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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