めた。
• 【呼吸器病学TOPICS 2018-19】閉塞性肺疾患 COPDに対するトリプル治療のエビデンスと適応

  福家 聡, 今野 哲  分子呼吸器病  23-  (1)  25  -29  2019/03
• 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  2019/02  [Not refereed][Not invited]
  
• 短期間の静注抗菌薬から経口抗菌薬に変更しても、良好な治療経過をたどったM.massiliense症の3例

  松本 宗大, 鈴木 雅, 山下 優, 武井 望, 木村 孔一, 長岡 健太郎, 今野 哲  日本サルコイドーシス/肉芽腫性疾患学会雑誌  38-  (サプリメント号)  81  -81  2018/10  [Not refereed][Not invited]
  
• 細胞性免疫不全を伴い種々の感染症を併発したGood症候群の1例

  西村 弘基, 松本 宗大, 鈴木 雅, 木村 裕樹, 武井 望, 山下 優, 木村 孔一, 長岡 健太郎, 今野 哲, 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  2018/10  [Not refereed][Not invited]
  
• 低用量でステロイド導入した肺サルコイドーシス症の検討

  木村 孔一, 今野 哲, 四十坊 典晴, 山田 嘉仁, 山口 哲生  日本サルコイドーシス/肉芽腫性疾患学会雑誌  38-  (サプリメント号)  72  -72  2018/10  [Not refereed][Not invited]
  
• 治療方針決定に難渋した気管支閉鎖症の一例

  石田 有莉子, 松本 宗大, 佐藤 一紀, 木村 孔一, 長岡 健太郎, 鈴木 雅, 今野 哲, 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)  102  -102  2018/10  [Not refereed][Not invited]
  
• 【アレルギー診療 総合トレーニング!】《再確認・アレルギー診療の実際》 病因アレルゲン同定の実際

  福居 嘉信, 今野 哲  Modern Physician  38-  (10)  1020  -1022  2018/10  

  ＜ポイント＞●病因となりうるアレルゲンは、その疾患ごとに異なる。●喘息では、ヒョウヒダニや動物由来のアレルゲンや真菌などの吸入アレルゲンが病因アレルゲンとして重要である。●アレルギー性鼻炎では、患者の生活圏における植生や花粉飛散時期を知っておく必要がある。●食物アレルギーでは、明らかな因果関係が想定される誘発症状の病歴と免疫学的検査の結果が一致する場合では食物経口負荷試験までは不要である。しかし、誘発された症状がアレルギー反応であるか疑わしい、複数の原因食物が疑われる、誘発閾値量や症状の重症度を決定したいなどの場合は、食物経口負荷試験を行う。●特異的IgE抗体が存在することは、当該アレルゲンへの「感作」を示しているものであり、それが必ずしも病因アレルゲンであるとは限らない。(著者抄録)
• 【もっとうまくいく! 病診連携の「伝え方」-わかりやすく伝えるための診療情報提供書作成のコツ】(第II章)<診療科別>コンサルトのポイント D.呼吸器科へコンサルト 喘息(治療)

  福家 聡, 今野 哲  内科  122-  (3)  551  -553  2018/09
• 【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  2018/08
• 【診断と治療のABC[135]喘息】(第3章)診断 慢性閉塞性肺疾患(COPD)との合併

  今野 哲  最新医学  別冊-  (喘息)  118  -122  2018/06  

  気管支喘息とCOPDの共通病態を考察するにあたり、両疾患の定義のアプローチの相違が指標となる。喘息-COPDオーバーラップ(ACO)という概念の提唱は、その定義を明確にするのが目的ではなく、今後高齢化社会を迎える本邦においては、純粋に気管支喘息あるいはCOPDと特徴づけられる患者よりも、両者の中間の病態を有する患者の方が多く存在するということを、改めて強調した点が重要である。今後は、気管支喘息やCOPDといった既存の疾患概念にとらわれず、慢性閉塞性疾患全体を再度見つめ直す必要性がある。(著者抄録)
• 【アンチテーゼとしての難治性呼吸器疾患の個別化医療】疾患の定義、診断とは?

  今野 哲  THE LUNG-perspectives  26-  (2)  125  -128  2018/05  

  慢性呼吸器疾患の多くは、その定義の曖昧さと、それぞれの疾患により定義に至る視点が異なるため、特に複数病態の合併症例をとらえることが困難となる。患者に診断を下すということは、決して病名をつけることが目的ではなく、個々の患者に対する最大のメリットとなる手段を見出すことである。これまで用いられてきた種々の疾患の定義をすべて否定する訳ではないが、特に難治性疾患の病態、複数疾患の合併病態を理解するには、これまでの疾患の理解および定義のみでは限界がみえてきたのも事実である。将来的には、現在使用されている病名をいったん忘れ、分子生物学的、あるいは単に治療反応性という観点で、疾患をとらえる必要があるのかもしれない。(著者抄録)
• 【咳、痰のみかた】咳と痰の原因となる疾患とは 咳喘息

  高橋 歩, 今野 哲  内科  121-  (5)  1163  -1165  2018/05  

  ＜文献概要＞■咳喘息は咳嗽を唯一の症状とする喘息の亜型である.■病態,臨床的特徴は喘息に類似し,治療も喘息と同様である.■典型的喘息に移行する場合もあり,早期の治療導入が必要である.■治療継続,アドヒランス向上のために患者への適切な説明も重要である.
• 日本人α1-アンチトリプシン欠乏症(AATD)患者におけるAlpha-1 MPの薬物動態

  瀬山 邦明, 貫和 敏博, 佐藤 匡, 鈴木 雅, 今野 哲, 高橋 和久, 西村 正治, Steinmann Kimberly, Sorrells Susan, 林 賢一  日本呼吸器学会誌  7-  (増刊)  258  -258  2018/03  [Not refereed][Not invited]
  
• 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  2018/03  [Not refereed][Not invited]
  
• 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  2018/03  [Not refereed][Not invited]
  
• 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  2018/03  [Not refereed][Not invited]
  
• 早期の経口抗菌薬スイッチ導入で、良好な治療経過をたどったM.massiliense症の3例

  松本 宗大, 鈴木 雅, 山下 優, 武井 望, 木村 孔一, 長岡 健太郎, 今野 哲, 西村 正治  日本呼吸器学会誌  7-  (増刊)  224  -224  2018/03  [Not refereed][Not invited]
  
• 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  2018/03  [Not refereed][Not invited]
  
• マクロライド抵抗性のマイコプラズマによる重症肺炎の1例

  松本 宗大, 長岡 健太郎, 山下 優, 武井 望, 木村 孔一, 鈴木 雅, 今野 哲, 石黒 信久, 西村 正治  日本呼吸器学会誌  7-  (増刊)  332  -332  2018/03  [Not refereed][Not invited]
  
• 【呼吸器病学TOPICS 2017-18】閉塞性肺疾患 COPDにおける喘息様フェノタイプと臨床経過 COPD cohort studyから

  鈴木 雅, 今野 哲  分子呼吸器病  22-  (1)  28  -30  2018/03
• 「特集/アレルギー疾患のバイオマーカー」に寄せる 副鼻腔CT、バイオマーカーからみた気管支喘息における上下気道の連関

  木村 孔一, 今野 哲  アレルギーの臨床  37-  (14)  1367  -1372  2017/12  [Not refereed][Not invited]
   

  喘息の難治化因子の一つとして副鼻腔炎の存在が知られているが、その詳細なメカニズムについては明らかでない。当施設で施行中の喘息コホート研究の結果からは、Th2反応を背景とした、上下気道に共通する好酸球性気道炎症の存在が示唆され、それによる下気道のリモデリングへの影響が考えられた。また、喘息における臨床研究では喫煙者は除外されていることが多く、喫煙者を含めた実臨床でのバイオマーカーの評価にも注意が必要である。(著者抄録)
• 【アレルギー疾患に対する生物学的製剤】内科 重症喘息患者のフェノタイプとエンドタイプ

  服部 健史, 今野 哲  アレルギー・免疫  24-  (12)  1618  -1623  2017/11  

  気管支喘息の臨床的特徴は多様であることから,単一の疾患ではなく症候群として捉えられてきた。その多様性から,病態生理学的指標に基づいて類似したフェノタイプの分類が検討され,近年は分子生物学的病態に基づいてエンドタイプの分類も検討されるようになった。特に重症喘息に対して個別化医療の観点からフェノタイプ,エンドタイプの解析が着目されている。(著者抄録)
• 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  2017/10/03  [Not refereed][Not invited]
  
• 専門医のためのアレルギー学講座 肥満とアレルギー 肥満と気管支喘息

  今野 哲  アレルギー  66-  (7)  919  -922  2017/08
• 【重症喘息-基礎から臨床まで-】喘息重症化因子 肥満

  今野 哲  最新医学  72-  (7)  968  -973  2017/07  

  肥満は,気管支喘息の病態に影響を及ぼす重要な要因の1つであるが,その影響は症状,呼吸機能,炎症等さまざまな機序が推定される.本邦は欧米と比較し肥満者の割合が低いが,一方で日本人は肥満に弱いという考えもあり,本邦での独自の検討が重要である.また,肥満が喘息炎症に与える影響は一方向性ではなく,肥満喘息患者全体に対する共通のアプローチはなく,個々による肥満が喘息病態に与える影響を慎重に考慮する必要がある.(著者抄録)
• 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  2017/05  [Not refereed][Not invited]
  
• 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  2017/05  [Not refereed][Not invited]
  
• 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  2017/03  [Not refereed][Not invited]
  
• 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  2017/03  [Not refereed][Not invited]
  
• 【呼吸器疾患と慢性炎症】炎症と気道過敏性

  福居 嘉信, 今野 哲  別冊Bio Clinica: 慢性炎症と疾患  6-  (1)  33  -37  2017/03  

  アレルゲンや冷気やタバコ煙の吸入や運動など、健常者では反応しない程度の弱い刺激によって気道が容易に収縮する性質を気道過敏性という。炎症と気道過敏性を伴う疾患の代表が喘息である。喘息では、気道炎症によって気道過敏性が亢進しているため、冷気やタバコ煙の吸入などによって、健常者よりも容易に気道が収縮し、喘鳴や呼吸困難や咳を発症する。気道過敏性の成因としては、(1)好酸球から放出される顆粒蛋白が気道上皮を傷害する、(2)M2ムスカリン受容体などの機能が障害されて気道平滑筋の収縮を抑制する力が弱まる、(3)炎症細胞が放出したサイトカインやケモカインに慢性的に曝露されることにより気道平滑筋の収縮の反応性が亢進する、(4)気道壁が肥厚することにより気道平滑筋の収縮時に気道抵抗がより大きく増加する、などが考えられている。(著者抄録)
• 粉じんばく露回避前後の経過を観察しえた超硬合金肺の1例

  今野 哲  産業医学ジャーナル  40-  (2)  15  -19  2017/03  

  症例は50歳女性で、42歳より8年間、超硬合金製品を研磨する作業に従事しており、防じんマスクは着用していなかった。乾性咳嗽が出現し、画像上び漫性小粒状影を指摘された。確定診断目的に右上葉および右下葉より胸腔鏡下肺生検(VATS肺生検)を施行し、病理学的に総気管支領域を中心にリンパ球浸潤を伴う線維化を認めた。超硬合金肺に特徴的とされる多核巨細胞はごくわずかに認めるのみで、いわゆるGIPの所見は認めなかった。肺組織中の元素分析を施行し、タングステンとコバルトの存在を確認した。X線吸収微細構造により標本に含まれるタングステンが炭化タングステンであることが証明され、超硬合金肺と診断した。診断後も勤務を継続し、作業をする際には、防じんマスクを使用するように指導したが、不快感、作業への支障を理由に徹底されなかった。確定診断後、症状・画像所見・呼吸機能検査所見はいずれも増悪した。職場が変更となったため完全に超硬合金のばく露から回避されたところ、呼吸器症状の改善を認めた。
• 【増え続けるアレルギー疾患-内科医にできる対策と治療】アレルギー疾患の予防 喫煙と気管支喘息,アレルギー

  今野 哲  内科  118-  (6)  1097  -1101  2016/12  

  喫煙は,われわれを取り巻く最大の環境要因であり,種々のアレルギー疾患に影響を及ぼす.喫煙がアレルギーに及ぼす影響を知ることは,アレルギー病態の解明の一助となり,また,日常生活における禁煙指導の重要性を示す根拠となりうる.気管支喘息をはじめとするアレルギー疾患においては,症状,アレルゲン感作,呼吸機能,炎症など,種々の側面に対する影響を考慮し検討する必要がある.(著者抄録)
• 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  2016/11  

  【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)
• 【気管支喘息-最新の診断と治療-】合併症・併存症を有する気管支喘息 気管支喘息と慢性閉塞性肺疾患(COPD) 共通病態の考察

  今野 哲  日本臨床  74-  (10)  1729  -1734  2016/10
• 【特発性間質性肺炎の最前線】分子サイズと肺胞 血液間動態が血清KL-6値に与える影響

  重村 雅彦, 今野 哲, 南須原 康行, 西村 正治  呼吸器内科  30-  (2)  118  -123  2016/08
• 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  2016/05/15  [Not refereed][Not invited]
  
• アレルギー用語解説シリーズ オステオポンチン

  今野 哲  アレルギー  65-  (3)  208  -209  2016/05
• 当院におけるESBL産生大腸菌とESBL非産生菌大腸菌による菌血症症例の比較検討

  中久保 祥, 長岡 健太郎, 鎌田 啓佑, 今野 哲, 西村 正治, 石黒 信久  感染症学雑誌  90-  (臨増)  253  -253  2016/03  [Not refereed][Not invited]
  
• MAST法にてスクリーニングされた喘息患者におけるアレルゲン特異的IgE抗体の検索 ImmunoCAPの意義

  飯島 弘晃, 金子 美子, 増子 裕典, 山田 英恵, 谷田貝 洋平, 坂本 透, 金本 幸司, 石川 博一, 斎藤 武文, 遠藤 健夫, 二宮 浩樹, 野村 明広, 児玉 孝秀, 金子 教宏, 國分 二三男, 牧田 比呂仁, 今野 哲, 西村 正治, 檜澤 伸之  アレルギー  64-  (9)  1242  -1253  2015/11  

  【目的】MASTと比較しImmunoCAPRは特異的IgE抗体検出力が高い.MASTでスクリーニングされた喘息患者に対しImmunoCAPによる精査が推奨される患者の特徴を検討する.【方法】MASTにて14種類の吸入抗原特異的IgE抗体がすべて陰性の48名(A群)とダニへの強い感作が認められた44名(B群)の喘息患者を対象とし,ゴキブリやガなどに対しImmunoCAPを実施した.【結果】A群の27.1%においてImmunoCAPが陽性となった.少なくとも一つのアレルゲンに対するImmunoCAP陽性と総IgE値とが関連した(p=0.0007).B群では,ゴキブリ,ガのImmunoCAP陽性率は各々27.8%,52.3%であり,これらの感作も総IgE値と関連した(p=0.0003).【結論】総IgE値が一定の値を超える喘息患者では,MASTが陽性でなくても,ゴキブリやガを含め幅広く吸入抗原に対し感作されている可能性があり,ImmunoCAPによるアレルゲン精査が有用である.(著者抄録)
• 【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  2015/10  

  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)
• 専門医のためのアレルギー学講座 加齢・生活習慣とアレルギー 喫煙と成人喘息、COPD

  今野 哲  アレルギー  64-  (8)  1127  -1133  2015/09
• アレルギー疾患の最新治療 気管支喘息診療に残された課題 難治性喘息の克服に向けて

  今野 哲  日本臨床皮膚科医会雑誌  32-  (5)  563  -565  2015/09
• 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  2015/05  

  [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)
• 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  2015/04  [Not refereed][Not invited]
  
• 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  2015/04  [Not refereed][Not invited]
  
• 呼吸機能関連遺伝子による喘息病態の検討

  山田 英恵, 谷田貝 洋平, 増子 裕典, 坂本 透, 飯島 弘晃, 内藤 隆志, 野口 恵美子, 広田 朝光, 玉利 真由美, 今野 哲, 西村 正治, 檜澤 伸之  日本呼吸器学会誌  4-  (増刊)  276  -276  2015/03  [Not refereed][Not invited]
  
• 【喘息とCOPDのオーバーラップ症候群(ACOS)をめぐって】病態・生理 遺伝子多型からみた気管支喘息とCOPDの共通病態の考察

  今野 哲  アレルギー・免疫  22-  (4)  540  -546  2015/03  

  呼吸器疾患におけるcommon diseaseである気管支喘息とCOPDは、いずれも多様な疾患であると理解されるようになり、病型の理解及び病型に基づく治療戦略が重要である。遺伝子多型研究は、両疾患の共通病態の理解において重要な役割を有し、我々はこれまでCCL5、CAT遺伝子に存在する機能的遺伝子多型より、両疾患の病型に基づく共通病態を考察した。また、気管支拡張薬(β2刺激薬、抗コリン薬)の効果においても、両疾患の枠を越えて両薬剤を選択する必要性を、遺伝子多型の観点より考察した。(著者抄録)
• 気管支喘息とCOPDの共通病態の理解 疫学研究、遺伝子多型およびコホート研究より

  今野 哲  呼吸  34-  (3)  325  -333  2015/03  

  呼吸器疾患におけるcommon diseaseである気管支喘息とCOPDは、いずれも多様な疾患であると理解されるようになり、病型の理解および病型に基づく治療戦略が重要である。遺伝子多型研究は、両疾患の共通病態の理解において重要な役割を有し、筆者らはこれまでCCL5、CAT遺伝子に存在する2つの機能的遺伝子多型より、両疾患の病型に基づく共通病態を考察した。また、当科で行った臨床研究により、両疾患の枠を越えて、気管支拡張薬(β2刺激薬、抗コリン薬)に反応する因子を同定した。現在当科では、喫煙者を含めた難治性喘息患者を登録し、前向きの観察研究を展開中であり、喫煙者を含めることにより喘息とCOPDのoverlap病態の考察が可能となり、今後の重要な検討事項として位置づけている。(著者抄録)
• 北海道大学における動物実験実施者等の実験動物への感作状況

  吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 橋野 聡, 森松 正美, 今野 哲, 有川 二郎, 石井 哲也, 澤村 正也, 上田 一郎  アレルギー  63-  (8)  1132  -1139  2014/09  [Not refereed][Not invited]
   

  【目的】北海道大学で発生したマウス咬傷によるアナフィラキシー事例を踏まえ,アレルギー予防対策の構築を目的として,動物実験を実施する学生及び職員の動物アレルギーの感作状況を調査した.【方法】齧歯類等の取扱者で同意を得た555名を対象に問診票と実験動物5種に対する特異的IgE抗体と好酸球数測定によるアレルギー健診を実施した.【結果】特異的IgE抗体陽性率(陽性者数/取扱者数)は,マウス14.1%(62/441名),ラット17.9%(50/279名),ハムスター18.8%(6/32名),モルモット17.4%(4/23名),ウサギ11.3%(12/106名)であった.マウス取扱者においては,動物に接触した時に何らかのアレルギー症状が現れる場合は,抗マウスIgE抗体陽性率が有意に高いことも判明した(38.1% vs 8.8%,p<0.01).【結論】動物取扱者の感作状況を把握するために,特異的IgE抗体検査を含む健診を実施することが有用であることが示された.(著者抄録)
• 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  2014/08  [Not refereed][Not invited]
   

  【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)
• 日本人高齢者における肥満と喫煙状態の関連について

  渡部 拓, 今野 哲, 辻野 一三, 伊藤 陽一, 佐藤 隆博, 谷口 正実, 秋山 一男, 赤澤 晃, 大塚 吉則, 西村 正治  日本老年医学会雑誌  51-  (3)  277  -278  2014/05  [Not refereed][Not invited]
  
• 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  2014/04  [Not refereed][Not invited]
  
• 【内科救急のファーストタッチ】疾患編 呼吸器疾患 気管支喘息

  福居 嘉信, 今野 哲  診断と治療  102-  (Suppl.)  229  -233  2014/03  

  1)まず、酸素投与が必要かどうか判断する。2)喘息なのか心不全なのか他の疾患なのかを考えながら、問診や診察や検査を行う。3)酸素投与が必要な状態であれば、喘息の増悪が疑われた時点で初期治療を始める。4)酸素を投与する際には、炭酸ガスナルコーシスに注意する。5)薬物治療では、β2刺激薬のネブライザー吸入、ステロイド薬の点滴、テオフィリン薬の点滴を通常行う。6)アスピリン喘息の可能性が高いと判断した場合、ステロイド薬の点滴にはデキサメタゾンやベタメタゾンを用いるほうが望ましい。(著者抄録)
• Current Opinion 気管支喘息における長時間作用性β2刺激薬(LABA)の位置づけ

  今野 哲  呼吸と循環  61-  (11)  1058  -1062  2013/11
• 脳死肺移植を施行した重症の肺高血圧を伴う肺ランゲルハンス細胞組織球症の一例

  吉田 貴之, 今野 哲, 辻野 一三, 佐藤 隆博, 大平 洋, 長井 桂, 谷野 美智枝, 羽賀 博典, 石津 明洋, 陳 豊史, 伊達 洋至, 西村 正治  日本サルコイドーシス/肉芽腫性疾患学会雑誌  33-  (サプリメント号)  52  -52  2013/10  [Not refereed][Not invited]
  
• 【サルコイドーシスのすべて】サルコイドーシスの疫学

  服部 健史, 今野 哲  成人病と生活習慣病  43-  (10)  1175  -1180  2013/10  

  罹患率は少なくとも1.01(男性0.73、女性1.28)で女性の発症割合が多い。男性の発症年齢ピークは女性よりも若く、女性では2峰性の年齢分布を認める。各都道府県の罹患率にばらつきはあるが、地理的・地域的集積性は明らかではない。眼、皮膚、神経、筋肉病変は女性に多く、びまん性肺野病変は男性に多く認められる。検査所見異常はデータ欠損や交絡因子の影響があり、慎重な解釈が必要である。肺病変の臨床経過は、年齢や自覚症状、肺外病変の存在の関与が示唆されているが、診断時に重症度や遷延性を予測する因子は不明のままである。欧米のサルコイドーシス患者の喫煙率は低く、発症に対する喫煙の抑制的な影響が示唆されているが、日本人サルコイドーシス患者の喫煙率は必ずしも低くはなく、喫煙の抑制的な影響は日本人では必ずしもあてはまらないかもしれない。(著者抄録)
• 【疾患感受性遺伝子解析による呼吸器疾患の病態解析】慢性炎症性呼吸器疾患における遺伝子多型研究の現状とその意義

  今野 哲  呼吸と循環  61-  (10)  897  -901  2013/10
• 【サルコイドーシス診断と治療の進歩】本邦サルコイドーシスの疫学研究

  服部 健史, 今野 哲  呼吸器内科  24-  (3)  193  -198  2013/09
• 間質性肺炎合併肺癌に対する化学療法施行状況の検討(HOT 1001)

  小島 哲弥, 朝比奈 肇, 藤田 結花, 高村 圭, 大泉 聡史, 原田 敏之, 河井 康孝, 木下 一郎, 佐々木 高明, 伊佐田 朗, 今野 哲, 秋田 弘俊, 磯部 宏, 西村 正治  日本呼吸器学会誌  2-  (増刊)  294  -294  2013/03  [Not refereed][Not invited]
  
• 動物実験従事者の動物アレルギー

  吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 森松 正美, 今野 哲, 有川 二郎  CAMPUS HEALTH  50-  (1)  316  -316  2013/03  [Not refereed][Not invited]
  
• 動物実験従事者の動物アレルギー

  吉村 彩, 武藏 学, 金子 壮朗, 大西 俊介, 折戸 智恵子, 川原 由佳子, 森松 正美, 今野 哲, 有川 二郎  CAMPUS HEALTH  49-  (4)  89  -89  2012/09  [Not refereed][Not invited]
  
• 北海道大学新入生における気管支喘息の有病率とその危険因子

  木村 孔一, 今野 哲, 伊佐田 朗, 前田 由起子, 武藏 学, 西村 正治  日本呼吸器学会誌  1-  (増刊)  156  -156  2012/03  [Not refereed][Not invited]
  
• 喘息患者における吸入抗原特異的IgE抗体検索について

  飯島 弘晃, 増子 裕典, 金子 美子, 坂本 透, 内藤 隆志, 広田 朝光, 玉利 真由美, 今野 哲, 西村 正治, 檜澤 伸之  日本呼吸器学会誌  1-  (増刊)  187  -187  2012/03  [Not refereed][Not invited]
  
• Bedside Teaching 気管支喘息におけるβ2刺激薬と抗コリン薬

  今野 哲  呼吸と循環  60-  (3)  309  -314  2012/03
• 北大生の気管支喘息、アレルギー性鼻炎有病率とその危険因子

  木村 孔一, 今野 哲, 伊佐田 朗, 前田 由起子, 西村 正治, 武藏 学  北海道医学雑誌  86-  (6)  296  -296  2011/11  [Not refereed][Not invited]
  
• 【気道リモデリングと血管リモデリングの比較】共通分子、遺伝子多型の観点から

  今野 哲  アレルギーの臨床  31-  (7)  592  -596  2011/07  

  心血管リモデリングと気道リモデリングは共通の病態を有し、多くの分子及びその関連pathwayと両病態との関与が報告されている。機能的意義をもつ遺伝子多型と両病態との関連を示す報告も数多く存在し、病態理解の一助となる。更に、心血管系疾患と気管支喘息の合併を示す疫学結果も報告されている。このように、複数の視点より、両病態の共通性が明らかにされつつあり、組織修復を根底とする両病態の相補的な理解は、病態解明、新規治療ターゲットの探索において重要である。(著者抄録)
• インターネット調査による本邦の喘息のecological study 有病率の地域差とその規定因子

  福冨 友馬, 谷口 正実, 今野 哲, 西村 正治, 大矢 幸弘, 吉田 幸一, 岡田 千春, 高橋 清, 中村 裕之, 秋山 一男, 赤澤 晃  日本呼吸器学会雑誌  49-  (増刊)  313  -313  2011/03  [Not refereed][Not invited]
  
• 血清総IgE値、吸入抗原特異的IgE抗体(MAST)を用いたクラスタ解析について 茨城県と北海道上士幌町との比較

  飯島 弘晃, 増子 裕典, 金子 美子, 坂本 透, 内藤 隆志, 広田 朝光, 玉利 真由美, 今野 哲, 西村 正治, 檜澤 伸之  日本呼吸器学会雑誌  49-  (増刊)  180  -180  2011/03  [Not refereed][Not invited]
  
• 稀な肺疾患 重複大動脈弓

  吉田 貴之, 今野 哲, 西村 正治  呼吸  30-  (1)  53  -56  2011/01  

  重複大動脈弓は先天性心血管奇形である血管輪の一形態であり、比較的稀な疾患である。本症は主に乳幼児期に発症し、左右大動脈弓による気管・食道の絞扼を反映して、呼吸器症状として喘鳴や呼吸困難、消化器症状として嚥下困難などを呈する。一方で軽症例では成人になってから無症状で発見されたり、運動誘発喘息と似た症状を呈することもある。本症の病態や治療などについて自験例を交えて報告する。(著者抄録)
• 【喘息とCOPDをめぐって 類似点と相違点】治療 気管支拡張薬の効果

  今野 哲, 西村 正治  アレルギー・免疫  17-  (12)  2026  -2033  2010/11  

  β2刺激薬、抗コリン薬に代表される気管支拡張薬は、気管支喘息、COPDなどの気流閉塞を来す慢性呼吸器疾患の重要な治療薬の1つであることは言うまでもない。気管支喘息においては、以前よりβ2刺激薬の安全性に関する問題が議論されているが、長時間作用性β2刺激薬(LABA)に関しては、いまだに結論には至っていない。一方、COPDにおいては、気管支拡張薬がCOPDの自然史をも変える可能性についての議論が展開されており、近年数多くの臨床研究の結果が報告されている。両疾患における気管支拡張薬の位置づけ、並びにその効果、安全性に対する正しい理解が重要である。(著者抄録)
• 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  2010/05  [Not refereed][Not invited]
   

  【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.(著者抄録)
• 本邦の成人喘息有病率とその危険因子 日本語版ECRHS調査票によるNationwide cross-sectional population-based study

  福冨 友馬, 谷口 正実, 中村 裕之, 小林 章雄, 今野 哲, 西村 正治, 河岸 由紀男, 岡田 千春, 谷本 安, 高橋 清, 烏帽子田 彰, 小田嶋 博, 中川 武正, 赤澤 晃, 秋山 一男, 厚生労働科学研究斑, 気管支喘息の有病率, 罹患率およびQO, に関する全年齢階級別全国調査に関する研究  日本呼吸器学会雑誌  48-  (増刊)  152  -152  2010/03  [Not refereed][Not invited]
  
• 喘息として加療されフローボリューム曲線が発見の契機となった成人重複大動脈弓の1例

  吉田 貴之, 今野 哲, 高橋 歩, 南須原 康行, 別役 智子, 西村 正治  日本呼吸器学会雑誌  48-  (3)  229  -234  2010/03  

  症例は15歳男性。運動時の喘鳴と呼吸困難を主訴に近医受診。運動誘発喘息、過換気症候群を疑われ、吸入ステロイド、吸入気管支拡張薬や抗不安薬の処方をうけるも明らかな改善を認めず、当科を受診した。喀痰検査や気道過敏性検査で明らかな気管支喘息の所見を認めず、呼吸機能検査のフローボリューム曲線で上気道閉塞パターンを認めた。胸部CTにて重複大動脈弓による気管狭窄の所見を認めた。大動脈弓離断術がおこなわれ、その後運動時の呼吸器症状は著明な改善を認めているが、術後1年後のフローボリューム曲線では上気道閉塞のパターンは残存している。本症例では血管走行異常の存在が見逃されたことが根治手術の遅延につながっており、上気道閉塞疾患の診断におけるフローボリューム曲線の有用性を強く示した1例であった。(著者抄録)
• 分娩後の肺野病変増悪に対して高用量ブデソニド吸入薬を用いたサルコイドーシスの1例

  伊佐田 朗, 今野 哲, 小池 隆夫, 西村 正治  日本サルコイドーシス/肉芽腫性疾患学会雑誌  29-  (1)  63  -67  2009/10  

  症例は,20歳時にサルコイドーシスと診断された女性.33歳時に第一子を出産.出産3ヵ月後より咳嗽,呼吸困難を認め,血清ACE活性の上昇,胸部X線写真にて肺野病変が出現したが,症状出現後約1年で自然軽快を認めた.34歳時に第二子を出産.出産3ヵ月後より,第一子出産後と同様の経過を認めたが,呼吸困難が強く,ブデソニド800μg/日の吸入が開始された.その後呼吸困難の改善を認め,約6ヵ月後には肺野病変の改善を認めた.41歳時に第三子を出産.出産2ヵ月後より呼吸困難,咳嗽の悪化を認め,ブデソニド1,600μg/日の吸入を開始した.その後,呼吸器症状の改善を認めた.分娩を契機にサルコドーシスが悪化することは知られているが,本症例では3度の分娩後いずれも肺野病変の悪化を認めた.本症例では,高用量のブデソニドの吸入が,呼吸器症状の改善に寄与したものと考えられた.(著者抄録)
• 【最近のCOPDと気管支喘息】COPDと気管支喘息の疫学

  今野 哲, 西村 正治  臨牀と研究  86-  (2)  145  -148  2009/02
• 結核との鑑別が問題となったサルコイドーシスの1例

  高橋 歩, 今野 哲, 服部 健史, 大野 重昭, 西村 正治  サルコイドーシス/肉芽腫性疾患  28-  (1)  69  -74  2008/10  

  症例は30歳男性.霧視を主訴に北海道大学病院眼科を受診,結核性ぶどう膜炎もしくはサルコイドーシス疑いと診断され,精査目的に当科紹介となった.胸部CTにて,縦隔,両側肺門リンパ節の軽度腫大を認めたが,血清ACE活性,γグロブリン値は正常範囲内であり,また,ツベルクリン反応,クオンティフェロンRTB-2G(QFT)は陽性であった.気管支肺胞洗浄検査では,リンパ球分画は13.6%と著増はなく,CD4/CD8は0.72と低値であった.コンベックス走査式超音波気管支鏡ガイド下生検(EBUS-TBNA)にて肉芽腫を認めたが,両疾患の鑑別には至らず,胸腔鏡下リンパ節生検を行い壊死を伴わない類上皮細胞肉芽腫を認めてサルコイドーシスと診断した.本症例はサルコイドーシスとして典型的でない種々の臨床検査所見を呈し,特に結核との鑑別が問題となった.当科で経験したサルコイドーシス患者の検査所見と共に,考察を加え報告する.(著者抄録)
• オステオポンチンとアレルギー

  黒川 真嗣, 今野 哲, Huang Shau-Ku, 足立 満  臨床免疫・アレルギー科  50-  (2)  204  -208  2008/08
• 重症持続型喘息患者におけるプロピオン酸フルチカゾン高用量からブデソニド高用量へ変更した際の臨床効果の検討

  伊佐田 朗, 今野 哲, 高橋 歩, 服部 健史, 前田 由紀子, 檜澤 伸之, 西村 正治  アレルギー・免疫  15-  (8)  1108  -1115  2008/07  

  北海道大学病院第一内科外来に通院している成人持続型気管支喘息患者で、プロピオン酸フルチカゾンのドライパウダー製剤(FP-DPI)800μg/日を8週間以上継続して投与したにもかかわらず、呼吸機能の改善が十分ではなかった患者を対象とし、ブデソニドのDPI製剤(BUD-DPI)1,600μg/日に変更し、臨床効果を検討した。効果の指標として、FEV1、対標準FEV1,V50,V25、喘息コントロールテスト(ACT)、安全性の評価として試験期間中の副作用発現を観察した。その結果、変更後16週まで評価のできた8症例では、V25を除く評価項目でFP-DPIの800μg/日投与時と比較し有意な改善が認められた。またBUD-DPI変更後に臨床上問題となるような有害事象の発現も認めなかった。FP-DPIの800μg/日投与にてコントロールが十分ではない気管支喘息患者に対しては、BUD-DPIの1,600μg/日投与に変更することで、呼吸機能および症状をより良好にコントロールできることが示唆された。(著者抄録)
• 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  2008/07  

  【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.(著者抄録)
• 【アレルギー疾患の遺伝】β刺激薬の薬理遺伝

  今野 哲, 西村 正治, 檜澤 伸之  アレルギー・免疫  15-  (7)  922  -927  2008/06  

  近年、吸入ステロイド(ICS)と共に喘息治療のコントローラーとして使用されている長時間作用性β2刺激薬(LABA)が、呼吸機能の悪化や喘息死の増加に関するとの報告がなされた。また、LABAを含むβ2刺激薬の臨床効果は、β2アドレナリン受容体遺伝子(ADRB2)の多型性の違いによるとの報告もある。薬剤反応性を規定する遺伝的要因を検討する際には、各人種による独自の検討が必要であり、よって、今後日本人における大規模な前向きの検討が必要であると考えられる。(著者抄録)
• 肺サルコイドーシスに対するコンベックス走査式超音波気管支鏡ガイド下生検と経気管支肺生検の有用性の検討

  水柿秀紀, 品川尚文, 今野哲, 伊藤健一郎, 竹内裕, 中野浩輔, 山田範幸, 朝比奈肇, 菊地英毅, 菊地順子, 大泉聡史, 本村文宏, 西村正治  気管支学  30-  (0)  S138  2008/05/20  [Not refereed][Not invited]
  
• 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  2008/05  

  【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,COPD 294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,COPD 5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,MAST26R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種類の抗原で判定することができた.上士幌町群ではシラカンバの抗体単独陽性例は5例で,これによりアトピー素因の頻度が2.3%増加した.【結語】抗原特異的IgE抗体の有無によってアトピー素因を定義した場合,検討するアレルゲンの数を増やしても,新たにアトピー素因ありと判定される人の数はそれに比例して増加せず,抗原特異的IgE抗体の測定によってアトピー素因を判定する場合,ほぼ10種類のアレルゲンを調べることで95%以上のアトピー素因を判定できると考えられた.(著者抄録)
• 喘息と遺伝学 網羅的遺伝子・蛋白質発現解析による、気管支喘息/アレルギー関連遺伝子・分子の探索

  今野 哲, 檜澤 伸之  International Review of Asthma  10-  (1)  42  -51  2008/02
• アレルギー疾患におけるオステオポンチンの関与

  今野 哲, 檜澤 伸之, 西村 正治, Huang Shua-Ku  臨床免疫・アレルギー科  48-  (6)  705  -710  2007/12
• 6.後縦隔脂肪肉腫による上部気管狭窄に対しT-tubeを挿入した1例(第23回 日本気管支学会北海道支部会)

  森岡 崇, 白井 真也, 今野 哲, 小西 純, 品川 尚文, 針生 寛之, 福元 伸一, 横内 浩, 白間 信行, 原田 敏之, 若林 修, 大泉 聡史, 小島 哲弥, 木下 一郎, 山崎 浩一, 西村 正治, 秋田 弘俊, 古田 康  気管支学 : 日本気管支研究会雑誌  24-  (4)  343  -343  2002/05/25  [Not refereed][Not invited]
  

Books etc

• ERS monograph

  Nizar NJ, Konno S (Joint workMechanisms underlying fixed airflow obstruction;exacerbations)
  2019
• Advances in medicine asthma

  Konno S (Joint workAsthma phenotype and endotype.)
  Springer Nature Singapore PteLtd. 2019

Association Memberships

• THE JAPAN SOCIETY FOR RESPIRATORY ENDOSCOPY   THE JAPAN LUNG CANCER SOCIETY   日本サルコイドーシス肉芽腫性疾患学会   JAPANESE SOCIETY FOR TUBERCULOSIS AND NONTUBERCULOUS MYCOBACTRIOSIS   THE JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES   JAPANESE SOCIETY OF ALLERGOLOGY   THE JAPANESE RESPIRATORY SOCIETY   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   American Thoracic Society   日本職業・環境アレルギー学会   日本循環器学会   日本肺高血圧・肺循環学会   

Research Projects

• ワクチン開発のための世界トップレベル研究開発拠点の形成事業

  国立研究開発法人日本医療研究開発機構：

  Date (from‐to) : 2022/10 -2027/09
• Deep phenotyping toward the precision medicine for chronic airway diseases

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2023/04 -2026/03 

  Author : 今野 哲, 村上 正晃, 鈴木 雅, 杉森 博行, 清水 薫子, 木村 孔一
• びまん性肺疾患に関する調査研究

  厚生労働科学研究費：

  Date (from‐to) : 2010/04 -2026/03
• 肺・気道特異的微小炎症関連因子、自己反応性T細胞の検出系およびニューロモデュレーション療法の開発

  国立研究開発法人日本医療研究開発機構：

  Date (from‐to) : 2022/04 -2025/03
• 環境省 水･大気環境局微小粒子状物質等疫学調査研究 肺機能発達への影響調査

  環境省：

  Date (from‐to) : 2011/04 -2024/03
• ストレスを介する疾病発症の分子メカニズムの解明とバイオマーカー検出技術創成

  日本医療研究開発機構 革新的先端研究開発支援事業：

  Date (from‐to) : 2023/10
• Potential role of club cell secretory protein (CC16) in development of obese asthma: findings from a birth cohort and animal studies

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2020/04 -2023/03 

  Author : Goudarzi Houman, 池田 敦子, 今野 哲

   

  1) Adult asthma cohort):BMI was significantly and monotonously associated with reduced circulating CC16 levels in adult asthmas patients. Also, CC16 was inversely associated with sputum eosinophils and blood periostin. 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 five years of follow-up (p for trend = 0.031). 2) Population 2 (birth cohort): Ongoing. 3) Animal study: The percentage of CC16-cells was reduced in the small airways of mice with obesity. In addition, serum CC16 levels were significantly lower in obese mice than in non-obese control mice. However, the serum levels of SP-A and SP-D, other products of club cells, did not vary between obese and non-obese control mice.
• アレルギー疾患の多様性、生活実態を把握するための疫学研究

  厚生労働行政推進調査事業費補助金 免疫・アレルギー疾患政策研究事業：

  Date (from‐to) : 2021/04 -2023/03
• 変異型新型コロナウイルスに対する診断・予防・治療法研究プラットフォームの開発

  国立研究開発法人日本医療研究開発機構：新興・再興感染症に対する革新的医薬品等開発推進研究事業

  Date (from‐to) : 2021/12 -2022/03
• 中等症のCOVID-19感染症と確定診断された患者を対象としたエリトラン(E5564)の多施設共同無作為化プラセボ対照二重盲検比較試験

  国立研究開発法人日本医療研究開発機構：医療技術実用化総合促進事業

  Date (from‐to) : 2021/04 -2022/03
• Assessment of morphology/function of cardiac and skeletal muscle in lung disease-associated pulmonary hypertension

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2018/04 -2021/03 

  Author : Tsujino Ichizo

   

  In lung disease-associated pulmonary hypertension (Lung-PH), right ventricular (RV) contractility was increased whereas RV-pulmonary arterial coupling was impaired. Alternatively, RV stiffness was increased, potentially causing RV diastolic dysfunction in these patients. The most common cause of death of Lung-PH patients was PH-related death (56%), followed by PH death (23%) and PH-unrelated death (21%). These results were different from those for pulmonary arterial hypertension (PAH) where PH itself was the most common cause of death (61%), and for group 4 PH where malignant disease at least partly contributed to the death by 60%. These findings were useful to further improve the management and outcome of patients with each PH type. Lastly, in the pathological evaluations of the autopsied lungs of interstitial lung disease (ILD), arteriopathy at the site of active fibrosis was more prominent in those with PH than those without it.
• Elucidation of similarities, differences, and overlap in obstructive pulmonary diseases by peripheral blood exosomal RNA analysis

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2017/04 -2021/03 

  Author : Suzuki Masaru

   

  Because of the difficulty in collecting high-quality peripheral blood exosomal RNA, we performed a comprehensive proteome analysis in peripheral blood to investigate the relationship between exosome-related proteins. Proteome analysis revealed that 365 plasma proteins were significantly different between COPD and severe asthma. Cluster analysis by using proteome profile data identified three clusters in COPD and four clusters in severe asthma. The protein groups involved in the clustering contained significantly more exosome markers. These results indicate that although there are differences in the plasma proteome profiles of COPD and severe asthma, exosomes are strongly associated with proteomic clustering in both diseases.
• Undertanding the heterogeity of chronic airway diseases and their potential treatment strategies based on phenoypes

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2020/03 

  Author : Masaharu Nishimura

   

  Hokkaido Severe Asthma Cohot Study: Adominal visceral and subcutaneous fat were assessed by computed tomography (CT) scan in 206 asthmatic subjects.We demonstraed that only abdominal visceral fat was associated with low AQLQ, higher gastroesophageal reflux disease (GERD) and depression scores. We have bee analyzed the factors associated with annual decline in FEV1 for 6 years follow-up and will present the data this year. PIRICA study:Now a total of 700 suvjects werte enrolled to this study. The final goal of the number of subjects will be 1150, and will be complerted by enf of this year.
• Comprehensive evaluation of emphysema, airways and blood volume in respiratory diseases

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2019/03 

  Author : Shimizu Kaoruko

   

  We revealed the different role of fractal dimension (D), which characterizes the size distribution of low attenuation clusters on CT and percent low attenuation volume (%LAV) as parameters regards long-term outcomes of chronic obstructive pulmonary disease (COPD), namely, decline in lung function, exacerbation, and survival.We also demonstrated the stronger correlations between transfer coefficients, %LAV and cross sectional area of small pulmonary vessels(CSA), compared with %DLco in chronic obstructive lung diseases such as bronchial asthma with/without smoking and COPD, which was published in Journal of applied physiology.We confirmed the values of pulmonary vasculature metrics on chest CT such as the ratio of the diameter of the pulmonary artery to the aorta (PA/Ao),CSA, and the diameter of the right inferior pulmonary vein.for the diagnosis and haemodynamic evaluation of pulmonary arterial hypertension (PAH).
• 環境化学物質の複合曝露による 喘息・アレルギー、免疫系へ及ぼす影響の解明

  環境研究総合推進費：

  Date (from‐to) : 2017/04 -2019/03
• 肥満が気管支喘息病態に及ぼす分子生物学的機序の解明

  文部科学省科学研究費補助金：基盤研究 (C)

  Date (from‐to) : 2017 -2019 

  Author : 今野 哲
• Effects of Aerobic vs. Anaerobic Culture on In-Vivo and In-Vivo Virulence of Streptococcus pneumoniae

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015/04 -2017/03 

  Author : Nagaoka Kentaro, KONNO SATOSHI, NISHIMURA MASAHARU

   

  In this study, we examined whether the culture condition of either aerobic or anaerobic might be influential to the virulence of Streptococcus pneumoniae, which is a facultative anaerobic bacterium. We here demonstrate that the virulence of S. pneumoniae is highly enhanced in vivo when pre-cultured under anaerobic condition compared with aerobic condition. This is the first report, which validated the difference of pathogenicity between aerobic and anaerobic condition. We consider that the results of our study is important for investigating the pathogenesis of facultative bacterium.
• Clinicopathological study on the pulmonary vasculopathy and right heart morphology/function in lung disease-associated pulmonary hypertension

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2014/04 -2017/03 

  Author : TSUJINO Ichizo

   

  We studied cases with lung disease-associated pulmonary hypertension and demonstrated remodeling of the pulmonary vasculature as well as the expression of target proteins of pulmonary vasodilators. The expression was also shown in myocardial tissue, suggesting favorable effects of pulmonary vasodilating treatment. In the clinical study, we showed significant improvement in the pulmonary vascular resistance and right heart morphology/function (published in the journal Pulmonary Circulation, 2017). We also notably shown elevations of blood insulin level, index of insulin resistance, and plasma concentration of BDNF, one of the myokines, in pulmonary hypertension patients. Lastly, in our study, clinical relevance of chest computed tomography-derived indices of pulmonary vascular system was examined and we found their usefulness in the diagnosis and hemodynamic evaluation of pulmonary hypertension.
• Understandin the pathogenesis of refratory airway diseases for establishing the personalize medicine

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2012/04 -2016/03 

  Author : Masaharu Nishimura

   

  A total of 206 astmatic subjefts (79 mild-to-moderate、127 severe) were enrolled in this study and several blood biomarkers were measured for all subjets. We found the blood periosrin, osteopntin, and CCL18 were signifiantly assoiated with blood/sputum eosinophils, IgE levels, exhaled nitric oxide fraction, and sinus sore in non-smoking subects. However, in smoking subjects, only periostin was assoiated with Th2-realted asthma phenotypes. In addition, only smoking subjects, these three markers were inversely associated with pulmonary functions. We reported these results in Ann Am Thorac Soc 2017. (in press)
• 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

  文部科学省科学研究費補助金：基盤研究（C）

  Date (from‐to) : 2014 -2016 

  Author : 今野 哲
• 気管支喘息、COPDの病態における組織因子(Tissue factor)、第7因子(F7)の関与

  文部科学省科学研究費補助金：基盤研究（C）

  Date (from‐to) : 2011 -2013 

  Author : 今野 哲
• Dehydroxymethylepoxyquinomicin(DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodeling in murine models of asthma

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2009 -2011 

  Author : NISHIMURA Masaharu, TODO Satoru, NASUHARA Yasuyuki, KONNO Satoshi

   

  DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in murine asthma model. It also inhibited parameters of airway remodeling including mucus production, peribronchial fibrosis and the expression ofα-smooth muscle actin. These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodeling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.
• Understanding the pathogenesis of severe airway diseases by large cohort studies

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2009 -2011 

  Author : NISHIMURA Masaharu, KONNO Satoshi, NASUHARA Yasuyuki, MAKITA Hironi

   

  The rate of annual change in post-bronchodilator FEV1 is highly variable over a period of 5 years among patients with COPD who receive appropriate therapy. Emphysema severity, which varies substantially even for the same spirometric stage, is independently associated with a rapid annual decline in FEV1. The presence of sustainers, who can maintain pulmonary function, warrants specific attention together with rapid decliners in clinical practice.
• 気道リモデリング、肺気腫形成におけるオステオポンチンの関与

  文部科学省科学研究費補助金：基盤研究（C）

  Date (from‐to) : 2008 -2010 

  Author : 今野 哲
• Common pathogenesis of asthma and COPD-Search for a novel classification based on molecular pathogenesis-

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2007 -2008 

  Author : HIZAWA Nobuyuki, NISHIMURA Masaharu, KONNO Satoshi

   

  肺はウイルス感染や喫煙、アレルゲン吸入などによって常に損傷と修復を繰り返している。本研究では肺においてこれらの外因に対する反応性を規定する複数の宿主因子が、気管支喘息とCOPDとの両者の病態に共通して関連していることを示した。将来的には、分子病態に基づいた慢性炎症性肺疾患の新たな分類、さらにはこれらの共通病態を標的とした新たな治療や予防の開発が期待される。
• 気管支喘息、アレルギー反応におけるオステオポンチンの意義

  文部科学省科学研究費補助金：若手研究（B）

  Date (from‐to) : 2006 -2007 

  Author : 今野 哲