慶應義塾研究者情報データベース

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

  Yagi K., Kondo M., Terai H., Asakura T., Kimura R., Takemura R., Tanaka H., Ohgino K., Masaki K., Namkoong H., Chubachi S., Miyata J., Kawada I., Kaido T., Mashimo S., Kobayashi K., Hirano T., Lee H., Sugihara K., Omori N., Watase M., Mochimaru T., Satomi R., Makino Y., Inoue T., Sayama K., Oyamada Y., Ishii M., Sato Y., Fukunaga K.

  Respiratory Investigation 63 （ 4 ） 610 - 616 2025年07月

  ISSN  22125345

  　概要を見る

  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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• Blood DNA virome associates with autoimmune diseases and COVID-19

  Sasa N., Kojima S., Koide R., Hasegawa T., Namkoong H., Hirota T., Watanabe R., Nakamura Y., Oguro-Igashira E., Ogawa K., Yata T., Sonehara K., Yamamoto K., Kishikawa T., Sakaue S., Edahiro R., Shirai Y., Maeda Y., Nii T., Chubachi S., Tanaka H., Yabukami H., Suzuki A., Nakajima K., Arase N., Okamoto T., Nishikawa R., Namba S., Naito T., Miyagawa I., Tanaka H., Ueno M., Ishitsuka Y., Furuta J., Kunimoto K., Kajihara I., Fukushima S., Miyachi H., Matsue H., Kamata M., Momose M., Bito T., Nagai H., Ikeda T., Horikawa T., Adachi A., Matsubara T., Ikumi K., Nishida E., Nakagawa I., Yagita-Sakamaki M., Yoshimura M., Ohshima S., Kinoshita M., Ito S., Arai T., Hirose M., Tanino Y., Nikaido T., Ichiwata T., Ohkouchi S., Hirano T., Takada T., Tazawa R., Morimoto K., Takaki M., Konno S., Suzuki M., Tomii K., Nakagawa A., Handa T., Tanizawa K., Ishii H., Ishida M., Kato T., Takeda N., Yokomura K., Matsui T., Uchida A., Inoue H., Imaizumi K., Goto Y., Kida H., Fujisawa T., Suda T., Yamada T., Satake Y., Ibata H., Saigusa M., Shirai T., Hizawa N., Nakata K., Imoto S., Kitagawa Y., Tokunaga K., Hasegawa N., Sato T., Ai M., Katayama K., Takano T.

  Nature Genetics 57 （ 1 ） 65 - 79 2025年01月

  ISSN  10614036

  　概要を見る

  Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

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• RSV infection in neonatal mice and gastrointestinal microbiome alteration contribute to allergic predisposition

  Ethridge A.D., Yagi K., Martínez L.A., Rasky A.J., Morris S.B., Falkowski N.R., Huffnagle G.B., Lukacs N.W.

  Mucosal Immunology 2025年

  ISSN  19330219

  　概要を見る

  Severe respiratory syncytial virus (RSV) infection during infancy is associated with a 2 to 4-fold increased risk for the development of wheezing and asthma. Recent studies have implicated microbiome changes, either within the lung or gut, during early life can also affect the development of pulmonary disease. Our studies demonstrate long-term gastrointestinal and lung microbiome changes following early life (EL) RSV infection. To determine the respective roles of ELRSV infection and the gut microbiome, we performed germ-free neonatal infection and microbiome colonization using a microbiome from an uninfected animal followed by cockroach allergen (CRA)-induced asthma 4 weeks later. Germ-free animals with ELRSV infection displayed increased airway disease that was diminished by microbiome colonization, including airway hyperreactivity (AHR), mucus, and eosinophil infiltration. To address the role of virus induced gastrointestinal microbiome alterations, we utilized GF mice conventionalized with RSV-associated or naive microbiomes followed by CRA-induced disease. Transfer of neonatal microbiome taken during acute RSV infection did not alter the allergic response to CRA. However, the transfer of a naive adult microbiome conferred protection from enhanced AHR in response to CRA whereas an RSV associated microbiome did not. Taken together, our data indicate that microbiome alteration and early life RSV infection both contribute to allergic predisposition.

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

  Tanaka H., Asakura T., Okamori S., Furuuchi K., Yagi M., Nakayama Y., Kuramoto J., Yagi K., Hase I., Kamata H., Fujiwara K., Nakao A., Masugi Y., Sato Y., Kanai Y., Namkoong H., Fukunaga K., Nakagawa T., Morimoto K., Fujita M., Hasegawa N.

  International Journal of Infectious Diseases 148 2024年11月

  ISSN  12019712

  　概要を見る

  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 noncavitary 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). Conclusion: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes.

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• Microbiome modifications by steroids during viral exacerbation of asthma and in healthy mice

  Yagi K., Ethridge A.D., Falkowski N.R., Huang Y.J., Elesela S., Huffnagle G.B., Lukacs N.W., Fonseca W., Asai N.

  American Journal of Physiology Lung Cellular and Molecular Physiology 327 （ 5 ） L646 - L660 2024年11月

  ISSN  10400605

  　概要を見る

  In the present studies, the assessment of how viral exacerbation of asthmatic responses with and without pulmonary steroid treatment alters the microbiome in conjunction with immune responses presents striking data. The overall findings identify that although steroid treatment of allergic animals diminished the severity of the respiratory syncytial virus (RSV)-induced exacerbation of airway function and mucus hypersecretion, there were local increases in IL-17 expression. Analysis of the lung and gut microbiome suggested that there are differences in RSV exacerbation that are further altered by fluticasone (FLUT) treatment. Using metagenomic inference software, PICRUSt2, we were able to predict that the metabolite profile produced by the changed gut microbiome was significantly different with multiple metabolic pathways and associated with specific treatments with or without FLUT. Importantly, measuring plasma metabolites in an unbiased manner, our data indicate that there are significant changes associated with chronic allergen exposure, RSV exacerbation, and FLUT treatment that are reflective of responses to the disease and treatment. In addition, the changes in metabolites appeared to have contributions from both host and microbial pathways. To understand if airway steroids on their own altered lung and gut microbiome along with host responses to RSV infection, naïve animals were treated with lung FLUT before RSV infection. The naïve animals treated with FLUT before RSV infection demonstrated enhanced disease that corresponded to an altered microbiome and the related PICRUSt2 metagenomic inference analysis. Altogether, these findings set the foundation for identifying important correlations of severe viral exacerbated allergic disease with microbiome changes and the relationship of host metabolome with a potential for early life pulmonary steroid influence on subsequent viral-induced disease.

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• A second update on mapping the human genetic architecture of COVID-19

  Kanai M., Andrews S.J., Cordioli M., Stevens C., Neale B.M., Daly M., Ganna A., Pathak G.A., Iwasaki A., Karjalainen J., Mehtonen J., Pirinen M., Chwialkowska K., Trankiem A., Balaconis M.K., Veerapen K., Wolford B.N., Ahmad H.F., von Hohenstaufen Puoti K.A., Boer C., Boua P.R., Butler-Laporte G., Cadilla C.L., Colombo F., Douillard V., Dueker N., Dutta A.K., El-Sherbiny Y.M., Eltoukhy M.M., Esmaeeli S., Faucon A., Fave M.J., Cadenas I.F., Francescatto M., Francioli L., Franke L., Fuentes M., Durán R.G., Cabrero D.G., Harry E.N., Jansen P., Szentpéteri J.L., Kaja E., Kirk C., Kousathanas A., Krieger J.E., Patel S.K., Lemaçon A., Limou S., Lió P., Marouli E., Marttila M.M., Medina-Gómez C., Michaeli Y., Migeotte I., Mondal S., Moreno-Estrada A., Moya L., Nakanishi T., Nasir J., Pasko D., Pearson N.M., Pereira A.C., Priest J., Prijatelj V., Prokic I., Teumer A., Várnai R., Romero-Gómez M., Roos C., Rosenfeld J., Ruolin L., Schulte E.C., Schurmann C., Sedaghati-khayat B., Shaheen D., Shivanathan I., Sipeky C., Sirui Z., Striano P., Tanigawa Y., Remesal A.U., Vadgama N., Vallerga C.L., van der Laan S., Verdugo R.A., Wang Q.S., Wei Z., Zainulabid U.A., Zárate R.N., Auton A., Shelton J.F., Shastri A.J., Weldon C.H., Filshtein-Sonmez T., Coker D., Symons A.

  Nature 621 （ 7977 ） E7 - E26 2023年09月

  ISSN  00280836

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