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Papers - Namkoong, Ho

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Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study.

Kensuke Nakagawara, Hirofumi Kamata, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Shiro Otake, Takahiro Fukushima, Tatsuya Kusumoto, Atsuho Morita, Shuhei Azekawa, Mayuko Watase, Takanori Asakura, Katsunori Masaki, Makoto Ishii, Akifumi Endo, Ryuji Koike, Hiroyasu Ishikura, Tohru Takata, Yasushi Matsushita, Norihiro Harada, Hiroyuki Kokutou, Takashi Yoshiyama, Kensuke Kataoka, Yoshikazu Mutoh, Masayoshi Miyawaki, Soichiro Ueda, Hiroshi Ono, Takuya Ono, Tomohisa Shoko, Hiroyuki Muranaka, Kodai Kawamura, Nobuaki Mori, Takao Mochimaru, Mototaka Fukui, Yusuke Chihara, Yoji Nagasaki, Masaki Okamoto, Masaru Amishima, Toshio Odani, Mayuko Tani, Koichi Nishi, Yuya Shirai, Ryuya Edahiro, Akira Ando, Naozumi Hashimoto, Shinji Ogura, Yuichiro Kitagawa, Toshiyuki Kita, Takashi Kagaya, Yasuhiro Kimura, Naoki Miyazawa, Tomoya Tsuchida, Shigeki Fujitani, Koji Murakami, Hirohito Sano, Yuki Sato, Yoshinori Tanino, Ryo Otsuki, Shuko Mashimo, Mizuki Kuramochi, Yasuo Hosoda, Yoshinori Hasegawa, Tetsuya Ueda, Yotaro Takaku, Takashi Ishiguro, Akiko Fujiwara, Naota Kuwahara, Hideya Kitamura, Eri Hagiwara, Yasushi Nakamori, Fukuki Saito, Yuta Kono, Shinji Abe, Tomoo Ishii, Takehiko Ohba, Yu Kusaka, Hiroko Watanabe, Makoto Masuda, Hiroki Watanabe, Yoshifumi Kimizuka, Akihiko Kawana, Yu Kasamatsu, Satoru Hashimoto, Yukinori Okada, Tomomi Takano, Kazuhiko Katayama, Masumi Ai, Atsushi Kumanogoh, Toshiro Sato, Katsushi Tokunaga, Seiya Imoto, Yuko Kitagawa, Akinori Kimura, Satoru Miyano, Naoki Hasegawa, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

BMC pulmonary medicine 23 ( 1 ) 146 - 146 2023.04

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

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Single-cell analyses and host genetics highlight the role of innate immune cells in COVID-19 severity.

Ryuya Edahiro, Yuya Shirai, Yusuke Takeshima, Shuhei Sakakibara, Yuta Yamaguchi, Teruaki Murakami, Takayoshi Morita, Yasuhiro Kato, Yu-Chen Liu, Daisuke Motooka, Yoko Naito, Ayako Takuwa, Fuminori Sugihara, Kentaro Tanaka, James B Wing, Kyuto Sonehara, Yoshihiko Tomofuji, Ho Namkoong, Hiromu Tanaka, Ho Lee, Koichi Fukunaga, Haruhiko Hirata, Yoshito Takeda, Daisuke Okuzaki, Atsushi Kumanogoh, Yukinori Okada

Nature genetics 2023.04

ISSN 1061-4036

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

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Characteristics and Clinical Effectiveness of COVID-19 Vaccination in Hospitalized Patients in Omicron-dominated Epidemic Wave - A Nationwide Study in Japan.

Hiromu Tanaka, Shotaro Chubachi, Takanori Asakura, Ho Namkoong, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Ho Lee, Mayuko Watase, Kaori Sakurai, Tatsuya Kusumoto, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 132 84 - 88 2023.04

ISSN 1201-9712

OBJECTIVES: Coronavirus disease (COVID-19) was severe in the Delta variant-dominated epidemic wave (fifth wave) in Japan. The clinical characteristics and effectiveness of COVID-19 vaccination are not fully understood in the Omicron variant-dominated wave (sixth and seventh waves), especially in hospitalized patients. We investigated the relationship between vaccination and disease severity in the Omicron-dominated wave and compared these variant-dominated waves. METHODS: The nationwide COVID-19 database (Japan COVID-19 Task Force) was used to compare clinical characteristics and critical outcome in patients hospitalized from Delta (5th, N=735) vs Omicron-dominated waves (6th, N=495; 7th, N=128). RESULTS: Patients in the sixth and seventh waves had a lower incidence of critical outcomes and respiratory outcomes, and a higher incidence of bacterial infection, although the mortality rate did not differ significantly between waves. In the sixth and seventh waves, 138 (27.9%) and 29 (22.7%) COVID-19 patients were unvaccinated, respectively. Multivariable analysis adjusted with previously reported factors revealed that the proportion of 1) critical outcomes and 2) respiratory outcomes decreased in a frequency-dependent manner; 1) (the number of vaccinations): 1-2 times, aOR 0.37 (95% CI; 0.20-0.69); 3-4 times: aOR 0.25 (95% CI; 0.11-0.58), 2) 1-2 times, aOR 0.43 (95% CI; 0.27-0.66); 3-4 times: aOR 0.36 (95% CI; 0.21-0.60). CONCLUSIONS: COVID-19 hospitalized patients with Omicron infections showed a lower incidence of critical outcomes than those with Delta infections, and COVID-19 vaccination may contribute to preventing respiratory failure.

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Use of the neutrophil-to-lymphocyte ratio and an oxygen requirement to predict disease severity in patients with COVID-19.

Takuya Ozawa, Takanori Asakura, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ko Lee, Takahiro Fukushima, Shiro Otake, Kensuke Nakagawara, Mayuko Watase, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Ryuya Edahiro, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Respiratory investigation 61 ( 4 ) 454 - 459 2023.04

ISSN 2212-5345

We investigated the association between complete blood count, including neutrophil-to-lymphocyte ratio (NLR) in combination with patient characteristics, and coronavirus disease (COVID-19) outcomes to identify the best prognostic indicator. We analyzed data of patients with confirmed COVID-19 from the nationwide database of the Japan COVID-19 Task Force between February 2020 and November 2021. A composite outcome was defined as the most severe condition, including noninvasive positive-pressure ventilation, high-flow nasal cannula, invasive mechanical ventilation, extracorporeal membrane oxygenation, or death. Of 2425 patients in the analysis, 472 (19.5%) experienced a composite outcome. NLR was the best predictor of composite outcomes, with an area under the curve (AUC) of 0.81, and a sensitivity and specificity of 72.3% and 75.7%, respectively, using a cut-off value of 5.04. The combination of NLR and an oxygen requirement on admission had the highest AUC (0.88). This simple combination may help identify patients at risk of progression to severe disease.

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特集ポストコロナ時代の感染症診療第II章　感染症診療各論 [4]呼吸器感染症 6　肺非結核性抗酸菌症

加治正憲, 南宮湖, 長谷川直樹

診断と治療 (診断と治療社) 111 ( 13 ) 121 - 125 2023.03

ISSN 0370999X

Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Yoshifumi Uwamino, Kengo Nagashima, Ayumi Yoshifuji, Shigeru Suga, Mizuho Nagao, Takao Fujisawa, Munekazu Ryuzaki, Yoshiaki Takemoto, Ho Namkoong, Masatoshi Wakui, Hiromichi Matsushita, Naoki Hasegawa, Yasunori Sato, Mitsuru Murata

npj Vaccines (Springer Science and Business Media LLC) 8 ( 1 ) 2023.03

Abstract

Tools that can be used to estimate antibody waning following COVID-19 vaccinations can facilitate an understanding of the current immune status of the population. In this study, a two-compartment-based mathematical model is formulated to describe the dynamics of the anti-SARS-CoV-2 antibody in healthy adults using serially measured waning antibody concentration data obtained in a prospective cohort study of 673 healthcare providers vaccinated with two doses of BNT162b2 vaccine. The datasets of 165 healthcare providers and 292 elderly patients with or without hemodialysis were used for external validation. Internal validation of the model demonstrated 97.0% accuracy, and external validation of the datasets of healthcare workers, hemodialysis patients, and nondialysis patients demonstrated 98.2%, 83.3%, and 83.8% accuracy, respectively. The internal and external validations demonstrated that this model also fits the data of various populations with or without underlying illnesses. Furthermore, using this model, we developed a smart device application that can rapidly calculate the timing of negative seroconversion.

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Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination.

Uwamino Y, Nagashima K, Yoshifuji A, Suga S, Nagao M, Fujisawa T, Ryuzaki M, Takemoto Y, Namkoong H, Wakui M, Matsushita H, Hasegawa N, Sato Y, Murata M

NPJ vaccines 8 ( 1 ) 33 2023.03

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Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Uwamino Yoshifumi, Nagashima Kengo, Yoshifuji Ayumi, Suga Shigeru, Nagao Mizuho, Fujisawa Takao, Ryuzaki Munekazu, Takemoto Yoshiaki, Namkoong Ho, Wakui Masatoshi, Matsushita Hiromichi, Hasegawa Naoki, Sato Yasunori, Murata Mitsuru

NPJ VACCINES 8 ( 1 ) 2023.03

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Humoral and cellular immune response dynamics in Japanese healthcare workers up to six months after receiving a third dose of BNT162b2 monovalent vaccine.

Yoshifumi Uwamino, Takashi Yokoyama, Yasunori Sato, Ayako Shibata, Toshinobu Kurafuji, Akiko Tanabe, Masayo Noguchi, Tomoko Arai, Akemi Ohno, Hiromitsu Yokota, Ho Namkoong, Tomoyasu Nishimura, Kenjiro Kosaki, Naoki Hasegawa, Masatoshi Wakui, Mitsuru Murata, Hiromichi Matsushita

Vaccine 41 ( 9 ) 1545 - 1549 2023.02

ISSN 0264-410X

Longitudinal data on the immune response from the first dose to several months after the third dose of COVID-19 vaccine are limited. We analyzed the immune response in 406 Japanese healthcare workers who received at least three doses of vaccine. The geometric mean anti-receptor binding domain IgG antibody titers and antigen-stimulated T-cell interferon-gamma levels after 6 months after receiving a third dose were similar to those 8 weeks after receiving a second dose. Humoral and cellular immunity induced by the third dose was more durable than that induced by the second dose. UMIN Clinical Trials Registry ID: UMIN000043340.

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Diagnostic significance of secondary bacteremia in patients with COVID-19.

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 29 ( 4 ) 422 - 426 2023.01

ISSN 1341-321X

OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

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Benefits and risks of haematopoietic stem cell transplantation for systemic sclerosis: A systematic review and meta-analysis

K Higashitani, K Takase-Minegishi, R Yoshimi, Y Kirino, N Hamada, ...

Modern Rheumatology 33 (2), 330-337 2023

Characteristics of patients with COVID-19 who have deteriorating chest X-ray findings within 48 hours: a retrospective cohort study

T Kusumoto, S Chubachi, H Namkoong, H Tanaka, H Lee, S Otake, ...

2023

Characteristics and Clinical Effectiveness of COVID-19 Vaccination in Hospitalized Patients in Omicron-dominated Epidemic Wave–A Nationwide Study in Japan

H Tanaka, S Chubachi, T Asakura, H Namkoong, S Azekawa, S Otake, ...

International Journal of Infectious Diseases 2023

Clinical significance of prediabetes, undiagnosed diabetes and diagnosed diabetes on critical outcomes in COVID‐19: Integrative analysis from the Japan COVID‐19 task force

T Fukushima, S Chubachi, H Namkoong, T Asakura, H Tanaka, H Lee, ...

Diabetes, Obesity and Metabolism 25 (1), 144-155 2023

Immune checkpoint inhibitor–induced arthralgia is tightly associated with improved overall survival in cancer patients

A Maeda, K Takase-Minegishi, Y Kirino, N Hamada, Y Kunishita, ...

Rheumatology 62 (4), 1451-1459 2023

Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Y Uwamino, K Nagashima, A Yoshifuji, S Suga, M Nagao, T Fujisawa, ...

npj Vaccines 8 (1), 33 2023

Incidence and Risk of Hematological Adverse Events Associated With Immune Checkpoint Inhibitors: A Systematic Literature Review and Meta-Analysis

T Ohashi, K Takase-Minegishi, A Maeda, N Hamada, R Yoshimi, Y Kirino, ...

Journal of Hematology 12 (2), 66-74 2023

Radiological Pleuroparenchymal Fibroelastosis Pattern in Nontuberculous Mycobacterial Pulmonary Disease: A Multicenter Retrospective Study

H Tanaka, T Asakura, S Okamori, K Furuuchi, M Yagi, K Yagi, I Hase, ...

B28. SOLVING THE PUZZLE OF BRONCHIECTASIS AND NONTUBERCULOUS MYCOBACTERIA … 2023

Impact of accumulative smoking exposure and chronic obstructive pulmonary disease on COVID-19 outcomes: Report based on findings from the Japan COVID-19 Task Force.

Mayuko Watase, Katsunori Masaki, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Takahiro Fukushima, Shiro Otake, Kensuke Nakagawara, Tatsuya Kusumoto, Takanori Asakura, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Yoshitaka Oyamada, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Ryuya Edahiro, Hirohito Sano, Yasunori Sato, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 128 121 - 127 2022.12

ISSN 1201-9712

OBJECTIVES: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors of severe coronavirus disease 2019 (COVID-19). However, limited literature exists on the effect of COPD and smoking on COVID-19 outcomes. This study examined the impact of smoking exposure in pack-years (PY) and COPD on COVID-19 outcomes among smokers in Japan. METHODS: The study included 1266 smokers enrolled by the Japan COVID-19 Task Force between February 2020 and December 2021. PY and COPD status were self-reported by patients. Patients were classified into the non-COPD (n=1151) and COPD (n=115) groups; the non-COPD group was further classified into <10 PY (n=293), 10-30 PY (n=497), and >30 PY (n=361). The study outcome was the need for invasive mechanical ventilation (IMV). RESULTS: The incidence of IMV increased with increasing PY and was highest in the COPD group (<10 PY=7.8%, 10-30 PY=12.3%, >30 PY=15.2%, COPD=26.1%; p<0.001). Significant association was found for IMV requirement in the >30 PY and COPD groups through univariate (odds ratio [OR]: >30 PY=2.11, COPD=4.14) and multivariate (OR: >30 PY=2.38; COPD=7.94) analyses. Increasing PY number was also associated with increased IMV requirement in patients aged <65 y. CONCLUSIONS: Cumulative smoking exposure was positively associated with COVID-19 outcomes in smokers.

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Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials

Fujiwara Yu, Horita Nobuyuki, Harrington Matthew, Namkoong Ho, Miyashita Hirotaka, Galsky Matthew D.

CANCER IMMUNOLOGY IMMUNOTHERAPY 71 ( 12 ) 2837 - 2848 2022.12

ISSN 0340-7004

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Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials.

Fujiwara Y, Horita N, Harrington M, Namkoong H, Miyashita H, Galsky MD

Cancer immunology, immunotherapy : CII 71 ( 12 ) 2837 - 2848 2022.12

ISSN 0340-7004

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Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study.

Kensuke Nakagawara, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Shuhei Azekawa, Shiro Otake, Takahiro Fukushima, Atsuho Morita, Mayuko Watase, Kaori Sakurai, Tatsuya Kusumoto, Takanori Asakura, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Ryuya Edahiro, Koji Murakami, Yasunori Sato, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Respiratory research 23 ( 1 ) 315 - 315 2022.11

ISSN 1465-9921

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Guillaume Butler-Laporte, Gundula Povysil, Jack A. Kosmicki, Elizabeth T. Cirulli, Theodore Drivas, Simone Furini, Chadi Saad, Axel Schmidt, Pawel Olszewski, Urszula Korotko, Mathieu Quinodoz, Elifnaz Çelik, Kousik Kundu, Klaudia Walter, Junghyun Jung, Amy D. Stockwell, Laura G. Sloofman, Daniel M. Jordan, Ryan C. Thompson, Diane Del Valle, Nicole Simons, Esther Cheng, Robert Sebra, Eric E. Schadt, Seunghee Kim-Schulze, Sacha Gnjatic, Miriam Merad, Joseph D. Buxbaum, Noam D. Beckmann, Alexander W. Charney, Bartlomiej Przychodzen, Timothy Chang, Tess D. Pottinger, Ning Shang, Fabian Brand, Francesca Fava, Francesca Mari, Karolina Chwialkowska, Magdalena Niemira, Szymon Pula, J Kenneth Baillie, Alex Stuckey, Antonio Salas, Xabier Bello, Jacobo Pardo-Seco, Alberto Gómez-Carballa, Irene Rivero-Calle, Federico Martinón-Torres, Andrea Ganna, Konrad J. Karczewski, Kumar Veerapen, Mathieu Bourgey, Guillaume Bourque, Robert JM Eveleigh, Vincenzo Forgetta, David Morrison, David Langlais, Mark Lathrop, Vincent Mooser, Tomoko Nakanishi, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Yanara Marincevic-Zuniga, Jessica Nordlund, Kelly M. Schiabor Barrett, William Lee, Alexandre Bolze, Simon White, Stephen Riffle, Francisco Tanudjaja, Efren Sandoval, Iva Neveux, Shaun Dabe, Nicolas Casadei, Susanne Motameny, Manal Alaamery, Salam Massadeh, Nora Aljawini, Mansour S. Almutairi, Yaseen M. Arabi, Saleh A. Alqahtani, Fawz S. Al Harthi, Amal Almutairi, Fatima Alqubaishi, Sarah Alotaibi, Albandari Binowayn, Ebtehal A. Alsolm, Hadeel El Bardisy, Mohammad Fawzy, Fang Cai, Nicole Soranzo, Adam Butterworth, Daniel H. Geschwind, Stephanie Arteaga, Alexis Stephens, Manish J. Butte, Paul C. Boutros, Takafumi N. Yamaguchi, Shu Tao, Stefan Eng, Timothy Sanders, Paul J. Tung, Michael E. Broudy, Yu Pan, Alfredo Gonzalez, Nikhil Chavan, Ruth Johnson, Bogdan Pasaniuc, Brian Yaspan, Sandra Smieszek, Carlo Rivolta, Stephanie Bibert, Pierre-Yves Bochud, Maciej Dabrowski, Pawel Zawadzki, Mateusz Sypniewski, Elżbieta Kaja, Pajaree Chariyavilaskul, Voraphoj Nilaratanakul, Nattiya Hirankarn, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Katsushi Tokunaga, Masaya Sugiyama, Yosuke Kawai, Takanori Hasegawa, Tatsuhiko Naito, Ho Namkoong, Ryuya Edahiro, Akinori Kimura, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga, Yukinori Okada, Seiya Imoto, Satoru Miyano, Serghei Mangul, Malak S. Abedalthagafi, Hugo Zeberg, Joseph J. Grzymski, Nicole L. Washington, Stephan Ossowski, Kerstin U. Ludwig, Eva C. Schulte, Olaf Riess, Marcin Moniuszko, Miroslaw Kwasniewski, Hamdi Mbarek, Said I. Ismail, Anurag Verma, David B. Goldstein, Krzysztof Kiryluk, Alessandra Renieri, Manuel A. R. Ferreira, J Brent Richards

PLOS Genetics (Public Library of Science (PLoS)) 18 ( 11 ) e1010367 - e1010367 2022.11

ISSN 1553-7404

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10<sup>-7</sup>). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

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Prophylactic antibiotics for postcataract surgery endophthalmitis: a systematic review and network meta-analysis of 6.8 million eyes.

Ai Kato, Nobuyuki Horita, Ho Namkoong, Eiichi Nomura, Nami Masuhara, Takeshi Kaneko, Nobuhisa Mizuki, Masaki Takeuchi

Scientific reports 12 ( 1 ) 17416 - 17416 2022.10

ISSN 2045-2322

To reveal optimal antibiotic prophylactic regimen for postoperative endophthalmitis (POE), we conducted systematic review and network meta-analysis. A total of 51 eligible original articles, including two randomized controlled trials, were identified. In total, 4502 POE cases occurred in 6,809,732 eyes (0.066%). Intracameral injection of vancomycin had the best preventive effect (odds ratio [OR] 0.03, 99.6% confidence interval [CI] 0.00-0.53, corrected P-value = 0.006, P-score = 0.945) followed by intracameral injection of cefazoline (OR 0.09, 99.6% CI 0.02-0.42, corrected P-value < 0.001, P-score = 0.821), cefuroxime (OR 0.18, 99.6% CI 0.09-0.35, corrected P-value < 0.001, P-score = 0.660), and moxifloxacin (OR 0.36, 99.6% CI 0.16-0.79, corrected P-value = 0.003, P-score = 0.455). While one randomized controlled trial supported each of intracameral cefuroxime and moxifloxacin, no randomized controlled trial evaluated vancomycin and cefazoline. Sensitivity analysis focusing on the administration route revealed that only intracameral injection (OR 0.19, 99.4% CI 0.12-0.30, corrected P-value < 0.001, P-score = 0.726) significantly decreased the risk of postoperative endophthalmitis. In conclusion, intracameral injection of either vancomycin, cefazoline, cefuroxime, or moxifloxacin prevented POE.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant.

Setsuko Mise-Omata, Mari Ikeda, Masaru Takeshita, Yoshifumi Uwamino, Masatoshi Wakui, Tomoko Arai, Ayumi Yoshifuji, Kensaku Murano, Haruhiko Siomi, Kensuke Nakagawara, Masaki Ohyagi, Makoto Ando, Naoki Hasegawa, Hideyuki Saya, Mitsuru Murata, Koichi Fukunaga, Ho Namkoong, Xiuyuan Lu, Sho Yamasaki, Akihiko Yoshimura

Journal of immunology (Baltimore, Md. : 1950) 209 ( 11 ) 2104 - 2113 2022.10

ISSN 0022-1767

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Neutralizing GM-CSF autoantibodies in pulmonary alveolar proteinosis, cryptococcal meningitis and severe nocardiosis.

Hélène Salvator, Aristine Cheng, Lindsey B Rosen, Peter R Williamson, John E Bennett, Anuj Kashyap, Li Ding, Kyung J Kwon-Chung, Ho Namkoong, Christa S Zerbe, Steven M Holland

Respiratory research 23 ( 1 ) 280 - 280 2022.10

ISSN 1465-9921

BACKGROUND: Anti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear. Therefore, we examined anti-GM-CSF autoantibodies to determine whether amount or neutralizing activity could distinguish between groups. METHODS: Plasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n = 15), cryptococcal meningitis (n = 15), severe nocardiosis (n = 5) or overlapping phenotypes (n = 6) were compared. The relative amount of aAb was assessed using a particle-based approach, reported as a mouse monoclonal anti-human GM-CSF as standard curve and expressed in an arbitrary Mouse Monoclonal Antibody Unit (MMAU). The neutralizing activity of the plasma was assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes. RESULTS: Anti-GM-CSF aAb relative amounts were higher in PAP patients compared to those with cryptococcosis (mean 495 ± 464 MMAU vs 197 ± 159 MMAU, p = 0.02); there was no difference with patients with nocardiosis (430 ± 493 MMAU) nor between the two types of infections. The dilution of plasma resulting in 50% inhibition of GM-CSF-induced pSTAT5 (approximate IC50) did not vary appreciably across groups of patients (1.6 ± 3.1%, 3.9 ± 6% and 1.8 ± 2.2% in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in the presence of 10 MMAU of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti-GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels. CONCLUSIONS: Despite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

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Clinical clustering with prognostic implications in Japanese COVID-19 patients: report from Japan COVID-19 Task Force, a nation-wide consortium to investigate COVID-19 host genetics.

Shiro Otake, Shotaro Chubachi, Ho Namkoong, Kensuke Nakagawara, Hiromu Tanaka, Ho Lee, Atsuho Morita, Takahiro Fukushima, Mayuko Watase, Tatsuya Kusumoto, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

BMC infectious diseases 22 ( 1 ) 735 - 735 2022.09

BACKGROUND: The clinical course of coronavirus disease (COVID-19) is diverse, and the usefulness of phenotyping in predicting the severity or prognosis of the disease has been demonstrated overseas. This study aimed to investigate clinically meaningful phenotypes in Japanese COVID-19 patients using cluster analysis. METHODS: From April 2020 to May 2021, data from inpatients aged ≥ 18 years diagnosed with COVID-19 and who agreed to participate in the study were collected. A total of 1322 Japanese patients were included. Hierarchical cluster analysis was performed using variables reported to be associated with COVID-19 severity or prognosis, namely, age, sex, obesity, smoking history, hypertension, diabetes mellitus, malignancy, chronic obstructive pulmonary disease, hyperuricemia, cardiovascular disease, chronic liver disease, and chronic kidney disease. RESULTS: Participants were divided into four clusters: Cluster 1, young healthy (n = 266, 20.1%); Cluster 2, middle-aged (n = 245, 18.5%); Cluster 3, middle-aged obese (n = 435, 32.9%); and Cluster 4, elderly (n = 376, 28.4%). In Clusters 3 and 4, sore throat, dysosmia, and dysgeusia tended to be less frequent, while shortness of breath was more frequent. Serum lactate dehydrogenase, ferritin, KL-6, D-dimer, and C-reactive protein levels tended to be higher in Clusters 3 and 4. Although Cluster 3 had a similar age as Cluster 2, it tended to have poorer outcomes. Both Clusters 3 and 4 tended to exhibit higher rates of oxygen supplementation, intensive care unit admission, and mechanical ventilation, but the mortality rate tended to be lower in Cluster 3. CONCLUSIONS: We have successfully performed the first phenotyping of COVID-19 patients in Japan, which is clinically useful in predicting important outcomes, despite the simplicity of the cluster analysis method that does not use complex variables.

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Immune Checkpoint Inhibitors Do Not Increase Short-Term Risk of Hypertension in Cancer Patients: a Systematic Literature Review and Meta-Analysis.

Shintaro Minegishi, Sho Kinguchi, Nobuyuki Horita, Ho Namkoong, Alexandros Briasoulis, Tomoaki Ishigami, Kouichi Tamura, Akira Nishiyama, Yuichiro Yano

Hypertension (Dallas, Tex. : 1979) 79 ( 11 ) 101161HYPERTENSIONAHA12219865 - 2621 2022.09

ISSN 0194-911X

BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

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Immune checkpoint inhibitor-induced arthralgia is tightly associated with improved overall survival in cancer patients.

Ayaka Maeda, Kaoru Takase-Minegishi, Yohei Kirino, Naoki Hamada, Yosuke Kunishita, Ryusuke Yoshimi, Akira Meguro, Ho Namkoong, Nobuyuki Horita, Hideaki Nakajima

Rheumatology (Oxford, England) 62 ( 4 ) 1451 - 1459 2022.09

ISSN 1462-0324

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs), arthralgia has been the most commonly reported musculoskeletal immune-related adverse events (irAEs). We aimed to characterise arthralgia and its association with overall survival (OS). METHODS: Randomised controlled trials (RCTs) reporting data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for arthralgia using a random effects model meta-analysis. Individual patient data were reconstructed from RCTs, assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14,377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20-1.56). Of the 369 patients in YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs; noticeably more frequently vs. those without arthralgia (OR 1.92, 95% CI 1.04-3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80-8.39). In the YCU registry, patients with (vs. without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17-0.65, P < 0.001). CONCLUSION: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS and patients' condition must be carefully evaluated to determine optimal management.

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Clinical significance of prediabetes, undiagnosed diabetes and diagnosed diabetes on critical outcomes in COVID-19: Integrative analysis from the Japan COVID-19 task force.

Takahiro Fukushima, Shotaro Chubachi, Ho Namkoong, Takanori Asakura, Hiromu Tanaka, Ho Lee, Shuhei Azekawa, Yukinori Okada, Ryuji Koike, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Diabetes, obesity & metabolism 25 ( 1 ) 144 - 155 2022.09

ISSN 1462-8902

AIM: Diabetes mellitus (DM) is a known risk factor for severe coronavirus disease 2019 (COVID-19), but the clinical impact of undiagnosed diabetes and prediabetes in COVID-19 are unclear particularly in Japan. We clarify the difference in clinical characteristics, including age, sex, body mass index and co-morbidities, laboratory findings and critical outcomes, in a large Japanese COVID-19 cohort without diabetes, with prediabetes, undiagnosed diabetes and diagnosed diabetes, and to identify associated risk factors. MATERIALS AND METHODS: This multicentre, retrospective cohort study used the Japan COVID-19 Task Force database, which included data on 2430 hospitalized COVID-19 patients from over 70 hospitals from February 2020 to October 2021. The prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes were estimated based on HbA1c levels or a clinical diabetes history. Critical outcomes were defined as the use of high-flow oxygen, invasive positive-pressure ventilation or extracorporeal membrane oxygenation, or death during hospitalization. RESULTS: Prediabetes, undiagnosed diabetes and diagnosed diabetes were observed in 40.9%, 10.0% and 23.0%, respectively. Similar to diagnosed diabetes, prediabetes and undiagnosed diabetes were risk factors for critical COVID-19 outcomes (adjusted odds ratio [aOR] [95% CI]: 2.13 [1.31-3.48] and 4.00 [2.19-7.28], respectively). HbA1c was associated with COVID-19 severity in prediabetes patients (aOR [95% CI]: 11.2 [3.49-36.3]), but not other groups. CONCLUSIONS: We documented the clinical characteristics and outcomes of Japanese COVID-19 patients according to HbA1c levels or diabetes co-morbidity. As well as undiagnosed and diagnosed diabetes, physicians should be aware of prediabetes related to COVID-19 severity.

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Identification of trypsin-degrading commensals in the large intestine.

Youxian Li, Eiichiro Watanabe, Yusuke Kawashima, Damian R Plichta, Zhujun Wang, Makoto Ujike, Qi Yan Ang, Runrun Wu, Munehiro Furuichi, Kozue Takeshita, Koji Yoshida, Keita Nishiyama, Sean M Kearney, Wataru Suda, Masahira Hattori, Satoshi Sasajima, Takahiro Matsunaga, Xiaoxi Zhang, Kazuto Watanabe, Jun Fujishiro, Jason M Norman, Bernat Olle, Shutoku Matsuyama, Ho Namkoong, Yoshifumi Uwamino, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa, Osamu Ohara, Ramnik J Xavier, Koji Atarashi, Kenya Honda

Nature 609 ( 7927 ) 582 - 589 2022.09

ISSN 0028-0836

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1-3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.

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Effects of mild obesity on outcomes in Japanese patients with COVID-19: a nationwide consortium to investigate COVID-19 host genetics.

Ho Lee, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Shiro Otake, Kensuke Nakagawara, Atsuho Morita, Takahiro Fukushima, Mayuko Watase, Tatsuya Kusumoto, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Nutrition & diabetes 12 ( 1 ) 38 - 38 2022.08

ISSN 2044-4052

BACKGROUND: Obesity is reported to be a risk factor for severe disease in patients with coronavirus disease 2019 (COVID-19). However, there are no specific reports on the risk of severe disease according to body mass index (BMI) in Japan. Thus, this study aimed to investigate the effect of obesity stratified by BMI on the severity of COVID-19 in the general Japanese population. METHODS: From February 2020 to May 2021, 1 837 patients aged ≥18 years were enrolled in the Japan COVID-19 Task Force. Patients with known BMI and disease severity were analyzed. Severity was defined as critical if the patient was treated in the intensive care unit, required invasive mechanical ventilation, or died. RESULTS: Class 1 obesity (25.0 ≤ BMI < 30.0 kg/m2), class 2 obesity (30.0 ≤ BMI < 35.0 kg/m2), and class 3 or 4 obesity (BMI ≥ 35 kg/m2) were present in 29%, 8%, and 3% of the cases, respectively. Multiple logistic regression analysis with known risk factors for critical illness indicated that class 2 obesity was an independent risk factor for oxygenation (adjusted odds ratio, 4.75) and critical cases (adjusted odds ratio, 1.81). Class 1 obesity and class 3 or 4 obesity were independent risk factors for oxygen administration (adjusted odds ratios 2.01 and 3.12, respectively), but not for critical cases. However, no differences in the mortality rates were observed between the BMI classes (P = 0.5104). CONCLUSION: Obesity is a risk factor for respiratory failure in Japanese patients with COVID-19, regardless of the degree of obesity. However, it may not cause severe COVID-19 in a dose-response relationship with BMI. COVID-19 patients with mild obesity may benefit from aggressive intensive care.

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Dynamics of antibody titers and cellular immunity among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine.

Yoshifumi Uwamino, Toshinobu Kurafuji, Kumiko Takato, Akiko Sakai, Akiko Tanabe, Masayo Noguchi, Yoko Yatabe, Tomoko Arai, Akemi Ohno, Yukari Tomita, Ayako Shibata, Hiromitsu Yokota, Wakako Yamasawa, Ho Namkoong, Yasunori Sato, Naoki Hasegawa, Masatoshi Wakui, Mitsuru Murata

Vaccine 40 ( 32 ) 4538 - 4543 2022.07

ISSN 0264-410X

BACKGROUND: The antibody titer is known to wane within months after receiving two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine. However, knowledge of the cellular immune response dynamics following vaccination is limited. This study to aimed to determine antibody and cellular immune responses following vaccination, and the incidence and determinants of breakthrough infection. METHODS: This prospective cohort study a 6-month follow-up period was conducted among Japanese healthcare workers. All participants received two doses of BNT162b2 vaccine. Anti-SARS-CoV-2 antibody titers and T-cell immune responses were measured in serum samples collected at several timepoints before and after vaccination. RESULTS: A total of 608 participants were included in the analysis. Antibody titers were elevated 3 weeks after vaccination and waned over the remainder of the study period. T-cell immune responses showed similar dynamics. Six participants without predisposing medical conditions seroconverted from negative to positive on the IgG assay for nucleocapsid proteins, indicating breakthrough SARS-CoV-2 infection. Five of the six breakthrough infections were asymptomatic. CONCLUSIONS: Both humoral and cellular immunity waned within 6 months after BNT162b2 vaccination. The incidence of asymptomatic breakthrough infection within 6 months after vaccination was approximately one percent. UMIN CLINICAL TRIALS REGISTRY ID: UMIN000043340.

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U-shaped association between abnormal serum uric acid levels and COVID-19 severity: Reports from the Japan COVID-19 Task Force.

Takahiro Fukushima, Shotaro Chubachi, Ho Namkoong, Shiro Otake, Kensuke Nakagawara, Hiromu Tanaka, Ho Lee, Atsuho Morita, Mayuko Watase, Tatsuya Kusumoto, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 122 747 - 754 2022.07

ISSN 1201-9712

OBJECTIVES: This study aimed to identify the relationship between abnormal serum uric acid levels or a history of hyperuricemia and coronavirus disease 2019 (COVID-19) severity in the Japanese population. METHODS: We included 1,523 patients enrolled in the Japan COVID-19 Task Force cohort between February 2020 and May 2021. We compared the clinical characteristics, including comorbidities, laboratory findings, and outcomes, particularly invasive mechanical ventilation (IMV), among patients with and without abnormal uric acid levels or a history of hyperuricemia. RESULTS: Patients with high serum uric acid levels were older and had higher body weights and body mass index than those without. In addition, the multiple logistic regression analysis revealed a significant association between high serum uric acid levels or a history of hyperuricemia and an increased risk of IMV (odds ratio (OR)=1.77; p=0.03/OR=1.56; p=0.04). Moreover, patients with low uric acid levels on admission were also associated significantly with the requirement of IMV (OR=5.09; p<0.0001). CONCLUSION: Abnormal serum uric acid levels or a history of hyperuricemia were significantly associated with COVID-19 severity in the Japanese cohort.

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system

Ozawa Takuya, Namkoong Ho, Takaya Risako, Takahashi Yusuke, Fukunaga Koichi, Enoki Yuki, Taguchi Kazuaki, Kizu Junko, Matsumoto Kazuaki, Hasegawa Naoki

BMC INFECTIOUS DISEASES 22 ( 1 ) 2022.06

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

Ozawa T, Namkoong H, Takaya R, Takahashi Y, Fukunaga K, Enoki Y, Taguchi K, Kizu J, Matsumoto K, Hasegawa N

BMC infectious diseases 22 ( 1 ) 580 2022.06

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Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

Takuya Ozawa, Ho Namkoong, Risako Takaya, Yusuke Takahashi, Koichi Fukunaga, Yuki Enoki, Kazuaki Taguchi, Junko Kizu, Kazuaki Matsumoto, Naoki Hasegawa

BMC infectious diseases 22 ( 1 ) 580 - 580 2022.06

BACKGROUND: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. METHODS: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. RESULTS: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The β value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type. CONCLUSIONS: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

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COMPARISON OF SARS-COV-2 VACCINE RESPONSE IN PATIENTS WITH INFLAMMATORY RHEUMATIC DISEASE; MRNA-1273 VACCINE INDUCES HIGHER HUMORAL IMMUNOGENICITY THAN BNT162B2

Kondo Y., Takeshita M., Uwamino Y., Namkoong H., Saito S., Kikuchi J., Hanaoka H., Suzuki K., Hasegawa N., Murata M., Kaneko Y.

ANNALS OF THE RHEUMATIC DISEASES 81 370 - 370 2022.06

ISSN 0003-4967

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広域抗菌薬に対するタイムアウト「KAERUプロジェクト」の効果

瀬山翔史, 池谷修, 内田翔, 宇野俊介, 南宮湖, 上蓑義典, 尾原秀明, 荒美幸, 高野八百子, 長谷川直樹

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) 37回 O50 - 1 2022.06

Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study.

Hiromu Tanaka, Takanori Asakura, Shoji Suzuki, Satoshi Okamori, Tatsuya Kusumoto, Takunori Ogawa, Shunsuke Uno, Atsuho Morita, Ho Lee, Ho Namkoong, Hirofumi Kamata, Yasunori Sato, Yoshifumi Uwamino, Tomoyasu Nishimura, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa

BMC pulmonary medicine 22 ( 1 ) 202 - 202 2022.05

ISSN 1471-2466

BACKGROUND: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. METHODS: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017-September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. RESULTS: Osteoporosis (T-score ≤ - 2.5) and osteopenia (T-score - 1 to - 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50-59-, 60-69-, and 70-79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07-1.18), female sex (aOR = 36.3; 95% CI = 7.57-174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14-1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07-41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. CONCLUSIONS: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

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特集 1ページでわかる内科疾患の診療ノート-"あたりまえ" のなかにある大事な視点第5章:感染症肺非結核性抗酸菌症

南宮湖

内科 (南江堂) 129 ( 4 ) 749 - 753 2022.04

ISSN 00221961

Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.

Shingo Kato, Mai Azuma, Kazuki Fukui, Sho Kodama, Naoki Nakayama, Hideya Kitamura, Eri Hagiwara, Takashi Ogura, Nobuyuki Horita, Ho Namkoong, Kazuo Kimura, Kouichi Tamura, Daisuke Utsunomiya

Heart and vessels 37 ( 9 ) 1570 - 1582 2022.03

ISSN 0910-8327

In this systematic review and meta-analysis, we sought to evaluate the prevalence of cardiac involvement in patients with COVID-19 using cardiac magnetic resonance imaging. A literature review was performed to investigate the left ventricular (LV) and right ventricular (RV) ejection fraction (EF), the prevalence of LV late gadolinium enhancement (LGE), pericardial enhancement, abnormality on T1 mapping, and T2 mapping/T2-weighted imaging (T2WI), and myocarditis (defined by modified Lake Louis criteria). Pooled mean differences (MD) between COVID-19 patients and controls for LVEF and RVEF were estimated using random-effects models. We included data from 10.462 patients with COVID-19, comprising 1.010 non-athletes and 9.452 athletes from 29 eligible studies. The meta-analysis showed a significant difference between COVID-19 patients and controls in terms of LVEF [MD = - 2.84, 95% confidence interval (CI) - 5.11 to - 0.56, p < 0.001] and RVEF (MD = - 2.69%, 95% CI - 4.41 to - 1.27, p < 0.001). However, in athletes, no significant difference was identified in LVEF (MD = - 0.74%, 95% CI - 2.41 to - 0.93, p = 0.39) or RVEF (MD = - 1.88%, 95% CI - 5.21 to 1.46, p = 0.27). In non-athletes, the prevalence of LV LGE abnormalities, pericardial enhancement, T1 mapping, T2 mapping/T2WI, myocarditis were 27.5% (95%CI 17.4-37.6%), 11.9% (95%CI 4.1-19.6%), 39.5% (95%CI 16.2-62.8%), 38.1% (95%CI 19.0-57.1%) and 17.6% (95%CI 6.3-28.9%), respectively. In athletes, these values were 10.8% (95%CI 2.3-19.4%), 35.4% (95%CI - 3.2 to 73.9%), 5.7% (95%CI - 2.9 to 14.2%), 1.9% (95%CI 1.1-2.7%), 0.9% (0.3-1.6%), respectively. Both LVEF and RVEF were significantly impaired in COVID-19 patients compared to controls, but not in athletes. In addition, the prevalence of myocardial involvement is not negligible in patients with COVID-19.

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Benefits and risks of Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis.

Kana Higashitani, Kaoru Takase-Minegishi, Ryusuke Yoshimi, Yohei Kirino, Naoki Hamada, Hideto Nagai, Maki Hagihara, Kenji Matsumoto, Ho Namkoong, Nobuyuki Horita, Hideaki Nakajima

Modern rheumatology 33 ( 2 ) 330 - 337 2022.03

ISSN 1439-7595

OBJECTIVES: We aimed to evaluate the efficacy and safety of hematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis (SSc). METHODS: A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide (IVCY). Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model. RESULTS: Of the 2,091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in IVCY, the Kaplan-Meier analysis showed a high survival rate 2 years post-transplant (log-rank, P=0.004). The pooled frequency of transplant-related death from 700 SSc patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade. CONCLUSION: HSCT is an effective treatment for SSc, but the optimal indications must be carefully determined by balancing the risks.

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Laryngitis after inhalation of liposomal amikacin.

Atsuho Morita, Ho Namkoong, Makoto Hosoya, Naoki Hasegawa

Clinical case reports 10 ( 2 ) e05350 2022.02

ISSN 2050-0904

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特集 COVID-19と腎臓病【総論】予後予測因子

田中拓, 南宮湖

腎と透析 (東京医学社) 92 ( 1 ) 35 - 40 2022.01

ISSN 03852156

Best regimens for treating chemo-naïve incurable squamous non-small cell lung cancer with a programmed death-ligand 1 tumor proportion score of 1%-49%: A network meta-analysis.

Nobuhiko Fukuda, Nobuyuki Horita, Ho Namkoong, Ayami Kaneko, Kohei Somekawa, Yoichi Tagami, Keisuke Watanabe, Yu Hara, Nobuaki Kobayashi, Takeshi Kaneko

Thoracic cancer 13 ( 1 ) 84 - 94 2022.01

ISSN 1759-7706

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. It is advisable to select the appropriate treatment based on characteristics of the cancer such as pathology, mutations, and programmed death-ligand 1 (PD-L1) levels. In this study, by remarking squamous NSCLC with low PD-L1 expression without mutations, we investigated the efficacy and safety of regimens that included molecularly targeted drugs such as immune checkpoint inhibitors (ICIs) through a network meta-analysis. METHODS: Databases were searched systematically to identify appropriate articles, in which randomized trials with incurable squamous NSCLC were described. Suitable studies were manually checked by two reviewers. A random model network meta-analysis was conducted, in which the primary outcome was the overall survival rate. RESULTS: We identified 48 studies, which included 16 391 patients. When a platinum + third-generation cytotoxic agent regimen (platinum regimen) was a reference, the platinum regimen + pembrolizumab (Pemb) yielded the best results in regard to the overall survival rate when compared with chemotherapy (hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.36-0.90, p = 0.016) followed by the platinum regimen + nivolumab (Niv) + ipilimumab (Ipi) (HR = 0.61, 95% CI = 0.44-0.84, p = 0.003). However, the efficacy of ICI monotherapy was not statistically different from that of the platinum regimen. CONCLUSIONS: The combination therapies, which were the platinum regimen + Pemb and the platinum regimen + Niv + Ipi, rather than ICI monotherapy were effective first-line agents for treating squamous NSCLC with low PD-L1 levels.

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Adverse events induced by nivolumab and ipilimumab combination regimens.

Kohei Somekawa, Nobuyuki Horita, Ayami Kaneko, Yoichi Tagami, Nobuhiko Fukuda, Hiromi Matsumoto, Ho Namkoong, Yu Fujiwara, Kaoru Minegishi, Takeshi Fukumoto, Keisuke Watanabe, Yu Hara, Nobuaki Kobayashi, Takeshi Kaneko

Therapeutic advances in medical oncology 14 17588359211058393 - 17588359211058393 2022

ISSN 1758-8340

Background: No meta-analysis has assessed the pooled frequencies of adverse events (AEs) induced by concomitant nivolumab plus ipilimumab regimen for anticancer-medications-naïve malignancies. Furthermore, no meta-analysis has compared detailed safety profiles between four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1) and four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3). Objectives of this study was estimating AE frequencies, and comparison of AE frequencies between N3I1 and N1I3 regimens. Methods: Four major electronic databases were searched; both interventional and observational studies were included. All primary cancer types were permitted. Patients should not have been previously treated with any anti-cancer medications. The frequency of AEs was pooled using a random-model meta-analysis using the generic inverse variance method. Protocol registration: UMIN000044090. Results: Forty articles representing 48 populations with 4,677 patients were included in the study. The pooled frequencies for key indicators were as follows: any AE, 81.3% (95% confidence interval (CI) 77.5-85.1); grade 3 or higher AE, 40.6% (95% CI: 35.7-45.5); serious AE, 32.7% (95% CI: 22.4-43.1); AE leading to discontinuation, 28.3% (95% CI: 23.7-32.8); and treatment-related death, 0.7% (95% CI: 0.4-1.1). AEs with the highest incidence were fatigue (27.9%, 95% CI: 22.6-33.3), followed by diarrhea (26.0%, 95% CI: 21.5-30.5), pruritus (24.6%, 95% CI: 20.3-28.8), rash (24.0% 95% CI: 19.3-28.7), and elevated aspartate aminotransferase (21.2%, 95% CI: 14.9-27.5). Subgroup analyses demonstrated that N3I1, compared to N1I3, less frequently induced any AE (N1I3 95.7%, N3I1 84.5%, p = 0.003), grade 3 or higher AE (N1I3 64.3%, N3I1 35.7%, p < 0.001), and serious AE (N1I3 61.4%, N3I1 47.8%, p = 0.004). Conclusions: Approximately 40% of patients had grade 3 or higher AE. The N3I1 regimen was substantiated to trigger fewer any AEs, high grade AEs, and serious AE than the N1I3 regimen.

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Best regimens for treating chemo‐naïve incurable squamous non‐small cell lung cancer with a programmed death‐ligand 1 tumor proportion score of 1%–49%: A network meta‐analysis

N Fukuda, N Horita, H Namkoong, A Kaneko, K Somekawa, Y Tagami, ...

Thoracic Cancer 13 (1), 84-94 2022

Association between ABO blood group/genotype and COVID-19 in a Japanese population (preprint)

T Kusumoto, S Chubachi, H Namkoong, H Tanaka, H Lee, S Azekawa, ...

2022

Association between ABO blood group/genotype and COVID-19 in a Japanese population

T Kusumoto, S Chubachi, H Namkoong, H Tanaka, H Lee, S Azekawa, ...

2022

Analysis of Adverse Drug Events in Pulmonary Mycobacterium avium Complex Disease Using Spontaneous Reporting System

H Namkoong, T Ozawa, R Takaya, Y Takahashi, K Fukunaga, Y Enoki, ...

2022

Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system

T Ozawa, H Namkoong, R Takaya, Y Takahashi, K Fukunaga, Y Enoki, ...

BMC infectious diseases 22 (1), 580 2022

Clinical clustering with prognostic implications in Japanese COVID-19 patients: report from Japan COVID-19 Task Force, a nation-wide consortium to investigate COVID-19 host …

S Otake, S Chubachi, H Namkoong, K Nakagawara, H Tanaka, H Lee, ...

BMC Infectious Diseases 22 (1), 735 2022

Immunohistochemical markers to diagnose primary squamous cell carcinoma of the lung: a meta-analysis of diagnostic test accuracy.

Hao Chen, Seigo Katakura, Nobuyuki Horita, Ho Namkoong, Ikuma Kato, Yu Hara, Nobuaki Kobayashi, Satoshi Fujii, Takeshi Kaneko

Therapeutic advances in medical oncology 14 17588359211065152 - 17588359211065152 2022

ISSN 1758-8340

Background: Inconsistent diagnostic test accuracies of immunohistological staining for squamous cell carcinoma (SQC) of the lung have been frequently reported. There have been few meta-analyses of the diagnostic accuracies of the immunohistochemical markers. Methods: A systematic review and meta-analysis were performed following standard guidelines for systematic reviews of diagnostic test accuracy. Immunohistochemical markers (p40, p63, CK5/6, and DSC3) were evaluated as index tests for SQC. The diagnostic odds ratio (DOR) was obtained by the DerSimonian-Laird variate model. Summary estimates of sensitivity and specificity were calculated using a bivariate model. The protocol registration ID is UMIN000041664. Results: The meta-analysis included 85 of the 1353 first-screened articles. The total number of patients was 17,893, which consisted 6151 SQC cases and 11,742 non-squamous non-small-cell lung cancer cases. The DOR was better for p40 (377, 95% confidence interval (CI) = 213-644, I 2 = 0%) than for CK5/6 (120, 95% CI = 78-184, I 2 = 2.5%), p63 (70, 95% CI = 55-88, I 2 = 9.1%), and DSC3 (94, 95% CI = 35-250, I 2 = 3.7%). Summary estimates of sensitivity and specificity were followings: p40 sensitivity 0.92 (95% CI = 0.89-0.95), specificity 0.94 (95% CI = 0.93-0.96); p63 sensitivity 0.92 (95% CI = 0.90-0.94), specificity 0.83 (95% CI = 0.80-0.86); CK5/6 sensitivity 0.90 (95% CI = 0.87-0.93), specificity 0.91 (95% CI = 0.89-0.93); DSC3 sensitivity 0.81 (95% CI = 0.73-0.88), and specificity 0.95 (95% CI = 0.85-0.98). Conclusion: P40 had the best DOR to diagnose SQC in non-small-cell lung carcinoma. Despite its lower sensitivity, DSC3 had the best specificity among the four markers and might be useful to rule-in the diagnosis of SQC.

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Identification of commensals and molecular components mediating trypsin degradation in the large intestine (preprint)

K Honda, K Atarashi, S Sasajima, Z Wang, K Nishiyama, T Matsunaga, ...

2022

Identification of commensals and molecular components mediating trypsin degradation in the large intestine

K Honda, K Atarashi, S Sasajima, Z Wang, K Nishiyama, T Matsunaga, ...

2022

Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Y Sato, Y Uwamino, K Nagashima, A Yoshifuji, S Suga, M Nagao, ...

2022

Early-Phase Adverse Effects and Management of Liposomal Amikacin Inhalation for Refractory Mycobacterium avium Complex Lung Disease in Real-World Settings.

Atsuho Morita, Ho Namkoong, Kazuma Yagi, Takanori Asakura, Makoto Hosoya, Hiromu Tanaka, Ho Lee, Takunori Ogawa, Tatsuya Kusumoto, Shuhei Azekawa, Kensuke Nakagawara, Hirofumi Kamata, Makoto Ishii, Koichi Fukunaga, Hiroyuki Ozawa, Naoki Hasegawa

Infection and drug resistance 15 4001 - 4011 2022

ISSN 1178-6973

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

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Dynamics of antibody responses, cellular immunity, and breakthrough infections among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA …

Y Uwamino, T Kurafuji, K Takato, A Sakai, A Tanabe, M Noguchi, ...

medRxiv, 2022.01. 29.22270052 2022

Development of Rheumatoid Arthritis in Cavitary Mycobacterium avium Pulmonary Disease: A Case Report of Successful Treatment with CTLA4-Ig (Abatacept).

Hiromu Tanaka, Takanori Asakura, Jun Kikuchi, Makoto Ishii, Ho Namkoong, Yuko Kaneko, Koichi Fukunaga, Naoki Hasegawa

Infection and drug resistance 15 91 - 97 2022

ISSN 1178-6973

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently administered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

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Detailed Analysis of the Impact of Clonal Hematopoiesis on the Risk of Severe COVID-19 Infection

R Saiki, H Namkoong, R Edahiro, K Sonehara, QS Wang, T Hasegawa, ...

Blood 140 (Supplement 1), 5747-5748 140 5747 - 5748 2022

ISSN 0006-4971

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Comprehensive Analysis of Long COVID in a Japanese Nationwide Prospective Cohort Study (preprint)

H Terai, M Ishii, R Takemura, H Namkoong, K Shimamoto, K Masaki, ...

2022

Comprehensive Analysis of Long COVID in a Japanese Nationwide Prospective Cohort Study

Hideki Terai, Makoto Ishii, Ryo Takemura, Ho Namkoong, Kyoko Shimamoto, Katsunori Masaki, Takae Tanosaki, Shotaro Chubachi, Emiko Matsuyama, Reina Hayashi, Takashi Shimada, Lisa Shigematsu, Fumimaro Ito, Masanori Kaji, Hatsuyo Takaoka, Momoko Kurihara, Kensuke Nakagawara, Saki Tomiyasu, Kotaro Sasahara, Ayaka Saito, Shiro Otake, Shuhei Azegawa, Masahiko Okada, Takahiro Fukushima, Atsuho Morita, Hiromu Tanaka, Keeya Sunata, Masato Asaoka, Miyuki Nishie, Taro Shinozaki, Toshiki Ebisudani, Yuto Akiyama, Akifumi Mitsuishi, Shingo Nakayama, Takunori Ogawa, Kaori Sakurai, Misato Kuwae, Kazuma Yagi, Keiko Ohgino, Jun Miyata, Hiroki Kabata, Shinnosuke Ikemura, Hirofumi Kamata, Hiroyuki Yasuda, Ichiro Kawada, Ryusei Kimura, Masahiro Kondo, Toshiki Iwasaki, Noriyuki Ishida, Gaku Hiruma, Naoki Miyazaki, Yoshiki Ishibashi, Sei Harada, Takanori Fujita, Daisuke Ito, Shogyoku Bun, Hajime Tabuchi, Sho Kanzaki, Eisuke Shimizu, Keitaro Fukuda, Jun Yamagami, Keigo Kobayashi, Toshiyuki Hirano, Takashi Inoue, Mizuha Hashiguchi, Junko Kagyo, Tetsuya Shiomi, Ho Lee, Kai Sugihara, Nao Omori, Koichi Sayama, Kengo Otsuka, Naoki Miyao, Toshio Odani, Takao Mochimaru, Ryosuke Satomi, Yoshitaka Oyamada, Keita Masuzawa, Takanori Asakura, Mayuko Watase, Sohei Nakayama, Yusuke Suzuki, Rie Baba, Satoshi Okamori, Daisuke Arai, Ichiro Nakachi, Naota Kuwahara, Akiko Fujiwara, Takenori Okada, Takashi Ishiguro, Taisuke Isono, Yasushi Makino, Shuko Mashimo, Tatsuya Kaido, Naoto Minematsu, Soichiro Ueda, Kazuhiro Minami, Rie Hagiwara, Tadashi Manabe, Takahiro Fukui, Yohei Funatsu, Hidefumi Koh, Takashi Yoshiyama, Hiroyuki Kokuto, Tatsuya Kusumoto, Ayano Oashi, Masayoshi Miyawaki, Fumitake Saito, Tetsuo Tani, Kota Ishioka, Saeko Takahashi, Morio Nakamura, Norihiro Harada, Hitoshi Sasano, Ai Nakamura, Yu Kusaka, Takehiko Ohba, Yasushi Nakano, Kazumi Nishio, Yukiko Nakajima, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Nobuhiro Kodama, Shunsuke Maeda, Satoshi Sakamoto, Masaki Okamoto, Yoji Nagasaki, Akira Umeda, Kasuya Miyagawa, Naoto Shimada, Kazuto Hagimura, Kengo Nagashima, Toshiro Sato, Yasunori Sato, Naoki Hasegawa, Toru Takebayashi, Jin Nakahara, Masaru Mimura, Kaoru Ogawa, Shigeto Shimmura, Kazuno Negishi, Kazuo Tsubota, Masayuki Amagai, Rei Goto, Yoko Ibuka, Yuko Kitagawa, Takanori Kanai, Koichi Fukunaga

SSRN Electronic Journal (Elsevier BV) 2022

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Incidence and Distinct Features of Immune Checkpoint Inhibitor-Related Myositis From Idiopathic

N Hamada, A Maeda, K Takase-Minegishi, Y Kirino, Y Sugiyama, ...

Autoimmune Myositis: From Immunological to Rheumatological Aspects 2022

POS0257 COMPARISON OF SARS-CoV-2 VACCINE RESPONSE IN PATIENTS WITH INFLAMMATORY RHEUMATIC DISEASE; mRNA-1273 VACCINE INDUCES HIGHER HUMORAL IMMUNOGENICITY THAN BNT162b2

Y Kondo, M Takeshita, Y Uwamino, H Namkoong, S Saito, J Kikuchi, ...

Annals of the Rheumatic Diseases 81 (Suppl 1), 370-370 2022

Mycoplasma pneumoniae beyond the COVID-19 pandemic: where is it?

PMM Sauteur, VJ Chalker, C Berger, R Nir-Paz, ML Beeton, S Pereyre, ...

The Lancet Microbe 3 (12), e897 2022

Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and efficacy to the Omicron variant.

S Mise-Omata, M Ikeda, M Takeshita, Y Uwamino, M Wakui, T Arai, ...

bioRxiv, 2022.07. 31.500554 2022

Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials

Y Fujiwara, N Horita, M Harrington, H Namkoong, H Miyashita, MD Galsky

Cancer Immunology, Immunotherapy 71 (12), 2837-2848 2022

Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19.

Hiromu Tanaka, Ho Lee, Atsuho Morita, Ho Namkoong, Shotaro Chubachi, Hiroki Kabata, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 113 74 - 81 2021.12

ISSN 1201-9712

BACKGROUND AND DESIGN: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. RESULTS: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45-71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. CONCLUSIONS: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

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Beneficial Effects of Apremilast on Genital Ulcers, Skin Lesions, and Arthritis in Patients With Behçet's Disease: A Systematic Review and Meta-Analysis.

Yuki Iizuka, Kaoru Takase-Minegishi, Lisa Hirahara, Yohei Kirino, Yutaro Soejima, Ho Namkoong, Nobuyuki Horita, Ryusuke Yoshimi, Masaki Takeuchi, Mitsuhiro Takeno, Nobuhisa Mizuki, Hideaki Nakajima

Modern rheumatology 32 ( 6 ) 1153 - 1162 2021.11

ISSN 1439-7595

OBJECTIVE: This study aimed to determine the clinical efficacy of apremilast for oral ulcers, extra-oral manifestations, and overall disease activity in patients with Behçet's disease (BD). METHODS: A systematic literature search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. Studies assessing the treatment effects of apremilast in BD were included. The odds ratios (ORs) of being symptom free for individual manifestations and mean difference (MD) of Behçet's Disease Current Activity Form (BDCAF) scores were calculated with 95% confidence intervals (CIs) at 12 and 24 weeks using a random-model meta-analysis. RESULTS: Of 259 screened articles, eight were included. After 12 weeks of apremilast treatment the OR of symptom-free was as followings: oral ulcers, 45.76 (95% CI, 13.23-158.31); genital ulcers, 4.56 (95% CI, 2.47-8.44); erythema nodosum, 3.59 (95% CI, 1.11-11.61); pseudofolliculitis, 2.81 (95% CI, 1.29-6.15); and arthritis, 3.55 (95% CI, 1.71-7.40). Furthermore, BDCAF scores at 12 weeks were significantly reduced (MD=-1.38; -1.78 to -0.99). However, the proportion of oral-ulcer free patients increased at 24 weeks (OR=14.88; 4.81 to 46.07). CONCLUSION: The currently accumulated data indicates an improvement in mucocutaneous and articular symptoms by short-term apremilast treatment in patients with BD.

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

Kensuke Nakagawara, Ho Namkoong, Hideki Terai, Katsunori Masaki, Takae Tanosaki, Kyoko Shimamoto, Ho Lee, Hiromu Tanaka, Satoshi Okamori, Hiroki Kabata, Shotaro Chubachi, Shinnosuke Ikemura, Hirofumi Kamata, Hiroyuki Yasuda, Ichiro Kawada, Makoto Ishii, Yoshiki Ishibashi, Sei Harada, Takanori Fujita, Daisuke Ito, Shogyoku Bun, Hajime Tabuchi, Sho Kanzaki, Eisuke Shimizu, Keitaro Fukuda, Jun Yamagami, Keigo Kobayashi, Toshiyuki Hirano, Takashi Inoue, Junko Kagyo, Tetsuya Shiomi, Keiko Ohgino, Koichi Sayama, Kengo Otsuka, Naoki Miyao, Toshio Odani, Yoshitaka Oyamada, Keita Masuzawa, Sohei Nakayama, Yusuke Suzuki, Rie Baba, Ichiro Nakachi, Naota Kuwahara, Takashi Ishiguro, Shuko Mashimo, Naoto Minematsu, Soichiro Ueda, Tadashi Manabe, Yohei Funatsu, Hidefumi Koh, Takashi Yoshiyama, Fumitake Saito, Kota Ishioka, Saeko Takahashi, Morio Nakamura, Ai Goto, Norihiro Harada, Yu Kusaka, Yasushi Nakano, Kazumi Nishio, Hiroki Tateno, Ryuya Edahiro, Yoshito Takeda, Atsushi Kumanogoh, Nobuhiro Kodama, Masaki Okamoto, Akira Umeda, Kazuto Hagimura, Toshiro Sato, Naoki Miyazaki, Ryo Takemura, Yasunori Sato, Toru Takebayashi, Jin Nakahara, Masaru Mimura, Kaoru Ogawa, Shigeto Shimmura, Kazuno Negishi, Kazuo Tsubota, Masayuki Amagai, Rei Goto, Yoko Ibuka, Naoki Hasegawa, Yuko Kitagawa, Takanori Kanai, Koichi Fukunaga

BMJ open respiratory research 8 ( 1 ) 2021.11

INTRODUCTION: The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. METHODS AND ANALYSIS: In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. ETHICS AND DISSEMINATION: This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

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Cardiac tamponade due to primary malignant pericardial mesothelioma diagnosed with surgical pericardial resection.

Naoki Kawakami, Miki Kawai, Ho Namkoong, Daisuke Arai, Soichiro Ueda, Kenichi Hamada, Ichiro Kawada, Naoki Hasegawa, Shuji Mikami, Hisao Asamura, Koichi Fukunaga

Journal of cardiology cases 24 ( 4 ) 149 - 152 2021.10

Primary malignant pericardial mesothelioma is an extremely rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. A 67-year-old male patient, an ex-smoker, complaining of progressive lethargy was referred to a hospital for investigation of persistent pericardial effusion. The pericardial fluid cytology was categorized as class Ⅲ. Thereafter, he was referred to our hospital for further evaluation. Fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed FDG accumulation in the pericardium and mediastinal lymph node. Surgical biopsy of the pericardium was performed through a subxiphoid approach for a definitive diagnosis. Histopathological examination revealed diffuse infiltration of the pericardium by a malignant tumor consisting of epithelioid cells with large round nuclei and prominent nucleoli, arranged in a tubular papillary pattern. Finally, the patient was diagnosed with primary malignant pericardial mesothelioma of epithelioid type. The patient died 6 weeks after admission. This diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and FDG PET to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit. <Learning objective: Primary malignant pericardial mesothelioma is a rare disease. Malignant disease of the pericardium is an infrequent cause of cardiac tamponade. Hence, cardiac tamponade in the context of primary malignant mesothelioma of the pericardium is an uncommon clinical scenario. However, this diagnosis must be considered in patients having unexplained massive pericardial effusion. Furthermore, we should consider prompt cytological analysis and fluorodeoxyglucose positron emission tomography to arrive rapidly at a definitive diagnosis to administer combination chemotherapy that may provide clinical benefit.>.

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ADAM10 Partially Protects Mice against Influenza Pneumonia by Suppressing Specific Myeloid Cell Population.

Satoshi Okamori, Makoto Ishii, Takanori Asakura, Shoji Suzuki, Ho Namkoong, Shizuko Kagawa, Ahmed E Hegab, Kazuma Yagi, Hirofumi Kamata, Tatsuya Kusumoto, Takunori Ogawa, Hayato Takahashi, Masaki Yoda, Keisuke Horiuchi, Naoki Hasegawa, Koichi Fukunaga

American journal of physiology. Lung cellular and molecular physiology 321 ( 5 ) L872-L884 - L884 2021.09

ISSN 1040-0605

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contribute to various immune responses; however, the role of ADAM10 in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. Adam10flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines such as TNF-α, IL-1b, and CCL2 were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

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Anal tuberculosis presenting as refractory perianal abscess.

Kotaro Sasahara, Keiichiro Kitahama, Satoshi Aiko, Ho Namkoong

Clinical case reports 9 ( 9 ) e04177 2021.09

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Rheumatoid arthritis with nontuberculous mycobacterial pulmonary disease: a retrospective, single-centre cohort study.

Hiroshi Takei, Naoshi Nishina, H O Namkoong, Katsuya Suzuki, Yoshifumi Uwamino, Naoki Hasegawa, Tsutomu Takeuchi

Modern rheumatology 32 ( 3 ) 534 - 540 2021.08

ISSN 1439-7595

OBJECTIVES: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a rare but important comorbidity of rheumatoid arthritis (RA). Our objective was to investigate the association between NTM-PD and RA, especially regarding the immunosuppressive treatment of RA such as biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We conducted a retrospective, single-centre cohort study. All RA patients regularly followed up at our rheumatology division in December 2012 were included in the study, and followed for 5 years. RESULTS: At baseline, 26 of 1639 RA patients had NTM-PD. During the observation period, 14 were newly diagnosed with NTM-PD. For new diagnosis of NTM-PD, bDMARD use at baseline was not a significant risk factor. Among the 40 patients with NTM-PD, 16 were treated with a total of 27 bDMARDs after NTM-PD diagnosis. They did not present with a greater exacerbation of NTM-PD than those not treated with bDMARDs (25 vs. 17%, p = .52). A total of 55 patients died, but nobody died of NTM-PD. NTM-PD was not associated with worse mortality in multivariate analysis (hazard ratio, 2.0; 95% CI, 0.6-6.4; p = .26). CONCLUSIONS: Biological DMARD was not associated with worse prognosis of NTM-PD. Careful use of bDMARDs could be tolerated in RA patients with NTM-PD.

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Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

Namkoong Ho, Omae Yosuke, Asakura Takanori, Ishii Makoto, Suzuki Shoji, Morimoto Kozo, Kawai Yosuke, Emoto Katsura, Oler Andrew J., Szymanski Eva P., Yoshida Mitsunori, Matsuda Shuichi, Yagi Kazuma, Hase Isano, Nishimura Tomoyasu, Sasaki Yuka, Asami Takahiro, Shiomi Tetsuya, Matsubara Hiroaki, Shimada Hisato, Hamamoto Junko, Jhun Byung Woo, Kim Su-Young, Huh Hee Jae, Won Hong-Hee, Ato Manabu, Kosaki Kenjiro, Betsuyaku Tomoko, Fukunaga Koichi, Kurashima Atsuyuki, Tettelin Herve, Yanai Hideki, Mahasirimongkol Surakameth, Olivier Kenneth N., Hoshino Yoshihiko, Koh Won-Jung, Holland Steven M., Tokunaga Katsushi, Hasegawa Naoki

EUROPEAN RESPIRATORY JOURNAL 58 ( 2 ) 2021.08

ISSN 0903-1936

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Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease.

Namkoong H, Omae Y, Asakura T, Ishii M, Suzuki S, Morimoto K, Kawai Y, Emoto K, Oler AJ, Szymanski EP, Yoshida M, Matsuda S, Yagi K, Hase I, Nishimura T, Sasaki Y, Asami T, Shiomi T, Matsubara H, Shimada H, Hamamoto J, Jhun BW, Kim SY, Huh HJ, Won HH, Ato M, Kosaki K, Betsuyaku T, Fukunaga K, Kurashima A, Tettelin H, Yanai H, Mahasirimongkol S, Olivier KN, Hoshino Y, Koh WJ, Holland SM, Tokunaga K, Hasegawa N, Nontuberculous Mycobacteriosis and Bronchiectasis – Japan Research Consortium (NTM-JRC)

The European respiratory journal 58 ( 2 ) 2021.08

ISSN 0903-1936

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The best regimens for chemo-naïve incurable non-squamous non-small cell lung cancer with a programmed death-ligand 1, tumor proportion score 1-49%: a network meta-analysis.

Nobuhiko Fukuda, Nobuyuki Horita, Seigo Katakura, Ho Namkoong, Ayami Kaneko, Kouhei Somekawa, Youichi Tagami, Keisuke Watanabe, Yu Hara, Nobuaki Kobayashi, Takeshi Kaneko

Translational lung cancer research 10 ( 8 ) 3550 - 3566 2021.08

ISSN 2218-6751

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. There is a rank order of the efficacy and safety of treatment options, including immune checkpoint inhibitors (ICIs), bevacizumab (Bev), and cytotoxic drugs. When patients have low programmed death-ligand 1 (PD-L1) expression, there are multiple options for treatment. In this study, we focused on ICI regimens in patients with non-squamous NSCLC with low PD-L1 expression and no driver alterations and assessed the efficacy of the regimens using network meta-analysis. Methods: Randomized trials for incurable chemo-naïve non-squamous NSCLC were collected through electronic searches. The data were independently extracted and cross-checked by two investigators. The primary outcome of this analysis was overall survival (OS). A frequentist weighted least-squares approach random-model network meta-analysis was applied. Results: Sixty-eight eligible studies and 22,619 patients were identified. Using a platinum + third-generation cytotoxic agent regimen (platinum regimen) as a reference, the platinum regimen + pembrolizumab (Pemb) [hazard ratio (HR) =0.55, 95% confidence interval (CI): 0.34-0.89, P=0.015] showed the best OS, followed by the platinum regimen + nivolumab (Niv) + ipilimumab (Ipi) (HR =0.61, 95% CI: 0.44-0.84, P=0.003) with no heterogeneity (I2=0%, P=0.348). Conclusions: The addition of Pemb or Niv/Ipi to platinum-based chemotherapy seems to be a good therapeutic option for non-squamous NSCLC with a PD-L1 tumor proportion score (TPS) of 1-49%.

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Diagnostic accuracy of Aspergillus-specific antibodies for chronic pulmonary aspergillosis: A systematic review and meta-analysis.

Keisuke Anan, Yuki Kataoka, Shinji Okabayashi, Ryohei Yamamoto, Ho Namkoong, Yosuke Yamamoto

Mycoses 64 ( 7 ) 701 - 715 2021.07

ISSN 0933-7407

We performed this study to provide the latest evidence of the diagnostic accuracy of all Aspergillus antibodies for chronic pulmonary aspergillosis (CPA). In this meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and other databases, until 19 March 2020, for studies that examined the diagnostic accuracy of each Aspergillus-specific antibody for CPA and assessed the risk of bias using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. We integrated the results using a hierarchical summary receiver operating characteristic (HSROC) model and calculated the point estimates of specificity with sensitivity fixed at 0.90 using the HSROC curve. We identified 32 published and one unpublished studies, including 75 studies on five antibody test types: 18 of precipitin test (2810 participants), 46 of IgG (8197), three of IgA (283), six of IgM (733) and two of combined IgG and IgM (IgG + IgM) (920). The results of specificity with sensitivity fixed at 0.90 were as follows: precipitin test, 0.93 (95% credible intervals: 0.86, 1.00); IgG, 0.90 (0.86, 0.95); IgA, 0.74 (0.00, 1.00); IgM, 0.50 (0.37, 0.53); IgG + IgM, 0.47 (0.00, 1.00). However, the precipitin test showed imprecision and instability in the sensitivity analysis. Most studies had a high risk of bias due to the case-control design. Although there is lack of applicability for malignancy or immunosuppressive patients, our study suggests a preference for IgG over other antibody tests in CPA screening. Particularly, IgG should be used as an adjunct when ruling out CPA.

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Longitudinal validity and prognostic significance of the St George's Respiratory Questionnaire in Mycobacterium avium complex pulmonary disease.

Takunori Ogawa, Takanori Asakura, Shoji Suzuki, Satoshi Okamori, Tatsuya Kusumoto, Yasunori Sato, Ho Namkoong, Hirofumi Kamata, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa

Respiratory medicine 185 106515 - 106515 2021.06

ISSN 0954-6111

BACKGROUND: Although previous cross-sectional studies showed the feasibility and clinical association of the St. George's Respiratory Questionnaire (SGRQ) in Mycobacterium avium complex pulmonary disease (MAC-PD), its longitudinal validity is poorly understood. We aimed to determine the longitudinal validity and prognostic significance of SGRQ. METHODS: In this prospective observational study conducted between May 2012 and August 2018, we evaluated 269 enrolled patients with MAC-PD and examined associations between baseline SGRQ total scores and mortality or clinical variables (anchors), including serum C-reactive protein levels and pulmonary function test results. RESULTS: Age- and sex-matched SGRQ scores indicated significantly greater impairment in patients with MAC-PD than in the general population (P < 0.001). On multivariable Cox proportional hazards regression analysis, the SGRQ total score ≥25 was an independent risk factor for mortality (adjusted hazard ratio, 5.90; 95% confidence interval, 1.65-37.7) as well as age, body mass index, and forced vital capacity (FVC). Mixed-effect model results showed a significant association between SGRQ symptom/total scores and forced expiratory volume in 1 s (FEV1), FVC, and diffusing carbon monoxide capacity. Older age, a positive smear, non-nodular/bronchiectatic form, and cavity regions were associated with SGRQ total score deterioration. Patients with a greater decline from baseline FEV1 (% predicted) exhibited significantly worse impairment in the SGRQ total score (mean ± SE, 4.69 ± 10.9 points, P = 0.001). CONCLUSIONS: SGRQ showed longitudinal validity in assessing disease severity and was sensitive to changes in patients with MAC-PD, especially changes in %FEV1. The SGRQ total score may be an important prognostic factor.

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R-CHOP Chemotherapy for Disseminated Mycobacterium avium Complex Disease due to Anti-Interferon-Gamma Autoantibodies: A Case Report.

Shunsuke Uno, Eisuke Uehara, Toshiki Kimura, Takuro Sakagami, Ho Namkoong, Sho Uchida, Yoshifumi Uwamino, Naoki Hasegawa

Open forum infectious diseases 8 ( 6 ) ofab181 2021.06

ISSN 2328-8957

A 77-year-old Japanese man with disseminated Mycobacterium avium complex (MAC) disease due to anti-interferon-gamma autoantibodies received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy because of non-Hodgkin lymphoma complication. The hepatobiliary nodules due to MAC resolved with R-CHOP and multidrug antimycobacterial treatment. R-CHOP could serve as an alternative adjunctive therapy for patients with anti-interferon-gamma autoantibodies.

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The effect of adding immune checkpoint inhibitors on the risk of pneumonitis for solid tumours: a meta-analysis of phase III randomised controlled trials.

Yu Fujiwara, Nobuyuki Horita, Ho Namkoong, Matthew D Galsky

European journal of cancer (Oxford, England : 1990) 150 168 - 178 2021.06

ISSN 0959-8049

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become one of the standard treatment options for solid tumours; however, treatment-related adverse events, including pneumonitis, sometimes disrupt the ongoing treatment. To evaluate the impact of ICI addition on the risk of pneumonitis, a meta-analysis was conducted. METHODS: Phase III randomised controlled trials comparing ICIs and conventional therapy with conventional therapy alone were selected by searching databases, including PubMed, Embase, Web of Science and Cochrane Library. The odds ratio (OR) of any grade and grade III-V pneumonitis was calculated. Meta-analysis was performed to compare the incidence of pneumonitis between the treatment arm with additional ICIs and the arm with conventional therapy. RESULTS: A total of 25 randomised controlled trials (RCTs) representing 16,343 patients for grade I-V and 23 RCTs with 15,006 patients for grade III-V pneumonitis were analysed. Adding ICIs was associated with a significant increase in pneumonitis (grade I-V: OR, 2.67, 95% confidence interval [CI]: 2.12-3.37, grade III-V: OR, 1.83, 95% CI: 1.26-2.65). In subgroup analyses based on the mechanism of action of ICIs, cancer types (lung and non-lung cancer) and each ICI, no significant difference in heterogeneity was observed. CONCLUSIONS: Adding ICIs to the conventional treatment for solid tumours significantly increased both grade I-V and grade III-V pneumonitis regardless of the mechanisms of ICIs and cancer type. These results would be helpful for oncologists to choose the appropriate treatment options using ICIs, particularly for patients with known risk factors of pneumonitis or interstitial lung disease.

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Clinical Features and Prognosis of Nontuberculous Mycobacterial Pleuritis: A Multicenter Retrospective Study.

Kazuma Yagi, Akihiro Ito, Keiji Fujiwara, Eriko Morino, Isano Hase, Yasushi Nakano, Takanori Asakura, Koji Furuuchi, Atsuho Morita, Takahiro Asami, Ho Namkoong, Fumitake Saito, Kozo Morimoto, Makoto Ishii, Yasunori Sato, Hiroki Tateno, Kazumi Nishio, Yoshitaka Oyamada, Koichi Fukunaga, Haruhito Sugiyama, Tadashi Ishida, Atsuyuki Kurashima, Naoki Hasegawa

Annals of the American Thoracic Society 18 ( 9 ) 1490 - 1497 2021.04

ISSN 1546-3222

RATIONALE: The clinical features and prognosis of nontuberculous mycobacterial (NTM) pleuritis and pleural effusion combined with NTM lung disease (NTM-LD) remain unclear. OBJECTIVES: To investigate the clinical features and prognosis of NTM pleuritis. METHODS: This retrospective observational study included patients with NTM pleuritis from January 2001 to June 2018 across eight hospitals in Japan. NTM pleuritis was defined by a positive culture of NTM from pleural effusion. We matched patients with Mycobacterium complex lung disease (MAC-LD) without pleuritis by sex and age to obtain comparative data and investigated the association between clinical parameters and prognosis. RESULTS: We identified 64 patients with NTM pleuritis (median age, 73 years; 37 female). The median follow-up duration was 11 months, and 27 patients died. Patients with MAC pleuritis had a significantly worse survival compared to matched patients with MAC-LD without pleuritis. Multivariate analysis revealed that pleuritis (adjusted hazard ratio [aHR], 6.99; 95% confidence interval [CI], 2.58-19.00) and underlying pulmonary diseases (aHR, 3.01; 95% CI, 1.44-6.28) were independently associated with all-cause mortality in MAC-LD patients. CONCLUSIONS: The prognosis of MAC pleuritis is poorer than that of MAC-LD without pleuritis. Pleuritis is an independent prognostic factor in patients with MAC-LD.

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Postoperative Radiotherapy for Completely Resected Masaoka/Masaoka-Koga Stage II/III Thymoma Improves Overall Survival: An Updated Meta-Analysis of 4746 Patients.

Yudai Tateishi, Nobuyuki Horita, Ho Namkoong, Tatsuji Enomoto, Atsuya Takeda, Takeshi Kaneko

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 ( 4 ) 677 - 685 2021.04

INTRODUCTION: Our systematic review and meta-analysis aimed to evaluate the effect of postoperative radiotherapy (PORT) on completely resected Masaoka/Masaoka-Koga (M/MK) stage II/III thymomas. METHODS: We systematically searched four online databases and included studies that compared surgery alone versus surgery plus a PORT for completely resected M/MK stage II/III thymoma. The multivariate-adjusted hazard ratios (HRs) of overall survival (OS) and disease-free survival were evaluated as the primary and secondary end points, respectively. We performed a subgroup analysis for OS with respect to M/MK stage II, III, and inseparable II/III cases. A generic inverse variance meta-analysis using a random model was conducted. RESULTS: Five studies including 4746 patients (among them, 2408 patients received PORT) met our selection criteria. A meta-analysis of these five studies revealed that PORT was associated with a significantly better OS (HR = 0.68, 95% confidence interval [CI]: 0.57-0.83, p < 0.001, I2 = 0%, p for heterogeneity = 0.97). Subgroup analyses for M/MK stage II disease (HR = 0.63, 95% CI: 0.44-0.91, p = 0.01, I2 = 0%, p for heterogeneity = 0.80) and M/MK stage III disease (HR = 0.72, 95% CI: 0.55-0.95, p = 0.02, I2 = 0%, p for heterogeneity = 0.84) revealed similar results. PORT was not associated with an improved disease-free survival (HR = 0.96, 95% CI: 0.70-1.33, p = 0.83, I2 = 0%, p for heterogeneity = 0.72). CONCLUSIONS: Currently available evidence from observational studies suggests PORT for patients with completely resected M/MK stage II/III thymoma. A randomized trial is warranted.

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ABO blood group as a risk factor for tuberculosis: A network meta-analysis.

Hao Chen, Nobuyuki Horita, Hiromi Matsumoto, Ho Namkoong, Yu Hara, Nobuaki Kobayashi, Takeshi Kaneko

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 104 701 - 707 2021.03

BACKGROUND: Despite numerous studies on ABO blood group and risk of tuberculosis, no consensus has been reached. METHODS: We conducted a systematic review following the Meta-Analysis of Observational Studies in Epidemiology group statement. English language articles providing odds ratio data regarding tuberculosis risk among ABO groups were eligible. Least-squares approach random-model network and random-model pairwise meta-analyses were conducted. The protocol-specified primary outcome was tuberculosis risk among ABO groups in the form of odds ratios calculated via a network meta-analysis. RESULTS: We identified 28 studies with 30 populations comprising 15,664 patients with tuberculosis and 254,610 controls. Subjects with AB blood type had a higher risk of becoming infected with tuberculosis than those with blood type O (odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.14-1.38), A (OR = 1.25, 95% CI: 1.14-1.38), and B (OR = 1.22, 95% CI: 1.11-1.34). Pairwise comparison revealed that AB blood type was a risk factor for tuberculosis with OR = 1.23 (95% CI: 1.02-1.48) compared to other blood types. Region-based subgroup analyses suggested that the AB blood group was a substantial risk in Africa (OR = 1.78, 95% CI: 1.39-2.28) and India (OR = 1.48, 95% CI: 1.14-1.92). CONCLUSIONS: AB blood group is a risk factor for tuberculosis of a substantial magnitude in Africa and India.

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Epidemiology of macrolide-resistant Mycoplasma pneumoniae by age distribution in Japan.

Naoki Kawakami, Ho Namkoong, Fumitake Saito, Masami Ishizaki, Masahiko Yamazaki, Keiko Mitamura

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 27 ( 1 ) 45 - 48 2021.01

ISSN 1341-321X

INTRODUCTION: Mycoplasma pneumoniae (M. pneumoniae) is the major pathogen involved in community-acquired pneumonia in all age groups. Resistance to macrolides, the first-line treatment for M. pneumoniae infection, is a major global public health concern. However, studies evaluating macrolide-resistant M. pneumoniae infection simultaneously in all ages are limited. This study aimed to determine the prevalence and clinical characteristics of macrolide-resistant M. pneumoniae infection in terms of age distribution. METHODS: We enrolled 292 patients in Tokyo, Japan, who visited Eiju General Hospital or Zama Children's Clinic in 2015-2016. Patients were tested using real-time PCR for M. pneumoniae DNA. PCR-positive patients (n = 151) were further selected and sequentially divided into preschool-aged children (≤5 years, n = 31), school-aged children (6-15 years, n = 101), adolescents (16-19 years, n = 5), and adults (≥20 years, n = 14). We then analyzed the M. pneumoniae infection clinical characteristics, prevalence of macrolide-resistant infection, and 23S rRNA domain V resistance-associated mutation status. RESULTS: We found insignificant differences in the prevalence of macrolide-resistant M. pneumoniae infection among all groups, clinical characteristics, and resistance-associated mutation status in patients with macrolide-resistant M. pneumoniae infection. We also found statistically higher prevalence of mutation-positive (n = 85) M. pneumoniae in patients previously treated with macrolide compared to the mutation-negative group (n = 66); 63.8% vs 11.1% (p < 0.001), respectively. CONCLUSIONS: We found no significant differences in both clinical characteristics and prevalence of macrolide-resistant M. pneumoniae infection among all ages. Also, previous macrolide treatment contributes to drug-resistance.

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Hydroxychloroquine and chloroquine for treatment of coronavirus disease 19 (COVID-19): a systematic review and meta-analysis of randomized and non-randomized controlled trials.

Risa Ebina-Shibuya, Ho Namkoong, Nobuyuki Horita, Hideaki Kato, Yu Hara, Nobuaki Kobayashi, Takeshi Kaneko

Journal of thoracic disease 13 ( 1 ) 202 - 212 2021.01

Background: Although the US government approved hydroxychloroquine (HCQ) and chloroquine (CQ) for hospitalized coronavirus disease 19 (COVID-19) patients, some studies denied efficacy of HCQ and CQ. We aimed to evaluate HCQ/CQ treatment for COVID-19. Methods: Five databases were searched on April 15, 2020, without publication date restriction. We followed both Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology statement reporting recommendations. A random-model meta-analysis was conducted to pool odds ratio (OR) and hazard ratio (HR). The quality of evidence for each outcome and the final recommendation was assessed using the GRADE guidelines of the American College of Chest Physicians. Results: We identified four randomized controlled trials (RCTs) and four observational studies with 2,063 COVID-19 cases. All-cause mortality was not affected by the administration of HCQ/CQ [OR: 1.05, 95% confidence interval (CI): 0.53-2.09, P=0.89]. No improvement of viral clearance was found neither by time-to-event analysis (HR: 1.19, 95% CI: 0.74-1.94, P=0.47) nor frequency on day 7 (OR: 1.47, 95% CI: 0.33-6.63, P=0.62). HCQ/CQ treatment increased the risk of the any adverse event with OR of 3.56 (95% CI: 1.62-7.83, P=0.002). Conclusions: HCQ/CQ failed to decrease the all-cause mortality (very low quality evidence) and did not improve viral clearance (low or very low quality evidence) but increased the risk of any adverse event (moderate quality evidence). Routine administration of HCQ/CQ for COVID-19 patients is not recommended (weak recommendation, Grade 2C).

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Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease.

Takanori Asakura, Yoshifumi Kimizuka, Tomoyasu Nishimura, Shoji Suzuki, Ho Namkoong, Yohei Masugi, Yasunori Sato, Makoto Ishii, Naoki Hasegawa

Respirology (Carlton, Vic.) 26 ( 1 ) 112 - 119 2021.01

Accepted, ISSN 1323-7799

BACKGROUND AND OBJECTIVE: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. METHODS: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). RESULTS: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. CONCLUSION: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

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Clinical characteristics of patients with coronavirus disease (COVID-19): preliminary baseline report of Japan COVID-19 Task Force, a nationwide consortium to investigate host …

H Tanaka, H Lee, A Morita, H Namkoong, S Chubachi, H Kabata, ...

International Journal of Infectious Diseases 113, 74-81 2021

Diagnostic accuracy of Aspergillus‐specific antibodies for chronic pulmonary aspergillosis: A systematic review and meta‐analysis

K Anan, Y Kataoka, S Okabayashi, R Yamamoto, H Namkoong, ...

Mycoses 64 (7), 701-715 2021

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

H Namkoong, Y Omae, T Asakura, M Ishii, S Suzuki, K Morimoto, Y Kawai, ...

European Respiratory Journal 58 (2) 2021

Incidence and Distinct Features of Immune Checkpoint Inhibitor-Related Myositis From Idiopathic Inflammatory Myositis: A Single-Center Experience With Systematic Literature Review and Meta-Analysis.

Naoki Hamada, Ayaka Maeda, Kaoru Takase-Minegishi, Yohei Kirino, Yumiko Sugiyama, Ho Namkoong, Nobuyuki Horita, Ryusuke Yoshimi, Hideaki Nakajima

Frontiers in immunology 12 803410 - 803410 2021

ISSN 1664-3224

Immune checkpoint inhibitor (ICI)-related myositis is a rare, potentially fatal condition that warrants further studies. Its incidence, clinical features, and prognosis remain poorly understood. To address these gaps, we conducted a systematic review and meta-analysis to evaluate the risk of myositis associated with ICI for solid tumors by analyzing phase III randomized controlled trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). To complement this analysis with clinical data, we evaluated published ICI case reports along with cases from our institutional registry. This registry comprised 422 patients treated with ICIs alone or in combination from September 2014 to June 2021. The analysis revealed an incidence of ICI-related myositis in 6,838 patients in 18 randomized controlled trials of 0.38% (odds ratio 1.96; 95% confidence interval 1.02-3.75) for patients receiving ICIs compared with controls. Detailed analysis of 88 cases from the literature search and our registry showed that myositis induced by PD-1 inhibitors was more frequent than that induced by anti-CTLA-4 agents, revealing a clinically diverse trend including myasthenia gravis and myocarditis. Importantly, having ptosis at the time of onset was significantly associated with the development of concomitant myocarditis (odds ratio 3.81; 95% CI 1.48-9.83), which is associated with poor prognosis. Regarding treatment, most patients received glucocorticoids, and some received immunosuppressants. Our study revealed the incidence of ICI-mediated myositis and the clinical features of myocarditis, highlighting the need for recognition and early intervention.

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The best regimens for chemo-naïve incurable non-squamous non-small cell lung cancer with a programmed death-ligand 1, tumor proportion score 1–49%: a network meta-analysis

N Fukuda, N Horita, S Katakura, H Namkoong, A Kaneko, K Somekawa, ...

Translational Lung Cancer Research 10 (8), 3550 2021

Serum Krebs von den Lungen‐6 level in the disease progression and treatment of Mycobacterium avium complex lung disease

T Asakura, Y Kimizuka, T Nishimura, S Suzuki, H Namkoong, Y Masugi, ...

Respirology 26 (1), 112-119 2021

Mapping the human genetic architecture of COVID-19

Writing group Writing group leaders Pathak Gita A. 6 Andrews Shea J. 7 Kanai ...

Nature 600 (7889), 472-477 600 ( 7889 ) 472 - + 2021

ISSN 0028-0836

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Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan (preprint)

H Namkoong, R Edahiro, K Fukunaga, Y Shirai, K Sonehara, H Tanaka, ...

2021

Incidence and distinct features of immune checkpoint inhibitor-related myositis from idiopathic inflammatory myositis: a single-center experience with systematic literature …

N Hamada, A Maeda, K Takase-Minegishi, Y Kirino, Y Sugiyama, ...

Frontiers in Immunology 12, 803410 2021

Susceptibility of the obese population to COVID-19.

Takefumi Kimura, Ho Namkoong

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 101 380 - 381 2020.12

Obesity is a risk factor for disease severity in individuals with coronavirus disease (COVID-19). However, the increased susceptibility of this population to COVID-19 is unclear. We outline several underlying mechanisms that may explain the relationship between obesity and COVID-19 severity. Obesity has an adverse effect on respiratory physiology because increased intra-abdominal adipose tissue can interfere with lung expansion, resulting in reduced lung compliance. Further, fat accumulation in the soft tissue of the pharynx can increase inspiratory resistance, and obesity may be associated with sleep apnea. Obesity is associated with several defects in cell-mediated immunity, including increased levels of pro-inflammatory cytokines. Impaired adipocyte-mediated immune function results in chronically high leptin levels, low adiponectin levels, and anti-inflammatory adipokines. Reduced physical activity can impair several steps of the immune response to viruses. Obesity also promotes a hypercoagulable state, leading to severe consequences. These factors may synergistically play a role in promoting the severity of the disease in obese individuals. A better understanding of the mechanisms by which obesity contributes to the severity of COVID-19 is important for developing more effective treatments.

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Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study.

Makoto Ishii, Hideki Terai, Hiroki Kabata, Katsunori Masaki, Shotaro Chubachi, Hiroki Tateno, Morio Nakamura, Kazumi Nishio, Hidefumi Koh, Risa Watanabe, Soichiro Ueda, Takeshi Terashima, Yusuke Suzuki, Kazuma Yagi, Naoki Miyao, Naoto Minematsu, Takashi Inoue, Ichiro Nakachi, Ho Namkoong, Satoshi Okamori, Shinnosuke Ikemura, Hirofumi Kamata, Hiroyuki Yasuda, Ichiro Kawada, Naoki Hasegawa, Koichi Fukunaga

The Journal of infection 81 ( 5 ) e3-e5 2020.11

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Clinical significance of anti-glycopeptidolipid-core IgA antibodies in patients newly diagnosed with Mycobacterium avium complex lung disease.

Shuichi Matsuda, Takanori Asakura, Kozo Morimoto, Shoji Suzuki, Keiji Fujiwara, Koji Furuuchi, Takeshi Osawa, Ho Namkoong, Makoto Ishii, Atsuyuki Kurashima, Koichiro Tatsumi, Ken Ohta, Naoki Hasegawa, Yuka Sasaki

Respiratory medicine 171 106086 - 106086 2020.09

BACKGROUND: Although recent studies have identified anti-glycopeptidolipid (GPL)-core IgA antibodies as a serodiagnostic test for Mycobacterium avium complex lung disease (MAC-LD), this test shows insufficient sensitivity. This study aimed to determine the clinical utility of these antibodies in assessing disease progression and the clinical characteristics of MAC-LD patients with negative antibody results. METHODS: We retrospectively reviewed the medical records of consecutive newly diagnosed, untreated MAC-LD patients in two referral hospitals. We evaluated the association of anti-GPL-core IgA antibody results with disease progression requiring treatment and the factors associated with negative antibody results. RESULTS: In total, 229 patients (161 females; median age, 71 years; 185 with nodular/bronchiectatic disease phenotype; 69 with cavitary lesions) were enrolled; 146 patients (64%) were anti-GPL-core IgA antibody-positive. Radiological severity scores were associated with anti-GPL-core IgA antibody titers. During the median 364-day follow-up, 114 patients (49.8%) required treatment. Multivariate Cox proportional hazards analysis showed that positive anti-GPL-core IgA antibody results, a younger age, the absence of malignancy, and the presence of cavitary lesions were associated with disease progression requiring treatment. Multivariate logistic analysis revealed that significant factors related to the negative antibody results included underlying pulmonary disease, lower radiological scores, chronic sinusitis, and macrolide monotherapy. CONCLUSION: In addition to cavitary lesions, anti-GPL-core IgA antibody positivity was associated with disease progression requiring treatment. Physicians should carefully use anti-GPL-core IgA antibody results for the diagnosis of patients with underlying pulmonary disease, chronic sinusitis, macrolide monotherapy, and lower radiological severity.

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National policies for paediatric universal BCG vaccination were associated with decreased mortality due to COVID-19.

Risa Ebina-Shibuya, Nobuyuki Horita, Ho Namkoong, Takeshi Kaneko

Respirology (Carlton, Vic.) 25 ( 8 ) 898 - 899 2020.08

Accepted

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Current national policies for infant universal bacille Calmette-Guérin vaccination were associated with lower mortality from coronavirus disease 2019.

Risa Ebina-Shibuya, Nobuyuki Horita, Ho Namkoong, Takeshi Kaneko

Clinical and experimental vaccine research 9 ( 2 ) 179 - 182 2020.07

An exciting debate has emerged whether bacille Calmette-Guérin (BCG) vaccination is effective for the coronavirus disease 2019 (COVID-19) pandemic. Some advocated that BCG-vaccinated people are less suffered from the virus because BCG vaccination is recommendedin COVID-19 high burden countries. However, the others objected because this seemingly attractive relationship is explainable with confounding factors. In a multiple regression with 171 countries adjusting socioeconomical and climatic covariates, countries with current universal pediatric BCG policy were associated with 30-fold (95% confidence interval, 17-52) decrease of COVID-19 mortality per population compared to countries without the policy.

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Detection of the early stage of spontaneous hemopneumothorax by CT attenuation values.

Yukiko Koike, Ho Namkoong, Sotaro Otake, Hisao Asamura

Clinical case reports 8 ( 7 ) 1321 - 1322 2020.07

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ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice.

Shoji Suzuki, Makoto Ishii, Takanori Asakura, Ho Namkoong, Satoshi Okamori, Kazuma Yagi, Hirofumi Kamata, Tatsuya Kusumoto, Shizuko Kagawa, Ahmed E Hegab, Masaki Yoda, Keisuke Horiuchi, Naoki Hasegawa, Tomoko Betsuyaku

American journal of physiology. Lung cellular and molecular physiology 318 ( 6 ) L1172-L1182 2020.06

Accepted

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.

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A decade of Gottron's papules, inverse Gottron's papules and mechanic's hand in anti-MDA5-associated interstitial lung disease with clinically amyopathic dermatomyositis.

Naoki Kawakami, Haruka Eda, Miho Nishiura, Ayaka Chaya, Fumitake Saito, Ho Namkoong

Oxford medical case reports 2020 ( 6 ) omaa039 2020.06

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Cavitary lesions emerged rapidly in Pseudomonas aeruginosa pneumonia.

Naoki Kawakami, Shin Ohara, Ho Namkoong

Clinical case reports (Wiley) 8 ( 3 ) 576 - 577 2020.03

Accepted

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Cardiac tamponade secondary to empyema.

Naoki Kawakami, Kohei Kushimoto, Fumitake Saito, Ho Namkoong

Clinical case reports (Wiley) 8 ( 3 ) 574 - 575 2020.03

Accepted

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Co-infection with SARS-CoV-2 and influenza A virus

S Azekawa, H Namkoong, K Mitamura, Y Kawaoka, F Saito

IDCases 20, e00775 2020

IL-6 and G-CSF production resulting from lung cancer in an HIV patient.

Naoki Kawakami, Ho Namkoong, Katsunori Masaki, Yutaka Kurebayashi, Masayuki Shimoda, Hiroshi Kotani, Hiroshi Fujiwara, Naoki Hasegawa

IDCases 19 e00693 2020

Accepted

Increasing reports have noted an increased prevalence of lung cancer in human immunodeficiency virus (HIV)-positive patients with poor prognosis. A 51-year-old HIV-positive man was diagnosed with stage IV squamous cell lung cancer. He had high grade spike intermittent fever and persistent elevation of the white blood cell count as well as C-reactive protein (CRP) levels. Although we suspected opportunistic infections, we did not detect any infection. The autopsy showed positive immunostaining for Interleukin-6 (IL-6) in plasma cells of the stromal regions and G-CSF in tumor cells, which were considered responsible for his significant tumor fever, leukocytosis and high titers of CRP. This case report highlights the need to consider cytokine-producing tumor as a differential diagnosis of fever and high inflammatory status in HIV-positive cancer patients.

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Host Genetic Analysis of Pulmonary NTM Disease and Non-CF Bronchietasis

H Namkoong, Y Omae, T Asakura, M Ishii, S Suzuki, K Morimoto, ...

C16. NTM DISEASE-NEW DATA AND CHANGING PARADIGMS, A4491-A4491 2020

Hidden disseminated extracutaneous AIDS-related Kaposi sarcoma.

Naoki Kawakami, Ho Namkoong, Masayuki Shimoda, Hiroshi Kotani, Hiroshi Fujiwara, Naoki Hasegawa

IDCases 19 e00716 2020

Accepted

A 68-year-old man with past medical history of multiple cerebral infarctions presented to our hospital with subacute paresis. His vital signs on presentation were normal, and his physical examination, other than his neurological findings, was unremarkable. Neurological examinations suggested cerebellar ataxia. Laboratory testing confirmed positive for human immunodeficiency virus (HIV) infection. His CD4-positive lymphocyte count was 45/μL, and HIV-RNA was 2.3 × 105 copies/mL. Brain computed tomography (CT) scan revealed multiple mass lesions and brain magnetic resonance imaging (MRI) with fluid-attenuated inversion-recovery (FLAIR) revealed periventricular hyperintensities, which suggested multiple malignant lymphoma and HIV encephalopathy. His state of consciousness had gradually worsened. Eventually, he died one month after admission. The autopsy unexpectedly showed disseminated Kaposi's sarcoma (KS). KS lesions were found in the stomach, small intestine, liver, spleen, mesentery and lungs. KS was not observed on his skin. Gross findings revealed multiple nodular lesions in each organ, and hematoxylin and eosin staining showed proliferation of spindle cells with vascular proliferation. Immunostaining was positive both for endothelial marker (CD31 and von Willebrand factor) and lymphatic endothelial marker (D2-40), which were consistent with KS.KS is the most common tumor in AIDS patients. It is caused by the human herpes-virus 8 infection. It manifests an indolent clinical course and mostly involves cutaneous lesions over the lower limbs, trunk and oral cavity. In this case, autopsy revealed disseminated KS pathologically, which was unrecognized before his death. This case highlights the possible existence of disseminated KS even without its cutaneous findings.

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Frequency of Bronchiectasis Related Variants in an Idiopathic Pulmonary Nontuberculous Mycobacteria (PNTM) Population in the National Institute of Allergy and Infectious …

K Kumar, M Similuk, M Walkiewicz, H Namkoong, A Oler, D Veltri, ...

C16. NTM DISEASE-NEW DATA AND CHANGING PARADIGMS, A4493-A4493 2020

Etiology and Health-Related Quality of Life in Non-Cystic Fibrosis Bronchiectasis and Nontuberculous Mycobacterial Pulmonary Disease: The First Analysis of the Japanese …

T Asakura, K Morimoto, A Ito, S Suzuki, E Morino, Y Oshitani, T Nakagawa, ...

B106. BREAKTHROUGHS IN NTM DIAGNOSIS AND TREATMENT, A4370-A4370 2020

Concern over a COVID-19-related BCG shortage

H Namkoong, N Horita, R Ebina-Shibuya

Int J Tuberc Lung Dis 24 (6), 642-643 2020

Multisystem inflammatory syndrome in children (MIS-C) with COVID-19: insights from simultaneous familial Kawasaki disease cases

R Ebina-Shibuya, H Namkoong, Y Shibuya, N Horita

International Journal of Infectious Diseases 97, 371-373 2020

Prevalence and Risk Factors for Osteoporosis in Patients with Pulmonary Nontuberculous Mycobacterial Disease

H Tanaka, T Asakura, S Suzuki, S Okamori, T Kusumoto, T Ogawa, ...

B106. BREAKTHROUGHS IN NTM DIAGNOSIS AND TREATMENT, A4361-A4361 2020

National policies for paediatric universal BCG vaccination were associated with decreased mortality due to COVID‐19

R Ebina‐Shibuya, N Horita, H Namkoong, T Kaneko

Respirology (Carlton, Vic.) 25 (8), 898 2020

Buffalo Chest Syndrome Following Esophagectomy.

Naoki Kawakami, Ho Namkoong

Internal medicine (Tokyo, Japan) 58 ( 16 ) 2413 - 2413 2019.08

Accepted

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Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis.

Nakwon Kwak, Margareth Pretti Dalcolmo, Charles L Daley, Geoffrey Eather, Regina Gayoso, Naoki Hasegawa, Byung Woo Jhun, Won-Jung Koh, Ho Namkoong, Jimyung Park, Rachel Thomson, Jakko van Ingen, Sanne M H Zweijpfenning, Jae-Joon Yim

The European respiratory journal 54 ( 1 ) 2019.07

Accepted

Treatment of Mycobacterium abscessus pulmonary disease (MAB-PD), caused by M. abscessus subsp. abscessus, M. abscessus subsp. massiliense or M. abscessus subsp. bolletii, is challenging.We conducted an individual patient data meta-analysis based on studies reporting treatment outcomes for MAB-PD to clarify treatment outcomes for MAB-PD and the impact of each drug on treatment outcomes. Treatment success was defined as culture conversion for ≥12 months while on treatment or sustained culture conversion without relapse until the end of treatment.Among 14 eligible studies, datasets from eight studies were provided and a total of 303 patients with MAB-PD were included in the analysis. The treatment success rate across all patients with MAB-PD was 45.6%. The specific treatment success rates were 33.0% for M. abscessus subsp. abscessus and 56.7% for M. abscessus subsp. massiliense For MAB-PD overall, the use of imipenem was associated with treatment success (adjusted odds ratio (aOR) 2.65, 95% CI 1.36-5.10). For patients with M. abscessus subsp. abscessus, the use of azithromycin (aOR 3.29, 95% CI 1.26-8.62), parenteral amikacin (aOR 1.44, 95% CI 1.05-1.99) or imipenem (aOR 7.96, 95% CI 1.52-41.6) was related to treatment success. For patients with M. abscessus subsp. massiliense, the choice among these drugs was not associated with treatment outcomes.Treatment outcomes for MAB-PD are unsatisfactory. The use of azithromycin, amikacin or imipenem was associated with better outcomes for patients with M. abscessus subsp. abscessus.

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Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice.

Ho Namkoong, Makoto Ishii, Hideki Fujii, Takahiro Asami, Kazuma Yagi, Shoji Suzuki, Shuhei Azekawa, Sadatomo Tasaka, Naoki Hasegawa, Tomoko Betsuyaku

Biochemical and biophysical research communications 513 ( 2 ) 405 - 411 2019.05

Accepted

Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO) mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV) (PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF) were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR) 7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.

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Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations.

Shinnosuke Ikemura, Hiroyuki Yasuda, Shingo Matsumoto, Mayumi Kamada, Junko Hamamoto, Keita Masuzawa, Keigo Kobayashi, Tadashi Manabe, Daisuke Arai, Ichiro Nakachi, Ichiro Kawada, Kota Ishioka, Morio Nakamura, Ho Namkoong, Katsuhiko Naoki, Fumie Ono, Mitsugu Araki, Ryo Kanada, Biao Ma, Yuichiro Hayashi, Sachiyo Mimaki, Kiyotaka Yoh, Susumu S Kobayashi, Takashi Kohno, Yasushi Okuno, Koichi Goto, Katsuya Tsuchihara, Kenzo Soejima

Proceedings of the National Academy of Sciences of the United States of America 116 ( 20 ) 10025 - 10030 2019.05

Accepted

Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of EGFR mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot EGFR mutations (n = 3,779) revealed that the majority (>90%) of cases with rare EGFR mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2 = 0.72, P = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare EGFR mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.

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Sitafloxacin-Containing Regimen for the Treatment of Refractory Mycobacterium avium Complex Lung Disease.

Takanori Asakura, Shoji Suzuki, Hanako Fukano, Satoshi Okamori, Tatsuya Kusumoto, Yoshifumi Uwamino, Takunori Ogawa, Matsuo So, Shunsuke Uno, Ho Namkoong, Mitsunori Yoshida, Hirofumi Kamata, Makoto Ishii, Tomoyasu Nishimura, Yoshihiko Hoshino, Naoki Hasegawa

Open forum infectious diseases 6 ( 4 ) ofz108 2019.04

Accepted

Background: Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods: We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFX-containing regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive sputum cultures for >6 months of macrolide-based standard therapy. Results: Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative sputum culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative sputum culture conversion. Conclusions: Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.

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Efficacy and safety of intermittent maintenance therapy after successful treatment of Mycobacterium avium complex lung disease.

Takanori Asakura, Taku Nakagawa, Shoji Suzuki, Ho Namkoong, Kozo Morimoto, Makoto Ishii, Atsuyuki Kurashima, Tomoko Betsuyaku, Kenji Ogawa, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 25 ( 3 ) 218 - 221 2019.03

Accepted

BACKGROUND: The optimal duration of antimicrobial therapy for Mycobacterium avium complex lung disease (MAC-LD) is unknown, and recurrence rates are high after treatment discontinuation. Intermittent therapy is recommended for the initial treatment of non-cavitary nodular/bronchiectatic MAC-LD. We hypothesized that intermittent maintenance therapy (IMT) could effectively prevent recurrence after successful treatment of MAC-LD. METHODS: Adult patients diagnosed with MAC-LD who received IMT after successful daily therapy (DT) between January 1, 2006 and December 31, 2016 were identified from clinical databases at three institutions in Japan. Treatment outcomes were evaluated for all patients. RESULTS: Of 38 patients (median age, 66 years; 29 women; nodular/bronchiectatic form, 29 patients) who received IMT after successful treatment, one was excluded due to death from an unknown cause, 1 month after IMT initiation. Finally, treatment outcomes were evaluated for 37 patients. Twenty-eight (76%) patients had sustained negative culture results over a median follow-up duration of 2.7 (interquartile range [IQR], 1.9-6.0) years, while six (16%) required switching to DT because of clinical deterioration over a median follow-up duration of 2.7 (IQR, 1.6-4.1) years. Favorable clinical outcomes were achieved for all patients who exhibited clinical deterioration. All patients tolerated the antimicrobials without discontinuation, and follow-up drug susceptibility testing showed negative results for clarithromycin-resistant MAC in the patients who experienced clinical deterioration. CONCLUSIONS: IMT after successful treatment may be a feasible option for patients with MAC-LD. Further studies should determine the population that would benefit from this strategy.

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Prognostic values of the Berlin definition criteria, blood lactate level, and fibroproliferative changes on high-resolution computed tomography in ARDS patients.

Tetsuro Kamo, Sadatomo Tasaka, Takeshi Suzuki, Takanori Asakura, Shoji Suzuki, Kazuma Yagi, Ho Namkoong, Makoto Ishii, Hiroshi Morisaki, Tomoko Betsuyaku

BMC pulmonary medicine 19 ( 1 ) 37 - 37 2019.02

Accepted

BACKGROUND: In the Berlin definition, acute respiratory distress syndrome (ARDS) is stratified into three stages according to oxygenation severity at the onset. The relevance between ARDS severity and prognosis varies among published reports and has not been verified, especially in Asian patients. METHODS: In this study, we examined the associations between the Berlin definition criteria and prognosis and clinical parameters, including high-resolution computed tomography (HRCT) scores of fibroproliferative changes of the lungs. One hundred fifty-three patients (45 females; mean age, 67 y/o), who met the Berlin definition and received treatment in our intensive care unit between January 2012 and December 2015, were enrolled. RESULTS: The severity of ARDS was mild in 42 patients, moderate in 71, and severe in 40. The underlying diseases included pneumonia in 56 patients and aspiration in 43. Forty-two (27.5%) patients were deceased within 30 days, and the 30-day mortality was 10% in mild ARDS, 23% in moderate, and 55% in severe, which were significantly different (P < 0.05). In the non-survivors, APACHE II, SOFA, and SAPS II scores were higher than in the survivors (P < 0.001). Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and increased HRCT scores were significantly associated with weaning failure and 30-day mortality of the patients with ARDS. CONCLUSIONS: These results suggested that the severity criteria in the Berlin definition might be associated with the prognosis of the patients. Blood lactate levels and HRCT score might be predictive of the outcome of patients with ARDS.

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First report of hepatobiliary <i>Mycobacterium avium</i> infection developing obstructive jaundice in a patient with neutralizing anti-interferon-gamma autoantibodies.

Namkoong H, Asakura T, Ishii M, Yoda S, Masaki K, Sakagami T, Iwasaki E, Yamagishi Y, Kanai T, Betsuyaku T, Hasegawa N

New microbes and new infections 27 4 - 6 2019.01

Accepted

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Ablation of ADAM17 protects against cigarette smoke-induced emphysema in mice

S Suzuki, M Ishii, T Asakura, H Namkoong, S Okamori, K Yagi, H Kamata, ...

European Respiratory Journal 54 (suppl 63) 2019

Development of lung cancer in patients with nontuberculous mycobacterial lung disease

T Kusumoto, T Asakura, S Suzuki, S Okamori, H Namkoong, H Fujiwara, ...

Respiratory investigation 57 (2), 157-164 2019

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

H Namkoong, Y Omae, T Asakura, M Yoshida, S Suzuki, K Morimoto, ...

A18. NTM: HOW, WHERE OR WHY DID I GET IT?, A1031-A1031 2019

First report of hepatobiliary Mycobacterium avium infection developing obstructive jaundice in a patient with neutralizing anti–interferon-gamma autoantibodies

H Namkoong, T Asakura, M Ishii, S Yoda, K Masaki, T Sakagami, ...

New Microbes and New Infections 27, 4-6 2019

Direct Reprogramming of Mouse Fibroblasts into Pulmonary Epithelial-Like Cells

T Kusumoto, M Ishii, M Yotsukura, AE Hegab, F Saito, J Hamamoto, ...

C62. FIBROBLAST BIOLOGY, A5341-A5341 2019

Longitudinal Validity and Prognostic Significance of the St George’s Respiratory Questionnaire in 269 Patients with Pulmonary Mycobacterium Avium Complex Disease

T Ogawa, T Asakura, S Suzuki, S Okamori, T Kusumoto, H Namkoong, ...

A106. NTM: BENCH TO BEDSIDE, A2542-A2542 2019

Retrospective evaluation of natural course in mild cases of Mycobacterium avium complex pulmonary disease.

Yoshifumi Kimizuka, Yoshihiko Hoshino, Tomoyasu Nishimura, Takahiro Asami, Yumi Sakakibara, Kozo Morimoto, Shinji Maeda, Noboru Nakata, Takayuki Abe, Shunsuke Uno, Ho Namkoong, Hiroshi Fujiwara, Yohei Funatsu, Kazuma Yagi, Toshihide Fujie, Makoto Ishii, Naohiko Inase, Satoshi Iwata, Atsuyuki Kurashima, Tomoko Betsuyaku, Naoki Hasegawa

PloS one 14 ( 4 ) e0216034 2019

Accepted

BACKGROUND: There is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease. METHODS: We conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model. RESULTS: Mean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV1), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and %FEV1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups. CONCLUSIONS: Mild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.

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Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis

N Kwak, MP Dalcolmo, CL Daley, G Eather, R Gayoso, N Hasegawa, ...

European Respiratory Journal 54 (1) 2019

Quantitative assessment of erector spinae muscles in patients with Mycobacterium avium complex lung disease.

Takanori Asakura, Yoshitake Yamada, Shoji Suzuki, Ho Namkoong, Satoshi Okamori, Tatsuya Kusumoto, Yuki Niijima, Akihiko Ozaki, Masahiro Hashimoto, Kazuma Yagi, Hirofumi Kamata, Yohei Funatsu, Makoto Ishii, Masahiro Jinzaki, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 145 66 - 72 2018.12

Accepted

BACKGROUND AND OBJECTIVE: No reports exist regarding skeletal muscle involvement in patients with Mycobacterium avium complex lung disease (MAC-LD). The cross-sectional area of the erector spinae muscles (ESMCSA) reflects physical activity and can be assessed by computed tomography (CT). We investigated the relationship between ESMCSA and physiological parameters and prognosis in MAC-LD patients. MATERIAL AND METHODS: In this prospective observational study, the ESMCSA was measured on single-slice axial CT images. MAC-LD patients and sex- and age-matched controls (non-MAC-LD participants) were evaluated. We evaluated the relationship between the ESMCSA and physiological parameters and prognosis. RESULTS: A total of 260 patients (209 female; median age, 69 years; 190 with nodular/bronchiectatic disease; 74 with cavitary lesions) were enrolled. The ESMCSA was not different between MAC-LD patients and controls. In MAC-LD patients, the ESMCSA was significantly associated with age, body mass index (BMI), pulmonary function, CT severity, and health-related quality of life (HRQL). Multivariate Cox proportional hazards analyses revealed that an ESMCSA < -1 standard derivation (hazards ratio [HR], 2.76; P = 0.047) was significantly associated with all-cause mortality, along with BMI < 18.5 kg/m2 (HR, 3.67; P = 0.02) and presence of cavitary lesions (HR, 5.84; P = 0.001). However, the ESMCSA was not significantly associated with all-cause mortality when current treatment status, % predicted functional vital capacity, and forced expiratory volume in 1 s were added to the analyses. CONCLUSIONS: Although the prognostic impact was limited, ESMCSA was significantly associated with HRQL and prognostic physiological parameters, such as BMI and pulmonary function.

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Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema.

Takanori Asakura, Makoto Ishii, Ho Namkoong, Shoji Suzuki, Shizuko Kagawa, Kazuma Yagi, Takaki Komiya, Takafumi Hashimoto, Satoshi Okamori, Hirofumi Kamata, Sadatomo Tasaka, Akio Kihara, Ahmed E Hegab, Naoki Hasegawa, Tomoko Betsuyaku

Mucosal immunology 11 ( 6 ) 1606 - 1620 2018.11

Accepted

Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

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Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus infection of the lip.

Ayaka Chaya, Masataka Sato, Ho Namkoong, Naoko Wada

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 75 80 - 81 2018.10

Accepted

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Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease.

Kazuma Yagi, Takanori Asakura, Ho Namkoong, Shoji Suzuki, Takahiro Asami, Satoshi Okamori, Tatsuya Kusumoto, Yohei Funatsu, Hirofumi Kamata, Tomoyasu Nishimura, Makoto Ishii, Tomoko Betsuyaku, Naoki Hasegawa

BMC pulmonary medicine 18 ( 1 ) 114 - 114 2018.07

Accepted

BACKGROUND: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. METHODS: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). RESULTS: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34-0.58; PCS score, ρ = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (- 0.29)-(- 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. CONCLUSIONS: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis.

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Asakura T, Ishii M, Ishii K, Suzuki S, Namkoong H, Okamori S, Kamata H, Yagi K, Funatsu Y, Betsuyaku T, Hasegawa N

International Journal of Tuberculosis and Lung Disease 22 ( 6 ) 695 - 703 2018.06

Accepted, ISSN 1027-3719

BACKGROUND: Little is known about the clinical characteristics and health-related quality of life (HQOL) of elderly patients with pulmonary Mycobacterium avium complex (pMAC) disease. OBJECTIVES: To evaluate HQOL using the 36-Item Short-Form Health Survey and St George's Respiratory Questionnaire (SGRQ) and to investigate the predictors of HQOL changes among elderly patients with pMAC disease. METHODS: This prospective cohort registry was conducted at Keio University Hospital, Tokyo, Japan, between May 2012 and July 2015 and included 84 patients with pMAC disease aged 75 years who had completed the HQOL questionnaire and 48 patients with pMAC disease who had been followed up and completed the HQOL questionnaire in cross-sectional and longitudinal analyses, respectively. RESULTS: In cross-sectional analyses, elderly patients with pMAC disease had significantly lower role-physical, general health, vitality, social functioning, role-emotional and role/social component scores than the general Japanese elderly population. Analysis of covariance revealed that patients with cavitary lesions had significantly worse physical functioning and SGRQ scores (P < 0.05). Longitudinal analysis showed that under-treatment, short duration of disease and positive sputum smear at baseline were predictors of worse HQOL at 12 months. CONCLUSIONS: Elderly patients with pMAC disease have reduced HQOL. Further large studies on HQOL are required to refine the use of this parameter in the treatment of these patients.

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Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease: A cross-sectional study.

Shoji Suzuki, Takanori Asakura, Ho Namkoong, Satoshi Okamori, Kazuma Yagi, Hirofumi Kamata, Yoshifumi Uwamino, Yohei Funatsu, Yasushi Nakano, Tomoyasu Nishimura, Makoto Ishii, Tamotsu Ebihara, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 138 1 - 6 2018.05

Accepted

RATIONALE: Little is known about the role of Aspergillus precipitating antibody (APAb) in patients with Mycobacterium avium complex lung disease (MAC-LD). OBJECTIVES: We investigated the clinical characteristics of patients with MAC-LD positive for APAb. METHODS: We conducted a cross-sectional study targeting patients with MAC-LD. APAb was checked in all participants. Clinical variables included laboratory data, pulmonary function, high-resolution computed tomography findings, and health-related quality of life. RESULTS: We analyzed 109 consecutive patients. Their median age was 68 years, and the median duration of MAC-LD was 4.8 years. Twenty (18.3%) patients tested positive for APAb. APAb-positive patients had significantly longer duration of MAC-LD (9.4 vs. 4.0 years, P = 0.017), more severe bronchiectasis evaluated by modified Reiff score (6.5 vs. 4, P = 0.0049), and lower forced expiratory volume in 1 s (%FEV1) (75.1% vs. 86.2%, P = 0.013) than APAb-negative patients. Analysis of covariance adjusted for background factors and underlying pulmonary disease revealed that %FEV1 was also significantly lower in patients with APAb (P = 0.045). Ten patients were newly diagnosed with chronic pulmonary aspergillosis (N = 5) or allergic bronchopulmonary aspergillosis (N = 5). CONCLUSIONS: APAb is associated with lower pulmonary function, and observed especially in patients with longer duration of MAC-LD and severe bronchiectasis, even in the absence of cavitary lesions.

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Clinical features of Mycoplasma pneumoniae pneumonia in older adults.

Naoki Kawakami, Ho Namkoong, Takanori Ohata, Shinji Sakaguchi, Fumitake Saito, Hideki Yuki

Geriatrics & gerontology international 18 ( 5 ) 814 - 816 2018.05

Accepted

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Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.

Ho Namkoong, Makoto Ishii, Hideki Fujii, Kazuma Yagi, Takahiro Asami, Takanori Asakura, Shoji Suzuki, Ahmed E Hegab, Hirofumi Kamata, Sadatomo Tasaka, Koji Atarashi, Nobuhiro Nakamoto, Satoshi Iwata, Kenya Honda, Takanori Kanai, Naoki Hasegawa, Shigeo Koyasu, Tomoko Betsuyaku

PLoS pathogens 14 ( 4 ) e1006955 2018.04

Accepted

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage-HLA-DR-CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides.

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[Tuberculous Pleurisy Diagnosed by Thoracoscopic Lung Biopsy].

Jun Yamamoto, Miho Nishiura, Takanori Ohata, Ho Namkoong, Shinji Sakaguchi, Fumitake Saito, Hideki Yuki

Kyobu geka. The Japanese journal of thoracic surgery 71 ( 3 ) 169 - 172 2018.03

Accepted, ISSN 0021-5252

A 44-year-old woman was referred to our hospital with pleural effusion and unknown fever. Mycobacterium tuberculosis was not detected by culture of pleural effusion and sputum and gastric fluid. Pleural fluid was serous and exudative, and cytological examination showed no malignant cells. Computed tomography revealed a little pleural thickening of the right middle lobe and massive pleural effusion. As acute pleurisy was suspected based on the findings of imaging studies, thoracoscopy was performed under general anesthesia. Many yellowish-white, small nodules were seen on the parietal pleura, and white small nodule were seen on the visceral pleura of the right middle lobe. Mycobacterium tuberculosis was not detected by culture and polymerase chain reaction for Mycobacterium tuberculosis( TB-PCR) of parietal pleura and pleural effusion, but was detected by only culture and TB-PCR of visceral pleura, yielding a diagnosis of tuberculous pleurisy. Her symptoms improved and the right pleural effusion decreased with isoniazid (INH), rifampicin (RFP), ethambutol (EB) and pyrazinamide(PZA) treatment.

Anti-inflammatory roles of mesenchymal stromal cells during acute Streptococcus pneumoniae pulmonary infection in mice.

Takahiro Asami, Makoto Ishii, Ho Namkoong, Kazuma Yagi, Sadatomo Tasaka, Takanori Asakura, Shoji Suzuki, Tetsuro Kamo, Satoshi Okamori, Hirofumi Kamata, Haiyue Zhang, Ahmed E Hegab, Naoki Hasegawa, Tomoko Betsuyaku

Cytotherapy 20 ( 3 ) 302 - 313 2018.03

Accepted

BACKGROUND: Pneumonia is the fourth leading cause of death worldwide, and Streptococcus pneumoniae is the most commonly associated pathogen. Increasing evidence suggests that mesenchymal stromal cells (MSCs) have anti-inflammatory roles during innate immune responses such as sepsis. However, little is known about the effect of MSCs on pneumococcal pneumonia. METHODS: Bone marrow-derived macrophages (BMDMs) were stimulated with various ligands in the presence or absence of MSC-conditioned medium. For in vivo studies, mice intranasally-inoculated with S. pneumoniae were intravenously treated with MSCs or vehicle, and various parameters were assessed. RESULTS: After stimulation with toll-like receptor (TLR) 2, TLR9 or TLR4 ligands, or live S. pneumoniae, TNF-α and interleukin (IL)-6 levels were significantly decreased, whereas IL-10 was significantly increased in BMDMs cultured in MSC-conditioned medium. In mice, MSC treatment decreased the number of neutrophils in bronchoalveolar lavage fluid (BALF) after pneumococcal infection, and this was associated with a decrease in myeloperoxidase activity in the lungs. Levels of proinflammatory cytokines, including TNF-α, IL-6, GM-CSF and IFN-γ, were significantly lower in MSC-treated mice, and the bacterial load in the lung after pneumococcal infection was significantly reduced. In addition, histopathologic analysis confirmed a decrease in the number of cells recruited to the lungs; however, lung edema, protein leakage into the BALF and levels of the antibacterial protein lipocalin 2 in the BALF were comparable between the groups. CONCLUSIONS: These results indicate that MSCs could represent a potential therapeutic application for the treatment of pneumonia caused by S. pneumoniae.

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Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients.

Kazuma Yagi, Kozo Morimoto, Makoto Ishii, Ho Namkoong, Satoshi Okamori, Takanori Asakura, Shoji Suzuki, Takahiro Asami, Yoshifumi Uwamino, Yohei Funatsu, Hiroshi Fujiwara, Hirofumi Kamata, Tomoyasu Nishimura, Tomoko Betsuyaku, Atsuyuki Kurashima, Naoki Hasegawa

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 67 65 - 69 2018.02

Accepted

BACKGROUND: Mycobacterium lentiflavum is a slow-growing non-tuberculous Mycobacterium that is often associated with an immunocompromised state and cervical lymphadenitis in young children. However, little is known about the clinical importance of pulmonary infection with M. lentiflavum in adults. METHODS: The medical records of all adults who met the diagnostic criteria of pulmonary M. lentiflavum disease at Keio University Hospital and Fukujuji Hospital from 2001 to 2015 were reviewed. In addition, the PubMed database was searched to identify further reported cases in non-HIV adults. RESULTS: Five cases of pulmonary M. lentiflavum disease were identified in the medical records search and 11 additional cases were identified in the literature review. Eleven of the total 16 cases were female, and 15 of 16 cases showed a nodular/bronchiectatic pattern on chest computed tomography imaging. No cases showed an aggressive clinical course of pulmonary M. lentiflavum disease, although one patient died of an exacerbation of underlying vasculitis and bacterial pneumonia. CONCLUSIONS: The clinical characteristics of pulmonary M. lentiflavum disease in adult patients were identified. This disease mainly affects females, displays a nodular/bronchiectatic pattern on chest computed tomography imaging, and does not demonstrate an aggressive clinical course. Further larger studies are needed to reveal detailed clinical features.

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Clinical Evaluation of the Immunochromatographic System Using Silver Amplification for the Rapid Detection of Mycoplasma pneumoniae.

Ho Namkoong, Masahiko Yamazaki, Masami Ishizaki, Ikumi Endo, Noriaki Harada, Megumi Aramaki, Yuko Tanaka, Sachiko Kaburagi, Masataka Ichikawa, Takanori Ohata, Shinji Sakaguchi, Fumitake Saito, Ayumi Nakao, Hideki Yuki, Keiko Mitamura

Scientific reports 8 ( 1 ) 1430 - 1430 2018.01

Accepted

Mycoplasma pneumoniae infection is conventionally diagnosed using serum antibody testing, microbial culture, and genetic testing. Recently, immunochromatography-based rapid mycoplasma antigen test kits have been developed and commercialised for rapid diagnosis of M. pneumoniae infection. However, as these kits do not provide sufficient sensitivity and specificity, a rapid test kit with improved accuracy is desired. The present prospective study evaluated a rapid M. pneumoniae diagnostic system utilizing a newly developed silver amplification immunochromatography (SAI) system. We performed dilution sensitivity test and the prospective clinical study evaluating the SAI system. The subjects of the clinical study included both children and adults. All patients suspected to have mycoplasma pneumonia (169 patients) were sequentially enrolled. Twelve patients did not agree to participate and 157 patients were enrolled in the study. The results demonstrate excellent performance of this system with 90.4% sensitivity and 100.0% specificity compared with real-time polymerase chain reaction. When compared with loop-mediated isothermal amplification (LAMP) methods, the results also demonstrate a high performance of this system with 93.0% sensitivity and 100.0% specificity. The SAI system uses a dedicated device for automatic analysis and reading, making it highly objective, and requires less human power, supporting its usefulness in clinical settings.

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Mycobacterium triplex pulmonary disease with acquired macrolide resistance in immunocompetent patients.

Matsuda S, Suzuki S, Morimoto K, Aono A, Nishio K, Asakura T, Sasaki Y, Namkoong H, Nishimura T, Ogata H, Hasegawa N, Kurashima A, Ishii M, Goto H

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 24 ( 6 ) 671 - 672 2018.01

Accepted, ISSN 1198-743X

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A Fulminant Case of Acute Respiratory Distress Syndrome Associated with Mycoplasma Pneumonia Treated with Nasal High-Flow Oxygen Therapy.

Naoki Kawakami, Ho Namkoong, Takanori Ohata, Shinji Sakaguchi, Fumitake Saito, Hideki Yuki

Case reports in critical care (Hindawi Limited) 2018 1067593 - 1067593 2018

Accepted

Introduction: The prognosis of mycoplasma pneumonia in adults is generally favorable, but a few patients show progression to acute respiratory distress syndrome (ARDS). We have described the management of a patient who showed progression of mycoplasma pneumonia to ARDS. Presentation of Case: A 26-year-old male patient with no significant past medical or social history presented with a 5-day history of fever. Following this, he was diagnosed with bacterial pneumonia and treated with tazobactam/piperacillin; however, he showed little clinical improvement with this treatment approach. We diagnosed the patient with mycoplasma pneumonia with an antigen test and treated him with azithromycin and prednisolone. Despite the appropriate antimicrobial therapy, his symptoms worsened and therefore we changed his oxygen therapy from a reservoir mask to nasal high-flow oxygen in addition to minocycline. Consequently, with this treatment, he recovered from severe mycoplasma pneumonia. Discussion: In patients with severe pneumonia who experience respiratory failure, it has been reported that nasal high-flow oxygen therapy is not inferior to noninvasive positive pressure ventilation therapy regarding intubation rate. In this case, induction of nasal high-flow oxygen therapy led to avoidance of ventilator management. This is a valuable case report highlighting the optimal outcome of nasal high-flow oxygen therapy in a fulminant case of acute respiratory distress syndrome. Conclusion: In patients who present with severe mycoplasma pneumonia with respiratory failure, nasal high-flow oxygen therapy can help reduce the needs for ventilator management including intubation.

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Analysis of Adverse Drug Events in Pulmonary Mycobacterium Avium Complex Disease Using the Japanese Adverse Drug Event Report (JADER) Database

H Namkoong, Y Takahashi, M Ishii, T Asakura, S Suzuki, H Kamata, ...

A106. NTM CLINICAL AND TRANSLATIONAL SCIENCE, A2595-A2595 2018

ADAM17 protects mice against elastase-induced emphysema via inactivation of CD62L

S Suzuki, M Ishii, T Asakura, H Namkoong, S Okamori, K Yagi, H Kamata, ...

European Respiratory Journal 52 (suppl 62) 2018

Comparison of antipseudomonal β-lactams for febrile neutropenia empiric therapy: authors' response

N Horita, Y Shibata, H Watanabe, H Namkoong, T Kaneko

Clinical Microbiology and Infection 24 (3), 325 2018

Comparison of antipseudomonal β-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis: authors' reply

N Horita, Y Shibata, H Watanabe, H Namkoong, T Kaneko

Clinical Microbiology and Infection 24 (6), 664-665 2018

Impact of six-minute walk test on health-related quality of life in pulmonary Mycobacterium avium complex disease

K Yagi, T Asakura, H Namkoong, S Suzuki, T Asami, S Okamori, ...

European Respiratory Journal 52 (suppl 62) 2018

The Protective Role of a Disintegrin and Metalloprotease (ADAM) 10 During Severe Influenza Virus Infection

S Okamori, M Ishii, T Asakura, S Suzuki, T Kusumoto, H Kamata, ...

B62. LUNG CYTOPROTECTION AND IMMUNITY DURING INFECTIONS, A3841-A3841 2018

The Development of Lung Cancer During Follow-Up of Patients with Mycobacterium Avium Complex Lung Disease

T Kusumoto, T Asakura, S Suzuki, S Okamori, H Namkoong, H Fujiwara, ...

A58. NON-TUBERCULOUS MYCOBACTERIA: OFF THE BEATEN TRACK, A1983-A1983 2018

Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+ Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary …

T Asakura, M Ishii, H Namkoong, S Suzuki, S Kagawa, K Yagi, T Komiya, ...

Mucosal Immunology 11 (6), 1606-1620 2018

Quantitative Assessment of Erector Spinae Muscles in Patients with Mycobacterium Avium Complex Lung Disease: Relationship of Disease Severity and Prognosis

T Asakura, S Suzuki, S Okamori, T Kusumoto, H Namkoong, K Yagi, ...

A106. NTM CLINICAL AND TRANSLATIONAL SCIENCE, A2598-A2598 2018

Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis

N Kwak, MP Dalcolmo, CL Daley, G Eather, R Gayoso, N Hasegawa, ...

대한결핵및호흡기학회 추계학술발표초록집 126, 150-150 2018

Tuberculous Pleurisy Diagnosed by Thoracoscopic Lung Biopsy

J Yamamoto, M Nishiura, T Ohata, H Namkoong, S Sakaguchi, F Saito, ...

Kyobu geka. The Japanese Journal of Thoracic Surgery 71 (3), 169-172 2018

Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease.

Hirofumi Kamata, Takanori Asakura, Shoji Suzuki, Ho Namkoong, Kazuma Yagi, Yohei Funatsu, Satoshi Okamori, Shunsuke Uno, Yoshifumi Uwamino, Hiroshi Fujiwara, Tomoyasu Nishimura, Makoto Ishii, Tomoko Betsuyaku, Naoki Hasegawa

BMC pulmonary medicine 17 ( 1 ) 198 - 198 2017.12

Accepted

BACKGROUND: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. METHODS: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. RESULTS: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). CONCLUSIONS: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

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Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis

N. Horita, Y. Shibata, H. Watanabe, H. Namkoong, T. Kaneko

CLINICAL MICROBIOLOGY AND INFECTION (ELSEVIER SCI LTD) 23 ( 10 ) 723 - 729 2017.10

Accepted, ISSN 1198-743X

Objectives: To compare the effectiveness and safety of antipseudomonal beta-lactam empiric monotherapy for febrile neutropenia by network meta-analysis.
Methods: Searches using Pubmed, Cochrane CENTRAL, EMBASE and Web of Science Core Collection were carried out in June 2016. English articles, non-English articles, full-length articles, short articles and conference abstracts were allowed. Eligible trial design was a parallel-group individual randomization. We included febrile neutropenia adult and paediatric patients undergoing chemotherapy for either solid tumours or haematological malignancies and treated with intravenous antipseudomonal beta-lactams for initial empiric therapy. Protocol was registered with PROSPERO ID 42016043377.
Results: Of 1275 articles detected by the search, 50 studies with 10 872 patients were finally included. Among the guideline-recommended cefepime, meropenem, imipenem/cilastatin, piperacillin/tazobactam and ceftazidime; imipenem/cilastatin showed the highest odds of treatment success without modification, which was the primary endpoint, based on the random-effect model network analysis. Ceftazidime was related to lower treatment success rate without modification compared with imipenem/cilastatin with OR of 0.71 (95% CI 0.57-0.89, p 0.006). Imipenem/cilastatin showed the lowest odds of all-cause death. Patients treated with cefepime had higher risk for all-cause death compared with those treated with imipenem/cilastatin (OR 2.05, 95% CI 1.11-3.78, p 0.029). Any adverse event was significantly more prevalent in the imipenem/cilastatin arm; however, there was no difference concerning adverse events leading to discontinuation.
Conclusions: Imipenem/cilastatin, piperacillin/tazobactam and meropenem may be reasonable first-choice medications for empiric therapy of febrile neutropenia. (C) 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity.

Tomoyasu Nishimura, Eiko Tamizu, Shunsuke Uno, Yoshifumi Uwamino, Hiroshi Fujiwara, Kazumi Nishio, Yasushi Nakano, Hirofumi Shiono, Ho Namkoong, Yoshihiko Hoshino, Satoshi Iwata, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 23 ( 10 ) 703 - 708 2017.10

Accepted

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.

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Clinical and radiological characteristics of patients with late-onset severe restrictive lung defect after hematopoietic stem cell transplantation.

Ho Namkoong, Makoto Ishii, Takehiko Mori, Hiroaki Sugiura, Sadatomo Tasaka, Masatoshi Sakurai, Yuya Koda, Jun Kato, Naoki Hasegawa, Shinichiro Okamoto, Tomoko Betsuyaku

BMC pulmonary medicine 17 ( 1 ) 123 - 123 2017.09

Accepted

BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPCs), which occur more than 3 months after allogeneic hematopoietic stem cell transplantation (HSCT), are major causes of morbidity and mortality after transplantation. Among LONIPCs, we occasionally treat patients with late-onset severe restrictive lung defect after HSCT; however, its clinical features have not been fully elucidated. METHODS: A retrospective chart review of a single center on cases of late-onset severe restrictive lung defect after HSCT was performed. Among 453 patients who survived longer than 100 days after allogeneic HSCT with evaluable spirometry data, 12 patients (2.6%) developed late-onset severe restrictive lung defect (i.e., vital capacity percent of predicted less than 60%). RESULTS: Median duration from transplantation to diagnosis of late-onset severe restrictive lung defect cases was 44.5 months. Major computed tomography (CT) finding was pleuroparenchymal thickening with volume loss, an evidence of fibrosis, predominantly in upper lobes (n = 7), which was consistent with pleuroparenchymal fibroelastosis. The remaining patients showed unclassifiable interstitial pneumonia pattern (n = 2) and airway-predominant pattern (n = 3). The diffusing capacity for carbon oxide tended to decrease, while the residual volume/total lung capacity ratio tended to increase after HSCT. Of 12 patients, 8 patients died and the median month from diagnosis to death was 33.5 months. Seven patients died of pulmonary or systemic infection, and one patient died due to relapse of the primary disease. CONCLUSION: Severe restrictive lung defect could develop in selected cases in the late-phase after HSCT and could be a unique clinical entity with specific radiographical findings.

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The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases.

Kazuma Yagi, Makoto Ishii, Ho Namkoong, Takahiro Asami, Osamu Iketani, Takanori Asakura, Shoji Suzuki, Hiroaki Sugiura, Yoshitake Yamada, Tomoyasu Nishimura, Hiroshi Fujiwara, Yohei Funatsu, Yoshifumi Uwamino, Tetsuro Kamo, Sadatomo Tasaka, Tomoko Betsuyaku, Naoki Hasegawa

BMC infectious diseases 17 ( 1 ) 558 - 558 2017.08

Accepted

BACKGROUND: In multidrug regimens, including an intravenous aminoglycoside (e.g. amikacin [AMK]) is recommended for difficult-to-treat non-tuberculous mycobacterial (NTM) lung diseases. We aimed to evaluate the efficacy, safety, and feasibility of inhaled AMK therapy in patients with difficult-to-treat NTM lung diseases in a retrospective chart review. METHODS: The study population consisted of patients with NTM lung diseases who received combination therapy, including inhaled AMK therapy, at Keio University Hospital (Tokyo, Japan), from January 2014 through May 2016. A total of 26 cases, consisting of 23 Mycobacterium avium complex (MAC) and three Mycobacterium abscessus complex (MABC) infections cases, were included in this study. The efficacy, safety, and feasibility of inhaled AMK therapy were retrospectively investigated. The Research Ethics Committee of Keio University Hospital approved this study, and informed consent was obtained from all patients. RESULTS: All 26 patients were culture-positive at enrolment. Twenty-three of the 26 patients (88.5%), including 21/23 MAC patients (91.3%) and 2/3 MABC patients (66.7%), were administered inhaled AMK therapy for >3 months. The proportion of patients who had clinical symptoms, including, cough and sputum, declined after inhalation AMK therapy. Ten of the 23 patients (43.5%) who received AMK inhalation, including 8/21 MAC (38.1%) and 2/2 MABC patients (100%), showed sputum conversion, defined as at least three consecutive negative sputum cultures. Seven of the 23 patients, including, 5/21 MAC and 2/2 MABC patients, showed improvements in high-resolution computed tomography imaging of the chest. In addition, the serum AMK trough levels before the second inhalation were <1.2 μg/mL in all 26 patients, with no occurrence of severe adverse events, such as renal toxicity. One patient (3.8%) experienced auditory toxicity, in the form of tinnitus. However, this symptom was reversible, after temporary interruption of AMK, the patient was able to safely resume the therapy. CONCLUSIONS: Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.

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Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease.

Takanori Asakura, Nobutaka Hayakawa, Naoki Hasegawa, Ho Namkoong, Ken Takeuchi, Shoji Suzuki, Makoto Ishii, Tomoko Betsuyaku, Yoshiaki Abe, Motofumi Ouchi

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 65 ( 2 ) 244 - 251 2017.07

Accepted

Background: Pulmonary resection along with multiple antimicrobial therapy has produced favorable outcomes at a few centers. However, little is known regarding the risk factors for long-term survival and microbiological recurrence after pulmonary resection for nontuberculous mycobacterial pulmonary disease (NTMPD). We evaluated the long-term outcomes of pulmonary resection, including microbiological recurrence and survival. Methods: This retrospective cohort study included 125 patients (median age, 60 years) with NTMPD treated by pulmonary resection at two referral centers between January 1994 and August 2015. Results: Postoperative complications occurred in 27 patients (22%). The complication rate after pneumonectomy was significantly higher than those after other types of pulmonary resection (odds ratio, 4.1; 95% confidence interval [CI], 1.6-10.3; P = .005). The median follow-up period was 7.1 years. While 19 patients experienced microbiological recurrence, 26 died. Multivariate analysis revealed pneumonectomy (adjusted hazard ratio [aHR], 0.12; 95% CI, .007-.66; P = .0098) and cavitary lesions after surgery (aHR, 6.73; 95% CI, 1.68-22.7; P = .0095) to be predictors of microbiological recurrence and old age (aHR, 1.06; 95% CI, 1.01-1.13; P = .016), low body mass index (BMI; aHR for every 1-kg/m2 increase, 0.72; 95% CI, .60-.85; P < .0001), pneumonectomy (aHR, 4.38; 95% CI, 1.78-11.3; P = .014), and remnant cavitary lesions (aHR, 3.53; 95% CI, 1.35-9.57; P = .011) to be predictors of poor prognosis. Conclusions: Patients who could benefit from pulmonary resection should be carefully selected considering age, BMI, remnant lesions after surgery, and type of pulmonary resection.

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Disseminated Mycobacterium genavense Infection in Patient with Adult-Onset Immunodeficiency.

Takanori Asakura, Ho Namkoong, Takuro Sakagami, Naoki Hasegawa, Kiyofumi Ohkusu, Akira Nakamura

Emerging infectious diseases 23 ( 7 ) 1208 - 1210 2017.07

Accepted

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Impact of cavity and infiltration on pulmonary function and health-related quality of life in pulmonary Mycobacterium avium complex disease: A 3-dimensional computed tomographic analysis.

Takanori Asakura, Yoshitake Yamada, Ho Namkoong, Shoji Suzuki, Yuki Niijima, Hirofumi Kamata, Yohei Funatsu, Kazuma Yagi, Satoshi Okamori, Hiroaki Sugiura, Makoto Ishii, Masahiro Jinzaki, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory medicine 126 9 - 16 2017.05

Accepted

BACKGROUND AND OBJECTIVES: Pulmonary Mycobacterium avium complex (pMAC) disease manifests as various types of lesions, such as infiltrates, nodules, cavities, and bronchiectasis. However, the important determinants for clinical parameters in lung involvement are poorly understood. The objective of this study was to obtain quantitative parameters by 3-dimensional CT, and investigate the relationship between these parameters and the pulmonary function tests (PFTs) and health-related quality of life. MATERIAL AND METHODS: Quantitative analysis using CT was performed in 67 pMAC patients. The relationship between new quantitative parameters for evaluating lung involvement using 3-dimensional CT and PFTs or St George's Respiratory Questionnaire (SGRQ) was evaluated. RESULTS: The ratio of infiltration to total lung volume showed significant correlation with the PFT results, especially the percent-predicted forced vital capacity (%FVC; ρ = -0.52), residual volume (ρ = -0.51), and total lung capacity (ρ = -0.59). The cavity volume was strongly correlated with the %FVC (ρ = -0.78) in the cavity group, while the ratio of infiltration to total lung volume was strongly correlated with the %FVC (ρ = -0.53) in the non-cavity group. The ratio of infiltration to total lung volume was significantly correlated with all SGRQ parameters (ρ = 0.41-0.52) in the non-cavity group. CONCLUSIONS: Infiltration was an important parameter for the PFTs and SGRQ in pMAC patients according to the 3-dimensional CT analysis. Moreover, cavity volume was an important parameter of the PFTs in the cavity group. Therefore, infiltration and cavity volume are key features for the management of pMAC disease.

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Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung.

Aoi Kuroda, Ahmed E Hegab, Gao Jingtao, Shuji Yamashita, Nobuyuki Hizawa, Tohru Sakamoto, Hideyasu Yamada, Satoshi Suzuki, Makoto Ishii, Ho Namkoong, Takanori Asakura, Mari Ozaki, Hiroyuki Yasuda, Junko Hamamoto, Shizuko Kagawa, Kenzo Soejima, Tomoko Betsuyaku

Respiratory research 18 ( 1 ) 69 - 69 2017.04

Accepted

BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. METHODS: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. RESULTS: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. CONCLUSIONS: ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

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Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001).

Masayoshi Miyawaki, Katsuhiko Naoki, Satoshi Yoda, Sohei Nakayama, Ryosuke Satomi, Takashi Sato, Shinnosuke Ikemura, Keiko Ohgino, Kota Ishioka, Daisuke Arai, Ho Namkoong, Kengo Otsuka, Masaki Miyazaki, Tetsuo Tani, Aoi Kuroda, Makoto Nishino, Hiroyuki Yasuda, Ichiro Kawada, Hidefumi Koh, Morio Nakamura, Takeshi Terashima, Fumio Sakamaki, Koichi Sayama, Tomoko Betsuyaku, Kenzo Soejima

Molecular and clinical oncology 6 ( 3 ) 409 - 414 2017.03

Accepted

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged ≥70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged <75 years (14.9 months) and those aged ≥75 years (19.0 months; P=0.226). Therefore, erlotinib was found to be effective and well-tolerated in elderly patients with previously treated NSCLC.

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A Laboratory-based Analysis of Nontuberculous Mycobacterial Lung Disease in Japan from 2012 to 2013.

Kozo Morimoto, Naoki Hasegawa, Kiyohiko Izumi, Ho Namkoong, Kazuhiro Uchimura, Takashi Yoshiyama, Yoshihiko Hoshino, Atsuyuki Kurashima, Jun Sokunaga, Shunsuke Shibuya, Masahiro Shimojima, Manabu Ato, Satoshi Mitarai

Annals of the American Thoracic Society (American Thoracic Society) 14 ( 1 ) 49 - 56 2017.01

Accepted

RATIONALE: Since 2010, mycobacterial examination results have been used widely to survey nontuberculous mycobacteria (NTM) lung disease. OBJECTIVES: To reveal the clinical and epidemiological status of NTM lung disease in Japan. METHODS: All data on the isolation and identification of mycobacteria in 2012 and 2013 were obtained from three dominant commercial laboratories in Japan. Pulmonary NTM disease was defined on the basis of bacteriological diagnostic criteria issued by the American Thoracic Society/Infectious Diseases Society of America. The coverage population was estimated using the ratio between national tuberculosis registration data and laboratory results for each of the eight regions of Japan. MEASUREMENTS AND MAIN RESULTS: A total of 113,313 mycobacterial specimens from 4,710 institutes were collected, and specimens from 26,059 patients tested positive for NTM cultures at least once. Among patients with positive cultures, 7,167 (27.5%) satisfied the American Thoracic Society/Infectious Diseases Society of America criteria for NTM lung disease, resulting in a 2-year prevalence rate of 24.0 per 100,000. Mycobacterium avium complex (MAC) was the most commonly isolated species (93.3%), and 29.0% of the patients from whom MAC was isolated satisfied the criteria for NTM lung disease. Individuals older than 70 years of age accounted for the majority of cases, and 65.5% of cases involved females. After MAC, Mycobacterium kansasii and Mycobacterium abscessus exhibited the highest (43.6%) and second-highest (37.1%) incidence per isolation, respectively. The prevalence of M. kansasii was highest in the Kinki region (P < 0.05), and M. abscessus had the greatest prevalence in the Kyushu-Okinawa region (P < 0.005). The proportion of Mycobacterium intracellulare in MAC cases was higher in the southwestern part of Japan than in other regions. The period prevalence was highest in the southwestern part of Japan, and the standardized prevalence ratio was highest in central regions. Evaluations of clarithromycin susceptibility revealed a clear binomial distribution. CONCLUSIONS: This investigation is the first laboratory-based study in which a large number of NTM isolated from clinical samples in Japan have been assessed. Although the calculated prevalence of NTM disease might be underestimated, the approach may prove useful for monitoring relative epidemiological data for NTM lung disease.

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Glycoprotein Nanotube Traps Influenza Virus

Shuta Yuge, Motofusa Akiyama, Makoto Ishii, Ho Namkoong, Kazuma Yagi, Yoko Nakai, Ryo Adachi, Teruyuki Komatsu

CHEMISTRY LETTERS (CHEMICAL SOC JAPAN) 46 ( 1 ) 95 - 97 2017.01

Accepted, ISSN 0366-7022

We report the synthesis, structure, and influenza A virus trapping capability of protein nanotubes with an internal wall of fetuin glycoprotein. The nanotubes were fabricated via the alternating layer-by-layer assembly of human serum albumin (HSA), poly-L-arginine (PLA), and fetuin into a track-etched polycarbonate (PC) membrane (pore size, 800 nm), followed by dissolution of the PC template. In an aqueous medium, the (PLA/HSA) 5PLA/fetuin nanotubes captured influenza A virus PR8 (H1N1) efficiently, as revealed by ELISA measurements.

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Susceptibility genes for nontuberculous mycobacterial disease.

Ho Namkoong, Naoki Hasegawa, Tomoko Betsuyaku

Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology (The Japan Society for Clinical Immunology) 40 ( 1 ) 60 - 67 2017

Accepted, ISSN 0911-4300

The number of patients with nontuberculous mycobacterial (NTM) disease is reportedly increasing both in Japan and worldwide. NTM diseases are classified into disseminated and pulmonary diseases based on their clinical characteristics. These two types of NTM diseases are thought to be controlled by different mechanisms. Disseminated NTM disease is caused by a defect in signal transduction of Th1 cellular immune responses, including the IFN-γ/IL-12 axis. The precise molecular mechanisms of disseminated NTM disease are understood in detail. Pulmonary NTM disease progression is associated with both bacterial factors as well as host factors. Furthermore, it is suggested that some susceptibility genes for NTM diseases may also exist. A previous study on the susceptibility genes for pulmonary NTM disease was performed using Single Nucleotide Polymorphism (SNP) analysis and microsatellite marker analysis. However, a number of challenges remain in terms of the reproducibility. The emergence of next generation sequencing enables genome-wide analysis, and further studies on the susceptibility genes for pulmonary NTM disease are expected in the future.

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A Case Of Cutis Laxa With Juvenile Emphysema Arising From Frameshift Mutations In Exon 30 Of The Elastin Gene (eln)

H Namkoong, M Ishii, K Yagi, S Chubachi, A Tsuji, K Kosaki, T Betsuyaku

C48. COPD: CASE REPORTS I, A5704-A5704 2017

D18 WHO DOES WHAT IN COPD: THE CELLULAR ORIGINS: S1p Receptor Modulation Expands Cd11b+ gr-1+ Cells And Inhibits Lymphocyte Infiltration In The Lungs And Ameliorate Murine …

T Asakura, M Ishii, H Namkoong, S Suzuki, S Kagawa, T Komiya, K Yagi, ...

American Journal of Respiratory and Critical Care Medicine 195 2017

Impact of cavity and infiltration on pulmonary function and health-related quality of life in pulmonary Mycobacterium avium complex disease: a 3-dimensional computed …

T Asakura, Y Yamada, H Namkoong, S Suzuki, Y Niijima, H Kamata, ...

Respiratory Medicine 126, 9-16 2017

Erlotinib as second‑or third‑line treatment in elderly patients with advanced non‑small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001)

M Miyawaki, K Naoki, S Yoda, S Nakayama, R Satomi, T Sato, S Ikemura, ...

Molecular and Clinical Oncology 6 (3), 409-414 2017

Protective role of a disintegrin and metalloprotease 17 (ADAM17) in elastase-induced emphysema in mice

S Suzuki, M Ishii, T Asakura, H Namkoong, S Okamori, K Yagi, H Kamata, ...

C73. NEW MECHANISMS AND THERAPIES IN COPD, A6273-A6273 2017

The Critical Role Of A Disintegrin And Metalloprotease (adam) 10 During Severe Influenza Virus Infection In Vivo And In Vitro

S Okamori, M Ishii, T Asakura, S Suzuki, H Kamata, H Namkoong, K Yagi, ...

B19. HOST RESPONSES TO INFLUENZA, A2921-A2921 2017

Susceptibility genes for nontuberculous mycobacterial disease.

H Namkoong, N Hasegawa, T Betsuyaku

Nihon Rinsho Men'eki Gakkai Kaishi= Japanese Journal of Clinical Immunology … 2017

S1p Receptor Modulation Expands Cd11b+ gr-1+ Cells And Inhibits Lymphocyte Infiltration In The Lungs And Ameliorate Murine Pulmonary Emphysema

T Asakura, M Ishii, H Namkoong, S Suzuki, S Kagawa, T Komiya, K Yagi, ...

D18. WHO DOES WHAT IN COPD: THE CELLULAR ORIGINS, A7042-A7042 2017

Macrolide-Resistant Mycobacterium avium Complex Lung Disease: Analysis of 102 Consecutive Cases.

Kozo Morimoto, Ho Namkoong, Naoki Hasegawa, Taku Nakagawa, Eriko Morino, Yuji Shiraishi, Kenji Ogawa, Kiyohiko Izumi, Jin Takasaki, Takashi Yoshiyama, Yoshihiko Hoshino, Shuichi Matsuda, Yuta Hayashi, Yuka Sasaki, Makoto Ishii, Atsuyuki Kurashima, Tomoyasu Nishimura, Tomoko Betsuyaku, Hajime Goto

Annals of the American Thoracic Society (American Thoracic Society) 13 ( 11 ) 1904 - 1911 2016.11

Accepted

RATIONALE: The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVES: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. METHODS: The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital. MEASUREMENTS AND MAIN RESULTS: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. CONCLUSIONS: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

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Beta-lactam plus macrolides or beta-lactam alone for community-acquired pneumonia: A systematic review and meta-analysis.

Nobuyuki Horita, Tatsuya Otsuka, Shusaku Haranaga, Ho Namkoong, Makoto Miki, Naoyuki Miyashita, Futoshi Higa, Hiroshi Takahashi, Masahiro Yoshida, Shigeru Kohno, Takeshi Kaneko

Respirology (Carlton, Vic.) 21 ( 7 ) 1193 - 200 2016.10

Accepted

It is unclear whether in the treatment of community-acquired pneumonia (CAP) beta-lactam plus macrolide antibiotics lead to better survival than beta-lactam alone. We report a systematic review and meta-analysis. Trials and observational studies published in English were included, if they provided sufficient data on odds ratio for all-cause mortality for a beta-lactam plus macrolide regimen compared with beta-lactam alone. Two investigators independently searched for eligible articles. Of 514 articles screened, 14 were included: two open-label randomized controlled trials (RCTs) comprising 1975 patients, one non-RCT interventional study comprising 1011 patients and 11 observational studies comprising 33 332 patients. Random-model meta-analysis yielded an odds ratio for all-cause death for beta-lactam plus macrolide compared with beta-lactam alone of 0.80 (95% CI 0.69-0.92, P = 0.002) with substantial heterogeneity (I(2) = 59%, P for heterogeneity = 0.002). Severity-based subgroup analysis and meta-regression revealed that adding macrolide had a favourable effect on mortality only for severe CAP. Of the two RCTs, one suggested that macrolide plus beta-lactam lead to better outcome compared with beta-lactam alone, while the other did not. Subgrouping based on study design, that is, RCT versus non-RCT, which was almost identical to subgrouping based on severity, revealed substantial inter-subgroup heterogeneity. Compared with beta-lactam alone, beta-lactam plus macrolide may decrease all-cause death only for severe CAP. However, this conclusion is tentative because this was based mainly on observational studies.

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Histone Deacetylase Inhibition Protects Mice Against Lethal Postinfluenza Pneumococcal Infection.

Kazuma Yagi, Makoto Ishii, Ho Namkoong, Hideki Fujii, Takahiro Asami, Shoji Suzuki, Takanori Asakura, Kosuke Mizoguchi, Tetsuro Kamo, Sadatomo Tasaka, Satoshi Iwata, Steven L Kunkel, Naoki Hasegawa, Tomoko Betsuyaku

Critical care medicine 44 ( 10 ) e980-7 2016.10

Accepted

OBJECTIVES: Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia. DESIGN: Prospective experimental study. SETTING: University research laboratory. SUBJECTS: C57BL/6 male mice. INTERVENTIONS: Mice were infected intranasally with 1.0 × 10 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate. MEASUREMENTS AND MAIN RESULTS: Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group. CONCLUSIONS: The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.

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Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001-2011: A case series and literature review.

Shoji Suzuki, Eriko Morino, Makoto Ishii, Ho Namkoong, Kazuma Yagi, Takanori Asakura, Takahiro Asami, Hiroshi Fujiwara, Yoshifumi Uwamino, Tomoyasu Nishimura, Sadatomo Tasaka, Tomoko Betsuyaku, Jin Takasaki, Satoshi Iwata, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 22 ( 9 ) 611 - 6 2016.09

Accepted

BACKGROUND: Mycobacterium scrofulaceum is a well-known pathogen associated with cervical lymphadenitis in children. However, pulmonary M. scrofulaceum disease is a rare condition with unknown clinical features. The present study aimed to clarify the clinical features of pulmonary M. scrofulaceum disease described in recent cases and reports. METHODS: We reviewed the medical records of all adult patients with pulmonary M. scrofulaceum disease at Keio University Hospital and the National Center for Global Health and Medicine Center Hospital between 2001 and 2011. We also conducted a review of the PubMed database to identify additional cases of pulmonary M. scrofulaceum disease in adults. RESULTS: Our study identified 8 cases of pulmonary M. scrofulaceum disease at the 2 identified institutions during our study period. Most cases were diagnosed in middle-aged and elderly men with underlying pulmonary diseases such as chronic obstructive pulmonary disease and Mycobacterium avium complex lung disease, as well as those with a history of pulmonary tuberculosis. In contrast, most previously reported cases identified through our literature review had a history of dust inhalation or underlying silicosis. Three of 8 cases at our institutions and 20 of 23 cases from the literature were treated with combination therapies. CONCLUSIONS: We conclude that in the recent histories of our institutions, pulmonary M. scrofulaceum disease has mainly occurred in patients with chronic pulmonary diseases. We further conclude that combination therapies that include clarithromycin might yield better patient outcomes.

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Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient settings: a case series.

Ho Namkoong, Kozo Morimoto, Tomoyasu Nishimura, Hiromu Tanaka, Hiroaki Sugiura, Yoshitake Yamada, Atsuko Kurosaki, Takanori Asakura, Shoji Suzuki, Hiroshi Fujiwara, Kazuma Yagi, Makoto Ishii, Sadatomo Tasaka, Tomoko Betsuyaku, Yoshihiko Hoshino, Atsuyuki Kurashima, Naoki Hasegawa

BMC infectious diseases 16 396 - 396 2016.08

Accepted

BACKGROUND: Mycobacterium abscessus (M. abscessus) pulmonary disease is a refractory chronic infectious disease. Options for treating M. abscessus pulmonary disease are limited, especially in outpatient settings. Among parenteral antibiotics against M. abscessus, intravenous amikacin (AMK) is expected to be an effective outpatient antimicrobial therapy. This study evaluated the clinical efficacy and safety of intravenous AMK therapy in outpatients with M. abscessus pulmonary disease. METHODS: This retrospective chart review of cases of M. abscessus pulmonary disease evaluated patient background data, AMK dosage and duration, sputum conversion, clinical symptoms radiological findings, and adverse events. M. massiliense was excluded on the basis of multiplex PCR assay. RESULTS: Thirteen patients (2 men and 11 women) with M. abscessus pulmonary disease were enrolled at 2 hospitals. The median age at the initiation of intravenous AMK treatment was 65 years (range: 50-86 years). Patients received a median AMK dose of 12.5 mg/kg (range: 8.3-16.2 mg/kg) for a median duration of 4 months (range: 3-9 months). The addition of intravenous AMK led to sputum conversion in 10 of 13 patients, and 8 patients continued to have negative sputum status 1 year after treatment. Approximately half of the patients showed improvement on chest high-resolution computed tomography. There were no severe adverse events such as ototoxicity, vestibular toxicity, and renal toxicity. CONCLUSIONS: Thrice weekly intravenous AMK administration in outpatient settings is effective and safe for patients with M. abscessus pulmonary disease.

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Pneumothorax associated with nontuberculous mycobacteria: A retrospective study of 69 patients.

Masako Ueyama, Takanori Asakura, Kozo Morimoto, Ho Namkoong, Shuichi Matsuda, Takeshi Osawa, Makoto Ishii, Naoki Hasegawa, Atsuyuki Kurashima, Hajime Goto

Medicine 95 ( 29 ) e4246 2016.07

Accepted

The incidence of nontuberculous mycobacterial pulmonary disease (NTMPD) is increasing worldwide. Secondary spontaneous pneumothorax occurs as a complication of underlying lung disease and is associated with higher morbidity, mortality, and recurrence than primary spontaneous pneumothorax. We here investigated the clinical features and long-term outcomes of pneumothorax associated with NTMPD.We conducted a retrospective study on consecutive adult patients with pneumothorax associated with NTMPD at Fukujuji Hospital and Keio University Hospital from January 1992 to December 2013. We reviewed the medical records of 69 such patients to obtain clinical characteristics, radiological findings, and long-term outcomes, including pneumothorax recurrence and mortality.The median age of the patients was 68 years; 34 patients were women. The median body mass index was 16.8 kg/m. Underlying pulmonary diseases mainly included chronic obstructive pulmonary disease and pulmonary tuberculosis. On computed tomography, nodules and bronchiectasis were observed in 46 (98%) and 45 (96%) patients, respectively. Consolidation, pleural thickening, interlobular septal thickening, and cavities were most common, and observed in 40 (85%), 40 (85%), 37 (79%), and 36 (77%) patients, respectively. Regarding pneumothorax treatment outcomes, complete and incomplete lung expansion were observed in 49 patients (71%) and 15 patients (22%), respectively. The survival rate after pneumothorax was 48% at 5 years. By the end of the follow-up, 33 patients had died, and the median survival was 4.4 years with a median follow-up period of 1.7 years. The rate of absence of recurrence after the first pneumothorax was 59% at 3 years. By the end of the follow-up, 18 patients had experienced pneumothorax recurrence. Furthermore, 12/18 patients (66%) with recurrent pneumothorax died during the study period. Twenty-three patients (70%) died because of NTMPD progression. Low body mass index (BMI) was a negative prognostic factor for pneumothorax associated with NTMPD in multivariate analysis (HR 0.79, 95% CI 0.64-0.96; P = 0.018)Patients with pneumothorax associated with NTMPD have advanced disease, a high rate of pneumothorax recurrence, and poor prognosis, regardless of the pneumothorax treatment used. Further improvements in early diagnosis of NTMPD and appropriate management in both NTMPD and NTMPD-associated pneumothorax are needed.

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Epidemiology of Pulmonary Nontuberculous Mycobacterial Disease, Japan.

Ho Namkoong, Atsuyuki Kurashima, Kozo Morimoto, Yoshihiko Hoshino, Naoki Hasegawa, Manabu Ato, Satoshi Mitarai

Emerging infectious diseases 22 ( 6 ) 1116 - 7 2016.06

Accepted

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Refractory tenosynovitis with 'rice bodies' in the hand due to Mycobacterium intracellulare.

Ho Namkoong, Keizo Fukumoto, Igen Hongo, Naoki Hasegawa

Infection 44 ( 3 ) 393 - 4 2016.06

Accepted

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Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression.

Saeko Takahashi, Makoto Ishii, Ho Namkoong, Ahmed E Hegab, Takahiro Asami, Kazuma Yagi, Mamoru Sasaki, Mizuha Haraguchi, Minako Sato, Naofumi Kameyama, Takanori Asakura, Shoji Suzuki, Sadatomo Tasaka, Satoshi Iwata, Naoki Hasegawa, Tomoko Betsuyaku

The Journal of infectious diseases 213 ( 6 ) 1018 - 30 2016.03

Accepted

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD)--typically caused by bacterial or viral infection--is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. METHODS: We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. RESULTS: In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. CONCLUSIONS: These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

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Disseminated Mycobacterium marinum Infection With a Destructive Nasal Lesion Mimicking Extranodal NK/T Cell Lymphoma: A Case Report.

Takanori Asakura, Makoto Ishii, Taku Kikuchi, Kaori Kameyama, Ho Namkoong, Noboru Nakata, Kayoko Sugita, Sadatomo Tasaka, Takayuki Shimizu, Yoshihiko Hoshino, Shinichiro Okamoto, Tomoko Betsuyaku, Naoki Hasegawa

Medicine 95 ( 11 ) e3131 2016.03

Accepted

Mycobacterium marinum is a ubiquitous waterborne organism that mainly causes skin infection in immunocompetent patients, and its disseminated infection is rare. Extranodal NK/T cell lymphoma, nasal type (ENKL) usually localizes at the nasal and/or paranasal area, but occasionally disseminates into the skin/soft tissue and gastrointestinal tract. Compromised immunity is a risk factor for developing nontuberculous mycobacterial (NTM) infection and malignant lymphoma, and the 2 diseases may share similar clinical presentation; however, only a few reports have described NTM infection mimicking malignant lymphoma.A 43-year-old Japanese man presented to our hospital complaining of multiple progressive skin nodules and purulent nasal discharge for 3 weeks. He was diagnosed with Crohn disease with refractory enteropathic arthritis and has been treated with anti-tumor necrosis factor alpha agents for 25 years. Fiberoptic nasal examination revealed septal perforation with hemorrhagic mucus and purulent rhinorrhea. Histological examination of the nasal septum revealed the infiltration of atypical medium-to-large-sized cells with erosion. The cells were positive for cytoplasmic CD3, granzyme B, and Epstein-Barr virus-encoded small RNA. Histological examination of the skin nodules and auricle also showed infiltration of atypical lymphocytes. The patient was tentatively diagnosed with ENKL, and chemotherapy was considered. However, the skin lesions decreased in size after discontinuation of immunosuppressive agents and minocycline administration. Two weeks later, nasal septum and lavage fluid and left leg skin cultures were positive for M marinum, and minocycline was discontinued. The skin and the nasal lesions improved after 2 months. To the best of our knowledge, this is the first case of disseminated M marinum infection with a destructive nasal lesion mimicking ENKL. The differentiation between M marinum infection and ENKL is clinically important because misdirected treatment leads to a poor prognosis. NTM infections including M marinum should be considered in differential diagnosis of ENKL. Bacterial cultures, pathological analysis, and close monitoring are required for the differentiation of ENKL and disseminated M marinum infection; both are serious diseases and early diagnostic distinction between them and immediate appropriate treatment will improve the patient's prognosis.

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Blue-Black Trachea as a Result of Minocycline-induced Hyperpigmentation.

Takanori Asakura, Shigenari Nukaga, Ho Namkoong, Kazuma Yagi, Shoji Suzuki, Makoto Ishii, Sadatomo Tasaka, Tomoko Betsuyaku, Naoki Hasegawa

American journal of respiratory and critical care medicine 193 ( 3 ) e5-6 2016.02

Accepted

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Fournier's gangrene: a surgical emergency.

Ho Namkoong, Makoto Ishii, Masayuki Koizumi, Tomoko Betsuyaku

Infection 44 ( 1 ) 143 - 4 2016.02

Accepted

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3-Deazaneplanocin A-An Inhibitor Of Histone Methyltransferase Ezh2-Exacerbates Elastase-Induced Emphysema In Mice

T Asakura, M Ishii, H Namkoong, K Yagi, S Suzuki, T Tanosaki, S Kagawa, ...

C70. THE NEXT NEW THERAPEUTIC TARGET? TRANSLATIONAL STUDIES OF COPD … 2016

Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001–2011: a case series and literature review

S Suzuki, E Morino, M Ishii, H Namkoong, K Yagi, T Asakura, T Asami, ...

Journal of Infection and Chemotherapy 22 (9), 611-616 2016

C70 THE NEXT NEW THERAPEUTIC TARGET? TRANSLATIONAL STUDIES OF COPD THERAPIES: 3-Deazaneplanocin A-An Inhibitor Of Histone Methyltransferase Ezh2-Exacerbates Elastase-Induced …

T Asakura, M Ishii, H Namkoong, K Yagi, S Suzuki, T Tanosaki, S Kagawa, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

C57 CELLULAR/MOLECULAR MECHANISMS AND TRANSLATIONAL ASPECTS OF RESPIRATORY INFECTIONS: Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired Ifn-Beta Induction …

H Namkoong, M Ishii, H Fujii, K Yagi, T Asakura, S Suzuki, H Kamata, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

C105 RESPIRATORY FAILURE: MECHANISTIC INSIGHTS FROM LUNG INJURY MODELS: Critical Role Of The Prostaglandin D2 Receptor Crth2 In Acute Lung Injury Caused By Lipopolysaccharide …

S Suzuki, M Ishii, T Asami, H Namkoong, K Yagi, T Asakura, H Kamata, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

Blue–Black Trachea as a Result of Minocycline-induced Hyperpigmentation

T Asakura, S Nukaga, H Namkoong, K Yagi, S Suzuki, M Ishii, S Tasaka, ...

American journal of respiratory and critical care medicine 193 (3), e5-e6 2016

Beta‐lactam plus macrolides or beta‐lactam alone for community‐acquired pneumonia: A systematic review and meta‐analysis

N Horita, T Otsuka, S Haranaga, H Namkoong, M Miki, N Miyashita, ...

Respirology 21 (7), 1193-1200 2016

B49 NON-TUBERCULOUS MYCOBACTERIAL DISEASE AND CASE REPORTS: Laboratory Based Survey For Pulmonary Non-Tuberculous Mycobacteriosis In Japan: 2012-213

K Morimoto, N Hasegawa, K Izumi, H Namkoong, K Uchimura, Y Hoshino, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

A53 RESPIRATORY FAILURE: RISK FACTORS AND OUTCOMES IN ARDS: The Berlin Definition Criteria Of Ards Severity Is Associated With Prognosis And Fibroproliferative Changes On High …

T Kamo, S Tasaka, T Suzuki, T Asakura, S Suzuki, K Yagi, H Namkoong, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient …

H Namkoong, K Morimoto, T Nishimura, H Tanaka, H Sugiura, Y Yamada, ...

BMC infectious diseases 16 (1), 1-9 2016

D32 PNEUMONIA: The Histone Deacetylase Inhibitor Trichostatin A Protects Mice Against Lethal Post-Influenza Pneumococcal Infection

K Yagi, M Ishii, H Namkoong, T Asami, T Asakura, S Suzuki, H Fujiwara, ...

American Journal of Respiratory and Critical Care Medicine 193, 1 2016

Critical Role Of The Prostaglandin D2 Receptor Crth2 In Acute Lung Injury Caused By Lipopolysaccharide (LPS)-Induced Shock In Mice

S Suzuki, M Ishii, T Asami, H Namkoong, K Yagi, T Asakura, H Kamata, ...

C105. RESPIRATORY FAILURE: MECHANISTIC INSIGHTS FROM LUNG INJURY MODELS … 2016

Laboratory Based Survey For Pulmonary Non-Tuberculous Mycobacteriosis In Japan: 2012-213

K Morimoto, N Hasegawa, K Izumi, H Namkoong, K Uchimura, Y Hoshino, ...

B49. NON-TUBERCULOUS MYCOBACTERIAL DISEASE AND CASE REPORTS, A3719-A3719 2016

The Histone Deacetylase Inhibitor Trichostatin A Protects Mice Against Lethal Post-Influenza Pneumococcal Infection

K Yagi, M Ishii, H Namkoong, T Asami, T Asakura, S Suzuki, H Fujiwara, ...

D32. PNEUMONIA, A6722-A6722 2016

The Berlin Definition Criteria Of Ards Severity Is Associated With Prognosis And Fibroproliferative Changes On High-Resolution CT

T Kamo, S Tasaka, T Suzuki, T Asakura, S Suzuki, K Yagi, H Namkoong, ...

A53. RESPIRATORY FAILURE: RISK FACTORS AND OUTCOMES IN ARDS, A1838-A1838 2016

Refractory tenosynovitis with ‘rice bodies’ in the hand due to Mycobacterium intracellulare

H Namkoong, K Fukumoto, I Hongo, N Hasegawa

Infection 44 (3), 393-394 2016

Pharmacokinetics of intravenous peramivir in the airway epithelial lining fluid of healthy volunteers.

Yohei Funatsu, Sadatomo Tasaka, Takahiro Asami, Ho Namkoong, Hiroshi Fujiwara, Osamu Iketani, Kazuma Yagi, Yoshifumi Kimizuka, Makoto Ishii, Tomoyasu Nishimura, Haruhiko Ogata, Satoshi Iwata, Tomoko Betsuyaku, Naoki Hasegawa

Antiviral therapy 21 ( 7 ) 621 - 625 2016

Accepted

BACKGROUND: Some subtypes of influenza virus, such as H5N1 and H7N9, cause severe viral pneumonia, for which the intraluminal concentration of the anti-influenza agent in the airway is critical. However, the pharmacokinetics of peramivir, the only available injectable neuraminidase inhibitor formulation, in the airway epithelial lining fluid (ELF) remains unclear. In this study, we aimed to determine the time course of peramivir in the pharyngeal ELF, bronchial ELF and plasma of healthy volunteers using bronchoscopic microsampling technique. METHODS: Six healthy volunteers were studied. After baseline plasma sampling, 0.3 g peramivir was intravenously injected over 0.5 h. ELF was obtained from the upper and lower airways using bronchoscopic microsampling at the end of the infusion (0.5 h) and after 1.0, 1.5, 2.0, 2.5, 3.0, 4.0 and 5.0 h. The concentrations of peramivir in the ELFs and in the plasma were quantified by LC/MS/MS analysis. RESULTS: The mean maximum concentration (Cmax) in pharyngeal ELF, bronchial ELF and plasma was 1.20 ±0.42, 9.60 ±2.30 and 50.52 ±17.51 ng/ml, respectively. The penetration ratio at Cmax in pharyngeal and bronchial ELFs was 2.4 and 19.0, respectively. The ratio of the area under the curve from 0 to infinity in pharyngeal and bronchial ELFs was 4.8 and 39.1 mg•min/l, respectively. CONCLUSIONS: The time course of peramivir concentration in the ELFs revealed that concentrations above the 50% inhibitory concentration value of influenza were achieved in the upper and lower airways. Therefore, peramivir could be an important treatment option for influenza viral pneumonia.

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Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired IFN-Beta Induction And Reduced Expressions Of Antimicrobial Peptides In Mice

H Namkoong, M Ishii, H Fujii, K Yagi, T Asakura, S Suzuki, H Kamata, ...

C57. CELLULAR/MOLECULAR MECHANISMS AND TRANSLATIONAL ASPECTS OF RESPIRATORY … 2016

Theory and strategy for Pneumococcal vaccines in the elderly.

Ho Namkoong, Makoto Ishii, Yohei Funatsu, Yoshifumi Kimizuka, Kazuma Yagi, Takahiro Asami, Takanori Asakura, Shoji Suzuki, Testuro Kamo, Hiroshi Fujiwara, Sadatomo Tasaka, Tomoko Betsuyaku, Naoki Hasegawa

Human vaccines & immunotherapeutics 12 ( 2 ) 336 - 43 2016

Accepted

Pneumonia is the fourth-leading cause of death globally, and Streptococcus pneumoniae is the most important causative pathogen. Because the incidence of pneumococcal diseases is likely to increase with the aging society, we should determine an optimal strategy for pneumococcal vaccination. While consensus indicates that 23-valent pneumococcal polysaccharide vaccine prevents invasive pneumococcal diseases (IPD), its effects on community-acquired pneumonia (CAP) remain controversial. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was released. The latest clinical study (CAPiTA study) showed that PCV13 reduced vaccine-type CAP and IPD. Based on these results, the Advisory Committee on Immunization Practices recommended initial vaccination with PCV13 for the elderly. Scientific evidence regarding immunosenescence is needed to determine a more ideal vaccination strategy for the elderly with impaired innate and adaptive immunity. Continuing research on the cost effectiveness of new vaccine strategies considering constantly changing epidemiology is also warranted.

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症例で学ぶ非結核性抗酸菌症 (第 1 回) 人間ドックで異常を指摘された中葉舌区陰影

南宮湖，倉島篤行，長谷川直樹

呼吸と循環= Respiration and circulation 64 (1), 79-82 2016

Health-related quality of life is inversely correlated with C-reactive protein and age in Mycobacterium avium complex lung disease: a cross-sectional analysis of 235 patients.

Takanori Asakura, Yohei Funatsu, Makoto Ishii, Ho Namkoong, Kazuma Yagi, Shoji Suzuki, Takahiro Asami, Tetsuro Kamo, Hiroshi Fujiwara, Yoshifumi Uwamino, Tomoyasu Nishimura, Sadatomo Tasaka, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory research 16 145 - 145 2015.12

Accepted

BACKGROUND: Mycobacterium avium complex (MAC) lung diseases generally cause chronic disease in immunocompetent hosts. Although a few studies have examined health-related quality of life (HRQL) in patients with MAC lung disease, there have been no large studies. This study aimed to evaluate HRQL and its correlation with clinical outcomes in MAC lung disease. METHODS: A cross-sectional study was conducted at Keio University Hospital to investigate the factors associated with HRQL in pulmonary nontuberculous mycobacterial diseases. MAC lung diseases were diagnosed according to the 2007 ATS/IDSA guidelines for nontuberculous mycobacterial diseases. The 36-item short form health survey (SF-36) was administered to assess clinical outcomes. Clinical variables included treatment status, latest haematological data, and bacterial smear and culture results. RESULTS: The SF-36 scores for the 235 patients (median age, 69 years; 45 men and 190 women) with MAC lung disease, except for the bodily pain and mental health subscale scores, were significantly lower than the Japanese population norms. In the multivariable analyses, current treatment for MAC and a positive sputum smear or culture within the past year were significantly associated with lower SF-36 scores. C-reactive protein (CRP) and age showed stronger inverse correlations with SF-36 scores. CONCLUSIONS: HRQL, especially the physical component, was impaired in patients with MAC lung diseases; this appears to be related with current treatment status, positive sputum smear or culture within the previous year, and particularly CRP and age. Further studies including qualitative assessments are needed to investigate the efficacy of CRP as a marker for progression or treatment response in MAC lung disease. TRIAL REGISTRATION: Clinical trial registered with UMIN ( UMIN000007964 ).

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Dry pleurisy complicating solitary pulmonary nodules caused by Mycobacterium avium: a case report.

Takanori Asakura, Makoto Ishii, Mizuha Haraguchi, Ikuo Kamiyama, Mitsutomo Kohno, Hiroyuki Sakamaki, Katsura Emoto, Yuichiro Hayashi, Hiroaki Sugiura, Ichiro Kawada, Kenzo Soejima, Ho Namkoong, Sadatomo Tasaka, Naoki Hasegawa, Tomoko Betsuyaku

Journal of medical case reports 9 238 - 238 2015.10

Accepted

INTRODUCTION: Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense (18)F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. CASE PRESENTATION: A 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense (18)F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. CONCLUSION: This is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.

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Successful resumption of tocilizumab for rheumatoid arthritis after resection of a pulmonary Mycobacterium avium complex lesion: a case report.

Ho Namkoong, Sadatomo Tasaka, Mitsuhiro Akiyama, Kazuma Yagi, Makoto Ishii, Katsuya Suzuki, Mitsutomo Kohno, Naoki Hasegawa, Tsutomu Takeuchi, Tomoko Betsuyaku

BMC pulmonary medicine 15 126 - 126 2015.10

Accepted

BACKGROUND: Biological agents inhibiting TNF-α and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. CASE PRESENTATION: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. CONCLUSION: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.

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Adjunctive Systemic Corticosteroids for Hospitalized Community-Acquired Pneumonia: Systematic Review and Meta-Analysis 2015 Update.

Nobuyuki Horita, Tatsuya Otsuka, Shusaku Haranaga, Ho Namkoong, Makoto Miki, Naoyuki Miyashita, Futoshi Higa, Hiroshi Takahashi, Masahiro Yoshida, Shigeru Kohno, Takeshi Kaneko

Scientific reports 5 14061 - 14061 2015.09

Accepted

Previous randomized controlled trials (RCTs) and meta-analyses evaluated the efficacy and safety of adjunctive corticosteroids for community-acquired pneumonia (CAP). However, the results from them had large discrepancies. The eligibility criteria for the current meta-analysis were original RCTs written in English as a full article that evaluated adjunctive systemic corticosteroids adding on antibiotic therapy targeting typical and/or atypical pathogen for treating hospitalized human CAP cases. Four investigators independently searched for eligible articles through PubMed, Embase, and Cochrane databases. Random model was used. The heterogeneity among original studies and subgroups was evaluated with the I(2) statistics. Of 54 articles that met the preliminary criteria, we found 10 eligible RCTs comprising 1780 cases. Our analyses revealed following pooled values by corticosteroids. OR for all-cause death: 0.80 (95% confidence interval (95% CI) 0.53-1.21) from all studies; 0.41 (95% CI 0.19-0.90) from severe-case subgroup; 0.21 (95% CI 0.0-0.74) from intensive care unit (ICU) subgroup. Length of ICU stay: -1.30 days (95% CI (-3.04)-0.44). Length of hospital stay: -0.98 days (95% CI (-1.26)-(-0.71)). Length to clinical stability: -1.16 days (95% CI (-1.73)-(-0.58)). Serious complications do not seem to largely increase by steroids. In conclusion, adjunctive systemic corticosteroids for hospitalized patients with CAP seems preferred strategies.

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Immune reconstitution inflammatory syndrome due to Mycobacterium avium complex successfully followed up using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in a patient with human immunodeficiency virus infection: A case report.

Ho Namkoong, Hiroshi Fujiwara, Makoto Ishii, Kazuma Yagi, Mizuha Haraguchi, Masako Matsusaka, Shoji Suzuki, Takanori Asakura, Takahiro Asami, Fumitake Saito, Koichi Fukunaga, Sadatomo Tasaka, Tomoko Betsuyaku, Naoki Hasegawa

BMC medical imaging 15 24 - 24 2015.07

Accepted

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18F-FDG PET/CT. CASE PRESENTATION: A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient's mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. CONCLUSION: We present a case of MAC-IRIS in an HIV-infected patient whose disease activity was successfully followed up using 18F-FDG PET/CT. Our data suggest that 18F-FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and assessing the appropriate duration of anti-mycobacterial chemotherapy for NTM-IRIS in HIV-infected patients.

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Fatal Fulminant Pneumonia Caused by Methicillin-Sensitive Staphylococcus aureus Negative for Major High-Virulence Factors Following Influenza B Virus Infection.

Katsunori Masaki, Makoto Ishii, Masaki Anraku, Ho Namkoong, Ryo Miyakawa, Takeshi Nakajima, Koichi Fukunaga, Katsuhiko Naoki, Sadatomo Tasaka, Kenzo Soejima, Koichi Sayama, Kayoko Sugita, Satoshi Iwata, Longzhu Cui, Hideaki Hanaki, Naoki Hasegawa, Tomoko Betsuyaku

The American journal of case reports 16 454 - 8 2015.07

Accepted

BACKGROUND: Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza virus infection is often fatal. In these cases, disease severity is typically determined by susceptibility to antimicrobial agents and the presence of high-virulence factors that are produced by Staphylococcus aureus, such as Panton-Valentine leukocidin (PVL). CASE REPORT: We describe a rare case of fatal community-acquired pneumonia caused by methicillin-sensitive Staphylococcus aureus (MSSA), which did not secrete major high-virulence factors and coexisted with influenza type B infection. The 32-year-old previously healthy male patient presented with dyspnea, high fever, and cough. His roommate had been diagnosed with influenza B virus infection 3 days earlier. Gram-positive clusters of cocci were detected in the patient's sputum; therefore, he was diagnosed with severe pneumonia and septic shock, and was admitted to the intensive care unit. Despite intensive antibiotic and antiviral treatment, he died of multiple organ failure 5 days after admission. His blood culture from the admission was positive for MSSA, and further analysis revealed that the strain was negative for major high-virulence factors, including PVL and enterotoxins, although influenza B virus RNA was detected by PCR. CONCLUSIONS: Physicians should pay special attention to patients with pneumonia following influenza and Staphylococcus aureus infection, as it may be fatal, even if the Staphylococcus aureus strain is PVL-negative and sensitive to antimicrobial agents.

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Recurrence of disseminated Mycobacterium avium complex disease in a patient with anti-gamma interferon autoantibodies by reinfection.

Tomoyasu Nishimura, Yukiko Fujita-Suzuki, Makoto Yonemaru, Kiyofumi Ohkusu, Takuro Sakagami, Stephen M Carpenter, Yoshihito Otsuka, Ho Namkoong, Ikuya Yano, Naoki Hasegawa

Journal of clinical microbiology 53 ( 4 ) 1436 - 8 2015.04

Accepted

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The diagnostic usefulness of 18F-fluorodoxyglucose-positron emission tomography/CT in SAPHO syndrome.

Ho Namkoong, Makoto Ishii, Sadatomo Tasaka, Tomoko Betsuyaku

BMJ case reports 2015 2015.03

Accepted

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Comparison of the immunogenicity and safety of polysaccharide and protein-conjugated pneumococcal vaccines among the elderly aged 80 years or older in Japan: an open-labeled randomized study.

Ho Namkoong, Yohei Funatsu, Kazunori Oishi, Yukihiro Akeda, Rika Hiraoka, Kei Takeshita, Takahiro Asami, Kazuma Yagi, Yoshifumi Kimizuka, Makoto Ishii, Sadatomo Tasaka, Yukio Suzuki, Satoshi Iwata, Tomoko Betsuyaku, Naoki Hasegawa

Vaccine 33 ( 2 ) 327 - 32 2015.01

Accepted

An open-labeled randomized study was conducted to compare the immunogenicity and safety of polysaccharide (PPV23) or protein-conjugated pneumococcal vaccine (PCV7) among the elderly aged 80 years or older. A total of 105 nursing home residents were enrolled in this study. We analyzed the geometric mean concentration (GMC) of serotype-specific immunoglobulin G (IgG) and the geometric mean titer (GMT) of the opsonization index (OI) for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. The GMCs of serotype-specific IgG and the GMTs of the OI significantly increased one month after vaccination in both groups for all seven serotypes evaluated. In the PCV7 group, study subjects with serotypes 4, 9V, 18C, and 23F exhibited statistically significant elevations in both serotype-specific IgGs and OIs compared to those of the PPV23 group. Both vaccines were tolerated without any severe adverse events, and no differences in systemic adverse events were observed between the two groups, although adverse reactions such as redness and localized swelling were more common in the PCV7 group. Our data demonstrated that the GMCs of serotype-specific IgG and the GMTs of the OI were higher in the PCV7 group compared to those in the PPV23 group. Our study also confirmed the safety of both the PCV7 and PPV23 vaccines in elderly people aged 80 years or older.

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Clarithromycin Expands CD11b+ Gr-1+ Cells To Ameliorate Post-Influenza Pneumococcal Pneumonia

H Namkoong, M Ishii, H Fujii, K Yagi, T Asakura, S Suzuki, T Kamo, ...

B106. HOST PATHOGEN INTERACTIONS I, A3800-A3800 2015

Cerebrospinal fluid dynamics at the lumbosacral level in patients with spinal stenosis

K Kim, DJ Kim, KD Kim, HJ Lee, CH Sohn, SG Chung, SW Chun, ...

Fluids and Barriers of the CNS 12 (1), 1-2 2015

C105 NONTUBERCULOUS MYCOBACTERIA EPIDEMIOLOGY: Nationwide Survey On The Epidemiology Of Pulmonary Nontuberculous Mycobacterial In Japan

H Namkoong, A Kurashima, K Morimoto, Y Hoshino, N Hasegawa, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

B106 HOST PATHOGEN INTERACTIONS I: Clarithromycin Expands Cd11b+ gr-1+ cells To Ameliorate Post-Influenza Pneumococcal Pneumonia

H Namkoong, M Ishii, H Fujii, K Yagi, T Asakura, S Suzuki, T Kamo, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

A56 (PATHO)-PHYSIOLOGY OF THE ALVEOLUS: Levels Of Soluble Receptor For Advanced Glycation End Products (srage) In Bronchoalveolar Lavage Fluid In Patients With Various Lung …

T Kamo, S Tasaka, Y Tokuda, T Asakura, S Suzuki, K Yagi, H Namkoong, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

A32 MICROBIAL INTERACTIONS AND HOST DEFENSE: The Critical Roles Of Tumor Necrosis Factor [alpha]-Converting Enzyme During Influenza Virus And Streptococcus Pneumoniae Infection …

S Suzuki, M Ishii, H Namkoong, K Yagi, T Asakura, S Tasaka, T Kamo, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

A21 GENETIC REGULATION OF CHRONIC AIRWAY INFLAMMATION: Role Of Histone Acetylation In Mice Coinfected With Influenza Virus And Streptococcus Pneumoniae

K Yagi, M Ishii, H Namkoong, T Asami, T Asakura, S Suzuki, H Fujiwara, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

A Case of Disseminated Cryptococcal Infection and Concurrent Lung Tuberculosis in a Patient under Steroid Therapy for Interstitial Pneumonia.

Aoi Kuroda, Sadatomo Tasaka, Kazuma Yagi, Takao Mochimaru, Tetsuo Tani, Ho Namkoong, Kyuto Tanaka, Yusuke Suzuki, Mami Hatano, Naoki Hasegawa, Yasunori Okada, Tomoko Betsuyaku

Case reports in pulmonology 2015 358926 - 358926 2015

Accepted

Both disseminated cryptococcal infection and tuberculosis occur in hosts with impaired cell-mediated immunity, but there have been few reports about the concurrent infections in patients without human immunodeficiency virus infection. A 64-year-old man, who had been taking corticosteroids for interstitial pneumonia, was diagnosed with disseminated cryptococcal infection. While the patient was receiving anticryptococcal therapy, pulmonary tuberculosis also emerged. The patient developed acute exacerbation of interstitial pneumonia and passed away. Based on the patient's clinical course, serial computed tomography images, and autopsy results, we believe that the preceding several months of corticosteroid treatment might have contributed to these coinfections in the lungs already vulnerable due to underlying fibrosis.

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肺非結核性抗酸菌症の薬物療法

南宮湖，長谷川直樹

呼吸器内科= Respiratory medicine/呼吸器内科編集委員会編 27 (1), 37-42 2015

Comparison of the immunogenicity and safety of polysaccharide and protein-conjugated pneumococcal vaccines among the elderly aged 80 years or older in Japan: an open-labeled …

H Namkoong, Y Funatsu, K Oishi, Y Akeda, R Hiraoka, K Takeshita, ...

Vaccine 33 (2), 327-332 2015

Immune reconstitution inflammatory syndrome due to Mycobacterium. 18F-fluorodeoxyglucose positron emission tomography-computed tomography in a patient …

H Namkoong, H Fujiwara, M Ishii, K Yagi, M Haraguchi, M Matsusaka, ...

BMC Medical Imaging 15 (1) 2015

Immune reconstitution inflammatory syndrome due to Mycobacterium avium complex successfully followed up using 18 F-fluorodeoxyglucose positron emission tomography-computed …

H Namkoong, H Fujiwara, M Ishii, K Yagi, M Haraguchi, M Matsusaka, ...

BMC medical imaging 15 (1), 1-6 2015

Health-Related Quality Of Life In 235 Patients With Mycobacterium Avium Complex Lung Disease In Japan

T Asakura, M Ishii, Y Funatsu, K Yagi, H Namkoong, S Suzuki, T Kamo, ...

D108. DIAGNOSIS AND MANAGEMENT OF NONTUBERCULOUS MYCOBACTERIA INFECTIONS … 2015

Drug therapy for pulmonary nontuberculous mycobacterial disease

H Namkoong, N Hasegawa

Japanese Journal of Chest Diseases 74 (10), 1084-1094 2015

D108 DIAGNOSIS AND MANAGEMENT OF NONTUBERCULOUS MYCOBACTERIA INFECTIONS: Health-Related Quality Of Life In 235 Patients With Mycobacterium Avium Complex Lung Disease In Japan

T Asakura, M Ishii, Y Funatsu, K Yagi, H Namkoong, S Suzuki, T Kamo, ...

American Journal of Respiratory and Critical Care Medicine 191, 1 2015

Levels Of Soluble Receptor For Advanced Glycation End Products (srage) In Bronchoalveolar Lavage Fluid In Patients With Various Lung Diseases

T Kamo, S Tasaka, Y Tokuda, T Asakura, S Suzuki, K Yagi, H Namkoong, ...

A56.(PATHO)-PHYSIOLOGY OF THE ALVEOLUS, A2051-A2051 2015

The Critical Roles Of Tumor Necrosis Factor α-Converting Enzyme During Influenza Virus And Streptococcus Pneumoniae Infection In Vivo And In Vitro

S Suzuki, M Ishii, H Namkoong, K Yagi, T Asakura, S Tasaka, T Kamo, ...

A32. MICROBIAL INTERACTIONS AND HOST DEFENSE, A1297-A1297 2015

Successful resumption of tocilizumab for rheumatoid arthritis after resection of a

H Namkoong, S Tasaka, M Akiyama, K Yagi, M Ishii, K Suzuki, M Kohno, ...

2015

Role Of Histone Acetylation In Mice Coinfected With Influenza Virus And Streptococcus Pneumoniae

K Yagi, M Ishii, H Namkoong, T Asami, T Asakura, S Suzuki, H Fujiwara, ...

A21. GENETIC REGULATION OF CHRONIC AIRWAY INFLAMMATION, A1071-A1071 2015

P27-2 左主気管支内腔へ突出する腫瘤を認めた MAC による免疫再構築症候群の一例 (炎症性疾患に対する気管支鏡診断, Poster セッション 27, 第 38 回日本呼吸器内視鏡学会学術集会)

南宮湖，藤原宏，八木一馬，松坂雅子，原口水葉，斎藤史武，石井誠， ...

気管支学 37 (Special), S292 2015

Nationwide Survey on the Epidemiology of Pulmonary Nontuberculous Mycobacterial in Japan

H Namkoong, A Kurashima, K Morimoto, Y Hoshino, N Hasegawa, ...

C105. NONTUBERCULOUS MYCOBACTERIA EPIDEMIOLOGY, A5268-A5268 2015

Levels of Soluble Receptor for Advanced Glycation End Products in Bronchoalveolar Lavage Fluid in Patients with Various Inflammatory Lung Diseases.

Tetsuro Kamo, Sadatomo Tasaka, Yuriko Tokuda, Shoji Suzuki, Takanori Asakura, Kazuma Yagi, Ho Namkoong, Makoto Ishii, Naoki Hasegawa, Tomoko Betsuyaku

Clinical medicine insights. Circulatory, respiratory and pulmonary medicine 9 ( Suppl 1 ) 147 - 54 2015

Accepted

Receptor for advanced glycation end products (RAGE) is a multiligand receptor of S100/calgranulins, high-mobility group box 1, and others, and it is associated with the pathogenesis of various inflammatory and circulatory diseases. The soluble form of RAGE (sRAGE) is a decoy receptor and competitively inhibits membrane-bound RAGE activation. In this study, we measured sRAGE levels in bronchoalveolar lavage fluid (BALF) of 78 patients, including 41 with interstitial pneumonia, 11 with sarcoidosis, 9 with respiratory infection, 7 with ARDS, 5 with lung cancer, and 5 with vasculitis. Among them, sRAGE was detectable in BALF of 73 patients (94%). In patients with ARDS and vasculitis, the sRAGE levels were significantly higher than in the control subjects and those with interstitial pneumonia. The sRAGE levels were positively correlated with total cell counts in BALF and serum levels of surfactant protein-D, lactate dehydrogenase, and C-reactive protein. There was an inverse correlation between PaO2/FIO2 ratio and sRAGE levels. These results indicate that sRAGE in BALF might be considered as a biomarker of lung inflammatory disorders, especially ARDS and vasculitis.

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綜説高齢者に対する肺炎球菌感染症予防戦略-23 価肺炎球菌多糖体ワクチンと 13 価肺炎球菌結合型ワクチン

南宮湖，長谷川直樹

呼吸と循環 63 (8), 754-761 2015

Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease: two case reports.

Kazuma Yagi, Makoto Ishii, Ho Namkoong, Takahiro Asami, Hiroshi Fujiwara, Tomoyasu Nishimura, Fumitake Saito, Yoshifumi Kimizuka, Takanori Asakura, Shoji Suzuki, Tetsuro Kamo, Sadatomo Tasaka, Tohru Gonoi, Katsuhiko Kamei, Tomoko Betsuyaku, Naoki Hasegawa

BMC infectious diseases 14 684 - 684 2014.12

Accepted

BACKGROUND: Pulmonary nocardiosis frequently occurs in immunocompromised hosts and in some immunocompetent hosts with chronic lung disease; however, few reports have described pulmonary nocardiosis with nontuberculous mycobacterial lung infection. Here we report for the first time two cases of pulmonary nocardiosis caused by Nocardia cyriacigeorgica associated with Mycobacterium avium complex (MAC) lung disease caused by M. avium. CASE PRESENTATION: Case 1 is that of a 72-year-old Japanese man with untreated MAC lung disease, who was diagnosed with rheumatoid arthritis and initiated on methotrexate. After 3 years of methotrexate therapy, the patient remained smear-negative and culture-positive for MAC, but also became smear-positive for Nocardia species. He received trimethoprim/sulfamethoxazole, and his symptoms and lung infiltrates improved. Case 2 is that of an immunocompetent 53-year-old Japanese woman with MAC lung disease, who was treated with a combined therapy of clarithromycin, rifampicin, ethambutol, and levofloxacin. MAC sputum culture was negative after 1 year of combined treatment, which was maintained for 2 years. After four treatment-free years, Nocardia species were occasionally isolated from her sputum, although MAC was rarely isolated from sputum cultures over the same period. In both cases, the Nocardia species were identified as the recently defined N. cyriacigeorgica by 16S ribosomal RNA gene sequencing. CONCLUSION: We report two cases of pulmonary nocardiosis caused by N. cyriacigeorgica associated with MAC lung disease caused by M. avium and suggest that N. cyriacigeorgica may be a major infective agent associated with MAC lung disease.

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Serum (1 → 3) β-D-glucan assay for discrimination between Pneumocystis jirovecii pneumonia and colonization.

Sadatomo Tasaka, Seiki Kobayashi, Kazuma Yagi, Takahiro Asami, Ho Namkoong, Wakako Yamasawa, Makoto Ishii, Naoki Hasegawa, Tomoko Betsuyaku

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 20 ( 11 ) 678 - 81 2014.11

Accepted

Polymerase chain reaction (PCR) technique is being increasingly used for the microbiological diagnosis of Pneumocystis pneumonia (PCP). As PCR is highly sensitive, it can be positive even in a patient with Pneumocystis colonization. In this study, we evaluated whether the β-d-glucan assay could be used to differentiate between PCP and Pneumocystis jirovecii colonization in immunocompromised patients with pulmonary infiltrates. We retrospectively evaluated data from 166 consecutive patients who underwent bronchoalveolar lavage for the diagnosis of PCP. Serum levels of β-d-glucan in the negative, colonization, probable PCP, and definite PCP groups were 20.2 ± 6.3, 48.8 ± 15.9, 89.9 ± 20.2, 224.9 ± 25.9 pg/mL, respectively. The β-D-glucan levels in the definite PCP group were significantly higher than those in the other 3 groups (p < 0.001). Serum β-d-glucan levels in patients with either definite or probable PCP (173.1 ± 18.8 pg/mL) were significantly greater than those in patients with colonization who had positive PCR results but improved without anti-PCP treatment (p < 0.002). The cut-off level for discrimination was estimated to be 33.5 pg/mL, with which the positive predictive value was 0.925. These results indicate that β-D-glucan is a useful marker to differentiate between PCP and Pneumocystis colonization. A positive β-D-glucan assay result might be a good indication to begin anti-PCP treatment.

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Pharmacokinetics of arbekacin in bronchial epithelial lining fluid of healthy volunteers.

Yohei Funatsu, Naoki Hasegawa, Hiroshi Fujiwara, Ho Namkoong, Takahiro Asami, Sadatomo Tasaka, Yoshifumi Kimizuka, Hirofumi Kamata, Makoto Ishii, Osamu Iketani, Haruhiko Ogata, Satoshi Iwata, Tomoko Betsuyaku

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 20 ( 10 ) 607 - 11 2014.10

Accepted

INTRODUCTION: Arbekacin is a unique aminoglycoside antibiotic with anti-methicillin-resistant Staphylococcus aureus activity. The efficacy of aminoglycosides is related to their serum maximum concentration. Local concentration of antibiotics in pulmonary epithelial lining fluid, rather than its serum concentration, can help determine its clinical efficacy more precisely for treatment of respiratory infectious disease. The objective of this study was to sequentially measure arbekacin concentration in epithelial lining fluid after infusion of a single clinically available dose. METHOD: After the initial blood sampling, arbekacin was intravenously infused into 6 healthy volunteers over 1 h. Epithelial lining fluid and serum samples were collected by bronchoscopic microsampling 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h after the start of 200 mg arbekacin infusion. RESULTS: Each probe sampled 10.1 ± 5.2 μl bronchial epithelial lining fluid. The sample dilution factor was 266.7 ± 157.1. Drug concentration was successfully measured in all but 2 of the epithelial lining fluid samples. The maximum concentration of arbekacin in epithelial lining fluid and serum was 10.4 ± 1.9 μg/ml and 26.0 ± 12.2 μg/ml, respectively. The ratio of the maximum drug concentration in the epithelial lining fluid to that in the serum was 0.47 ± 0.19. CONCLUSIONS: The maximum concentration of epithelial lining fluid reached levels that would effectively treat most clinical strains of methicillin-resistant S. aureus.

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The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly.

Ho Namkoong, Youjyu Kameyama, Hiroyuki Yasuda, Sohei Nakayama, Hiroshi Kaneko, Chieko Kawashima, Tomoko Terajima, Kayoko Maezawa, Takeshi Hayashi, Mitsuru Sandoh, Makoto Ishii, Sadatomo Tasaka, Akiko Kanayama, Intetsu Kobayashi, Tomoko Betsuyaku, Junko Kizu, Satoshi Iwata, Yoshitake Sato, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 20 ( 6 ) 356 - 60 2014.06

Accepted

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients.

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A51 NEW INSIGHTS INTO PATHOGENS AND HOST DEFENSE: Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired Ifn-Beta Induction In Mice

H Namkoong, M Ishii, H Fujii, T Asami, K Yagi, F Saito, H Fujiwara, ...

American Journal of Respiratory and Critical Care Medicine 189, 1 2014

Clinical And Bacteriological Evaluations During Observation Of Mycobacterium Avium Complex Lung Disease Without Treatment

Y Kimizuka, M Ishii, Y Hoshino, T Asami, T Nishimura, S Maeda, S Tasaka, ...

C30. LATE BREAKING ABSTRACTS IN DISEASE TREATMENT AND CLINICAL OUTCOMES … 2014

CLARITHROMYCIN EXPANDS CD11B+ GR-1+ CELLS TO PROTECT AGAINST LPS-INDUCED LETHAL SHOCK

H Namkoong, M Ishii, H Fujii, T Asami, K Yagi, H Fujiwara, F Saitoh, ...

SHOCK 41, 18-18 2014

C30 LATE BREAKING ABSTRACTS IN DISEASE TREATMENT AND CLINICAL OUTCOMES: Clinical And Bacteriological Evaluations During Observation Of Mycobacterium Avium Complex Lung Disease …

Y Kimizuka, M Ishii, Y Hoshino, T Asami, T Nishimura, S Maeda, S Tasaka, ...

American Journal of Respiratory and Critical Care Medicine 189, 1 2014

B60 POTPOURRI OF INJ-OURRI: NON-EPITHELIAL CONTRIBUTIONS TO LUNG INJURY AND REPAIR: Critical Roles Of Enhancer Of Zeste Homolog 2 (ezh2) During Influenza A Virus Infection

K Yagi, M Ishii, H Namkoong, T Asami, H Fujiwara, T Nishimura, F Saito, ...

American Journal of Respiratory and Critical Care Medicine 189, 1 2014

Critical Roles Of Enhancer Of Zeste Homolog 2 (ezh2) During Influenza A Virus Infection

K Yagi, M Ishii, H Namkoong, T Asami, H Fujiwara, T Nishimura, F Saito, ...

B60. POTPOURRI OF INJ-OURRI: NON-EPITHELIAL CONTRIBUTIONS TO LUNG INJURY AND … 2014

Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired Ifn-Beta Induction In Mice

H Namkoong, M Ishii, H Fujii, T Asami, K Yagi, F Saito, H Fujiwara, ...

A51. NEW INSIGHTS INTO PATHOGENS AND HOST DEFENSE, A1713-A1713 2014

SHOCK SOCIETY THIRTY-SEVENTH ANNUAL CONFERENCE ON SHOCK

G Promenade, G ABC, M West, J Cuschieri, J Pessin, C Kolka, ...

2014

[Case report; A case of acute respiratory failure following influenza virus infection successfully treated by direct hemoperfusion using a polymyxin B immobilized fiber column].

Daisuke Arai, Koichi Fukunaga, Kentaro Fujii, Ho Namkoong, Mizuha Haraguchi, Yohei Funatsu, Katsuhiko Naoki, Sadatomo Tasaka, Tomoko Betsuyaku

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 ( 2 ) 429 - 32 2013.02

Accepted, ISSN 0021-5384

Case report; A case of acute respiratory failure following influenza virus infection successfully treated by direct hemoperfusion using a polymyxin B immobilized fiber column

D Arai, K Fukunaga, K Fujii, H Namkoong, M Haraguchi, Y Funatsu, ...

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal … 2013

Clarithromycin Expands CD11b+ Gr-1+ Cells To Protect Against LPS-Induced Lethal Shock And Polymicrobial Sepsis

H Namkoong, M Ishii, H Fujii, T Asami, K Yagi, Y Funatsu, H Fujiwara, ...

C22. NEW INSIGHTS INTO ACUTE LUNG INJURY, A3856-A3856 2013

Diet-Induced Obesity Modulates The Macrophage Response To Influenza Virus Infection

T Nakagawa, M Ishii, H Namkoong, H Fujii, T Asami, K Yagi, F Saito, ...

A50. ADVANCES IN UNDERSTANDING OF INFECTIOUS IMMUNOLOGY IN VIRAL DISEASES … 2013

Effects Of Histone Deacetylase Inhibitor Trichostatin A During Influenza A Virus Infection In Vivo And In Vitro

K Yagi, M Ishii, H Fujii, K Mizoguchi, H Namkoong, T Asami, Y Funatsu, ...

D31. RESPIRATORY TRACT INFECTION AND INFLAMMATION: FROM ANIMAL MODELS TO … 2013

In Vitro Effect Of 14-Hydroxy Clarithromycin, A Major Metabolite Of Clarithromycin, On Cytokine Expressions In Murine Macrophages And Dendritic Cells During Influenza A Virus …

Y Matsui, M Ishii, H Namkoong, H Fujii, T Asami, K Yagi, F Saito, ...

A50. ADVANCES IN UNDERSTANDING OF INFECTIOUS IMMUNOLOGY IN VIRAL DISEASES … 2013

The Efficacy Of Amikacin In Combination With Standard Regimen To Patients With Nontuberculous Mycobacterial Infection

H Tanaka, Y Funatsu, H Namkoong, K Yagi, T Asami, H Fujiwara, ...

C106. ADVANCES IN NON-TUBERCULOUS MYCOBACTERIAL DISEASE, A5117-A5117 2013

Retrospective observation of mycobacterium avium complex lung disease followed without treatment

Y Kimizuka, T Asami, M Ishii, S Tasaka, H Namkoong, H Fujiwara, ...

European Respiratory Journal 42 (Suppl 57) 2013

Research Article Modulation of Murine Macrophage TLR7/8-Mediated Cytokine Expression by Mesenchymal Stem Cell-Conditioned Medium

T Asami, M Ishii, H Fujii, H Namkoong, S Tasaka, K Matsushita, K Ishii, ...

2013

Penetration and pharmacokinetics of peramivir in upper and lower airway epithelia and plasma

Y Funatsu, N Hasegawa, H Namkoong, T Asami, H Fujiwara, Y Kimizuka, ...

European Respiratory Journal 42 (Suppl 57) 2013

P8 Prostaglandin D2 receptor CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis

M Ishii, K Asano, H Namkoong, S Tasaka, J Miyata, S Kagawa, ...

International Journal of Antimicrobial Agents, S43 2013

P298 Clinical and radiological features of Mycobacterium avium complex lung disease observed without chemotherapy

Y Kimizuka, T Asami, M Ishii, S Tasaka, H Namkoong, H Fujiwara, ...

International Journal of Antimicrobial Agents, S136 2013

P24 Pharmacokinetics of peramivir in upper and lower airway epithelia and plasma

Y Funatsu, N Hasegawa, H Namkoong, T Asami, H Fujiwara, Y Kimizuka, ...

International Journal of Antimicrobial Agents, S48-S49 2013

P1-2-4 上気道及び下気道におけるペラミビルの薬物動態 (合併症・安全対策-1, 一般演題ポスター, 第 36 回日本呼吸器内視鏡学会学術集会)

舩津洋平，長谷川直樹，南宮湖，浅見貴弘，藤原宏，君塚善文，田坂定智， ...

気管支学 35 (Special), S194 2013

Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium.

Takahiro Asami, Makoto Ishii, Hideki Fujii, Ho Namkoong, Sadatomo Tasaka, Kenichi Matsushita, Ken Ishii, Kazuma Yagi, Hiroshi Fujiwara, Yohei Funatsu, Naoki Hasegawa, Tomoko Betsuyaku

Mediators of inflammation 2013 264260 - 264260 2013

Accepted

Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor- κ B (NF- κ B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF- κ B signaling contributed to the low production of TNF- α . Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection.

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Mesenchymal Stem Cell-Conditioned Medium Modulates Murine Macrophage Cytokine Expression Induced By Tlr7/8 Ligand Stimulation And Influenza A Virus Infection

T Asami, M Ishii, H Fujii, H Namkoong, K Yagi, Y Funatsu, Y Kimizuka, ...

D28. MAKING REPARATIONS: MESENCHYMAL STEM CELLS AND FIBROCYTES IN LUNG … 2013

インフルエンザウイルス感染後の急性呼吸不全に併発した敗血症性ショックに対してポリミキシン B 固定化線維カラムによる直接血液灌流療法が奏効した 1 例

荒井大輔，福永興壱，藤井健太郎，南宮湖，原口水葉，舩津洋平， ...

日本内科学会雑誌 102 (2), 429-432 2013

Cytokine profile of bronchoalveolar lavage fluid in patients with combined pulmonary fibrosis and emphysema.

Sadatomo Tasaka, Kosuke Mizoguchi, Yohei Funatsu, Ho Namkoong, Wakako Yamasawa, Makoto Ishii, Naoki Hasegawa, Tomoko Betsuyaku

Respirology (Carlton, Vic.) 17 ( 5 ) 814 - 20 2012.07

Accepted

BACKGROUND AND OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper lobe emphysema together with lower lobe fibrosis. The aim of this study was to examine whether cytokine levels in the alveolar space are associated with emphysematous changes superimposed on pulmonary fibrosis. METHODS: Consecutive patients (n = 102), diagnosed with pulmonary fibrosis were retrospectively evaluated. Cytokine levels and differential cell counts in bronchoalveolar lavage (BAL) fluid, pulmonary function, computed tomography (CT) scores and levels of serum markers were compared between patients with or without emphysema. RESULTS: Among the 102 patients (14 females, mean age 68 years), 38 (37%) had evidence of upper lobe emphysema on computed tomography (CT). Levels of epithelial neutrophil activating peptide 78 (ENA-78/CXCL5) and interleukin (IL)-8/CXCL8 in BAL fluid were significantly higher in patients with emphysema. Vital capacity (VC, % predicted) was greater, and ratio of forced expiratory volume in 1 s/forced vital capacity and diffusing capacity of carbon monoxide (DL(CO))/alveolar volume (V(A)) were lower in patients with emphysema. CXCL8 and CXCL5 levels were associated with percentage or absolute numbers of neutrophils in BAL fluid. In addition, CXCL8 levels were inversely correlated with VC and DL(CO)/V(A), and positively correlated with composite physiological index (CPI) and the extent of areas of low attenuation on CT. CONCLUSIONS: Increased CXC chemokine levels in the airspaces may be associated with emphysematous lung changes in patients with pulmonary fibrosis.

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CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis.

Makoto Ishii, Koichiro Asano, Ho Namkoong, Sadatomo Tasaka, Kosuke Mizoguchi, Takahiro Asami, Hirofumi Kamata, Yoshifumi Kimizuka, Hiroshi Fujiwara, Yohei Funatsu, Shizuko Kagawa, Jun Miyata, Ken Ishii, Masataka Nakamura, Hiroyuki Hirai, Kinya Nagata, Steven L Kunkel, Naoki Hasegawa, Tomoko Betsuyaku

Journal of immunology (Baltimore, Md. : 1950) 188 ( 11 ) 5655 - 64 2012.06

Accepted

Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2(-/-)) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2(-/-) mice, blunting CLP-induced lethality in CRTH2(-/-) mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2(-/-) mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2(-/-) mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.

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Clarithromycin Modulates Cytokine Expression Profiles In Murine Macrophages And Dendritic Cells During Influenza A Virus Infection

M Wakatabe, M Ishii, H Namkoong, H Fujii, T Asami, Y Funatsu, ...

D36. INFLUENCES AND OUTCOMES OF RESPIRATORY VIRAL INFECTIONS, A5718-A5718 2012

Clinical Characteristics Of Late-Onset Idiopathic Pneumonia Syndrome With Severe Restrictive Lung Deficit After Hematopoietic Stem Cell Transplantation

H Namkoong, M Ishii, S Tasaka, N Hasegawa, H Sugiura, M Sakurai, ...

C47. TOPICS IN TRANSPLANT MEDICINE, A4473-A4473 2012

Cytokine profiles of bronchoalveolar lavage fluid in patients with combined pulmonary fibrosis and emphysema

S Tasaka, K Mizoguchi, Y Funatsu, H Namkoong, W Yamasawa, M Ishii, ...

European Respiratory Journal 40 (Suppl 56) 2012

Evaluation of cytokines and chemokines in bronchoalveolar lavage fluid of patients with collagen vascular disease-associated interstitial pneumonitis

Y Tokuda, S Tasaka, H Namkoong, T Asami, Y Funatsu, Y Kimizuka, ...

D104. CONNECTIVE TISSUE DISEASE RELATED-INTERSTITIAL LUNG DISEASE: CLINICAL … 2012

Modulatory Roles Of Mesenchymal Stem Cell-Conditioned Media On Cytokine Expressions In Murine Macrophages And Dendritic Cells During Influenza A Virus Infection

T Asami, M Ishii, H Fujii, H Namkoong, Y Funatsu, Y Kimizuka, S Tasaka, ...

D36. INFLUENCES AND OUTCOMES OF RESPIRATORY VIRAL INFECTIONS, A5713-A5713 2012

A clustering based schema matching scheme for improving matching correctness of web service interfaces

Byoungoh Kim, Namkoong Ho, Dongman Lee, Soon J. Hyun

Proceedings - 2011 IEEE International Conference on Services Computing, SCC 2011 488 - 495 2011

An interface adapter is used to allow a client application to transparently work with a service available in the local environment by converting the interface of an originally requested service into that of the available service. To generate adapters for users, interface matching is the first job to find out all the possible method matching pairs between a source interface and a target interface. Existing method matching schemes compare the schemas of source and target interfaces but they have low recall and precision because they only consider signatures and names of interfaces. For solving these problems, we propose a cluster-based schema matching scheme. By clustering methods in terms of parameter similarity, the proposed scheme can match methods more precisely than existing schema matching schemes. Then, we detect incorrect matches based on the analysis of incorrect method matching pairs. © 2011 IEEE.

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Critical Roles Of Prostaglandin D2 Receptor CRTH2 In A Mice Model Of Polymicrobial Sepsis

M Ishii, N Hasegawa, K Mizoguchi, H Namkoong, S Kagawa, ...

B104. TRANSLATING SEPSIS: EPIDEMIOLOGY TO MECHANISMS, A3866-A3866 2011

Diagnostic value of bronchoalveolar lavage and lymphocyte transformation test in drug-induced lung disease

Y Kimizuka, S Tasaka, W Yamasawa, M Ishii, H Kamata, H Fujiwara, ...

European Respiratory Journal 38 (Suppl 55) 2011

P19-4 薬剤性肺障害における末梢血リンパ球幼弱化反応および気管支肺胞洗浄液所見の比較検討 (びまん性/BAL, ポスター 19, 第 34 回日本呼吸器内視鏡学会学術集会)

君塚善文，田坂定智，山澤稚子，石井誠，鎌田浩史，藤原宏，舩津洋平， ...

気管支学 33 (Special), S270 2011

The Comparison Of Clinical Outcome Between Clarithromycin Resistant And Sensitive Mycobacterium Avium Complex Pulmonary Disease

H Namkoong, N Hasegawa, Y Kimizuka, S Tasaka, M Ishii, H Kamata, ...

A105. NONTUBERCULOUS MYCOBACTERIA: PATHOPHYSIOLOGY TO TREATMENT, A2405-A2405 2011

PROSTAGLANDIN D2 RECEPTOR CRTH2 IS A CRITICAL REGULATOR IN A MICE MODEL OF POLYMICROBIAL SEPSIS

M Ishii, K Asano, H Namkoong, S Kagawa, M Nakamura, H Hirai, ...

SHOCK 35, 7-7 2011

Effects of Agaricus blazei Murill extract on sensitivity to chemotherapeutic agents in HeLa cells and its resistant sublines

K Takara, Y Shin, Y Obata, N Kitada, N Ohnishi, T Yokoyama

Journal of dietary supplements 5 (3), 283-292 2008

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