Details of a Researcher - KURONUMA Kouji

Papers - KURONUMA Kouji

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Rapid and Integrated Bacterial Evolution Analysis unveils gene mutations and clinical risk of Klebsiella pneumoniae.

Kojiro Uemura, Toyotaka Sato, Soh Yamamoto, Noriko Ogasawara, Jirachaya Toyting, Kotaro Aoki, Akira Takasawa, Masayuki Koyama, Atsushi Saito, Takayuki Wada, Kaho Okada, Yurie Yoshida, Koji Kuronuma, Chie Nakajima, Yasuhiko Suzuki, Motohiro Horiuchi, Kenichi Takano, Satoshi Takahashi, Hirofumi Chiba, Shin-Ichi Yokota

Nature communications 16 ( 1 ) 2917 - 2917 2025.03 [International journal]

Bacteria continually evolve. Previous studies have evaluated bacterial evolution in retrospect, but this approach is based on only speculation. Cohort studies are reliable but require a long duration. Additionally, identifying which genetic mutations that have emerged during bacterial evolution possess functions of interest to researchers is an exceptionally challenging task. Here, we establish a Rapid and Integrated Bacterial Evolution Analysis (RIBEA) based on serial passaging experiments using hypermutable strains, whole-genome and transposon-directed sequencing, and in vivo evaluations to monitor bacterial evolution in a cohort for one month. RIBEA reveals bacterial factors contributing to serum and antimicrobial resistance by identifying gene mutations that occurred during evolution in the major respiratory pathogen Klebsiella pneumoniae. RIBEA also enables the evaluation of the risk for the progression and the development of invasive ability from the lung to blood and antimicrobial resistance. Our results demonstrate that RIBEA enables the observation of bacterial evolution and the prediction and identification of clinically relevant high-risk bacterial strains, clarifying the associated pathogenicity and the development of antimicrobial resistance at genetic mutation level.

JANISでは把握が困難な中小規模病院における緑膿菌の薬剤耐性の状況

藤谷好弘, 富樫篤生, 齋藤充史, 黒沼幸治, 高橋聡

日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 ( 日本感染症学会・日本化学療法学会 ) 98回・72回 np255 - np255 2024.05

当院改修時におけるアスペルギルス対策の評価

黒沼幸治, 中江舞美, 韮澤慎也, 富樫篤生, 藤谷好弘, 齋藤充史, 高橋聡

感染症学雑誌 ( (一社)日本感染症学会 ) 98 ( 2 ) 281 - 281 2024.03

当院改修時におけるアスペルギルス対策の評価

黒沼幸治, 中江舞美, 韮澤慎也, 富樫篤生, 藤谷好弘, 齋藤充史, 高橋聡

感染症学雑誌 ( (一社)日本感染症学会 ) 98 ( 2 ) 281 - 281 2024.03

間質性肺疾患における気管支肺胞洗浄液中の肺胞マクロファージの代謝活性についての検討

萬谷峻史, 齋藤充史, 佐藤達也, 山口美樹, 亀田優美, 佐久間裕司, 黒沼幸治, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 13 ( 増刊 ) 341 - 341 2024.03

結核の診断に時間を要した肺外結核の2例

小林拓海, 齋藤充史, 小玉賢太郎, 高橋守, 黒沼幸治, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 13 ( 増刊 ) 395 - 395 2024.03

The impact of respiratory reactance in oscillometry on survival in patients with idiopathic pulmonary fibrosis.

Tatsuru Ishikawa, Hirotaka Nishikiori, Yuki Mori, Keiko Fujino, Atsushi Saito, Mamoru Takahashi, Koji Kuronuma, Shiro Hinotsu, Hirofumi Chiba

BMC pulmonary medicine 24 ( 1 ) 10 - 10 2024.01 [International journal]

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test. RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

手洗器の水栓口や給水システムの汚染による緑膿菌の感染伝播

藤谷好弘, 中江舞美, 佐藤勇樹, 韮澤慎也, 富樫篤生, 齋藤充史, 黒沼幸治, 高橋聡

感染症学雑誌 ( (一社)日本感染症学会 ) 98 ( 1 ) 119 - 119 2024.01

COVID-19患者における血清レクチン値についての検討

竹中遥, 齋藤充史, 黒沼幸治, 千葉弘文

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 54 28 - 29 2023.08

Factors affecting the sensitivity of quantitative severe acute respiratory syndrome coronavirus 2 antigen test.

Yuki Sato, Ryosei Murai, Ryo Kobayashi, Atsuo Togashi, Yoshihiro Fujiya, Koji Kuronuma, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 29 ( 8 ) 754 - 758 2023.08 [International journal]

INTRODUCTION: The accuracy of nucleic acid amplification tests (NAATs) is affected by various factors; however, studies examining the factors affecting the accuracy of quantitative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test (QAT) are limited. METHODS: A total of 347 nasopharyngeal samples were collected from patients with coronavirus disease 2019 (COVID-19), and the date of onset was obtained from the electronic medical records. The SARS-CoV-2 antigen level was measured using Lumipulse Presto SARS-CoV-2 Ag (Presto), while NAAT was performed using the Ampdirect 2019-nCoV Detection Kit. RESULTS: Presto had a sensitivity rate of 95.1% (95% confidence interval: 92.8-97.4) in detecting the SARS-CoV-2 antigen in 347 samples. The number of days from symptom onset to sample collection was negatively correlated with the amount of antigen (r = -0.515) and sensitivity of Presto (r = -0.711). The patients' age was lower in the Presto-negative samples (median age, 39 years) compared with that in the Presto-positive samples (median age, 53 years; p < 0.01). A significant positive correlation was observed between age (excluding teenagers) and Presto sensitivity (r = 0.764). Meanwhile, no association was found between the mutant strain, sex, and Presto results. CONCLUSION: Presto is useful for the accurate diagnosis of COVID-19 owing to its high sensitivity when the number of days from symptom onset to sample collection is within 12 days. Furthermore, age may affect the results of Presto, and this tool has a relatively low sensitivity in younger patients.

COVID-19患者における血清レクチン値についての検討

竹中遥, 齋藤充史, 黒沼幸治, 千葉弘文

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 54 28 - 29 2023.08

COVID-19の濃厚接触者が陽性となる要因の検討

中江舞美, 藤谷好弘, 富樫篤生, 中村広士, 斎藤充史, 黒沼幸治, 高橋聡

日本環境感染学会総会プログラム・抄録集 ( (一社)日本環境感染学会 ) 38回 382 - 382 2023.06

ゲノム解析は同時期に複数病棟で発生したCOVID-19クラスター事例の全体像の把握に有用である

藤谷好弘, 中江舞美, 中村広士, 富樫篤生, 齋藤充史, 黒沼幸治, 高橋聡, 大久保和洋, 川代愛梨, 田宮和真

日本環境感染学会総会プログラム・抄録集 ( (一社)日本環境感染学会 ) 38回 271 - 271 2023.06

Pseudo-outbreak of Mycobacterium lentiflavum at a general hospital in Japan.

Yutaro Nagano, Koji Kuronuma, Yasuo Kitamura, Kanami Nagano, Hayato Yabe, Sayaka Kudo, Toyotaka Sato, Shinya Nirasawa, Mami Nakae, Motohiro Horiuchi, Shin-Ichi Yokota, Yoshihiro Fujiya, Atsushi Saito, Satoshi Takahashi, Hirofumi Chiba

Infection control and hospital epidemiology 1 - 7 2023.04 [International journal]

BACKGROUND: Mycobacterium lentiflavum is a slow-growing nontuberculous mycobacterium that is widely distributed in soil and water systems, but it is sometimes pathogenic to humans. Although cases of M. lentiflavum infections are rare, 22 isolates of M. lentiflavum were identified at a single hospital in Japan. We suspected a nosocomial outbreak; thus, we conducted transmission pattern and genotype analyses. METHODS: Cases of M. lentiflavum isolated at Kushiro City General Hospital in Japan between May 2020 and April 2021 were analyzed. The patient samples and environmental culture specimens underwent whole-genome sequencing (WGS). Additionally, we retrospectively collected clinical data from patient medical records. RESULTS: Altogether, 22 isolates of M. lentiflavum were identified from sputum and bronchoalveolar lavage samples. Clinically, the instances with M. lentiflavum isolates were considered contaminants. In the WGS analysis, 19 specimens, including 18 patient samples and 1 environmental culture from the hospital's faucet, showed genetic similarity. The frequency of M. lentiflavum isolation decreased after we prohibited the use of taps where M. lentiflavum was isolated. CONCLUSIONS: WGS analysis identified that the cause of M. lentiflavum pseudo-outbreak was the water used for patient examinations, including bronchoscopy.

間質性肺疾患を有する難治性咳嗽に対してのP2X3受容体拮抗薬の有効性の検討

高橋知之, 齋藤充史, 萬谷峻史, 池田貴美之, 黒沼幸治, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 12 ( 増刊 ) 216 - 216 2023.03

SARS-CoV-2ワクチン接種後の長期的抗体価推移と次期接種のタイミングの検討

藤谷好弘, 中江舞美, 富樫篤生, 齋藤充史, 黒沼幸治, 高橋聡

日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 ( 日本感染症学会・日本化学療法学会 ) 97回・71回 O - 127 2023.03

Klebsiella pneumoniaeにおける遺伝子変異頻度と病原性の関連性評価

上村幸二朗, 佐藤豊孝, 黒沼幸治, 高橋聡, 横田伸一

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 71 ( 2 ) 179 - 179 2023.03

Analysis of diagnostic performance and factors causing nonspecific reactions in SARS-CoV-2 rapid antigen detection tests.

Natsuki Narumi, Takashi Kondo, Yuki Sato, Yuki Katayama, Shinya Nirasawa, Masachika Saeki, Yuki Yakuwa, Yoshihiro Fujiya, Koji Kuronuma, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 29 ( 2 ) 157 - 162 2023.02 [International journal]

INTRODUCTION: Early diagnosis and appropriate infection control are important to prevent the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we aimed to assess the diagnostic performance of SARS-CoV-2 rapid antigen detection (RAD) tests and the factors that cause nonspecific reactions. METHODS: Nasopharyngeal swab specimens (n = 100), sputum specimens (n = 10), and lithium-heparin plasma samples (n = 100) were collected. We evaluated Espline®SARS-CoV-2 (Espline) and SARS-CoV-2 Rapid Antigen Test that also known as STANDARD Q® (STANDARD Q), with reverse transcription-polymerase chain reaction (RT-PCR) and Lumipulse® Presto SARS-CoV-2 Ag as reference tests. In addition, we investigated the effects of inadequate pretreatment methods and five potential causes of nonspecific reactions. RESULTS: The sensitivities of Espline and STANDARD Q were 60% and 57%, respectively, and their specificity was 100%. It was confirmed that the judgment line for the positive insufficiently mixed specimens was faint. A false-positive result was observed with STANDARD Q when sputum was used as a specimen to investigate judgment the effect of viscosity. CONCLUSIONS: Espline and STANDARD Q show good sensitivity for specimens with Ct values less than 25, but specimens collected within 9 days of symptom onset may still give false negatives. The test should be performed carefully, and the results should be judged comprehensively, taking into account clinical symptoms and patient background.

Protective effect of Bifidobacterium longum BB536 against nausea caused by pirfenidone in a mouse model of pellagra.

Koji Kuronuma, Natsumi Susai, Tomohiro Kuroita, Takeshi Yoshioka, Atsushi Saito, Hirofumi Chiba

Bioscience of microbiota, food and health 42 ( 3 ) 195 - 202 2023 [Domestic journal]

Pellagra is caused by abnormal intake and/or use of nicotinic acid and is known in part to be induced by the use of medications such as isoniazid or pirfenidone. We previously investigated atypical phenotypes of pellagra, such as nausea, using a mouse model of pellagra and found that gut microbiota play an important role in the development of these phenotypes. Here, we investigated the effect of Bifidobacterium longum BB536 on pellagra-related nausea caused by pirfenidone in our mouse model. Our pharmacological data indicated that pirfenidone (PFD) causes modulation of the gut microbiota profile, which appeared to play an important role in the development of pellagra-related nausea. A gut microbiota-mediated protective effect of B. longum BB536 against nausea caused by PFD was also identified. Finally, the urinary ratio of nicotinamide/N-methylnicotinamide was shown to be a biomarker of pellagra-like adverse effects induced by PFD, and it may contribute to the prevention of these effects in patients with idiopathic pulmonary fibrosis.

Serum Testosterone Is Associated With the Severity of COVID-19.

Ema Suzuki, Koji Kuronuma, Ryosei Murai, Yoshihiro Fujiya, Atsushi Saito, Hirofumi Chiba, Satoshi Takahashi

In vivo (Athens, Greece) 37 ( 5 ) 2314 - 2319 2023 [International journal]

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is more likely to be severe in men than in women. Its association with sex hormones as an aggravating factor for male patients has been attracting attention. This study aimed to investigate whether serum testosterone is associated with the aggravation of COVID-19. PATIENTS AND METHODS: Serum testosterone concentrations in 116 male patients with COVID-19 and residual serum were measured and examined upon their admission to Sapporo Medical University Hospital between February 1, 2020 and March 31, 2021. RESULTS: Blood samples collected from these patients with COVID-19 were analyzed. The serum testosterone levels were 2.19±1.35, 1.29±0.88, and 0.75±0.58 ng/ml in mild, moderate, and severe groups, respectively. Patients with severe COVID-19 on admission had lower testosterone levels (p<0.001). At a cutoff level of 1.31 ng/ml, the area under the curve for the comparison of severe with non-severe cases was 0.825. Furthermore, serum testosterone levels negatively correlated with C-reactive protein and serum amyloid A levels but positively correlated with calcium, zinc, C3, and C4. CONCLUSION: In male patients with COVID-19, low serum testosterone levels correlated with disease severity, accompanied by a strong inflammatory reaction and proportion of complement consumption.

The Soluble Lectin Families as Novel Biomarkers for COVID-19 Pneumonia.

Haruka Takenaka, Atsushi Saito, Koji Kuronuma, Keigo Moniwa, Hirotaka Nishikiori, Satoshi Takahashi, Hirofumi Chiba

In vivo (Athens, Greece) 37 ( 4 ) 1721 - 1728 2023 [International journal]

BACKGROUND/AIM: The lung-specific soluble lectins, SP-A and SP-D have been clinically used to diagnose interstitial lung disease, but their clinical significance in COVID-19 remains controversial. This study was undertaken to determine their association with other lectins (MBL and FCN1), disease severity, and radiographs in COVID-19 patients. PATIENTS AND METHODS: A total of 131 patients with COVID-19 admitted in the Sapporo Medical University Hospital between May 22 and September 19, 2021, were enrolled in the study. Data including demographics, medical history, symptoms, signs, laboratory findings, and radiological images were collected from the patients' medical records. Chest computed tomography (CT) scanning was performed at admission. Serum levels of surfactant protein A and D (SP-A and SP-D), mannose-binding lectin (MBL) and ficolin1 (FCN1) were measured using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Compared to the control group, the COVID-19 group had significantly higher serum SP-A and FCN1 levels on admission (SP-A: 59.60±38.89 vs. 35.61±11.22 ng/ml; p<0.01, FCN1: 542.45±506.04 vs. 250.6±161.1 ng/ml; p<0.01). The severe group in COVID-19 had significantly higher serum SP-D and lower MBL levels than the non-severe group (SP-D: 141.7±155.7 vs. 61.41±54.54 ng/ml; p<0.01, MBL: 1,670±1,240 vs. 2,170±1,140 ng/ml; p<0.05). SP-D strongly reflected the degree of imaging findings, whereas SP-A showed a significant correlation, albeit slightly weaker than SP-D. Conversely, MBL and FNC1 were not significantly correlated with imaging findings. CONCLUSION: Among soluble serum lectins, SP-A and SP-D may be more sensitive to CT findings than reported disease biomarkers such as IL-6, LDH, and CRP due to their lung-specific characteristics.

COVID-19における血清レクチン値の臨床バイオマーカーとしての有用性についての検討

齋藤充史, 黒沼幸治, 富樫篤生, 藤谷好弘, 高橋聡

日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集 ( 日本感染症学会東日本地方会・日本化学療法学会東日本支部 ) 71回・69回 125 - 125 2022.10

当院における10年間のvanC保有腸球菌菌血症の特徴から見る治療において重要なこと

藤谷好弘, 佐藤勇樹, 富樫篤生, 齋藤充史, 黒沼幸治, 高橋聡

日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集 ( 日本感染症学会東日本地方会・日本化学療法学会東日本支部 ) 71回・69回 118 - 118 2022.10

男性COVID-19患者の血清テストステロン値は重症度と関連する

黒沼幸治, 鈴木瑛真, 村井良精, 中江舞美, 藤谷好弘, 齋藤充史, 高橋聡

日本感染症学会東日本地方会学術集会・日本化学療法学会東日本支部総会合同学会プログラム・抄録集 ( 日本感染症学会東日本地方会・日本化学療法学会東日本支部 ) 71回・69回 125 - 125 2022.10

Pneumocystis jirovecii Pneumonia Associated with COVID-19 in Patients with Interstitial Pneumonia.

Tomoyuki Takahashi, Atsushi Saito, Koji Kuronuma, Hirotaka Nishikiori, Hirofumi Chiba

Medicina (Kaunas, Lithuania) 58 ( 9 ) 2022.08 [International journal]

Here, we report two cases of patients with interstitial pneumonia (IP) on steroids who developed Pneumocystis jirovecii pneumonia (PJP) following coronavirus disease 2019 (COVID-19) infection. Case 1: A 69-year-old man on 10 mg of prednisolone (PSL) daily for IP developed new pneumonia shortly after his COVID-19 infection improved and was diagnosed with PJP based on chest computed tomography (CT) findings and elevated serum β-D-glucan levels. Trimethoprim-sulfamethoxazole (TMP-SMZ) was administered, and the pneumonia resolved. Case 2: A 70-year-old woman taking 4 mg/day of PSL for IP and rheumatoid arthritis developed COVID-19 pneumonia, which resolved mildly, but her pneumonia flared up and was diagnosed as PJP based on CT findings, elevated β-D-glucan levels, and positive polymerase chain reaction for P. jirovecii DNA in the sputum. The autopsy revealed diffuse alveolar damage, increased collagen fiver and fibrotic foci, mucinous component accumulation, and the presence of a P. jirovecii cyst. In conclusion, steroids and immunosuppressive medications are well-known risk factors for PJP. Patients with IP who have been taking these drugs for a long time are frequently treated with additional steroids for COVID-19; thus, PJP complications should be avoided in such cases.

Viral load may impact the diagnostic performance of nasal swabs in nucleic acid amplification test and quantitative antigen test for SARS-CoV-2 detection.

Yoshihiro Fujiya, Yuki Sato, Yuki Katayama, Shinya Nirasawa, Mikako Moriai, Masachika Saeki, Yuki Yakuwa, Ikumi Kitayama, Koichi Asanuma, Koji Kuronuma, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 11 ) 1590 - 1593 2022.08 [International journal]

INTRODUCTION: Compared to nasopharyngeal swabs (NPS), there has been insufficient evaluation of the diagnostic performance of nasal swabs (NS) for the detection of severe acute respiratory coronavirus 2 (SARS-CoV-2) in the nucleic acid amplification test (NAAT) and quantitative SARS-CoV-2 antigen test (QAT). METHODS: We prospectively compared healthcare worker-collected and flocked NS within nine days after symptom onset to paired NPS to detect SARS-CoV-2 in NAAT and QAT on the fully automated Lumipulse system. The agreement between sample types was evaluated, and cycle threshold (Ct) values and antigen levels were used as surrogate viral load measures. RESULTS: Sixty sets of NPS and NS samples were collected from 40 patients with COVID-19. The overall agreements between NAAT and QAT samples were 76.7% and 65.0%, respectively. In NAAT, the Ct value of NS was significantly higher, 5.9, than that of NPS. Thirty-nine (95.1%) NS tested positive in 41 positive-paired NPS with Ct ≤ 30. The negative correlation was observed between antigen levels of NS in QAT and Ct values of NS in NAAT (r = -0.88). In QAT, the antigen level of NS was significantly lower than that of NPS. Thirty-six (90.0%) NS tested positive in 40 positive-paired NPS with antigen levels >100 pg/mL, which were collected significantly earlier than those with antigen levels ≤100 pg/mL. CONCLUSIONS: In NAAT and QAT, NS had limited performance in detecting SARS-CoV-2 compared to NPS. However, NS may be helpful for patients with COVID-19 with high viral loads or those in the early stages of the illness.

Genotypes and transmission routes of noroviruses causing sporadic acute gastroenteritis among adults and children, Japan, 2015-2019.

Saho Honjo, Koji Kuronuma, Yoshihiro Fujiya, Mami Nakae, Susumu Ukae, Hiroshi Nihira, Masaki Yamamoto, Yusuke Akane, Kenji Kondo, Satoshi Takahashi, Hirokazu Kimura, Hiroyuki Tsutsumi, Yukihiko Kawasaki, Takeshi Tsugawa

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 104 105348 - 105348 2022.08 [International journal]

Noroviruses (NoVs) are major causes of acute viral gastroenteritis at all ages worldwide. The molecular epidemiology of sporadic cases remains poorly understood, especially in adults. Additionally, no studies have analyzed the transmission route in sporadic acute gastroenteritis. In this study, we investigated cases of very mild sporadic NoV acute gastroenteritis in adults (medical staff) who do not visit the outpatient clinic and child outpatients. We also evaluated genotype differences between adults and children and possible transmission routes in adults during 5 years. The number of NoV positives were 58 in adults and 124 in children. In adults, the NoV positivity rate in this study was higher (64.4%) than that in previous reports of outpatients (10%) and inpatients (5%) in the United State. This finding suggested that the NoV positivity rate might be high in adults with very mild acute gastroenteritis. In adults, human-to-human transmission rates from children and food-borne transmission (raw oysters) were 21.6% (11/51) and 19.6% (10/51), respectively. Among adults, GII.2, GII.4, and GII.17 were the predominant genotypes, with rates of 32.7%, 30.9%, and 21.8%, respectively. Among children, GII.4 and GII.2 were the predominant genotypes, with rates of 45.5% and 40.6%, respectively. GII.17 was only detected in 0.8% (1/123) of children. Trends in NoV genotypes are expected to differ depending on the patient's age. Investigating sporadic cases including the patient's background (age and transmission route) may be helpful to monitor the trend of NoV strains, forecast prevalent NoV GII genotypes, and develop NoV vaccines.

Does the timing of saliva collection affect the diagnosis of SARS-CoV-2 infection?

Yuki Katayama, Ryosei Murai, Mikako Moriai, Shinya Nirasawa, Masachika Saeki, Yuki Yakuwa, Yuki Sato, Koichi Asanuma, Yoshihiro Fujiya, Koji Kuronuma, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 7 ) 1012 - 1014 2022.07 [International journal]

We evaluated the optimal timing of saliva sample collection to diagnose the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We obtained 150 saliva samples at four specific time points from 13 patients with confirmed SARS-CoV-2 infection. The time points were (1) early morning (immediately after waking), (2) immediately after breakfast before tooth brushing, (3) 2 h after breakfast, and (4) before lunch. On the 2nd hospital day, patients collected saliva at the four time points by themselves. We collected samples at two time points, (1) and (3), from the 3rd hospital day to day 9 following symptom onset. In 52 samples collected at the four time points, there was no significant difference. Meanwhile, there was no significant difference in the positive proportion or the viral load between the two time points in both analyses by the day from symptom onset and by all samples. In this study, there was no difference in the positive proportions in saliva collected at various time points within 9 days after symptom onset. The timing of saliva collection was not affected by the diagnosis of SARS-CoV-2 infection.

Comparative study of rapid antigen testing and two nucleic acid amplification tests for influenza virus detection.

Yuki Sato, Shinya Nirasawa, Masachika Saeki, Yuki Yakuwa, Mayumi Ono, Ryo Kobayashi, Hirotaka Nakafuri, Ryosei Murai, Yoshihiro Fujiya, Koji Kuronuma, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 7 ) 1033 - 1036 2022.07 [International journal]

INTRODUCTION: This study aimed to evaluate rapid antigen detection (RAD) and rapid nucleic acid amplification tests (NAATs) to detect influenza virus (IV). METHODS: The conventional RAD test (Quick Chaser Flu A, B: QC), using silver amplified immunochromatography (Quick Chaser Auto Flu A, B: QCA), as well as two NAATs (Xpert Xpress Flu/RSV: Xpert, cobas Influenza A/B & RSV: cobas) were evaluated using nasopharyngeal swabs from suspected cases of influenza. A reference method was performed using real-time reverse transcription polymerase chain reaction according to the manual of the Japanese National Institute of Infectious Disease (NIID). RESULTS: From a total of 177 samples, 51 were positive according to the NIID assay. The kappa (κ) coefficient in Xpert and cobas for influenza A virus (IAV)/influenza B virus (IBV) was 1.00, which was the highest among the four detection assays. However, the κ coefficients in QC and QCA for IAV/IBV were 0.71-0.77 and 0.87-0.89, respectively. The sensitivities of the RAD tests were 41.7% in QC and 50.0% in QCA at < 6 h after onset, and 100.0% in both QC and QCA at 24-48 h after onset. The cycle threshold (Ct) values were significantly lower in the group in which all detection assays were positive for IAV. CONCLUSIONS: Xpert and cobas have comparable analytical performances and are highly useful as influenza virus detection assays. QC and QCA could show false negatives frequently in the early stage of infection and when viral load is low.

COVID-19肺炎重症度予測マーカーとしてのIL-6、INF-λ3、NGALの検討

黒沼幸治, 中江舞美, 藤谷好弘, 高橋聡, 齋藤充史, 安田健人, 千葉弘文

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 70 ( Suppl.A ) 299 - 299 2022.05

COVID-19 臨床経過予測因子 COVID-19肺炎重症度予測マーカーとしてのIL-6、INF-λ3、NGALの検討

齋藤充史, 安田健人, 黒沼幸治, 中江舞美, 藤谷好弘, 高橋聡, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 11 ( 増刊 ) 153 - 153 2022.04

胸部X線写真から線維化性間質性肺疾患を検出するAIソフトウェアの性能検証研究

錦織博貴, 黒沼幸治, 廣田健一, 鈴木朋浩, 池田貴美之, 森勇樹, 浅井悠一郎, 本田聖和, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 11 ( 増刊 ) 301 - 301 2022.04

COVID-19 臨床経過予測因子 COVID-19肺炎重症度予測マーカーとしてのIL-6、INF-λ3、NGALの検討

齋藤充史, 安田健人, 黒沼幸治, 中江舞美, 藤谷好弘, 高橋聡, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 11 ( 増刊 ) 153 - 153 2022.04

N-glycosylation regulates MET processing and signaling.

Atsushi Saitou, Yoshihiro Hasegawa, Naoki Fujitani, Shigeru Ariki, Yasuaki Uehara, Ukichiro Hashimoto, Atsushi Saito, Koji Kuronuma, Kunio Matsumoto, Hirofumi Chiba, Motoko Takahashi

Cancer science 113 ( 4 ) 1292 - 1304 2022.01 [International journal]

MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non-small cell lung cancer. MET contains 11 potential N-glycosylation sites, but the site-specific roles of these N-glycans have not been elucidated. We report herein that these N-glycans regulate the proteolytic processing of MET and HGF induced MET signaling, and that this regulation is site specific. Inhibitors of N-glycosylation were found to suppress the processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO-K1 cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using mass spectrometry. The results indicated that most sites were fully glycosylated and that the dominant population was the complex-type. To examine the effects of the deletion of N-glycans of MET, we prepared endogenous-MET-knockout Flp-In CHO cells and transfected them with a series of N-glycan deletion mutants of MET. The results showed that several N-glycans are implicated in the processing of MET. The findings also suggested that the N-glycans of the SEMA domain of MET positively regulate HGF signaling, and the N-glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing, cell surface expression, and signaling were significantly suppressed in the case of the all-N-glycan deletion mutant. The overall findings suggest that N-glycans of MET affect the status and the function of the receptor in a site-specific manner.

ファビピラビルおよびデキサメタゾン投与開始時期とCOVID-19臨床転帰の関連性

伊部裕太, 石郷友之, 藤居賢, 藤谷好弘, 黒沼幸治, 高橋聡

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 70 ( 1 ) 164 - 165 2022.01

Self-reported Smell and Taste Disorders in Patients With COVID-19: A Japanese Single-center Study.

Keisuke Yamamoto, Yoshihiro Fujiya, Koji Kuronuma, Noriko Ogasawara, Tsuyoshi Ohkuni, Shin-Ichi Yokota, Satoshi Takahashi, Kenichi Takano

In vivo (Athens, Greece) 36 ( 2 ) 918 - 924 2022 [International journal]

BACKGROUND/AIM: Smell and taste disorders are among the most common symptoms of COVID-19. However, the relationship between smell and taste disorders and systemic symptoms is not fully understood in Japan. PATIENTS AND METHODS: Questionnaires were mailed to 105 of 111 COVID-19 patients who were hospitalized at our hospital between March and July 2020 in Japan. RESULTS: A total of 74 patients (response rate: 70.5%) completed the survey. Of these, six patients (8.1%) presented with smell disorders only, 16 (21.6%) presented with taste disorders only, and 17 (23.0%) presented with both smell and taste disorders. The mean Visual Analog Scale for smell and taste was 0.5 and 20, respectively, at the time of the most severe symptoms. CONCLUSION: Among COVID-19 patients in Japan, smell and taste disorders are often followed by fever and may not be the first symptoms. Sense of smell is particularly impaired. These symptoms often improve, although they sometimes persist for a long time as sequelae.

【肺免疫から肺疾患を考える】肺疾患とマイクロバイオーム

齋藤充史, 黒沼幸治, 千葉弘文

呼吸器内科 ( (有)科学評論社 ) 40 ( 6 ) 551 - 556 2021.12

COVID-19肺炎におけるバイオマーカーとしての血清SP-AおよびSP-Dの有用性

千葉弘文, 齋藤充史, 黒沼幸治, 茂庭慶悟, 高橋弘毅

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 52 31 - 31 2021.10

新型コロナウイルスN501Y変異株感染入院患者が従来の退院基準を満たした日におけるCt値および抗原量に関する検討

藤谷好弘, 佐藤勇樹, 韮澤慎也, 中村広士, 中江舞美, 津川毅, 黒沼幸治, 高橋聡, 片山雄貴, 米澤仁, 村井良精, 盛合美加子, 四十坊典晴

病原微生物検出情報月報 ( 国立感染症研究所 ) 42 ( 10 ) 233 - 234 2021.10

Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients.

Satoshi Fujii, Yuta Ibe, Tomoyuki Ishigo, Hirotoshi Inamura, Yusuke Kunimoto, Yoshihiro Fujiya, Koji Kuronuma, Hiromasa Nakata, Masahide Fukudo, Satoshi Takahashi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 7 ) 1051 - 1057 2021.04 [International journal]

INTRODUCTION: The antiviral drug favipiravir has been shown to have in vitro antiviral activity against severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2). In this study, we investigated the clinical benefits and initiation of favipiravir treatment in patients with non-severe coronavirus-disease-2019 (COVID-19). METHODS: This study was a single-center retrospective cohort study. Receiver operating characteristic curves were drawn to calculate the area under the curve, and the optimal cut-off values for the time to initiate favipiravir treatment were calculated to predict defervescence within seven days. Univariate and multivariate Cox regression analyses were performed to identify potential influencing factors of defervescence. This was defined as a body temperature of less than 37 °C for at least 2 days. RESULTS: Data from 41 patients were used for the efficacy assessment. The days from the onset of fever to defervescence showed a positive correlation with the duration from the onset of fever to initiation of favipiravir treatment (r = 0.548, P < 0.001). The optimal cut-off value was the administration of favipiravir on day 4. Patients were assigned to two groups based on the optimal cut-off value from onset to initiation of favipiravir treatment: early treatment group (within 4-days) and late treatment group (more than 4-days). In the multivariate analysis, when adjusted for age, sex, and days from onset to initiation of favipiravir treatment, the significant factors were male sex and days of initiation of the favipiravir treatment. CONCLUSIONS: We recommend that if favipiravir is to be used for treatment, it should be initiated as early as possible.

Invasive pneumococcal disease affected the fatal outcome in a COVID-19 patient.

Koji Kuronuma, Naofumi Bunya, Bin Chang, Yoshihiro Fujiya, Kazunori Oishi, Eichi Narimatsu, Satoshi Takahashi, Hirofumi Chiba

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 7 ) 1108 - 1111 2021.04 [International journal]

A 68-year-old man experienced fever and cough and was referred to a hospital for day 4. He had a positive reverse transcription-polymerase chain reaction result for severe acute respiratory syndrome coronavirus-2. On day 12, his PaO2/FiO2 ratio worsened to 120 and he was transferred to Sapporo Medical University Hospital for treatment using extracorporeal membrane oxygenation. Venous blood cultures were positive for Streptococcus pneumoniae, which were serotype 3, mucoid-type, and penicillin susceptible. Coinfections with coronavirus disease-2019 and invasive pneumococcal disease are rare; however, they are associated with a higher case fatality than either of the conditions manifesting alone.

ピルフェニドンの抗線維化作用におけるTRPV4の役割

黒沼幸治, 大塚満雄, 若林雅人, 吉岡健, 小林智史, 亀田優美, 森岡靖英, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 10 ( 増刊 ) 258 - 258 2021.04

鼻腔ぬぐい液および抗原定量検査の臨床的有効性に関する検討

藤谷好弘, 黒沼幸治, 高橋聡

感染症学雑誌 ( (一社)日本感染症学会 ) 95 ( 臨増 ) 251 - 251 2021.04

【呼吸器疾患とマイクロバイオーム】特発性肺線維症における肺マイクロバイオーム研究の展開

黒沼幸治, 齋藤充史, 千葉弘文

呼吸臨床 ( COSMIC ) 5 ( 4 ) 1/5 - 5/5 2021.04

特発性肺線維症(idiopathic pulmonary fibrosis:IPF)は進行性に肺の線維化を来す予後不良の疾患である。近年肺マイクロバイオームの解析により,IPFの進行と肺マイクロバイオータの多様性喪失(dysbiosis)との相関やIPFの病態形成と微生物の関わりに関する新たな知見が得られている。今後マイクロバイオーム解析がIPFの診断や治療の発展に寄与し,新規治療法の開発が進むことが期待されている。(著者抄録)

COVID-19肺炎重症度予測マーカーとしての血清SP-A,D値の検討

齋藤充史, 黒沼幸治, 小玉賢太郎, 茂庭慶悟, 高橋聡, 高橋弘毅, 千葉弘文

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 10 ( 増刊 ) 272 - 272 2021.04

臨床応用を目指した肺胞微石症の基礎および治療法の検討

齋藤充史, 高宮里奈, 藤谷直樹, 有木茂, 黒沼幸治, 千葉弘文, 高橋素子, 高橋弘毅

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 51 32 - 33 2021.03

臨床応用を目指した肺胞微石症の基礎および治療法の検討

齋藤充史, 高宮里奈, 藤谷直樹, 有木茂, 黒沼幸治, 千葉弘文, 高橋素子, 高橋弘毅

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 51 32 - 33 2021.03

Characteristics of COVID-19 patients admitted into two hospitals in sapporo, Japan: Analyses and insights from two outbreak waves.

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

Respiratory investigation 59 ( 2 ) 180 - 186 2021.03 [Refereed] [International journal]

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.

肺多型癌に対しCBDCA+nab-PTX+Pembrolizumab療法を施行した3例

村尾公太郎, 小林智史, 高橋由紀乃, 石川立, 浅井悠一郎, 森勇樹, 池田貴美之, 高橋守, 黒沼幸治, 千葉弘文

肺癌 ( (NPO)日本肺癌学会 ) 61 ( 1 ) 64 - 64 2021.02

Acute eosinophilic pneumonia accompanied with COVID-19: a case report.

Koutaro Murao, Atsushi Saito, Koji Kuronuma, Yoshihiro Fujiya, Satoshi Takahashi, Hirofumi Chiba

Respirology case reports 8 ( 9 ) e00683 2020.12 [International journal]

We report a case of acute eosinophilic pneumonia (AEP) triggered by coronavirus disease 2019 (COVID-19) infection. A 77-year-old man experienced left-sided chest pain and shortness of breath. Reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) revealed a positive result, and he was treated with favipiravir, ciclesonide, and lascufloxacin, but he showed poor improvement. On the other hand, computed tomography (CT) images were atypical for COVID-19 infection, and the elevation of eosinophil was found in blood and the fluid obtained by bronchoscopy. So, we clinically diagnosed this case as AEP. Administration of prednisolone dramatically improved the patient's clinical condition and chest radiograph findings, which were consistent with the clinical course of AEP. This case suggests the importance of considering the complications of AEP when treating patients with COVID-19 infection.

高周波凝固法が有効であった多発気管・気管支乳頭腫の1例

宮坂友紀, 宮島さつき, 関川元基, 佐々原正幸, 小玉賢太郎, 斎藤充史, 高橋守, 黒沼幸治, 千葉弘文

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 42 ( 6 ) 575 - 575 2020.11

嗅覚障害が持続する新型コロナウイルス感染症患者は退院後も経過に注意すべきである

藤谷好弘, 黒沼幸治, 高橋聡

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 68 ( Suppl.A ) 302 - 302 2020.09

自己免疫疾患関連間質性肺炎のバイオマーカーの検討

亀田優美, 大塚満雄, 長谷川武宏, 吉田真穂, 近藤孝美, 黒沼幸治, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 9 ( 増刊 ) 294 - 294 2020.08

本邦における肺胞微石症の一症例とモデルマウスを用いた病態解析

齋藤充史, 高宮里奈, 有木茂, 黒沼幸治, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 9 ( 増刊 ) 254 - 254 2020.08

本邦における肺胞微石症の一症例とモデルマウスを用いた病態解析

齋藤充史, 高宮里奈, 有木茂, 黒沼幸治, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 9 ( 増刊 ) 254 - 254 2020.08

Erratum: Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis (BMC Pulm Med (2020) 20: 27 DOI: 10.1186/s12890-020-1060-y)

Takumi Yoshikawa, Mitsuo Otsuka, Hirofumi Chiba, Kimiyuki Ikeda, Yuki Mori, Yasuaki Umeda, Hirotaka Nishikiori, Koji Kuronuma, Hiroki Takahashi

BMC Pulmonary Medicine ( BioMed Central Ltd. ) 20 ( 1 ) 2020.05

Respiratory reactance in forced oscillation technique reflects disease stage and predicts lung physiology deterioration in idiopathic pulmonary fibrosis

Yuki Mori, Hirotaka Nishikiori, Hirofumi Chiba, Gen Yamada, Koji Kuronuma, Hiroki Takahashi

Respiratory Physiology and Neurobiology ( Elsevier B.V. ) 275 2020.04

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease. Although pulmonary function test (PFT) is useful for evaluating the progression of IPF, obtaining adequate results in advanced cases can be challenging. Conversely, the forced oscillation technique (FOT) can be noninvasively performed, even in patients with severely deteriorated lung function. In this study, the usefulness of FOT for the evaluation of IPF disease status was investigated. Methods: We analyzed the PFT and FOT data of 97 patients with IPF. Results: The respiratory reactance (Xrs) components of FOT, especially in the inspiratory phase, correlated with the PFT values. Patients with advanced disease had significantly lower reactance at 5 Hz (X5), higher resonant frequency (Fres) and low-frequency reactance area (ALX). The longitudinal deterioration of Xrs was also observed. Moreover, X5 in the inspiratory phase predicted subsequent lung capacity deterioration. Conclusion: The Xrs components of FOT, especially in the inspiratory phase, reflected restrictive ventilatory impairment and disease severity in patients with IPF.

Haemophilus influenzaeのキノロン系抗菌薬耐性に関与する遺伝子変異の解析

本田宏幸, 佐藤豊孝, 黒沼幸治, 高橋聡, 高橋弘毅, 横田伸一

感染症学雑誌 ( (一社)日本感染症学会 ) 94 ( 臨増 ) 317 - 317 2020.03

肺MAC症における血清L-Ficolinの意義

黒沼幸治, 小林智史, 斎藤充史, 池田貴美之, 大塚満雄, 千葉弘文, 有木茂, 高橋素子, 高橋弘毅

分子呼吸器病 ( (株)先端医学社 ) 24 ( 1 ) 84 - 87 2020.03

肺Mycobacterium avium complex(MAC)症患者におけるL-Ficolinの役割について検討した。肺MAC症患者61例を対象とし、対照群は呼吸器疾患を有していない健常者30例とした。血清L-Ficolinは対照群30例に比べ、肺MAC症患者群61例で有意に低値であった(1.69±1.27μg/mL vs.3.96±1.42μg/mL:p<0.001)。ROC解析結果にもとづくcut off値は2.48μg/mLであった(AUC 0.90、感度83.6%、特異度86.7%)。胸部画像所見からMAC症の病型別にL-Ficolin値について検討した。その結果、血清L-Ficolinは結節・気管支拡張型では線維空洞型に比べて有意に低値であった。さらにMAC症の重症度の評価としてHRCTスコアリング法を用いて検討した。HRCTスコアは高値であれば重症と考えられるが、高値群で有意に低値であった。次にM.aviumとL-Ficolinの直接相互作用について検討を行った。In vitroの実験で精製L-FicolinはM.aviumに濃度依存性に結合した。また、M.avium細胞壁主成分であるリポアラビノマンナンとL-Ficolinも特異的な結合を認めた。培地中でのM.aviumの増殖にL-Ficolinやサーファクタント蛋白質A、D(SP-A、SP-D)が及ぼす影響を調べた。以前の検討からSP-Aは増殖抑制効果を示し、SP-Dは影響を及ぼさないことが分かっていたため、比較のために用いた。L-FicolinはM.aviumの増殖を有意に抑制した。また、抑制効果はL-Ficolin濃度依存性であった。

なるほど微生物学講座-不思議なミクロの世界- インフルエンザ菌におけるβ-ラクタムおよびキノロン系抗菌薬耐性に関する分子遺伝学的解析

佐藤豊孝, 本田宏幸, 黒沼幸治, 高橋聡, 横田伸一

感染症学雑誌 ( (一社)日本感染症学会 ) 94 ( 臨増 ) 142 - 142 2020.03

Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis

Takumi Yoshikawa, Mitsuo Otsuka, Hirofumi Chiba, Kimiyuki Ikeda, Yuki Mori, Yasuaki Umeda, Hirotaka Nishikiori, Koji Kuronuma, Hiroki Takahashi

BMC Pulmonary Medicine ( BioMed Central ) 20 ( 1 ) 2020.01

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. Methods: We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. Results: Forty-nine patients were included (pirfenidone, 23 nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months-6.0% vs 16.7%, 6 months-10.2% vs 20.2%, KL-6: 3 months-9.2% vs 6.7%, 6 months-15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r =-0.46 and r =-0.39, p < 0.01, respectively) and %DLco (r =-0.67 and r =-0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively). Conclusions: Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

In Vitro Derivation of Fluoroquinolone-Resistant Mutants from Multiple Lineages of Haemophilus influenzae and Identification of Mutations Associated with Fluoroquinolone Resistance.

Hiroyuki Honda, Toyotaka Sato, Masaaki Shinagawa, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Koji Kuronuma, Satoshi Takahashi, Hiroki Takahashi, Shin-Ichi Yokota

Antimicrobial agents and chemotherapy 64 ( 2 ) 2020.01 [Refereed] [International journal]

Haemophilus influenzae is a pathogenic bacterium that causes respiratory and otolaryngological infections. The increasing prevalence of β-lactamase-negative high-level ampicillin-resistant H. influenzae (high-BLNAR) is a clinical concern. Fluoroquinolones are alternative agents to β-lactams. However, the emergence and increasing prevalence of fluoroquinolone-resistant H. influenzae have been reported. The current risk of fluoroquinolone resistance in H. influenzae (especially in high-BLNAR) has not yet been evaluated. Here, we examined the development of fluoroquinolone resistance in fluoroquinolone-susceptible clinical H. influenzae isolates in vitro during passaging in the presence of moxifloxacin (from 0.03 to 128 mg/liter). Twenty-nine isolates were examined. Seventeen isolates (58.6%) showed reduced moxifloxacin susceptibility, and 10 of these 17 isolates (34.5% of all isolates) exceeded the Clinical and Laboratory Standards Institute breakpoint for moxifloxacin (MIC of >1 mg/liter) after repeat cultivation on moxifloxacin-containing agar. Seven of these ten isolates were high-BLNAR and represented multiple lineages. We identified 56 novel mutations in 45 genes induced during the development of fluoroquinolone resistance, except the defined quinolone resistance-determining regions (Ser84Leu and Asp88Tyr/Gly/Asn in GyrA and Gly82Asp, Ser84Arg, and Glu88Lys in ParC). Glu153Leu and ΔGlu606 in GyrA, Ser467Tyr and Glu469Asp in GyrB, and ompP2 mutations were novel mutations contributing to fluoroquinolone resistance in H. influenzae In conclusion, H. influenzae clinical isolates from multiple lineages can acquire fluoroquinolone resistance by multiple novel mutations. The higher rate of derivation of fluoroquinolone-resistant H. influenzae from high-BLNAR than β-lactamase-negative ampicillin-susceptible isolates (P = 0.01) raises the possibility of the emergence and spread of fluoroquinolone-resistant high-BLNAR in the clinical setting.

CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases-associated interstitial lung disease and interstitial pneumonia with autoimmune features.

Masami Kameda, Mitsuo Otsuka, Hirofumi Chiba, Koji Kuronuma, Takehiro Hasegawa, Hiroki Takahashi, Hiroki Takahashi

PloS one 15 ( 11 ) e0241719 2020 [International journal]

INTRODUCTION: Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by varying degrees of lung inflammation and/or fibrosis. We investigated biomarkers to infer whether patients with collagen vascular diseases associated ILD (CVD-ILD) and interstitial pneumonia with autoimmune features (IPAF) benefit from immunosuppressive therapy. MATERIALS AND METHODS: We retrospectively investigated patients with CVD-ILD, IPAF, and idiopathic pulmonary fibrosis (IPF) between June 2013 and May 2017 at our department. First, we assessed differences in serum and bronchoalveolar lavage fluid (BALF) levels of cytokines between groups. Second, we assessed the associations of patient's clinical variables with serum and BALF levels of those cytokines that were different between groups. Finally, we assessed the associations of diagnosis and response to immunosuppressive therapy with serum levels of those cytokines that were different between groups. RESULTS: We included 102 patients (51 with IPF, 35 with IPAF, and 16 with CVD-ILD). Serum and BALF levels of CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with IPAF or CVD-ILD compared with those in patients with IPF. BALF levels of CXCL9 and CXCL10 were correlated with the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9 and CXCL10 were correlated with BALF levels. Serum levels of CXCL9, CXCL10, and CXCL11 were correlated C-reactive protein, percent predicted forced vital capacity, alveolar-arterial oxygen difference, and the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9, CXCL10, and CXCL11 showed moderate accuracy to distinguish patients with CVD-ILD from those with IPAF and IPF. Pre-treatment serum levels of CXCL9 and CXCL11 showed strong positive correlations with the annual forced vital capacity changes in patients with IPAF and CVD-ILD treated with immunosuppressive drugs. CONCLUSIONS: Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity.

IgG4関連疾患に合併したM.avium症の1例

澤井健之, 梅田泰淳, 須藤悠太, 浅井悠一郎, 高橋洋平, 小林智史, 森勇樹, 錦織博貴, 黒沼幸治, 山本元久, 高橋弘毅

日本サルコイドーシス/肉芽腫性疾患学会雑誌 ( 日本サルコイドーシス ) 39 ( 1-2 ) 113 - 113 2019.10

Insufficient serum L-ficolin is associated with disease presence and extent of pulmonary Mycobacterium avium complex disease.

Kobayashi T, Kuronuma K, Saito A, Ikeda K, Ariki S, Saitou A, Otsuka M, Chiba H, Takahashi S, Takahashi M, Takahashi H

Respiratory research 20 ( 1 ) 224 - 224 2019.10 [Refereed] [International journal]

BACKGROUND: The incidence of infectious disease caused by nontuberculous mycobacteria is increasing worldwide. Pulmonary Mycobacterium avium complex (MAC) disease is difficult to treat with chemotherapy, and its mechanism of infection, infection route, disease onset, and severity remain unknown. Ficolins are oligomeric defense lectins. L-ficolin plays an important role in innate immunity. This study's aim was to identify L-ficolin's role in patients with pulmonary MAC disease. METHODS: Between April 2011 and September 2017, 61 Japanese patients with pulmonary MAC disease were seen at our hospital. A control group, comprising 30 healthy individuals, without respiratory disease were enrolled in our study. The relationship between serum L-ficolin levels and disease severity was assessed, and L-ficolin's antibacterial role was examined. RESULTS: Serum L-ficolin levels were significantly lower in patients with pulmonary MAC disease than in healthy subjects (1.69 ± 1.27 μg/ml vs. 3.96 ± 1.42 μg/ml; p < 0.001). The cut-off value, based on receiver operating characteristic (ROC) analysis results, was 2.48 μg/ml (area under the curve (AUC) 0.90, sensitivity and specificity 83.6 and 86.7%, respectively). Serum L-ficolin levels were significantly lower in the patients with nodular bronchiectatic type disease compared with the patients with fibrocavitary type disease and were lower in the high-resolution computed tomography high-scoring group compared with low-scoring group. An in vitro analysis showed that purified recombinant L-ficolin bound to M. avium and its major cell wall component, lipoarabinomannan, in a concentration-dependent manner. In addition, recombinant L-ficolin suppressed M. avium growth in a concentration-dependent manner. CONCLUSIONS: Insufficient serum L-ficolin is associated with disease progression in pulmonary MAC disease, and the level of serum L-ficolin is a possible biomarker. TRIAL REGISTRATION: This study is registered with UMIN ( UMIN000022392 ).

自己免疫性肺胞蛋白症の2例症例を通して病態形成を考える

池田貴美之, 千葉弘文, 萬谷峻史, 澤井健之, 齋藤充史, 梅田泰淳, 錦織博貴, 黒沼幸治, 大塚満雄, 高橋弘毅

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 50 48 - 50 2019.10

Autoimmune Pulmonary Alveolar Proteinosis Diagnosed after Exposure to a Fire Extinguisher Containing Silica Powder.

Takafumi Yorozuya, Kimiyuki Ikeda, Hirofumi Chiba, Atsushi Saito, Koji Kuronuma, Hirotaka Nishikiori, Satsuki Miyajima, Mamoru Takahashi, Takumi Yoshikawa, Youhei Takahashi, Tetsuya Taya, Yuki Mori, Yasuaki Umeda, Mitsuo Otsuka, Hiroshi Moriyama, Hiroki Takahashi

Internal medicine (Tokyo, Japan) 58 ( 14 ) 2067 - 2072 2019.07 [Domestic journal]

We herein report a case of autoimmune pulmonary alveolar proteinosis (PAP) diagnosed after one-time exposure to silica powder. Owing to the misuse of a silica-containing fire extinguisher and the inhalation of large amounts of its powder, the patient experienced prolonged cough and visited our hospital. The findings of chest computed tomography and surgical lung biopsy specimens led to the diagnosis of PAP. Interestingly, the presence of anti-GM-CSF antibody was detected; therefore, both autoimmune characteristics and exposure to large amounts of silica may have caused the development of PAP in this patient. This case provides important insight into the mechanisms leading to the onset of PAP.

結核性膝関節炎を先行発症した結核性胸膜炎の1例

小林智史, 浅井悠一朗, 池田貴美之, 梅田泰明, 亀田優美, 錦織博貴, 黒沼幸治, 大塚満雄, 千葉弘文, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 41 ( Suppl. ) S355 - S355 2019.06

結核性胸膜炎を契機に診断しえた滑膜型結核性膝関節炎の1例

小林智史, 黒沼幸治, 池田貴美之, 錦織博貴, 千葉弘文, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 94 ( 6 ) 395 - 400 2019.06

症例は74歳男性。骨髄線維症に対しJAK阻害薬を、特発性器質化肺炎に対しprednisoloneを内服していた。37℃台の発熱および右膝関節痛のため、近医整形外科を受診したが原因が判明せず対症療法となっていた。4ヵ月後、左胸水貯留による呼吸困難を認めたため、精査目的に当科紹介入院となった。胸水所見および採血で結核菌特異的インターフェロンγ遊離試験(IGRA)が陽性であることから結核性胸膜炎を疑い局所麻酔下胸腔鏡検査による壁側胸膜生検を施行したが、リンパ球主体の炎症細胞浸潤を呈する非特異的な炎症所見しか得られず確定診断には至らなかった。肺外結核の合併が考えられたため、膝関節滑膜生検を整形外科に依頼した。病理所見で、リンパ球主体の炎症細胞浸潤を伴う乾酪壊死巣とラングハンス巨細胞を認め、結核感染症に矛盾しなかった。抗結核薬治療を開始したところ症状は著明に改善した。最終的に胸水および壁側胸膜、膝関節滑膜生検組織より結核菌が培養され確定診断に至った。結核性膝関節炎に結核性胸膜炎を合併した稀な症例を経験したので報告する。(著者抄録)

無症状で発見された気管支内過誤腫の一例

梅田泰淳, 浅井悠一郎, 小林智史, 池田貴美之, 錦織博貴, 高橋守, 黒沼幸治, 大塚満雄, 千葉弘文, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 41 ( Suppl. ) S282 - S282 2019.06

Immunogenicity of pneumococcal vaccines in comorbid autoimmune and chronic respiratory diseases

Koji Kuronuma, Hiroki Takahashi

Human Vaccines and Immunotherapeutics ( Taylor and Francis Inc. ) 15 ( 4 ) 859 - 862 2019.04

Streptococcus pneumoniae causes pneumonia, meningitis, otitis media, and bacteremia. The mortality and morbidity of invasive pneumococcal disease are high among adults aged > 65 years or those with underlying chronic or immunosuppressive conditions. A recent systematic review showed that patients treated with immunosuppressive agents have impaired immune responses to pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine compared with healthy subjects. A more favorable response is observed in patients treated with tumor necrosis factor-alpha-blocking agents compared with those treated with other immunosuppressive agents. Low systemic corticosteroid doses do not affect the responses to pneumococcal vaccines. Patients with human immunodeficiency virus and idiopathic pulmonary fibrosis receiving immunosuppressive therapy exhibit decreased immunogenicity to pneumococcal vaccines. The effects of T-cell-dependent PCV possibly depend on host memory B cells in some disease conditions. Several immunosuppressive therapy types and disease conditions may affect the responses to pneumococcal vaccines. Immunization should be administered before immunosuppressive medication initiation whenever possible.

肺MAC症患者におけるL-Ficolinの役割の検討

小林智史, 黒沼幸治, 池田貴美之, 錦織博貴, 千葉弘文, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 94 ( 3 ) 251 - 251 2019.03

当院における迅速発育菌感染症の臨床的検討

黒沼幸治, 小林智史, 池田貴美之, 錦織博貴, 千葉弘文, 品川雅明, 高橋聡, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 94 ( 3 ) 267 - 267 2019.03

非結核性抗酸菌症血清L-Ficolin低値が肺MAC症の発症に関連する

小林智史, 黒沼幸治, 齋藤充史, 池田貴美之, 大塚満雄, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 8 ( 増刊 ) 158 - 158 2019.03

骨髄線維症に対するJAK阻害薬使用中に結核性膝関節炎と結核性胸膜炎を発症した1例

錦織博貴, 小林智史, 池田貴美之, 黒沼幸治, 千葉弘文, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 94 ( 3 ) 236 - 236 2019.03

血管内異物除去用スネアを用いて異物を除去した小児気管支異物の1例

小玉賢太郎, 長尾喬生, 吉川匠, 多屋哲也, 池田貴美之, 宮島さつき, 高橋守, 黒沼幸治, 大塚満雄, 千葉弘文, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 41 ( 1 ) 91 - 92 2019.01

結核性膝関節炎を先行発症した結核性胸膜炎の1例

小林智史, 本田宏幸, 斎藤充史, 錦織博貴, 黒沼幸治, 高橋弘毅

感染症学雑誌 ( (一社)日本感染症学会 ) 93 ( 1 ) 100 - 101 2019.01

特発性肺線維症における肺マイクロバイオーム研究の展開

黒沼幸治, 齋藤充史, 池田貴美之, 大塚満雄, 千葉弘文, 高橋弘毅

日本肺サーファクタント・界面医学会雑誌 ( 日本肺サーファクタント・界面医学会 ) 49 1 - 7 2018.10

以前は無菌であると考えられていた気道の上皮表面には、健康な状態でも多様な微生物叢が存在することが明らかとなり、特発性肺線維症(IPF)の患者は微生物叢の異常がある可能性が示唆されている。IPFの肺マイクロバイオームを検討することにより、予後予測のバイオマーカーや治療の新たな標的を探索することが可能になる。最近の研究では、IPFにおける肺微生物叢変化に対する宿主応答と病因との関連性が解明され始めている。

特発性肺線維症における肺マイクロバイオームについての検討

高橋洋平, 齋藤充史, 池田貴美之, 小林智史, 黒沼幸治, 千葉弘文, 佐々木泰史, 高橋弘毅

日本サルコイドーシス/肉芽腫性疾患学会雑誌 ( 日本サルコイドーシス ) 38 ( 1-2 ) 104 - 104 2018.10

Multiclonal Expansion and High Prevalence of β-Lactamase-Negative Haemophilus influenzae with High-Level Ampicillin Resistance in Japan and Susceptibility to Quinolones.

Hiroyuki Honda, Toyotaka Sato, Masaaki Shinagawa, Yukari Fukushima, Chie Nakajima, Yasuhiko Suzuki, Tsukasa Shiraishi, Koji Kuronuma, Satoshi Takahashi, Hiroki Takahashi, Shin-Ichi Yokota

Antimicrobial agents and chemotherapy 62 ( 9 ) 2018.09 [Refereed] [International journal]

β-Lactam-resistant Haemophilus influenzae is a clinical concern. A high prevalence (>40%) of β-lactamase-negative high-level ampicillin-resistant H. influenzae (high-BLNAR) isolates in Japan has been reported. However, the reasons for the expansion are unknown. High-BLNAR strains possess an amino acid substitution, either Asn526Lys (group III) or Arg517His (group III-like) in addition to Ser385Thr, in penicillin-binding protein 3 (PBP3). To determine the current prevalence of high-BLNAR strains and the mechanisms behind their expansion in Japan, their prevalence, PBP3 types, multilocus sequence types, and susceptibilities to quinolones approved in Japan as alternatives were determined. Sixty percent of H. influenzae clinical isolates (62/104 isolates) were β-lactamase-negative ampicillin-resistant H. influenzae (BLNAR) strains. Among BLNAR isolates, 92% (57/62 isolates) were high-BLNAR strains. Most isolates were classified as belonging to group III, which contained many genotypes (11 PBP3 types and 25 sequence types). These results indicated that the expansion of high-BLNAR isolates was multiclonal and such strains are still predominant in Japanese clinical settings. One high-BLNAR isolate harbored the novel amino acid substitution Asn526Met in addition to Ser385Thr in PBP3, suggesting a new group (group IV). No quinolone-resistant H. influenzae isolates were identified. The MICs for the quinolones (moxifloxacin, garenoxacin, and tosufloxacin) were similar to that for levofloxacin, whereas sitafloxacin exhibited a lower MIC. However, we obtained 4 H. influenzae isolates with decreased quinolone susceptibility with the amino acid substitution Ser84Leu in GyrA, and 3 of those isolates were high-BLNAR isolates. In summary, this study shows that multiclonal high-BLNAR strains predominate in a Japanese university hospital. Isolates remain sensitive to quinolones, but vigilance is required to prevent the development of fluoroquinolone resistance in high-BLNAR strains.

Contribution of Novel Amino Acid Alterations in PmrA or PmrB to Colistin Resistance in mcr-Negative Escherichia coli Clinical Isolates, Including Major Multidrug-Resistant Lineages O25b:H4-ST131-H30Rx and Non-x.

Toyotaka Sato, Tsukasa Shiraishi, Yoshiki Hiyama, Hiroyuki Honda, Masaaki Shinagawa, Masaru Usui, Koji Kuronuma, Naoya Masumori, Satoshi Takahashi, Yutaka Tamura, Shin-Ichi Yokota

Antimicrobial agents and chemotherapy 62 ( 9 ) 2018.09 [International journal]

Colistin is a last-line drug for multidrug-resistant Gram-negative bacteria. We previously reported four plasmid-mediated colistin resistance (mcr) gene-negative colistin-resistant Escherichia coli clinical isolates, including the major pathogenic and fluoroquinolone-resistant strains O25b:H4-ST131-H30Rx (isolates SRE34 and SRE44; MIC for colistin = 16 mg/liter), non-x (SME296; MIC = 8 mg/liter), and O18-ST416 (SME222; MIC = 4 mg/liter). In this study, we investigated the colistin resistance mechanism and identified novel amino acid substitutions or deletions in the PmrAB two-component system that activates eptA (encoding a phosphoethanolamine transferase) and arnT (encoding an undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase) in all colistin-resistant isolates. SRE34 possessed deletion Δ27-45 (LISVFWLWHESTEQIQLFE) in PmrB, SRE44 possessed substitution L105P in PmrA, and both SME222 and SME296 included substitution G206D in PmrB. Matrix-assisted laser desorption ionization-time of flight mass spectrometry revealed that lipid A is modified with phosphoethanolamine in all four isolates. Deletion of pmrAB decreased colistin MICs to 0.5 mg/liter and lowered eptA and arnT expression. Chromosomal replacement of mutated pmrA or pmrB in colistin-susceptible O25b:H4-ST131 strain SME98 (colistin MIC = 0.5 mg/liter) increased the colistin MIC to that of the respective parent colistin-resistant isolate. In addition, SME98 mutants in which pmrAB was replaced with mutated pmrAB showed no significant differences in bacterial growth and competition culture from the parent strain, except for the mutant with L105P in PmrA, whose growth was significantly suppressed in the presence of the parent strain. In conclusion, some O25b:H4-ST131 strains appear to acquire colistin resistance via phosphoethanolamine modification of lipid A through amino acid changes in PmrAB, and the amino acid changes in PmrB do not influence bacterial growth.

Response to pneumococcal vaccine in interstitial lung disease patients: Influence of systemic immunosuppressive treatment.

Koji Kuronuma, Hiroyuki Honda, Tessei Mikami, Atsushi Saito, Kimiyuki Ikeda, Mitsuo Otsuka, Hirofumi Chiba, Gen Yamada, Toyotaka Sato, Shin-Ichi Yokota, Hiroki Takahashi

Vaccine 36 ( 33 ) 4968 - 4972 2018.08 [Refereed] [International journal]

BACKGROUND: Interstitial lung diseases (ILD) are severe respiratory diseases, and ILD patients are treated with corticosteroid and immunosuppressive agents. However, it is unclear whether these medications influence the response of pneumococcal vaccine. OBJECTIVES: We examined the immunogenicity of pneumococcal vaccines (PPSV23 and PCV13) in ILD patients undergoing immunosuppressive treatment. METHODS: ILD patients who were regularly followed at the outpatient clinic were enrolled. Sera were collected before and 4-8 weeks after vaccination. Serotype-specific immunoglobulin G (IgG) concentrations against pneumococcal serotype 19F were measured by ELISA. RESULTS: IgG concentrations to serotype 19F were increased in all groups in response to the vaccine. Both PCV13 and PPSV23 induced IgG concentrations in patients immunized for the first time. Response rates for the ILD group were comparable with those for the ILD group undergoing corticosteroid therapy. Only idiopathic pulmonary fibrosis patients undergoing immunosuppressive therapy had a significantly lower response.

Whole genome analysis of a multidrug-resistant Streptococcus pneumoniae isolate from a patient with invasive pneumococcal infection developing disseminated intravascular coagulation.

Yasuo Ohkoshi, Toyotaka Sato, Takayuki Wada, Yukari Fukushima, Hiromi Murabayashi, Yasunari Takakuwa, Kaoru Nishiyama, Hiroyuki Honda, Tsukasa Shiraishi, Koji Kuronuma, Hiroki Takahashi, Chie Nakajima, Yasuhiko Suzuki, Shin-Ichi Yokota

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 24 ( 8 ) 674 - 681 2018.08 [International journal]

Multidrug-resistant Streptococcus pneumoniae strains were isolated from blood and sputum of a patient with disseminated intravascular coagulation in Sapporo city, Japan. These antibiograms were only susceptible to vancomycin, linezolid, daptomycin, some carbapenems, and some fluoroquinolones. Identical antibiograms, serotypes (19F), and sequence types (ST10017) suggested a shared origin of these isolates. Only one ST10017 strain has been isolated in the same city in Japan previously (2014), and the 2014 isolate is still susceptible to macrolides. The whole genome of the blood-derived isolate was sequenced. The strain harbored resistance mutations in parC, gyrA, pbp1a, pbp2a, pbp2b, and pbp2x, and harbored the resistance genes, ermB and tetM. The nucleotide sequences of parC and pbp2x genes of strain MDRSPN001 were clearly different from those of other S. pneumoniae strains and were similar to those of oral streptococci strains. These findings suggest that strain MDRSPN001 has been rapidly and drastically evolving multidrug resistance by gene replacement and accumulation of genes originating from other strains, such as oral streptococci, Streptococcus mitis.

侵襲性肺炎球菌感染症患者から分離された多剤耐性肺炎球菌の解析

本田宏幸, 佐藤豊孝, 大越康雄, 村林広美, 小林智史, 齋藤充史, 錦織博貴, 黒沼幸治, 高橋弘毅, 横田伸一

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 66 ( Suppl.A ) 289 - 289 2018.04

肺MAC症患者におけるL-Ficolinの役割の検討

小林智史, 齋藤充史, 本田宏幸, 錦織博貴, 黒沼幸治, 高橋弘毅

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 66 ( Suppl.A ) 347 - 347 2018.04

結核感染を合併したStreptococcus salivariusおよびStreptococcus mitis/oralisによる肺膿瘍の1例

小林智史, 本田宏幸, 斎藤充史, 錦織博貴, 黒沼幸治, 高橋弘毅

感染症学雑誌 ( (一社)日本感染症学会 ) 92 ( 2 ) 229 - 230 2018.03

EGFR遺伝子変異陽性肺腺癌患者における予後予測因子としてのSP-Dの有用性

梅田泰淳, 長谷川喜弘, 大塚満雄, 黒沼幸治, 高橋素子, 高橋弘毅

日本内科学会雑誌 ( (一社)日本内科学会 ) 107 ( Suppl. ) 176 - 176 2018.02

Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis.

Takahashi Y, Saito A, Chiba H, Kuronuma K, Ikeda K, Kobayashi T, Ariki S, Takahashi M, Sasaki Y, Takahashi H

Respiratory research 19 ( 1 ) 34 2018.02 [Refereed]

Poorer Prognosis of Idiopathic Pleuroparenchymal Fibroelastosis Compared with Idiopathic Pulmonary Fibrosis in Advanced Stage

Makoto Shioya, Mitsuo Otsuka, Gen Yamada, Yasuaki Umeda, Kimiyuki Ikeda, Hirotaka Nishikiori, Koji Kuronuma, Hirofumi Chiba, Hiroki Takahashi

Canadian Respiratory Journal ( Hindawi Limited ) 2018 2018

Objective. Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare disease characterized by predominant upper lobe pulmonary fibrosis of unknown etiology. However, the prognosis of IPPFE has not been discussed. We investigated the clinical characteristics and prognostic factors of IPPFE and idiopathic pulmonary fibrosis (IPF). Methods. We performed a retrospective cohort study on 375 consecutive idiopathic interstitial pneumonia patients between April 2004 and December 2014. Among them, we diagnosed IPPFE and IPF patients using high-resolution computed tomography radiological criteria. Results. Twenty-nine IPPFE patients (9 males, 20 females) and 67 IPF patients (54 males, 13 females) were enrolled. IPPFE patients were significantly more likely to be females and nonsmokers and had lower body mass index, lower values of predicted percentage of forced vital capacity (%FVC), and a higher residual volume-to-total lung capacity ratio than IPF patients. Survival analysis revealed that they had significantly poorer prognosis than IPF patients in GAP (gender, age, and physiology) stages II + III. %FVC and GAP index independently predict mortality in patients with IPPFE. Conclusions. Patients with IPPFE showed poorer prognosis in the advanced stage than patients with IPF. %FVC and GAP index are independent predictors of survival in patients with IPPFE.

Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients

Y. Umeda, Y. Hasegawa, M. Otsuka, S. Ariki, R. Takamiya, A. Saito, Y. Uehara, H. Saijo, K. Kuronuma, H. Chiba, H. Ohnishi, Y. Sakuma, H. Takahashi, Y. Kuroki, M. Takahashi

Oncogene 36 ( 46 ) 6432 - 6445 2017.11

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.

Surfactant protein A down-regulates epidermal growth factor receptor by mechanisms different from those of surfactant protein D.

Yoshihiro Hasegawa, Motoko Takahashi, Shigeru Ariki, Atsushi Saito, Yasuaki Uehara, Rina Takamiya, Koji Kuronuma, Hirofumi Chiba, Yuji Sakuma, Hiroki Takahashi, Yoshio Kuroki

The Journal of biological chemistry 292 ( 45 ) 18565 - 18576 2017.11 [International journal]

We recently reported that the lectin surfactant protein D (SP-D) suppresses epidermal growth factor receptor (EGFR) signaling by interfering with ligand binding to EGFR through an interaction between the carbohydrate-recognition domain (CRD) of SP-D and N-glycans of EGFR. Here, we report that surfactant protein A (SP-A) also suppresses EGF signaling in A549 human lung adenocarcinoma cells and in CHOK1 cells stably expressing human EGFR and that SP-A inhibits the proliferation and motility of the A549 cells. Results with 125I-EGF indicated that SP-A interferes with EGF binding to EGFR, and a ligand blot analysis suggested that SP-A binds EGFR in A549 cells. We also found that SP-A directly binds the recombinant extracellular domain of EGFR (soluble EGFR or sEGFR), and this binding, unlike that of SP-D, was not blocked by EDTA, excess mannose, or peptide:N-glycosidase F treatment. We prepared a collagenase-resistant fragment (CRF) of SP-A, consisting of CRD plus the neck domain of SP-A, and observed that CRF directly binds sEGFR but does not suppress EGF-induced phosphorylation of EGFR in or proliferation of A549 cells. These results indicated that SP-A binds EGFR and down-regulates EGF signaling by inhibiting ligand binding to EGFR as well as SP-D. However, unlike for SP-D, SP-A lectin activity and EGFR N-glycans were not involved in the interaction between SP-A and EGFR. Furthermore, our results suggested that oligomerization of SP-A is necessary to suppress the effects of SP-A on EGF signaling.

Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone

Kimiyuki Ikeda, Masanori Shiratori, Hirofumi Chiba, Hirotaka Nishikiori, Keiki Yokoo, Atsushi Saito, Yoshihiro Hasegawa, Koji Kuronuma, Mitsuo Otsuka, Gen Yamada, Hiroki Takahashi

RESPIRATORY MEDICINE ( W B SAUNDERS CO LTD ) 131 184 - 191 2017.10 [Refereed]

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal pulmonary disease with poor prognosis. Pirfenidone, the first antifibrotic drug, suppresses the decline in forced vital capacity (FVC) and improves prognosis in some, but not all, patients with IPF; therefore, an indicator for identifying improved outcomes in pirfenidone therapy is desirable. This study aims to clarify whether baseline parameters can be predictors of disease progression and prognosis in patients with IPF treated with pirfenidone. Methods: We retrospectively investigated patients with IPF who started treatment with pirfenidone between December 2008 and November 2014 at the Sapporo Medical University Hospital. Patients treated with pirfenidone for >6 months were enrolled in this study and were observed until November 2015. We investigated the association of clinical characteristics, pulmonary function test results, and blood examination results at the start of pirfenidone with the outcome of patients. Results: Sixty patients were included in this study. In multivariate logistic regression analysis, % predicted FVC and serum surfactant protein (SP)-D levels were predictors of a >10% decline in FVC in the initial 12 months. In the Cox proportional hazards model, these two factors predicted progression-free survival. Pack-years, % predicted diffusing capacity for carbon monoxide, and SP-D levels predicted overall survival. Conclusions: The serum SP-D level was a predictor of disease progression and prognosis in patients with IPF treated with pirfenidone. In addition, this analysis describes the relative usefulness of other clinical parameters at baseline in estimating the prognosis of patients with IPF who are candidates for pirfenidone therapy. (C) 2017 Elsevier Ltd. All rights reserved.

Deterioration of regulatory B cells and activation of follicular helper T cells in idiopathic interstitial pneumonias patients

Asai Yuichiro, Chiba Hirofumi, Kondoh Syun, Nishikiori Hirotaka, Takahashi Mamoru, Kuronuma Koji, Otsuka Mitsuo, Yamada Gen, Kamekura Ryuta, Ichimiya Shingo, Takahashi Hiroki

EUROPEAN RESPIRATORY JOURNAL 50 2017.09 [Refereed]

高周波スネアによる腫瘍切除術を施行した気管支発生の炎症性筋線維芽細胞腫瘍の1例

浅井悠一郎, 梅田泰淳, 黒沼幸治, 横山早織, 近藤瞬, 須藤悠太, 小林智史, 亀田優美, 錦織博貴, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 39 ( 5 ) 386 - 391 2017.09

背景. 炎症性筋線維芽細胞腫瘍(inflammatory myofibroblastic tumor:IMT)は、炎症細胞浸潤を伴う筋線維芽細胞の増殖からなる稀な腫瘍である。今回、我々は気管支内腔にポリープ状に増殖したIMTに対して、気管支鏡下に高周波スネアによる切除を行った。症例. 56歳の男性。咳嗽、喘鳴、血痰を主訴に近医を受診した。胸部CTで右主気管支内腔に結節性病変を認めた。FDG-PETで同部位に一致した集積亢進を認め、悪性腫瘍が疑われたため、精査・治療を目的に当科に紹介となった。気管支鏡検査では右主気管支内腔に軟骨輪側に基部をもつポリープ状腫瘍を認めた。画像所見から基部は比較的小範囲に限局していると推定されたため、高周波スネアによる気管支鏡下腫瘍切除術を施行した。病理組織検査では、異型性に乏しい核を有する紡錘形細胞の束状増殖に加え、背景にはリンパ球と形質細胞を主体とした細胞浸潤を認めることから、IMTと診断した。さらに1ヵ月後に切除断端にargon plasma coagulationを追加した。切除後1年4ヵ月が経過したが再発を認めていない。結論. 気管支内腔にポリープ状に増殖したIMTに対する気管支鏡下腫瘍切除術は、有用な治療法の一つになりうると考えられた。(著者抄録)

Volatile Organic Compounds in Exhaled Breath of Idiopathic Pulmonary Fibrosis for Discrimination from Healthy Subjects

Yu-ichi Yamada, Gen Yamada, Mitsuo Otsuka, Hirotaka Nishikiori, Kimiyuki Ikeda, Yasuaki Umeda, Hirofumi Ohnishi, Koji Kuronuma, Hirofumi Chiba, Joerg Ingo Baumbach, Hiroki Takahashi

LUNG ( SPRINGER ) 195 ( 2 ) 247 - 254 2017.04 [Refereed]

Purpose Human breath analysis is proposed with increasing frequency as a useful tool in clinical application. We performed this study to find the characteristic volatile organic compounds (VOCs) in the exhaled breath of patients with idiopathic pulmonary fibrosis (IPF) for discrimination from healthy subjects. Methods VOCs in the exhaled breath of 40 IPF patients and 55 healthy controls were measured using a multi-capillary column and ion mobility spectrometer. The patients were examined by pulmonary function tests, blood gas analysis, and serum biomarkers of interstitial pneumonia. Results We detected 85 VOC peaks in the exhaled breath of IPF patients and controls. IPF patients showed 5 significant VOC peaks; p-cymene, acetoin, isoprene, ethylbenzene, and an unknown compound. The VOC peak of p-cymene was significantly lower (p < 0.001), while the VOC peaks of acetoin, isoprene, ethylbenzene, and the unknown compound were significantly higher (p < 0.001 for all) compared with the peaks of controls. Comparing VOC peaks with clinical parameters, negative correlations with VC (r =-0.393, p = 0.013), %VC (r =-0.569, p < 0.001), FVC (r = -0.440, p = 0.004), %FVC (r =-0.539, p < 0.001), DLco (r =-0.394, p = 0.018), and %DLco (r =-0.413, p = 0.008) and a positive correlation with KL-6 (r = 0.432, p = 0.005) were found for p-cymene. Conclusion We found characteristic 5 VOCs in the exhaled breath of IPF patients. Among them, the VOC peaks of p-cymene were related to the clinical parameters of IPF. These VOCs may be useful biomarkers of IPF.

Surfactant protein A (SP-A) and SP-A-derived peptide attenuate chemotaxis of mast cells induced by human β-defensin 3.

Yasuaki Uehara, Motoko Takahashi, Masaki Murata, Atsushi Saito, Rina Takamiya, Yoshihiro Hasegawa, Koji Kuronuma, Hirofumi Chiba, Jiro Hashimoto, Norimasa Sawada, Hiroki Takahashi, Yoshio Kuroki, Shigeru Ariki

Biochemical and biophysical research communications 485 ( 1 ) 107 - 112 2017.03 [International journal]

Human β-defensin 3 (hBD3) is known to be involved in mast cell activation. However, molecular mechanisms underlying the regulation of hBD3-induced mast cell activation have been poorly understood. We previously reported that SP-A and SP-A-derived peptide 01 (SAP01) regulate the function of hBD3. In this study, we focused on the effects of SP-A and SAP01 on the activation of mast cells induced by hBD3. SAP01 directly bound to hBD3. Mast cell-mediated vascular permeability and edema in hBD3 administered rat ears were decreased when injected with SP-A or SAP01. Compatible with the results in rat ear model, both SP-A and SAP01 inhibited hBD3-induced chemotaxis of mast cells in vitro. Direct interaction between SP-A or SAP01 and hBD3 seemed to be responsible for the inhibitory effects on chemotaxis. Furthermore, SAP01 attenuated hBD3-induced accumulation of mast cells and eosinophils in tracheas of the OVA-sensitized inflammatory model. SP-A might contribute to the regulation of inflammatory responses mediated by mast cells during infection.

非HIV患者におけるST合剤使用困難ニューモシスチス肺炎に対するアトバコンの使用経験

小林智史, 齊藤充史, 錦織博貴, 黒沼幸治, 高橋弘毅

感染症学雑誌 ( (一社)日本感染症学会 ) 91 ( 1 ) 93 - 93 2017.01

【肺炎への最新アプローチ-ジェネラリストの立場とスペシャリストの視点から】治療その他の治療薬や管理高齢者肺炎への対応インフルエンザワクチンと肺炎球菌ワクチンの最近の考え方プレベナーとニューモバックス

黒沼幸治, 本田宏幸

Medicina ( (株)医学書院 ) 54 ( 1 ) 106 - 108 2017.01

Congenital Pulmonary Vein Atresia in an Adult.

Koji Kuronuma, Tomofumi Kobayashi, Youhei Takahashi, Hiroki Takahashi

Internal medicine (Tokyo, Japan) 56 ( 7 ) 877 - 878 2017 [Domestic journal]

Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes

Mitsuo Otsuka, Masanori Shiratori, Hirofumi Chiba, Koji Kuronuma, Yasushi Sato, Yoshiro Niitsu, Hiroki Takahashi

EXPERIMENTAL LUNG RESEARCH ( TAYLOR & FRANCIS INC ) 43 ( 6-7 ) 271 - 282 2017 [Refereed]

Background: Pulmonary fibrosis is a life-threatening pathological state of progressive interstitial lung diseases, such as idiopathic pulmonary fibrosis. Myofibroblasts are known to play a critical role in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the inhibitory effect of a small interfering RNA (siRNA) on a collagen-specific chaperone heat shock protein 47 (HSP47). The siRNA was preferentially delivered to myofibroblasts in a bleomycin (BLM)-induced pulmonary fibrosis rat model using siRNA against HSP47, encapsulated in a vitamin A-coupled liposome (VA-lip-siRNA HSP47). Methods and Results: Male Sprague-Dawley rats were treated with an intratracheal injection of BLM or phosphate buffered saline followed by an intravenous injection of VA-lip-siRNA HSP47 three times per week under preventive administration schedules from day 1 to day 21 and therapeutic administration schedules from day 15 to day 35. The expression of HSP47 after the treatment was assessed by immunoblotting. The specific delivery of VA-lip-siRNA HSP47 conjugated with 6'-carboxyfluoresce into myofibroblasts was examined by immunofluorescence staining. The effect of VA-lip-siRNA HSP47 on fibrosis was analyzed by morphological and biochemical methods. Preferential delivery of VA-lip-siRNA HSP47 to myofibroblasts in fibrotic areas in BLM-treated rats was verified by immunofluorescence staining. Treatment of VA-lip-siRNA HSP47 clearly suppressed HSP47 expression and induced apoptosis of myofibroblasts in the lung of BLM-treated rats. Hydroxyproline levels and inflammatory cytokines in the lungs, and the number of inflammatory cells in the bronchial alveolar lavage of BLM-treated rats were significantly suppressed by the treatment. Morphological assessment showed that VA-lip-siRNA HSP47 also significantly improved the morphological pulmonary fibrosis of BLM-treated rats in both preventive and therapeutic schedules. Conclusions: These results suggest that VA-lip-siRNA HSP47 improves pulmonary fibrosis in not only preventive, but also therapeutic schedules, and thus, this drug delivery system should provide a novel therapy for refractory pulmonary fibrosis.

Validation of the Japanese disease severity classification and the GAP model in Japanese patients with idiopathic pulmonary fibrosis

Shun Kondoh, Hirofumi Chiba, Hirotaka Nishikiori, Yasuaki Umeda, Koji Kuronuma, Mitsuo Otsuka, Gen Yamada, Hirofumi Ohnishi, Mitsuru Mori, Yasuhiro Kondoh, Hiroyuki Taniguchi, Sakae Homma, Hiroki Takahashi

Respiratory Investigation ( Elsevier B.V. ) 54 ( 5 ) 327 - 333 2016.09 [Refereed]

Background The clinical course of idiopathic pulmonary fibrosis (IPF) shows great inter-individual differences. It is important to standardize the severity classification to accurately evaluate each patient׳s prognosis. In Japan, an original severity classification (the Japanese disease severity classification, JSC) is used. In the United States, the new multidimensional index and staging system (the GAP model) has been proposed. The objective of this study was to evaluate the model performance for the prediction of mortality risk of the JSC and GAP models using a large cohort of Japanese patients with IPF. Methods This is a retrospective cohort study including 326 patients with IPF in the Hokkaido prefecture from 2003 to 2007. We obtained the survival curves of each stage of the GAP and JSC models to perform a comparison. In the GAP model, the prognostic value for mortality risk of Japanese patients was also evaluated. Results In the JSC, patient prognoses were roughly divided into two groups, mild cases (Stages I and II) and severe cases (Stages III and IV). In the GAP model, there was no significant difference in survival between Stages II and III, and the mortality rates in the patients classified into the GAP Stages I and II were underestimated. Conclusions It is difficult to predict accurate prognosis of IPF using the JSC and the GAP models. A re-examination of the variables from the two models is required, as well as an evaluation of the prognostic value to revise the severity classification for Japanese patients with IPF.

Surfactant protein D is a useful biomarker for monitoring acute lung injury in rats

Makoto Murata, Mitsuo Otsuka, Noriyuki Ashida, Gen Yamada, Koji Kuronuma, Hirofumi Chiba, Hiroki Takahashi

Experimental Lung Research ( Taylor and Francis Ltd ) 42 ( 6 ) 314 - 321 2016.07

Purpose: The purpose of this study is to investigate the serial changes in the SP-D concentrations of serum and bronchoalveolar lavage fluid (BALF) in a bleomycin-induced lung injury rat model and compare them with the levels of conventional biochemical markers. Materials and Methods: Male Wister rats were anesthetized and intratracheally administered bleomycin (1.0 mg/kg). We evaluated the histological changes and SP-D expression of their lung tissues. We also measured the concentrations of SP-D, albumin, and lactate dehydrogenase (LDH) and the numbers of various types of cells in BALF, and the serum levels of SP-D and conventional markers, including LDH, high mobility group box 1, monocyte chemoattractant protein-1, and C-reactive protein. Results: The BALF SP-D level increased and peaked on day 3, and then gradually decreased. These variations were significantly correlated with the changes in the BALF albumin level and granulocyte cell count. The serum SP-D level increased from day 5, peaked on day 10, and then gradually decreased until day 28. The changes in the serum SP-D level accurately reflected the extent of the histological changes caused by the lung injury. On the other hand, the serum levels of conventional biomarkers were only elevated for a few days or did not change during the study period. Conclusions: The SP-D level is the most useful marker of the severity of lung injuries. These results suggest that the measurement of SP-D levels is an additional tool for monitoring acute lung injuries in rats.

高周波スネアによる気管支鏡下腫瘍摘出術を施行した気管支原発炎症性筋線維芽腫瘍の一例

黒沼幸治, 梅田泰淳, 横山早織, 高橋知之, 柳昌弘, 近藤瞬, 浅井悠一郎, 小林智史, 汐谷心, 亀田優美, 錦織博貴, 大塚満雄, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 38 ( Suppl. ) S309 - S309 2016.05

免疫グロブリン製剤補充により改善を認めた原発性免疫不全症に伴う気管支拡張症の1例

小林智史, 錦織博貴, 黒沼幸治, 高橋弘毅

感染症学雑誌 ( (一社)日本感染症学会 ) 90 ( 3 ) 398 - 399 2016.05

北海道における成人侵襲性肺炎球菌感染症症例のサーベイランス

黒沼幸治, 小林智史, 錦織博貴, 常彬, 大石和徳, 高橋弘毅

感染症学雑誌 ( (一社)日本感染症学会 ) 90 ( 3 ) 376 - 376 2016.05

内視鏡・画像診断気管支鏡検査における呼吸器内科医による迅速細胞診の有用性の検討

梅田泰淳, 大塚満雄, 小林智史, 汐谷心, 池田貴美之, 亀田優美, 黒沼幸治, 高橋守, 山田玄, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 5 ( 増刊 ) 162 - 162 2016.03

SP-AおよびSP-A由来ペプチドはヒトβ-デフェンシン3による肥満細胞の遊走を抑制する

有木茂, 上原康昭, 村田雅樹, 高宮里奈, 長谷川喜弘, 斎藤充史, 千葉弘文, 黒沼幸治, 高橋素子, 高橋弘毅, 黒木由夫

分子呼吸器病 ( (株)先端医学社 ) 20 ( 1 ) 120 - 123 2016.03

北海道における外国籍結核患者とそのHIV感染症合併の現状

池田貴美之, 錦織博貴, 近藤瞬, 小林智史, 多屋哲也, 森勇樹, 汐谷心, 黒沼幸治, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 91 ( 2 ) 33 - 39 2016.02

[背景と目的]国際交流の発展に伴い、北海道においても外国籍のHIV合併結核患者を経験するようになり、その実態を把握する必要がある。[方法]2001年1月から2014年9月までに北海道内で発生した外国籍の結核患者および外国籍のHIV合併結核患者に関するアンケート調査を行った。前者については各保健所に、後者についてはエイズ治療拠点病院および結核病床を有する病院に、調査用紙を郵送し回答を得た。[結果]各保健所の調査では、外国籍の結核患者は71名であった。20〜30歳代の若年層が中心で、職業は留学生や職業研修生が多かった。国籍はアジア地域が中心であったが、アフリカ地域も7名みられた。発症から受診までの期間が1ヵ月以上である患者は21%で、一部で受診の遅延がみられた。発見方法も多くが医療機関の直接受診であった。エイズ治療拠点病院および結核病床を有する病院の調査では、外国籍のHIV合併結核患者は4名であった。全て20〜30歳代で、サハラ以南のアフリカ国籍だった。[考察]入国時の胸部X線による健診の徹底と、発症時の医療機関の受け入れ態勢の整備が重要と考えられた。また、結核とHIVの二重感染が多発している地域を母国とする結核患者の場合は、HIVの感染の有無を積極的に確認する必要がある。(著者抄録)

[THE CURRENT SITUATION OF FOREIGN TUBERCULOSIS PATIENTS AND THEIR CONCURRENT HIV INFECTION IN HOKKAIDO].

Kimiyuki Ikeda, Hirotaka Nishikiori, Shun Kondo, Tomofumi Kobayashi, Tetsuya Taya, Yuki Mori, Makoto Shioya, Koji Kuronuma, Hiroki Takahashi

Kekkaku : [Tuberculosis] 91 ( 2 ) 33 - 9 2016.02 [Domestic journal]

BACKGROUND AND PURPOSE: According to recent news, patients with concurrent tuberculosis (TB) and human immunodeficiency virus (HIV) infection are increasingly common worldwide. This study aimed to investigate whether TB/HIV co-infected patients are visiting Hokkaido. METHOD: We conducted a questionnaire survey regarding foreign patients infected with TB or TB/HIV who visited Hokkaido between January 2001 and September 2014. We mailed questionnaires to health centers, AIDS treatment care hospitals, and TB hospitals in Hokkaido prefecture. RESULTS: Seventy-one TB patients were of foreign nationality according to the answers obtained from health centers. Most of them were foreign students or occupational trainees between 20-30 years old. Approximately half these patients were from East Asia, and 7 patients were from Africa. As 21 % of the patients with TB who visited medical examination were over 1 month from disease onset, and the delay in visiting was recognized. The TB infection was mostly detected coincidentally during the physician visit. In the hospital survey, four TB patients with HIV were of foreign nationality. They were also of the age group from 20-30 years and hailed from sub-Saharan Africa. DISCUSSION: During immigration, medical examination by performing a chest radiograph is important. If the immigrant hails from an area where TB and HIV co-infection is common, it is necessary to confirm whether HIV infection is present.

気管支内腔に発生した炎症性筋線維芽腫瘍に対し高周波スネアによる気管支鏡下腫瘍摘出術を施行した1例

横山早織, 高橋知之, 柳昌弘, 近藤瞬, 浅井悠一郎, 小林智史, 梅田泰淳, 汐谷心, 亀田優美, 錦織博貴, 黒沼幸治, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 38 ( 1 ) 55 - 55 2016.01

A Case of Recurrent Cryptogenic Organizing Pneumonia Complicated by Primary Pulmonary Malignant Lymphoma

Umeda Yasuaki, Otsuka Mitsuo, Kuronuma Koji, Kodera Yuki, Kondo Shun, Taya Tetsuya, Ikeda Kimiyuki, Shioya Makoto, Chiba Hirofumi, Yamada Gen, Takahashi Hiroki

The Journal of the Japan Society for Respiratory Endoscopy ( The Japan Society for Respiratory Endoscopy ) 38 ( 2 ) 134 - 139 2016

Background. Cryptogenic organizing pneumonia (COP) usually responds well to corticosteroid treatment and typically has a good prognosis. However, a few cases are refractory to corticosteroid treatment. Immunosuppressant drugs are associated with an increased risk of malignant lymphoproliferative disorders. Case. A 63-year-old man presented with a history of cough for a month. High resolution computed tomography (HRCT) of the chest showed air-space consolidation predominantly in both lungs. We diagnosed COP by transbronchial lung biopsy (TBLB) specimens. Clinical data and HRCT findings were improved by prednisolone therapy, but recurrent exacerbation occurred during steroid tapering. Although, we re-examined the abnormal lesions in the left lower lobe by video-assisted thoracoscopy and those in the right lower lobe by TBLB, histopathological examinations of all lesions revealed organizing pneumonia. We continued immunosuppressive therapy with a combination of prednisolone and immunosuppressive agents. However, lung lesions gradually deteriorated. In order to obtain a histopathological diagnosis again, we performed TBLB from the right lower lobe. Histopathological examination revealed lung invasion of diffuse large B cell type lymphoma. Conclusion. We experienced a rare case of recurrent COP complicated by primary pulmonary malignant lymphoma. It is necessary to pay attention to the possibility that malignant lymphoma may be involved in recurrent COP during immunosuppressive therapy.

IgG補充療法により改善を認めた原発性免疫不全症に伴う気管支拡張症の1例

小林智史, 黒沼幸治, 高橋弘毅

Therapeutic Research ( ライフサイエンス出版(株) ) 36 ( 6 ) 557 - 558 2015.06

呼吸器内科医による気管支鏡検査における迅速細胞診の有用性の検討

梅田泰淳, 大塚満雄, 小林智史, 汐谷心, 池田貴美之, 亀田優美, 成田欣史, 北田順也, 黒沼幸治, 高橋守, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 37 ( Suppl. ) S290 - S290 2015.05

続発性難治性気胸に対しEWSを用いて気管支充填術を施行した7症例の検討

小林智史, 黒沼幸治, 梅田泰淳, 汐谷心, 成田欣史, 亀田優美, 北田順也, 大塚満雄, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 37 ( Suppl. ) S247 - S247 2015.05

血痰を契機に発見された心房細動カテーテルアブレーション後の肺静脈狭窄症の1例

夏井坂元基, 亀田優美, 大塚満雄, 黒沼幸治, 北田順也, 成田欣史, 梅田泰淳, 横尾慶紀, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 37 ( 1 ) 87 - 93 2015.01

背景. 肺静脈狭窄症は稀な疾患であり、先天性のものと術後に起こるものがある。術後発症例ではカテーテルアブレーション治療によるものと、総肺静脈還流異常症の矯正などの外科的手術によるものがある。症例. 57歳男性。2008年4月および2010年4月に発作性心房細動に対しカテーテルアブレーション治療を施行された。2011年1月頃よりしばしば血痰を認めるようになった。2011年8月の胸部単純CT上、左上下葉に浸潤影、すりガラス病変、小葉間隔壁肥厚を認め、さらに胸部造影CTにて左肺の上肺静脈の完全閉塞と下肺静脈の狭窄を認めた。また、肺換気血流シンチグラムでの左肺の血流低下・換気正常のミスマッチ、さらに経食道心エコーでの左下肺静脈狭窄所見を認めた。気管支鏡検査では気管支粘膜の浮腫と粘膜下血管増生を認めた。以上より、血痰の原因は心房細動カテーテルアブレーション後に生じた左肺静脈狭窄症と診断した。左下肺静脈狭窄部へステントを留置し、狭窄肺静脈の開大を得た。結論. 血痰の原因は多岐にわたるが、本症例のようにアブレーション治療などの既往がある際には、医原性の肺静脈狭窄症も鑑別に入れるべきである。(著者抄録)

Distinct compartmentalization of SP-A and SP-D in the vasculature and lungs of patients with idiopathic pulmonary fibrosis

Hirotaka Nishikiori, Hirofumi Chiba, Shigeru Ariki, Koji Kuronuma, Mitsuo Otsuka, Masanori Shiratori, Kimiyuki Ikeda, Atsushi Watanabe, Yoshio Kuroki, Hiroki Takahashi

BMC PULMONARY MEDICINE ( BIOMED CENTRAL LTD ) 14 196 2014.12 [Refereed]

Background: Surfactant proteins SP-A and SP-D are useful biomarkers in diagnosis, monitoring, and prognosis of idiopathic pulmonary fibrosis (IPF). Despite their high structural homology, their serum concentrations often vary in IPF patients. This retrospective study aimed to investigate distinct compartmentalization of SP-A and SP-D in the vasculature and lungs by bronchoalveolar lavage fluid (BALF)/serum analysis, hydrophilicity and immunohistochemistry. Methods: We included 36 IPF patients, 18 sarcoidosis (SAR) patients and 20 healthy subjects. Low-speed centrifugal supernatants of BALF (Sup-1) were obtained from each subject. Sera were also collected from each patient. Furthermore, we separated Sup-1 of IPF patients into hydrophilic supernatant (Sup-2) and hydrophobic precipitate (Ppt) by high-speed centrifugation. We measured SP-A and SP-D levels of each sample with the sandwich ELISA technique. We analyzed the change of the BALF/serum level ratios of the two proteins in IPF patients and their hydrophilicity in BALF. The distribution in the IPF lungs was also examined by immunohistochemical staining. Results: In BALF, SP-A levels were comparable between the groups; however, SP-D levels were significantly lower in IPF patients than in others. Although IPF reduced the BALF/serum level ratios of the two proteins, the change in concentration of SP-D was more evident than SP-A. This suggests a higher disease impact for SP-D. Regarding hydrophilicity, although more than half of the SP-D remained in hydrophilic fractions (Sup-2), almost all of the SP-A sedimented in the Ppt with phospholipids. Hydrophilicity suggests that SP-D migrates into the blood more easily than SP-A in IPF lungs. Immunohistochemistry revealed that SP-A was confined to thick mucus-filling alveolar space, whereas SP-D was often intravascular. This data also suggests that SP-D easily leaks into the bloodstream, whereas SP-A remains bound to surfactant lipids in the alveolar space. Conclusions: The current study investigated distinct compartmentalization of SP-A and SP-D in the vasculature and lungs. Our results suggest that serum levels of SP-D could reflect pathological changes of the IPF lungs more incisively than those of SP-A.

気管内挿管後の炎症性肉芽腫性閉塞に対し気管支鏡下電気焼灼術(高周波スネア)が有効であった1例

田中優子, 宮島さつき, 森勇樹, 梅田泰淳, 汐谷心, 成田欣史, 亀田優美, 北田順也, 黒沼幸治, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 36 ( 6 ) 681 - 682 2014.11

PZA、LVFX、TH、KMによる治療が奏効した多剤耐性肺結核の1例

本田宏幸, 森勇樹, 梅田泰淳, 汐谷心, 成田欣史, 亀田優美, 北田順也, 黒沼幸治, 千葉弘文, 山田玄, 高橋弘毅

結核 ( (一社)日本結核・非結核性抗酸菌症学会 ) 89 ( 5 ) 588 - 588 2014.05

血痰で発見されたカテーテルアブレーション後肺静脈狭窄症の1例

亀田優美, 黒沼幸治, 夏井坂元基, 梅田泰淳, 成田欣史, 北田順也, 大塚満雄, 千葉弘文, 山田玄, 高橋弘毅

気管支学 ( (NPO)日本呼吸器内視鏡学会 ) 36 ( Suppl. ) S216 - S216 2014.03

111In骨髄シンチグラフィが治療効果判定に有用だった肺小細胞癌・骨髄転移の1例

森勇樹, 亀田優美, 小寺祐貴, 斎藤淳, 梅田泰淳, 汐谷心, 成田欣史, 北田順也, 黒沼幸治, 大塚満雄, 千葉弘文, 山田玄, 高橋弘毅

肺癌 ( (NPO)日本肺癌学会 ) 53 ( 7 ) 917 - 917 2013.12

当科における最近の肺非結核性抗酸菌症の臨床的検討

亀田優美, 山田玄, 黒沼幸治, 大塚満雄, 千葉弘文, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 2 ( 増刊 ) 216 - 216 2013.03

血清SP-D異常低値を呈する肺癌症例の検討

成田欣史, 黒沼幸治, 近藤瞬, 梅田泰淳, 汐谷心, 亀田優美, 北村康夫, 北田順也, 大塚満雄, 千葉弘文, 山田玄, 高橋弘毅

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 2 ( 増刊 ) 230 - 230 2013.03

Detection of N-glycolyated gangliosides in non-small-cell lung cancer using GMR8 monoclonal antibody.

Nobuyoshi Hayashi, Hirofumi Chiba, Koji Kuronuma, Shinji Go, Yoshihiro Hasegawa, Motoko Takahashi, Shinsei Gasa, Atsushi Watanabe, Tadashi Hasegawa, Yoshio Kuroki, Jinichi Inokuchi, Hiroki Takahashi

Cancer science 104 ( 1 ) 43 - 7 2013.01 [Refereed] [International journal]

Gangliosides are glycosphingolipids found on the cell surface. They act as recognition molecules or signal modulators and regulate cell proliferation and differentiation. N-glycolylneuraminic acid (NeuGc)-containing gangliosides have been detected in some neoplasms in humans, although they are usually absent in normal human tissues. Our aim was to evaluate the presence of NeuGc-containing gangliosides including GM3 (NeuGc) and assess their relationship with the prognosis of non-small-cell lung cancer (NSCLC). NeuGc-containing ganglioside expression in NSCLC tissues was analyzed immunohistochemically using the mouse monoclonal antibody GMR8, which is specific for gangliosides with NeuGc alpha 2,3Gal-terminal structures. On the basis of NeuGc-containing ganglioside expression, we performed survival analysis. We also investigated the differences in the effects of GM3 (N-acetylneuraminic acid [NeuAc]) and GM3 (NeuGc) on inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase in A431 cells. As a result, the presence of NeuGc-containing gangliosides was evident in 86 of 93 (93.5%) NSCLC samples. The NSCLC patients with high NeuGc-containing ganglioside expression had a low overall survival rate and a significantly low progression-free survival rate. In the in vitro study, the inhibitory effect of GM3 on EGFR tyrosine kinase in A431 cells after exposure to GM3 (NeuGc) was lower than that after exposure to GM3 (NeuAc). In conclusion, NeuGc-containing gangliosides including GM3 (NeuGc) are widely expressed in NSCLC, and NeuGc-containing ganglioside expression is associated with patient survival. The difference in the effects of GM3 (NeuGc) and GM3 (NeuAc) on the inhibition of EGFR tyrosine kinase might contribute to improvement in the prognosis of NSCLC patients.

エンドサイトスコピーを用いた腫瘍性病変の観察

池田貴美之, 山田裕一, 梅田泰淳, 亀田優美, 成田欣史, 錦織博貴, 宮島さつき, 北田順也, 黒沼幸治, 大塚満雄, 山田玄, 高橋弘毅

肺癌 ( (NPO)日本肺癌学会 ) 52 ( 5 ) 788 - 788 2012.10

ゲフィチニブ投与後にアルカリフォスファターゼ・フレア現象を呈した肺腺癌の2例

亀田優美, 梅田泰淳, 汐谷心, 成田欣史, 北村康夫, 北田順也, 宮島さつき, 黒沼幸治, 大塚満雄, 山田玄, 高橋弘毅

肺癌 ( (NPO)日本肺癌学会 ) 52 ( 5 ) 793 - 793 2012.10

Pulmonary surfactant protein A protects lung epithelium from cytotoxicity of human β-defensin 3.

Saito A, Ariki S, Sohma H, Nishitani C, Inoue K, Ebata N, Takahashi M, Hasegawa Y, Kuronuma K, Takahashi H, Kuroki Y

The Journal of biological chemistry ( 18 ) 287 ( 18 ) 15034 - 15043 2012.04 [Refereed]

A Case of Adult T Cell Leukemia/Lymphoma Presenting as Severe Tracheal Stenosis

Kengo Otsuka, Koji Kuronuma, Mitsuo Otsuka, Junya Kitada, Yoshifumi Narita, Hirotoshi Homma, Satsuki Miyajima, Yasuo Kitamura, Yosuke Suzuki, Motoki Natsuizaka, Hiroshi Yasui, Hiroshi Ikeda, Toshiaki Hayashi, Tadao Ishida, Yasuhisa Shinomura, Hiroko Noguchi, Hiroki Takahashi

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 50 ( 21 ) 2637 - 2641 2011 [Refereed]

A 57-year-old woman was referred to our hospital for further examination of a tracheal stenosis shown on computed tomography findings. Bronchoscopy revealed multiple protruding tumors in the lumen of the trachea. Cytological findings of the cell block material from pleural effusion indicated that the T-cell lymphoma was composed of pleomorphic lymphoid cells. Serum human T-cell leukemia virus type1 antibody was positive and supported the clinical diagnosis of ATLL. Systemic chemotherapy induced the remarkable improvement of the lesions, the infiltrative lung shadow and the soft tissue neoplasm. We report a rare case of adult T cell leukemia/lymphoma (ATLL) with endobronchial involvement.

ゲフィチニブ奏効後耐性化した肺腺癌に対してエルロチニブへの変更が有効であった当院における経験例

角俊行, 成田欣史, 北村康夫, 北田順也, 本間裕敏, 黒沼幸治, 大塚満雄, 工藤和実, 村上聖司, 山田玄, 田中裕士, 高橋弘毅

肺癌 ( (NPO)日本肺癌学会 ) 50 ( 7 ) 946 - 947 2010.12

Pulmonary collectins enhance phagocytosis of Mycobacterium avium through increased activity of mannose receptor.

Kudo K, Sano H, Takahashi H, Kuronuma K, Yokota S, Fujii N, Shimada K, Yano I, Kumazawa Y, Voelker DR, Abe S, Kuroki Y

Journal of Immunology 172 ( 12 ) 7592 - 602 2004 [Refereed]

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