Papers - Uwamino, Yoshifumi

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019–2020: General view of the pathogens' antibacterial susceptibility

Tokimatsu I., Matsumoto T., Tsukada H., Fujikura Y., Miki M., Morinaga Y., Sato J., Wakamura T., Kiyota H., Tateda K., Yanagisawa H., Sasaki T., Ikeda H., Horikawa H., Takahashi H., Seki M., Mori Y., Takeda H., Kurai D., Hasegawa N., Uwamino Y., Kudo M., Yamamoto M., Nagano Y., Nomura S., Tetsuka T., Hosokai M., Aoki N., Yamamoto Y., Iinuma Y., Mikamo H., Suematsu H., Maruyama T., Kawabata A., Sugaki Y., Nakamura A., Fujikawa Y., Fukumori T., Ukimura A., Kakeya H., Niki M., Yoshida K., Kobashi Y., Tokuyasu H., Yatera K., Ikegami H., Fujita M., Matsumoto T., Yanagihara K., Matsuda J., Hiramatsu K., Shinzato T.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy)  29 ( 8 ) 731 - 743 2023.08

ISSN  1341321X

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The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were β-lactamase-producing ampicillin resistant and β-lactamase-negative ampicillin resistant, respectively. Extended-spectrum β-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-β-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

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Differences among epitopes recognized by neutralizing antibodies induced by SARS-CoV-2 infection or COVID-19 vaccination

Yamamoto S., Yamayoshi S., Ito M., Sakai-Tagawa Y., Nakachi I., Baba R., Kamimoto S., Ogura T., Hagiwara S., Kato H., Nakajima H., Uwamino Y., Yagi K., Sugaya N., Nagai H., Saito M., Adachi E., Koga M., Tsutsumi T., Duong C., Okuda M., Murakami J., Furusawa Y., Ujie M., Iwatsuki-Horimoto K., Yotsuyanagi H., Kawaoka Y.

iScience (iScience)  26 ( 7 ) 107208 2023.07

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SARS-CoV-2 has gradually acquired amino acid substitutions in its S protein that reduce the potency of neutralizing antibodies, leading to decreased vaccine efficacy. Here, we attempted to obtain mutant viruses by passaging SARS-CoV-2 in the presence of plasma samples from convalescent patients or vaccinees to determine which amino acid substitutions affect the antigenicity of SARS-CoV-2. Several amino acid substitutions in the S2 region, as well as the N-terminal domain (NTD) and receptor-binding domain (RBD), affected the neutralization potency of plasma samples collected from vaccinees, indicating that amino acid substitutions in the S2 region as well as those in the NTD and RBD affect neutralization by vaccine-induced antibodies. Furthermore, the neutralizing potency of vaccinee plasma samples against mutant viruses we obtained or circulating viruses differed among individuals. These findings suggest that genetic backgrounds of vaccinees influence the recognition of neutralizing epitopes.

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Healthcare costs for hospitalized COVID-19 patients in a Japanese university hospital: a cross-sectional study.

Uno S, Goto R, Honda K, Tokuda M, Kamata H, Chubachi S, Yamamoto R, Sato Y, Homma K, Uchida S, Namkoong H, Uwamino Y, Sasaki J, Fukunaga K, Hasegawa N

Cost effectiveness and resource allocation : C/E 21 ( 1 ) 43 2023.07

ISSN  1478-7547

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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 (Nature Genetics)  55 ( 5 ) 753 - 767 2023.05

ISSN  10614036

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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 Utility of a Mycobacterium Multiplex PCR Detection Panel for Tuberculosis and Nontuberculous Mycobacterial Infections.

Yoshifumi Uwamino, Akio Aono, Yu Tomita, Kozo Morimoto, Masahiro Kawashima, Hirofumi Kamata, Yuka Sasaki, Hideaki Nagai, Naoki Hasegawa, Satoshi Mitarai

Microbiology spectrum (Microbiology spectrum)  11 ( 3 ) e0516222 2023.04

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The prevalence of nontuberculous mycobacterial diseases is increasing worldwide, and tuberculosis remains highly prevalent. Rapid and accurate microbial diagnoses of both tuberculosis and nontuberculous mycobacterial infections are required. A novel PCR-reverse sequence-specific oligonucleotide probe (PCR-rSSO) method-based mycobacterial detection panel (Myco-Panel) test was developed for the rapid identification of 30 mycobacterial species and subspecies. Clinical respiratory samples were collected from patients with suspected or confirmed tuberculosis and nontuberculous mycobacterial lung disease and those with other respiratory diseases. Myco-Panel tests were performed on the samples, and liquid mycobacterial culture and identification were performed for reference according to housekeeping gene sequences of mycobacteria in positive culture tubes. Furthermore, to assess the detection performance for several mycobacterial species rarely recovered in Japan, the accuracy of the Myco-Panel test was investigated using stock mycobacterial type strains and clinical isolates. A total of 178 clinical respiratory samples were analyzed. The Myco-Panel and sequence-based identification results for mycobacterial cultures were 83.1% concordant (kappa coefficient, 0.785 [95% confidence interval, 0.716 to 0.854]). The Myco-Panel correctly identified 281 of the 283 type strains and clinical isolates tested. The Myco-Panel test could accurately detect several mycobacterial species from clinical respiratory samples and mycobacterial suspensions. Rapid and accurate identification of pathogens using respiratory samples is possible using the Myco-Panel. IMPORTANCE Species identification is important for the diagnosis of mycobacterial infections and decisions on treatment regimens. The Myco-Panel test accurately detects clinically common mycobacterial species that cause respiratory infections from clinical respiratory samples and mycobacterial suspensions. The rapid identification of multiple mycobacterial species will provide clinically useful information for the management of patients. Although we understand that the current diagnostic criteria require mycobacterial culture results in general for the diagnosis of nontuberculous mycobacterial infection, mycobacterial culture examination is a time-consuming process. The detection of potentially causative agents directly from clinical samples will aid in practical diagnosis and decision-making for rapid treatment initiation. This is a new laboratory method for species identification, and evaluating its performance is important.

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

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

npj Vaccines (Springer Science and Business Media LLC)  8 ( 1 ) 33 2023.03

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Abstract

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

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Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections.

Lisa M Bramer, Robert D Hontz, Amie J Eisfeld, Amy C Sims, Young-Mo Kim, Kelly G Stratton, Carrie D Nicora, Marina A Gritsenko, Athena A Schepmoes, Osamu Akasaka, Michiko Koga, Takeya Tsutsumi, Morio Nakamura, Ichiro Nakachi, Rie Baba, Hiroki Tateno, Shoji Suzuki, Hideaki Nakajima, Hideaki Kato, Kazunari Ishida, Makoto Ishii, Yoshifumi Uwamino, Keiko Mitamura, Vanessa L Paurus, Ernesto S Nakayasu, Isaac K Attah, Andrew G Letizia, Katrina M Waters, Thomas O Metz, Karen Corson, Yoshihiro Kawaoka, Vincent R Gerbasi, Hiroshi Yotsuyanagi, Kiyoko Iwatsuki-Horimoto

Heliyon (Heliyon)  9 ( 3 ) e13795 2023.03

ISSN  24058440

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The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics and correlative analysis of an immunologically naïve SARS-CoV-2 clinical cohort from blood plasma of uninfected controls, mild, and severe infections. Consistent with previous observations, severe patient populations showed an elevation of pulmonary surfactant levels. Intriguingly, mild patients showed a statistically significant elevation in the carnosine dipeptidase modifying enzyme (CNDP1). Mild and severe patient populations showed a strong elevation in the metabolite L-cystine (oxidized form of the amino acid cysteine) and enzymes with roles in glutathione metabolism. Neutrophil extracellular traps (NETs) were observed in both mild and severe populations, and NET formation was higher in severe vs. mild samples. Our correlative analysis suggests a potential protective role for CNDP1 in suppressing PSPB release from the pulmonary space whereas NET formation correlates with increased PSPB levels and disease severity. In our discussion we put forward a possible model where NET formation drives pulmonary occlusions and CNDP1 promotes antioxidation, pleiotropic immune responses, and vasodilation by accelerating histamine synthesis.

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

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

Vaccine (Vaccine)  41 ( 9 ) 1545 - 1549 2023.02

ISSN  0264410X

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

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

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

Infection and drug resistance (Infection and Drug Resistance)  16   3955 - 3963 2023

ISSN  1178-6973

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

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

Mise-Omata S., Ikeda M., Takeshita M., Uwamino Y., Wakui M., Arai T., Yoshifuji A., Murano K., Siomi H., Nakagawara K., Ohyagi M., Ando M., Hasegawa N., Saya H., Murata M., Fukunaga K., Namkoong H., Lu X., Yamasaki S., Yoshimura A.

Journal of Immunology (Journal of Immunology)  209 ( 11 ) 2104 - 2113 2022.12

ISSN  00221767

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Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR62 circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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

Mise-Omata S, Ikeda M, Takeshita M, Uwamino Y, Wakui M, Arai T, Yoshifuji A, Murano K, Siomi H, Nakagawara K, Ohyagi M, Ando M, Hasegawa N, Saya H, Murata M, Fukunaga K, Namkoong H, Lu X, Yamasaki S, Yoshimura A

Journal of immunology (Baltimore, Md. : 1950) 209 ( 11 ) 2104 - 2113 2022.12

ISSN  0022-1767

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

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

Journal of immunology (Baltimore, Md. : 1950) 209 ( 11 ) 2104 - 2113 2022.12

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

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Age-Stratified Seroprevalence of SARS-CoV-2 Antibodies before and during the Vaccination Era, Japan, February 2020-March 2022.

Seiya Yamayoshi, Kiyoko Iwatsuki-Horimoto, Moe Okuda, Michiko Ujie, Atsuhiro Yasuhara, Jurika Murakami, Calvin Duong, Taiki Hamabata, Mutsumi Ito, Shiho Chiba, Ryo Kobayashi, Satoshi Takahashi, Keiko Mitamura, Masao Hagihara, Akimichi Shibata, Yoshifumi Uwamino, Naoki Hasegawa, Toshiaki Ebina, Akihiko Izumi, Hideaki Kato, Hideaki Nakajima, Norio Sugaya, Yuki Seki, Asef Iqbal, Isamu Kamimaki, Masahiko Yamazaki, Yoshihiro Kawaoka, Yuki Furuse

Emerging infectious diseases (Emerging Infectious Diseases)  28 ( 11 ) 2198 - 2205 2022.11

ISSN  10806040

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Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020-March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.

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Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccines by using an IFN-γ release assay.

Masatoshi Wakui, Yoshifumi Uwamino, Yoko Yatabe, Terumichi Nakagawa, Akiko Sakai, Toshinobu Kurafuji, Ayako Shibata, Yukari Tomita, Masayo Noguchi, Akiko Tanabe, Tomoko Arai, Akemi Ohno, Hiromitsu Yokota, Shunsuke Uno, Wakako Yamasawa, Yasunori Sato, Mari Ikeda, Akihiko Yoshimura, Naoki Hasegawa, Hideyuki Saya, Mitsuru Murata

European journal of immunology (European Journal of Immunology)  52 ( 12 ) 1961 - 1971 2022.10

ISSN  00142980

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Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

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

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

Journal of immunology (Baltimore, Md. : 1950)  2022.10

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

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In vitro effects of diazabicyclooctane β-lactamase inhibitors relebactam and nacubactam against three subspecies of Mycobacterium abscessus complex.

Kana Misawa, Tomoyasu Nishimura, Shoko Kashimura, Yuki Enoki, Kazuaki Taguchi, Shunsuke Uno, Yoshifumi Uwamino, Kazuaki Matsumoto, Naoki Hasegawa

International journal of antimicrobial agents (International Journal of Antimicrobial Agents)  60 ( 5-6 ) 106669 - 106669 2022.09

ISSN  09248579

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BACKGROUND: Mycobacterium abscessus complex (MABC) pulmonary disease is notoriously difficult to treat due to intrinsic resistance to many common antibiotics. MABC is β-lactam-resistant as it produces class A β-lactamases, such as blaMab, which are inhibited by diazabicyclooctane (DBO) β-lactamase inhibitors. OBJECTIVES: To investigate the microbiological effects of the combination of β-lactam and DBO β-lactamase inhibitors (relebactam and nacubactam) against MABC and determine if the effects are associated with the MABC subspecies and colony morphotypes. METHODS: We evaluated the antimicrobial susceptibility of three type strains and 20 clinical isolates of MABC to the combination of seven β-lactams with relebactam or nacubactam by broth microdilution checkerboard assays. For these strains, we assessed blaMab expression levels by quantitative real-time polymerase chain reaction and the genotypic diversity by 18-locus variable number tandem repeat assay. RESULTS: Relebactam and nacubactam lowered the minimum inhibitory concentrations of β-lactams, especially imipenem, meropenem, tebipenem, against MABC. There was no difference in efficacy of combination treatment between three subspecies, but rough morphotypes tended to be less susceptible than smooth morphotypes. There were no differences in blaMab expression levels and genotypic diversity between the morphotypes. CONCLUSIONS: The combination of β-lactam with relebactam or nacubactam improved the efficacy of β-lactams against all MABC subspecies, but higher concentrations of β-lactams are needed for rough morphotypes.

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Identification of trypsin-degrading commensals in the large intestine.

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

Nature (Nature)  609 ( 7927 ) 582 - 589 2022.09

ISSN  00280836

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

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

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

Vaccine (Vaccine)  40 ( 32 ) 4538 - 4543 2022.07

ISSN  0264410X

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

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

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

BMC pulmonary medicine (BMC Pulmonary Medicine)  22 ( 1 ) 202 - 202 2022.05

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

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The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals

Uwamino Y., Yokoyama T., Shimura T., Nishimura T., Sato Y., Wakui M., Kosaki K., Hasegawa N., Murata M.

Vaccine (Vaccine)  40 ( 13 ) 1928 - 1931 2022.03

ISSN  0264410X

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The reduced vaccine efficacy against the SARS-CoV-2 variant lineage B. 1.351 (beta variant) containing the E484K and N501Y mutations is well known. The E484K mutation in SARS-CoV-2 is thought to be responsible for weakened humoral immunity. Vaccine efficacy against the R.1 lineage, which contains the E484K mutation but not the N501Y mutation, is uncertain. Serum samples were collected from 100 healthy Japanese participants three weeks after receiving the second dose of the BNT162b2 vaccine, and serum neutralization antibody titers were measured against five SARS-CoV-2 variants. The geometric mean neutralization titers measured for the original and R.1 lineages were equivalent (91.90 ± 2.40 and 102.67 ± 2.28, respectively), whereas a low titer was measured for the beta variant (18.03 ± 1.92). Although further investigations with other variant strains and serum samples are essential, our results imply that the weakened humoral response is not caused solely by the E484K mutation. (UMIN000043340).

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The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals.

Uwamino Y, Yokoyama T, Shimura T, Nishimura T, Sato Y, Wakui M, Kosaki K, Hasegawa N, Murata M

Vaccine 40 ( 13 ) 1928 - 1931 2022.03

ISSN  0264-410X

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The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals.

Yoshifumi Uwamino, Takashi Yokoyama, Takako Shimura, Tomoyasu Nishimura, Yasunori Sato, Masatoshi Wakui, Kenjiro Kosaki, Naoki Hasegawa, Mitsuru Murata

Vaccine 40 ( 13 ) 1928 - 1931 2022.03

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The reduced vaccine efficacy against the SARS-CoV-2 variant lineage B. 1.351 (beta variant) containing the E484K and N501Y mutations is well known. The E484K mutation in SARS-CoV-2 is thought to be responsible for weakened humoral immunity. Vaccine efficacy against the R.1 lineage, which contains the E484K mutation but not the N501Y mutation, is uncertain. Serum samples were collected from 100 healthy Japanese participants three weeks after receiving the second dose of the BNT162b2 vaccine, and serum neutralization antibody titers were measured against five SARS-CoV-2 variants. The geometric mean neutralization titers measured for the original and R.1 lineages were equivalent (91.90 ± 2.40 and 102.67 ± 2.28, respectively), whereas a low titer was measured for the beta variant (18.03 ± 1.92). Although further investigations with other variant strains and serum samples are essential, our results imply that the weakened humoral response is not caused solely by the E484K mutation. (UMIN000043340).

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医療従事者における新型コロナウイルスの感染状況調査

西村 知泰, 森 正明, 長谷川 直樹, 上蓑 義典, 宇野 俊介

大和証券ヘルス財団研究業績集 ((公財)大和証券ヘルス財団)   ( 45 ) 32 - 35 2022.03

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医療従事者におけるCOVID-19の適切な感染対策を検討するため、血清抗体検査の陽性率から感染状況を推測した。さらに、血清抗体陽性者と陰性者の背景や臨床情報を比較し、感染者の特徴や感染危険因子を探索した。本大学医学部と大学病院に所属する医療従事者に対して2020年8月に実施した定期検査の際に、研究参加同意の得られた2341人を対象とした。COVID-19の既往歴のある21人を除外した2320人におけるIgG抗体陽性者は20人(0.862%)であった。年齢や職種では抗体陽性率に有意差はなかったが、性別は男性の方が有意に抗体陽性率が高かった。抗体陽性者は何らかの症状、特に嗅覚障害や味覚障害、発熱があった者で多かった。医療機関におけるCOVID-19の集団感染を防ぐために、医療従事者は適切な標準感染予防策と感染予防経路別予防策を実施し、発熱や嗅覚・味覚障害といった症状が出現した際は速やかに就業を中止すべきであると考えられた。

The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals

Yoshifumi Uwamino, Takashi Yokoyama, Takako Shimura, Tomoyasu Nishimura, Yasunori Sato, Masatoshi Wakui, Kenjiro Kosaki, Naoki Hasegawa, Mitsuru Murata

VACCINE (ELSEVIER SCI LTD)  40 ( 13 ) 1928 - 1931 2022.03

ISSN  0264-410X

　View Summary

The reduced vaccine efficacy against the SARS-CoV-2 variant lineage B. 1.351 (beta variant) containing the E484K and N501Y mutations is well known. The E484K mutation in SARS-CoV-2 is thought to be responsible for weakened humoral immunity. Vaccine efficacy against the R.1 lineage, which contains the E484K mutation but not the N501Y mutation, is uncertain. Serum samples were collected from 100 healthy Japanese participants three weeks after receiving the second dose of the BNT162b2 vaccine, and serum neutralization antibody titers were measured against five SARS-CoV-2 variants. The geometric mean neutralization titers measured for the original and R.1 lineages were equivalent (91.90 +/- 2.40 and 102.67 +/- 2. 28, respectively), whereas a low titer was measured for the beta variant (18.03 +/- 1.92). Although further investigations with other variant strains and serum samples are essential, our results imply that the weakened humoral response is not caused solely by the E484K mutation. (UMIN000043340). (c) 2022 Elsevier Ltd. All rights reserved.

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Young age, female sex, and presence of systemic adverse reactions are associated with high post-vaccination antibody titer after two doses of BNT162b2 mRNA SARS-CoV-2 vaccination: An observational study of 646 Japanese healthcare workers and university staff.

Yoshifumi Uwamino, Toshinobu Kurafuji, Yasunori Sato, Yukari Tomita, Ayako Shibata, Akiko Tanabe, Yoko Yatabe, Masayo Noguchi, Tomoko Arai, Akemi Ohno, Hiromitsu Yokota, Wakako Yamasawa, Shunsuke Uno, Tomoyasu Nishimura, Naoki Hasegawa, Hideyuki Saya, Masatoshi Wakui, Mitsuru Murata

Vaccine (Vaccine)  40 ( 7 ) 1019 - 1025 2022.02

ISSN  0264410X

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BACKGROUND: SARS-CoV-2 vaccination has started worldwide, including Japan. Although high rates of vaccine response and adverse reactions of BNT162b2 vaccine have been reported, knowledge about the relationship between sex differences and antibody response is limited. Furthermore, it is uncertain whether adverse reactions are associated with the vaccine response. METHODS: This prospective observational study included 673 Japanese participants working in a medical school and its affiliated hospital in Tokyo, Japan (UMIN000043340). Serum samples were collected before the first dose and three weeks after the second dose of BNT162b2 vaccine, and antibody titers against the receptor-binding domain of the spike protein of SARS-CoV-2 were measured. Answers to questionnaires about background characteristics and adverse reactions were obtained at the time of sample collection, and the relationship between antibody titers was analyzed. RESULTS: After excluding participants who did not complete receiving two doses of vaccination or two series of serum sample collection, 646 participants were analyzed. Although all participants became sero-positive after vaccination, antibody titers were highly variable among individuals (260.9-57,399.7A U/mL), with a median titer of 13478.0AU/mL. Mean titer was higher in females than in males and higher in young (≤45 years old) participants than in aged (>45 years old) participants. Participants who experienced adverse reactions demonstrated a higher antibody titer after vaccination than those without adverse reactions. Multivariable analysis demonstrated that young age, female sex, and adverse reactions after the second dose were independently related to higher antibody titers after the second dose. DISCUSSION: A favorable antibody response was observed after two doses of BNT162b2 vaccination among mostly healthy Japanese participants, especially among female and young participants. Although further investigation is essential, our results imply that the systemic adverse reactions (i.e., fever and general fatigue) are associated with a higher antibody response that indicates the acquisition of humoral immunity.

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Pro108Ser mutation of SARS-CoV-2 3CLpro reduces the enzyme activity and ameliorates the clinical severity of COVID-19.

Kodai Abe, Yasuaki Kabe, Susumu Uchiyama, Yuka W Iwasaki, Hirotsugu Ishizu, Yoshifumi Uwamino, Toshiki Takenouchi, Shunsuke Uno, Makoto Ishii, Takahiro Maruno, Masanori Noda, Mitsuru Murata, Naoki Hasegawa, Hideyuki Saya, Yuko Kitagawa, Koichi Fukunaga, Masayuki Amagai, Haruhiko Siomi, Makoto Suematsu, Kenjiro Kosaki

Scientific reports (Scientific Reports)  12 ( 1 ) 1299 - 1299 2022.01

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Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.

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COVID-19 vaccine induced interstitial lung disease.

Ayumi Yoshifuji, Kota Ishioka, Yuya Masuzawa, Shuntaro Suda, Saori Murata, Yoshifumi Uwamino, Motoko Fujino, Hiromi Miyahara, Naoki Hasegawa, Munekazu Ryuzaki, Haruhiko Hoshino, Kazuhiko Sekine

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  28 ( 1 ) 95 - 98 2022.01

ISSN  1341321X

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A 60-year-old man presented with dyspnea four days after the second dose of the coronavirus disease (COVID-19) vaccine. Imaging revealed extensive ground-glass opacification. Blood tests were notable for elevated KL-6 levels. Bronchoalveolar lavage fluid analysis showed increased lymphocyte-dominant inflammatory cells and decreased CD4/CD8 ratio. These findings were consistent with the diagnosis of drug-induced interstitial lung disease (DIILD). To the best of our knowledge, this has never been reported in previous literature. Treatment with glucocorticoids relieved his symptoms. This paper highlights that although extremely rare, COVID-19 vaccine could cause DIILD, and early diagnosis and treatment are crucial to improve patient outcomes.

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Usefulness of the FilmArray Meningitis/Encephalitis Panel in diagnosis of central nervous system infection after allogeneic hematopoietic stem cell transplantation.

Takehiko Mori, Yuya Koda, Jun Kato, Masatoshi Sakurai, Yoshifumi Uwamino, Naoki Hasegawa

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer (Supportive Care in Cancer)  30 ( 1 ) 5 - 8 2022.01

ISSN  09414355

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PURPOSE: The BioFire FilmArray® Meningitis/Encephalitis Panel (FAMEP) is designed to rapidly and accurately detect common multiple pathogens that cause central nervous system (CNS) infection, including viruses, bacteria, and yeast. The FAMEP's usefulness in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) has not been fully evaluated. This retrospective study evaluated the usefulness of the FAMEP in the screening for CNS infection after allogeneic HSCT. METHODS: Cerebrospinal fluid (CSF) was obtained from 12 patients to evaluate the causes of CNS disorders after allogeneic HSCT, and the FAMEP was applied. RESULTS: The median day of the FAMEP evaluations was 27 days post-transplant (range, 0-390). Human herpesvirus 6 (HHV-6) was detected in three patients and cytomegalovirus was detected in one patient, leading to the diagnosis of encephalitis/myelitis. In three patients (HHV-6, n = 2; CMV, n = 1), the presence of the viruses was confirmed by conventional real-time polymerase chain reaction (PCR). However, in the remaining patient with HHV-6 detected by the AMEP, HHV-6 was not detected by real-time PCR at the onset but was detected 7 days later. The treatments for the detected viruses improved the clinical conditions in the four patients. CONCLUSIONS: Our results suggest that the FAMEP can be a useful sensitive assay in the screening and diagnosis of CNS viral infections after allogeneic HSCT.

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Mycobacterium abscessus complexに対するNacubactamとβラクタム薬の併用効果

三澤 可奈, 西村 知泰, 榎木 裕紀, 田口 和明, 宇野 俊介, 上蓑 義典, 松元 一明, 長谷川 直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会)  70 ( 1 ) 162 - 163 2022.01

ISSN  1340-7007

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection.

Osamu Iketani, Akari Komeya, Yuki Enoki, Kazuaki Taguchi, Shunsuke Uno, Yoshifumi Uwamino, Kazuaki Matsumoto, Junko Kizu, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  28 ( 1 ) 61 - 66 2022.01

ISSN  1341321X

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INTRODUCTION: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. METHODS: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. RESULTS: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4-1.8) μg·h/mL vs. 21.5 (IQR, 17.7-32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9-10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3-9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. CONCLUSIONS: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

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Efficient automated semi-quantitative urine culture analysis via BD Urine Culture App.

Yoshifumi Uwamino, Mika Nagata, Wataru Aoki, Ai Kato, Miho Daigo, Osamu Ishihara, Hirotaka Igari, Rika Inose, Naoki Hasegawa, Mitsuru Murata

Diagnostic microbiology and infectious disease (Diagnostic Microbiology and Infectious Disease)  102 ( 1 ) 115567 - 115567 2022.01

ISSN  07328893

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We aimed to assess the clinical utility of BD KiestraTM Urine Culture App (UCA). High concordance rates were observed between the urine culture colony counts obtained by medical technologists and those produced using UCA. This application may increase the efficiency of obtaining semi-quantitative urine culture results.

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Mapping the human genetic architecture of COVID-19

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

Nature (Nature)  600 ( 7889 ) 472 - 477 2021.12

ISSN  00280836

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

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Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.

Yuko Sato, Koji Atarashi, Damian R Plichta, Yasumichi Arai, Satoshi Sasajima, Sean M Kearney, Wataru Suda, Kozue Takeshita, Takahiro Sasaki, Shoki Okamoto, Ashwin N Skelly, Yuki Okamura, Hera Vlamakis, Youxian Li, Takeshi Tanoue, Hajime Takei, Hiroshi Nittono, Seiko Narushima, Junichiro Irie, Hiroshi Itoh, Kyoji Moriya, Yuki Sugiura, Makoto Suematsu, Nobuko Moritoki, Shinsuke Shibata, Dan R Littman, Michael A Fischbach, Yoshifumi Uwamino, Takashi Inoue, Akira Honda, Masahira Hattori, Tsuyoshi Murai, Ramnik J Xavier, Nobuyoshi Hirose, Kenya Honda

Nature (Nature)  599 ( 7885 ) 458 - 464 2021.11

ISSN  00280836

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Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.

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Virucidal Effect of the Mesoscopic Structure of CAC-717 on Severe Acute Respiratory Syndrome Coronavirus-2.

Takashi Yokoyama, Tomoyasu Nishimura, Yoshifumi Uwamino, Kenjiro Kosaki, Koichi Furusaki, Rumiko Onishi, Takashi Onodera, Makoto Haritani, Katsuaki Sugiura, Rikio Kirisawa, Naoki Hasegawa

Microorganisms (Microorganisms)  9 ( 10 )  2021.10

ISSN  2076-2607

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Here, the virucidal effect of calcium bicarbonate with a mesoscopic structure (CAC-717) on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was determined. Assays showed that CAC-717 had a strong virucidal effect on all examined SARS-CoV-2 isolates, including variant strains. The viral infectivity decreased within 15 s, and the virucidal activity of CAC-717 at a 1:49 ratio was similar to that of ethanol disinfectant. CAC-717 neutralization eliminated this virucidal effect, indicating that the alkaline condition of CAC-717 is important for virus inactivation and is an indicator of its mesoscopic structure and virucidal activity. The virucidal effect was observed in the presence of organic matter (bovine serum albumin). CAC-717 is a non-invasive and non-flammable substance with a low environmental burden, and its usefulness as a novel disinfectant has been confirmed.

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SARS-CoV-2 Infection among Medical Institution Faculty and Healthcare Workers in Tokyo, Japan.

Tomoyasu Nishimura, Yoshifumi Uwamino, Shunsuke Uno, Shoko Kashimura, Toshikimi Shiraki, Toshinobu Kurafuji, Maasa Morita, Masayo Noguchi, Tatsuhiko Azegami, Nobuko Yamada-Goto, Ayano Murai-Takeda, Hirokazu Yokoyama, Kazuyo Kuwabara, Suzuka Kato, Minako Matsumoto, Aya Hirata, Miho Iida, Sei Harada, Tamami Ishizaka, Kana Misawa, Mitsuru Murata, Hideyuki Saya, Masayuki Amagai, Yuko Kitagawa, Tsutomu Takeuchi, Masaaki Mori, Toru Takebayashi, Naoki Hasegawa

Internal medicine (Tokyo, Japan) (Internal Medicine)  60 ( 16 ) 2569 - 2575 2021.08

ISSN  09182918

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Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in medical institutions, this study estimated the SARS-CoV-2 infection rate among healthcare workers (HCWs) in Tokyo, Japan, and determined the specific findings for mild coronavirus disease 2019 (COVID-19) cases. Methods This study analyzed the results of serologic tests to detect immunoglobulin G antibodies against SARS-CoV-2 and evaluated the demographic and clinical characteristics of the faculty and HCWs at a Tokyo medical institution in August 2020. The demographic and clinical characteristics of participants with antibody-positive results were compared to those of participants with antibody-negative results. Materials This study recruited 2,341 faculty and HCWs at a Tokyo medical institution, 21 of whom had a COVID-19 history. Results Of the 2,320 participants without a COVID-19 history, 20 (0.862%) had positive serologic test results. A fever and dysgeusia or dysosmia occurred with greater frequency among the participants with positive test results than in those with negative results [odds ratio (OR), 5.475; 95% confidence interval (CI), 1.960-15.293 and OR, 24.158; 95% CI, 2.693-216.720, respectively]. No significant difference was observed in the positivity rate between HCWs providing medical care for COVID-19 patients using adequate protection and other HCWs (OR, 2.514; 95% CI, 0.959-6.588). Conclusion To reduce the risk of COVID-19 spread in medical institutions, faculty and HCWs should follow standard and necessary transmission-based precautions, and those with a fever and dysgeusia or dysosmia should excuse themselves from work as soon as possible.

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

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

Modern rheumatology (Modern Rheumatology)  32 ( 3 ) 534 - 540 2021.08

ISSN  14397595

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

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Meningitis caused by Listeria monocytogenes in a locally advanced cervical cancer patient with pyometra: A case report.

Yusuke Matoba, Hiroshi Nishio, Koji Sekiguchi, Shunsuke Uno, Kenta Masuda, Makiko Hiramatsu, Mio Takahashi, Maki Oishi, Yoshifumi Uwamino, Sho Uchida, Yugaku Daté, Tohru Morisada, Kouji Banno, Jin Nakahara, Daisuke Aoki

Gynecologic oncology reports (Gynecologic Oncology Reports)  37   100799 - 100799 2021.08

ISSN  2352-5789

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Locally advanced cervical cancer occasionally induces pyometra, but there have been no reports of meningitis where pyometra is the cause of infection. Here, we report a case of Listeria monocytogenes meningitis related to pyometra during concurrent chemoradiotherapy (CCRT) in a cervical cancer patient. The patient, a 77-year-old woman, was diagnosed with Stage IIB (FIGO 2018) cervical adenocarcinoma, and CCRT was initiated. Pyometra was exacerbated during CCRT, and after her first brachytherapy, she presented at our hospital with fever and decreased consciousness level. After admission to the Intensive Care Unit, the patient lost consciousness and experienced frequent seizures; tracheal intubation was required. Whole-body computed tomography revealed pyometra; therefore, transvaginal removal of the abscess was performed. Laboratory tests and vital signs indicated septic shock, and meropenem was administered. L. monocytogenes was detected in the abscess from the uterine cavity and the blood cultures on the third day of hospitalization. A lumbar puncture was performed on the same day to investigate whether the patient had meningitis. A FilmArray meningitis/encephalitis panel test of the spinal fluid revealed L. monocytogenes. After the diagnosis of meningitis with L. monocytogenes, ampicillin and gentamicin were started, and the blood test results gradually improved. Five months after the initial episode, her consciousness recovered, however she still received mechanical ventilatory support. L. monocytogenes infections can occur in patients undergoing chemotherapy, even without the use of steroids or immunosuppressive agents. In cases with pyometra, intrauterine manipulation can increase the risk of severe infection.

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Three cases of otitis media caused by Mycobacterium abscessus subsp. abscessus: Importance of medical treatment and efficacy of surgery.

Yuri Nishiyama, Takanori Nishiyama, Sho Kanzaki, Naoki Oishi, Masato Fujioka, Hiroyuki Yamada, Chihiro Ebisuno, Mayumi Kaiho, Yoshifumi Uwamino, Hanako Fukano, Yoshihiko Hoshino, Naoki Hasegawa, Kaoru Ogawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  27 ( 8 ) 1251 - 1257 2021.08

ISSN  1341321X

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This study aimed to assess the clinical presentation, antibiotic therapy, surgery, and outcomes in patients with otitis media caused by Mycobacterium abscessus subsp. abscessus and discuss the efficacy of surgery. This is a retrospective case review of three patients diagnosed with otomastoiditis caused by M. abscessus subsp. abscessus. All patients had refractory otorrhea. One patient had granulation tissue in the tympanic membrane. They received medical treatment and underwent surgery. Otorrhea was resolved several months after the initiation of long-term multiantibiotic therapy in all cases. The timing of surgery varied among patients. Before initiating antibiotic therapy, mastoidectomy was performed to achieve definitive diagnosis in two patients, and wound dehiscence developed in these patients. Two patients underwent debridement after the initiation of multiantibiotic therapy. After antibiotic administration, tympanoplasty was performed to improve hearing in one patient. All patients achieved culture negativity after treatment, and no recurrences have been noted. From three cases, it is suggested that the mainstay of treatment for M. abscessus subsp. abscessus is long-term multiantibiotic therapy, and surgery itself may have little effect on achieving ear dryness. Thus, in most patients, drug therapy should be prioritized. Considering postoperative complications, surgery before achieving ear dryness should be avoided, except in emergency cases. In addition, if the diagnosis is not confirmed by repeated bacteriological tests, mastoidectomy should be performed to collect specimens. Tympanoplasty for hearing loss or eardrum perforation is recommended after discontinuation of medications.

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Universal Polymerase Chain Reaction Screening for Severe Acute Respiratory Syndrome Coronavirus 2 in Asymptomatic Patients Before Hospital Admission in Tokyo, Japan.

Sho Uchida, Yoshifumi Uwamino, Shunsuke Uno, Mika Nagata, Wataru Aoki, Mitsuru Murata, Yuko Kitagawa, Naoki Hasegawa

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology (Journal of Clinical Virology)  142   104915 - 104915 2021.07

ISSN  13866532

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OBJECTIVES: Universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., the causative agent of coronavirus disease 2019 [COVID-19]) polymerase chain reaction (PCR) screening before admission has been adopted by several hospitals to prevent nosocomial SARS-CoV-2 transmission from asymptomatic and pre-symptomatic patients. However, screening usefulness remains unclear because it depends on the regional COVID-19 prevalence, and only a few large-scale studies have been reported. Here we describe the universal PCR screening performed in our hospital before admission of more than 12,000 patients and their attendants to evaluate the usefulness of the screening. METHODS: We retrospectively described the universal PCR screening results for asymptomatic patients and their attendants before planned admissions at a hospital in Tokyo, Japan, from August 3, 2020, through March 31, 2021. Nasopharyngeal swab samples were collected at an in-hospital PCR center. RESULTS: In total, 12,133 persons (11,859 asymptomatic patients and 274 attendants) underwent PCR screening; nine (0.07%) tested positive for SARS-CoV-2 RNA. CONCLUSIONS: Universal PCR screening may be useful for the advanced detection of SARS-CoV-2 infected patients with or without symptoms, which can be a potential source of nosocomial SARS-CoV-2 transmission.

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Accuracy of rapid antigen detection test for nasopharyngeal swab specimens and saliva samples in comparison with RT-PCR and viral culture for SARS-CoV-2 detection.

Yoshifumi Uwamino, Mika Nagata, Wataru Aoki, Terumichi Nakagawa, Rika Inose, Hiromitsu Yokota, Yuri Furusawa, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Yoshihiro Kawaoka, Naoki Hasegawa, Mitsuru Murata

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  27 ( 7 ) 1058 - 1062 2021.07

ISSN  1341321X

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INTRODUCTION: Rapid antigen detection (RAD) tests are convenient tools for detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinics, and testing using saliva samples could decrease the risk of infection during sample collection. This study aimed to assess the accuracy of the SARS-CoV-2 RAD for testing of nasopharyngeal swab specimens and saliva samples in comparison with the RT-PCR tests and viral culture for detecting viable virus. METHODS: One hundred seventeen nasopharyngeal swab specimens and 73 saliva samples with positive results on RT-PCR were used. Residual samples were assayed using a commercially available RAD test immediately, and its positivity was determined at various time points during the clinical course. The concordance between 54 nasopharyngeal swab samples and saliva samples that were collected simultaneously was determined. Viral culture was performed on 117 samples and compared with the results of the RAD test. RESULTS: The positive rate of RAD test using saliva samples was low throughout the clinical course. Poor concordance was observed between nasopharyngeal swab specimens and saliva samples (75.9%, kappa coefficient 0.310). However, a substantially high concordance between the RAD test and viral culture was observed in both nasopharyngeal swab specimens (86.8%, kappa coefficient 0.680) and saliva samples (95.1%, kappa coefficient 0.643). CONCLUSIONS: The sensitivity of the SARS-CoV-2 RAD test was insufficient, particularly for saliva samples. However, a substantially high concordance with viral culture suggests its potential utility as an auxiliary test for estimating SARS-CoV-2 viability.

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Assessment of humoral responses in COVID-19 using various quantitative antibody tests

Wakui M., Uwamino Y., Kurafuji T., Noguchi M., Ohno A., Yokota H., Kikuchi H., Hasegawa N., Saya H., Murata M.

Annals of Clinical Biochemistry (Annals of Clinical Biochemistry)  58 ( 4 ) 368 - 376 2021.07

ISSN  00045632

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Background: Quantitative antibody tests are expected to be useful in diagnostics of COVID-19 and investigation of herd immunity against SARS-CoV-2. To make it proper to perform them, understanding of the immunological aspects is critically important. The present study aimed to assess humoral responses in COVID-19 using various quantitative antibody tests. Methods: Four quantitative antibody tests that are different in targeted antigens, detectable immunoglobulin classes and avidity were used. Diagnosis was confirmed by RT-PCR for SARS-CoV-2 detection. Antibody titres of 117 samples collected from 24 COVID-19 patients and 23 non-COVID-19 patients were measured to evaluate correlations between different tests. For 24 COVID-19 patients, antibody titres measured at various time points after the onset or the RT-PCR diagnosis were subjected to assessment of humoral responses. Results: Correlations between tests were observed to some degree, although there were discrepancies putatively due to differences in measurement principle. Seronegative COVID-19 was diagnosed for some patients, in whom antibody titres were less than the cut-off value in each test throughout the time courses. IgG seroconversion without prior IgM seroconversion most frequently occurred, while predominance of IgM responses over IgG responses was observed in some severe cases. Viral burdens estimated according to threshold cycle values at the RT-PCR seemed to impact antibody responses. Conclusions: The results provide insights into the nature of humoral responses to SARS-CoV-2 and diagnostic performance of antibody tests.

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Digestive Decolonization of Colorectal Carriage of Vancomycin-resistant Enterococcus faecium in a Japanese Adult: A Case Report.

Shunsuke Uno, Yaoko Takano, Osamu Iketani, Tomohiro Abiko, Tomoru Miwa, Kosaku Nanki, Tomohiro Kurihara, Yuko Tamura, Miyuki Ara, Yoshifumi Uwamino, Masayoshi Shinjoh, Takehiko Mori, Naoki Hasegawa

Internal medicine (Tokyo, Japan) (Internal Medicine)  61 ( 2 ) 249 - 252 2021.06

ISSN  09182918

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Patients with vancomycin-resistant Enterococcus (VRE) colonization should be managed in an isolation room with contact precautions. We herein report a patient whose colorectal carriage of VRE was successfully decolonized using concomitant bowel irrigation with polyethylene glycol, probiotics, and oral antimicrobials, linezolid and orally-administered daptomycin, for release from isolation and contact precautions. We therefore would like to suggest a potential strategy for managing patients with VRE colonization.

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Potential biomarker enhancing the activity of tuberculosis, hsa-miR-346.

Shunsuke Uno, Tomoyasu Nishimura, Kazumi Nishio, Asami Kohsaka, Eiko Tamizu, Yasushi Nakano, Junko Kagyo, Yukiko Nakajima, Ryosuke Arai, Hanako Hasegawa, Kenichi Arakawa, Shoko Kashimura, Ryota Ishii, Naoki Miyazaki, Yoshifumi Uwamino, Naoki Hasegawa

Tuberculosis (Edinburgh, Scotland) (Tuberculosis)  129   102101 - 102101 2021.06

ISSN  14729792

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OBJECTIVES: To determine the usefulness of hsa-miR-346, a potential biomarker enhancing the activity of non-tuberculous mycobacterial diseases, as a biomarker of tuberculosis activity. METHODS: We investigated whether hsa-miR-346 is secreted by human macrophages infected with Mycobacterium tuberculosis (M. tuberculosis) in an in vitro study. In addition, a cross-sectional study was conducted first to evaluate whether serum hsa-miR-346 is elevated in patients with tuberculosis compared with that in healthy individuals. Second, we conducted a retrospective study to evaluate whether anti-tuberculosis treatment reduces serum hsa-miR-346 levels. RESULTS: Log hsa-miR-346 levels were significantly elevated in the supernatant of human macrophages infected with M. tuberculosis in a dose-dependent manner. The mean serum log hsa-miR-346 levels were -15.48 (-15.76 to -15.21) in patients with tuberculosis and -16.12 (-16.29 to -15.95) in healthy volunteers, which significantly differed. In addition, hsa-miR-346 significantly decreased at 2 months from starting an anti-tuberculosis treatment. CONCLUSIONS: We consider hsa-miR-346 as a potential biomarker enhancing the tuberculosis activity.

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

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

Open forum infectious diseases (Open Forum Infectious Diseases)  8 ( 6 ) ofab181 2021.06

ISSN  2328-8957

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

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Retrospective study of the efficacy and safety of metronidazole and vancomycin for Clostridioides difficile infection.

Kana Misawa, Osamu Iketani, Yuki Enoki, Kazuaki Taguchi, Shunsuke Uno, Yoshifumi Uwamino, Naoki Hasegawa, Kazuaki Matsumoto

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  27 ( 10 ) 1407 - 1412 2021.05

ISSN  1341321X

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INTRODUCTION: According to the Japanese guidelines for the management of Clostridioides difficile infection (CDI), the first choice is metronidazole (MNZ) for non-severe cases and vancomycin (VCM) for severe cases. However, the appropriateness of this first choice in Japanese patients is unclear. We therefore evaluated the appropriateness of the CDI management guidelines and the incidence of adverse drug reactions. METHODS: The electronic chart data at Keio University Hospital between January 2012 and June 2019 were retrospectively reviewed. The response rate, the relapse rate, and the adverse reaction rate of treatment for CDI using MNZ or VCM were investigated according to the disease severity. Factorial analysis associated with the response, relapse, and adverse reaction was also performed. RESULTS: In the 352 patients surveyed, no significant difference was observed in the response rate between MNZ and VCM regardless of the severity of CDI. The presence of cancer was a factor related to the persistence of diarrheal symptoms and older age was a risk factor for relapse. MNZ induced nausea significantly more frequently than VCM, and young age and female sex were risk factors for nausea. CONCLUSION: As no significant difference was observed in the response rate of CDI between MNZ and VCM, the Japanese CDI management guidelines, which recommend MNZ as the first choice, were demonstrated to be appropriate. Attention to nausea was also suggested to be necessary when administering MNZ to young females.

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Evaluation of the usability of various rapid antibody tests in the diagnostic application for COVID-19

Uwamino Y., Wakui M., Aoki W., Kurafuji T., Yanagita E., Morita M., Nagata M., Inose R., Noguchi M., Yokota H., Hasegawa N., Saya H., Murata M.

Annals of Clinical Biochemistry (Annals of Clinical Biochemistry)  58 ( 3 ) 174 - 180 2021.05

ISSN  00045632

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Background: The usability of laboratory tests related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critically important for the world undergoing the COVID-19 pandemic. The present study aimed to assess the diagnostic usability of rapid tests for the detection of antibody against SARS-CoV-2 through comparison of their results with the results of reverse transcription polymerase chain reaction (RT-PCR) test for the detection of SARS-CoV-2 genomic RNA and with the results of a quantitative test for antibody detection. Methods: Serum samples were collected from 18 patients undergoing RT-PCR testing for SARS-CoV-2. Twelve patients were RT-PCR positive while six were negative. A quantitative test based on chemiluminescent immunoassay and three rapid tests based on immunochromatography were performed to detect anti-SARS-CoV-2 IgG and IgM. Results: All the antibody tests exhibited poor sensitivity at the timing of initial RT-PCR diagnosis. IgG responses occurring prior to or simultaneously with IgM responses were observed through not only the quantitative test but also the three rapid tests. Based on concordance with the quantitative test results, the large variance among the three rapid tests was revealed. Conclusions: All antibody tests were unsatisfactory to replace RT-PCR for the early diagnosis of COVID-19. Rapid antibody tests as well as a quantitative antibody test were useful in the assessment of immune responses in COVID-19. The obvious variance among the three rapid tests suggested limited accuracy and difficult standardization. Diagnostic usability of rapid antibody tests for COVID-19 should be investigated rigorously.

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The real-time reverse transcription-polymerase chain reaction threshold cycle values for severe acute respiratory syndrome coronavirus 2 predict the prognosis of coronavirus disease 2019 pneumonia.

Takahiro Fukushima, Hiroki Kabata, Ryo Yamamoto, Tomohiro Suhara, Yoshifumi Uwamino, Yasushi Kondo, Katsunori Masaki, Hirofumi Kamata, Hiromasa Nagata, Koichiro Homma, Yuko Kaneko, Makoto Ishii, Junichi Sasaki, Hiroshi Morisaki, Naoki Hasegawa, Koichi Fukunaga

Respiratory investigation (Respiratory Investigation)  59 ( 3 ) 360 - 363 2021.05

ISSN  22125345

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The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

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ステロイドによりヒストプラスマ腫が再活性化し播種性ヒストプラスマ症を引き起こした日本人高齢男性の一例

小林 慧悟, 朝倉 崇徳, 川田 一郎, 藤島 清太郎, 岩田 敏, 梅山 隆, 片野 晴隆, 上蓑 義典, 宮崎 義継, 亀井 克彦, 長谷川 直樹

感染症学雑誌 ((一社)日本感染症学会)  95 ( 臨増 ) 299 - 299 2021.04

ISSN  0387-5911

Incomplete humoral response including neutralizing antibodies in asymptomatic to mild COVID-19 patients in Japan

Masaru Takeshita, Naoshi Nishina, Saya Moriyama, Yoshimasa Takahashi, Yoshifumi Uwamino, Mika Nagata, Wataru Aoki, Katsunori Masaki, Makoto Ishii, Hideyuki Saya, Yasushi Kondo, Yuko Kaneko, Katsuya Suzuki, Koichi Fukunaga, Tsutomu Takeuchi

VIROLOGY (ACADEMIC PRESS INC ELSEVIER SCIENCE)  555   35 - 43 2021.03

ISSN  0042-6822

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The pandemic of COVID-19 is still ongoing, and many studies on serum antibodies have been reported, however, there are few studies about asymptomatic and mild patients. In this study, we enrolled 44 COVID-19 patients with relatively mild disease and 48 pre-pandemic controls. We measured serum antibodies against extracellular domain, S1 domain, and receptor-binding domain of Spike and N protein, examined neutralization titers by authentic virus neutralization assay and newly-developed bead/cell-based Spike-ACE2 inhibition assay, and compared them with clinical features. Most of these antibodies, including neutralizing titers, were mutually correlated, and the production of antibodies were associated with low Ct values of PCR test, disease severity, symptoms especially pneumonia, lymphopenia, and serological test including CRP, LD, D-dimer, and procalcitonin. Notably, 87.5% of asymptomatic and 23.5% of mild patients did not have antibody against SARS-CoV-2. Our results revealed the inadequate acquisition of humoral immunity in patients with asymptomatic and mild COVID-19 patients.

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Two case reports of Mycobacterium marinum infection with psoriatic arthritis treated by tumor necrosis factor‐α inhibitors

Yuki Furuichi, Yoshihiro Ito, Keiji Tanese, Miho Mukai, Yoshifumi Uwamino, Naoki Hasegawa, Masayuki Amagai, Noriko Umegaki‐Arao

The Journal of Dermatology (Wiley)  48 ( 2 ) e106-e107 - e107 2021.02

ISSN  03852407

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CT screening for COVID-19 in asymptomatic patients before hospital admission.

Sho Uchida, Shunsuke Uno, Yoshifumi Uwamino, Masahiro Hashimoto, Shunsuke Matsumoto, Hideaki Obara, Masahiro Jinzaki, Yuko Kitagawa, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  27 ( 2 ) 232 - 236 2021.02

ISSN  1341321X

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INTRODUCTION: In the novel coronavirus disease (COVID-19) pandemic era, it is essential to rule out COVID-19 effectively to prevent transmission in both communities and medical facilities. According to previous reports in high prevalence areas, CT screening may be useful in the diagnosis of COVID-19. However, the value of CT screening in low prevalence areas has scarcely been reported. METHODS: This report examines the diagnostic efficacy of CT screening before admission to a hospital in Tokyo. We conducted a retrospective analysis at Keio University Hospital from April 6, 2020, through May 29, 2020. We set up an outpatient screening clinic on April 6 for COVID-19, administering both PCR with nasopharyngeal swabs and chest CT for all patients scheduled for surgery under general anesthesia. RESULTS: A total of 292 asymptomatic patients were included in this study. There were three PCR-positive patients, and they all had negative CT findings, which revealed that both the sensitivity and positive predictive value of CT (PPV) were 0%. There were nine CT-positive patients; the specificity and the negative predictive value (NPV) were 96.9% and 98.9%, respectively. CONCLUSION: CT screening was not useful in low prevalence areas at this time in Tokyo, even with the inclusion of the most prevalent phase. Given that the utility of CT screening depends on disease prevalence, the criteria for performing CT screening based on the prevalence of COVID-19 should be established.

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Stability of antimicrobial agents in an elastomeric infusion pump used for outpatient parenteral antimicrobial therapy.

Mutsumi Akahane, Yuki Enoki, Reika Saiki, Yukitaka Hayashi, Kana Hiraoka, Kyoka Honma, Marina Itagaki, Mai Gotoda, Kozue Shinoda, Satomi Hanyu, Yuna Hamamura, Taichi Miyajima, Chihiro Ito, Kazuaki Taguchi, Shunsuke Uno, Yoshifumi Uwamino, Osamu Iketani, Naoki Hasegawa, Kazuaki Matsumoto

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (International Journal of Infectious Diseases)  103   464 - 468 2021.02

ISSN  12019712

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OBJECTIVES: The long-term stability of antimicrobials dissolved in infusion solution is necessary to establish and spread the outpatient parenteral antimicrobial therapy (OPAT). In this study, we evaluated the stability of antimicrobial agents dissolved in infusion solutions. METHODS: The antimicrobial agents were dissolved in infusion solutions and kept at 25 °C and 31.1 °C for 24 h or 4 °C for 10 days in a polypropylene tube or an elastomeric infusion pump. The stability was measured by high-performance liquid chromatography. RESULTS AND CONCLUSION: The residual ratio of cefazolin (CEZ), cefmetazole (CMZ), piperacillin (PIPC), and tazobactam (TAZ) at 31.1 °C for 24 h was as follows: 95.7 ± 3.0%, 94.8 ± 0.9%, 102.6 ± 1.8%, and 103.9 ± 3.6% in saline, respectively; 94.7 ± 3.0%, 94.3 ± 1.5%, 106.1 ± 3.0%, and 107.3 ± 2.4% in 5% dextrose solution, respectively. The residual ratio of these antimicrobials at 4 °C for 10 days was maintained above 90% in both saline and 5% dextrose solution. The residual ratio of all the above antimicrobials in an elastomeric infusion pump at 31.1 °C for 24 h was equivalent to that in the polypropylene tube. On the other hand, doripenem and meropenem were not stable in any infusion solution at 31.1 °C. CEZ, CMZ, and PIPC/TAZ dissolved in saline or 5% dextrose solution can be used in OPAT with continuous infusion pumps.

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Identification of B.1.346 Lineage of SARS-CoV-2 in Japan: Genomic Evidence of Re-entry of Clade 20C

Kodai Abe, Takako Shimura, Toshiki Takenouchi, Yuka W. Iwasaki, Hirotsugu Ishizu, Yoshifumi Uwamino, Shunsuke Uno, Jun Gotoh, Natsuo Tachikawa, Yuriko Takeuchi, Junpei Katayama, Hiroyuki Nozaki, Susumu Fujii, Shikou Seki, Morio Nakamura, Kazuhiro Uda, Takahiko Misumi, Jun Ishihara, Kenichiro Yamada, Toshio Kanai, Shinji Murai, Kazuhiro Araki, Tamotsu Ebihara, Haruhiko Siomi, Naoki Hasegawa, Yuko Kitagawa, Masayuki Amagai, Makoto Suematsu, Kenjiro Kosaki

The Keio Journal of Medicine (Keio Journal of Medicine)  70 ( 2 ) 44 - 50 2021

ISSN  0022-9717

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SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.

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Control of a Nosocomial Outbreak of COVID-19 in a University Hospital.

Sei Harada, Shunsuke Uno, Takayuki Ando, Miho Iida, Yaoko Takano, Yoshiki Ishibashi, Yoshifumi Uwamino, Tomoyasu Nishimura, Ayano Takeda, Sho Uchida, Aya Hirata, Mizuki Sata, Minako Matsumoto, Ayano Takeuchi, Hideaki Obara, Hirokazu Yokoyama, Koichi Fukunaga, Masayuki Amagai, Yuko Kitagawa, Toru Takebayashi, Naoki Hasegawa

Open forum infectious diseases 7 ( 12 ) ofaa512 2020.12

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Background: Nosocomial spread of coronavirus disease 2019 (COVID-19) causes clusters of infection among high-risk individuals. Controlling this spread is critical to reducing COVID-19 morbidity and mortality. We describe an outbreak of COVID-19 in Keio University Hospital, Japan, and its control and propose effective control measures. Methods: When an outbreak was suspected, immediate isolation and thorough polymerase chain reaction (PCR) testing of patients and health care workers (HCWs) using an in-house system, together with extensive contact tracing and social distancing measures, were conducted. Nosocomial infections (NIs) were defined as having an onset or positive test after the fifth day of admission for patients and having high-risk contacts in our hospital for HCWs. We performed descriptive analyses for this outbreak. Results: Between March 24 and April 24, 2020, 27 of 562 tested patients were confirmed positive, of whom 5 (18.5%) were suspected as NIs. For HCWs, 52 of 697 tested positive, and 40 (76.9%) were considered NIs. Among transmissions, 95.5% were suspected of having occurred during the asymptomatic period. Large-scale isolation and testing at the first sign of outbreak terminated NIs. The number of secondary cases directly generated by a single primary case found before March 31 was 1.74, compared with 0 after April 1. Only 4 of 28 primary cases generated definite secondary infection; these were all asymptomatic. Conclusions: Viral shedding from asymptomatic cases played a major role in NIs. PCR screening of asymptomatic individuals helped clarify the pattern of spread. Immediate large-scale isolation, contact tracing, and social distancing measures were essential to containing outbreaks.

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Pro108Ser mutant of SARS-CoV-2 3CLpro reduces the enzymatic activity and ameliorates COVID-19 severity in Japan

Kodai Abe, Yasuaki Kabe, Susumu Uchiyama, Yuka Iwasaki W., Hirotsugu Ishizu, Yoshifumi Uwamino, Toshiki Takenouchi, Shunsuke Uno, Makoto Ishii, Maruno Takahiro, Noda Masanori, Mitsuru Murata, Naoki Hasegawa, Hideyuki Saya, Yuko Kitagawa, Koichi Fukunaga, Masayuki Amagai, Haruhiko Siomi, Makoto Suematsu, Kenjiro Kosaki

(Cold Spring Harbor Laboratory)   2020.11

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SARS-CoV-2 genome accumulates point mutations constantly. However, whether non-synonymous mutations affect COVID-19 severity through altering viral protein function remains unknown. SARS-CoV-2 genome sequencing revealed that the number of non-synonymous mutations correlated inversely with COVID-19 severity in Tokyo Metropolitan area. Phylogenic tree analyses identified two predominant groups which were differentiated by a set of six-point mutations (four non-synonymous amino acid mutations). Among them, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations among β-coronaviruses. Patients with these mutations (N = 48) indicated significantly lower odds ratio for developing hypoxia which required supplemental oxygen (odds ratio 0.24 [95% CI 0.07-0.88, p-value = 0.032]) after adjustments for age and sex, versus those lacking this haplotype in the canonical Clade 20B (N = 37). The Pro108Ser 3CLpro enzyme in vitro decreases in the activity by 58%, and the hydrogen/deuterium exchange mass spectrometry reveals that mechanisms for reduced activities involve structural perturbation at the substrate-binding region which is positioned behind and distant from the 108th amino acid residue of the enzyme. This mutant strain rapidly outcompeted pre-existing variants to become predominant in Japan. Our results may benefit the efforts underway to design small molecular compounds or antibodies targeting 3CLpro.

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受診・治療中断を繰り返した患者への服薬継続支援

戸蒔 祐子, 宇野 俊介, 藤澤 大介, 矢永 由里子, 小谷 宙, 西松 直美, 上田 裕美, 根岸 昌功, 河村 祐貴子, 河野 小夜子, 和山 郁美, 滝口 紗彩, 的場 由木, 浦澤 智佐, 小倉 由美子, 新田 七恵, 佐久川 裕美, 上蓑 義典, 藤原 宏, 長谷川 直樹

日本エイズ学会誌 ((一社)日本エイズ学会)  22 ( 4 ) 452 - 452 2020.11

ISSN  1344-9478

受診・治療中断を繰り返した患者への服薬継続支援

戸蒔 祐子, 宇野 俊介, 藤澤 大介, 矢永 由里子, 小谷 宙, 西松 直美, 上田 裕美, 根岸 昌功, 河村 祐貴子, 河野 小夜子, 和山 郁美, 滝口 紗彩, 的場 由木, 浦澤 智佐, 小倉 由美子, 新田 七恵, 佐久川 裕美, 上蓑 義典, 藤原 宏, 長谷川 直樹

日本エイズ学会誌 ((一社)日本エイズ学会)  22 ( 4 ) 452 - 452 2020.11

ISSN  1344-9478

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

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

BMC pulmonary medicine 20 ( 1 ) 262 - 262 2020.10

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

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Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections.

Kensuke Nakagawara, Katsunori Masaki, Yoshifumi Uwamino, Hiroki Kabata, Sho Uchida, Shunsuke Uno, Takanori Asakura, Takeru Funakoshi, Sho Kanzaki, Makoto Ishii, Naoki Hasegawa, Koichi Fukunaga

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 99   19 - 22 2020.10

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This study investigated, using cycle threshold (Ct) qPCR values, the association between symptoms and viral clearance in 57 patients with asymptomatic/mild SARS-CoV-2 infection. Patients with olfactory/taste disorders (OTDs) exhibited lower qPCR Ct values and longer time to negative qPCR than those without OTDs, suggesting an association between OTDs and high viral burden.

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Accuracy and stability of saliva as a sample for reverse transcription PCR detection of SARS-CoV-2.

Yoshifumi Uwamino, Mika Nagata, Wataru Aoki, Yuta Fujimori, Terumichi Nakagawa, Hiromitsu Yokota, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Toshiki Shiraki, Sho Uchida, Shunsuke Uno, Hiroki Kabata, Shinnosuke Ikemura, Hirofumi Kamata, Makoto Ishii, Koichi Fukunaga, Yoshihiro Kawaoka, Naoki Hasegawa, Mitsuru Murata

Journal of clinical pathology (Journal of Clinical Pathology)  74 ( 1 ) 67 - 68 2020.09

ISSN  00219746

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Complete Genome Sequence of Mycolicibacterium sp. Strain NIID-NTM18, Isolated from Cardiac Implantable Electronic Device Infection and Most Similar to Mycolicibacterium litorale.

Hanako Fukano, Hiroshi Miyama, Seiji Takatsuki, Aki Hirabayashi, Masato Suzuki, Mitsunori Yoshida, Yoshifumi Uwamino, Naoki Hasegawa, Yoshihiko Hoshino

Microbiology resource announcements 9 ( 36 )  2020.09

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Mycolicibacterium litorale is a rapidly growing mycobacterial organism with unknown pathogenic features. Here, we report the complete genome sequence of Mycolicibacterium sp. strain NIID-NTM18, which was isolated from a cardiac implantable electronic device infection and which is most similar to M. litorale This sequence will provide essential information for future studies of the pathogenicity of these mycobacteria.

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Clostridioides difficile感染症に対するメトロニダゾールとバンコマイシンの有効性及び安全性評価

三澤 可奈, 池谷 修, 榎木 裕紀, 田口 和明, 松元 一明, 宇野 俊介, 上蓑 義典, 長谷川 直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会)  68 ( Suppl.A ) 339 - 339 2020.09

ISSN  1340-7007

Gene Xpertを用いた空気予防策解除の妥当性評価

上蓑 義典, 宇野 俊介, 鎌田 浩史, 西村 知泰, 石井 誠, 長谷川 直樹

結核 ((一社)日本結核・非結核性抗酸菌症学会)  95 ( 5 ) 122 - 122 2020.09

ISSN  0022-9776

Does the patient truly not have congenital anomalies of the kidney and urinary tract? Urinary tract infection caused by Gardnerella vaginalis.

Takuma Ohnishi, Shinya Asato, Ayaka Maeda, Mika Nagata, Yoshifumi Uwamino, Isamu Kamimaki

Pediatrics international : official journal of the Japan Pediatric Society 62 ( 8 ) 1009 - 1010 2020.08

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The rough colony morphotype of Mycobacterium avium exhibits high virulence in human macrophages and mice.

Tomoyasu Nishimura, Masayuki Shimoda, Eiko Tamizu, Shunsuke Uno, Yoshifumi Uwamino, Shoko Kashimura, Ikuya Yano, Naoki Hasegawa

Journal of medical microbiology 69 ( 7 ) 1020 - 1033 2020.07

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Introduction. The incidence of Mycobacterium avium complex (MAC) pulmonary disease (MAC PD), a refractory chronic respiratory tract infection, is increasing worldwide. MAC has three predominant colony morphotypes: smooth opaque (SmO), smooth transparent (SmT) and rough (Rg).Aim. To determine whether colony morphotypes can predict the prognosis of MAC PD, we evaluated the virulence of SmO, SmT and Rg in mice and in human macrophages.Methodology. We compared the characteristics of mice and human macrophages infected with the SmO, SmT, or Rg morphotypes of M. avium subsp. hominissuis 104. C57BL/6 mice and human macrophages derived from peripheral mononuclear cells were used in these experiments.Results. In comparison to SmO- or SmT-infected mice, Rg-infected mice revealed severe pathologically confirmed pneumonia, increased lung weight and increased lung bacterial burden. Rg-infected macrophages revealed significant cytotoxicity, increased bacterial burden, secretion of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CCL5 and CCL3), and formation of cell clusters. Rg formed larger bacterial aggregates than SmO and SmT. Cytotoxicity, bacterial burden and secretion of IL-6, CCL5 and CCL3 were induced strongly by Rg infection, and were decreased by disaggregation of the bacteria.Conclusion.M. avium Rg, which is associated with bacterial aggregation, has the highest virulence among the predominant colony morphotypes.

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Clinical Utility of SARS-CoV-2 Whole Genome Sequencing in Deciphering Source of Infection

Toshiki Takenouchi, Yuka W. Iwasaki, Sei Harada, Hirotsugu Ishizu, Yoshifumi Uwamino, Shunsuke Uno, Asami Osada, Naoki Hasegawa, Mitsuru Murata, Toru Takebayashi, Koichi Fukunaga, Hideyuki Saya, Yuko Kitagawa, Masayuki Amagai, Haruhiko Siomi, Kenjiro Kosaki

The Journal of hospital infection (Cold Spring Harbor Laboratory)  107   40 - 4 2020.05

ISSN  01956701

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The novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 is a major threat to humans. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary care medical center. Whole viral genome sequencing detected the haplotype of the SARS-CoV-2 genome and the two clusters were successfully distinguished by the viral genome haplotype. Concurrently, there were nine COVID-19 patients clinically unlinked to clusters #1 or #2 that necessitated the determination of the source of infection. Such patients had similar haplotypes to that in cluster #2 but were devoid of two rare mutations characteristic to cluster #2. This suggested that these nine cases of "probable community infection" indeed had community infection and were not derived from cluster #2. Whole viral genome sequencing of SARS-CoV-2 is a powerful measure not only for monitoring the global trend of SARS-CoV-2 but also for identifying the source of infection of COVID-19 at a level of institution.

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Showering is associated with Mycobacterium avium complex lung disease: An observational study in Japanese women.

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

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  26 ( 3 ) 211 - 214 2020.03

ISSN  1341321X

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Mycobacterium avium complex refers to a group of environmental bacteria which inhabit water and soil. Although Mycobacterium avium complex is capable of causing refractory lung infections, the risk factors for Mycobacterium avium complex lung disease are still unclear. This study aimed to determine the associations between Mycobacterium avium complex lung disease and soil or water exposure. Using questionnaires along with clinical data, we compared soil exposure, along with bathtub bathing and showering habits between 172 women with Mycobacterium avium complex lung disease and 339 women without Mycobacterium avium complex infection as controls. Showering was found to be independently associated with the presence of Mycobacterium avium complex lung disease (adjusted odds ratio 5.72, 95%, confidence interval 1.99 to 16.46). Although the mean age of the groups was different, an age-matched sub-analysis yielded similar results. These results indicate that showering may be a risk factor for Mycobacterium avium complex lung disease.

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Effect of refrigeration of blood samples in lithium-heparin tubes on QuantiFERON TB Gold Plus test result.

Yoshifumi Uwamino, Akiko Sakai, Tomoyasu Nishimura, Masayo Noguchi, Shunsuke Uno, Hiroshi Fujiwara, Masaaki Mori, Masatoshi Wakui, Mitsuru Murata, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  26 ( 3 ) 312 - 314 2020.03

ISSN  1341321X

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The QuantiFERON TB Gold Plus (QFT-Plus) test is a newly approved interferon-gamma releasing assay test for detecting latent tuberculosis. Although blood samples for QFT test can be refrigerated for 48 h in lithium-heparin tubes according to package inserts, no published data are available on the effects of sample refrigeration on the test results. We conducted a clinical study that aimed to elucidate whether sample refrigeration for 48 h affects QFT-Plus test results. We collected 2 blood samples each from 40 participants for QFT-Plus; one sample was refrigerated before incubation for QFT-Plus assay, while the other sample was incubated soon after collection and treated as control. After comparing QFT-Plus test results of refrigerated samples and control samples, the concordance rate and kappa coefficient between them were 95% and 0.90, respectively. Thus, blood samples for QFT-Plus test can be refrigerated for 48 h in lithium-heparin tubes without influencing the test results.

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Clostridioides difficile感染症治療薬の有効性と安全性に関する検討

三澤 可奈, 池谷 修, 榎木 裕紀, 田口 和明, 松元 一明, 宇野 俊介, 上蓑 義典, 長谷川 直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会)  68 ( 2 ) 274 - 274 2020.03

ISSN  1340-7007

バンコマイシンの周術期投与におけるレッドネック症候群発症リスクに関する検討

池谷 修, 宇野 俊介, 上蓑 義典, 尾原 秀明, 栗原 智宏, 早川 智久, 石川 春樹, 高野 八百子, 松元 一明, 長谷川 直樹, 新庄 正宜, 森 毅彦

日本化学療法学会雑誌 ((公社)日本化学療法学会)  68 ( 2 ) 291 - 291 2020.03

ISSN  1340-7007

The annual risk of tuberculosis infection in newly hired researchers and healthcare workers using interferon-gamma release assay in Japan.

Tomoyasu Nishimura, Masaki Ota, Masaaki Mori, Yaoko Takano, Hiroshi Fujiwara, Yoshifumi Uwamino, Shunsuke Uno, Naoki Hasegawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  26 ( 8 ) 818 - 822 2020

ISSN  1341321X

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The tuberculosis (TB) notification rate in Japan is gradually decreasing but has not yet achieved "pre-elimination," defined by the World Health Organization. To effectively tackle, control, and eliminate TB, estimating and monitoring the annual risk of TB infection (ARI) using tuberculin skin testing (TST) to understand the dynamics of TB epidemiology are significantly important. However, studies estimating ARIs using TST are few considering that Bacillus Calmette-Guérin vaccination coverage is high in Japan. This was a single-center, cross-sectional study conducted between January 2011 and December 2018 in Tokyo area where interferon-gamma release assays (IGRAs) were performed in newly hired researchers of Keio University School of Medicine and healthcare workers of Keio University Hospital to determine TB infection. We estimated the prevalence of TB infection and ARI based on their IGRA results. Among the 3908 subjects, 83 (2.124%) had positive IGRA results. Multiple logistic regression analysis revealed that age was a significant risk factor for positive IGRA result (adjusted odds ratio, 1.046). The ARIs were 0.049%-0.156% between 1986 and 2004, midyears of TB infection, but have not significantly decreased over approximately two decades. To decrease the risk of TB infection, advanced strategies to control and eliminate TB in Tokyo area are significantly required.

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5.非重症例に対するClostridioides difficile感染症治療薬の有効性に関する検討

池谷 修, 三澤 可奈, 宇野 俊介, 上蓑 義典, 内田 翔, 高野 八百子, 松元 一明, 長谷川 直樹

日本臨床腸内微生物学会誌 (日本臨床腸内微生物学会)  22 ( 1 ) 34 - 34 2020

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

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

BMC infectious diseases (BMC Infectious Diseases)  19 ( 1 ) 1055 - 1055 2019.12

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

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Moraxella catarrhalisを含む複数菌種が検出された頸椎化膿性脊椎炎の1例

荒 美幸, 宇野 俊介, 上蓑 義典, 永田 美香, 池谷 修, 長谷川 直樹

日本臨床微生物学会雑誌 ((一社)日本臨床微生物学会)  30 ( Suppl.1 ) 307 - 307 2019.12

ISSN  2434-866X

QuantiFERON TBゴールドプラスの検体のヘパリン管採血と,その冷蔵保存による検査結果への影響

酒井 昭子, 上蓑 義典, 西村 知泰, 森 正明, 宇野 俊介, 藤原 宏, 村田 満, 長谷川 直樹

日本臨床微生物学会雑誌 ((一社)日本臨床微生物学会)  30 ( Suppl.1 ) 295 - 295 2019.12

ISSN  2434-866X

Recovery of FRI-5 carbapenemase at a Japanese hospital where FRI-4 carbapenemase was discovered.

Yoshifumi Uwamino, Hiroaki Kubota, Takashi Sasaki, Asami Kosaka, Mie Furuhashi, Shunsuke Uno, Jun Kudoh, Mitsuru Murata, Naoki Hasegawa

The Journal of antimicrobial chemotherapy 74 ( 11 ) 3390 - 3392 2019.11

ISSN  1460-2091

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Evaluation for optimal dosing of vancomycin in patients with different physical types.

Mari Hashimoto, Osamu Iketani, Naoki Ichinose, Yuki Enoki, Kazuaki Taguchi, Shunsuke Uno, Yoshifumi Uwamino, Naoki Hasegawa, Kazuaki Matsumoto

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  25 ( 9 ) 735 - 737 2019.09

ISSN  1341321X

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The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m2 were assigned to the lean group, those with a BMI of 18.5-24.9 kg/m2 were assigned to the standard group, and those with a BMI of ≥25 kg/m2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15-20 μg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15-20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.

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

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

Medicine (Medicine)  98 ( 17 ) e15264 2019.04

ISSN  0025-7974

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

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

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

Open forum infectious diseases (Open Forum Infectious Diseases)  6 ( 4 ) ofz108 2019.04

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

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リネゾリドにより低ナトリウム血症から痙攣を発症した患者

山本 冴華, 田口 和明, 榎木 裕紀, 松元 一明, 池谷 修, 宇野 俊介, 上蓑 義典, 長谷川 直樹

日本薬学会年会要旨集 ((公社)日本薬学会)  139年会 ( 4 ) 131 - 131 2019.03

ISSN  0918-9823

全自動多項目遺伝子検査FilmArray血液培養パネルが抗菌薬選択に及ぼす影響

上蓑 義典, 宇野 俊介, 池谷 修, 長谷川 直樹, 村田 満

日本化学療法学会雑誌 ((公社)日本化学療法学会)  67 ( Suppl.A ) 236 - 236 2019.03

ISSN  1340-7007

リネゾリド血中濃度上昇に伴い低ナトリウム血症が発現した症例

田口 和明, 榎木 裕紀, 松元 一明, 池谷 修, 宇野 俊介, 上蓑 義典, 長谷川 直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会)  67 ( Suppl.A ) 292 - 292 2019.03

ISSN  1340-7007

Campylobacter fetusによる右内腸骨動脈感染性動脈瘤の1例

猪瀬 里夏, 上蓑 義典, 永田 美香, 上遠野 保裕, 柴田 綾子, 宇野 俊介, 藤原 宏, 松原 健太郎, 尾原 秀明, 長谷川 直樹, 村田 満

日本臨床微生物学会雑誌 ((一社)日本臨床微生物学会)  29 ( 1 ) 17 - 20 2018.12

ISSN  2434-866X

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Campylobacter fetusはグラム陰性らせん状小桿菌である。ヒトでは妊婦や基礎疾患をもつ易感染性患者における菌血症、感染性動脈瘤などの起因菌として知られているが、免疫不全のない宿主における感染性動脈瘤の報告は少ない。60代男性、20年前にC型肝炎治療歴がある以外には著患なし。38℃台の発熱と持続する右側腹部痛にて受診し、造影CT検査にて右内腸骨動脈瘤を指摘され手術目的で入院した。入院5日目に入院時に採取した血液培養よりグラム陰性らせん状桿菌を検出した。また、切除された動脈瘤壁の組織培養からもグラム陰性らせん状桿菌を検出し、C.fetusと同定された。文献検索では、C.fetusによる感染性動脈瘤は腹部大動脈が多く、免疫不全を認めない例における内腸骨動脈感染性動脈瘤の報告例は限られていた。(著者抄録)

全自動遺伝子検査装置ELITe InGeniusによる便検体からのClostridioides difficileトキシン遺伝子検出性能評価

香坂 亜沙美, 宮下 雪子, 上蓑 義典, 石原 治, 猪狩 嘉孝, 永田 美香, 猪瀬 里夏, 宇野 俊介, 村田 満, 長谷川 直樹

日本臨床微生物学会雑誌 ((一社)日本臨床微生物学会)  29 ( Suppl.1 ) 392 - 392 2018.12

ISSN  2434-866X

Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump.

Tomomi Nakamura, Yuki Enoki, Shunsuke Uno, Yoshifumi Uwamino, Osamu Iketani, Naoki Hasegawa, Kazuaki Matsumoto

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Elsevier B.V.)  24 ( 10 ) 856 - 859 2018.10

ISSN  1341321X

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Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 °C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 °C (101.7 ± 1.4% and 92.9 ± 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 °C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 °C (99.7 ± 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps.

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16S rRNA解析により起因菌を確認し得た肺放線菌症の1例

江田 はるか, 南宮 湖, 上蓑 義典, 大畠 孝則, 阪口 真之, 斎藤 史武, 大塚 喜人, 長谷川 直樹, 結城 秀樹

日本内科学会雑誌 ((一社)日本内科学会)  107 ( 10 ) 2162 - 2167 2018.10

ISSN  0021-5384

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40代女性。健診の胸部X線で異常陰影を指摘された。胸部X線、胸部CT所見にて右肺尖部の空洞病変と右上肺野の粒状影が認められた。胸部CTで右上葉に空洞病変を認め、周囲に粒状影・浸潤影を伴う限局性の薄い胸膜肥厚を有していた。気管支洗浄液一般細菌培養でコロニーを認めたが少数であったため、菌種同定目的に16SrRNA解析を行った。その結果、Actinomyces odontolyticusで肺放線菌症と診断された。ペニシリン系抗菌薬の静注を行ったところ、浸潤影は縮小し改善傾向となった。

基準範囲とパニック値 パニック値

上蓑 義典, 村田 満

臨床病理 (日本臨床検査医学会)  66 ( 9 ) 986 - 992 2018.09

ISSN  0047-1860

チーム医療における臨床検査異常データ・パニック値の検査室対応 慶應義塾大学病院におけるパニック値報告制度改善の取り組み

上蓑 義典, 柴田 綾子, 村田 満

臨床病理 (日本臨床検査医学会)  66 ( 7 ) 777 - 782 2018.07

ISSN  0047-1860

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

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

Respir Med (Respiratory Medicine)  138   1 - 6 2018.05

ISSN  09546111

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

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Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients

Yagi, K, Morimoto, K, Ishii, M, Namkoong, H, Okamori, S, Asakura, T, Suzuki, S, Asami, T, Uwamino, Y, Funatsu, Y, Fujiwara, H, Kamata, H, Nishimura, T, Betsuyaku, T, Kurashima, A, Hasegawa, N

Int J Infect Dis (International Journal of Infectious Diseases)  67   65 - 69 2018.02

ISSN  12019712

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BACKGROUND: Mycobacterium lentiflavum organisms are slow-growing nontuberculous mycobacteria often associated with immunocompromised state and cervical lymphadenitis in young children. However, little is known about the clinical importance of pulmonary infection with M. lentiflavum in adults. METHODS: We reviewed the medical records of all adults who met the diagnostic criteria of pulmonary M. lentiflavum disease at Keio University Hospital and Fukujuji Hospital from 2001 to 2015. We also reviewed literature in the PubMed database to identify reported cases in non-human immunodeficiency virus (HIV) adults. RESULTS: Our study presented five cases, and a literature review identified 11 additional cases of pulmonary M. lentiflavum disease. Eleven of 16 cases, including a literature review, were female, and 15 of 16 cases showed a nodular/bronchiectatic (NB) pattern on the chest CT images. Although one patient died of exacerbation of underlying vasculitis and bacterial pneumonia, no cases showed an aggressive clinical course of pulmonary M. lentiflavum disease. CONCLUSIONS: We have identified the clinical characteristics of pulmonary M. lentiflavum disease in adult patients, which main

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AMR専門検討会を通じた当院におけるAMR対策の取り組み

上蓑 義典, 高野 八百子, 池谷 修, 猪瀬 里夏, 宇野 俊介, 藤原 宏, 新庄 正宜, 長谷川 直樹

日本環境感染学会総会プログラム・抄録集 ((一社)日本環境感染学会)  33回   239 - 239 2018.02

イエローカードを用いた介入が手指衛生遵守率に及ぼす効果の検証

河西 貴子, 高野 八百子, 宇野 俊介, 上蓑 義典, 藤原 宏, 新庄 正宜, 長谷川 直樹

日本環境感染学会総会プログラム・抄録集 ((一社)日本環境感染学会)  33回   428 - 429 2018.02

FRI-4 carbapenemase-producing Enterobacter cloacae complex isolated in Tokyo, Japan

Kubota, H, Uwamino, Y, Matsui, M, Sekizuka, T, Suzuki, Y, Okuno, R, Uchitani, Y, Ariyoshi, T, Aoki, W, Suzuki, S, Kuroda, M, Shinkai, T, Yokoyama, K, Sadamasu, K, Funakoshi, T, Murata, M, Hasegawa, N, Iwata, S

J Antimicrob Chemother (Journal of Antimicrobial Chemotherapy)  73 ( 11 ) 2969 - 2972 2018

ISSN  03057453

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A carbapenem-resistant Enterobacter cloacae complex isolated in Tokyo, Japan, produced a carbapenemase that was detected by a Carba NP test and a modified carbapenem inactivation method, but none of the &#039;Big Five&#039; carbapenemase genes was detected by PCR. This study aimed to identify the carbapenemase.|Carbapenemase genes were screened by WGS. Next, we generated a recombinant plasmid in which the carbapenemase gene was inserted. We also extracted the carbapenemase gene-carrying plasmid from the E. cloacae complex. The effects of both plasmids on the antibiotic susceptibility of Escherichia coli were then tested. The carbapenemase gene-carrying plasmid in the E. cloacae complex was completely sequenced.|A novel carbapenemase gene, blaFRI-4, encoded an amino acid sequence that was 93.2% identical to French imipenemase (FRI-1). E. coli transformed with blaFRI-4 showed reduced carbapenem susceptibility. A complete sequence of the blaFRI-4-carrying 98 508 bp IncFII/IncR plasmid (pTMTA61661) showed that blaFRI-4 and the surrounding region (18.7 kb) were duplicated.|The FRI-4-producing E. cloacae complex was isolated in Japan, whereas all other FRI variants have been found in Europe,

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

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

BMC pulmonary medicine (BIOMED CENTRAL LTD)  17 ( 1 ) 198 - 198 2017.12

ISSN  1471-2466

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

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全自動遺伝子検査装置ELITe InGeniusによる菌液からのESBL遺伝子検出性能評価

香坂 亜沙美, 上蓑 義典, 鈴木 武尊, 猪瀬 里夏, 昆 亜紀子, 永田 美香, 柴田 綾子, 宇野 俊介, 藤原 宏, 村田 満, 長谷川 直樹

日本臨床微生物学雑誌 ((一社)日本臨床微生物学会)  28 ( Suppl.1 ) 430 - 430 2017.12

ISSN  0917-5059

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

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

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

ISSN  1341-321X

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

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

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

BMC infectious diseases (BIOMED CENTRAL LTD)  17 ( 1 ) 558 - 558 2017.08

ISSN  1471-2334

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

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16S rRNA解析により起因菌を確認し得た肺放線菌症の1例

江田 はるか, 南宮 湖, 大畠 孝則, 上蓑 義典, 阪口 真之, 大塚 喜人, 長谷川 直樹, 結城 秀樹

日本内科学会関東地方会 (日本内科学会-関東地方会)  634回   26 - 26 2017.07

Rapid Detection and Typing of Carbapenemase Genes from Carbapenem-Resistant Enterobacteriaceae Isolates Collected in a Japanese Hospital Using the Xpert Carba-R Assay.

Yoshifumi Uwamino, Kayoko Sugita, Naoki Hasegawa, Tomoyasu Nishimura, Hiroshi Fujiwara, Satoshi Iwata

Japanese journal of infectious diseases (NATL INST INFECTIOUS DISEASES)  70 ( 1 ) 124 - 125 2017.01

ISSN  1344-6304

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The First Case Report of Acute Cholangitis and Bacteremia Due to Neisseria subflava.

Yoshifumi Uwamino, Kayoko Sugita, Eisuke Iwasaki, Hiroshi Fujiwara, Tomoyasu Nishimura, Naoki Hasegawa, Satoshi Iwata

Internal medicine (Tokyo, Japan) (JAPAN SOC INTERNAL MEDICINE)  56 ( 2 ) 221 - 223 2017

ISSN  0918-2918

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We herein report a case of acute cholangitis and bacteremia caused by a commensal Neisseria species, Neisseria subflava, in an 82-year-old man with cholangiocarcinoma. Emergency endoscopic nasobiliary drainage and cefoperazone/sulbactam therapy were effective. Gram negative coccobacilli were isolated from both blood and bile cultures on 5% sheep blood agar. The isolate was identified as N.subflava biovar perflava by mass spectrometry, a sequence analysis of the 16S rRNA, and biochemical testing. Although biliary infections due to commensal Neisseria are extremely rare, this case demonstrates the possibility of its occurrence in patients undergoing bile duct treatment.

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カンジダ血症におけるCare Bundle「ACTIONs BUNDLE 2014」チェックリストの有効性の検討

上蓑 義典, 長谷川 直樹, 猪瀬 里夏, 青木 渉, 永田 美香, 荒 美幸, 昆 亜紀子, 上遠野 保裕, 宇野 俊介, 岩田 敏, 村田 満

日本臨床微生物学雑誌 ((一社)日本臨床微生物学会)  27 ( Suppl. ) 274 - 274 2016.12

ISSN  0917-5059

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

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

Journal of Infection and Chemotherapy (Elsevier B.V.)  22 ( 9 ) 611 - 616 2016.09

ISSN  1437-7780

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

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

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

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

ISSN  1341-321X

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

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Middle-aged to elderly women have a higher asymptomatic infection rate with Mycobacterium avium complex, regardless of body habitus.

Tomoyasu Nishimura, Yukiko Fujita-Suzuki, Masaaki Mori, Stephen M Carpenter, Hiroshi Fujiwara, Yoshifumi Uwamino, Eiko Tamizu, Ikuya Yano, Hiroshi Kawabe, Naoki Hasegawa

Respirology (Carlton, Vic.) (WILEY-BLACKWELL)  21 ( 3 ) 553 - 5 2016.04

ISSN  1323-7799

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Mycobacterium avium complex (MAC) pulmonary disease is prevalent in middle-aged to elderly women with a thin body habitus. By comparing the rate of serologically diagnosed asymptomatic MAC infection and body mass index among 1033 healthy subjects, we find that middle-aged to elderly women became infected with MAC, regardless of their body habitus.

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ドルテグラビルによる薬剤性肝障害の2例について

藤原 宏, 長谷川 直樹, 須藤 弘二, 加藤 真吾, 上蓑 義典, 南宮 湖, 岩田 敏

感染症学雑誌 ((一社)日本感染症学会)  90 ( 臨増 ) 341 - 341 2016.03

ISSN  0387-5911

Clinical Features of Community-Acquired Helicobacter cinaedi Bacteremia.

Yoshifumi Uwamino, Kiyoharu Muranaka, Ryota Hase, Yoshihito Otsuka, Naoto Hosokawa

Helicobacter (WILEY-BLACKWELL)  21 ( 1 ) 24 - 8 2016.02

ISSN  1083-4389

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BACKGROUND: There are growing numbers of reports concerning the clinical and pathological features of Helicobacter cinaedi (H. cinaedi) bacteremia; however, few reports have discussed the features of this condition in healthy individuals. PATIENTS AND METHODS: A retrospective observational study was conducted at a Japanese tertiary care hospital to assess the clinical features of community-acquired H. cinaedi. All patients in whom H. cinaedi was isolated between January 2009 and March 2014 were identified from the hospital database. RESULTS: Of the 28 patients included in the study, 12 had community-acquired H. cinaedi bacteremia. The most common clinical feature was cellulitis (n = 17). However, nearly half of the patients with healthcare-associated or nosocomial-associated bacteremia displayed no symptoms with the exception of fever. Most patients were successfully treated with a 14-day regime of third-generation cephalosporins or tetracycline. CONCLUSIONS: Our results show that H. cinaedi infections are quite common in immunocompetent community-dwelling individuals.

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

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

Respiratory Research (BioMed Central Ltd.)  16 ( 1 )  2015.12

ISSN  1465-993X

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

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

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

Respiratory research 16   145 - 145 2015.12

ISSN  1465-9921

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

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Pseudomonas psychrotolerans菌血症の1例

上蓑 義典, 橋本 幸平, 戸口 明宏, 大塚 喜人, 細川 直登

日本臨床微生物学雑誌 ((一社)日本臨床微生物学会)  25 ( 1 ) 52 - 56 2014.12

ISSN  0917-5059

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下咽頭癌にて治療中の62歳男性が嚥下困難の増悪により入院した。入院33日目に発熱し,その際に採取された血液培養2セット中2セットよりグラム陰性桿菌の検出を認めた。検出した桿菌は黄色色素産生性のコロニーを形成し,16S rRNA解析により,Pseudomonas psychrotoleransと同定された。菌血症の他には明らかな感染巣を認めず,Piperacillin/Tazobactamおよび,ClindamycinとCiprofloxacinの併用療法により軽快した。P.psychrotoleransは,我々が検索した限りでは過去に小動物や環境からの検出報告はあるが,ヒトからの検出報告はない。本例はヒトにおけるP.psychrotolerans感染症の初報告である。(著者抄録)

[The first trial of OPAT (outpatient parenteral antimicrobial therapy) with continuous infusions in Japan].

Ryota Hase, Naoto Hosokawa, Shunsuke Uno, Takahiro Mikawa, Yoshifumi Uwamino, Kiyoharu Muranaka

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 88 ( 3 ) 269 - 74 2014.05

ISSN  0387-5911

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OPAT (Outpatient Parenteral Antimicrobial Therapy) is widely utilized in various countries. Although once-daily parenteral antimicrobials are often prescribed in outpatient clinics, the term "OPAT" is not commonly used, and no well-organized OPAT practice has been reported in Japan. We implemented OPAT with continuous infusion using elastomeric infusion devices, which are commonly used in Australia and Singapore. We collected data about diseases, organisms, antimicrobials, treatment duration, bed days saved, outcome, readmission rate and cost reductions of all patients who were treated with OPAT with continuous infusions from July 2012 till June 2013. Ten patients (5 osteomyelitis, 4 abscess and 1 endocarditis) were treated and only one patient discontinued therapy due to the side effects of the antimicrobial. The most commonly targeted organism was Staphylococcus aureus. Cefazolin was the most frequently prescribed antimicrobial. The median OPAT days were 15 (range 4-29 days). Total bed days saved were 159. A peripherally inserted central catheter (PICC) was inserted for all patients and only one had to change the PICC during the treatment. Eight patients were cured and 2 were improved. No patient needed readmission. The estimated medical cost reduction was 1,655,930 yen, that is approximately 16,000 US dollars. Administration with continuous infusion makes it possible to continue the optimal parenteral antimicrobials for outpatients, which avoids prescribing unnecessary once-daily antimicrobials with a broader spectrum. Our experience shows OPAT with continuous infusion is safe and feasible practice not only for improving the QOL of patients but also for efficient bed utilization and medical cost savings.

[Plasmodium malariae malaria with more than a 4-month incubation period: difficult to distinguish from a relapse of Plasmodium vivax malaria].

Ryota Hase, Yoshifumi Uwamino, Kiyoharu Muranaka, Kentaro Tochitani, Misa Sogi, Hidetaka Kitazono, Naoto Hosokawa

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 87 ( 4 ) 446 - 50 2013.07

ISSN  0387-5911

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We report herein on a case of Plasmodium malariae malaria with more than a 4-month incubation period. A 35-year-old Japanese man who first presented to our clinic with fever and history of travel to Papua New Guinea was suspected of having Plasmodium vivax malaria based on peripheral smear results. We admitted him and initiated treatment with mefloquine. After two days of therapy, he became afebrile. We discharged him, and P. vivax was later confirmed with PCR. We started mefloquine prophylaxis for a planned trip to Papua New Guinea. After his return, a standard dose of primaquine (15 mg x 14 days) was prescribed for a radical cure of P. vivax. About 4 months after his last visit to Papua New Guinea, he returned to our clinic with fever. We suspected a relapse of P. vivax malaria and admitted him for a second time. After two days of mefloquine therapy, his symptoms improved. We discharged him and restarted a higher dose of primaquine (30 mg x 14 days) therapy for a radical cure of P. vivax. Subsequently, the PCR test revealed the parasite was P. malariae and not P. vivax. Only 13 cases of Plasmodium malariae malaria have been reported in Japan during the past 10 years. Blood-stage schizonticides such as mefloquine is not active against the liver stage. Therefore, the use of these drugs for prophylaxis will not be effective for prevention of malaria if its liver stage is longer than the duration of effective chemoprophylaxis. Although the incubation period of P. malariae is typically 13 to 28 days, it occasionally lasts for months or even years. Careful attention should be given to the possibility that P. malariae occasionally has a long incubation period even in the absence of the hypnozoite stage.

三日熱マラリアの再発との判別が困難であった4ヵ月以上の潜伏期間の後に発症した四日熱マラリアの1例

馳 亮太, 上蓑 義典, 村中 清春, 杤谷 健太郎, 曽木 美佐, 北薗 英隆, 細川 直登

感染症学雑誌 ((一社)日本感染症学会)  87 ( 4 ) 446 - 450 2013.07

ISSN  0387-5911

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35歳男。パプアニューギニアから帰国後8日目から約1週間持続する発熱と関節痛を主訴に受診し、三日熱マラリアの診断で入院となった。メフロキン内服にて症状は改善た。退院11日後に再度パプアニューギニアへ渡航した。1週間の滞在後帰国し予防内服は4週間継続した。その後、他院にてプリマキンによる根治治療を14日間施行され無症状で経過していたが、最終渡航から約4ヵ月後に2週間持続する間欠的な発熱、咳嗽を認めたため再受診した。ギムザ染色で赤血球内の輪状体を確認した。複数の輪状体を含む赤血球は存在しなかった。輪状体の寄生している赤血球の膨化は明らかではなかった。寄生率は0.06%と低値であった。再びメフロキン内服を開始したが、前回眩暈の副作用が強かったため、投与量を減量した。治療後すぐに解熱し咳嗽も改善したため退院となった。G6PD(グルコース-6-リン酸脱酵素)欠損がないことを確認し、プリマキンを増量して14日間の根治治療を行った。その後、PCR検査にて4日熱マラリアの単独感染であったことが判明した。

[A case of tetanus originating from ulcerated breast cancer].

Daisuke Taniyama, Ryusuke Yamamoto, Yoshifumi Uwamino, Mitsuo Kitahara

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 87 ( 3 ) 385 - 8 2013.05

ISSN  0387-5911

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We report herein on a rare case of tetanus originating from ulcerated breast cancer. A 60-year-old homeless woman was admitted to our hospital because of lockjaw. On admission, a physical examination revealed tachypnea, trismus, opisthotonus and an ulcerated right breast. There was no other skin soft tissue damage. A diagnosis of tetanus was entertained from the lockjaw and opisthotonus. Tetanus globulin, tetanus toxoid, penicillin and respiratory support were initiated. Later, a right total mastectomy was performed, and the diagnosis of breast cancer was made, however, gram positive bacilli were not detected and Clostridiuum tetani (C. tetani) was not cultured. It is conceivable that the ulcerated breast was contaminated with C. tetani due to the patients living conditions.