Papers - KURONUMA Kouji

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

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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.

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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]

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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.

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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]

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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.

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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]

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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 ).

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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]

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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.

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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

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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

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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.

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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

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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]

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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.

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