Details of a Researcher - Nishimura, Tomoyasu

Papers - Nishimura, Tomoyasu

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Factors affecting motivation for receiving a booster dose of the COVID-19 vaccine among Japanese university students and staff: a cross-sectional questionnaire survey

Uchida S., Uno S., Kondo M., Uwamino Y., Namkoong H., Nishimura T., Misawa K., Kashimura S., Yamato K., Ishizaka T., Nagashima K., Kitagawa Y., Hasegawa N.

Scientific Reports 14 ( 1 ) 2024.12

Understanding the factors that influence people’s decisions regarding vaccination is essential to promote vaccination. We aimed to clarify the motivations for receiving booster vaccines. We conducted a paper-based questionnaire distributed during January–February 2022 involving students and faculty staff who received the first COVID-19 vaccination at the mass vaccination program during June–September 2021 at Keio University. A total of 1725 participants were enrolled, and all completed the survey. Among these, 64.9% reported a significant adverse event (AEs) affecting daily life after the second vaccine. “Fear of severe COVID-19 illness” (72.6%) was the most common reason for getting vaccinated, followed by “concern of infecting others” (68.4%) and “fear of COVID-19 infection itself” (68.3%). Television emerged as the most influential source of information (80%), followed by university information (50.2%) and social networking sites (42.8%). Multivariate analysis revealed “fear of severe COVID-19 illness”, “fear of COVID-19 infection itself”, and “trust in the efficacy and safety of the vaccines in general” were significantly correlated with willingness to receive paid vaccinations. The severity of AEs and source of information were not related to participants’ willingness to receive booster vaccinations. Participants with positive reasons for vaccination were more likely to accept a third dose.

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Minimum inhibitory concentrations of azithromycin in clinical isolates of Mycobacterium avium complex in Japan

Uwamino Y., Aoki W., Inose R., Kamoshita Y., Mikita K., Namkoong H., Nishimura T., Matsushita H., Hasegawa N.

Microbiology Spectrum 12 ( 6 ) 2024.06

The latest guidelines include azithromycin as a preferred regimen for treating Mycobacterium avium complex (MAC) pulmonary disease. However, serially collected susceptibility data on clinical MAC isolates are limited, and no breakpoints have been determined. We investigated the minimum inhibitory concentrations (MICs) of azithromycin and clarithromycin for all MAC strains isolated in 2021 from a single center in Japan, excluding duplicates. The MICs were determined using a panel based on the microbroth dilution method, according to the latest Clinical and Laboratory Standards Institute recommendations. The MICs were determined for 318 MAC strains. Although there was a significant positive correlation between the MICs of azithromycin and clarithromycin, the MICs of azithromycin tended to be higher than those of clarithromycin. Among the cases in which the strains were isolated, 18 patients initiated treatment, including azithromycin treatment, after sample collection. Some patients infected with stains with relatively high azithromycin MICs achieved a microbiological cure with azithromycin-containing regimens. This study revealed a higher MIC distribution for azithromycin than clarithromycin, raising questions about the current practice of estimating azithromycin susceptibility based on the clarithromycin susceptibility test result. However, this was a single-center study that included only a limited number of cases treated with azithromycin. Therefore, further multicenter studies that include a greater number of cases treated with azithromycin are warranted to verify the distribution of azithromycin MICs and examine the correlation between azithromycin MICs and treatment effectiveness. IMPORTANCE The macrolides serve as key drugs in the treatment of pulmonary Mycobacterium avium complex infection, and the administration of macrolide should be guided by susceptibility test results. Azithromycin is recommended as a preferred choice among macrolides, surpassing clarithromycin; however, drug susceptibility testing is often not conducted, and clarithromycin susceptibility is used as a surrogate. This study represents the first investigation into the minimum inhibitory concentration of azithromycin on a scale of several hundred clinical isolates, revealing an overall tendency for higher minimum inhibitory concentrations compared with clarithromycin. The results raise questions about the appropriateness of using clarithromycin susceptibility test outcomes for determining the administration of azithromycin. This study highlights the need for future discussions on the clinical breakpoints of azithromycin, based on large-scale clinical research correlating azithromycin susceptibility with treatment outcomes.

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New polycyclic tetramate macrolactams with antimycobacterial activity produced by marine-derived Streptomyces sp. KKMA-0239

Shigeno S., Kadowaki M., Nagai K., Hosoda K., Terahara T., Nishimura T., Hasegawa N., Tomoda H., Ohshiro T.

Journal of Antibiotics 77 ( 5 ) 265 - 271 2024.05

ISSN 00218820

During our screening for anti-mycobacterial agents against Mycobacterium avium complex (MAC), two new polycyclic tetramate macrolactams (PTMs), named hydroxycapsimycin (1) and brokamycin (2), were isolated along with the known PTM, ikarugamycin (3), from the culture broth of marine-derived Streptomyces sp. KKMA-0239. The relative structures of 1 and 2 were elucidated by spectroscopic data analyses, including 1D and 2D NMR. Furthermore, the absolute configuration of 1 was confirmed by a single-crystal X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate antimycobacterial activities against MAC, including clinically isolated drug-resistant M. avium.

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Mavintramycin A is a promising antibiotic for treating Mycobacterium avium complex infectious disease

Hosoda K., Koyama N., Shigeno S., Nishimura T., Hasegawa N., Kanamoto A., Ohshiro T., Tomoda H.

Antimicrobial Agents and Chemotherapy 68 ( 3 ) 2024.03

ISSN 00664804

Mycobacterium avium complex (MAC) is a serious disease that is mainly caused by infection with the non-tuberculous mycobacteria (NTM), Mycobacterium avium and Mycobacterium intracellulare. Seven new compounds, designated mavintramycins A–G (1–7), were isolated along with structurally related compounds, including amicetin (9) and plicacetin (10), from the culture broth of Streptomyces sp. OPMA40551 as anti-MAC compounds that were active against M. avium and M. intracellulare. Among them, mavintramycin A showed the most potent and selective inhibition of M. avium and M. intracellulare. Furthermore, mavintramycin A was active against more than 40 clinically isolated M. avium, including multidrug-resistant strains, and inhibited the growth of M. avium in a persistent infection cell model using THP-1 macrophages. Mavintramycin A also exhibited in vivo efficacy in silkworm and mouse infection assays with NTM. An experiment to elucidate its mechanism of action revealed that mavintramycin A inhibits protein synthesis by binding to 23S ribosomal RNA in NTM. Mavintramycin A, with a different chemical structure from those of clinically used agents, is a promising drug candidate for the treatment of MAC infectious disease.

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

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

Journal of Gastroenterology 59 ( 3 ) 195 - 208 2024.03

ISSN 09441174

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

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Optimal incubation duration of liquid cultures for assessing culture negative conversion in patients with Mycobacterium avium complex and Mycobacterium abscessus pulmonary diseases

Uwamino Y., Hasegawa N., Kamoshita Y., Inose R., Aoki W., Nagata M., Namkoong H., Nishimura T., Matsushita H.

European Journal of Clinical Microbiology and Infectious Diseases 2024

ISSN 09349723

Purpose: Mycobacterial liquid culturing typically requires six weeks or longer, primarily because of the slow growth rate of Mycobacterium tuberculosis. This study aimed to evaluate the potential of shortening the duration of mycobacterial liquid culturing in healthcare settings with high prevalence rates of non-tuberculous mycobacteria. Methods: We retrospectively analyzed the relationship between mycobacterial species and time to positive testing of liquid cultures from sputum samples using the Mycobacteria Growth Indicator Tube system over a 3.5-year period beginning in July 2020 at a university hospital in Japan. Results: We analyzed 15,147 sputum culture samples and found a 1.1% positivity rate for Mycobacterium tuberculosis complex, while the rates for Mycobacterium avium complex and Mycobacterium abscessus were 17.6% and 2.1%, respectively. The median time to positivity was 17 days for Mycobacterium tuberculosis complex, 9 days for Mycobacterium avium complex, and 4 days for Mycobacterium abscessus. Comparing a 4-week culture period with an eight-week period, the positivity rates for Mycobacterium avium complex and Mycobacterium abscessus were 97.0% and 99.4%, respectively. Conclusion: In settings with a high incidence of non-tuberculous mycobacteria, the basic liquid culturing period can be safely shortened to 4 weeks without significantly compromising detection sensitivity, except for the samples that are highly suspected to contain tuberculosis, extremely slow-growing mycobacteria, smear-positive, or nucleic acid amplification testing positive.

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

Morita A., Yagi K., Asakura T., Namkoong H., Sato Y., Ogawa T., Kusumoto T., Suzuki S., Tanaka H., Lee H., Okamori S., Azekawa S., Nakagawara K., Kaji M., Nagao G., Funatsu Y., Kimizuka Y., Kamata H., Nishimura T., Ishii M., Fukunaga K., Hasegawa N.

BMC Pulmonary Medicine (BMC Pulmonary Medicine) 23 ( 1 ) 2023.12

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

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Inactivation of nontuberculous mycobacteria by gaseous ozone treatment

Misawa K., Nishimura T., Kashimura S., Hasegawa N.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 29 ( 6 ) 628 - 630 2023.06

ISSN 1341321X

Nontuberculous mycobacteria (NTM) are environmental bacteria resistant to many common disinfectants and ultraviolet radiation. Inhalation of aerosols generated from NTM-containing water and soil causes NTM lung disease, especially in people with underlying lung diseases and decreased immunity. To prevent healthcare-acquired NTM infections, it is important to eradicate NTM living in hospital environments. Therefore, we evaluated the efficacy of gaseous ozone for the inactivation of NTM, namely Mycobacterium (M.) avium, M. intracellulare, M. kansasii, M. abscessus subsp. abscessus and M. abscessus subsp. massiliense. Gaseous ozone treatment at 1 ppm for 3 h reduced the bacterial number of all strains by more than 97%. Gaseous ozone treatment could be a practical, effective and convenient disinfection method for NTM living in hospital environments.

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Characterization of DNA Gyrase Activity and Elucidation of the Impact of Amino Acid Substitution in GyrA on Fluoroquinolone Resistance in Mycobacterium avium

Thapa J., Chizimu J.Y., Kitamura S., Akapelwa M.L., Suwanthada P., Miura N., Toyting J., Nishimura T., Hasegawa N., Nishiuchi Y., Gordon S.V., Nakajima C., Suzuki Y.

Microbiology Spectrum (Microbiology Spectrum) 11 ( 3 ) 2023.05

Mycobacterium avium, a member of the M. avium complex (MAC), is the major pathogen contributing to nontuberculous mycobacteria (NTM) infections worldwide. Fluoroquinolones (FQs) are recommended for the treatment of macrolide-resistant MACs. The association of FQ resistance and mutations in the quinolone resistance-determining region (QRDR) of gyrA of M. avium is not yet clearly understood, as many FQ-resistant clinical M. avium isolates do not have such mutations. This study aimed to elucidate the role of amino acid substitution in the QRDR of M. avium GyrA in the development of FQ resistance. We found four clinical M. avium subsp. hominissuis isolates with Asp-to-Gly change at position 95 (Asp95Gly) and Asp95Tyr mutations in gyrA that were highly resistant to FQs and had 2- to 32-fold-higher MICs than the wild-type (WT) isolates. To clarify the contribution of amino acid substitutions to FQ resistance, we produced recombinant WT GyrA, GyrB, and four GyrA mutant proteins (Ala91Val, Asp95Ala, Asp95Gly, and Asp95Tyr) to elucidate their potential role in FQ resistance, using them to perform FQ-inhibited DNA supercoiling assays. While all the mutant GyrAs contributed to the higher (1.3- to 35.6-fold) FQ 50% inhibitory concentration (IC50) than the WT, Asp95Tyr was the most resistant mutant, with an IC50 15- to 35.6-higher than that of the WT, followed by the Asp95Gly mutant, with an IC50 12.5- to 17.6-fold higher than that of the WT, indicating that these amino acid substitutions significantly reduced the inhibitory activity of FQs. Our results showed that amino acid substitutions in the gyrA of M. avium contribute to FQ resistance. IMPORTANCE The emergence of fluoroquinolone (FQ) resistance has further compounded the control of emerging Mycobacterium avium-associated nontuberculous mycobacteria infections worldwide. For M. avium, the association of FQ resistance and mutations in the quinolone resistance-determining region (QRDR) of gyrA is not yet clearly understood. Here, we report that four clinical M. avium isolates with a mutation in the QRDR of gyrA were highly resistant to FQs. We further clarified the impact of mutations in the QRDR of GyrA proteins by performing in vitro FQ-inhibited DNA supercoiling assays. These results confirmed that, like in Mycobacterium tuberculosis, mutations in the QRDR of gyrA also strongly contribute to FQ resistance in M. avium. Since many FQ-resistant M. avium isolates do have these mutations, the detailed molecular mechanism of FQ resistance in M. avium needs further exploration.

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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

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

Uwamino Y., Yokoyama T., Sato Y., Shibata A., Kurafuji T., Tanabe A., Noguchi M., Arai T., Ohno A., Yokota H., Namkoong H., Nishimura T., Kosaki K., Hasegawa N., Wakui M., Murata M., Matsushita H.

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

ISSN 0264410X

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

Tanaka H., Asakura T., Suzuki S., Okamori S., Kusumoto T., Ogawa T., Uno S., Morita A., Lee H., Namkoong H., Kamata H., Sato Y., Uwamino Y., Nishimura T., Ishii M., Fukunaga K., Hasegawa N.

BMC Pulmonary Medicine (BMC Pulmonary Medicine) 22 ( 1 ) 2022.12

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

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

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

Nature Communications (Nature Communications) 13 ( 1 ) 2022.12

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

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

Misawa K., Nishimura T., Kashimura S., Enoki Y., Taguchi K., Uno S., Uwamino Y., Matsumoto K., Hasegawa N.

International Journal of Antimicrobial Agents (International Journal of Antimicrobial Agents) 60 ( 5-6 ) 2022.11

ISSN 09248579

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 morphotype. Methods: The antimicrobial susceptibility of three type strains and 20 clinical isolates of MABC to the combination of seven β-lactams with relebactam or nacubactam was evaluated using broth microdilution checkerboard assays. For these strains, expression levels of blaMab were assessed using quantitative real-time polymerase chain reaction and genotypic diversity was evaluated using 18-locus variable number tandem repeat assay. Results: Relebactam and nacubactam lowered the minimum inhibitory concentrations of β-lactams, particularly imipenem, meropenem, and 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 were needed for rough morphotypes.

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

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

Nature (Nature) 609 ( 7928 ) 754 - 760 2022.09

ISSN 00280836

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

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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

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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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

Uwamino Y., Kurafuji T., Sato Y., Tomita Y., Shibata A., Tanabe A., Yatabe Y., Noguchi M., Arai T., Ohno A., Yokota H., Yamasawa W., Uno S., Nishimura T., Hasegawa N., Saya H., Wakui M., Murata M.

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

ISSN 0264410X

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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Evaluation of IS1245 LAMP in Mycobacterium avium and the influence of host-related genetic diversity on its application

Akapelwa M.L., Kapalamula T.F., Ouchi-Aizu Y., Hang'ombe B.M., Nishiuchi Y., Gordon S.V., Solo E.S., Tamaru A., Nishimura T., Hasegawa N., Morimoto K., Fukushima Y., Suzuki Y., Nakajima C.

Diagnostic Microbiology and Infectious Disease (Diagnostic Microbiology and Infectious Disease) 101 ( 4 ) 2021.12

ISSN 07328893

Early detection and treatment are paramount for the timely control of Mycobacterium avium infections. Herein, we designed a LAMP assay targeting a widely used species-specific marker IS1245 for the rapid detection of M. avium and evaluated its applicability using human (n = 137) and pig (n = 91) M. avium isolates from Japan. The developed assay could detect as low as 1 genome copy of M. avium DNA within 30 minutes. All 91 (100%) M. avium isolates from pigs were detected positive while all other tested bacterial species were negative. Interestingly, among the 137 clinical M. avium isolates, 41 (30%) were undetectable with this LAMP assay as they lacked IS1245, the absence of which was revealed by PCR and whole-genome sequencing. These findings highlighted genotypic differences in M. avium strains from humans and pigs in Japan and how this diversity can influence the applicability of a detection tool across different geographic areas and hosts.

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Virucidal effect of the mesoscopic structure of cac-717 on severe acute respiratory syndrome coronavirus-2

Yokoyama T., Nishimura T., Uwamino Y., Kosaki K., Furusaki K., Onishi R., Onodera T., Haritani M., Sugiura K., Kirisawa R., Hasegawa N.

Microorganisms (Microorganisms) 9 ( 10 ) 2021.10

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

Namkoong H., Omae Y., Asakura T., Ishii M., Suzuki S., Morimoto K., Kawai Y., Emoto K., Oler A.J., Szymanski E.P., Yoshida M., Matsuda S., Yagi K., Hase I., Nishimura T., Sasaki Y., Asami T., Shiomi T., Matsubara H., Shimada H., Hamamoto J., Jhun B.W., Kim S.Y., Huh H.J., Won H.H., Ato M., Kosaki K., Betsuyaku T., Fukunaga K., Kurashima A., Tettelin H., Yanai H., Mahasirimongkol S., Olivier K.N., Hoshino Y., Koh W.J., Holland S.M., Tokunaga K., Hasegawa N.

European Respiratory Journal (European Respiratory Journal) 58 ( 2 ) 2021.08

ISSN 09031936

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

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

Uno S., Nishimura T., Nishio K., Kohsaka A., Tamizu E., Nakano Y., Kagyo J., Nakajima Y., Arai R., Hasegawa H., Arakawa K., Kashimura S., Ishii R., Miyazaki N., Uwamino Y., Hasegawa N.

Tuberculosis (Tuberculosis) 129 2021.07

ISSN 14729792

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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Sars-cov-2 infection among medical institution faculty and healthcare workers in tokyo, japan

Nishimura T., Uwamino Y., Uno S., Kashimura S., Shiraki T., Kurafuji T., Morita M., Noguchi M., Azegami T., Yamada-Goto N., Murai-Takeda A., Yokoyama H., Kuwabara K., Kato S., Matsumoto M., Hirata A., Iida M., Harada S., Ishizaka T., Misawa K., Murata M., Saya H., Amagai M., Kitagawa Y., Takeuchi T., Mori M., Takebayashi T., Hasegawa N.

Internal Medicine (Internal Medicine) 60 ( 16 ) 2569 - 2575 2021

ISSN 09182918

Objective To consider effective measures against severe acute respiratory syndrome coronavirus 2 (SARSCoV- 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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Control of a Nosocomial Outbreak of COVID-19 in a University Hospital

Harada S., Uno S., Ando T., Iida M., Takano Y., Ishibashi Y., Uwamino Y., Nishimura T., Takeda A., Uchida S., Hirata A., Sata M., Matsumoto M., Takeuchi A., Obara H., Yokoyama H., Fukunaga K., Amagai M., Kitagawa Y., Takebayashi T., Hasegawa N.

Open Forum Infectious Diseases (Open Forum Infectious Diseases) 7 ( 12 ) 1 - 9 2020.12

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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The distributions of hematologic and biochemical values in healthy high-school adolescents in Japan

Azegami T., Nishimura T., Murai-Takeda A., Yamada-Goto N., Sato Y., Mori M.

PLoS ONE (PLoS ONE) 15 ( 11 November ) 2020.11

Laboratory tests of adolescents are often interpreted by using reference intervals derived from adults, even though these populations differ in their physical and physiologic characteristics and disease susceptibility. Therefore, to examine the distribution of laboratory values specific for adolescents, we analyzed hematologic and biochemical measurements obtained from 12,023 healthy Japanese adolescents (ages 15 through 18 years; male, 9165; female, 2858) during 2009 through 2018. Distributions were shown as medians with 95% (2.5th and 97.5th percentiles) of values and were compared with those from previous studies that examined similar Asian populations. There were some differences between hematologic parameters, serum creatinine and uric acid concentration, and lipid levels of Japanese adults and adolescents. In comparison with other Asian populations, the distributions of serum uric acid and high-density–lipoprotein cholesterol in the present study were slightly higher than those in the other studies. Although further research is need, the distributions of hematologic and biochemical tests in adolescents may have the potential to facilitate the early identification and management of disease in this population.

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

Uno S., Asakura T., Morimoto K., Yoshimura K., Uwamino Y., Nishimura T., Hoshino Y., Hasegawa N.

BMC Pulmonary Medicine (BMC Pulmonary Medicine) 20 ( 1 ) 2020.10

© 2020 The Author(s). 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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Showering is associated with Mycobacterium avium complex lung disease: An observational study in Japanese women

Uwamino Y., Nishimura T., Sato Y., Tamizu E., Uno S., Mori M., Fujiwara H., Kawabe H., Murata M., Hasegawa N.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 3 ) 211 - 214 2020.03

ISSN 1341321X

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 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

Uwamino Y., Sakai A., Nishimura T., Noguchi M., Uno S., Fujiwara H., Mori M., Wakui M., Murata M., Hasegawa N.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 3 ) 312 - 314 2020.03

ISSN 1341321X

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 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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Infiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma

Shima T., Shimoda M., Shigenobu T., Ohtsuka T., Nishimura T., Emoto K., Hayashi Y., Iwasaki T., Abe T., Asamura H., Kanai Y.

Cancer Science (Cancer Science) 111 ( 2 ) 727 - 738 2020.02

ISSN 13479032

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti–PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8+ cytotoxic T cells and FoxP3+ regulatory T cells. Among these immune cells, TAM and CD8+ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8+ T cells are known to induce tumor PD-L1 expression via interferon-ɣ production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8+ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co–culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-β inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.

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Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease

Asakura T., Kimizuka Y., Nishimura T., Suzuki S., Namkoong H., Masugi Y., Sato Y., Ishii M., Hasegawa N.

Respirology (Respirology) 2020

ISSN 13237799

© 2020 Asian Pacific Society of Respirology Background and objective: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. Methods: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). Results: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. Conclusion: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

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

Nishimura T., Ota M., Mori M., Takano Y., Fujiwara H., Uwamino Y., Uno S., Hasegawa N.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 2020

ISSN 1341321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 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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The rough colony morphotype of Mycobacterium avium exhibits high virulence in human macrophages and mice

Nishimura T., Shimoda M., Tamizu E., Uno S., Uwamino Y., Kashimura S., Yano I., Hasegawa N.

Journal of Medical Microbiology (Journal of Medical Microbiology) 69 ( 7 ) 1020 - 1033 2020

ISSN 00222615

© 2020 Microbiology Society. All rights reserved. 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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Low serum estradiol levels are related to Mycobacterium avium complex lung disease: A cross-sectional study

Uwamino Y., Nishimura T., Sato Y., Tamizu E., Asakura T., Uno S., Mori M., Fujiwara H., Ishii M., Kawabe H., Murata M., Hasegawa N.

BMC Infectious Diseases (BMC Infectious Diseases) 19 ( 1 ) 2019.12

© 2019 The Author(s). 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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Sitafloxacin-containing regimen for the treatment of refractory mycobacterium avium complex lung disease

Asakura T., Suzuki S., Fukano H., Okamori S., Kusumoto T., Uwamino Y., Ogawa T., So M., Uno S., Namkoong H., Yoshida M., Kamata H., Ishii M., Nishimura T., Hoshino Y., Hasegawa N.

Open Forum Infectious Diseases (Open Forum Infectious Diseases) 6 ( 4 ) 2019.04

© The Author(s) 2019. 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 STFXcontaining 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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Retrospective evaluation of natural course in mild cases of Mycobacterium avium complex pulmonary disease

Kimizuka Y., Hoshino Y., Nishimura T., Asami T., Sakakibara Y., Morimoto K., Maeda S., Nakata N., Abe T., Uno S., Namkoong H., Fujiwara H., Funatsu Y., Yagi K., Fujie T., Ishii M., Inase N., Iwata S., Kurashima A., Betsuyaku T., Hasegawa N.

PLoS ONE (PLoS ONE) 14 ( 4 ) 2019.04

© 2019 Kimizuka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background There is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease. Methods We conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model. Results Mean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV 1 ), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and % FEV 1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups. Conclusions Mild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.

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Clinico-microbiological analysis of 121 patients with pulmonary Mycobacteroides abscessus complex disease in Japan – An NTM-JRC study with RIT

Morimoto Kozo, Nakagawa Taku, Asami Takahiro, Morino Eriko, Fujiwara Hiroshi, Hase Isano, Tsujimoto Yoshie, Izumi Kiyohiko, Hayashi Yuta, Matsuda Shuichi, Murase Yoshiro, Yano Ryozo, Takasaki Jin, Betsuyaku Tomoko, Aono Akio, Goto Hajime, Nishimura Tomoyasu, Sasaki Yuka, Hoshino Yoshihiko, Kurashima Atsuyuki, Ato Manabu, Ogawa Kenji, Hasegawa Naoki, Mitarai Satoshi

Respiratory Medicine 145 14 - 20 2018.12

ISSN 0954-6111

Rationale: No comprehensive analysis has previously been performed to evaluate the clinical aspects of and microbiological evidence associated with Mycobacteroides abscessus complex (MABC) infection in a region, such as Japan, with a low MABC incidence. Objectives: This study aimed to clarify the clinicopathological characteristics of MABC, which included clinical relatedness to erm(41) sequevar, phenotype (as colony morphology and minimum inhibitory concentration), and genotype. Methods: A total of 121 MABC patients (68 with M. abscessus subsp. abscessus and 53 with M. abscessus subsp. massiliense) were recruited into this retrospective clinical-biological study from tertiary hospitals in Japan between 2004 and 2014. Results: Approximately 30% of MABC patients had a history of previous nontuberculous mycobacterium (NTM) disease. Furthermore, 24.8% of the patients had another concomitant NTM infection after they were diagnosed with MABC. Fewer than 10% of the patients in the M. abscessus group had T28C in erm(41). While we observed a higher conversion rate for M. massiliense than for M. abscessus (72.4% and 34.8%, respectively, p = 0.002), recurrence remained relatively common for M. massiliense (31.0%). In the M. abscessus patients, the MIC of clarithromycin (CLR) was significantly lower on day 3 in patients with a better treatment response than in refractory patients (The median MIC; 0.75 μg/ml v.s 2.0 μg/ml, p = 0.03). There was no significant relation between clinical manifestations and variable number of tandem repeat genotypes. Conclusions: Because the history and simultaneous isolation of other NTM in MABC infection are relatively common, these information should be carefully translated into clinical actions. The evaluation of early CLR resistance in M. abscessus and the erm(41) functions should be important to improve the treatment strategy.

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Estimating latent tuberculosis infection using interferon-γ release assay, Japan

Nishimura Tomoyasu, Ota Masaki, Mori Masaaki, Hasegawa Naoki, Kawabe Hiroshi, Kato Seiya

Emerging Infectious Diseases 24 ( 11 ) 2111 - 2113 2018.11

ISSN 1080-6040

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Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease

Yagi Kazuma, Asakura Takanori, Namkoong Ho, Suzuki Shoji, Asami Takahiro, Okamori Satoshi, Kusumoto Tatsuya, Funatsu Yohei, Kamata Hirofumi, Nishimura Tomoyasu, Ishii Makoto, Betsuyaku Tomoko, Hasegawa Naoki

BMC Pulmonary Medicine 18 ( 1 ) 2018.07

ISSN 1471-2466

Background: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. Methods: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). Results: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34-0.58; PCS score, ρ = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (- 0.29)-(- 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. Conclusions: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis.

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School-age children and adolescents suspected of having been to be infected with pertussis in Japan

Yasui Yosuke, Mitsui Toshikatsu, Nishimura Tomoyasu, Uchida Keiko, Inokuchi Mikako, Mori Masaaki, Tokumura Mitsuaki, Nakayama Tetsuo

Vaccine 36 ( 20 ) 2910 - 2915 2018.05

ISSN 0264-410X

Many countries including Japan have adapted acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP). DTaP vaccine coverage is approximately >90%, but pertussis re-emergence has been observed since 2000 in Japan. In the present study, anti-pertussis antibodies were investigated among school-age children and adolescents from 2013 to 2015. The positive rate of anti-pertussis toxin (PT) antibodies was higher among children aged 12–13 years (60.0%. 95%CI; 56.0–63.9%) in 2014 and 18–19 years (73.0%. 95%CI; 61.4–82.6%) in 2013, compared with 6–7 years (47.1%. 95%CI; 40.7–53.6%). The mean PT antibody titer was higher among children aged 12–13 years (23.8 EU/ml. 95%CI; 21.9–25.8) in 2014 and 18–19 years (29.3 EU/ml. 95%CI; 23.0–35.6) in 2013, compared with 6–7 years (18.3 EU/ml. 95%CI; 15.5–21.2). Distributions of pertussis antibodies and mean titers at their same grade of school-age were similar from 2013 to 2015. Although school-age children were immunized with 4 doses of DTaP, the data suggested the decay of vaccine-acquired immunity and possibility of asymptomatic infection in school age, indicating the additional DTaP vaccination before the entry of elementary school, preventing household contact.

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Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease

Suzuki Shoji, Asakura Takanori, Namkoong Ho, Okamori Satoshi, Yagi Kazuma, Kamata Hirofumi, Uwamino Yoshifumi, Funatsu Yohei, Nakano Yasushi, Nishimura Tomoyasu, Ishii Makoto, Ebihara Tamotsu, Betsuyaku Tomoko, Hasegawa Naoki

Respiratory Medicine 138 1 - 6 2018.05

ISSN 0954-6111

Rationale: Little is known about the role of Aspergillus precipitating antibody (APAb) in patients with Mycobacterium avium complex lung disease (MAC-LD). Objectives: We investigated the clinical characteristics of patients with MAC-LD positive for APAb. Methods: We conducted a cross-sectional study targeting patients with MAC-LD. APAb was checked in all participants. Clinical variables included laboratory data, pulmonary function, high-resolution computed tomography findings, and health-related quality of life. Results: We analyzed 109 consecutive patients. Their median age was 68 years, and the median duration of MAC-LD was 4.8 years. Twenty (18.3%) patients tested positive for APAb. APAb-positive patients had significantly longer duration of MAC-LD (9.4 vs. 4.0 years, P = 0.017), more severe bronchiectasis evaluated by modified Reiff score (6.5 vs. 4, P = 0.0049), and lower forced expiratory volume in 1 s (%FEV₁) (75.1% vs. 86.2%, P = 0.013) than APAb-negative patients. Analysis of covariance adjusted for background factors and underlying pulmonary disease revealed that %FEV₁ was also significantly lower in patients with APAb (P = 0.045). Ten patients were newly diagnosed with chronic pulmonary aspergillosis (N = 5) or allergic bronchopulmonary aspergillosis (N = 5). Conclusions: APAb is associated with lower pulmonary function, and observed especially in patients with longer duration of MAC-LD and severe bronchiectasis, even in the absence of cavitary lesions.

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Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients

Yagi Kazuma, Morimoto Kozo, Ishii Makoto, Namkoong Ho, Okamori Satoshi, Asakura Takanori, Suzuki Shoji, Asami Takahiro, Uwamino Yoshifumi, Funatsu Yohei, Fujiwara Hiroshi, Kamata Hirofumi, Nishimura Tomoyasu, Betsuyaku Tomoko, Kurashima Atsuyuki, Hasegawa Naoki

International Journal of Infectious Diseases 67 65 - 69 2018.02

ISSN 1201-9712

Background Mycobacterium lentiflavum is a slow-growing non-tuberculous Mycobacterium that is often associated with an immunocompromised state and cervical lymphadenitis in young children. However, little is known about the clinical importance of pulmonary infection with M. lentiflavum in adults. Methods The medical records of all adults who met the diagnostic criteria of pulmonary M. lentiflavum disease at Keio University Hospital and Fukujuji Hospital from 2001 to 2015 were reviewed. In addition, the PubMed database was searched to identify further reported cases in non-HIV adults. Results Five cases of pulmonary M. lentiflavum disease were identified in the medical records search and 11 additional cases were identified in the literature review. Eleven of the total 16 cases were female, and 15 of 16 cases showed a nodular/bronchiectatic pattern on chest computed tomography imaging. No cases showed an aggressive clinical course of pulmonary M. lentiflavum disease, although one patient died of an exacerbation of underlying vasculitis and bacterial pneumonia. Conclusions The clinical characteristics of pulmonary M. lentiflavum disease in adult patients were identified. This disease mainly affects females, displays a nodular/bronchiectatic pattern on chest computed tomography imaging, and does not demonstrate an aggressive clinical course. Further larger studies are needed to reveal detailed clinical features.

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Natural history of Mycobacterium fortuitum pulmonary infection presenting with migratory infiltrates

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

BMC Infectious Diseases 18 ( 1 ) 2018.01

ISSN 1471-2334

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

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Risk of tuberculosis infection among health care workers and nursing students in Japan

Nishimura Tomoyasu, Ota Masaki, Mori Masaaki, Fujiwara Hiroshi, Takano Yaoko, Kato Seiya, Kawabe Hiroshi, Hasegawa Naoki

Journal of Infection and Chemotherapy 2018.01

ISSN 1341-321X

It is important to evaluate the risk of tuberculosis (TB) infection among health care workers (HCWs) and nursing students in Japan to propose the optimal countermeasure against new TB infection for them. To estimate the annual incidence of TB infection in HCWs at a Japanese university hospital without TB wards and in nursing students at a Japanese university using interferon-gamma release assay (IGRA). Serial IGRAs were prospectively conducted on the HCWs between August 2010 and December 2015. For nursing students, two IGRA tests were conducted before commencement of clinical training and at employment as nurses between April 2007 and December 2015. A total of 328 HCWs and 298 nursing students were followed for 670.15 and 1212.80 person-years, respectively. Assuming IGRA-positive conversions were all attributable to true infection, the incidence of TB infection in HCWs and nursing students was 0.149/100 and 0.0825/100 person-years, respectively. At a Japanese university hospital without TB wards and a Japanese university, the annual incidence of TB infection among HCWs and nursing students estimated from serial IGRA results was low, but continued vigilance for the prevention of TB infection is essential.

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

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

BMC Pulmonary Medicine 17 ( 1 ) 2017.12

ISSN 1471-2466

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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Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

Zhao X., Khan N., Gan H., Tzelepis F., Nishimura T., Park S. Y., Divangahi M., Remold H. G.

Mucosal Immunology 10 ( 6 ) 1553 - 1568 2017.11

ISSN 1933-0219

Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host M •, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected M • is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma - extra large (Bcl-x L). RIPK3-deficient M • are able to better control bacterial growth in vitro and in vivo. Mechanistically, cytosolic RIPK3 translocates to the mitochondria where it promotes necrosis and blocks caspase 8-activation and apoptosis via Bcl-x L. Furthermore, necrosis is associated with stabilization of hexokinase II on the mitochondria as well as cyclophilin D-dependent mitochondrial permeability transition. Collectively, these events upregulate the level of reactive oxygen species to induce necrosis. Thus, in Mtb-infected M •, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.

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

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

BMC Infectious Diseases 17 ( 1 ) 2017.08

ISSN 1471-2334

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 >3months. 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 <1.2μg/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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Hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity

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

Journal of Infection and Chemotherapy 2017

ISSN 1341-321X

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 first case report of acute cholangitis and bacteremia due to Neisseria subflava

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

Internal Medicine 56 ( 2 ) 221 - 223 2017

ISSN 0918-2918

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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Rapid detection and typing of carbapenemase genes from carbapenem-resistant enterobacteriaceae isolates collected in a Japanese hospital using the Xpert Carba-R assay

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

Japanese Journal of Infectious Diseases 70 ( 1 ) 124 - 125 2017

ISSN 1344-6304

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Macrolide-resistant mycobacterium avium complex lung disease

Morimoto Kozo, Namkoong Ho, Hasegawa Naoki, Nakagawa Taku, Morino Eriko, Shiraishi Yuji, Ogawa Kenji, Izumi Kiyohiko, Takasaki Jin, Yoshiyama Takashi, Hoshino Yoshihiko, Matsuda Shuichi, Hayashi Yuta, Sasaki Yuka, Ishii Makoto, Kurashima Atsuyuki, Nishimura Tomoyasu, Betsuyaku Tomoko, Goto Hajime

Annals of the American Thoracic Society 13 ( 11 ) 1904 - 1911 2016.11

ISSN 2325-6621

Rationale: The management of macrolide-resistant Mycobacterium aviumcomplex (MR-MAC)pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). Objectives: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. Methods: The medical records of 102 consecutive cases with MR-MACpulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014were reviewed.The data of 311 consecutive caseswith MDR-TB were extracted from the medical data at Fukujuji Hospital. Measurements and Main Results: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. Conclusions: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

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Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001–2011

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

Journal of Infection and Chemotherapy 22 ( 9 ) 611 - 616 2016.09

ISSN 1341-321X

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

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Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient settings

Namkoong Ho, Morimoto Kozo, Nishimura Tomoyasu, Tanaka Hiromu, Sugiura Hiroaki, Yamada Yoshitake, Kurosaki Atsuko, Asakura Takanori, Suzuki Shoji, Fujiwara Hiroshi, Yagi Kazuma, Ishii Makoto, Tasaka Sadatomo, Betsuyaku Tomoko, Hoshino Yoshihiko, Kurashima Atsuyuki, Hasegawa Naoki

BMC Infectious Diseases 16 ( 1 ) 2016.08

ISSN 1471-2334

Background: Mycobacterium abscessus (M. abscessus) pulmonary disease is a refractory chronic infectious disease. Options for treating M. abscessus pulmonary disease are limited, especially in outpatient settings. Among parenteral antibiotics against M. abscessus, intravenous amikacin (AMK) is expected to be an effective outpatient antimicrobial therapy. This study evaluated the clinical efficacy and safety of intravenous AMK therapy in outpatients with M. abscessus pulmonary disease. Methods: This retrospective chart review of cases of M. abscessus pulmonary disease evaluated patient background data, AMK dosage and duration, sputum conversion, clinical symptoms radiological findings, and adverse events. M. massiliense was excluded on the basis of multiplex PCR assay. Results: Thirteen patients (2 men and 11 women) with M. abscessus pulmonary disease were enrolled at 2 hospitals. The median age at the initiation of intravenous AMK treatment was 65 years (range: 50-86 years). Patients received a median AMK dose of 12.5 mg/kg (range: 8.3-16.2 mg/kg) for a median duration of 4 months (range: 3-9 months). The addition of intravenous AMK led to sputum conversion in 10 of 13 patients, and 8 patients continued to have negative sputum status 1 year after treatment. Approximately half of the patients showed improvement on chest high-resolution computed tomography. There were no severe adverse events such as ototoxicity, vestibular toxicity, and renal toxicity. Conclusions: Thrice weekly intravenous AMK administration in outpatient settings is effective and safe for patients with M. abscessus pulmonary disease.

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

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

Respirology 21 ( 3 ) 553 - 555 2016.04

ISSN 1323-7799

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Pharmacokinetics of intravenous peramivir in the airway epithelial lining fluid of healthy volunteers

Funatsu Yohei, Tasaka Sadatomo, Asami Takahiro, Namkoong Ho, Fujiwara Hiroshi, Iketani Osamu, Yagi Kazuma, Kimizuka Yoshifumi, Ishii Makoto, Nishimura Tomoyasu, Ogata Haruhiko, Iwata Satoshi, Betsuyaku Tomoko, Hasegawa Naoki

Antiviral Therapy 21 ( 7 ) 621 - 625 2016

ISSN 1359-6535

Background: Some subtypes of influenza virus, such as H5N1 and H7N9, cause severe viral pneumonia, for which the intraluminal concentration of the anti-influenza agent in the airway is critical. However, the pharmacokinetics of peramivir, the only available injectable neuraminidase inhibitor formulation, in the airway epithelial lining fluid (ELF) remains unclear. In this study, we aimed to determine the time course of peramivir in the pharyngeal ELF, bronchial ELF and plasma of healthy volunteers using bronchoscopic microsampling technique. Methods: Six healthy volunteers were studied. After baseline plasma sampling, 0.3 g peramivir was intravenously injected over 0.5 h. ELF was obtained from the upper and lower airways using bronchoscopic microsampling at the end of the infusion (0.5 h) and after 1.0, 1.5, 2.0, 2.5, 3.0, 4.0 and 5.0 h. The concentrations of peramivir in the ELFs and in the plasma were quantified by LC/MS/MS analysis. Results: The mean maximum concentration (C_max) in pharyngeal ELF, bronchial ELF and plasma was 1.20 ±0.42, 9.60 ±2.30 and 50.52 ±17.51 ng/ml, respectively. The penetration ratio at C_max in pharyngeal and bronchial ELFs was 2.4 and 19.0, respectively. The ratio of the area under the curve from 0 to infinity in pharyngeal and bronchial ELFs was 4.8 and 39.1 mg•min/l, respectively. Conclusions: The time course of peramivir concentration in the ELFs revealed that concentrations above the 50% inhibitory concentration value of influenza were achieved in the upper and lower airways. Therefore, peramivir could be an important treatment option for influenza viral pneumonia.

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Health-related quality of life is inversely correlated with C-reactive protein and age in Mycobacterium avium complex lung disease

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

Respiratory Research 2015.12

ISSN 1465-9921

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

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Recurrence of disseminated Mycobacterium avium complex disease in a patient with anti-gamma interferon autoantibodies by reinfection

Nishimura Tomoyasu, Fujita-Suzuki Yukiko, Yonemaru Makoto, Ohkusu Kiyofumi, Sakagami Takuro, Carpenter Stephen M., Otsuka Yoshihito, Namkoong Ho, Yano Ikuya, Hasegawa Naoki

Journal of Clinical Microbiology 53 ( 4 ) 1436 - 1438 2015.04

ISSN 0095-1137

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Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease

Yagi Kazuma, Ishii Makoto, Namkoong Ho, Asami Takahiro, Fujiwara Hiroshi, Nishimura Tomoyasu, Saito Fumitake, Kimizuka Yoshifumi, Asakura Takanori, Suzuki Shoji, Kamo Tetsuro, Tasaka Sadatomo, Gonoi Tohru, Kamei Katsuhiko, Betsuyaku Tomoko, Hasegawa Naoki

BMC Infectious Diseases 14 684 2014

BACKGROUND: Pulmonary nocardiosis frequently occurs in immunocompromised hosts and in some immunocompetent hosts with chronic lung disease; however, few reports have described pulmonary nocardiosis with nontuberculous mycobacterial lung infection. Here we report for the first time two cases of pulmonary nocardiosis caused by Nocardia cyriacigeorgica associated with Mycobacterium avium complex (MAC) lung disease caused by M. avium.CASE PRESENTATION: Case 1 is that of a 72-year-old Japanese man with untreated MAC lung disease, who was diagnosed with rheumatoid arthritis and initiated on methotrexate. After 3 years of methotrexate therapy, the patient remained smear-negative and culture-positive for MAC, but also became smear-positive for Nocardia species. He received trimethoprim/sulfamethoxazole, and his symptoms and lung infiltrates improved. Case 2 is that of an immunocompetent 53-year-old Japanese woman with MAC lung disease, who was treated with a combined therapy of clarithromycin, rifampicin, ethambutol, and levofloxacin. MAC sputum culture was negative after 1 year of combined treatment, which was maintained for 2 years. After four treatment-free years, Nocardia species were occasionally isolated from her sputum, although MAC was rarely isolated from sputum cultures over the same period. In both cases, the Nocardia species were identified as the recently defined N. cyriacigeorgica by 16S ribosomal RNA gene sequencing.CONCLUSION: We report two cases of pulmonary nocardiosis caused by N. cyriacigeorgica associated with MAC lung disease caused by M. avium and suggest that N. cyriacigeorgica may be a major infective agent associated with MAC lung disease.

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The prostaglandin E₂ receptor EP4 is integral to a positive feedback loop for prostaglandin E₂ production in human macrophages infected with Mycobacterium tuberculosis

Nishimura Tomoyasu, Zhao Xiaomin, Gan Huixian, Koyasu Shigeo, Remold Heinz G.

FASEB Journal 27 ( 9 ) 3827 - 3836 2013.09

ISSN 0892-6638

Prostaglandin E₂ (PGE₂) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mφs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE₂ receptor EP2. However, human Mφs also express EP4, a PGE₂ receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mφs have been unclear. EP4 antagonist addition to H37Rainfected Mφs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase- 1 (mPGES-1), which are involved in PGE₂ production. Moreover, H37Ra infection induced PGE₂ production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mφs, PGE₂ production induced by pathogen recognition receptors/p38 MAPK signaling is upregulated by EP4-triggered signaling to maintain an effective PGE₂ concentration.-Nishimura, T., Zhao, X., Gan, H., Koyasu, S., and Remold, H. G. The prostaglandin E ₂ receptor EP4 is integral to a positive feedback loop for prostaglandin E₂ production in human macrophages infected with Mycobacterium tuberculosis.

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IL-1β promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation

Jayaraman Pushpa, Sada-Ovalle Isabel, Nishimura Tomoyasu, Anderson Ana C., Kuchroo Vijay K., Remold Heinz G., Behar Samuel M.

Journal of Immunology 190 ( 8 ) 4196 - 4204 2013.04

ISSN 0022-1767

In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to down-regulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis-infected macrophages stimulates IL-1β secretion, which is essential for survival in the mouse model. Why IL-1β is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1β directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1β and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth.

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Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis

Behar S. M., Martin C. J., Booty M. G., Nishimura T., Zhao X., Gan H. X., Divangahi M., Remold H. G.

Mucosal Immunology 4 ( 3 ) 279 - 287 2011.05

ISSN 1933-0219

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E 2 (proapoptotic) and lipoxin (LX)A 4 (pronecrotic). Although PGE 2 protects against necrosis, virulent Mtb induces LXA 4 and inhibits PGE 2 production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.

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Elevated serum adiponectin level in patients with mycobacterium avium-intracellulare complex pulmonary disease

Tasaka Sadatomo, Hasegawa Naoki, Nishimura Tomoyasu, Yamasawa Wakako, Kamata Hirofumi, Shinoda Hiromi, Kimizuka Yoshifumi, Fujiwara Hiroshi, Hirose Hiroshi, Ishizaka Akitoshi

Respiration 79 ( 5 ) 383 - 387 2010.04

ISSN 0025-7931

Background: Patients with Mycobacterium avium-intracellulare complex (MAC) pulmonary disease often suffer from weight loss. Adipokines are factors secreted by adipocytes, including leptin and adiponectin, as well as some inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Body mass index (BMI) is known to be inversely correlated with adiponectin and positively with leptin, TNF-α, and IL-6. Objective: We aimed to evaluate the levels of serum adipokines, including adiponectin, leptin, TNF-α, and IL-6 in patients with MAC pulmonary disease. Methods: Forty consecutive patients with MAC pulmonary disease (8 males; median age 62 years; median BMI 18.1) were examined. Serum levels of adiponectin, leptin, TNF-α, and IL-6 were measured with ELISA. Age-, sex- and BMI-matched healthy subjects served as controls. Results: Serum adiponectin was significantly elevated in patients with MAC pulmonary disease compared with the controls (p < 0.01). In both the patients and controls, serum adiponectin levels were inversely correlated with BMI (p < 0.05). No significant correlation was observed between serum adiponectin levels and C-reactive protein or lung function. Serum leptin levels, which were positively correlated with BMI, did not differ between patients and controls. Serum levels of TNF-α and IL-6 were significantly greater in patients with MAC pulmonary disease than in controls. The levels of TNF-α and IL-6 were not correlated with BMI and other adipokines examined. Conclusion: The results of the present study indicate that, in patients with MAC pulmonary disease, adiponectin is inappropriately secreted and may play a role in the pathophysiology of the disease.

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Therapeutic effects of various initial combinations of chemotherapy including clarithromycin against Mycobacterium avium complex pulmonary disease

Hasegawa Naoki, Nishimura Tomoyasu, Ohtani Sumire, Takeshita Kei, Fukunaga Koichi, Tasaka Sadatomo, Urano Tetsuya, Ishii Koudou, Miyairi Mamoru, Ishizaka Akitoshi

Chest 136 ( 6 ) 1569 - 1575 2009.12

ISSN 0012-3692

Background: The objective of this study was to find an optimal initial combination chemotherapy that includes clarithromycin (CAM) for treatment-naive patients with Mycobacterium avium complex (MAC) pulmonary disease, as assessed by microbiological conversion using a Mycobacterium growth indicator tube (MGIT). Methods: Thirty-four patients with treatment-naive MAC pulmonary disease (determined using 1997 American Thoracic Society criteria) were evaluated retrospectively. They demonstrated a nodular and bronchiectatic pattern without cavity on high-resolution CT (HRCT) scans. The following three regimens were administered: regimen A (n = 9) consisted of CAM (400 mg/d), ethambutol (EB) [750 mg/d], and rifampicin (RFP) [450 mg/d]; regimen B (n = 12) consisted of CAM (800 mg/d), EB (750 mg/d), and RFP (450 mg/d); and regimen C (n = 13) consisted of CAM (800 mg/d), EB (1,000 mg/d), and RFP (600 mg/d) during the first 2 months followed by a reduction of the dosage of EB from 1,000 to 750 mg/d. Gender, age, BMI, and HRCT scan finding scores were not significantly different among the three groups. Chemotherapy was continued for 18 months. Sputum culture was periodically assessed by MGIT. Results: Culture conversion at 18 months in regimen A (55.6%), which included a daily dosage of 400 mg of CAM (9.5 mg/kg), was significantly inferior to that in regimen B (91.7%), which included daily 800 mg of CAM (17.6 mg/kg; p < 0.05), but regimen B and C (92.3%) showed no between-group difference after > 18 months of chemotherapy. Conclusions: The higher dose of CAM allowed for better culture conversion. Daily combination chemotherapy that includes CAM (800 mg) seems appropriate as an initial treatment against treatment-naive patients with nodular and bronchiectatic MAC pulmonary disease.

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Effects of tnf-α-converting enzyme inhibition on acute lung injury induced by endotoxin in the rat

Shimizu Mie, Hasegawa Naoki, Nishimura Tomoyasu, Endo Yoshihiko, Shiraishi Yoshiki, Yamasawa Wakako, Koh Hidefumi, Tasaka Sadatomo, Shimada Hisato, Nakano Yasushi, Fujishima Seitaro, Yamaguchi Kazuhiro, Ishizaka Akitoshi

Shock 32 ( 5 ) 535 - 540 2009.11

ISSN 1073-2322

We studied the effects of TNF-converting enzyme inhibition with Y-41654, which down-regulates the production of soluble TNF-α (sTNF-α), on acute lung injury induced by intratracheal administration of LPS. We first verified in vitro that pretreatment of isolated alveolar macrophages from Sprague-Dawley male rats with 20 μL of 0.1-mM Y-41654, decreased significantly (P < 0.05) the concentration of sTNF-α in cell supernatants induced by 10 μg/mL of LPS. We then studied four groups of rats (each n = 10) including 1) a control group, 2) an LPS group (300 μg /kg, instilled intratracheally), 3) a Y-41654 group, and 4) a treatment group treated with Y-41654 after LPS instillation. Y-41654, 10 mg/kg in 0.7 mL of phosphate-buffered saline, was administered (i.v.), 15 min before and 0.5, 1.5, 2.5, and 3.5 h after saline or LPS instillation. The animals were observed for 4 h. In the animals treated with Y-41654, the concentrations of sTNF-α and protein in bronchoalveolar lavage fluid, and the number of neutrophils in lung tissue and bronchoalveolar lavage fluid were significantly lower at 4 h than in the LPS group (P < 0.05). In conclusion, sTNF-α plays an important role in the development of acute lung injury induced by intratracheal administration of LPS, in part modulating neutrophil kinetics.

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Serodiagnostic contributions of antibody titers against mycobacterial lipid antigens in mycobacterium avium complex pulmonary disease

Nishimura Tomoyasu, Hasegawa Naoki, Fujita Yukiko, Yano Ikuya, Ishizaka Akitoshi

Clinical Infectious Diseases 49 ( 4 ) 529 - 535 2009.08

ISSN 1058-4838

Background. Although the incidence of pulmonary tuberculosis is decreasing, the number of immunocompetent patients with Mycobacterium avium complex (MAC) pulmonary disease is steadily increasing. Therefore, albeit not contagious, MAC pulmonary disease needs to be diagnosed rapidly and accurately. We examined the serodiagnostic contributions of serum immunoglobulin G antibody titers against the species-specific and -common mycobacterial lipid antigens in the diagnosis of MAC pulmonary disease. Methods. Serum samples were obtained from 65 patients with MAC pulmonary disease, 15 patients with suspected MAC disease, 25 patients with pulmonary tuberculosis, 10 patients with Mycobacterium kansasii disease, and 100 healthy volunteers (control subjects). We measured the serum immunoglobulin G antibody titers against trehalose monomycolate (TMM-M) and apolar-glycopeptidolipid (GPL), lipid antigens extracted from MAC. Results. In patients with MAC pulmonary disease, the antibody titers against TMM-M and apolar-GPL were significantly higher than those in the other patient groups or in the control subjects. By receiver operator characteristic curve analysis, an optical density of 0.27, corresponding to the optimal cutoff antibody titer against TMM-M, was associated with a sensitivity of 89.2% and a specificity of 97.0%, and an optical density of 0.33, corresponding to the optimal cutoff antibody titer against apolar-GPL, was associated with a sensitivity of 89.2% and a specificity of 94.0%. Conclusions. Measurements of antibody titers against TMM-M and apolar-GPL would be useful in the diagnosis of MAC pulmonary disease and in the differential diagnosis of mycobacterial pulmonary disease.

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Concentrations of clarithromycin and active metabolite in the epithelial lining fluid of patients with Mycobacterium avium complex pulmonary disease

Hasegawa Naoki, Nishimura Tomoyasu, Watabnabe Masazumi, Tasaka Sadatomo, Nakano Yasushi, Yamazaki Koichi, Hashimoto Satoru, Nishimura Masahiro, Ishizaka Akitoshi

Pulmonary Pharmacology and Therapeutics 22 ( 3 ) 190 - 193 2009.06

ISSN 1094-5539

Objectives: Clarithromycin (CAM) is widely accepted for the treatment of Mycobacterium avium complex (MAC) pulmonary diseases. This study measured (a) the concentrations of CAM and its active metabolite (14OH-CAM) in bronchial epithelial lining fluid (ELF) obtained by bronchoscopic microsampling (BMS), and (b) the minimal inhibitory concentrations (MIC) of CAM for each MAC isolate. Methods: We studied eight patients with MAC pulmonary disease treated with oral CAM, 400 (n = 4) or 800 (n = 4) mg/day. BMS was performed 3 h after the last CAM dose, and the concentrations of CAM and 14OH-CAM were measured in ELF collected from the diseased and normal contralateral pulmonary segments, and in serum. Results: The mean ± SEM ELF concentrations of CAM (23.85 ± 7.64 μg/ml) and CAM + 14OH-CAM (28.71 ± 8.37 μg/ml) in the 800 mg/day treatment group were significantly higher than in the 400 mg/day group (7.48 ± 2.58 μg/ml and 9.63 ± 2.99 μg/ml, respectively; both p < 0.05), while the serum concentrations were similar in both groups. In both treatment groups, the mean ELF concentrations sampled from diseased and normal segments were higher than the MIC against MAC isolates. The mean ELF concentration of CAM in the 400 mg/day treatment group was <8 μg/ml (the breakpoint concentration of CAM against M. avium recommended by the Clinical Laboratories Standards Institute), while the mean concentration in the 800 mg/day treatment group was >8 μg/ml. Conclusion: These observations suggest that CAM, 800 mg/day, is an appropriate dose to treat MAC pulmonary disease, and prevent its spread from diseased to non-diseased lung segments.

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Bronchoscopic microsampling to analyze the epithelial lining fluid of patients with pulmonary Mycobacterium avium complex disease

Nishimura Tomoyasu, Hasegawa Naoki, Watanabe Masazumi, Takebayashi Toru, Tasaka Sadatomo, Ishizaka Akitoshi

Respiration 76 ( 3 ) 338 - 343 2008.09

ISSN 0025-7931

Background: A new bronchoscopic microsampling (BMS) probe has recently been developed, which allows the minimally invasivecollection of epithelial lining fluid (ELF) simultaneously from multiple sites. While the number of immunocompetent patients with pulmonary Mycobacterium avium complex(MAC) disease is growing, the precise pathogenesis of the disease remains to be clarified. Objectives: This study aimed to measure biochemical markers in the ELF of patients with pulmonary MAC disease using BMS. Methods: We studied 8 healthy volunteers (controls) and 8 patients with pulmonary MAC disease. In the patients, ELF was collected from visibly abnormal (involved) and normal (uninvolved) sites using high-resolution computed tomography (HRCT). Results: The concentration of IFN-γ (means ± SEM) was significantly higher in patient ELF sampled from involved (26.62 ± 9.66 pg/ml) than from uninvolved sites (5.33 ± 1.44 pg/ml; p < 0.05) or from normal controls (<1.56 pg/ml; p < 0.05). In most patients, there was no difference in IFN-γ concentrations between the involved and uninvolved sites. The concentration of KL-6 in ELF was significantly higher in the involved (793 ± 108 U/ml) than in the uninvolved sites (192 ± 43 U/ml;p < 0.05) or in normal controls (186 ± 38 U/ml;p < 0.05). Conclusions: The specific inflammatory reaction caused by MAC infection might not be limited to sites that were visibly abnormal on HRCT. Although further improvement has to be considered, BMS may help to increase the understanding of the pathogenesis of various respiratory disorders.

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Accuracy of an interferon-γ release assay to detect active pulmonary and extra-pulmonary tuberculosis

Nishimura T., Hasegawa Naoki, Mori M., Takebayashi T., Harada N., Higuchi K., Tasaka S., Ishizaka A.

International Journal of Tuberculosis and Lung Disease 12 ( 3 ) 269 - 274 2008.03

ISSN 1027-3719

OBJECTIVE: To examine the performance of an interferon-gamma (IFN-γ) release assay (QuantiFERON-TB 2G assay [QFT-G]) to detect Mycobacterium tuberculosis infection in a Japanese general hospital, for the diagnosis of active pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB). DESIGN: We prospectively examined the performance of QFT-G in 194 patients suspected of active TB. Diagnosis was confirmed by 1) positive M. tuberculosis cultures, or 2) clinical manifestations or laboratory or pathological findings consistent with active TB and response to specific therapy. RESULTS: Three patients with indeterminate QFT-G results were excluded. Among the remaining 191 patients, 77 had active TB. When the cut-off concentration of IFN-γ was set at 0.35 IU/ml, as recommended by the manufacturer, the assay was positive in 69 patients and negative in 122. The sensitivity of the assay was 76.6% in all patients, 74.5% in the 47 patients with PTB and 80.0% in the 30 patients with EPTB. The overall specificity of the assay was 91.2%. CONCLUSION: Although the specificity of the QFT-G to detect active TB was high and its sensitivity low, it was as accurate for the detection of active EPTB as for PTB when the 0.35 IU/ml INF-γ cut-off concentration was used.

Comparison of 5 day short-course therapies for secondary infection in patients with chronic respiratory disease using gatifloxacin and levofloxacin

Nakamura Morio, Hasegawa Naoki, Miyao Naoki, Nakajima Takahiro, Terashima Takeshi, Sakamaki Fumio, Hiraoka Rika, Matsubara Hiroaki, Oyamada Yoshitaka, Yonemaru Makoto, Nishio Kazumi, Shimada Naoto, Kawada Ichiro, Naoki Katsuhiko, Tasaka Sadatomo, Nishimura Tomoyasu, Ishizaka Akitoshi

Japanese Journal of Chemotherapy 55 ( 6 ) 451 - 462 2007.11

ISSN 1340-7007

[Objective]: This study was conducted in patients of secondary infection with chronic respiratory disease in order to compare 5 day short-course therapies employing gatifloxacin(GFLX) and levofloxacin(LVFX). In addition to the shortening of treatment periods, we also investigated the economic efficiency of this medical treatment. [Materials and methods]: A total of 74 patients with secondary infection in chronic respiratory disease were enrolled and treated with the study drugs. The study was conducted between September, 2006 and April, 2007 at Keio University Hospital and its affiliated hospitals and clinics. This was a randomized study in which patients were randomly assigned to one of the following two treatment groups: GFLX group (200 mg twice daily for patients aged ≧ 65 years and 400 mg twice daily in patients aged < 65 years), LVFX group (400 mg twice daily). The duration of antibiotic therapy was 5 days. [Results]: 61 patients (GFLX group: 32, LVFX group: 29) were evaluated for the efficacy of the medications, 74 patients (GFLX group: 37, LVFX group: 37) were evaluated for side effects, and 63 patients (GFLX group: 30, LVFX group: 33) were evaluated for abnormal laboratory results from a total of 74 patients. Clinical efficacy was 90.6% (29/32) in the GFLX group and 89.7% (26/29) in the LVFX group. Side effects were observed in 2 cases in the GFLX group, and 2 abnormal laboratory results were observed (1 in the GFLX group and 1 in the LVFX group). These cases were all mild in nature. [Conclusion]: Conventional management recommends 7-14 days of antibiotic therapy for secondary infection in patients with chronic respiratory disease. However, the optimum duration of treatment is less clear. This study suggests that for secondary infection in chronic respiratory disease, 5 day short-course therapy employing antibiotics therapy can be clinically successful. In terms of the economic efficiency of this medical treatment, GFLX is superior to LVFX due to the lower cost of this drug. These results show that therapy involving a 5 day short-course using GFLX is of greater benefit than therapy involving the use of LVFX.

Serum indicators for the diagnosis of pneumocystis pneumonia

Tasaka Sadatomo, Hasegawa Naoki, Kobayashi Seiki, Yamada Wakako, Nishimura Tomoyasu, Takeuchi Tsutomu, Ishizaka Akitoshi

Chest 131 ( 4 ) 1173 - 1180 2007.04

ISSN 0012-3692

Background: The diagnosis of pneumocystis pneumonia (PCP) is difficult because it requires microscopic examination to identify pneumocystis from induced sputum or BAL fluid. Study objective: To evaluate the usefulness of four serum markers - lactate dehydrogenase (LDH), (1→3) β-D-glucan (β-D-glucan), KL-6, and C-reactive protein (CRP) - in the diagnosis of PCP. Design: Case-control retrospective study. Patients and measurements: We reviewed the medical records of 295 consecutive patients who underwent BAL for the diagnosis of PCP. Differential cell counts in BAL fluid and serum levels of LDH, β-D-glucan, KL-6, and CRP were examined. Oxygenation index was determined using arterial oxygen tension and inspiratory oxygen concentration. Results: Based on the microscopic examination of BAL fluid, 57 patients were PCP positive and 238 patients were PCP negative. There were no significant differences in cell count or differentials in BAL fluid between the positive and negative cases. Serum levels of LDH, β-D-glucan, and KL-6 were significantly higher in PCP-positive patients (p < 0.01). Receiver operating characteristic curves suggest that β-D-glucan was the most reliable indicator. The cut-off level of β-D-glucan was estimated to be 31.1 pg/mL, with which the positive and negative predictive values were 0.610 and 0.980, respectively. In PCP-positive patients, the oxygenation index was decreased and correlated with LDH. Both LDH and β-D-glucan levels were correlated with the proportion of neutrophils in BAL fluid. Conclusions: Serum β-D-glucan is a reliable marker for the diagnosis of PCP. Since BAL procedure is invasive, measuring β-D-glucan should be considered as a primary modality for a diagnosis of PCP, especially for patients with severe respiratory failure.

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New rapid detection test with a combination of polymerase chain reaction and immunochromatographic assay for Mycobacterium tuberculosis complex

Suzuki Takeshi, Tanaka Masao, Otani Sumire, Matsuura Shiro, Sakaguchi Yoshiaki, Nishimura Tomoyasu, Ishizaka Akitoshi, Hasegawa Naoki

Diagnostic Microbiology and Infectious Disease 56 ( 3 ) 275 - 280 2006.11

ISSN 0732-8893

Recently, we had developed a polymerase chain reaction (PCR)-immunochromatographic assay (ICA) method for Mycobacterium tuberculosis and examined its clinical utility among 138 sputa of patients under suspicion of pulmonary tuberculosis. According to the results of fluorochrome staining of acid-fast bacillus, which were confirmed by Ziehl-Neelsen staining, these were 83 specimens (-), 7 specimens (±), 30 specimens (1+), 8 specimens (2+), and 10 specimens (3+). These specimens included 4 groups: group 1, 41 specimens of smear (±)∼(3+) with culture-positive M. tuberculosis; group 2, 11 specimens of smear (-) with culture-positive M. tuberculosis; group 3, 12 specimens of smear (±)∼(1+) with culture-positive nontuberculosis mycobacterium (NTM); and group 4, 9 specimens of smear (-) with culture-positive NTM. The positive results of PCR-ICA test and Amplicor M. tuberculosis (Amplicor MTB) test for M. tuberculosis are as follows: group 1, 40 positive by PCR-ICA and 39 positive by Amplicor MTB from 41 specimens; group 2, 1 positive by PCR-ICA and 5 positive by Amplicor MTB from 11 specimens; group 3, 0 positive by both tests from 12 specimens; and group 4, 0 positive by both tests from 9 specimens. None of NTM-positive specimens from groups 3 and 4 reacted on the PCR-ICA test for M. tuberculosis.

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Small cell lung cancer with Sjögren's syndrome and Lambert-Eaton myasthenic syndrome

Nishimura Tomoyasu, Tasaka Sadatomo, Yamada Wakako, Hasegawa Naoki, Soejima Kenzo, Sayama Koichi, Asano Koichirou, Ishizaka Akitoshi

Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society 44 ( 10 ) 775 - 778 2006.10

ISSN 1343-3490

A 72-year-old man was admitted to our hospital with complaints of dry mouth, muscle weakness of the lower limbs and gait disturbance. The patient had dry mouth, dry eyes, positive anti-SS-B antibody and salivary gland inflammation. Sjögren's syndrome was diagnosed. Since muscle weakness of the lower limbs and gait disturbance were not compatible with Sjögren's syndrome, we considered the possibility of paraneoplastic syndrome. Serum levels of CEA, NSE and ProGRP were elevated. Chest roentgenogram and CT showed a nodular lesion in the right upper lobe of the lung and swollen lymph nodes in the hilum and mediastinum. Small cell lung cancer was diagnosed by bronchoscopy. Anti-P/Q-type Ca2+ channel antibody was positive. Electromyogram showed a reduction in the amplitude of the evoked muscle action potential response after slow repetitive stimulation and did not show a reduction after rapid repetitive stimulation. Based on these findings, we made a diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). Concurrent chemoradiotherapy induced an improvement of muscle weakness of the lower limbs. LEMS is frequently associated with a malignant tumor and an autoimmune disorder. We thought that in this patient, the presentation of LEMS was apparent because he had both Sjögren's syndrome and small cell lung cancer.

Effects of initial passage of endotoxin through the liver on the extent of acute lung injury in a rat model

Shimada Hisato, Hasegawa Naoki, Koh Hidefumi, Tasaka Sadatomo, Shimizu Mie, Yamada Wakako, Nishimura Tomoyasu, Amakawa Kazuhisa, Kohno Mitsutomo, Sawafuji Makoto, Nakamura Kayoko, Fujishima Seitaro, Yamaguchi Kazuhiro, Ishizaka Akitosi

Shock 26 ( 3 ) 311 - 315 2006.09

ISSN 1073-2322

We hypothesized that the extent of acute lung injury (ALI) caused by lipopolysaccharide (LPS) is modified with its initial passage through the liver. We tested this hypothesis by administering LPS, 5 mg/kg, or saline to 120 male Wistar rats via the portal vein (PV) or the inferior vena cava (IVC) over 1 h. Four experimental groups of rats were administered saline into the PV, saline into the IVC, LPS into the PV (LPS-PV group), and LPS into the IVC (LPS-IVC group), respectively. At 15 and 30 min after onset of Chromium-LPS infusion, the γ counts in the liver were higher in the LPS-PV group than that in the LPS-IVC group. The ratio of Iodine-albumin counts in lung tissue to that in plasma per unit of weight (as an assessment of pulmonary microvascular permeability) at 240 min after onset of LPS stimulation, the accumulation of polymorphonuclear cell (assessed by myeloperoxidase activity) and the concentration of tumor necrosis factor α in the lung at 60 and 240 min after onset of LPS infusion, were higher in the LPS-IVC group than in the LPS-PV group. Significant differences in several factors indicative of inflammation and in the extent of LPS-induced ALI were observed after the onset of LPS infusion, depending on whether it was delivered via the PV or the IVC. These observations suggest that the entrapping of LPS during its initial passage through the hepatic circulation may attenuate LPS-induced ALI within 4 h of initiation of LPS stimulation.

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Clinical features of Pneumocystis pneumonia in patients with systemic lupus erythematosus

Tasaka Sadatomo, Hasegawa Naoki, Yamada Wakako, Saito Fumitake, Nishimura Tomoyasu, Ishizaka Akitoshi

Nihon Koky¿ki Gakkai zasshi = the journal of the Japanese Respiratory Society. 44 ( 9 ) 613 - 619 2006.09

ISSN 1343-3490

Systemic lupus erythematosus (SLE) is often associated with various opportunistic infections, particularly during treatment with corticosteroids or immunosuppressants. We studied the clinical characteristics of 15 patients with SLE who underwent diagnostic bronchoalveolar lavage (BAL) and compared 6 patients with confirmed Pneumocystis pneumonia (PcP+), with 9 patients without Pneumocystis pneumonia (PcP-). The serum concentrations of beta-D-glucan and KL-6 were significantly higher in PcP+ than in PcP- patients, whereas serum LDH was similar in both groups. The serum concentrations of complement, a marker of SLE activity, and of IgG did not predict the presence of PcP. In all patients, the overall cell and lymphocyte counts were increased in the BAL fluid, without any significant difference between the PcP+ and PcP- groups. Ground-glass opacities on chest computed tomography, and oxygenation impairment (PaO2/FiO2<200Torr) were more common in PcP+ than PcP- patients. We concluded that, in patients with SLE, serum beta-D-glucan and KL-6 might be useful in the diagnosis of PcP, particularly when severe hypoxemia precludes BAL.

Usefulness of QuantiFERON®TB-2G in contact investigation of a tuberculosis outbreak in a university

Funayama Kazushi, Tsujimoto Aiko, Mori Masaaki, Yamamoto Hiromi, Fujiwara Keiko, Nishimura Tomoyasu, Hasegawa Naoki, Horiguchi Itsuko, Mori Toru, Marui Eiji

Kekkaku 80 ( 7 ) 527 - 534 2005.07

ISSN 0022-9776

[Purpose]: This study examined the usefulness of QuantiFERON®TB-2G (QFT) i.e., a novel technique for detecting tuberculosis infection based on the whole blood interferon-gamma response to specific antigens, in the investigation of a tuberculosis outbreak among university students. [Subjects and Method]: One university student was diagnosed as smear-positive pulmonary tuberculosis. In order to determine the extent of tuberculosis infection among contact students, tuberculin skin tests and QFT were performed on the close-contact group (220 people), as well as on the non-close-contact group (242 people). [Results]: Nine students were found to be TB either clinically or on the X-ray screening in the contact investigation. In the close-contact group, the QFT-positive rate was 32.7%. The proportion of those exhibiting tuberculin reactions with erythema diameters of 30 mm or larger was 57.7%. In the non-close-contact group, the QFT-positive rate was only 0.8 %, as expected from the current healthy Japanese youths of this age. In contrast, strong tuberculin reactions with erythema of 30 mm or larger were seen in 18.2% in the latter group, most likely due to the previous history of BCG vaccination. [Conclusion]: QFT was clearly demonstrated to be a useful method for diagnosing tuberculosis infection, especially among subjects who show tuberculin reactivity due to past BCG vaccination. At the same time, the current criteria for the indication of chemoprophylaxis based on the strong tuberculin reaction were considered to be unreliable, causing many subjects with strong reactions to be given unnecessary preventive medications.

Autoimmune pancreatitis with pseudocysts

Nishimura Tomoyasu, Masaoka Tatsuhiro, Suzuki Hidekazu, Aiura Kouichi, Nagata Hiroshi, Ishii Hiromasa

Journal of Gastroenterology 39 ( 10 ) 1005 - 1010 2004.10

ISSN 0944-1174

A 47-year-old woman was admitted to our hospital with complaints of fever, upper abdominal pain, and back pain. The serum amylase, C-reactive protein (CRP), and IgG (especially IgG₄) were elevated, and abdominal computed tomography (CT) revealed diffuse enlargement of the pancreas and pseudocysts. Endoscopic retrograde pancreatography (ERP) revealed diffuse irregular narrowing of the main pancreatic duct. Histopathological examination of the pancreatic tissue showed fibrotic change with lymphocytic infiltration. Based on these findings, we diagnosed this case as a case of autoimmune pancreatitis. This case also fully satisfied the diagnostic criteria for autoimmune pancreatitis established by the Japan Pancreas Society in 2002. Few reports have been published on cases of autoimmune pancreatitis complicated by the formation of pseudocysts in the pancreas. We, therefore, report this case here to emphasize that cases of autoimmune pancreatitis can be complicated by the development of pseudocysts.

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