2023年, 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
今野 哲

2019年, 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
今野 哲

2019年, 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
今野 哲

2018年, 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
今野 哲

2017年, 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年, 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年, 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
今野 哲

2010年, 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
今野 哲

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

2005年, 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
今野 哲

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

Impact of wheat sensitization on wheeze and T2 phenotypes in general population of children
Houman Goudarzi, Atsuko Ikeda, Yu Ait Bamai, Isao Yokota, Chihiro Miyashita, Wilfried Karmaus, Reiko Kishi, Satoshi Konno
Journal of Allergy and Clinical Immunology: Global, 3, 4, 2024年11月
研究論文（学術雑誌）, Background: The association between sensitization to specific aeroallergens and outcomes in patients with asthma is well researched; however, the association between childhood-onset wheeze/asthma and sensitization to various aeroallergens and food allergens in the general pediatric population remains poorly understood. Objective: We sought to investigate the association between sensitization to common aeroallergens and food allergens with wheeze and type 2 (T2) inflammation in the general pediatric population. Methods: Specific IgEs against 9 aeroallergens and 4 food allergens were measured in the prospective Hokkaido birth cohort of 428 school-age children (age ∼10 years). Wheeze and other allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Blood eosinophil count and fractional exhaled nitric oxide level were assessed as T2 biomarkers. The Isle of Wight birth cohort in the United Kingdom was used for replication analysis (n = 1032). Results: The prevalence of sensitization to at least 1 aeroallergen and food allergen was 70.5% and 22.3%, respectively. A significant association between wheeze and sensitization to aeroallergens such as ragweed, Japanese cedar, mugwort, and pet dander was found. However, the association between wheeze and wheat sensitization was highly significant (Hokkaido birth cohort: odds ratio, 4.67; 95% CI, 1.98-11.01; Isle of Wight birth cohort, odds ratio, 4.01; 95% CI, 1.78-9.07). Sensitization to most aeroallergens, though not any food allergen, was associated with the T2-high phenotype. Conclusions: Sensitization to wheat may be an important risk factor for wheeze/asthma development, especially the pathogenesis of T2-non/low asthma, independent of aeroallergens, in the general pediatric population.

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

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

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年04月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年03月11日, ［国際誌］
英語

Evaluation of the Loopamp SARS-CoV-2 detection kit using saliva for the detection of SARS-CoV-2 Omicron
Oguri Satoshi, Iwasaki Sumio, Inao Tasuku, Yokota Isao, Murakami Kaoru, Tanaka Kumiko, Hayasaka Kasumi, Fujisawa Shinichi, Watanabe Chiaki, Konno Satoshi, Murakami Masaaki, Teshima Takanori
Laboratory Medicine International, 3, 3, 70, 73, Japanese Society of Laboratory Medicine, 2024年
英語, Aims: The Omicron variant of SARS-CoV-2 spreads more rapidly than ancestral lineages. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) provides results more rapidly than reverse-transcription
polymerase chain reaction (RT-PCR). However, the reliability in detecting omicrons variant is still unclear due
to possible differences in target sequences.

Methods: Fifty-one saliva specimens, which were positive for the Omicron variant SARS-CoV-2 by real-time RT-PCR and sequencing of the S region, were subjects for this study. The RT-LAMP assay was performed using
the Loopamp SARS-CoV-2 detection kit with (n=51) or without it (n=50).

Results: The RT-LAMP assay following RNA extraction from saliva specimens had a sensitivity of 100% (95%CI: 93.0–100.0%) with 0.969 Kendall’s coefficient of concordance between LAMP threshold time and PCR cycle
threshold value. Forty-five of fifty (90.0%, 95%CI: 78.2–96.7%) specimens positive were also positive by RTLAMP
without RNA extraction.

Conclusions: The Omicron variant was effectively detected in saliva by RT-LAMP using saliva specimens and RNA extraction could improve its efficacy.

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年01月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年12月05日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Notably, few studies have evaluated the recent changes in the prevalence of allergic diseases in young adults. Studies examining the risk of allergy in two populations with similar social backgrounds, other than the region in which they live, are rare. METHODS: First-year students from Hokkaido University were enrolled in this study between 2011 and 2019. A questionnaire survey was conducted to determine the annual prevalence of current wheeze, seasonal allergic rhinitis (SAR), and perennial allergic rhinitis (PAR) in nonsmoking young adults. Trends in the presence of these disease conditions were evaluated based on their hometowns (Hokkaido and outside Hokkaido separately) due to the low prevalence of cedar pollen allergies in Hokkaido. The association between these disease conditions and body mass index (BMI) was also assessed. RESULTS: The prevalence of current wheeze and PAR food allergies did not change in both regions. SAR showed a significantly increasing trend; however, the prevalence of SAR was higher among those whose place of origin was not Hokkaido. Current wheeze was positively associated with obesity (p < 0.05), whereas the high prevalence of SAR was not associated with body weight. In contrast, a lean body type was significantly associated with a higher prevalence of PAR (p < 0.05). DISCUSSION/CONCLUSION: The prevalence of current wheeze was stable and that of PAR has decreased over the past 9 years. However, the prevalence of SAR in Hokkaido has been increasing in Japanese young adults. A differential association between current wheeze and BMI was observed when comparing PAR and SAR.

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

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年11月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年11月01日, ［国内誌］
英語, 研究論文（学術雑誌）

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年11月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月24日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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年08月15日, ［国際誌］
英語, 研究論文（学術雑誌）, 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年07月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年06月30日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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年04月14日, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

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, Springer Science and Business Media LLC, 2023年03月30日
研究論文（学術雑誌）

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年03月02日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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, 45, 2, 89, 97, (一社)日本呼吸器内視鏡学会, 2023年03月
日本語, 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, 45, 2, 89, 97, (NPO)日本呼吸器内視鏡学会, 2023年03月
日本語

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年02月19日, ［国際誌］
英語, 研究論文（学術雑誌）, 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年01月31日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The factors associated with longitudinal changes in diffusing capacity remain unclear among patients with COPD. Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are major emphysema subtypes that may have distinct clinical-physiological impacts in these patients. RESEARCH QUESTION: Are CLE and PSE differently associated with longitudinal changes in diffusing capacity and mortality in patients with COPD? STUDY DESIGN AND METHODS: This pooled analysis included 399 patients with COPD from two prospective observational COPD cohorts. CLE and PSE were visually assessed on CT scan according to the Fleischner Society statement. The diffusing capacity and transfer coefficient of the lung for carbon monoxide (Dlco and KCO) and FEV1 were evaluated at least annually over a 5-year period. Mortality was recorded over 10 years. Longitudinal changes in FEV1, Dlco, and KCO and mortality were compared between mild or less severe and moderate or more severe CLE and between present and absent PSE in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. RESULTS: The Dlco and KCO decline was weakly associated with FEV1 and greater in GOLD stage 3 or above than in GOLD stages 1 and 2. Furthermore, moderate or more severe CLE, but not present PSE, was associated with steeper declines in Dlco for GOLD stages 1 and 3 or higher and KCO for all GOLD stages independent of age, sex, height, and smoking history. The moderate or more severe CLE, but not present PSE, was associated with additional FEV1 decline and higher 10-year mortality among patients with GOLD stage 3 or higher . INTERPRETATION: A CT scan finding of moderate or more severe CLE, but not PSE, was associated with a subsequent accelerated impairment in diffusing capacity and higher long-term mortality in severe GOLD stage among patients with COPD.

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

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年11月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年11月21日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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年11月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年11月, ［国際誌］
英語, 研究論文（学術雑誌）, 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, Elsevier BV, 2022年11月
研究論文（学術雑誌）

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, Wiley, 2022年10月
研究論文（学術雑誌）

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

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年09月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月02日, ［国際誌］
英語, 研究論文（学術雑誌）, 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年07月22日, ［国内誌］
英語, 研究論文（学術雑誌）, 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年06月29日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

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

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

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, Frontiers Media SA, 2022年05月05日
研究論文（学術雑誌）, 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年05月, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 111, 5, 984, 989, (一社)日本内科学会, 2022年05月
日本語

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, Elsevier BV, 2022年05月, ［査読有り］
英語, 研究論文（学術雑誌）

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年04月27日, ［国際誌］
英語, 研究論文（学術雑誌）, 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年04月04日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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年04月, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 62, 2, 107, 114, (NPO)日本肺癌学会, 2022年04月
日本語, 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年04月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年04月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年03月05日, ［国内誌］
英語, 研究論文（学術雑誌）, 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, Elsevier BV, 2022年03月
研究論文（学術雑誌）

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

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年, ［国際誌］
英語, 研究論文（学術雑誌）, 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年12月, ［国際誌］
英語, 研究論文（学術雑誌）, 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年11月22日, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

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

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年09月12日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月23日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月06日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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年07月31日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年07月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年07月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年06月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: In chronic obstructive pulmonary disease (COPD), chest computed tomography (CT) provides clinically important cardiovascular findings, which include diameter of pulmonary artery (PA), its ratio to the diameter of the aorta (PA:A ratio), and coronary artery calcium score (CACS). The clinical importance of these cardiovascular findings has not been fully assessed in Japan, where cardiovascular morbidity and/or mortality is reported to be much less compared with Western counterparts. METHODS: PA diameter and PA:A ratio were measured in 172 and 130 patients with COPD who enrolled in the Hokkaido COPD cohort study and the Kyoto University cohort, respectively. CACS was measured in 131 and 128 patients in each cohort. RESULTS: While the highest quartile group in PA diameter was associated with higher all-cause mortality compared to the lowest quartile group in both cohorts, individual assessments of PA:A ratio and CACS were not associated with the long-term clinical outcomes. When PA diameter and CACS were combined, patients with PA enlargement (diameter >29.5 mm) and/or coronary calcification (score >440.8) were associated with higher all-cause mortality in both cohorts. CONCLUSION: Combined assessment of PA enlargement and CACS was associated with poor prognosis, which provides a clinical advantage in management of patients with COPD even in geographical regions with lower risk of cardiovascular diseases.

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年06月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年05月21日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Recently, deep learning applications in medical imaging have been widely applied. However, whether it is sufficient to simply input the entire image or whether it is necessary to preprocess the setting of the supervised image has not been sufficiently studied. This study aimed to create a classifier trained with and without preprocessing for the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification using CT images and to evaluate the classification accuracy of the GOLD classification by confusion matrix. According to former GOLD 0, GOLD 1, GOLD 2, and GOLD 3 or 4, eighty patients were divided into four groups (n = 20). The classification models were created by the transfer learning of the ResNet50 network architecture. The created models were evaluated by confusion matrix and AUC. Moreover, the rearranged confusion matrix for former stages 0 and ≥1 was evaluated by the same procedure. The AUCs of original and threshold images for the four-class analysis were 0.61 ± 0.13 and 0.64 ± 0.10, respectively, and the AUCs for the two classifications of former GOLD 0 and GOLD ≥ 1 were 0.64 ± 0.06 and 0.68 ± 0.12, respectively. In the two-class classification by threshold image, recall and precision were over 0.8 in GOLD ≥ 1, and in the McNemar-Bowker test, there was some symmetry. The results suggest that the preprocessed threshold image can be possibly used as a screening tool for GOLD classification without pulmonary function tests, rather than inputting the normal image into the convolutional neural network (CNN) for CT image learning.

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

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, (一社)日本呼吸器学会, 2021年05月
日本語, 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年04月30日, ［査読有り］, ［国際誌］
英語

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年04月03日, ［査読有り］, ［最終著者］, ［国際誌］
英語

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

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年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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年03月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年03月, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts. Patients and Methods: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group (<-0.17 kg/year), no change group (-0.17 to ≤0.20 kg/year), and weight gain group (>0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247). Results: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort. Conclusion: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.

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

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

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

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年, ［査読有り］, ［最終著者］, ［国際誌］
英語, 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年12月24日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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年11月18日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年09月17日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We recently reported that severe asthma patients with frequent exacerbations showed high blood eosinophil counts (Eo) and fractions of exhaled nitric oxide (FeNO) compared with non-exacerbators. However, we did not determine exact cutoff values related to exacerbation. The aim of this study was to determine the cutoff values of Eo and FeNO that could be related to the exacerbation of severe asthma. We also aimed to confirm the clinical utility of Th2 markers related to exacerbation. METHODS: This study included 105 severe asthma patients who completed a three-year follow-up of a severe asthma cohort study, including smokers. Three Th2 markers were selected, viz., Eo, FeNO, and positive atopic status. Regarding Eo and FeNO, we determined the cutoff values for the definition of "positive" Th2 features using receiver operating characteristic curve analyses, based on the comparisons between frequent exacerbators and other patients. RESULTS: The cutoff values for positive Th2 features were Eo ≥ 250 cells/μL and FeNO ≥31 ppb. Sixteen patients (15.2%) had no Th2 features, 40 (38.1%) had one, 25 (23.8%) had two, and 24 (22.9%) had three. A high number of positive Th2 features was significantly associated with exacerbation frequencies over three years (p < 0.05). Similarly, compared to patients with one or no Th2 features, those with three Th2 features had a significantly higher probability of having more than one exacerbation (p < 0.05). CONCLUSIONS: The cutoff values determined in the current analysis were good predictors of future exacerbations in severe asthma patients.

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年09月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 42, 5, 441, 447, (NPO)日本呼吸器内視鏡学会, 2020年09月
日本語, 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年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年08月22日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 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.

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年08月, ［査読有り］, ［国際誌］
英語

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, SAGE PUBLICATIONS INC, 2020年07月
英語, 研究論文（学術雑誌）, 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, 9, 4, 233, 238, (一社)日本呼吸器学会, 2020年07月
日本語, 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, 42, 4, 343, 348, (NPO)日本呼吸器内視鏡学会, 2020年07月
日本語, 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年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年06月21日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語

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年05月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年05月, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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.

Honeycomb lung-like structures resulting from clustering of traction bronchiectasis distally in sarcoidosis
Michiru Sawahata, Noriharu Shijubo, Takeshi Johkoh, Koichi Hagiwara, Satoshi Konno, Tetsuo Yamaguchi
Respirology Case Reports, 8, 3, Wiley-Blackwell Publishing Ltd, 2020年04月01日
英語, 研究論文（学術雑誌）, Gene expression profiles of patients with progressive sarcoidosis, most of whom had evidence of fibrosis on imaging, have been reported to be similar to those of patients with inflammatory hypersensitivity pneumonitis, while expression profiles in progressive sarcoidosis did not resemble those of idiopathic pulmonary fibrosis. However, it is not known whether specific parenchymal features discerned on computed tomography (CT) imaging can predict development of fibrosis in pulmonary fibrosis. We herein describe a rare case of pulmonary sarcoidosis with honeycomb lung-like structures developing as a result of concentration of traction bronchiectasis distally, predominantly in both lower lung fields, which developed through shrinkage of consolidations comprising a “central–peripheral band” detected in a woman in her 60s, with non-caseating epithelioid granuloma. To our knowledge, this is the first case demonstrating the distinctive morphology and developmental process of honeycomb lung-like structures in fibrotic pulmonary sarcoidosis.

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年04月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

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年03月, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2020年02月15日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月, ［査読有り］, ［国際誌］
英語, BACKGROUND: Fractal dimension (D) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. METHODS: Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). RESULTS: In the Hokkaido COPD cohort, higher %LAV, but not D, was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D, but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. CONCLUSION: These well-established cohorts clarify the different prognostic roles of %LAV and D, whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

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, W.B. Saunders Ltd, 2020年01月01日
英語, 研究論文（学術雑誌）, 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.

Computed tomography images of fibrotic pulmonary sarcoidosis leading to chronic respiratory failure
Michiru Sawahata, Takeshi Johkoh, Takeshi Kawanobe, Chiyoko Kono, Yosikazu Nakamura, Masashi Bando, Koichi Hagiwara, Tamiko Takemura, Fumikazu Sakai, Noriharu Shijubo, Satoshi Konno, Tetsuo Yamaguchi
Journal of Clinical Medicine, 9, 1, MDPI, 2020年01月01日
英語, 研究論文（学術雑誌）, Background: There is currently no consensus on the morphology of severe fibrotic pulmonary sarcoidosis, and we examined computed tomography (CT) findings and progression. Methods: We analyzed findings in 10 consecutive patients (three men, seven women) with pulmonary sarcoidosis requiring oxygen therapy for chronic respiratory failure, who were extracted from >
2500 sarcoidosis patients (three hospitals, 2000–2018). Patients with comorbidities causing chronic respiratory failure were excluded. Results: Predominant findings were consolidations along the bronchovascular bundles comprising ‘central-peripheral band’, traction bronchiectasis, peripheral cysts/bullae, and upper lobe shrinkage. Traction bronchiectasis arose from opacities comprising ‘central-peripheral band’. Clustering of traction bronchiectasis at the distal side formed honeycomb lung-like structures in three patients. Upper lobe shrinkage progressed in seven patients together with progression of consolidations, ‘central-peripheral band’, traction bronchiectasis clusters, and cysts, while patients without shrinkage included two patients with severe multiple cysts without traction bronchiectasis. Restrictive ventilatory impairment developed in most patients. Pulmonary hypertension (PH) was detected radiologically in five patients, and chronic progressive pulmonary aspergillosis (CPPA) in four patients. Conclusions: During progression, consolidations comprising ‘central-peripheral band’ progressed together with traction bronchiectasis clusters and peripheral cysts, resulting in upper lobe shrinkage. This may lead to respiratory failure with possible complications such as PH and CPPA.

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

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

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年, ［査読有り］, ［最終著者］, ［国際誌］
英語, 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年, ［査読有り］, ［最終著者］, ［国際誌］
英語, 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年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. PATIENTS AND METHODS: The enrolled patients had treatment-naïve, advanced NSCLC with ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4-6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7-84.8) vs. 47.6% (95% CI: 28.3-67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0-10.2) vs. 4.1 months (95% CI: 3.3-5.4) (HR, 0.60 [95% CI, 0.30-1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8-not reached) vs. 11.9 months (95% CI: 7.3-17.4) (HR, 0.56 [95% CI, 0.24-1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. CONCLUSION: Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.

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, 2019年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年10月, ［査読有り］, ［最終著者］, ［国際誌］
英語, 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, 2019年09月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年09月, ［査読有り］, ［国際誌］
英語, 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, 2019年09月, ［査読有り］, ［国際共著］
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, 2019年04月19日, ［査読有り］, ［国際誌］
英語, 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年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, Microbiology Society, 2019年03月01日
研究論文（学術雑誌）, 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年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Long-term decline in lung function is generally considered to be progressive in individuals with established chronic obstructive pulmonary disease (COPD), despite the presence of intersubject variation. We hypothesized that the annualized rate of decline in forced expiratory volume in 1 second (FEV1) would not be constant among different time periods in the natural history of established COPD. We compared the annual change rates in FEV1 during the first 5 years and the last 5 years, estimated separately using a linear mixed-effects model in 10-year survivors (n = 110). The subjects were classified into three FEV1 decline groups, based on the 25th and 75th percentile values in each time period. The rates of FEV1 changes, calculated from the first 5 years and the last 5 years, did not correlate with each other among 10-year survivors; the subjects of each FEV1 decline group during the first 5 years did not consistently remain in the same FEV1 decline group during the last 5 years. Smoking status and exacerbation frequency were not associated with decline in FEV1. In conclusion, the disease activity, which is often expressed as annualized change in FEV1, might be changeable either way over years in patients with established COPD.

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年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［査読有り］, ［国際誌］
英語, Purpose: Alpha-1 antitrypsin deficiency is associated with the development of chronic obstructive pulmonary disease (COPD), whereas increased levels of serum alpha-1antitrypsin occur in response to inflammation. The effects of alpha-1 antitrypsin levels on the clinical course of COPD had been unclear. We investigated the association of serum alpha-1 antitrypsin levels with the clinical course of COPD patients based on data from a 10-year prospective cohort study. Patients and methods: We analyzed 278 COPD patients who participated in the Hokkaido COPD cohort study and who did not meet the criteria for alpha-1 antitrypsin deficiency. We divided the subjects into 3 groups according to quartiles of serum alpha-1 antitrypsin levels at baseline: lower group (<116 mg/dL, n = 66); middle group (116 to ≤141 mg/dL, n = 145); and higher group (>141 mg/dL, n = 67). The annual change in forced expiratory volume in 1 s (FEV1) and events of COPD exacerbation were monitored during the first 5 years, and mortality was followed-up during the entire 10 years. Results: At baseline, the higher group showed lower body mass index; higher computed tomography emphysema score; lower diffusing capacity; higher levels of acute-phase proteins; and higher blood neutrophil counts. Longitudinal analyses revealed that in the higher group, the annual decline in FEV1 was rapid and the 10-year mortality was higher, but there was no association between serum alpha-1 antitrypsin levels and time to first exacerbation. Conclusion: COPD subjects with higher serum alpha-1 antitrypsin levels were associated with a worse systemic inflammation status and higher 10-year mortality.

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, 199, AMER THORACIC SOC, 2019年, ［査読有り］
英語, 研究論文（学術雑誌）

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年, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, Nature Publishing Group, 2018年12月01日, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年11月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Previous studies have shown the association of anthropometric measures with poor asthma symptoms, especially among women. However, the potential influence of visceral adiposity on asthma symptoms has not been investigated well. OBJECTIVE: In this study, we have evaluated whether visceral adiposity is related to poor adult asthma symptoms independent of anthropometric measures and sex. If this relationship presented, we investigated whether it is explained by influence on pulmonary functions and/or obesity-related comorbidities. METHODS: We analyzed data from 206 subjects with asthma from Japan. In addition to anthropometric measures (body mass index and waist circumference), abdominal visceral and subcutaneous fat were assessed by computed tomography scan. Quality of life was assessed using the Japanese version of the Asthma Quality of Life Questionnaire. RESULTS: All obesity indices had inverse association with reduced asthma quality of life among females. However, only the visceral fat area showed a statistical inverse association with Asthma Quality of Life Questionnaire in males. Only abdominal visceral fat was associated with higher gastroesophageal reflux disease and depression scores. Although all obesity indices showed inverse association with functional residual capacity, only visceral fat area had a significant inverse association with FEV1 % predicted, independent of other obesity indices. CONCLUSIONS: Regardless of sex, abdominal visceral fat was associated with reduced asthma quality of life independent of other obesity indices, and this may be explained by the impact of abdominal visceral fat on reduced FEV1 % predicted and higher risk for gastroesophageal reflux disease and depression. Therefore, visceral adiposity may have more clinical influence than any other obesity indices on asthma symptoms.

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年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, Elsevier B.V., 2018年10月15日, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Background: Childhood allergies are dynamic and associated with environmental factors. The influence of prenatal maternal smoking and obesity on childhood allergies and their comorbidities remains unclear, especially in prospective cohorts with serial longitudinal observations. Objective: We examined time trends in the prevalence and comorbidity of childhood allergies, including wheeze, eczema, and rhinoconjunctivitis, using a large-scale, population-based birth cohort in Japan, and assessed the effects of prenatal maternal smoking and BMI on the risk of childhood allergies. Methods: Parents completed the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires about symptoms of allergies and their risk factors at age 1, 2, 4, and 7 years. Complete data from all pre- and postnatal questionnaires at age 1, 2, 4, and 7 were available for 3296 mother–child pairs. Results: We observed significant overlap of childhood allergies at 1, 2, 4, and 7 years. Maternal serum cotinine during pregnancy was associated with increased risk of wheezing in the children at age 1, 2, and 4 but disappeared at age 7. In contrast, maternal cotinine levels were inversely associated with the prevalence of eczema in children at age 7. We additionally observed that maternal pre-pregnancy BMI, not children's BMI, had a positive association with wheeze and an inverse association with eczema in 7-year-old children, respectively. We did not find any association of examined maternal factors and rhinoconjunctivitis. Conclusions: We demonstrated contrasting association of prenatal maternal smoking and high BMI with postnatal wheeze and eczema. For precise assessment of allergy-associated risk factors, we need to contrast risk factors for different allergic diseases since focusing solely on one allergic disease may result in misleading information on the role of different risk factors.

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, 2018年10月, ［査読有り］, ［筆頭著者］, ［国内誌］
英語, 研究論文（学術雑誌）, 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, 2018年07月, ［査読有り］, ［筆頭著者］

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

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

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, Public Library of Science, 2018年02月01日, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, Future Medicine Ltd., 2018年02月01日, ［査読有り］
英語, 研究論文（学術雑誌）, 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.
Konno S, Taniguchi N, Makita H, Nakamaru Y, Shimizu K, Shijubo N, Fuke S, Takeyabu K, Oguri M, Kimura H, Maeda Y, Suzuki M, Nagai K, Ito YM, Wenzel SE, Nishimura M, HiCARAT Investigators ‡, HiCARAT Investigators
Annals of the American Thoracic Society, 15, 1, 33, 41, American Thoracic Society, 2018年01月01日, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Rationale: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. Objectives: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. Methods: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics.Clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Results: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. Conclusions: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

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

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, 2018年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2018年, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Background: Many studies have attempted to clarify the factors associated with serum periostin levels in asthmatic patients. However, these results were based on studies of subjects mainly characterized by high eosinophil counts, which may present as an obstacle for clarification in the identification of other factors associated with serum periostin levels. The aim of this study was to determine the factors associated with serum periostin levels in healthy subjects. We also assessed some factors in asthmatic subjects to confirm their extrapolation for management of asthma. Methods: Serum periostin levels were measured in 230 healthy subjects. Clinical factors of interest included body mass index (BMI) and allergic rhinitis (AR). Additionally, we confirmed whether these factors were associated with serum periostin in 206 asthmatic subjects. We further evaluated several obesity-related parameters, such as abdominal fat distribution and adipocytokine levels. Results: Smoking status, blood eosinophil count, total immunoglobulin E, and the presence of AR were associated with serum periostin in healthy subjects. There was a negative association between BMI and serum periostin in both healthy and asthmatic subjects, while there was a tendency of a positive association with AR in asthmatic subjects. There were no differential associations observed for subcutaneous and abdominal fat in relation to serum periostin in asthmatic subjects. Serum periostin was significantly associated with serum levels of adiponectin, but not with leptin. Conclusions: Our results provided clarity as to the factors associated with serum periostin levels, which could be helpful in the interpretation of serum periostin levels in clinical practice.

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, AMER ASSOC IMMUNOLOGISTS, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, WILEY, 2017年11月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, JAPANESE SOCIETY ALLERGOLOGY, 2017年10月, ［査読有り］
英語, 研究論文（学術雑誌）, 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 β2-agonist and anticholinergic agent in COPD: Their different associations with exacerbation.
Konno S, Makita H, Suzuki M, Shimizu K, Kimura H, Kimura H, Nishimura M, Hokkaido COPD Cohort, Study Investigators
Respiratory medicine, 127, 14, 20, W B SAUNDERS CO LTD, 2017年06月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Background: Acute bronchodilator response (BDR) is a potential phenotypic characteristic of COPD. However, the clinical factors associated with BDR in patients with COPD remain unclear, particularly for BDR to anticholinergic agents.
Objectives: We aimed to clarify the clinical factors associated with BDR to beta 2-agonist and/or anticholinergic agent, considering time-associated variations of BDR. We also evaluated the association between BDR and clinical course of COPD.
Methods: We analyzed 152 subjects who participated in the Hokkaido COPD cohort study. We repeatedly measured BDR to salbutamol (400 mu g) or oxitropium (400 mu g) three times for each every 6 months alternately over 3 years. Reversibility was defined by >= 12% and >= 200 mL increase in FEV1 over baseline. All subjects were classified into three groups based on the BDR stability; consistently reversible, consistently irreversible, and inconsistent. We compared baseline clinical characteristics and the 5-year clinical course of COPD among the three groups.
Results: For either agent, the mean blood eosinophil count was significantly higher in those with consistently reversible than those with consistently irreversible (p < 0.05). The subjects with consistently reversible to oxitropium (p < 0.05), but not to salbutamol (p = 0.56), showed increased risk of exacerbation compared with the other two groups.
Conclusion: We identified the distinct clinical characteristics of COPD associated with acute BDR status. Increased cholinergic airway tone, which is reflected in the higher BDR only to anticholinergic agent, but not to beta 2-agonist, may be associated with exacerbation in COPD. (C) 2017 Elsevier Ltd. All rights reserved.

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

Understanding the complex interactions between obesity and asthma
Satoshi Konno
Japanese Journal of Allergology, 66, 7, 919, 922, Japanese Society of Allergology, 2017年, ［査読有り］, ［筆頭著者］
日本語, 研究論文（学術雑誌）

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

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, UNIV CHICAGO PRESS, 2016年12月, ［査読有り］
英語, 研究論文（学術雑誌）, 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.

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

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, MOSBY-ELSEVIER, 2016年07月, ［査読有り］
英語

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, PUBLIC LIBRARY SCIENCE, 2016年03月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, PUBLIC LIBRARY SCIENCE, 2016年01月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2016年, ［査読有り］
日本語, 研究論文（学術雑誌）, Background: Long-acting β2-agomsts (LABA) and leukotnene receptor antagonists (LTRA) are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. In our previous study, the Gly16Arg genotype of the β2-adrenergic receptor (ADRB2) gene did not influence the differential bronchodilator effect of salmeterol versus montelukast as an add-on therapy to ICS within 16 weeks of follow-up (the J-Blossom study). Methods: We examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast usmg the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/mm) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes. Results: Although none of 4 genes were associated with ΔPEFsal - ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Glyl6Arg, was associated with ΔPEFsal - ΔPEFmon (p=0.0032). Conclusion: Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chrome adult asthma.

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, BIOMED CENTRAL LTD, 2015年08月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, OCEAN SIDE PUBLICATIONS INC, 2015年07月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, ELSEVIER IRELAND LTD, 2015年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background and objective: The reliability of CT assessment of regional bronchodilation is not universally accepted. In this study, using our proprietary 3D-CT software, we first examined airway inner luminal area (Ai) before and after inhalation of SFC in a group of COPD patients and then evaluated the same parameters for two sets of CT data obtained from clinically stable subjects with no intervention.
Methods: We conducted CT at deep inspiration and pulmonary function tests before and one week after inhalation of SFC in 23 COPD patients. As a non-intervention group, we used two sets of CT data obtained with one-year interval in another group of subjects who demonstrated stable pulmonary function (n=8). We measured Ai at the mid-portions of 3rd to 6th generation in 8 bronchi of the right lung, a total of 32 identical sites before and after intervention.
Results: The average bronchodilation at all sites (Delta Ai%: 28.2 + 4.1 (SE)%) (r= 0.65, p < 0.001) and that of each generation significantly correlated with % improvement of FEV1 (Delta FEV1%), which increased from 1.40 +/- 0.10L to 1.58 +/- 0.10L. When subjects were classified into two groups in terms of mean Delta FEV1%, even the poor responders (Delta FEV1% <14% above baseline, n=13) displayed significantly larger Delta Ai% compared with the non-intervention group (19.1 +/- 4.6% versus 2.1 +/- 3.9%). Inter-observer variability for overall AAi% was within acceptable levels.
Conclusions: CT can reliably detect the regional bronchodilation in 3rd to 6th generation airways when Delta FEV1 is as small as 180 ml on average. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) system (http://www.umin.ac.jp/No. UMIN 000002668). (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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, 191, AMER THORACIC SOC, 2015年05月
英語, 研究論文（学術雑誌）

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

放射光XRF およびXAFS を用いた 超硬合金肺病理標本中の元素分析
宇尾基弘, 和田敬広, 杉山知子, 中野郁夫, 木村清延, 谷口菜津子, 猪又崇志, 今野 哲, 西村正治
X線分析の進歩, 46, 46, 177, 186, アグネ技術センター, 2015年03月, ［査読有り］
日本語, 研究論文（学術雑誌）

Historical transition of management of sarcoidosis　　　　　　　　　　　　　　　
Inomata M, Konno S, Azuma A
W J Respir., 28, 4, 16, 2015年, ［査読有り］, ［招待有り］, ［筆頭著者］
英語

Smoking and adult asthma, COPD
Satoshi Konno
Japanese Journal of Allergology, 64, 8, 1127, 1134, Japanese Society of Allergology, 2015年, ［査読有り］
日本語, 研究論文（学術雑誌）

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, Japanese Society of Allergology, 2015年, ［査読有り］
日本語, 研究論文（学術雑誌）, 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.
Suzuki M, Makita H, Östling J, Thomsen LH, Konno S, Nagai K, Shimizu K, Pedersen JH, Ashraf H, Bruijnzeel PL, Maciewicz RA, Nishimura M, Hokkaido COPD Cohort Study, Danish Lung Cancer Screening Trial Investigators
Annals of the American Thoracic Society, 11, 10, 1511, 1519, American Thoracic Society, 2014年12月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Methods: Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the results were validated using data of 226 subjects with and 268 subjects without airflow limitation, mainly white, from the 4-year COPD Quantification by Computed Tomography, Biomarkers, and Quality of Life (CBQ) study conducted in Denmark. The plasma samples were measured using Human CardiovascularMAP (Myriad RBM, Austin, TX), which could analyze 50 biomarkers potentially linked with inflammatory, metabolic, and tissue remodeling pathways, and single ELISAs were used to confirm the results.
Measurements and Main Results: Higher plasma adiponectin levels and a lower leptin/adiponectin ratio at enrollment were significantly associated with an annual decline in FEV1 even after controlling for age, sex, height, and body mass index in the Hokkaido COPD cohort study (P = 0.003, P = 0.004, respectively). A lower plasma leptin/adiponectin ratio was also significantly associated with an annual decline in FEV<
inf>
1<
/inf>
in subjects with airflow limitation in the CBQ study (P = 0.014), the patients of which had largely different clinical characteristics compared with the Hokkaido COPD cohort study. There were no significant associations between lung function decline and adipokine levels in subjects without airflow limitation.
Conclusions: A lower leptin/adiponectin ratio was associated with lung function decline in patients with COPD in two independent Japanese and Western cohort studies of populations of different ethnicity. Measure of systemic adipokines may provide utility in predicting patients with COPD at higher risk of lung function decline.
Rationale: The rate of annual change in FEV<
inf>
1<
/inf>
is highly variable among patients with chronic obstructive pulmonary disease (COPD). Reliable blood biomarkers are needed to predict prognosis.
Objectives: To explore plasma biomarkers associated with an annual change in FEV<
inf>
1<
/inf>
in patients with COPD.

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, WILEY-BLACKWELL, 2014年11月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, +, ELSEVIER SCIENCE INC, 2014年07月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Background: Catalase (CAT) is a part of the active antioxidant defense system and has been studied with regard to its association with asthma and chronic obstructive pulmonary disease (COPD), which are heterogeneous obstructive pulmonary diseases characterized by chronic airway inflammation. We hypothesized that the CAT gene might be involved in the common pathogenesis underlying asthma and COPD.
Objective: To evaluate the association of CAT polymorphisms with specific phenotypes of asthma and COPD to identify the common underlying pathophysiologic mechanisms of these 2 diseases.
Methods: The -262C> T and -21A> T polymorphisms in the CAT gene were genotyped in 493 individuals with asthma, 265 with COPD, and 1,076 healthy controls. Asthmatic patients were categorized according to smoking status (smokers and nonsmokers) and age at onset (early onset and adult onset) as part of a casecontrol study. In patients with COPD, visual scoring (computed tomographic score) was assessed to determine emphysema severity, which was used to evaluate associations with CAT gene polymorphisms.
Results: Overall, the -262C> T and -21A> T polymorphisms were not associated with asthma. However, the -262CT+TT genotype was significantly associated with adult-onset asthma in smokers (P = .005), and a significant interaction between smoking status and the effect of -262C> T genotype on asthma were observed (P = .01). In patients with COPD, this genotype was significantly associated with a low computed tomographic score (P = .03), which indicates a nonemphysematous type of COPD.
Conclusion: The present study indicates that the CAT gene is involved in the common pathogenesis underlying adult-onset asthma in smokers and the nonemphysematous type of COPD. (C) 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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, EUROPEAN RESPIRATORY SOC JOURNALS LTD, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, LIPPINCOTT WILLIAMS & WILKINS, 2014年05月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, Background
Long-acting beta 2-agonists and leukotriene receptor antagonists are two principal agents that can be added to inhaled corticosteroids (ICS) for patients with asthma that is not adequately controlled by ICS alone. The Gly16Arg genotype of the beta 2-adrenergic receptor (ADRB2) gene may influence the bronchodilator effects of beta 2-agonists. We hypothesized that differential responses to long-acting beta 2-agonists or leukotriene receptor antagonists might be determined partly by the Gly16Arg polymorphism in Japanese asthma patients.
Materials and methods
This randomized, genotype-stratified, two-period crossover study included 80 patients with mild-to-moderate asthma (35 Arg/Arg and 45 Gly/Gly individuals). The primary study outcome was the difference in peak expiratory flow (Delta PEF) (Delta PEF, l/min) by genotype after 16 weeks of treatment with salmeterol (Delta PEFsal) or montelukast (Delta PEFmon). In addition, multivariate analyses were used to identify independent factors that were predictive of responses to each treatment.
Results
The mean Delta PEFsal-Delta PEFmon was 19.3 +/- 46.6 among Arg/Arg individuals and 16.8 +/- 51.5 among Gly/Gly individuals, indicating that the Gly16Arg genotype did not influence the differential bronchodilator effect of the two agents. Multivariate analysis showed that higher peripheral eosinophil counts were associated with better response to salmeterol (P < 0.05).
Conclusion
The Gly16Arg genotype did not influence the differential bronchodilator effect of salmeterol or montelukast as an add-on therapy to ICS within 16 weeks of follow-up. Higher peripheral eosinophil counts may be associated with better responses to salmeterol in combination with ICS.

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

アレルゲン特異的IgE反応性から分類した喘息フェノタイプ Thymic stromal lymphopoietin(TSLP)遺伝子と喫煙の役割
飯島 弘晃, 山田 英恵, 谷田貝 洋平, 金子 美子, 内藤 隆志, 坂本 透, 増子 裕典, 広田 朝光, 玉利 真由美, 今野 哲, 西村 正治, 檜澤 伸之
アレルギー, 63, 1, 33, 44, (一社)日本アレルギー学会, 2014年02月, ［査読有り］
日本語, 【背景・目的】吸入抗原感作は喘息病態の重要な要素の一つである.我々はこれまでに外来刺激に対する自然免疫センサーであり,向アレルギー性の作用を有するthymic stromal lymphopoietin(TSLP)の遺伝子多型が喘息発症と関連すること,さらには喫煙の影響を受けながら,吸入アレルゲンに対する感作パターンと関連することを報告した.本研究の目的は,吸入アレルゲンに対する感作パターンに基づいた喘息のフェノタイプ分類を行い,その臨床的特徴を明らかにすること,さらに各フェノタイプとTSLP遺伝子との関連を喫煙の有無によって層別化し検討することである.【方法】茨城県および上士幌町在住の成人喘息患者(N=294),非喘息健常者(N=1571)を対象に問診,血清総IgE,multiple antigen simultaneous test(MAST)-26および呼吸機能測定を行い,茨城地区(N=1651),上士幌地区(N=214)でそれぞれクラスター解析によるアトピー分類を行った.今回は特に喘息患者に着目し,Dust Mite dominant(A,N=82),Multiple Pollen(B,N=14),Cedar dominant(C,N=44),Low reactivity(D,N=154)の4群の喘息フェノタイプの臨床的特徴を検討した.既に喘息との関連が報告されているTSLP遺伝子における機能的single nucleotide polymorphism(SNP)であるrs2289276及びrs3860933と,それぞれの喘息フェノタイプとの関連を,非喘息健常成人を対照とした多項ロジスティック解析により検討した.【結果】喘息A群には若年者が多く,血清総IgE値が最も高く,呼吸機能も低値であった.喘息B群はイネ科花粉をはじめとした多数の抗原に感作され,喘息C群はスギ飛散地域のみで形成された.喘息D群は高齢女性に多く,血清総IgE値と抗原感作の程度が最も低かった.喫煙者において,TSLP遺伝子の機能的SNPs(rs2289276,rs3860933)が喘息D群と有意に関連した(OR 2.11[1.36-3.30]及び2.11[1.34-3.33]).【考察】アトピー分類によって臨床的に特徴的な4つの喘息フェノタイプが同定された.アレルゲン感作の関与が少ない成人喘息の発症には,喫煙を介したTSLPの発現亢進が重要な役割を果たしている可能性がある.(著者抄録)

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, JAPAN SOC INTERNAL MEDICINE, 2014年, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2014年, ［査読有り］, ［責任著者］
日本語, 研究論文（学術雑誌）, Purpose: To investigate changes in the prevalence of adult asthma and allergic rhinitis from 2006 to 2011 in Kamishihoro, a town in Hokkaido, Japan.
Methods: The Japanese edition of the European Community Respiratory Health Survey questionnaire was completed by 1472 residents aged from 20 to 81 years old. (718 men, 749 women). The age and gender distribution of respondents matched that of respondents in 2006.
Results: Response rates were 98.1% in 2011 and 95.8% in 2006. Wheezing in the last 12 months was reported by 10.7% of men and 8.3% of women in 2011, compared to 12.9% and 9.8%, respectively, in 2006. The questions "Have you ever had asthma?" followed by "Was this confirmed by a doctor?" both received positive answers from 7.9% of men and 7.5% of women in 2011, compared to 5.7% and 6.3%, respectively, in 2006. The rate of current smoking was 34.8% in men and 14.7% in women in 2011, compared to 42.8% and 17.2%, respectively, in 2006. A "Yes" answer to the questionnaire item, "Do you have any nasal allergies, including hay fever?" (defining allergic rhinitis) was given by 23.2% of men and 25.4% of women in 2011, compared to 17.6% and 23.0%, respectively, in 2006. The prevalence of allergic rhinitis was increased, particularly among younger respondents.
Conclusion: Rates of current asthma and allergic rhinitis increased, whereas the rate of wheezing in the past 12 months decreased from 2006 to 2011. Optimal treatment of asthma might be related to these trends.

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, Japanese Society of Allergology, 2014年, ［査読有り］
日本語, 研究論文（学術雑誌）, 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, PUBLIC LIBRARY SCIENCE, 2013年12月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, 2013年11月, ［査読有り］, ［国際誌］

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

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, 7, 2013年10月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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.

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, ELSEVIER SCIENCE BV, 2013年09月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, 3, 2013年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, JAPANESE SOCIETY ALLERGOLOGY, 2013年03月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, WILEY-BLACKWELL, 2012年08月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, 5, 2012年05月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, BIOMED CENTRAL LTD, 2012年05月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, AMER THORACIC SOC, 2012年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Rationale: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes.
Objectives: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity.
Methods: A total of 279 eligible patients with COPD(stages I-IV: 26,45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient.
Measurements and Main Results: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32 +/- 24 (SD) ml/yr (n = 261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63 +/- 2, -31 +/- 1, and -2 +/- 1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils.
Conclusions: Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

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, KARGER, 2012年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, OCEAN SIDE PUBLICATIONS INC, 2012年01月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, WALTER DE GRUYTER & CO, 2012年, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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 β2-agonist and anticholinergic agents in Japanese patients with chronic obstructive pulmonary disease.
Konno S, Makita H, Hasegawa M, Nasuhara Y, Nagai K, Betsuyaku T, Hizawa N, Nishimura M
Pharmacogenetics and genomics, 21, 11, 687, 693, 11, 2011年11月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, WILEY-BLACKWELL, 2011年10月, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］, ［国際共著］
英語, 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, W B SAUNDERS CO LTD, 2011年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Few studies have directly compared airway remodelling assessed by computed tomography (CT) between asthma and chronic obstructive pulmonary disease (COPD). The present study was conducted to determine whether there are any differences between the two diseases with similar levels of airflow limitation under clinically stable conditions.
Methods: Subjects included older male asthmatic patients (n = 19) showing FEV(1)/FVC <70% with smoking history less than 5-pack/year. Age- and sex-matched COPD patients (n = 28) who demonstrated similar airflow limitation as asthmatic patients and age-matched healthy non-smokers (n = 13) were recruited. Using proprietary software, eight airways were selected in the right lung, and wall area percent (WA%) and airway luminal area (Ai) were measured at the mid-portion of the 3rd to 6th generation of each airway. For comparison, the average of eight measurements per generation was recorded.
Results: FEV(1)% predicted and FEV(1)/FVC was similar between asthma and COPD (82.3 +/- 3.3% vs. 77.6 +/- 1.8% and 57.7 +/- 1.6% vs. 57.9 +/- 1.4%). At any generation, WA% was larger and Ai was smaller in asthma, both followed by COPD and then controls. Significant differences were observed between asthma and controls in WA% of the 3rd to 5th generation and Ai of any generation, while no differences were seen between COPD and controls. There were significant differences in Ai of any generation between asthma and COPD.

[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, 2011年05月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, 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, INFORMA HEALTHCARE, 2010年12月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, A 49-year-old woman, who had been diagnosed with asthma, showed a bilateral diffuse pattern of small centrilobular nodules on CT. Laboratory data revealed peripheral eosinophilia and a marked increase in total serum IgE levels. The nodules detected on CT were initially considered to be associated with bronchiolar infiltration of eosinophils. Pathological findings from thoracoscopy revealed infiltration of eosinophils into the airway lumen and walls, goblet cell hyperplasia, and thickening of the basement membrane in large bronchi, consistent with asthma. However, hyperplastic lymphoid follicles with reactive germinal centers were observed along the bronchioles. The follicles had no evidence of monoclonality suggested by immunohistological analysis, and no remarkable infiltrates of eosinophils, suggesting follicular bronchiolitis (FB). After treatment with prednisolone, the small diffuse nodules improved markedly, and peripheral eosinophilia and total serum IgE levels also decreased. To the best of our knowledge, this is the first documented case report of FB associated with asthma, eosinophilia, and elevated IgE with a definite pathophysiological diagnosis.

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

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, NATURE PUBLISHING GROUP, 2010年12月, ［査読有り］
英語

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

[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, 2010年09月, ［査読有り］

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, NATURE PUBLISHING GROUP, 2010年06月, ［査読有り］, ［国際共著］
英語, 研究論文（学術雑誌）, 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

側胸部痛を主訴に受診し, 全肺野に多発する嚢胞性病変を認めた症例
今野 哲, 西村 正治
日本内科学会雑誌, 99, 5, 1130, 1131, The Japanese Society of Internal Medicine, 2010年05月10日
日本語

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, OCEAN SIDE PUBLICATIONS INC, 2010年05月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, SPRINGER, 2010年04月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, NATURE PUBLISHING GROUP, 2010年03月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, 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, JAPAN SOC INTERNAL MEDICINE, 2010年, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, KARGER, 2010年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, 5, 2010年, ［査読有り］, ［責任著者］
日本語, 研究論文（学術雑誌）, 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, WILEY-V C H VERLAG GMBH, 2009年12月, ［査読有り］, ［筆頭著者, 責任著者］, ［国際共著］
英語, 研究論文（学術雑誌）, 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, SPRINGER, 2009年12月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌）, Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African-American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African-American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African-American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.

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, WILEY-BLACKWELL PUBLISHING, INC, 2009年08月, ［査読有り］, ［責任著者］, ［国際共著］
英語, 研究論文（学術雑誌）, 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, 2009年07月, ［査読有り］, ［責任著者］, ［国内誌］
日本語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2009年, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, KARGER, 2009年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, TAYLOR & FRANCIS LTD, 2008年11月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, EUROPEAN RESPIRATORY SOC JOURNALS LTD, 2008年08月, ［査読有り］
英語, 研究論文（学術雑誌）, 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], 57, 6, 713, 721, 6, 2008年06月, ［査読有り］
日本語, 【背景】β_2アドレナリン受容体(ADRB2)遺伝子の16番アミノ酸におけるグリシン(Gly)からアルギニン(Arg)への変化は受容体の機能的変化をもたらす.長期間のβ_2刺激薬投与により,特にArg/Arg患者では呼吸機能の悪化が報告されている.本研究では日本人喘息患者を対象にArg16Gly多型のβ_2刺激薬長期連用による呼吸機能への影響を検討した.【方法】対象は気管支喘息患者128人(Arg/Arg群64人,Gly/Gly群64人).β_2刺激薬を少なくとも6ヵ月間以上使用した長期連用群と非連用群に分類し,各遺伝子型群におけるβ_2刺激薬連用の有無による1秒量の変化を比較検討した.【結果】Gly/Gly群ではβ_2刺激薬連用によって,より大きな1秒量の改善が認められた(p=0.027-0.041).Arg/Arg群では連用群と非連用群との間に1秒量の改善に差はなかった.【結論】Arg/Arg型の日本人喘息患者においてβ_2刺激薬連用の有用性が小さく,ADRB2遺伝子が治療効果に影響を与えていると考えられた.

[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, 2008年05月, ［査読有り］

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年01月, ［査読有り］
英語, 研究論文（学術雑誌）

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, 7, 2008年, ［査読有り］
日本語, 研究論文（学術雑誌）, Purpose: To investigate the prevalence of adult asthma and allergic rhinitis, and to analyze associations between smoking habit, obesity and disease in Kamishihoro town, Hokkaido. Methods: The Japanese edition of the European Community Respiratory Health Survey (ECRHS) Questionnaire was completed by 3096 residents (men: 1520, women: 1576) who ranged in age from 18 to 81. Results: Among the respondents, 12.9% of the males and 9.8% of the females responded "Yes" to the questionnaire item, "Wheezing at any time in the last 12 months" (defined as having asthma) and 17.6% of the males and 23.0% of the females responded "Yes" to the question, "Do you have any nasal allergies including hay fever?" (defined as having allergic rhinitis). This prevalence tended to be higher among younger respondents. Smoking habit and obesity were significantly associated with wheezing over the last 12 months, but not with allergic rhinitis. Conclusion: Smoking habit and obesity are significantly associated with asthma in Kamishihoro town, located in a rural area of Hokkaido, Japan. © 2008 Japanese Society of Allergology.

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, JAPAN SOC INTERNAL MEDICINE, 2007年, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, KARGER, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, 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, AMER THORACIC SOC, 2006年11月, ［査読有り］, ［国際共著］
英語, 研究論文（学術雑誌）, 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, MARY ANN LIEBERT INC, 2006年08月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, AMER COLL CHEST PHYSICIANS, 2006年08月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, BLACKWELL PUBLISHING, 2006年07月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, MOSBY, INC, 2006年04月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, BLACKWELL PUBLISHING, 2006年02月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, 6, 2006年, ［査読有り］
日本語, 研究論文（学術雑誌）, 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, Japanese Society of Allergology, 2006年, ［査読有り］, ［招待有り］, ［筆頭著者］, ［国際共著］
英語, 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, AMER COLL CHEST PHYSICIANS, 2005年10月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, MOSBY-ELSEVIER, 2005年06月, ［査読有り］, ［筆頭著者］
英語

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, MOSBY-ELSEVIER, 2005年05月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, MARY ANN LIEBERT INC, 2005年05月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, 6, 2004年, ［査読有り］
日本語, 研究論文（学術雑誌）, 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, EDITRICE KURTIS S R L, 2002年12月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, AMER THORACIC SOC, 2002年09月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, BLACKWELL MUNKSGAARD, 2002年05月, ［査読有り］
英語

(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, MOSBY, INC, 2001年11月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌）, 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, MOSBY, INC, 2001年07月, ［査読有り］
英語, 研究論文（学術雑誌）, 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, MOSBY, INC, 2001年06月, ［査読有り］
英語, 研究論文（学術雑誌）

[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, 1998年04月, ［査読有り］
日本語

ガイドラインのワンポイント解説 喘息予防・管理ガイドライン2021
福居 嘉信, 今野 哲, アレルギー, 73, 4, 320, 322, 2024年06月
(一社)日本アレルギー学会, 日本語

肺カルチノイド術後再発に対して放射性核種標識ペプチド療法を行った1例
佐藤 祐麻, 榊原 純, 黒木 俊宏, 松野 吉宏, 平田 健司, 今野 哲, 日本呼吸器学会誌, 13, 2, 49, 53, 2024年03月
症例は47歳男性.定型肺カルチノイドに対して右肺中葉切除4年後に肝転移再発で各種全身治療後,病勢進行を認めた.ソマトスタチン受容体シンチグラフィで肝転移に集積,免疫組織染色で肝転移生検検体と肺手術検体にてソマトスタチン受容体2陽性を認め,放射性核種標識ペプチド療法(peptide receptor radionuclide therapy:PRRT)を行った.4コース投与後肝転移は縮小し病勢進行なく経過している.(著者抄録), (一社)日本呼吸器学会, 日本語

気管支喘息診療に残された課題 コロナ禍を通して診療の目標設定について思うこと
今野 哲, 日本内科学会雑誌, 112, 3, 501, 506, 2023年03月
(一社)日本内科学会, 日本語

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, 111, 5, 984, 989, 2022年05月
66歳男性。全身倦怠感、全身浮腫を主訴に、前医にて両側滲出性胸水を指摘され、精査目的に当科紹介入院となった。血液検査や画像検査、胸水検査では特異的所見を認めず、局所麻酔下の胸腔鏡検査にて胸膜に多発結節性病変を認め、病理組織像および気管支鏡検査所見より、サルコイドーシス(組織診断群)と診断された。経過中に眼症状は認めず、プレドニゾロンによる内服治療を開始したところ、全身浮腫や両側胸水は改善傾向にあった。, (一社)日本内科学会, 日本語

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年06月
(一社)日本アレルギー学会, 日本語

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年05月
(一社)日本内科学会, 日本語

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年05月
(一社)日本内科学会, 日本語

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年05月
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), (一社)日本呼吸器学会, 日本語

北海道大学病院における新型コロナウイルス感染症の流行に伴う職務上の影響にかかわる調査結果
阿部 結希, 清水 薫子, 中司 展人, 船木 典子, 長堀 紀子, 菅原 満, 澁谷 斉, 高橋 久美子, 北川 善政, 今野 哲, 渥美 達也, 日本医師会雑誌, 150, 1, 95, 100, 2021年04月
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), (公社)日本医師会, 日本語

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年11月
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), (一社)日本呼吸器学会, 日本語

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年09月
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), (一社)日本呼吸器学会, 日本語

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年09月
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), (一社)日本アレルギー学会, 日本語

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年02月
「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。, (一社)日本アレルギー学会, 日本語

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年01月
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), (一社)日本呼吸器学会, 日本語

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

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年08月
(一社)日本アレルギー学会, 日本語

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

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年03月
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。, (公財)産業医学振興財団, 日本語

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年11月
【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), (一社)日本アレルギー学会, 日本語

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年05月
(一社)日本アレルギー学会, 日本語

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年11月
【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), (一社)日本アレルギー学会, 日本語

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年09月
(一社)日本アレルギー学会, 日本語

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年09月
日本臨床皮膚科医会, 日本語

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年05月
[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), 日本職業・環境アレルギー学会, 日本語

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年09月
【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), (一社)日本アレルギー学会, 日本語

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

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年10月
日本サルコイドーシス, 日本語

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年09月, ［国内誌］
(公社)全国大学保健管理協会, 日本語

気管支喘息及び鼻炎における血清総IgE値及び末梢血好酸球数の検討
高橋 歩, 今野 哲, 伊佐田 朗, 服部 健史, 清水 薫子, 清水 健一, 谷口 菜津子, 高橋 大輔, 谷口 正実, 赤澤 晃, 檜澤 伸之, 西村 正治, アレルギー, 59, 5, 536, 544, 2010年05月
【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), (一社)日本アレルギー学会, 日本語

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年03月
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), (一社)日本呼吸器学会, 日本語

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年10月
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), 日本サルコイドーシス, 日本語

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年10月
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), 日本サルコイドーシス, 日本語

北海道上士幌町における成人喘息、アレルギー性鼻炎有病率 特に喫煙及び肥満との関連について
清水 薫子, 今野 哲, 清水 健一, 伊佐田 朗, 高橋 歩, 服部 健史, 前田 由起子, 高橋 大輔, 高橋 清, 中川 武正, 谷口 正実, 秋山 一男, 赤澤 晃, 檜澤 伸之, 西村 正治, アレルギー, 57, 7, 835, 842, 2008年07月
【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), (一社)日本アレルギー学会, 日本語

アトピー素因の判定に必要なアレルゲン数の検討
服部 健史, 今野 哲, 清水 薫子, 清水 健一, 伊佐田 朗, 高橋 歩, 前田 由起子, 牧田 比呂仁, 澤崎 健, 檜澤 伸之, 西村 正治, アレルギー, 57, 5, 543, 551, 2008年05月
【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), (一社)日本アレルギー学会, 日本語

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年05月25日
日本呼吸器内視鏡学会, 日本語

ERS monograph　　　　　　　　　　　　　　　
Nizar NJ, Konno S, Mechanisms underlying fixed airflow obstruction;exacerbations
2019年, ［共著］

Advances in medicine asthma　　　　　　　　　　　　　　　
Konno S, Asthma phenotype and endotype.
Springer Nature Singapore PteLtd., 2019年, ［共著］

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　　　　　　　　　　　　　　　
2022年10月 - 2027年09月
国立研究開発法人日本医療研究開発機構, 研究分担者

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

びまん性肺疾患に関する調査研究　　　　　　　　　　　　　　　
2010年04月 - 2026年03月
厚生労働科学研究費, 研究分担者

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　　　　　　　　　　　　　　　
2022年04月 - 2025年03月
国立研究開発法人日本医療研究開発機構, 研究分担者

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　　　　　　　　　　　　　　　
2011年04月 - 2024年03月
環境省, 研究分担者

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　　　　　　　　　　　　　　　
2023年10月
日本医療研究開発機構 革新的先端研究開発支援事業, 研究分担者

Potential role of club cell secretory protein (CC16) in development of obese asthma: findings from a birth cohort and animal studies
科学研究費助成事業
2020年04月01日 - 2023年03月31日
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.
日本学術振興会, 基盤研究(C), 北海道大学, 20K10425

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　　　　　　　　　　　　　　　
2021年04月 - 2023年03月
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, 研究分担者

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　　　　　　　　　　　　　　　
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
2021年12月 - 2022年03月
国立研究開発法人日本医療研究開発機構, 研究分担者, 20fk0108471h0001

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　　　　　　　　　　　　　　　
医療技術実用化総合促進事業
2021年04月 - 2022年03月
国立研究開発法人日本医療研究開発機構, 研究分担者

肺疾患合併肺高血圧症における心筋および骨格筋評価系の確立と臨床応用
科学研究費助成事業
2018年04月01日 - 2021年03月31日
辻野 一三, 今野 哲, 大平 洋, 真鍋 徳子
Lung-PH症例では右室収縮能は代償的に亢進するも、右室・肺動脈カップリングは障害されていた。右室拡張能では、弛緩能は保たれているが、硬さが増しており、これらはPAHに類似した右室機能異常と捉えられた。
死因解析ではLung-PH症例は、PH関連死、特に呼吸不全死が多く、PAHや4群PHと異なっていた。今後Lung-PHの予後改善を実現する上で、PHに加え背景肺疾患に対する適切な対処が重要であることが示唆された。
血管病理の解析では、線維化が進行中の領域における肺動脈リモデリングの有無・程度がPHの合併をある程度規定することが示唆された。
日本学術振興会, 基盤研究(C), 北海道大学, 18K08129

末梢血エクソソームRNA解析による閉塞性肺疾患の類似性・相違点・合併病態の解明
科学研究費助成事業
2017年04月01日 - 2021年03月31日
鈴木 雅, 今野 哲
質の高い末梢血エクソソームRNA収集に困難を極めたため、末梢血中の網羅的プロテオーム解析を行い、エクソソーム関連蛋白との関わりを検討した。COPDと難治性喘息の間には365の蛋白発現の有意な相違を認めた。プロテオームプロファイルによるクラスター解析により、COPDでは3つ、難治性喘息では4つのクラスターが同定された。そのクラスタリングに関与する蛋白群には有意にエクソソームマーカーが多く含まれていた。以上より、COPDと難治性喘息の血漿プロテオームプロファイルには違いがあるものの、両疾患のプロテオームによるクラスタリングにはエクソソームが強く関連していることが示された。
日本学術振興会, 基盤研究(C), 北海道大学, 17K09600

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


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

呼吸器疾患における気腫・気道・血流の総合的評価法の確立
科学研究費助成事業
2016年04月01日 - 2019年03月31日
清水 薫子, 今野 哲, 牧田 比呂仁
低吸収クラスターサイズの増大を反映し、初期段階の肺胞破壊を鋭敏に検出するフラクタル次元とlow attenuation volumeのCOPDにおける長期予後予測因子としての役割を検討し、現在論文投稿中である。非喫煙/喫煙喘息における肺拡散能力とCT画像上の肺気腫、肺末梢血管パラメーターとの関連を検討し、Journal of applied physiologyに受理された。
肺動脈性肺高血圧症においてCT画像による血管病変パラメーターの診断・病態評価における妥当性を検討し、European Journal of Radiologyに受理された。
日本学術振興会, 基盤研究(C), 北海道大学, 16K09525

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　　　　　　　　　　　　　　　
2017年04月 - 2019年03月
環境研究総合推進費, 研究分担者

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　　　　　　　　　　　　　　　
基盤研究 (C)
2017年 - 2019年
今野 哲
文部科学省科学研究費補助金, 研究代表者, 競争的資金

肺炎球菌の嫌気培養による病原性の変化の検討
科学研究費助成事業
2015年04月01日 - 2017年03月31日
長岡 健太郎, 今野 哲, 西村 正治
本研究では、通性嫌気性菌である肺炎球菌の下気道における病原性が、嫌気培養により好気培養と比較してどのように変化するかを検証した。嫌気培養後の肺炎球菌はオートリシンの産生亢進がみられず、より長期に安定すること、好気培養による肺炎と同等以上の肺炎を起こすことが明らかになった。本研究は、通性嫌気性菌の嫌気環境と好気環境での病原性の違いを示した初めての研究となる。肺炎球菌のみならず、病原細菌の臨床・基礎研究などを考える上で有用な知見と考えられた。
日本学術振興会, 若手研究(B), 北海道大学, 15K19583

呼吸器疾患に伴う肺高血圧症の肺血管および右心系に関する臨床病理学的検討
科学研究費助成事業
2014年04月01日 - 2017年03月31日
辻野 一三, 今野 哲, 谷野 美智枝
肺疾患合併肺高血圧症（R-PH）における肺血管と心臓（特に右心系）の形態・機能解析を行った。病理学的検索では、肺血管のリモデリングと同時に肺血管拡張薬の標的蛋白質の局在を証明し、将来的な肺血管拡張療法の適応に係る重要な知見と考えられた。臨床研究では、肺血管拡張薬がR-PH症例の肺血管抵抗低下に加え右心系指標も改善することを英文誌に発表した。そのほか、血液検査にてインスリン濃度、インスリン抵抗性指標およびマイオカインの上昇を見出し、さらに右心系指標として注目される右室収縮能、右室・肺動脈カップリングの障害を確認した。また肺高血圧症における胸部CT指標の有用性も検証、発表した。
日本学術振興会, 基盤研究(C), 北海道大学, 26461150

難治性気道疾患の病態解明と個別化治療への展開
科学研究費助成事業
2012年04月01日 - 2016年03月31日
西村 正治, 鈴木 雅, 今野 哲, 長井 桂, 牧田 比呂仁
北海道難治性喘息に登録された206名（軽症～中等症79名、重症127名）の気管支喘息患者に対して、血中の種々のバイオマーカーの測定を終了した。その結果、非喫煙者においては、血清periostin、osteopontin、CCL18と好酸球性気道炎症、FeNO、副鼻腔スコアとの関連を見出した。しかし、喫煙者においては、血清pesiotsitnのみが好酸球性炎症との関連を認めた。いっぽう、呼吸機能に関しては、非喫煙者では,、これらのbiomarkersとの負の関連を認めたが、喫煙者ではその関連は認めなかった。これれらの結果は、Ann Am Thrac Soc 2017に報告した。
日本学術振興会, 基盤研究(A), 北海道大学, 24249049

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　　　　　　　　　　　　　　　
基盤研究（C）
2014年 - 2016年
今野 哲
文部科学省科学研究費補助金, 研究代表者, 競争的資金

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　　　　　　　　　　　　　　　
基盤研究（C）
2011年 - 2013年
今野 哲
文部科学省科学研究費補助金, 研究代表者, 競争的資金

難治性喘息に対する創薬への挑戦-新規NF-kB阻害薬(DHMEQ)の可能性-
科学研究費助成事業
2009年 - 2011年
西村 正治, 藤堂 省, 南須原 康行, 今野 哲
新規NF-kB阻害薬であるDHMEQは、種々の慢性炎症性疾患モデルにおける効果が報告されている。本研究では、マウス喘息モデルにおいて、DHMEQは、好酸球性気道炎症、気道線維化を有意に抑制することが見出された。更には、in vitroを用いた系において、気道上皮細胞からのケモカインの抑制、Th2細胞からのサイトカイン産生を抑制することが示された。DHMEQは、気管支喘息における新規治療薬となる可能性が示唆された。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 21659206

大規模コホート研究による難治性気道疾患の病態解明と個別化治療への展開
科学研究費助成事業
2009年 - 2011年
西村 正治, 今野 哲, 南須原 康行, 牧田 比呂仁
慢性閉塞性肺疾患(COPD)患者における1秒量の経年変化は、必ずしもすべての症例で進行性ではなく、5年間にわたり1秒量経年変化が維持される症例も認め、症例により様々である。この結果は、COPDが常に進行性であるという、疾患概念を覆すものであり、治療の重要性を示す。
また、1秒量経年変化が急速に低下する群では、気腫病変の重症度が、気流閉塞の重症度とは独立した寄与因子であった。この結果は、今後の臨床研究において新しい病型分類に基づいた評価、解析が必要性を示している。
日本学術振興会, 基盤研究(B), 北海道大学, 21390253

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　　　　　　　　　　　　　　　
基盤研究（C）
2008年 - 2010年
今野 哲
文部科学省科学研究費補助金, 研究代表者, 競争的資金

喘息と慢性閉塞性肺疾患との共通病態の解明-分子病態に基づく新たな分類を目指して-
科学研究費助成事業
2007年 - 2008年
桧澤 伸之, 西村 正治, 今野 哲
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。
日本学術振興会, 基盤研究(C), 筑波大学, 19590876

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　　　　　　　　　　　　　　　
若手研究（B）
2006年 - 2007年
今野 哲
文部科学省科学研究費補助金, 研究代表者, 競争的資金