Details of a Researcher - Fukunaga, Koichi

Papers - Fukunaga, Koichi

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Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study

Terai H., Ishii M., Takemura R., Namkoong H., Shimamoto K., Masaki K., Tanosaki T., Chubachi S., Matsuyama E., Hayashi R., Shimada T., Shigematsu L., Ito F., Kaji M., Takaoka H., Kurihara M., Nakagawara K., Tomiyasu S., Sasahara K., Saito A., Otake S., Azekawa S., Okada M., Fukushima T., Morita A., Tanaka H., Sunata K., Asaoka M., Nishie M., Shinozaki T., Ebisudani T., Akiyama Y., Mitsuishi A., Nakayama S., Ogawa T., Sakurai K., Irie M., Yagi K., Ohgino K., Miyata J., Kabata H., Ikemura S., Kamata H., Yasuda H., Kawada I., Kimura R., Kondo M., Iwasaki T., Ishida N., Hiruma G., Miyazaki N., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Haraguchi M., Kagyo J., Shiomi T., Lee H., Sugihara K., Omori N., Sayama K., Otsuka K., Miyao N., Odani T., Watase M., Mochimaru T., Satomi R., Oyamada Y., Masuzawa K., Asakura T., Nakayama S., Suzuki Y., Baba R., Okamori S., Arai D., Nakachi I., Kuwahara N., Fujiwara A., Oakada T., Ishiguro T., Isosno T., Makino Y., Mashimo S., Kaido T., Minematsu N., Ueda S., Minami K., Hagiwara R., Manabe T., Fukui T.

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

Kusumoto T., Chubachi S., Namkoong H., Tanaka H., Lee H., Azekawa S., Otake S., Nakagawara K., Fukushima T., Morita A., Watase M., Sakurai K., Asakura T., Masaki K., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Edahiro R., Sano H., Sato Y., Okada Y., Koike R., Kitagawa Y., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

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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Clinical characteristics of patients with COVID-19 harboring detectable intracellular SARS-CoV-2 RNA in peripheral blood cells

Tanaka H., Namkoong H., Chubachi S., Irie S., Uwamino Y., Lee H., Azekawa S., Otake S., Nakagawara K., Fukushima T., Watase M., Kusumoto T., Masaki K., Kamata H., Ishii M., Okada Y., Takano T., Imoto S., Koike R., Kimura A., Miyano S., Ogawa S., Kanai T., Sato T.A., Fukunaga K.

International Journal of Infectious Diseases 135 41 - 44 2023.10

ISSN 12019712

Objectives: Although SARS-CoV-2 RNAemia has been reported to strongly impact patients with severe COVID-19, the clinical characteristics of patients with COVID-19 harboring detectable intracellular SARS-CoV-2 RNA remain unknown. Methods: We included adult patients who had developed COVID-19 between February and September 2020. Total white blood cells derived from the buffy coat of peripheral whole blood were used to detect SARS-CoV-2 RNA using the Illumina COVIDSeq test. We compared the clinical characteristics between patients with and without detected viral RNA (detected and undetected groups). Results: Among the 390 patients included, 17 harbored SARS-CoV-2 RNA in peripheral white blood cells. All 17 patients required oxygen support during the disease course and had higher intensive care unit admission (52.9% vs 28.9%, P = 0.035), mortality (17.7% vs 3.5%, P = 0.004), kidney dysfunction (severe, 23.5% vs 6.4%, P = 0.029), and corticosteroid treatment rates (76.5% vs 46.5%, P = 0.016) than those of patients in the undetected group. Conclusion: We propose that patients with circulating intracellular SARS-CoV-2 RNA in the peripheral blood exhibited the most severe disease course.

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Differential impacts between fat mass index and fat-free mass index on patients with COPD

Shimada T., Chubachi S., Otake S., Sakurai K., Sasaki M., Iijima H., Tanabe N., Tanimura K., Shimizu K., Shirahata T., Suzuki M., Sato S., Nakamura H., Asano K., Fukunaga K.

Respiratory Medicine 217 2023.10

ISSN 09546111

Background: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients. Methods: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared. Results: The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (KCO). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores. Conclusion: FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.

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Real-world impact of dupilumab on asthma disease burden in Japan: The CROSSROAD study

Fukunaga K., Tagaya E., Ishida M., Sunaga Y., Koshiba R., Yokoyama A.

Allergology International 72 ( 4 ) 537 - 544 2023.10

ISSN 13238930

Background: Dupilumab, a human monoclonal anti-interleukin (IL)-4Ra antibody blocks the shared receptor component of IL-4 and IL-13, drivers of type 2 inflammation. Dupilumab is approved for severe/refractory asthma inadequately controlled by existing therapies, but knowledge of its effect on real-world disease burden is lacking. This study investigates real-world effects of dupilumab on asthma exacerbation risk and oral corticosteroid (OCS) use in Japanese individuals with asthma. Methods: This retrospective, cohort study used a Japanese insurance claims database to identify patients who started dupilumab between 26 March 2019–31 May 2020. Patients were followed for ±365 days from dupilumab initiation. The study primarily assessed the annual incidence rate of severe asthma exacerbations occurring simultaneously with hospitalizations or OCS bursts. Secondary and exploratory endpoints assessed OCS dosage and duration, and healthcare resource utilization (HRU), respectively. Results: At dupilumab initiation (N = 215), mean age was 57.2 years, 41.9% of patients were aged ≥65 years, and 59.5% were female. Dupilumab significantly reduced the annual incidence of severe asthma exacerbations from 1.29 to 0.74 (95% confidence interval, 0.44–0.76) per patient per year. Mean OCS dosage decreased from 10.4 to 7.2 mg/day in chronic OCS users; median frequency of OCS bursts decreased from 3 to 0. Both unscheduled outpatient visits (35.8% vs 29.8%) and hospitalizations (21.9% vs 12.1%) decreased. Mean (standard deviation) duration of hospitalization also decreased from 6.7 (27.6) to 2.2 (8.1) days. Conclusions: Japanese patients with asthma who received dupilumab had reduced incidence rates of severe asthma exacerbations, OCS use, and HRU over 12 months.

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The burden of systemic corticosteroid use in asthma management in Asia

Dhar R., Rhee C.K., Perng D.W., Fukunaga K., Ip M.S.M., Juthong S., Koh M.S., Li J., Sharma S., Wiyono W.H.

Respirology 28 ( 8 ) 744 - 757 2023.08

ISSN 13237799

For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience exacerbations, may require systemic corticosteroids (SCSs) to maintain asthma control. Although SCS are highly effective in this regard, even modest exposure to these medications can increase the risk for long-term, adverse health outcomes, such as type 2 diabetes, renal impairment, cardiovascular disease and overall mortality. Clinical and real-world data from studies investigating asthma severity, control and treatment practices around the globe have suggested that SCS are overused in asthma management, adding to the already substantial healthcare burden experienced by patients. Throughout Asia, although data on asthma severity, control and SCS usage are limited and vary widely among countries, available data strongly suggest a pattern of overuse consistent with the broader global trend. Coordinated changes at the patient, provider, institutional and policy levels, such as increasing disease awareness, promoting better adherence to treatment guidelines and increasing availability of safe and effective alternatives to SCS, are likely necessary to reduce the SCS burden for patients with asthma in Asia.

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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

Tanaka H., Chubachi S., Namkoong H., Sato Y., Asakura T., Lee H., Azekawa S., Otake S., Nakagawara K., Fukushima T., Watase M., Sakurai K., Kusumoto T., Kondo Y., Masaki K., Kamata H., Ishii M., Kaneko Y., Hasegawa N., Ueda S., Sasaki M., Izumo T., Inomata M., Miyazawa N., Kimura Y., Suzuki Y., Harada N., Ichikawa M., Takata T., Ishikura H., Yoshiyama T., Kokuto H., Murakami K., Sano H., Ueda T., Kuwahara N., Fujiwara A., Ogura T., Inoue T., Asami T., Mutoh Y., Nakachi I., Baba R., Nishi K., Tani M., Kagyo J., Hashiguchi M., Oguma T., Asano K., Nishikawa M., Watanabe H., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Open Forum Infectious Diseases 10 ( 7 ) 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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Use of the neutrophil-to-lymphocyte ratio and an oxygen requirement to predict disease severity in patients with COVID-19

Ozawa T., Asakura T., Chubachi S., Namkoong H., Tanaka H., Lee K., Fukushima T., Otake S., Nakagawara K., Watase M., Masaki K., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Edahiro R., Murakami K., Okada Y., Koike R., Kitagawa Y., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

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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Characteristics and clinical effectiveness of COVID-19 vaccination in hospitalized patients in Omicron-dominated epidemic wave – a nationwide study in Japan

Tanaka H., Chubachi S., Asakura T., Namkoong H., Azekawa S., Otake S., Nakagawara K., Fukushima T., Lee H., Watase M., Sakurai K., Kusumoto T., Masaki K., Kamata H., Ishii M., Hasegawa N., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

International Journal of Infectious Diseases 132 84 - 88 2023.07

ISSN 12019712

Objectives: 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 outcomes in patients hospitalized with Delta (fifth, N = 735) vs Omicron-dominated waves (sixth, N = 495; seventh, 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%) patients with COVID-19 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. Thus, (1) (the number of vaccinations): 1-2 times: adjusted odds ratio (aOR) 0.37 (95% confidence interval [CI]; 0.20-0.69); 3-4 times: aOR 0.25 (95% CI; 0.11-0.58); and (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: Patients hospitalized with COVID-19 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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Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s

Irie M., Kabata H., Sasahara K., Kurihara M., Shirasaki Y., Kamatani T., Baba R., Matsusaka M., Koga S., Masaki K., Miyata J., Araki Y., Kikawada T., Kabe Y., Suematsu M., Yamagishi M., Uemura S., Moro K., Fukunaga K.

Cell Reports 42 ( 6 ) 2023.06

Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s. The expression of ANXA1 decreases when ILC2s activate, but it increases autonomously as the activation subsides. Lentiviral vector-based gene transfer experiments show that ANXA1 suppresses the activation of human ILC2s. Mechanistically, ANXA1 regulates the expression of the metallothionein family genes, including MT2A, which modulate intracellular zinc homeostasis. Furthermore, increased intracellular zinc levels play an essential role in the activation of human ILC2s by promoting the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and GATA3 expression. Thus, the ANXA1/MT2A/zinc pathway is identified as a cell-intrinsic metalloregulatory mechanism for human ILC2s.

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Potent neutralizing broad-spectrum antibody against SARS-CoV-2 generated from dual-antigen-specific B cells from convalescents

Takeshita M., Fukuyama H., Kamada K., Matsumoto T., Makino-Okamura C., Lin Q., Sakuma M., Kawahara E., Yamazaki I., Uchikubo-Kamo T., Tomabechi Y., Hanada K., Hisano T., Moriyama S., Takahashi Y., Ito M., Imai M., Maemura T., Furusawa Y., Yamayoshi S., Kawaoka Y., Shirouzu M., Ishii M., Saya H., Kondo Y., Kaneko Y., Suzuki K., Fukunaga K., Takeuchi T.

iScience 26 ( 6 ) 2023.06

Several antibody therapeutics have been developed against SARS-CoV-2; however, they have attenuated neutralizing ability against variants. In this study, we generated multiple broadly neutralizing antibodies from B cells of convalescents, by using two types of receptor-binding domains, Wuhan strain and the Gamma variant as bait. From 172 antibodies generated, six antibodies neutralized all strains prior to the Omicron variant, and the five antibodies were able to neutralize some of the Omicron sub-strains. Structural analysis showed that these antibodies have a variety of characteristic binding modes, such as ACE2 mimicry. We subjected a representative antibody to the hamster infection model after introduction of the N297A modification, and observed a dose-dependent reduction of the lung viral titer, even at a dose of 2 mg/kg. These results demonstrated that our antibodies have certain antiviral activity as therapeutics, and highlighted the importance of initial cell-screening strategy for the efficient development of therapeutic antibodies.

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Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma

Masaki K., Miyata J., Kamatani T., Tanosaki T., Mochimaru T., Kabata H., Suzuki Y., Asano K., Betsuyaku T., Fukunaga K.

Asian Pacific Journal of Allergy and Immunology 41 ( 2 ) 113 - 120 2023.06

ISSN 0125877X

Background: Poor adherence to inhaled corticosteroid (ICS) therapy is a common reason for worsened asthma control. Objective: We investigated the characteristics of patients with moderate to severe asthma who showed poor adherence to therapy, to identify the barriers for optimal ICS therapy in a real-world observational cohort. Methods: We enrolled patients aged ≥ 20 years presenting with moderate to severe asthma who were enrolled at 18 hospitals in Japan. According to the Global Initiative for Asthma 2018 steps 3–5, the patients were considered as moderate to severe asthmatic. At inclusion, clinical information was obtained using a self-completed questionnaire. Poor adherence was defined as skipping the ICS therapy for more than once a week or inability to recognize the necessity of daily ICS therapy. Adherence Starts with Knowledge 20 (ASK-20) questionnaire was used to evaluate the cause of therapy incompliance. Results: Of the total 85 participants, 19 (22%) showed poor adherence. The median age at diagnosis in the poor adherence group was 10.0 years (interquartile range [IQR], 3.0–50.0), and that in the good adherence group was 41.0 years (18.5–51.5; P = 0.050). The scores for the ASK-20 items related to the “resistance to taking too much medicine” and “compliance with the number of dosing” demonstrated statistically significant differences between patients diagnosed with asthma during their childhood and others. Conclusion: Age at diagnosis is an independent risk factor to predict poor ICS adherence among adults with moderate to severe asthma.

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

Azekawa S., Chubachi S., Asakura T., Namkoong H., Sato Y., Dahiro R., Lee H., Tanaka H., Otake S., Nakagawara K., Fukushima T., Watase M., Sakurai K., Kusumoto T., Masaki K., Kamata H., Ishii M., Hasegawa N., Okada Y., Koike R., Kitagawa Y., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

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

Nakagawara K., Kamata H., Chubachi S., Namkoong H., Tanaka H., Lee H., Otake S., Fukushima T., Kusumoto T., Morita A., Azekawa S., Watase M., Asakura T., Masaki K., Ishii M., Endo A., Koike R., Ishikura H., Takata T., Matsushita Y., Harada N., Kokutou H., Yoshiyama T., Kataoka K., Mutoh Y., Miyawaki M., Ueda S., Ono H., Ono T., Shoko T., Muranaka H., Kawamura K., Mori N., Mochimaru T., Fukui M., Chihara Y., Nagasaki Y., Okamoto M., Amishima M., Odani T., Tani M., Nishi K., Shirai Y., Edahiro R., Ando A., Hashimoto N., Ogura S., Kitagawa Y., Kita T., Kagaya T., Kimura Y., Miyazawa N., Tsuchida T., Fujitani S., Murakami K., Sano H., Sato Y., Tanino Y., Otsuki R., Mashimo S., Kuramochi M., Hosoda Y., Hasegawa Y., Ueda T., Takaku Y., Ishiguro T., Fujiwara A., Kuwahara N., Kitamura H., Hagiwara E., Nakamori Y., Saito F., Kono Y., Abe S., Ishii T., Ohba T., Kusaka Y., Watanabe H., Masuda M., Watanabe H., Kimizuka Y., Kawana A., Kasamatsu Y., Hashimoto S., Okada Y., Takano T., Katayama K., Ai M., Kumanogoh A., Sato T., Tokunaga K., Imoto S., Kitagawa Y., Kimura A., Miyano S., Hasegawa N., Ogawa S., Kanai T., Fukunaga K.

Journal of Infection and 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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Executive summary: Japanese guidelines for adult asthma (JGL) 2021

Niimi A., Fukunaga K., Taniguchi M., Nakamura Y., Tagaya E., Horiguchi T., Yokoyama A., Yamaguchi M., Nagata M.

Allergology International 72 ( 2 ) 207 - 226 2023.04

ISSN 13238930

Asthma is characterized by chronic airway inflammation, variable airway narrowing, and sensory nerve irritation, which manifest as wheezing, dyspnea, chest tightness, and cough. Longstanding asthma may result in airway remodeling and become intractable. Despite the increased prevalence of asthma in adults, asthma-associated deaths have decreased in Japan (0.94 per 100,000 people in 2020). The goals of asthma treatment include the control of symptoms and reduction of future risks. A functional partnership between physicians and patients is indispensable for achieving these goals. Long-term management with medications and the elimination of triggers and risk factors are fundamental to asthma treatment. Asthma is managed via four steps of pharmacotherapy (“controllers”), ranging from mild to intensive treatments, depending on disease severity; each step involves daily administration of an inhaled corticosteroid, which varies from low to high dosage. Long-acting β2 agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs. Allergen immunotherapy is a new option that is employed as a controller treatment. Further, as of 2021, anti-IgE antibody, anti-IL-5 and anti-IL-5 receptor α-chain antibodies, and anti-IL-4 receptor α-chain antibodies are available for the treatment of severe asthma. Bronchial thermoplasty can be performed for asthma treatment, and its long-term efficacy has been reported. Algorithms for their usage have been revised. Comorbidities, such as allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease, and aspirin-exacerbated respiratory disease, should also be considered during the treatment of chronic asthma. Depending on the severity of episodes, inhaled short-acting β2 agonists, systemic corticosteroids, short-acting muscarinic antagonists, oxygen therapy, and other approaches are used as needed (“relievers”) during exacerbation.

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Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma

Ebisudani T., Hamamoto J., Togasaki K., Mitsuishi A., Sugihara K., Shinozaki T., Fukushima T., Kawasaki K., Seino T., Oda M., Hanyu H., Toshimitsu K., Emoto K., Hayashi Y., Asakura K., Johnson T.A., Terai H., Ikemura S., Kawada I., Ishii M., Hishida T., Asamura H., Soejima K., Nakagawa H., Fujii M., Fukunaga K., Yasuda H., Sato T.

Cell Reports 42 ( 3 ) 2023.03

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

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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

Watase M., Masaki K., Chubachi S., Namkoong H., Tanaka H., Lee H., Fukushima T., Otake S., Nakagawara K., Kusumoto T., Asakura T., Kamata H., Ishii M., Hasegawa N., Oyamada Y., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Edahiro R., Sano H., Sato Y., Okada Y., Koike R., Kitagawa Y., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

International Journal of Infectious Diseases 128 121 - 127 2023.03

ISSN 12019712

Objectives: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for severe 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 was 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). A 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 years. Conclusion: Cumulative smoking exposure was positively associated with COVID-19 outcomes in smokers.

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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

Fukushima T., Chubachi S., Namkoong H., Asakura T., Tanaka H., Lee H., Azekawa S., Okada Y., Koike R., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

Diabetes, Obesity and 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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Current summary of clinical studies on anti-TSLP antibody, Tezepelumab, in asthma

Kurihara M., Kabata H., Irie M., Fukunaga K.

Allergology International 72 ( 1 ) 24 - 30 2023.01

ISSN 13238930

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a vital role in the induction of type 2 inflammation via both innate and acquired immune cascades. Tezepelumab, a human IgG2 monoclonal antibody that inhibits the binding of TSLP to the TSLP receptor, is the latest biologic for asthma. To evaluate the efficacy and mechanism of tezepelumab in asthma, the PATHWAY, NAVIGATOR, NOZOMI, UPSTREAM, CASCADE, SOURCE, and DESTINATION studies have been conducted. These results suggested that tezepelumab is a broad-target biologic, which is expected to be effective in patients with poorly controlled moderate to severe asthma regardless of the phenotype, although its efficacy in oral corticosteroids-dependent asthma, biological mechanism in non-type 2 phenotype, and long-term safety remain unknown. In this review, we summarize the results of clinical trials of tezepelumab in asthma and discuss the differences between tezepelumab and other biologics.

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