Details of a Researcher - Asakura, Takanori

Papers - Asakura, Takanori

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Direct reprogramming of mouse fibroblasts into self-renewable alveolar epithelial-like cells.

Atsuho Morita, Makoto Ishii, Takanori Asakura, Masaya Yotsukura, Ahmed E Hegab, Tatsuya Kusumoto, Ho Namkoong, Takunori Ogawa, Yuhki Nakatake, Mayumi Oda, Fumitake Saito, Hirofumi Kamata, Junko Hamamoto, Satoshi Okamori, Toshiki Ebisudani, Hiroyuki Yasuda, Shinya Sugimoto, Yuta Kuze, Masahide Seki, Yutaka Suzuki, Naoki Hasegawa, Hisao Asamura, Hideo Watanabe, Minoru Ko, Toshiro Sato, Masaki Ieda, Koichi Fukunaga

NPJ Regenerative medicine 10 ( 1 ) 30 - 30 2025.12

Direct reprogramming is a breakthrough technology that can alter the fate of cells without the passage of stem cells. However, direct reprogramming of somatic cells into pulmonary alveolar epithelial cells has not yet been achieved. Here, we report the direct reprogramming of mouse tail tips and embryonic fibroblasts into induced pulmonary alveolar epithelial-like cells (iPULs) using four transcription factor-coding genes (Nkx2-1, Foxa1, Foxa2, and Gata6) and three-dimensional culture. The iPULs showed lamellar body-like structures and displayed key properties of pulmonary alveolar epithelial cells. Although the potential for iPULs to morphologically differentiate into alveolar epithelial type 1 cells was limited in vitro, the intratracheal administration of iPULs in a bleomycin-induced mouse model of pulmonary fibrosis led to their integration into the alveolar surface, where they formed both alveolar epithelial type 1 and type 2-like cells. Thus, reprogrammed fibroblasts may represent a new source of pulmonary alveolar epithelial cells for regenerative medicine.

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Predicting coronavirus disease 2019 severity using explainable artificial intelligence techniques

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

Scientific Reports (Springer Science and Business Media LLC) 15 ( 1 ) 9459 - 9459 2025.12

Predictive models for determining coronavirus disease 2019 (COVID-19) severity have been established; however, the complexity of the interactions among factors limits the use of conventional statistical methods. This study aimed to establish a simple and accurate predictive model for COVID-19 severity using an explainable machine learning approach. A total of 3,301 patients ≥ 18 years diagnosed with COVID-19 between February 2020 and October 2022 were included. The discovery cohort comprised patients whose disease onset fell before October 1, 2020 (N = 1,023), and the validation cohort comprised the remaining patients (N = 2,278). Pointwise linear and logistic regression models were used to extract 41 features. Reinforcement learning was used to generate a simple model with high predictive accuracy. The primary evaluation was the area under the receiver operating characteristic curve (AUC). The predictive model achieved an AUC of ≥ 0.905 using four features: serum albumin levels, lactate dehydrogenase levels, age, and neutrophil count. The highest AUC value was 0.906 (sensitivity, 0.842; specificity, 0.811) in the discovery cohort and 0.861 (sensitivity, 0.804; specificity, 0.675) in the validation cohort. Simple and well-structured predictive models were established, which may aid in patient management and the selection of therapeutic interventions.

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Impact of long COVID on the health-related quality of life of Japanese patients: A prospective nationwide cohort study.

Kazuma Yagi, Masahiro Kondo, Hideki Terai, Takanori Asakura, Ryusei Kimura, Ryo Takemura, Hiromu Tanaka, Keiko Ohgino, Katsunori Masaki, Ho Namkoong, Shotaro Chubachi, Jun Miyata, Ichiro Kawada, Tatsuya Kaido, Shuko Mashimo, Keigo Kobayashi, Toshiyuki Hirano, Ho Lee, Kai Sugihara, Nao Omori, Mayuko Watase, Takao Mochimaru, Ryosuke Satomi, Yasushi Makino, Takashi Inoue, Koichi Sayama, Yoshitaka Oyamada, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

Respiratory investigation 63 ( 4 ) 610 - 616 2025.07

ISSN 22125345

BACKGROUND: Various prolonged systemic symptoms, forming the long coronavirus disease (COVID), have been observed in patients who have recovered from the acute phase of COVID-19. Although previous studies have reported that COVID-19 impacts health-related quality of life (HRQoL), the associations of long COVID symptoms and clinical characteristics with HRQoL remain unclear. This study aimed to clarify these associations using nationwide Japanese epidemiological data. METHODS: A prospective nationwide cohort study was conducted on patients with COVID-19 between January 2020 and February 2021 at 26 participating medical institutions in Japan. Various long COVID symptoms and HRQoL scores at 3, 6, and 12 months following diagnosis were collected from 986 participants. Generalized estimating equations (GEE) were used to explore the association between HRQoL scores evaluated using the short form-8 (SF-8), long COVID symptoms, and baseline clinical characteristics. RESULTS: Patients who had one long COVID symptom showed a significantly lower physical component summary score (PCS) and mental component summary score (MCS) compared with those without any symptoms at all time points after diagnosis. GEE revealed that long COVID symptoms, including dyspnea, fatigue, headache, and muscle weakness, were significantly associated with worse PCS, whereas poor concentration, sleep disorders, fatigue, and headache were significantly associated with worse MCS. Severity-related baseline parameters for patients with COVID-19 were significantly associated with worse PCS scores, although these factors were not significantly associated with worse MCS scores. CONCLUSIONS: Long COVID symptoms were associated with lower physical and mental HRQoL. Severe outcomes of COVID-19 impacted PCS but not MCS.

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Sectm1a Depletion Promotes Neutrophil Recruitment during Pneumococcal Pneumonia

Hiromu Tanaka, Hirofumi Kamata, Makoto Ishii, Takanori Asakura, Ho Namkoong, Kensuke Nakagawara, Atsuho Morita, Tatsuya Kusumoto, Shuhei Azekawa, Masanori Kaji, Genta Nagao, Naoki Fukunaga, Tomoyasu Nishimura, Keisuke Asakura, Naoki Hasegawa, Koichi Fukunaga

American Journal of Respiratory Cell and Molecular Biology 73 ( 1 ) 60 - 72 2025.07

ISSN 10441549

Airway epithelial cells (AECs) play an essential role in the immune response during bacterial pneumonia. Secreted and transmembrane 1a (Sectm1a) is specifically expressed in AECs during early Streptococcus pneumoniae (SP) infection. However, its function remains largely unexplored. Here, we aimed to clarify the function of Sectm1a during serotype 3 pneumococcal pneumonia primarily using an in vivo mouse model. Our findings showed that type Ⅰ interferons (IFNs) directly induced Sectm1a expression in AECs. Sectm1a depletion in an in vivo mouse model improved survival rate and enhanced the clearance of intrapulmonary bacterial burden at an early stage of SP infection. Correspondingly, Sectm1a depletion increased the count of intrapulmonary γδT cells, promoted IL-17A production by these cells, and enhanced intrapulmonary neutrophil responses against SP. Notably, IL-17A production in the isolated lung γδT cells was directly suppressed by Sectm1a ex vivo. Furthermore, Sectm1a depletion altered the migration and activation markers of γδT cells in vivo, indicating that the AEC-derived Sectm1a is associated with the phenotypes of γδT cells. These findings suggest that type Ⅰ IFNs may play an important role via AEC-derived Sectm1a in this model, and Sectm1a signaling modulates excessive neutrophil inflammation and influences bacterial clearance by directly altering γδT cell functions during pneumococcal pneumonia. In summary, this study demonstrates that the type Ⅰ IFN-Sectm1a pathway could be a potential target to modify the acute response to bacterial pneumonia.

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STAT3-dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome.

Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther Jr, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Eszter Vladar, Wanda K O'Neal, Richard C Boucher Jr, Gang Chen

American journal of respiratory and critical care medicine 2025.05

RATIONALE: Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense. OBJECTIVES: To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES. METHODS: STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology; and bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR/Cas9), were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1β)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. MEASUREMENTS AND MAIN RESULTS: STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 mutations reduced CFTR mRNA and protein levels, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and post-IL1β exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a γ-secretase inhibitor restored HES6 expression, improved ciliogenesis in STAT3 R382W mutant cells. CONCLUSIONS: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.

Impact of smoking on gut microbiota and short-chain fatty acids in human and mice: Implications for COPD

Shiro Otake, Shotaro Chubachi, Junki Miyamoto, Yuri Haneishi, Tetsuya Arai, Hideto Izuka, Takashi Shimada, Kaori Sakurai, Shinichi Okuzumi, Hiroki Kabata, Takanori Asakura, Jun Miyata, Junichiro Irie, Koichiro Asano, Hidetoshi Nakamura, Ikuo Kimura, Koichi Fukunaga

Mucosal Immunology (Elsevier BV) 18 ( 2 ) 353 - 365 2025.04

Accepted, ISSN 19330219

We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.

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Intermittent versus Daily Therapy for Noncavitary Mycobacterium avium Complex Pulmonary Disease: An Open-label Randomized Trial

Taku Nakagawa, Kohei Fujita, Mari Miki, Akihiro Ito, Ho Namkoong, Takanori Asakura, Kozo Morimoto, Naoki Hasegawa, Toshiyuki Kita, Akira Watanabe, Kazunari Tsuyuguchi, Masahiro Kawashima, Ayako Shiozawa, Satoru Watanabe, Atsuo Sato, Tatsuo Kato, Yoshifumi Kimizuka, Hiroaki Harada, Kaori Fujita, Akiko M Saito, Hiroya Hashimoto, Yoshikazu Inoue, Kenji Ogawa

Annals of the American Thoracic Society 2025.03

Rationale: Patients with noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex pulmonary disease (MAC-PD) are treated intermittently three times a week, although no randomized controlled trials have been conducted comparing three times weekly to daily therapy. Objectives: To assess the tolerability, safety, and efficacy of intermittent versus daily treatment in patients with previously untreated noncavitary NB MAC-PD Methods: In an open-label study, patients were randomly assigned to the intermittent therapy group receiving clarithromycin 1000 mg, rifampicin 600 mg, and ethambutol 25 mg/kg (maximum 1000 mg) three days a week, or the daily therapy group receiving clarithromycin 800 mg, rifampicin 450 mg, and ethambutol 15 mg/kg (maximum 750 mg) daily for one year. The primary endpoint was the proportion of patients requiring modification of the initial treatment regimen. Results: Twenty-one Japanese hospitals participated in the study, enrolling 141 patients between May 2019 and December 2021. The full analysis set included 138 participants (intermittent therapy = 70; daily therapy = 68). There were no significant differences between the intermittent and daily therapy groups in terms of the regimen modification rate (20.0% (14/70) versus 33.8% (23/68); adjusted odds ratio 0.48, 95% confidence interval 0.22 to 1.05; p=0.06) or culture conversion (70.3% vs. 80.0%, p=0.53), time to culture conversion (28.0 vs. 28.5 days, p=0.89), improvement in chest CT findings (60.9% vs. 71.0%, p=0.30), or clarithromycin resistance development (1.4% vs. 0%, p=1.00). Elevated AST (16.9% vs. 41.2%, p=0.003) and ALT (18.3% vs. 44.1%, p=0.002) were more common in the daily treatment group, while elevated bilirubin (11.3% vs. 1.5%, p=0.04) and dysgeusia (14.1% vs. 1.5%, p=0.01) were more common in the intermittent treatment group. The daily treatment group exhibited a greater absolute change in the 36-Item Short Form Survey physical aspect score (-2.5 points) than the intermittent treatment group (2.1 points) (p=0.01). Conclusion: Intermittent treatment was not significantly better tolerated than daily treatment for noncavitary NB MAC-PD. However, further studies with larger numbers of patients are needed. Clinical trial registration available at: https://jrct.niph.go.jp/en-top. ID: jRCTs031190008.

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Coronary Artery Calcification on Chest Computed Tomography as a Predictor of Cardiovascular Adverse Events in Patients With COVID-19 ― A Multicenter Retrospective Study in Japan ―

Mayuko Watase, Yusuke Shiraishi, Shotaro Chubachi, Naoya Tanabe, Tomoki Maetani, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Takashi Shimada, Shuhei Azekawa, Shiro Otake, Takahiro Fukushima, Kensuke Nakagawara, Katsunori Masaki, Hideki Terai, Takao Mochimaru, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Circulation Journal (Japanese Circulation Society) 89 ( 3 ) 373 - 381 2025.03

ISSN 13469843

BACKGROUND: Coronary artery calcification (CAC) detected through chest computed tomography (CT) strongly predicts cardiovascular events in asymptomatic individuals undergoing primary prevention. Few studies with limited sample sizes have investigated the predictive value of CAC for cardiovascular complications in COVID-19. This study examined the impact of CAC on cardiovascular complications using a large-scale COVID-19 database. METHODS AND RESULTS: This multicenter retrospective cohort study used data from the Japan COVID-19 Task Force database. After exclusion based on missing information, 1,109 patients with COVID-19 were included. The Agatston score was used to evaluate CAC, dividing the population into 3 groups based on calcification degree (no, moderate, and severe CAC). The primary outcome was cardiovascular complications; the secondary outcome was critical outcomes. The severe CAC group had a higher rate of cardiovascular complications than the other groups. Multivariable analysis, considering COVID-19 severity factors, identified severe CAC as independently associated with cardiovascular complications but not with critical outcomes. Subgroup analysis revealed that, in patients without hypertension, diabetes, cardiovascular disease, or chronic kidney disease, severe CAC was significantly correlated with cardiovascular complications, whereas this association was not observed in patients with these underlying conditions. CONCLUSIONS: Patients with COVID-19 and severe CAC had increased cardiovascular complications, and identifying cardiovascular and pulmonary findings on chest CT is essential. Measuring CAC via non-electrocardiogram-gated CT helps predict patient risk.

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The relationship between long COVID, labor productivity, and socioeconomic losses in Japan: A cohort study

Shunichiro Konishi, Katsunori Masaki, Kyoko Shimamoto, Yoko Ibuka, Rei Goto, Ho Namkoong, Shotaro Chubachi, Hideki Terai, Takanori Asakura, Jun Miyata, Shuhei Azekawa, Kensuke Nakagawara, Hiromu Tanaka, Atsuho Morita, Norihiro Harada, Hitoshi Sasano, Ai Nakamura, Yu Kusaka, Takehiko Ohba, Yasushi Nakano, Kazumi Nishio, Yukiko Nakajima, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Koichi Fukunaga

IJID Regions (Elsevier BV) 14 100495 - 100495 2025.03

ISSN 2772-7076

OBJECTIVES: We examined shifts in labor productivity and their economic ramifications among adult patients with long COVID in Japan. METHODS: A total of 396 patients were categorized into three groups based on symptom progression: non-long COVID, long COVID recovered, and long COVID persistent. Patient-reported outcomes were assessed at three time intervals: 3, 6, and 12 months after COVID-19 diagnosis. Labor productivity was gauged through presenteeism and absenteeism, measured using the World Health Organization Health and Work Performance Questionnaire. RESULTS: Long COVID was observed in 52.7% of patients, and 29.3% of all the patients continued to experience long COVID symptoms 1 year after diagnosis. At all three time points (3, 6, and 12 months after diagnosis), the long COVID persistent group showed a statistically significant difference in absolute presenteeism compared with the non-long COVID and long COVID recovered groups (P <0.01). Economic loss owing to decrease in labor productivity was calculated as $21,659 per year in the long COVID persistent group and $9008 per year in the long COVID recovered group (P <0.01). CONCLUSION: The study's results revealed a notable decline in labor productivity over time, underscoring the importance of early detection and intervention to mitigate the socio-economic repercussions of long COVID, in addition to its health implications.

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Erector Spinae Muscle to Epicardial Visceral Fat Ratio on Chest CT Predicts the Severity of Coronavirus Disease 2019

Takashi Shimada, Tomoki Maetani, Shotaro Chubachi, Naoya Tanabe, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Mayuko Watase, Yusuke Shiraishi, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Kaoruko Shimizu, Susumu Sato, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Journal of Cachexia, Sarcopenia and Muscle (Wiley) 16 ( 1 ) e13721 2025.02

ISSN 21905991

ABSTRACT

Background

Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID‐19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID‐19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID‐19.

Methods

We analysed data from 1074 COVID‐19 patients enrolled in the Japan COVID‐19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high‐flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios.

Results

The low ESM/EAT group (n = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, p < 0.001) and mortality (2.55% vs. 0.69%, p = 0.019) than the high ESM/EAT group (n = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22–3.66) independently of the known COVID‐19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle‐related comorbidities and pneumonia volume.

Conclusion

The low ESM/EAT ratio in COVID‐19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID‐19 practice.

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Long COVID among the first three waves of COVID-19 in Japan: a multicentre cohort study.

Hatsuyo Takaoka, Ichiro Kawada, Gaku Hiruma, Kengo Nagashima, Hideki Terai, Noriyuki Ishida, Ho Namkoong, Takanori Asakura, Katsunori Masaki, Jun Miyata, Shotaro Chubachi, Keiko Ohgino, Kengo Otsuka, Naoki Miyao, Toshio Odani, Mayuko Watase, Rie Baba, Satoshi Okamori, Daisuke Arai, Ichiro Nakachi, Naota Kuwahara, Akiko Fujiwara, Takenori Okada, Takashi Ishiguro, Taisuke Isono, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

BMJ open respiratory research 11 ( 1 ) 2024.12

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 significantly impacts Japan with a high number of infections and deaths reported. Long coronavirus disease (COVID) characterised by persistent symptoms after COVID-19 has gained recognition but varies across studies. This study aimed to investigate the differences in long COVID among patients hospitalised during Japan's first three waves of the pandemic. DESIGN: Multicentre prospective cohort study. SETTING: 26 medical facilities across Japan between February 2020 and February 2021. PARTICIPANTS: In total, 1066 hospitalised patients diagnosed with COVID-19 were included with 206, 301 and 559 patients in the first, second and third waves, respectively. Data were collected using electronic data capture and patient-reported outcome forms. PRIMARY AND SECONDARY OUTCOME MEASURES: Long COVID was assessed at 3, 6 and 12 months after COVID-19 diagnosis. RESULTS: Significant differences were observed between the waves in various baseline and clinical characteristics such as age, body mass index (BMI), comorbidities, the severity of COVID-19, complications and treatment during hospitalisation. Long COVID, particularly dyspnoea, was most prevalent in the first wave. Multivariate logistic regression analysis confirmed a significant positive association between the first wave and long COVID including dyspnoea after adjusting for age, sex, BMI, smoking status and COVID-19 severity. CONCLUSIONS: Patients hospitalised during the first wave had a higher risk of experiencing long COVID, especially dyspnoea, than those hospitalised during the other waves. These findings underscore the need for continued monitoring and managing long COVID in COVID-19 survivors, particularly in those hospitalised during the first wave. TRIAL REGISTRATION NUMBER: UMIN000042299.

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Corrigendum to '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' [IJID 128 (2023) 121-127].

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 151 107322 - 107322 2024.12

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Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19.

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

BMC infectious diseases 24 ( 1 ) 527 - 527 2024.12

BACKGROUND: Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes. METHODS: This retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression. RESULTS: The prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03-1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36-2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64-4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08-3.23, P = 0.025) only. CONCLUSIONS: Clinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

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The first Japanese case of autosomal dominant cutis laxa with a frameshift mutation in exon 30 of the elastin gene complicated by small airway disease with 8 years of follow-up.

Masanori Kaji, Ho Namkoong, Shotaro Chubachi, Hiromu Tanaka, Takanori Asakura, Mizuha Haraguchi Hashiguchi, Mamiko Yamada, Tomoko Uehara, Hisato Suzuki, Naoya Tanabe, Yoshitake Yamada, Taiki Nozaki, Takeshi Ouchi, Atsutoshi Tsuji, Kenjiro Kosaki, Naoki Hasegawa, Koichi Fukunaga

BMC pulmonary medicine 24 ( 1 ) 481 - 481 2024.12

BACKGROUND: Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear. CASE PRESENTATION: A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests (expiratory volume in one second (FEV1)/forced vital capacity (FVC): 34.85%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%). Pulmonary function tests also indicated small airway disease (%FEF50%, 7.9%; %FEF75%, 5.7%; and %FEF25-75%, 6.8%). Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene (ELN). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD) from 37.84% to 46.61% over the 8-year follow-up, despite the absence of overt changes in CT findings, specifically the lack of normal increase in lung attenuation on expiratory CT scan. Over the same follow-up interval, there was a modest reduction of 25.6 mL/year in FEV1 coupled with a significant increase in %RV. Pulmonary function test metrics, reflective of small airway disease, exhibited a continual decline; specifically, %FEF50%, %FEF75%, and %FEF25-75% diminished from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively. CONCLUSIONS: This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN, accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a mild reduction in FEV1. These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs.

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Chronic obstructive pulmonary disease, asthma, and mechanical ventilation are risk factors for dyspnea in patients with long COVID: A Japanese nationwide cohort study.

Emiko Matsuyama, Jun Miyata, Hideki Terai, Naoki Miyazaki, Toshiki Iwasaki, Kengo Nagashima, Mayuko Watase, Keeya Sunata, Ho Namkoong, Takanori Asakura, Katsunori Masaki, Shotaro Chubachi, Keiko Ohgino, Ichiro Kawada, Kazuhiro Minami, Rie Hagiwara, Soichiro Ueda, Takashi Yoshiyama, Hiroyuki Kokuto, Tatsuya Kusumoto, Ayano Oashi, Masayoshi Miyawaki, Fumitake Saito, Tetsuo Tani, Kota Ishioka, Saeko Takahashi, Morio Nakamura, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

Respiratory investigation 62 ( 6 ) 1094 - 1101 2024.11

ISSN 22125345

BACKGROUND: Patients often experience multiple prolonged symptoms following acute coronavirus disease 2019 (COVID-19) recovery, defined as long coronavirus disease (COVID). Patients with long COVID may experience dyspnea during acute and post-acute phases. Therefore, this study aimed to identify specific risk factors for dyspnea in patients with long COVID. METHODS: Hospitalized patients with COVID-19, aged ≥18 years, were enrolled in this multicenter cohort study conducted at 26 medical institutions across Japan. Clinical data during hospitalization and patient-reported outcomes after discharge at the 3, 6, and 12-month follow-ups were retrieved from medical records and paper-based or smartphone application-based questionnaires, respectively. RESULTS: Generalized linear mixed model (GLMM) analysis of prolonged dyspnea at each time point during follow-up showed that this symptom was associated with chronic obstructive pulmonary disease (COPD) (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.31-5.74), asthma (OR, 2.21; 95%CI, 1.17-4.16), and ventilator management (OR, 3.10; 95%CI, 1.65-5.83). In addition, patients with COPD (44.4%) and ventilator management (25.0%) were more frequently associated with delayed dyspnea onset. The generalized estimating equations analysis results with multiple imputed datasets, conducted as a sensitivity analysis, confirmed the adjusted GLMM analysis results. CONCLUSIONS: Prolonged dyspnea was associated with COPD, asthma, and severe infection that required mechanical ventilation in the Japanese population with long COVID. Further investigation is needed to clarify its mechanism and develop prophylactic and therapeutic strategies for dyspnea in patients with long COVID.

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Efficacy and safety of long-term macrolide therapy for non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis

Natsuki Nakagawa, Masashi Ito, Takanori Asakura, Nobuyuki Horita, Yasushi Obase, Hiroshi Mukae

Respiratory Investigation 62 ( 6 ) 1079 - 1087 2024.11

ISSN 22125345

BACKGROUND: Long-term macrolide therapy for non-cystic fibrosis bronchiectasis (NCFB) can play a significant role. However, such data are insufficient regarding the efficacy against severe exacerbation and adverse effects, including the emergence of macrolide-resistant pathogens and prolonged macrolide use beyond 1 year. METHODS: Randomized controlled trials (RCTs) and prospective observational studies comparing the efficacy and safety of macrolides and placebo in adult patients with NCFB were screened on April 10, 2024. The primary outcome was severe exacerbation frequency. RESULTS: Ten RCTs ≤1 year study durations were included. Most studies mainly included patients with a history of >2 exacerbations. Macrolides had a tendency to reduce the frequency of severe exacerbations compared with placebo (odds ratio = 0.54, 95% confidence interval (CI) = 0.25-1.18). Macrolides significantly reduced the frequency of exacerbations (rate ratio = 0.58, 95% CI = 0.48-0.69), prolonged the time to first exacerbation (rate ratio = 0.41, 95% CI = 0.30-0.55), improved the changes in SGRQ scores [mean difference (MD) = -3.99, 95% CI = -4.63-3.44] and percent predicted forced expiratory volume in 1 s (MD = -2.30, 95% CI = 0.26-4.33), and reduced sputum volume (gram) (MD = -7.44, 95% CI = -9.15-5.74). Additionally, macrolides did not increase drug-related adverse events leading to discontinuation. Qualitative SR of pathogens indicated macrolides might increase the number of macrolide-resistant oropharyngeal and sputum pathogens and the emergence of Pseudomonas aeruginosa. CONCLUSIONS: Our results support macrolide therapy for patients with NCFB. Studies with an observation period of >1 year or those focusing on patients with/without a minimal exacerbation history are required to determine the long-term effects on patients with NCFB.

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Distinctive clinical features of radiological pleuroparenchymal fibroelastosis with nontuberculous mycobacterial pulmonary disease: A multicenter retrospective cohort study.

Hiromu Tanaka, Takanori Asakura, Satoshi Okamori, Koji Furuuchi, Mitsuaki Yagi, Yuji Nakayama, Junko Kuramoto, Kazuma Yagi, Isano Hase, Hirofumi Kamata, Keiji Fujirawa, Akira Nakao, Yohei Masugi, Yasunori Sato, Yae Kanai, Ho Namkoong, Koichi Fukunaga, Taku Nakagawa, Kozo Morimoto, Masaki Fujita, Naoki Hasegawa

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 148 107233 - 107233 2024.11

ISSN 12019712

OBJECTIVES: To compare the characteristics and prognosis of patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) with pleuroparenchymal fibroelastosis (PPFE) with those of patients with nodular/bronchiectatic (NB) and fibrocavitary (FC) NTM-PD. METHODS: This multicenter, retrospective, observational study enrolled 32 patients with NTM-PPFE (median age: 70.5 years, 15 females) from six institutions in Japan from January 2003 to December 2018. Their clinical characteristics, and response to therapy were compared with age- and sex-matched cohorts of patients with non-cavitary NB and cavitary NB/FC NTM-PD. RESULTS: Patients with NTM-PPFE had a lower body mass index and a higher standard NTM-PD therapy initiation rate than patients with other NTM-PD types. Sputum culture conversion rates were comparable between groups; however, patients with NTM-PPFE had a higher incidence of treatment-related adverse events, including optic neuropathy associated with high-dose ethambutol therapy, lower percent predicted forced vital capacity values, higher serum Krebs von den Lungen 6 (KL-6) levels, and poorer treatment outcomes than the other groups. Cox regression revealed that NTM-PPFE was an independent risk factor for death/pneumothorax (adjusted hazard ratio: 35.3, 95% confidence interval: 3.90-4692). CONCLUSIONS: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes.

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Combined use of serum ferritin and KL-6 levels as biomarkers for predicting COVID-19 severity

Hiromu Tanaka, Erika Toya, Shotaro Chubachi, Ho Namkoong, Takanori Asakura, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Mayuko Watase, Kaori Sakurai, 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

Respiratory Investigation (Elsevier BV) 62 ( 6 ) 1132 - 1136 2024.11

ISSN 22125345

OBJECTIVES: To assess the value of serum ferritin and Krebs von den Lungen-6 (KL-6) levels for predicting severe COVID-19 (death or requirement for invasive mechanical ventilation [IMV]/high-flow oxygen). METHODS: Data were analyzed on 2495 patients with COVID-19 from February 2020 to November 2022 using data from a nationwide COVID-19 database. RESULTS: Patients with high KL-6 and low ferritin levels were older with more comorbidities and higher mortality rates, whereas those with high ferritin and low KL-6 levels were younger, predominantly male, and more likely to need IMV. A high level of both markers was strongly associated with critical outcomes (adjusted odds ratio: 13.6, 95% confidence interval: 8.58-21.5). The combination of both markers had higher predictive value than either marker alone (area under the curve: 0.709, 0.745, and 0.781 for KL-6, ferritin, and KL-6 + ferritin, respectively). CONCLUSIONS: The combination of both markers accurately predicted COVID-19 severity.

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Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations.

Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Wanda K O'Neal, Richard C Boucher, Gang Chen

bioRxiv : the preprint server for biology 2024.08

RATIONALE: Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense. OBJECTIVES: To identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection. METHODS: STAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1β) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. MEASUREMENTS AND MAIN RESULTS: Mucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1β exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a γ-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. CONCLUSIONS: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.

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Social impact of brain fog and analysis of risk factors: Long COVID in Japanese population.

Lisa Shigematsu, Ryusei Kimura, Hideki Terai, Yu Mimura, Daisuke Ito, Shogyoku Bun, Ho Namkoong, Takanori Asakura, Shotaro Chubachi, Katsunori Masaki, Keiko Ohgino, Jun Miyata, Ichiro Kawada, Makoto Ishii, Ryo Takemura, Soichiro Ueda, Takashi Yoshiyama, Hiroyuki Kokuto, Tatsuya Kusumoto, Ayano Oashi, Masayoshi Miyawaki, Fumitake Saito, Tetsuo Tani, Kota Ishioka, Saeko Takahashi, Morio Nakamura, Yasunori Sato, Koichi Fukunaga

Annals of clinical and translational neurology 11 ( 8 ) 2188 - 2200 2024.08

OBJECTIVE: To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID-19). METHODS: We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID-19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. RESULTS: The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C-reactive protein and elevated D-dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. INTERPRETATIONS: This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

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CT-derived vertebral bone mineral density is a useful biomarker to predict COVID-19 outcome.

Shuhei Azekawa, Tomoki Maetani, Shotaro Chubachi, Takanori Asakura, Naoya Tanabe, Yusuke Shiraishi, Ho Namkoong, Hiromu Tanaka, Takashi Shimada, Takahiro Fukushima, Shiro Otake, Kensuke Nakagawara, Mayuko Watase, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Bone 184 117095 - 117095 2024.07

ISSN 87563282

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future.

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Development of allergic bronchopulmonary aspergillosis in a patient with nontuberculous mycobacterial-pulmonary disease successfully treated with dupilumab: A case report and literature review.

Ryuta Onozato, Jun Miyata, Takanori Asakura, Ho Namkoong, Koichiro Asano, Naoki Hasegawa, Koichi Fukunaga

Respirology case reports 12 ( 7 ) e01432 2024.07

Pulmonary manifestations in patients with allergic bronchopulmonary aspergillosis (ABPA) and nontuberculous mycobacterial-pulmonary disease (NTM-PD) include bronchiectasis and mucus plugging. A 68-year-old woman, treated with antibiotics and inhaled corticosteroids for NTM-PD and asthma, presented with fever and wheezing. ABPA was diagnosed based on laboratory findings (elevated peripheral blood eosinophil counts and serum total IgE levels and positive Aspergillus-specific IgE and IgG) and imaging observation of a high-attenuation mucus plug. Systemic prednisolone was avoided to prevent NTM-PD progression. Dupilumab, a monoclonal antibody that blocks IL-4/13, was introduced to improve the clinical findings. Herein, we discuss the pathophysiological mechanisms underlying this rare comorbidity.

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Lung volume measurement using chest CT in COVID-19 patients: a cohort study in Japan.

Shiro Otake, Yusuke Shiraishi, Shotaro Chubachi, Naoya Tanabe, Tomoki Maetani, Takanori Asakura, Ho Namkoong, Takashi Shimada, Shuhei Azekawa, Kensuke Nakagawara, Hiromu Tanaka, Takahiro Fukushima, Mayuko Watase, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Naoki Hasegawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

BMJ open respiratory research 11 ( 1 ) 2024.04

OBJECTIVE: This study aimed to investigate the utility of CT quantification of lung volume for predicting critical outcomes in COVID-19 patients. METHODS: This retrospective cohort study included 1200 hospitalised patients with COVID-19 from 4 hospitals. Lung fields were extracted using artificial intelligence-based segmentation, and the percentage of the predicted (%pred) total lung volume (TLC (%pred)) was calculated. The incidence of critical outcomes and posthospitalisation complications was compared between patients with low and high CT lung volumes classified based on the median percentage of predicted TLCct (n=600 for each). Prognostic factors for residual lung volume loss were investigated in 208 patients with COVID-19 via a follow-up CT after 3 months. RESULTS: The incidence of critical outcomes was higher in the low TLCct (%pred) group than in the high TLCct (%pred) group (14.2% vs 3.3%, p<0.0001). Multivariable analysis of previously reported factors (age, sex, body mass index and comorbidities) demonstrated that CT-derived lung volume was significantly associated with critical outcomes. The low TLCct (%pred) group exhibited a higher incidence of bacterial infection, heart failure, thromboembolism, liver dysfunction and renal dysfunction than the high TLCct (%pred) group. TLCct (%pred) at 3 months was similarly divided into two groups at the median (71.8%). Among patients with follow-up CT scans, lung volumes showed a recovery trend from the time of admission to 3 months but remained lower in critical cases at 3 months. CONCLUSION: Lower CT lung volume was associated with critical outcomes, posthospitalisation complications and slower improvement of clinical conditions in COVID-19 patients.

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Asthma is a risk factor for general fatigue of long COVID in Japanese nation-wide cohort study.

Keeya Sunata, Jun Miyata, Hideki Terai, Emiko Matsuyama, Mayuko Watase, Ho Namkoong, Takanori Asakura, Katsunori Masaki, Shotaro Chubachi, Keiko Ohgino, Ichiro Kawada, Norihiro Harada, Hitoshi Sasano, Ai Nakamura, Yu Kusaka, Takehiko Ohba, Yasushi Nakano, Kazumi Nishio, Yukiko Nakajima, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Makoto Ishii, Koichi Fukunaga

Allergology international : official journal of the Japanese Society of Allergology 73 ( 2 ) 206 - 213 2024.04

ISSN 13238930

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. METHODS: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. CONCLUSIONS: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

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Levels of environmental contamination with SARS-CoV-2 in hospital rooms and salivary viral loads of patients with coronavirus disease 2019.

Hidehito Matsui, Yusuke Suzuki, Sohei Nakayama, Takanori Asakura, Osamu Takeuchi, Kaori Kusatsugu, Chihiro Ueda, Eri Nakajima, Yumiko Suzuki, Harumi Endo, Miho Sugamata, Yukiko Takarabe, Yukie Yamaguchi, Kazuhito Horie, Yoshikazu Kobayashi, Satoshi Kuronuma, Yasuo Imoto, Hideaki Hanaki

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 30 ( 4 ) 315 - 322 2024.04

ISSN 1341321X

BACKGROUND: Clarifying the presence of viable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rather than SARS-CoV-2 viral RNA in inpatient rooms is important for infection control of coronavirus disease 2019 (COVID-19). In this study, we investigated levels of viral RNA and viable virus on environmental surfaces and in patient saliva. METHODS: Environmental samples from 23 sites in hospital rooms were collected every other day until patient discharge. Saliva specimens and samples from the inner surface of patient masks were also collected. Additionally, environmental samples were collected from 46 sites in hospital rooms on discharge day. The samples were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and plaque assays. RESULTS: The 10 enrolled cases were classified as mild COVID-19, and patients were discharged after 6-9 days. The viral RNA was detected in 12.4% (105/849) of serially collected environmental samples during hospitalization, whereas viable virus was detected only in 0.47% (4/849), which were from sinks and tap levers. Although all patients recovered, three cases retained viable virus in the last saliva specimen collected. In the 15 discharged rooms, viral RNA was detected in 6.6% (45/682) of the samples, and viable virus was detected in only one sample from the sink. CONCLUSIONS: Although environmental surfaces surrounding patients with COVID-19 were frequently contaminated with viral RNA, the presence of viable virus was rare and limited only to areas around sinks. These results suggest that contact infection risk via fomites in hospital rooms is extremely rare.

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Calcium channel blockers may reduce the development of long COVID in females.

Takuya Ozawa, Ryusei Kimura, Hideki Terai, Ryo Takemura, Ho Namkoong, Masahiro Kondo, Keitaro Fukuda, Kazuma Yagi, Takanori Asakura, Katsunori Masaki, Shotaro Chubachi, Jun Miyata, Keiko Ohgino, Ichiro Kawada, Junko Kagyo, Toshio Odani, Naota Kuwahara, Ichiro Nakachi, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

Hypertension research : official journal of the Japanese Society of Hypertension 47 ( 4 ) 934 - 943 2024.04

ISSN 09169636

With the rising numbers of patients infected with severe acute respiratory syndrome coronavirus 2, long coronavirus disease 2019 (COVID-19)-a sequelae of COVID-19-has become a major problem. Different sexes and age groups develop different long COVID symptoms, and the risk factors for long COVID remain unclear. Therefore, we performed subgroup analyses of patients with COVID-19, classifying them into different groups. In this multicenter cohort study, using an original questionnaire, we examined patients (≥18 years old) diagnosed with COVID-19 from November 2020 to March 2022 and hospitalized at participating medical facilities. In total, 1066 patients were registered (361 female, 620 male). Hypertension was the most common comorbidity (n = 344; 32.5%). Females with hypertension were significantly less likely to develop long COVID symptoms than those without hypertension (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27-0.98; p = 0.043). In females, Ca channel blocker administration, rather than having hypertension, was significantly associated with reductions in the frequency of alopecia (OR 0.14, 95% CI 0.03-0.67, p = 0.015), memory impairment (OR 0.14, 95% CI 0.02-0.82, p = 0.029), sleeping disorders (OR 0.17, 95% CI 0.04-0.67, p = 0.012), tinnitus (OR 0.23, 95% CI 0.05-0.98, p = 0.047), sputum (OR 0.31, 95% CI 0.10-0.92, p = 0.035), and fever (OR 0.33, 95% CI 0.12-0.93, p = 0.036). Several long COVID symptoms, including alopecia, were significantly negatively associated with Ca channel-blocker administration in female patients with long COVID. Calcium channel blockers may reduce the development of long COVID in females.

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Gastrointestinal symptoms in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study

Matsubara Y., Kiyohara H., Mikami Y., Nanki K., Namkoong H., Chubachi S., Tanaka H., Azekawa S., Sugimoto S., Yoshimatsu Y., Sujino T., Takabayashi K., Hosoe N., Sato T., Ishii M., Hasegawa N., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Fukunaga K., Kanai T., Chubachi S., Fukushima T., Tanaka H., Lee H., Otake S., Nakagawara K., Morita A., Watase M., Sakurai K., Ogawa T., Kusumoto T., Masaki K., Kabata H., Ikemura S., Okamori S., Terai H., Kamata H., Uchida S., Uno S., Hasegawa N., Takahashi K., Sasano H., Kitagawa Y., Harada N., Takagi H., Nakamura A., Naito T., Hiki M., Matsushita Y., Aoki R., Harada S., Sasaki J., Morisaki H., Uwamino Y., Mikami Y., Ishihara R., Sugimoto S., Yoshimatsu Y., Nishimura T., Sato T., Ueda T., Azuma M., Saito R., Sado T., Miyazaki Y., Sato R., Haruta Y., Nagasaki T., Hasegawa Y., Yasui Y., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Tagaya E.

Journal of Gastroenterology 59 ( 3 ) 195 - 208 2024.03

ISSN 09441174

Background: Research on whether gastrointestinal symptoms correlate with the severity of Coronavirus Disease 2019 (COVID-19) has been inconclusive. This study aimed to clarify any associations between gastrointestinal symptoms and the prognosis of COVID-19. Methods: We collected data from the Japanese nationwide registry for COVID-19 to conduct a retrospective cohort study. Data from 3498 Japanese COVID-19 patients, diagnosed at 74 facilities between February 2020 and August 2022, were analyzed in this study. Hospitalized patients were followed up until discharge or transfer to another hospital. Outpatients were observed until the end of treatment. Associations between gastrointestinal symptoms and clinical outcomes were investigated using multivariable-adjusted logistic regression models. Results: The prevalence of diarrhea, nausea/vomiting, abdominal pain, and melena were 16.6% (581/3498), 8.9% (311/3498), 3.5% (121/3498), and 0.7% (23/3498), respectively. In the univariable analysis, admission to intensive care unit (ICU) and requirement for mechanical ventilation were less common in patients with diarrhea than those without (ICU, 15.7% vs. 20.6% (p = 0.006); mechanical ventilation, 7.9% vs. 11.4% (p = 0.013)). In the multivariable-adjusted analysis, diarrhea was associated with lower likelihood of ICU admission (adjusted odds ratio (aOR), 0.70; 95% confidence interval (CI), 0.53–0.92) and mechanical ventilation (aOR, 0.61; 95% CI, 0.42–0.89). Similar results were obtained in a sensitivity analysis with another logistic regression model that adjusted for 14 possible covariates with diarrhea (ICU; aOR, 0.70; 95% CI, 0.53–0.93; mechanical ventilation; aOR 0.62; 95% CI, 0.42–0.92). Conclusions: Diarrhea was associated with better clinical outcomes in COVID-19 patients.

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Prognostic significance of hypertension history and blood pressure on admission in Japanese patients with coronavirus disease 2019: integrative analysis from the Japan COVID-19 Task Force.

Kaori Sakurai, Shotaro Chubachi, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Shuhei Azekawa, Takashi Shimada, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Ho Lee, Mayuko Watase, 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

Hypertension research : official journal of the Japanese Society of Hypertension 47 ( 3 ) 639 - 648 2024.03

ISSN 09169636

The effect of preexisting hypertension on coronavirus disease 2019 (COVID-19) prognosis remains controversial. Additionally, no studies have compared the association between blood pressure (BP) indices on admission and COVID-19 outcomes using preexisting hypertension status. Therefore, this study aimed to investigate the association between preexisting hypertension and COVID-19 outcomes in Japanese patients with COVID-19 and assess the impact of BP indices on admission on clinical outcomes in patients with and without preexisting hypertension. Preexisting hypertension presence was confirmed based on the patient's clinical history. Critical outcomes were defined as high-flow oxygen use, non-invasive and invasive positive-pressure ventilation, extracorporeal membrane oxygenation, or death during hospitalization. Preexisting hypertension was observed in 64.6% of the patients. Multivariable logistic regression analysis of severe COVID-19 risk factors indicated that preexisting hypertension was independently associated with critical outcomes [adjusted odds ratio (OR): 1.35; 95% confidence interval (CI): 1.05-1.73]. Low or high BP and high pulse pressure on admission were associated with critical outcomes in patients without preexisting hypertension [OR for systolic BP < 100 mmHg: 2.13, 95% CI: 1.21-3.75; OR for high BP stage 2 (160-179 systolic and/or 100-109 mmHg diastolic BP): 2.13, 95% CI: 1.27-3.58; OR for pulse pressure ≥60 mmHg: 1.68, 95% CI: 1.14-2.48]. Preexisting hypertension is a risk factor for critical outcomes in Japanese patients with COVID-19. BP indices are useful biomarkers for predicting COVID-19 outcomes, particularly in patients without preexisting hypertension. Thus, hypertension history, systolic BP, and pulse pressure should be assessed to predict severe COVID-19 outcomes.

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Integrated assessment of computed tomography density in pectoralis and erector spinae muscles as a prognostic biomarker for coronavirus disease 2019.

Kensuke Nakagawara, Yusuke Shiraishi, Shotaro Chubachi, Naoya Tanabe, Tomoki Maetani, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Takashi Shimada, Shuhei Azekawa, Shiro Otake, Takahiro Fukushima, Mayuko Watase, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Clinical nutrition (Edinburgh, Scotland) 43 ( 3 ) 815 - 824 2024.03

ISSN 02615614

UNLABELLED: BACKGROUND ＆ AIMS: Muscle quantification using chest computed tomography (CT) is a useful prognostic biomarker for coronavirus disease 2019 (COVID-19). However, no studies have evaluated the clinical course through comprehensive assessment of the pectoralis and erector spinae muscles. Therefore, we compared the impact of the areas and densities of these muscles on COVID-19 infection outcome. METHODS: This multicenter retrospective cohort study was conducted by the COVID-19 Task Force. A total of 1410 patients with COVID-19 were included, and data on the area and density of the pectoralis and erector spinae muscles on chest CT were collected. The impact of each muscle parameter on the clinical outcome of COVID-19 was stratified according to sex. The primary outcome was the percentage of patients with severe disease, including those requiring oxygen supplementation and those who died. Additionally, 167 patients were followed up for changes in muscle parameters at three months and for the clinical characteristics in case of reduced CT density. RESULTS: For both muscles, low density rather than muscle area was associated with COVID-19 severity. Regardless of sex, lower erector spinae muscle density was associated with more severe disease than pectoralis muscle density. The muscles were divided into two groups using the receiver operating characteristic curve of CT density, and the population was classified into four (Group A: high CT density for both muscles, Group B: low CT density for pectoralis and high for erector spinae muscle. Group C: high CT density for pectoralis and low for erector spinae muscle, Group D: low CT density for both muscles). In univariate analysis, Group D patients exhibited worse outcomes than Group A (OR: 2.96, 95% CI: 2.03-4.34 in men; OR: 3.02, 95% CI: 2.66-10.4 in women). Multivariate analysis revealed that men in Group D had a significantly more severe prognosis than those in Group A (OR: 1.82, 95% CI: 1.16-2.87). Moreover, Group D patients tended to have the highest incidence of other complications due to secondary infections and acute kidney injury during the clinical course. Longitudinal analysis of both muscle densities over three months revealed that patients with decreased muscle density over time were more likely to have severe cases than those who did not. CONCLUSIONS: Muscle density, rather than muscle area, predicts the clinical outcomes of COVID-19. Integrated assessment of pectoralis and erector spinae muscle densities demonstrated higher accuracy in predicting the clinical course of COVID-19 than individual assessments.

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Pneumocystis Pneumonia in Locally Advanced Breast Cancer Despite Prophylactic Use of Trimethoprim-Sulfamethoxazole During Prednisolone Treatment for a Pembrolizumab-Induced Immune-Related Adverse Event: A Case Report.

Yudai Kaneda, Kenji Gonda, Takanori Asakura, Masahiro Wada, Toyoaki Sawano, Tomohiro Kurokawa, Kazunoshin Tachibana, Akihiko Ozaki

Cureus 16 ( 3 ) e56868 2024.03

Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is insufficient information on PCP occurrence despite TMP-SMX prophylaxis. We encountered a 57-year-old woman with locally advanced breast cancer developing PCP despite prophylactic intake of TMP-SMX, during treatment with prednisolone for Stevens-Johnson syndrome (SJS) induced by pembrolizumab. This case underscores the need to pay attention to the possibility of PCP development even during TMP-SMX prophylaxis. Dosage and duration adjustments according to the patient's condition and weight may be required.

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Cluster analysis of long COVID in Japan and association of its trajectory of symptoms and quality of life.

Fumimaro Ito, Hideki Terai, Masahiro Kondo, Ryo Takemura, Ho Namkoong, Takanori Asakura, Shotaro Chubachi, Keita Masuzawa, Sohei Nakayama, Yusuke Suzuki, Mizuha Hashiguchi, Junko Kagyo, Tetsuya Shiomi, Naoto Minematsu, Tadashi Manabe, Takahiro Fukui, Yohei Funatsu, Hidefumi Koh, Katsunori Masaki, Keiko Ohgino, Jun Miyata, Ichiro Kawada, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

BMJ open respiratory research 11 ( 1 ) 2024.02

BACKGROUND: Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL). METHODS: This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis. RESULTS: Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year. CONCLUSIONS: We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID. TRIAL REGISTRATION NUMBER: The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

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Proximal and Distal Bronchioles Contribute to the Pathogenesis of Non-Cystic Fibrosis Bronchiectasis (NCFB).

Takanori Asakura, Kenichi Okuda, Gang Chen, Hong Dang, Takafumi Kato, Yu Mikami, Stephen A Schworer, Rodney C Gilmore, Giorgia Radicioni, Padraig Hawkins, Selene Margarita Barbosa Cardenas, Minako Saito, Anne Marie Cawley, Gabriela De la Cruz, Michael Chua, Neil E Alexis, Yohei Masugi, Peadar G Noone, Carla M P Ribeiro, Mehmet Kesimer, Kenneth N Olivier, Naoki Hasegawa, Scott H Randell, Wanda K O'Neal, Richard C Boucher

American journal of respiratory and critical care medicine 209 ( 4 ) 374 - 389 2024.02

ISSN 1073449X

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objective: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC), identified proximal and distal bronchioles in excised NCFB lungs. RNA-ISH and IHC assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial (HBE) cultures tested IL-1α/β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas/section area were increased in proximal, but not distal, bronchioles in NCFB vs control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated non-ectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β-expressing macrophages. NCFB sterile sputum supernatants induced HBE MUC5B/MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, IL-1β-producing macrophages in mucus plugs, and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia.

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Comparing minimum inhibitory concentrations of amikacin for pulmonary Mycobacterium avium complex disease: An analysis of culture media differences.

Atsuho Morita, Ho Namkoong, Yoshifumi Uwamino, Satoshi Mitarai, Akio Aono, Takanori Asakura, Kazuma Yagi, Hiromu Tanaka, Shuhei Azekawa, Kensuke Nakagawara, Masanori Kaji, Genta Nagao, Hirofumi Kamata, Hiromichi Matsushita, Koichi Fukunaga, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 30 ( 2 ) 159 - 163 2024.02

ISSN 1341321X

Mycobacterium avium complex (MAC) is considered a paramount microbe, especially in East Asia, including Japan. The commonly used commercial Minimum Inhibitory Concentrations (MIC) assay using Middlebrook 7H9 (7H9) medium deviates from the latest Clinical and Laboratory Standards Institute (CLSI) guidelines. Alternatively, measurement with cation-adjusted Mueller-Hinton broth (CAMHB) that conforms to CLSI standards is not yet widely available. Following the approval and commercialization of amikacin liposome inhalation suspension (ALIS) in 2021, a more precise evaluation of amikacin (AMK) susceptibility in MAC is necessary for treatment decisions. In the present study, 33 sputum samples were extracted from 27 patients, and MICs of AMK were compared between the frequently used 7H9 and the recommended CAMHB of the isolated MAC strains. The history of exposure to aminoglycosides for each sample was also added as clinical information. The findings indicated that there was only an 18% concordance rate in MIC between the two media, with 19 samples (58%) indicating lower MICs in 7H9 relative to CAMHB. The 17 samples had a history of exposure to aminoglycosides for periods ranging from 1.5 to 28 months. Specifically, 10 samples were exposed to amikacin by inhalation and intravenous injection, and the remaining seven samples had a history of ALIS inhalation. Samples with a prior utilization of aminoglycosides were significantly predisposed to developing resistance to ALIS compared to those without such a history (P = 0.046). Physicians are encouraged to scrutinize the findings of susceptibility testing utilizing CLSI-endorsed MIC assay using CAMHB medium to ascertain the optimal therapeutic approach.

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COVID-19 vaccine effectiveness against severe COVID-19 requiring oxygen therapy, invasive mechanical ventilation, and death in Japan: A multicenter case-control study (MOTIVATE study).

Takeshi Arashiro, Maki Miwa, Hidenori Nakagawa, Junpei Takamatsu, Kunihiro Oba, Satoshi Fujimi, Hitoshi Kikuchi, Takamasa Iwasawa, Fumiko Kanbe, Keisuke Oyama, Masayuki Kanai, Yoshitaka Ogata, Takanori Asakura, Takahiro Asami, Keiko Mizuno, Manabu Sugita, Torahiko Jinta, Yusuke Nishida, Hideaki Kato, Kazuaki Atagi, Taiki Higaki, Yoshio Nakano, Takeya Tsutsumi, Kent Doi, Shu Okugawa, Akihiro Ueda, Akira Nakamura, Toru Yoshida, Kaoru Shimada-Sammori, Keiki Shimizu, Yasuo Fujita, Yasumi Okochi, Kentaro Tochitani, Asuka Nakanishi, Hiroshi Rinka, Daisuke Taniyama, Asase Yamaguchi, Toshio Uchikura, Maiko Matsunaga, Hiromi Aono, Masanari Hamaguchi, Kentaro Motoda, Sohei Nakayama, Kei Yamamoto, Hideaki Oka, Katsushi Tanaka, Takeshi Inoue, Mieko Kobayashi, Shigeki Fujitani, Maki Tsukahara, Saki Takeda, Ashley Stucky, Tadaki Suzuki, Chris Smith, Martin Hibberd, Koya Ariyoshi, Yuji Fujino, Yuzo Arima, Shinhiro Takeda, Satoru Hashimoto, Motoi Suzuki

Vaccine 42 ( 3 ) 677 - 688 2024.01

ISSN 0264410X

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron.

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Epicardial adipose tissue measured from analysis of adipose tissue area using chest CT imaging is the best potential predictor of COVID-19 severity.

Takahiro Fukushima, Tomoki Maetani, Shotaro Chubachi, Naoya Tanabe, Takanori Asakura, Ho Namkoong, Hiromu Tanaka, Takashi Shimada, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Mayuko Watase, Yusuke Shiraishi, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Metabolism: clinical and experimental 150 155715 - 155715 2024.01

ISSN 00260495

BACKGROUND: Computed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue. AIM: The purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient database, we analyzed the associations of chest subcutaneous, chest visceral, abdominal subcutaneous, and Abd-VAT areas with COVID-19 outcomes. In addition, the clinical significance of central obesity, commonly disregarded by BMI, was examined. METHODS: This retrospective cohort study evaluated patients with COVID-19 aged ≥18 years In Japan. Data including from chest CT images collected between February 2020 and October 2022 in four hospitals of the Japan COVID-19 Task Force were analyzed. Patient characteristics and COVID-19 severity were compared according to the adipose tissue areas (chest and abdominal subcutaneous adipose tissue [Chest-SAT and Abd-SAT], EAT, and Abd-VAT) calculated from chest CT images. RESULTS: We included 1077 patients in the analysis. Patients with risk factors of severe COVID-19 such as old age, male sex, and comorbidities had significantly higher areas of EAT and Abd-VAT. High EAT area but not high Abd-VAT area was significantly associated with COVID-19 severity (adjusted odds ratio (aOR): 2.66, 95 % confidence interval [CI]: 1.19-5.93). There was no strong correlation between BMI and VAT. Patients with high VAT area accounted for 40.7 % of the non-obesity population (BMI < 25 kg/m2). High EAT area was also significantly associated with COVID-19 severity in the non-obesity population (aOR: 2.50, 95 % CI: 1.17-5.34). CONCLUSIONS: Our study indicated that VAT is significantly associated with COVID-19 severity and that EAT is the best potential predictor for risk stratification in COVID-19 among adipose tissue areas. Body composition assessment using EAT is an appropriate marker for identifying obesity patients overlooked by BMI. Considering the next pandemic of the global health crisis, our findings open new avenues for implementing appropriate body composition assessments based on CT imaging.

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Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study.

Masahiko Okada, Noriyuki Ishida, Sho Kanzaki, Ichiro Kawada, Kengo Nagashima, Hideki Terai, Gaku Hiruma, Ho Namkoong, Takanori Asakura, Katsunori Masaki, Keiko Ohgino, Jun Miyata, Shotaro Chubachi, Nobuhiro Kodama, Shunsuke Maeda, Satoshi Sakamoto, Masaki Okamoto, Yoji Nagasaki, Akira Umeda, Kazuya Miyagawa, Hisato Shimada, Kazuhiro Minami, Rie Hagiwara, Makoto Ishii, Yasunori Sato, Koichi Fukunaga

OTO open 8 ( 1 ) e120 2024.01

OBJECTIVE: This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. STUDY DESIGN: Prospective cohort study. SETTING: A multicenter study involving 26 medical facilities in Japan. METHODS: Inclusion criteria were patients aged ≥18 years old with a confirmed COVID-19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient-reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. RESULTS: Patients with high albumin, low C-reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282-6.526) for taste disorders and 3.534 (95% CI, 1.382-9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. CONCLUSION: The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID-19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

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Spinal tuberculosis in Afghanistan: A 2019-2020 study of patients in Kabul hospitals

Qaderi F., Mashid I., Gachkar L., Martellucci M., Qaderi S., Ozaki A., Haghbin Toutounchi A., Taheriazam A., Asakura T., Gholipoor Talemi H., Mohammady N., Shabani M.

Public Health Challenges 2 ( 4 ) 2023.12

Background: Tuberculosis (TB) is endemic in many low-income countries, which can affect the spine in 1%–5% of those with an active infection. This study reports the clinical characteristics of patients admitted for spinal TB in Kabul, Afghanistan, a country with very limited resources. Methods: This was a descriptive study among 26 patients treated for spinal TB in three major referral hospitals in Kabul, Afghanistan, between March 2019 and April 2020. The sociodemographic and clinical details, gender, age, site of infection, presenting complaints, signs, and symptoms of the patients were retrieved from their medical records. Summary statistics were analyzed using SPSS version 20. Ethics approval was obtained from the ethics committee of Shahid Beheshti University of Medical Sciences in Tehran, Iran. Results: Data were available for 26 patients with spinal TB admitted consecutively. The mean age of the sample was 38.2 years (SD 17.5), and there were 16 males and 10 females. Median time from symptom onset to hospital admission was 60 days. The most common diagnostic imaging technique used was magnetic resonance imaging (92.3%), followed by computed tomography (7.7%). The majority of the lesions involved the lumbar spine (61.4%), followed by the thoracolumbar spine (30.8%). Back pain was the most common manifestation in 21 patients (80.8%), and varying degrees of neurological impairment were found in 16 (61.5%) patients. There were no deaths among the patients up to the discharge date. Conclusions: This study describes the clinical characteristics of spinal TB among patients in Kabul, Afghanistan. It is essential to strengthen preventive strategies and to improve health awareness about clinical features of spinal TB in patients with chronic back pain even in the absence of signs of TB.

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Longitudinal significance of six-minute walk test in patients with nontuberculous mycobacterial pulmonary disease: an observational study.

Atsuho Morita, Kazuma Yagi, Takanori Asakura, Ho Namkoong, Yasunori Sato, Takunori Ogawa, Tatsuya Kusumoto, Shoji Suzuki, Hiromu Tanaka, Ho Lee, Satoshi Okamori, Shuhei Azekawa, Kensuke Nakagawara, Masanori Kaji, Genta Nagao, Yohei Funatsu, Yoshifumi Kimizuka, Hirofumi Kamata, Tomoyasu Nishimura, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa

BMC pulmonary medicine 23 ( 1 ) 247 - 247 2023.12

BACKGROUND: The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. METHODS: Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. RESULTS: The median age [interquartile range] of the patients was 67 [63-74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361-470] m and 1 [0-2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. CONCLUSIONS: The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient's condition and tailor their healthcare environment.

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Longitudinal long COVID symptoms in Japanese patients after COVID-19 vaccinations.

Kensuke Nakagawara, Atsuho Morita, Ho Namkoong, Hideki Terai, Shotaro Chubachi, Takanori Asakura, Hiromu Tanaka, Fumimaro Ito, Emiko Matsuyama, Masanori Kaji, Ayaka Saito, Hatsuyo Takaoka, Masahiko Okada, Keeya Sunata, Mayuko Watase, Kazuma Yagi, Keiko Ohgino, Jun Miyata, Hirofumi Kamata, Ichiro Kawada, Keigo Kobayashi, Toshiyuki Hirano, Takashi Inoue, Junko Kagyo, Tetsuya Shiomi, Kengo Otsuka, Naoki Miyao, Toshio Odani, Rie Baba, Daisuke Arai, Ichiro Nakachi, Soichiro Ueda, Yohei Funatsu, Hidefumi Koh, Kota Ishioka, Saeko Takahashi, Morio Nakamura, Toshiro Sato, Naoki Hasegawa, Yuko Kitagawa, Takanori Kanai, Makoto Ishii, Koichi Fukunaga

Vaccine: X 15 100381 - 100381 2023.12

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

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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 2023.12

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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Cough and sputum in long COVID are associated with severe acute COVID-19: a Japanese cohort study.

Mayuko Watase, Jun Miyata, Hideki Terai, Keeya Sunata, Emiko Matsuyama, Takanori Asakura, Ho Namkoong, Katsunori Masaki, Kazuma Yagi, Keiko Ohgino, Shotaro Chubachi, Ichiro Kawada, Takao Mochimaru, Ryosuke Satomi, Yoshitaka Oyamada, Keigo Kobayashi, Toshiyuki Hirano, Takashi Inoue, Ho Lee, Kai Sugihara, Nao Omori, Koichi Sayama, Shuko Mashimo, Yasushi Makino, Tatsuya Kaido, Makoto Ishii, Koichi Fukunaga

Respiratory research 24 ( 1 ) 283 - 283 2023.12

ISSN 14659921

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

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Clinical utilization of artificial intelligence-based COVID-19 pneumonia quantification using chest computed tomography - a multicenter retrospective cohort study in Japan.

Hiromu Tanaka, Tomoki Maetani, Shotaro Chubachi, Naoya Tanabe, Yusuke Shiraishi, Takanori Asakura, Ho Namkoong, Takashi Shimada, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Mayuko Watase, Hideki Terai, Mamoru Sasaki, Soichiro Ueda, Yukari Kato, Norihiro Harada, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Yoshitake Yamada, Masahiro Jinzaki, Toyohiro Hirai, Yukinori Okada, Ryuji Koike, Makoto Ishii, Naoki Hasegawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Respiratory research 24 ( 1 ) 241 - 241 2023.12

ISSN 14659921

BACKGROUND: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions. METHODS: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions. RESULTS: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions. CONCLUSIONS: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19.

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Clinical features of Japanese patients with gastrointestinal long-COVID symptoms.

Kazuma Yagi, Takanori Asakura, Hideki Terai, Keiko Ohgino, Katsunori Masaki, Ho Namkoong, Shotaro Chubachi, Jun Miyata, Ichiro Kawada, Nobuhiro Kodama, Satoshi Sakamoto, Akira Umeda, Takashi Ishiguro, Makoto Ishii, Koichi Fukunaga

JGH open : an open access journal of gastroenterology and hepatology 7 ( 12 ) 998 - 1002 2023.12

Gastrointestinal (GI) long-COVID symptoms, including diarrhea and abdominal pain, have been reported in patients with long-COVID. However, the clinical features of patients with GI long-COVID symptoms remain unclear. We conducted a large-scale prospective cohort study focusing on the clinical characteristics of patients with GI long-COVID symptoms in Japan. Among 943 COVID-19 patients, 58 patients (6.2%) had GI long-COVID symptoms. The health-related quality of life (QOL) parameters (the Short Form-8 [SF-8] and Euro Quality of Life 5 Dimensions 5 level [EQ-5D-5L]) at 12 months after diagnosis in patients with GI long-COVID symptoms were significantly lower than in those without GI long-COVID symptoms (P < 0.0001). Moreover, patients with GI long-COVID symptoms had more varied long-COVID symptoms compared to patients without GI long-COVID symptoms.

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

Tatsuya Kusumoto, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Atsuho Morita, Mayuko Watase, 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

Scientific reports 13 ( 1 ) 22054 - 22054 2023.12

The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). We investigated the clinical and genetic characteristics and prognosis of patients with worsening CXR findings during early hospitalization. We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases, high body temperature, and increased serum aspartate aminotransferase, potassium, and C-reactive protein levels were independent risk factors for rapid deterioration of CXR findings. Risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients. This study revealed the clinical features, genetic features, and risk factors associated with rapid deterioration of CXR findings, a poor prognostic factor in patients with COVID-19.

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

Tatsuya Kusumoto, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Atsuho Morita, Mayuko Watase, Kaori Sakurai, 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, Hirohito Sano, Yasunori Sato, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Annals of hematology 102 ( 11 ) 3239 - 3249 2023.11

ISSN 09395555

An association between coronavirus disease 2019 (COVID-19) and the ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Little is known about the association between COVID-19 and ABO genotype. This study investigated the association between COVID-19 and ABO blood group/genotype in a large Japanese population. All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1790 Japanese COVID-19 patients whose DNA was used for a genome-wide association study. We compared the ABO blood group/genotype in a healthy population (n = 611, control) and COVID-19 patients and then analyzed their associations and clinical outcomes. Blood group A was significantly more prevalent (41.6% vs. 36.8%; P = 0.038), and group O was significantly less prevalent (26.2% vs. 30.8%; P = 0.028) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Furthermore, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00-3.37)]. In ABO genotype analysis, only genotype AB was an independent risk factor for most severe diseases compared with genotype OO. Blood group O is protective, whereas group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of the "most" severe disease.

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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 Azekawa, 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 Irie, 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 Haraguchi, Junko Kagyo, Tetsuya Shiomi, Ho Lee, Kai Sugihara, Nao Omori, Koichi Sayama, Kengo Otsuka, Naoki Miyao, Toshio Odani, Mayuko Watase, Takao Mochimaru, Ryosuke Satomi, Yoshitaka Oyamada, Keita Masuzawa, Takanori Asakura, Sohei Nakayama, Yusuke Suzuki, Rie Baba, Satoshi Okamori, Daisuke Arai, Ichiro Nakachi, Naota Kuwahara, Akiko Fujiwara, Takenori Oakada, Takashi Ishiguro, Taisuke Isosno, 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 Goto, Yu Kusaka, Takehiko Ohba, Yasushi Nakano, Kazumi Nishio, Yukiko Nakajima, Shoji Suzuki, Shuichi Yoshida, Hiroki Tateno, Nobuhiro Kodama, Maeda Shunsuke, Satoshi Sakamoto, Masaki Okamoto, Yoji Nagasaki, Akira Umeda, Kazuya Miyagawa, Hisato 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

Respiratory investigation 61 ( 6 ) 802 - 814 2023.11

ISSN 22125345

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

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Propensity-Score Matched Analysis of the Effectiveness of Baricitinib in Patients With Coronavirus Disease 2019 (COVID-19) Using Nationwide Real-World Data: An Observational Matched Cohort Study From the Japan COVID-19 Task Force.

Hiromu Tanaka, Shotaro Chubachi, Ho Namkoong, Yasunori Sato, Takanori Asakura, Ho Lee, Shuhei Azekawa, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, Mayuko Watase, Kaori Sakurai, Tatsuya Kusumoto, Yasushi Kondo, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Yuko Kaneko, Naoki Hasegawa, Soichiro Ueda, Mamoru Sasaki, Takehiro Izumo, Minoru Inomata, Naoki Miyazawa, Yasuhiro Kimura, Yusuke Suzuki, Norihiro Harada, Masako Ichikawa, Tohru Takata, Hiroyasu Ishikura, Takashi Yoshiyama, Hiroyuki Kokuto, Koji Murakami, Hirohito Sano, Tetsuya Ueda, Naota Kuwahara, Akiko Fujiwara, Takashi Ogura, Takashi Inoue, Takahiro Asami, Yoshikazu Mutoh, Ichiro Nakachi, Rie Baba, Koichi Nishi, Mayuko Tani, Junko Kagyo, Mizuha Hashiguchi, Tsuyoshi Oguma, Koichiro Asano, Masanori Nishikawa, Hiroki Watanabe, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Open forum infectious diseases 10 ( 7 ) ofad311 2023.07

BACKGROUND: To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib. METHODS: This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls. RESULTS: Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17). CONCLUSIONS: Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.

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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.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 132 84 - 88 2023.07

ISSN 12019712

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 2023.07

ISSN 22125345

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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Serum KL-6 levels predict clinical outcomes and are associated with MUC1 polymorphism in Japanese patients with COVID-19.

Shuhei Azekawa, Shotaro Chubachi, Takanori Asakura, Ho Namkoong, Yasunori Sato, Ryuya Edahiro, Ho Lee, Hiromu Tanaka, Shiro Otake, Kensuke Nakagawara, Takahiro Fukushima, 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

BMJ open respiratory research 10 ( 1 ) 2023.05

BACKGROUND: Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19. METHODS: This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated. RESULTS: Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p<0.001). Serum KL-6 levels ≥304 U/mL independently predicted critical outcomes (adjusted OR (aOR) 3.47, 95% CI 2.44 to 4.95). Moreover, multivariable logistic regression analysis with age and sex indicated that the MUC1 variant was independently associated with increased serum KL-6 levels (aOR 0.24, 95% CI 0.28 to 0.32) but not significantly associated with critical outcomes (aOR 1.11, 95% CI 0.80 to 1.54). CONCLUSION: Serum KL-6 levels predicted critical outcomes in Japanese patients with COVID-19 and were associated with the MUC1 variant. Therefore, serum KL-6 level is a potentially useful biomarker of critical COVID-19 outcomes.

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

Edahiro R., Shirai Y., Takeshima Y., Sakakibara S., Yamaguchi Y., Murakami T., Morita T., Kato Y., Liu Y.C., Motooka D., Naito Y., Takuwa A., Sugihara F., Tanaka K., Wing J.B., Sonehara K., Tomofuji Y., Wang Q.S., Hasegawa T., Saiki R., Hyugaji T., Shimizu E., Katayama K., Kanai M., Naito T., Sasa N., Yamamoto K., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Ichikawa M., Nakamura A., Harada S., Sandhu Y., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K., Ueda T., Azuma M., Saito R., Sado T.

Nature Genetics 55 ( 5 ) 753 - 767 2023.05

ISSN 10614036

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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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 2023.04

ISSN 1341321X

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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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.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 128 121 - 127 2023.03

ISSN 12019712

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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An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2.

Katherine C Barnett*, Yuying Xie*, Takanori Asakura*, Dingka Song, Kaixin Liang, Sharon A Taft-Benz, Haitao Guo, Shuangshuang Yang, Kenichi Okuda, Rodney C Gilmore, Jennifer F Loome, Thomas H Oguin Iii, Gregory D Sempowski, Scott H Randell, Mark T Heise, Yu Leo Lei, Richard C Boucher, Jenny P-Y Ting

Cell host & microbe 31 ( 2 ) 243 - 259.e6 2023.02

ISSN 19313128

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19.

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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 2023.01

ISSN 14628902

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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Nasopharyngeal Mycobacterium abscessus Infection: A Case Report and Literature Review.

Masanori Kaji, Ho Namkoong, Genta Nagao, Shuhei Azekawa, Kensuke Nakagawara, Hiromu Tanaka, Atsuho Morita, Takanori Asakura, Hirofumi Kamata, Yoshifumi Uwamino, Mitsunori Yoshida, Koichi Fukunaga, Naoki Hasegawa

Infection and drug resistance 16 3955 - 3963 2023

BACKGROUND: Mycobacterium abscessus (M. abscessus) is a rapidly growing bacterium (RGM) that causes refractory pulmonary and extrapulmonary infections. However, studies investigating pharyngeal and laryngeal M. abscessus infections are limited. CASE PRESENTATION: A 41-year-old immunocompetent woman complaining of bloody sputum was referred to our hospital. Although her sputum culture tested positive for M. abscessus subsp. abscessus, radiological findings were not indicative of pulmonary infection or sinusitis. Further diagnostic workup, including laryngeal endoscopy and positron emission tomography/computed tomography (PET/CT), confirmed the presence of nasopharyngeal M. abscessus infection. The patient was initially treated with intravenous amikacin, imipenem/cilastatin, azithromycin, and clofazimine for 28 days, after which the patient was provided with amikacin, azithromycin, clofazimine, and sitafloxacin for four months. After the completion of antibiotic therapy, the patient showed negative results on sputum smear and culture and normal findings on PET/CT and laryngeal endoscopy. Whole-genome sequencing of this strain revealed that it belonged to the ABS-GL4 cluster, which has a functional erythromycin ribosomal methylase gene, although it is not a major lineage in non-cystic fibrosis (CF) patients in Japan and Taiwan and in CF patients in European countries. We conducted a literature review and identified seven patients who developed pharyngeal/laryngeal non-tuberculous mycobacterium (NTM) infection. Four of the eight patients had a history of immunosuppressant use, including steroids. Seven of the eight patients responded well to their treatment regimens. CONCLUSION: Patients whose sputum culture tests are positive for NTM and who meet the diagnostic criteria for NTM infection but do not have intrapulmonary lesions should be evaluated for otorhinolaryngological infections. Our case series revealed that immunosuppressant use is a risk factor for pharyngeal/laryngeal NTM infection and that patients with pharyngeal/laryngeal NTM infections respond relatively well to antibiotic therapy.

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Epidemiological characteristics of nontuberculous mycobacteriosis and bronchiectasis: comparative study using national mortality statistics from 1970 to 2015 in Japan.

Kozo Morimoto, Kazuro Iwai, Takashi Yoshiyama, Masashi Ito, Fumiko Uesugi, Takanori Asakura, Takeshi Osawa, Koji Furuuchi, Atsuyuki Kurashima, Keiji Fujiwara, Naoki Hasegawa, Yoshiaki Tanaka, Kudoh Shoji, Yuji Shiraishi, Satoshi Mitarai, Manabu Ato, Ken Ohta

ERJ open research 9 ( 1 ) 2023

BACKGROUND: This study assessed longitudinal national data on mortality due to nontuberculous mycobacteriosis (NTMosis) and bronchiectasis and the association between the two diseases. METHODS: We analysed the national death statistics of Japan from 1970 to 2015. The International Classification of Disease (ICD) codes were used to extract the relevant data. Crude mortality, age-adjusted mortality and standardised mortality rates were calculated using vital statistics and the population in 2000. We also identified domestic publications related to NTMosis and bronchiectasis with an internet-based search system. RESULTS: The total number of bronchiectasis-related deaths remained at the same level, which was approximately 1000, for 45 years, although the number of deaths has consistently decreased in males but increased in females since the mid-1990s. A substantial increasing trend in females was also observed for NTMosis in the same period. The age-adjusted mortality data showed an increase in mortality in women due to NTMosis and confirmed the trend in bronchiectasis in women. The patterns in the number of domestic reports showed a recent slight increase in bronchiectasis and a marked increase in NTMosis. CONCLUSIONS: The trends in bronchiectasis-related mortality differed by sex. The epidemiological trends in the two diseases were associated, especially in elderly females since the mid-1990s. It is suggested that pulmonary NTMosis without pre-existing bronchiectasis might be a leading cause of postinfectious bronchiectasis in Japan.

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Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration

Yu Mikami, Barbara R. Grubb, Troy D. Rogers, Hong Dang, Takanori Asakura, Pradeep Kota, Rodney C. Gilmore, Kenichi Okuda, Lisa C. Morton, Ling Sun, Gang Chen, Jason A. Wykoff, Camille Ehre, Juan Vilar, Catharina van Heusden, Alessandra Livraghi-Butrico, Martina Gentzsch, Brian Button, M. Jackson Stutts, Scott H. Randell, Wanda K. O’Neal, Richard C. Boucher

Science Translational Medicine (American Association for the Advancement of Science (AAAS)) 15 ( 699 ) eabo7728 2023

Accepted, ISSN 19466234

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O 2 , airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased EGLN3 expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na + and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of β and γENaC (epithelial Na + channel) subunit expression. The combination of increased Na + absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA–in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.

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ALK-positive lung adenocarcinoma in a patient with rheumatoid arthritis with long-term treatment for organizing pneumonia: A case report.

Kazuhito Horie, Takanori Asakura, Keita Masuzawa, Hideki Terai, Sohei Nakayama, Yusuke Suzuki

Medicine 101 ( 49 ) e32159 2022.12

ISSN 00257974

RATIONALE: Rheumatoid arthritis (RA) causes inflammation in various organs including the lungs. Pulmonary manifestations include inflammation of the pleura, vasculature, airway, and parenchyma, including interstitial lung disease (ILD). RA-organizing pneumonia (OP) is the third most common cause of RA-ILD. Cases of OP coexisting/complicated with lung cancer have been reported. Therefore, lung cancer can represent a diagnostic challenge, especially in patients with underlying pulmonary diseases including OP. PATIENT CONCERNS: An 81-year-old woman with a 12-year history of RA-OP underwent multiple transbronchial lung biopsies (TBLBs), all of which resulted in no malignant findings. She was treated with prednisolone (PSL) depending on the deteriorated infiltrations. At admission, chest computed tomography (CT) images showed exacerbation of left S8 consolidation on chest CT. Additionally, her RA activity was exacerbated, and PSL dose was increased to 30 mg/day, which resulted in improved dyspnea and consolidation. Accordingly, PSL dose was gradually decreased. However, 6 months later, when PSL dose was 11 mg/d, due to a worsening of consolidation and the joint symptoms of RA, PSL dose was increased to 20 mg/d and tacrolimus 2 mg/d was administered. 3 months after the increase in PSL dose, dyspnea improved and PSL dose was reduced to 15 mg/d; however, she was admitted to our hospital because of low back pain. DIAGNOSIS: Spinal magnetic resonance imaging showed bone metastases in the third and fifth lumbar vertebrae, and lung cancer was suspected as the primary tumor on CT. INTERVENTIONS: TBLB was performed on the left B8 infiltrate, which showed no evidence of malignancy in the previous TBLB. OUTCOMES: Pathological examination of TBLB on the left B8 revealed an adenocarcinoma that was positive for anaplastic lymphoma kinase. LESSONS: Physicians should be aware of the development of lung cancer in regions with OP, even after a partial response to corticosteroid therapy.

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Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer.

Naofumi Kameyama, Takashi Sato, Daisuke Arai, Daisuke Fujisawa, Mari Takeuchi, Ichiro Nakachi, Ichiro Kawada, Hiroyuki Yasuda, Shinnosuke Ikemura, Hideki Terai, Shigenari Nukaga, Yasushi Nakano, Toshiyuki Hirano, Naoto Minematsu, Takanori Asakura, Takashi Kamatani, Kyuto Tanaka, Shoji Suzuki, Masayoshi Miyawaki, Katsuhiko Naoki, Koichi Fukunaga, Kenzo Soejima

JCO oncology practice 18 ( 12 ) E1977 - E1986 2022.12

ISSN 26881527

PURPOSE: Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors. METHODS: Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined. RESULTS: Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale. CONCLUSION: Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

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Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.

Takafumi Kato*, Takanori Asakura*, Caitlin E Edwards, Hong Dang, Yu Mikami, Kenichi Okuda, Gang Chen, Ling Sun, Rodney C Gilmore, Padraig Hawkins, Gabriela De la Cruz, Michelle R Cooley, Alexis B Bailey, Stephen M Hewi, Daniel S Chertow, Alain C Borczuk, Steven Salvatore, Fernando J Martinez, Leigh B Thorne, Frederic B Askin, Camille Ehre, Scott H Randell, Wanda K O'Neal, Ralph S Baric, Richard C Boucher

American journal of respiratory and critical care medicine 206 ( 11 ) 1336 - 1352 2022.12

ISSN 1073449X

RATIONALE: The incidence and sites of mucus accumulation, and molecular regulation of mucin gene expression, in COVID-19 lung disease have not been reported. OBJECTIVES: Characterize incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. METHODS: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by AB-PAS and immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. SARS-CoV-2-infected human bronchial epithelial (HBE) cultures were utilized to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. MEASUREMENTS AND MAIN RESULTS: MUC5B and variably MUC5AC RNA levels were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the sub-acute/chronic disease phase following SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of COVID-19 subjects in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days post inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days post inoculation. SARS-CoV-2 infection of HBE cultures induced expression of EGFR ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways, or dexamethasone administration, reduced SARS-CoV-2-induced mucin expression. CONCLUSIONS: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation post SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Characteristics of hospitalized patients with COVID-19 during the first to fifth waves of infection: a report from the Japan COVID-19 Task Force.

Ho Lee, Shotaro Chubachi, Ho Namkoong, Takanori Asakura, 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

BMC infectious diseases 22 ( 1 ) 935 - 935 2022.12

ISSN 2186-5884

BACKGROUND: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. METHODS: We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. RESULTS: Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. CONCLUSIONS: We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

Wang Q.S., Edahiro R., Namkoong H., Hasegawa T., Shirai Y., Sonehara K., Tanaka H., Lee H., Saiki R., Hyugaji T., Shimizu E., Katayama K., Kanai M., Naito T., Sasa N., Yamamoto K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Ichikawa M., Nakamura A., Harada S., Sandhu Y., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K., Ueda T., Azuma M., Saito R., Sado T., Miyazaki Y., Sato R., Haruta Y., Nagasaki T., Yasui Y., Hasegawa Y., Mutoh Y., Kimura T., Sato T.

Nature Communications 13 ( 1 ) 2022.12

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

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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 2022.12

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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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 2022.12

ISSN 14659921

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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Clinical utility of whole body diffusion-weighted imaging in an immunocompetent adult with atypical cat scratch disease.

Jin Kagatani, Takanori Asakura, Katsutoshi Sekine, Hiromi Watanabe, Miki Kawada, Kiyofumi Ohkusu, Takashi Koyama

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 11 ) 1558 - 1561 2022.11

ISSN 1341321X

BACKGROUND: Cat scratch disease (CSD) is an infectious disease caused by Bartonella henselae. CSD follows a typical course, characterized by regional lymphadenopathy. In atypical CSD, the lesions spread to systemic organs and can cause fever of unknown origin (FUO). A previous study showed the usefulness of whole-body magnetic resonance imaging (WB-MRI) without diffusion-weighted imaging (DWI) in the diagnosis of FUO, but there are no studies on the clinical utility of whole-body DWI (WB-DWI). We herein report the case of an immunocompetent young man in whom contrast-enhanced CT-unidentifiable multiple liver abscess and osteomyelitis were successfully detected by WB-DWI. Follow up with a liver biopsy helped confirm an atypical CSD diagnosis. CASE PRESENTATION: A 23-year-old previously healthy man was admitted for a 19-day history of high fever despite 3-day treatment by azithromycin. His physical examination was unremarkable and contrast-enhanced CT showed only a low attenuated area in the right lobe of the liver, indicating a cyst. WB-DWI revealed multiple nodular lesions of hypo-diffusion in the liver, spine, and pelvic region. The biopsy specimens of the liver abscess showed no evidence of tuberculosis/malignancy and the polymerase chain reaction (PCR) test of liver abscess aspirate showed positive findings for B. henselae, confirming the diagnosis of CSD. He completed minocycline monotherapy for a total of 60 days without any deterioration. CONCLUSIONS: WB-DWI can be useful for the diagnosis of atypical CSD with hepatic and bone involvement, which can cause FUO in young immunocompetent adults.

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SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice.

Kenneth H Dinnon 3rd, Sarah R Leist, Kenichi Okuda, Hong Dang, Ethan J Fritch, Kendra L Gully, Gabriela De la Cruz, Mia D Evangelista, Takanori Asakura, Rodney C Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E Gralinski, Jamie L Everman, Satria P Sajuthi, Mark R Zweigart, Stephanie Dong, Jennifer McBride, Michelle R Cooley, Jesse B Hines, Miriya K Love, Steve D Groshong, Alison VanSchoiack, Stefan J Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E Zumwalt, Lisa M Barton, Eric J Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B Thorne, Muthu K Sakthivel, Yueh Z Lee, James S Hagood, Jason R Mock, Max A Seibold, Wanda K O'Neal, Stephanie A Montgomery, Richard C Boucher, Ralph S Baric

Science translational medicine 14 ( 664 ) eabo5070 2022.09

ISSN 19466234

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

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DOCK2 is involved in the host genetics and biology of severe COVID-19

Namkoong H., Edahiro R., Takano T., Nishihara H., Shirai Y., Sonehara K., Tanaka H., Azekawa S., Mikami Y., Lee H., Hasegawa T., Okudela K., Okuzaki D., Motooka D., Kanai M., Naito T., Yamamoto K., Wang Q.S., Saiki R., Ishihara R., Matsubara Y., Hamamoto J., Hayashi H., Yoshimura Y., Tachikawa N., Yanagita E., Hyugaji T., Shimizu E., Katayama K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Aoki R., Nakamura A., Harada S., Sasano H., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K.

Nature 609 ( 7928 ) 754 - 760 2022.09

ISSN 00280836

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

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SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13.

Cameron B Morrison, Caitlin E Edwards, Kendall M Shaffer, Kenza C Araba, Jason A Wykoff, Danielle R Williams, Takanori Asakura, Hong Dang, Lisa C Morton, Rodney C Gilmore, Wanda K O'Neal, Richard C Boucher, Ralph S Baric, Camille Ehre

Proceedings of the National Academy of Sciences of the United States of America 119 ( 16 ) e2119680119 2022.04

ISSN 00278424

Significance Gaining insights into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) high transmissibility and the role played by inflammatory mediators in viral proliferation are critical to investigating new therapeutic targets against COVID-19. Electron microscopy reveals important SARS-CoV-2 features, including the combination of large, rapidly released viral clusters and the massive shedding of epithelial cells packed with virions. Interleukin-13 (IL-13), a Th2 cytokine up-regulated in allergic asthma and associated with less severe COVID-19, protects against SARS-CoV-2 viral and cell shedding. Using gene expression analyses and biochemical assays, IL-13 is shown to affect viral entry, replication, and cell-to-cell transmission. Given the broad spectrum of COVID-19 clinical symptoms, it is important to elucidate intrinsic factors that modulate viral load and spreading mechanisms.

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Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.

Oisin F McElvaney, Takanori Asakura, Suzanne L Meinig, Jose L Torres-Castillo, Robert S Hagan, Claudie Gabillard-Lefort, Mark P Murphy, Leigh B Thorne, Alain Borczuk, Emer P Reeves, Ross E Zumwalt, Yu Mikami, Tomas P Carroll, Kenichi Okuda, Grace Hogan, Oliver J McElvaney, Jennifer Clarke, Natalie L McEvoy, Patrick W Mallon, Cormac McCarthy, Ger Curley, Matthew C Wolfgang, Richard C Boucher, Noel G McElvaney

EBioMedicine 77 103894 - 103894 2022.03

BACKGROUND: Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. METHODS: Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. FINDINGS: AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. INTERPRETATION: There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. FUNDING: NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

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A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies.

Kenneth H Dinnon, Sarah R Leist, Kenichi Okuda, Hong Dang, Ethan J Fritch, Kendra L Gully, Gabriela De la Cruz, Mia D Evangelista, Takanori Asakura, Rodney C Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E Gralinski, Jamie L Everman, Satria P Sajuthi, Mark R Zweigart, Stephanie Dong, Jennifer McBride, Michelle R Cooley, Jesse B Hines, Miriya K Love, Steve D Groshong, Alison VanSchoiack, Stefan J Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E Zumwalt, Lisa M Barton, Eric J Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B Thorne, Muthu K Sakthivel, Yueh Z Lee, James S Hagood, Jason R Mock, Max A Seibold, Wanda K O'Neal, Stephanie A Montgomery, Richard C Boucher, Ralph S Baric

bioRxiv : the preprint server for biology 2022.02

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

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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

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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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

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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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature 600 ( 7889 ) 472 - 477 2021.12

ISSN 00280836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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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 2021.11

ISSN 10400605

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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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 2021.09

ISSN 23296933

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

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

The European respiratory journal 58 ( 2 ) 2021.08

ISSN 09031936

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

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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 (Elsevier BV) 185 106515 - 106515 2021.08

ISSN 09546111

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 (FEV<inf>1</inf>), 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 FEV<inf>1</inf> (% 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 %FEV<inf>1.</inf> The SGRQ total score may be an important prognostic factor.

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Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.

Kenichi Okuda, Hong Dang, Yoshihiko Kobayashi, Gianni Carraro, Satoko Nakano, Gang Chen, Takafumi Kato, Takanori Asakura, Rodney C Gilmore, Lisa C Morton, Rhianna E Lee, Teresa Mascenik, Wei-Ning Yin, Selene Margarita Barbosa Cardenas, Yvonne K O'Neal, Caroline E Minnick, Michael Chua, Nancy L Quinney, Martina Gentzsch, Carlton W Anderson, Andrew Ghio, Hirotoshi Matsui, Takahide Nagase, Lawrence E Ostrowski, Barbara R Grubb, John C Olsen, Scott H Randell, Barry R Stripp, Purushothama Rao Tata, Wanda K O'Neal, Richard C Boucher

American journal of respiratory and critical care medicine 203 ( 10 ) 1275 - 1289 2021.05

ISSN 1073449X

RATIONALE: Identification of the specific cell types expressing CFTR is required for precision medicine therapies for cystic fibrosis (CF). However, a full characterization of CFTR expression in normal human airway epithelia is missing. OBJECTIVES: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. METHODS: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells. MEASUREMENTS AND MAIN RESULTS: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airway superficial epithelia, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion in culture tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells, and not ionocytes. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells. CONCLUSIONS: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.

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Complete Genome Sequence of Mycobacterium heckeshornense JCM 15655T, Closely Related to a Pathogenic Nontuberculous Mycobacterial Species, Mycobacterium xenopi.

Mitsunori Yoshida, Hanako Fukano, Takanori Asakura, Masato Suzuki, Yoshihiko Hoshino

Microbiology resource announcements 10 ( 10 ) 2021.03

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A novel DNA chromatography method to discriminate Mycobacterium abscessus subspecies and macrolide susceptibility.

Mitsunori Yoshida, Sotaro Sano, Jung-Yien Chien, Hanako Fukano, Masato Suzuki, Takanori Asakura, Kozo Morimoto, Yoshiro Murase, Shigehiko Miyamoto, Atsuyuki Kurashima, Naoki Hasegawa, Po-Ren Hsueh, Satoshi Mitarai, Manabu Ato, Yoshihiko Hoshino

EBioMedicine 64 103187 - 103187 2021.02

BACKGROUND: The clinical impact of infection with Mycobacterium (M.) abscessus complex (MABC), a group of emerging non-tuberculosis mycobacteria (NTM), is increasing. M. abscessus subsp. abscessus/bolletii frequently shows natural resistance to macrolide antibiotics, whereas M. abscessus subsp. massiliense is generally susceptible. Therefore, rapid and accurate discrimination of macrolide-susceptible MABC subgroups is required for effective clinical decisions about macrolide treatments for MABC infection. We aimed to develop a simple and rapid diagnostic that can identify MABC isolates showing macrolide susceptibility. METHODS: Whole genome sequencing (WGS) was performed for 148 clinical or environmental MABC isolates from Japan to identify genetic markers that can discriminate three MABC subspecies and the macrolide-susceptible erm(41) T28C sequevar. Using the identified genetic markers, we established PCR based- or DNA chromatography-based assays. Validation testing was performed using MABC isolates from Taiwan. FINDING: We identified unique sequence regions that could be used to differentiate the three subspecies. Our WGS-based phylogenetic analysis indicated that M. abscessus carrying the macrolide-susceptible erm(41) T28C sequevar were tightly clustered, and identified 11 genes that were significantly associated with the lineage for use as genetic markers. To detect these genetic markers and the erm(41) locus, we developed a DNA chromatography method that identified three subspecies, the erm(41) T28C sequevar and intact erm(41) for MABC in a single assay within one hour. The agreement rate between the DNA chromatography-based and WGS-based identification was 99·7%. INTERPRETATION: We developed a novel, rapid and simple DNA chromatography method for identification of MABC macrolide susceptibility with high accuracy. FUNDING: AMED, JSPS KAKENHI.

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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 13237799

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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Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.

Hiroaki Katsura, Vishwaraj Sontake, Aleksandra Tata, Yoshihiko Kobayashi, Caitlin E Edwards, Brook E Heaton, Arvind Konkimalla, Takanori Asakura, Yu Mikami, Ethan J Fritch, Patty J Lee, Nicholas S Heaton, Richard C Boucher, Scott H Randell, Ralph S Baric, Purushothama Rao Tata

Cell stem cell 27 ( 6 ) 890 - 904 2020.10

Accepted

Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirror features of COVID-19 lungs, including emergence of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases.

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Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis.

Shunsuke Uno, Takanori Asakura, Kozo Morimoto, Kimio Yoshimura, Yoshifumi Uwamino, Tomoyasu Nishimura, Yoshihiko Hoshino, Naoki Hasegawa

BMC pulmonary medicine 20 ( 1 ) 262 - 262 2020.10

Accepted

BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

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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

Accepted

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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SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.

Yixuan J Hou, Kenichi Okuda, Caitlin E Edwards, David R Martinez, Takanori Asakura, Kenneth H Dinnon 3rd, Takafumi Kato, Rhianna E Lee, Boyd L Yount, Teresa M Mascenik, Gang Chen, Kenneth N Olivier, Andrew Ghio, Longping V Tse, Sarah R Leist, Lisa E Gralinski, Alexandra Schäfer, Hong Dang, Rodney Gilmore, Satoko Nakano, Ling Sun, M Leslie Fulcher, Alessandra Livraghi-Butrico, Nathan I Nicely, Mark Cameron, Cheryl Cameron, David J Kelvin, Aravinda de Silva, David M Margolis, Alena Markmann, Luther Bartelt, Ross Zumwalt, Fernando J Martinez, Steven P Salvatore, Alain Borczuk, Purushothama R Tata, Vishwaraj Sontake, Adam Kimple, Ilona Jaspers, Wanda K O'Neal, Scott H Randell, Richard C Boucher, Ralph S Baric

Cell 182 ( 2 ) 429 - 446 2020.07

Accepted

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

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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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Complete Genome Sequence of Mycobacterium xenopi JCM15661T, Obtained Using Nanopore and Illumina Sequencing Technologies.

Mitsunori Yoshida, Hanako Fukano, Takanori Asakura, Junzo Hisatsune, Yoshihiko Hoshino

Microbiology resource announcements 9 ( 10 ) 2020.03

Accepted

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Placental transmogrification of the lung masquerading as difficult-to-treat pneumonia.

K Horiuchi, T Asakura, S Sakaguchi, F Saito, J Yamamoto

QJM : monthly journal of the Association of Physicians 113 ( 3 ) 213 - 214 2020.03

Accepted, ISSN 1460-2725

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Correction to: Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

Yoshifumi Uwamino, Tomoyasu Nishimura, Yasunori Sato, Eiko Tamizu, Takanori Asakura, Shunsuke Uno, Masaaki Mori, Hiroshi Fujiwara, Makoto Ishii, Hiroshi Kawabe, Mitsuru Murata, Naoki Hasegawa

BMC infectious diseases 20 ( 1 ) 131 - 131 2020.02

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Long-Lasting Response to Nivolumab for a Patient With Lynch Syndrome-Associated Lung Adenocarcinoma.

Keita Masuzawa, Takanori Asakura, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Kawada, Sosuke Takaoka, Yuichiro Hayashi, Takeshi Nakajima, Masami Arai, Koichi Fukunaga, Kenzo Soejima

JCO precision oncology 4 2020

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Pneumothorax associated with giant bullous emphysema and mediastinum deviation.

Kohei Horiuchi, Takanori Asakura, Junichi Ochi, Fumitake Saito

BMJ case reports 12 ( 12 ) 2019.12

Accepted

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Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.

Yoshifumi Uwamino, Tomoyasu Nishimura, Yasunori Sato, Eiko Tamizu, Takanori Asakura, Shunsuke Uno, Masaaki Mori, Hiroshi Fujiwara, Makoto Ishii, Hiroshi Kawabe, Mitsuru Murata, Naoki Hasegawa

BMC infectious diseases 19 ( 1 ) 1055 - 1055 2019.12

Accepted

BACKGROUND: The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women. METHODS: This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age- and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age- and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE). RESULTS: Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 μg/dL vs. 114.0 μg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age- and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001). CONCLUSIONS: Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.

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Superior vena cava syndrome.

K Horiuchi, T Asakura, F Saito, T Asakura

QJM : monthly journal of the Association of Physicians 112 ( 9 ) 703 - 704 2019.09

Accepted

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Rhabdomyolysis diagnosed in an older woman with dementia on examination after a wandering episode.

Kohei Horiuchi, Takanori Asakura, Nobuhiro Ikeda

Geriatrics & gerontology international 19 ( 9 ) 956 - 957 2019.09

Accepted, ISSN 1444-1586

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Successful osimertinib treatment in a patient who exhibited intramedullary spinal cord metastases of lung adenocarcinoma with an acquired EGFR T790M mutation.

Kohei Horiuchi, Takanori Asakura, Shinji Sakaguchi, Fumitake Saito

BMJ case reports 12 ( 6 ) 2019.06

Accepted

Intramedullary spinal cord metastases (ISCMs) of non-small cell lung cancer (NSCLC) constitute a serious if infrequent complication, characterised by rapid progression of neurological deficits, with poor prognosis. We describe a 52-year-old man with ISCMs secondary to lung adenocarcinoma who acquired the T790M mutation of the epidermal growth factor receptor (EGFR) after previous use of a first-generation EGFR tyrosine kinase inhibitor (TKI); he was successfully treated with osimertinib. This is the first report of the use of osimertinib in ISCMs: due to its high central nervous system activity, osimertinib could be useful for treating ISCMs secondary to NSCLC in patients who exhibit the T790M mutation.

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The eggs of Paragonimiasis westermani in bronchial lavage fluid.

K Masaki, T Asakura, I Nakachi

QJM : monthly journal of the Association of Physicians 112 ( 6 ) 463 - 464 2019.06

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Adenovirus type 5 community-acquired pneumonia in an immunocompetent patient.

Katsunori Masaki, Takanori Asakura, Kaori Sakurai, Kiyofumi Ohkusu

BMJ case reports 12 ( 4 ) 2019.04

Accepted

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Bilateral chylothorax associated with osteophytes in an elderly patient.

Kohei Horiuchi, Takanori Asakura, Shinji Sakaguchi, Fumitake Saito

BMJ case reports 12 ( 4 ) 2019.04

Accepted

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Disseminated histoplasmosis from a calcified lung nodule after long-term corticosteroid therapy in an elderly Japanese patient: A case report.

Keigo Kobayashi, Takanori Asakura, Ichiro Kawada, Hanako Hasegawa, Shotaro Chubachi, Kentaro Ohara, Junko Kuramoto, Hiroaki Sugiura, Seitaro Fujishima, Satoshi Iwata, Takashi Umeyama, Harutaka Katano, Yoshifumi Uwamino, Yoshitsugu Miyazaki, Katsuhiko Kamei, Naoki Hasegawa, Tomoko Betsuyaku

Medicine 98 ( 17 ) e15264 2019.04

Accepted

RATIONALE: Histoplasmosis occurs most commonly in Northern and Central America and Southeast Asia. Increased international travel in Japan has led to a few annual reports of imported histoplasmosis. Healed sites of histoplasmosis lung infection may remain as nodules and are often accompanied by calcification. Previous studies in endemic areas supported the hypothesis that new infection/reinfection, rather than reactivation, is the main etiology of symptomatic histoplasmosis. No previous reports have presented clinical evidence of reactivation. PATIENT CONCERNS: An 83-year-old Japanese man was hospitalized with general fatigue and high fever. He had been treated with prednisolone at 13 mg/d for 7 years because of an eczematous skin disease. He had a history of travel to Los Angeles, Egypt, and Malaysia 10 to 15 years prior to admission. Five years earlier, computed tomography (CT) identified a solitary calcified nodule in the left lingual lung segment. The nodule size remained unchanged throughout a 5-year observation period. Upon admission, his respiratory condition remained stable while breathing room air. CT revealed small, randomly distributed nodular shadows in the bilateral lungs, in addition to the solitary nodule. DIAGNOSIS: Disseminated histoplasmosis, based on fungal staining and cultures of autopsy specimens. INTERVENTIONS: The patient's fever continued despite several days of treatment with meropenem, minocycline, and micafungin. Although he refused bone marrow aspiration, isoniazid, rifampicin, ethambutol, and prednisolone were administered for a tentative diagnosis of miliary tuberculosis. OUTCOMES: His fever persisted, and a laboratory examination indicated severe thrombocytopenia with disseminated intravascular coagulation. He died on day 43 postadmission. During autopsy, the fungal burden was noted to be higher in the calcified nodule than in the disseminated nodules of the lung, suggesting a pathogenesis involving endogenous reactivation of the nodule and subsequent hematogenous and lymphatic spread. LESSONS: Physicians should consider histoplasmosis in patients with calcified nodules because the infection may reactivate during long-term corticosteroid therapy.

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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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Infectious tenosynovitis of the long head of the biceps caused by methicillin-resistant Staphylococcus aureus in a patient with diabetes and small cell lung cancer.

Kohei Horiuchi, Takanori Asakura, Yuki Bessho, Fumitake Saito

BMJ case reports 12 ( 3 ) 2019.03

Accepted

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Development of lung cancer in patients with nontuberculous mycobacterial lung disease.

Tatsuya Kusumoto, Takanori Asakura, Shoji Suzuki, Satoshi Okamori, Ho Namkoong, Hiroshi Fujiwara, Kazuma Yagi, Hirofumi Kamata, Makoto Ishii, Tomoko Betsuyaku, Naoki Hasegawa

Respiratory investigation (Elsevier {BV}) 57 ( 2 ) 157 - 164 2019.03

Accepted

BACKGROUND: As lung cancer development in patients with nontuberculous mycobacterial lung disease (NTM-LD) has never been reported, we investigated its incidence and clinical characteristics. METHODS: Prospective observational cohort registry (from June 2012 to June 2017), and retrospective identification by the International Classification of Diseases, tenth revision (between March 2010 and March 2018), were used to identify NTM-LD patients aged ≥20 years who developed lung cancer. RESULTS: Eight patients (two men and six women, one with smoking history), having Mycobacterium avium complex lung disease (MAC-LD) were identified. Four were identified from retrospective chart reviews and four from the prospective observational cohort registry (n = 361, 289 women; 311 never-smokers). All patients underwent chest computed tomography (CT) at least once a year. The incidence rate of lung cancer developing in NTM-LD patients was 124.6 per 100,000 patient-years, which was higher than the lung cancer rate in Japan. The mean age at diagnosis of MAC-LD and lung cancer was 63.6 and 74.4 years, respectively. The most common lung cancer types were adenocarcinoma (six patients) followed by squamous cell carcinoma (two patients). Lung cancer was diagnosed at early and advanced clinical stages in seven and one patients, respectively. Outcomes were favorable, except in two patients: one with advanced stage disease, and another with poor performance status. CONCLUSIONS: We identified the clinical characteristics of eight MAC-LD patients who developed lung cancer. NTM-LD may be a risk factor for lung cancer development. Periodic follow-up with chest CT might contribute to early diagnosis and curative therapy for lung cancer.

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Superior vena cava syndrome.

Horiuchi K, Asakura T, Saito F

QJM : monthly journal of the Association of Physicians 2019.03

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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 (Elsevier {BV}) 25 ( 3 ) 218 - 221 2019.03

Accepted, ISSN 1341-321X

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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Black pleural effusion caused by pancreatic pseudocyst rupture.

Sho Ishigaki, Misato Kuwae, Makoto Ishii, Takanori Asakura, Soichiro Ueda, Tomoko Betsuyaku

Clinical case reports (Clinical Case Reports) 7 ( 2 ) 385 - 386 2019.02

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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, E Iwasaki, Y Yamagishi, T Kanai, T Betsuyaku, N Hasegawa

New microbes and new infections 27 4 - 6 2019.01

Accepted

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Airway M Cells Arise in the Lower Airway Due to RANKL Signaling and Reside in the Bronchiolar Epithelium Associated With iBALT in Murine Models of Respiratory Disease.

Shunsuke Kimura, Mami Mutoh, Meri Hisamoto, Hikaru Saito, Shun Takahashi, Takanori Asakura, Makoto Ishii, Yutaka Nakamura, Junichiro Iida, Koji Hase, Toshihiko Iwanaga

Frontiers in immunology 10 1323 - 1323 2019

Accepted

Microfold (M) cells residing in the follicle-associated epithelium of mucosa-associated lymphoid tissues are specialized for sampling luminal antigens to initiate mucosal immune responses. In the past decade, glycoprotein 2 (GP2) and Tnfaip2 were identified as reliable markers for M cells in the Peyer's patches of the intestine. Furthermore, RANKL-RANK signaling, as well as the canonical and non-canonical NFκB pathways downstream, is essential for M-cell differentiation from the intestinal stem cells. However, the molecular characterization and differentiation mechanisms of M cells in the lower respiratory tract, where organized lymphoid tissues exist rarely, remain to be fully elucidated. Therefore, this study aimed to explore M cells in the lower respiratory tract in terms of their specific molecular markers, differentiation mechanism, and functions. Immunofluorescence analysis revealed a small number of M cells expressing GP2, Tnfaip2, and RANK is present in the lower respiratory tract of healthy mice. The intraperitoneal administration of RANKL in mice effectively induced M cells, which have a high capacity to take up luminal substrates, in the lower respiratory epithelium. The airway M cells associated with lymphoid follicles were frequently detected in the pathologically induced bronchus-associated lymphoid tissue (iBALT) in the murine models of autoimmune disease as well as pulmonary emphysema. These findings demonstrate that RANKL is a common inducer of M cells in the airway and digestive tracts and that M cells are associated with the respiratory disease. We also established a two-dimensional culture method for airway M cells from the tracheal epithelium in the presence of RANKL successfully. This model may be useful for functional studies of M cells in the sampling of antigens at airway mucosal surfaces.

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Lung cancer masquerading as fungus-associated mucoid impaction.

Kohei Horiuchi, Takanori Asakura, Shinji Sakaguchi, Fumitake Saito

BMJ case reports 11 ( 1 ) 2018.12

Accepted

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Recurrence of allergic bronchopulmonary aspergillosis after adjunctive surgery for aspergilloma: a case report with long-term follow-up.

Kohei Horiuchi, Takanori Asakura, Naoki Hasegawa, Fumitake Saito

BMC pulmonary medicine 18 ( 1 ) 185 - 185 2018.12

Accepted

BACKGROUND: Coexistence of aspergilloma and allergic bronchopulmonary aspergillosis (ABPA) has rarely been reported. Although the treatment for ABPA includes administration of corticosteroids and antifungal agents, little is known about the treatment for coexisting aspergilloma and ABPA. Furthermore, the impact of surgical resection for aspergilloma on ABPA is not fully understood. Here, we present an interesting case of recurrent ABPA with long-term follow-up after surgical resection of aspergilloma. CASE PRESENTATION: A 53-year-old man with a medical history of tuberculosis was referred to our hospital with cough and dyspnea. Imaging revealed multiple cavitary lesions in the right upper lobe of the lung, with a fungus ball and mucoid impaction. The eosinophil count, total serum immunoglobulin E (IgE), and Aspergillus-specific IgE levels were elevated. Specimens collected on bronchoscopy revealed fungal filaments compatible with Aspergillus species. Based on these findings, a diagnosis of ABPA with concomitant aspergilloma was made. Although treatment with corticosteroids and antifungal agents was administered, the patient's respiratory symptoms persisted. Therefore, he underwent lobectomy of the right upper lobe, which resulted in a stable condition without the need for medication. Twenty-three months after discontinuation of medical treatment, his respiratory symptoms gradually worsened with a recurrence of elevated eosinophil count and total serum IgE. Imaging revealed recurrent bronchiectasis and cavities with mucoid impaction in the right lower lobe, suggesting relapse of aspergilloma and ABPA. Corticosteroids and antifungal agents were re-administered; aspergilloma improved slightly over a 5-year period, and ABPA remained well controlled with low-dose prednisolone (5 mg/day). CONCLUSIONS: We describe the long-term follow-up outcomes of a patient with concomitant ABPA and aspergilloma, who underwent surgical resection for aspergilloma. Physicians should carefully monitor patients with coexisting ABPA and aspergilloma, as the condition may relapse after remission, even despite surgical resection for aspergilloma. Additionally, surgical resection for aspergilloma could result in resolution of ABPA.

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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, ISSN 0954-6111

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, ISSN 1933-0219

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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Perfusion Defect-Concordant Progression of Unilateral Refractory Pulmonary Mycobacterium avium Complex Disease.

Takanori Asakura, Yoshitake Yamada, Makoto Ishii, Toshiki Ebisudani, Soichiro Ueda, Tomoko Betsuyaku, Naoki Hasegawa

American journal of respiratory and critical care medicine (American Thoracic Society) 198 ( 6 ) 803 - 804 2018.09

Accepted, ISSN 1073-449X

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Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: a case report.

Keigo Kobayashi, Takanori Asakura, Makoto Ishii, Soichiro Ueda, Hidehiro Irie, Hiroyuki Ozawa, Kohei Saitoh, Isao Kurihara, Hiroshi Itoh, Tomoko Betsuyaku

BMC pulmonary medicine 18 ( 1 ) 142 - 142 2018.08

Accepted

BACKGROUND: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. CASE PRESENTATION: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. CONCLUSIONS: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

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Development of Necrotizing Myopathy Following Interstitial Lung Disease with Anti-signal Recognition Particle Antibody.

Tatsuya Kusumoto, Satoshi Okamori, Keita Masuzawa, Takanori Asakura, Naoshi Nishina, Shotaro Chubachi, Katsuhiko Naoki, Koichi Fukunaga, Tomoko Betsuyaku

Internal medicine (Tokyo, Japan) 57 ( 14 ) 2045 - 2049 2018.07

Accepted, ISSN 0918-2918

A 72-year-old man was admitted due to dyspnea on exertion with interstitial shadows and elevated serum creatinine kinase (CK). Despite a close examination, which included magnetic resonance imaging (MRI), we could not diagnose myopathy. Prednisolone was administered and gradually tapered. One year later, anti-signal recognition particle (SRP) antibody was confirmed and he was re-admitted for hypoxemia with elevated CK. MRI revealed muscle edema and a histopathological examination of a muscle biopsy specimen showed necrotizing myopathy. Prednisolone, cyclosporine, and intravenous immunoglobulin were administered. Physicians should carefully monitor muscle symptoms and serum CK levels in cases of interstitial lung disease with anti-SRP antibodies.

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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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Anti-aminoacyl tRNA synthetase antibody-positive clinically amyopathic dermatomyositis.

T Ebisudani, T Asakura, S Ueda, M Ishii, T Betsuyaku

QJM : monthly journal of the Association of Physicians 111 ( 6 ) 425 - 426 2018.06

Accepted

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

The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 22 ( 6 ) 695 - 703 2018.06

Accepted, ISSN 1027-3719

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

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

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 24 ( 6 ) 671 - 672 2018.06

Accepted

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Bilateral upper lobe Pneumocystis pneumonia during aerosolized pentamidine prophylaxis.

Y Ohara, T Asakura, S Ueda, Y Yamada, M Ishii, T Betsuyaku

QJM : monthly journal of the Association of Physicians 111 ( 5 ) 337 - 338 2018.05

Accepted

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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, ISSN 0954-6111

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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Perfusion Defect-concordant Progression of Unilateral Refractory Pulmonary MAC Disease

Asakura, T, Yamada, Y, Ishii, M, Ebisudani, T, Ueda, S, Betsuyaku, T, Hasegawa, N

Am J Respir Crit Care Med 2018.05

Accepted, ISSN 1535-4970

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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, ISSN 1553-7366

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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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, ISSN 1465-3249

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 (Elsevier {BV}) 67 65 - 69 2018.02

Accepted, ISSN 1201-9712

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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Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates: a case report with microbiological analysis.

Satoshi Okamori, Takanori Asakura, Tomoyasu Nishimura, Eiko Tamizu, Makoto Ishii, Mitsunori Yoshida, Hanako Fukano, Yuichiro Hayashi, Masaki Fujita, Yoshihiko Hoshino, Tomoko Betsuyaku, Naoki Hasegawa

BMC infectious diseases 18 ( 1 ) 1 - 1 2018.01

Accepted

BACKGROUND: Presence of Mycobacterium fortuitum in respiratory tracts usually indicates mere colonization or transient infection, whereas true pulmonary infection occurs in patients with gastroesophageal disease. However, little is known about the diagnostic indications for true M. fortuitum pulmonary infection and the natural history of the disease. CASE PRESENTATION: A 59-year-old man was referred to our hospital for treatment against M. fortuitum pulmonary infection. Fifteen years before the referral, he underwent total gastrectomy, after which he experienced esophageal reflux symptoms. After the referral, the patient was closely monitored without antimicrobial therapy because of mild symptoms and no pathological evidence of M. fortuitum pulmonary infection. During the observation, chest imaging showed migratory infiltrates. Two years after the referral, his lung biopsy specimen revealed foamy macrophages and multinucleated giant cells, indicating lipoid pneumonia. However, he was continually monitored without any treatment because there was no evidence of nontuberculous mycobacterial infection. Four years after the referral, he developed refractory pneumonia despite receiving adequate antibiotic therapy. After confirmation of granulomatous lesions, multiple antimicrobial therapy for M. fortuitum resulted in a remarkable improvement with no exacerbation for over 5 years. Random amplified polymorphic DNA polymerase chain reaction analysis revealed identical M. fortuitum strains in seven isolates from six sputum and one intestinal fluid specimens obtained during the course of the disease. CONCLUSIONS: We have described a patient with M. fortuitum pulmonary infection who presented with migratory infiltrates. The pathological evidence and microbiological analysis suggested that M. fortuitum pulmonary infection was associated with lipoid pneumonia and chronic exposure to gastrointestinal fluid. Therefore, physicians should carefully monitor patients with M. fortuitum detected from lower respiratory tract specimens and consider antimicrobial therapy for M. fortuitum infection when the patient does not respond to adequate antibiotic therapy against common pneumonia pathogens.

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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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Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports.

Satoshi Okamori, Takanori Asakura, Keita Masuzawa, Hiroyuki Yasuda, Hirofumi Kamata, Makoto Ishii, Tomoko Betsuyaku

Medicine 96 ( 49 ) e9081 2017.12

Accepted, ISSN 0025-7974

RATIONAL: The efficacy of nintedanib, a multitarget receptor tyrosine kinase inhibitor, has been demonstrated in recent randomized controlled trials involving patients with idiopathic pulmonary fibrosis (IPF). However, accelerated disease progression after nintedanib discontinuation has never been reported. PATIENT CONCERNS: We report 2 cases involving patients with a history of IPF who presented with respiratory deterioration at 3 weeks after the discontinuation of nintedanib therapy for IPF. Neither patient fulfilled the definition of "acute exacerbation of IPF" on unilateral computed tomography. DIAGNOSES: Accelerated disease progression after the discontinuation of nintedanib therapy for IPF. INTERVENTIONS: One patient received steroid therapy. The other patient refused to undergo steroid therapy. OUTCOMES: The first patient showed that the affected lobe exhibited volume loss with traction bronchiectasis after receiving steroid therapy, and succumbed to pneumothorax after 3 months. The other patient was transferred to another hospital because of a decline in his general condition. LESSONS: To our knowledge, this report is the first to document accelerated disease progression after the discontinuation of nintedanib therapy for IPF. Although the accurate mechanism remains unclear, the effects of nintedanib against vascular endothelial growth factor and platelet-derived growth factor receptor may play a role. Our findings suggest that physicians should carefully monitor patients with IPF after nintedanib discontinuation.

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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, ISSN 1058-4838

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, ISSN 1080-6040

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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 (Elsevier {BV}) 126 9 - 16 2017.05

Accepted, ISSN 0954-6111

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, ISSN 1465-993X

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Pulmonary Cryptococcosis Developed from a Nodule after Treatment with Infliximab for Arthritis Associated with Ulcerative Colitis.

Takanori Asakura, Daisuke Arai, Makoto Ishii, Hiroshi Takei, Hiroaki Sugiura, Tsutomu Takeuchi, Tomoko Betsuyaku

Annals of the American Thoracic Society 14 ( 4 ) 603 - 605 2017.04

Accepted, ISSN 2329-6933

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Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis.

Keita Masuzawa, Takanori Asakura, Makoto Ishii, Hiroyuki Yasuda, Hiroaki Sugiura, Tomoko Betsuyaku

IDCases 9 36 - 37 2017

Accepted

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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 - e987 2016.10

Accepted, ISSN 0090-3493

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Successful treatment of non-small-cell lung cancer with afatinib and a glucocorticoid following gefitinib- and erlotinib-induced interstitial lung disease: A case report.

Tetsuo Tani, Katsuhiko Naoki, Takanori Asakura, Toshiyuki Hirano, Shoji Suzuki, Keita Masuzawa, Hanako Hasegawa, Aoi Kuroda, Hiroyuki Yasuda, Makoto Ishii, Kenzo Soejima, Tomoko Betsuyaku

Molecular and clinical oncology 5 ( 4 ) 488 - 490 2016.10

Accepted, ISSN 2049-9450

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-induced interstitial lung disease (ILD) may be a life-threatening condition that may develop during treatment of lung cancer patients harboring EGFR mutations. We herein present the case of a 41-year-old female patient diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion). The patient was treated with gefitinib followed by erlotinib and developed ILD induced by both EGFR-TKIs; furthermore, the patient acquired resistance to EGFR-TKI treatment. A repeat biopsy revealed a T790M mutation, which is associated with resistance to first-generation EGFR-TKIs, along with an exon 19 deletion identified by cytology of the pleural fluid. Treatment with afatinib and prednisolone resulted in tumor shrinkage, without worsening of the ILD. The present case demonstrated that combination treatment with afatinib and a glucocorticoid may be effective for the treatment of lung cancer patients who develop EGFR-TKI-induced ILD.

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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, ISSN 1341-321X

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 ( 1 ) 396 - 396 2016.08

Accepted

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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, ISSN 0025-7974

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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Streptococcus pneumoniae-induced purpura fulminans.

T Asakura, A Higuchi, N Mori

QJM : monthly journal of the Association of Physicians 109 ( 7 ) 499 - 500 2016.07

Accepted

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Finger Fractures as an Early Manifestation of Primary Hyperparathyroidism Among Young Patients: A Case Report of a 30-Year-Old Male With Recurrent Osteoporotic Fractures.

Akihiko Ozaki, Tetsuya Tanimoto, Eiki Yamagishi, Shunsuke Sato, Manabu Tsukada, Toyoaki Sawano, Claire Leppold, Kenji Tsuda, Takanori Asakura, Masaharu Tsubokura, Shigeaki Kato, Masahiro Kami, Hiromichi Ohira

Medicine 95 ( 20 ) e3683 2016.05

Accepted, ISSN 0025-7974

Osteoporosis and osteoporotic fractures represent a substantial health burden, and predominantly affect the elderly. Younger generations may also develop these conditions because of various predisposing conditions, including primary hyperparathyroidism. However, little information is available regarding early skeletal manifestations of primary hyperparathyroidism.A 30-year-old Japanese male presented with pain in his left wrist, and was diagnosed with a distal radius fracture. During surgery, we noticed decreased bone strength of the fracture site. Further investigation found osteoporosis and primary hyperparathyroidism owing to a solitary parathyroid adenoma, which was resected without significant complications. History revealed that the patient suffered a metacarpal bone fracture of his right fifth bone 6 months earlier. Although serial x-rays at that time had shown rapidly developed cortical bone erosion around the fractured finger, the possibility of primary hyperparathyroidism was overlooked because of poor awareness of the condition, leading to a 6-month delay in the diagnosis of primary hyperparathyroidism.Clinicians should be aware that finger fractures may be an early skeletal manifestation of primary hyperparathyroidism that can help achieve a prompt diagnosis of the condition, especially when they occur in young adults in the absence of major trauma.

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Multiple nodular lesions following Pneumocystis pneumonia in a non-HIV immunocompromised patient.

Takanori Asakura, Naofumi Kameyama, Makoto Ishii, Ichiro Kawada, Sadatomo Tasaka, Kenzo Soejima, Tomoko Betsuyaku

Clinical case reports 4 ( 5 ) 528 - 30 2016.05

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, ISSN 0022-1899

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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, ISSN 0025-7974

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 - e6 2016.02

Accepted, ISSN 1073-449X

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Intimal Sarcoma of the Pulmonary Artery Treated with Pazopanib.

Yohei Funatsu, Miwa Hirayama, Junichi Shiraishi, Takanori Asakura, Misa Wakaki, Erina Yamada, Kazuyuki Fujimoto, Ryosuke Satomi, Shunsuke Inaki, Yuya Murata, Yoshitaka Oyamada

Internal medicine (Tokyo, Japan) 55 ( 16 ) 2197 - 202 2016

Accepted, ISSN 0918-2918

Intimal sarcoma is a rare disease with a poor prognosis. We herein report the case of a 71-year-old man with intimal sarcoma of the pulmonary artery treated with pazopanib. The tumor showed regression after 1 month of treatment. Hand-foot syndrome led to cessation of pazopanib, which triggered a disease flare. Pazopanib should be considered in patients with intimal sarcoma of the pulmonary artery that is unresectable or recurrent after surgery or cytotoxic chemotherapy. We must be careful about drug cessation, as it can lead to a disease flare.

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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, ISSN 2164-5515

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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 ( 1 ) 145 - 145 2015.12

Accepted, ISSN 1465-9921

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 ( 1 ) 238 - 238 2015.10

Accepted

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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 ( 1 ) 24 - 24 2015.07

Accepted

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A massive cavitary lesion invading the chest wall.

Takanori Asakura, Yohei Funatsu, Takahiko Oyama, Katsutaka Mineura, Arafumi Maeshima, Takashi Okabe, Hironori Ueno, Takahiro Yano, Yoshitaka Oyamada, Ryoichi Kato

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 34 117 - 8 2015.05

Accepted, ISSN 1201-9712

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Roving eye movements in a patient with hypoglycemic coma.

Takanori Asakura, Nobuaki Mori

Clinical case reports 3 ( 5 ) 335 - 6 2015.05

Accepted

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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 (Libertas Academica Ltd.) 9 ( Suppl 1 ) 147 - 54 2015

Accepted, ISSN 1179-5484

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Small Cell Lung Cancer Expressing Glutamate Decarboxylase with Latent Autoimmune Diabetes in Adults.

Takanori Asakura, Shuichi Yoshida, Arafumi Maeshima, Kazuyuki Fujimoto, Rie Jo, Kyoko Iwase, Yoshitaka Oyamada

Internal medicine (Tokyo, Japan) 54 ( 23 ) 3035 - 7 2015

Accepted, ISSN 0918-2918

Small cell lung cancer (SCLC) causes paraneoplastic syndromes, such as diabetes mellitus, by eliciting the expression of various antibodies including anti-glutamate decarboxylase (GAD) antibody. A 62-year-old woman presented to our hospital with a 1-week history of progressive dyspnea and difficulty in walking. Computed tomography showed a tumor obstructing the left bronchus and obstructive lung abscesses with pleural effusions. A biopsy during bronchoscopy revealed SCLC, and the clinical stage was ultimately determined to be IIIB. SCLC was complicated by diabetes mellitus with high titers of serum anti-GAD antibody. An immunohistochemical analysis showed GAD expression in the cancer cells, which is a novel finding.

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Portosystemic Encephalopathy without Liver Cirrhosis Masquerading as Depression.

Takanori Asakura, Nobutake Ito, Takahiro Sohma, Nobuaki Mori

Internal medicine (Tokyo, Japan) 54 ( 13 ) 1619 - 22 2015

Accepted, ISSN 0918-2918

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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 ( 1 ) 684 - 684 2014.12

Accepted

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Efficacy of empirical therapy with non-carbapenems for urinary tract infections with extended-spectrum beta-lactamase-producing Enterobacteriaceae.

Takanori Asakura, Masayuki Ikeda, Akira Nakamura, Satoshi Kodera

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 29 91 - 5 2014.12

Accepted, ISSN 1201-9712

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Thiamine-responsive pulmonary hypertension.

Takanori Asakura, Satoshi Kodera, Junji Kanda, Masayuki Ikeda

BMJ case reports 2013 2013.01

Accepted

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