Papers - MIYAZAKI Taiga
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Miyazaki T, Hosogaya N, Fukushige Y, Takemori S, Morimoto S, Yamamoto H, Hori M, Ozawa Y, Shiko Y, Inaba Y, Kurokawa T, Hanaoka H, Iwanami S, Kim K, Iwami S, Watashi K, Miyazawa K, Umeyama T, Yamagoe S, Miyazaki Y, Wakita T, Sumiyoshi M, Hirayama T, Izumikawa K, Yanagihara K, Mukae H, Kawasuji H, Yamamoto Y, Tarumoto N, Ishii H, Ohno H, Yatera K, Kakeya H, Kichikawa Y, Kato Y, Matsumoto T, Saito M, Yotsuyanagi H, Kohno S
Microbiology spectrum 11 ( 3 ) e0431122 2023.5
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Microbiology Spectrum
Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARSCoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms.
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Nakada-Motokawa N, Miyazaki T, Ueda T, Yamagishi Y, Yamada K, Kawamura H, Kakeya H, Mukae H, Mikamo H, Takesue Y, Kohno S
Mycoses 64 ( 12 ) 1498 - 1507 2021.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Mycoses
Background: Several severity indexes have been reported for critically ill patients. The Pitt bacteremia score (PBS) is commonly used to predict the risk of mortality in patients with bacteraemia. Objectives: To develop a scoring system for predicting mortality in candidaemia patients. Methods: Medical records at five Japanese tertiary hospitals were reviewed. Factors associated with mortality were analysed using logistic regression modelling. The discriminatory power of scoring models was evaluated by assessing the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: In total, 422 candidaemia patients were included. Higher PBS, dialysis and retainment of central venous catheter were independent risk factors for all-cause 30-day mortality. However, among the five PBS components, fever was not associated with mortality; therefore, we developed a modified version of the PBS (mPBS) by replacing fever with dialysis. AUC for PBS and mPBS were 0.74 (95% confidence interval [CI]: 0.68–0.80) and 0.76 (95% CI: 0.71–0.82), respectively. The increase in predictive ability of mPBS for 30-day mortality was statistically significant as assessed by NRI (0.24, 95% CI: 0.01–0.46, p =.04) and IRI (0.04, 95% CI: 0.02–0.06, p =.0008). When patients were stratified by mPBS into low (scores 0–3), moderate (4–7) and high risk (≥8), there were significant differences among the survival curves (p <.0001, log-rank test), and 30-day mortality rates were 13.8% (40/290), 36.8% (28/76) and 69.4% (34/49), respectively. Conclusions: mPBS can be a useful tool for predicting mortality in candidaemia patients.
DOI： 10.1111/myc.13380
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Kim K.S., Iwanami S., Oda T., Fujita Y., Kuba K., Miyazaki T., Ejima K., Iwami S.
Life Science Alliance 4 ( 10 ) 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Life Science Alliance
The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.
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Iwanami S., Ejima K., Su Kim K., Noshita K., Fujita Y., Miyazaki T., Kohno S., Miyazaki Y., Morimoto S., Nakaoka S., Koizumi Y., Asai Y., Aihara K., Watashi K., Thompson R.N., Shibuya K., Fujiu K., Perelson A.S., Iwami S., Wakita T.
PLoS Medicine 18 ( 7 ) 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS Medicine
Background Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials Methods and findings A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d-1 (95% CI: 1.06 to 1.27 d-1), 0.777 d-1 (0.716 to 0.838 d-1), and 0.450 d-1 (0.378 to 0.522 d-1) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. Conclusions In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.
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Revisiting the guidelines for ending isolation for covid-19 patients Reviewed
Jeong Y.D., Ejima K., Kim K.S., Iwanami S., Bento A.I., Fujita Y., Jung I.H., Aihara K., Watashi K., Miyazaki T., Wakita T., Iwami S., Ajelli M.
eLife 10 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：eLife
Since the start of the COVID-19 pandemic, two mainstream guidelines for defining when to end the isolation of SARS-CoV-2-infected individuals have been in use: the one-size-fits-all approach (i.e. patients are isolated for a fixed number of days) and the personalized approach (i.e. based on repeated testing of isolated patients). We use a mathematical framework to model within-host viral dynamics and test different criteria for ending isolation. By considering a fixed time of 10 days since symptom onset as the criterion for ending isolation, we estimated that the risk of releasing an individual who is still infectious is low (0–6.6%). However, this policy entails lengthy unnecessary isolations (4.8–8.3 days). In contrast, by using a personalized strategy, similar low risks can be reached with shorter prolonged isolations. The obtained findings provide a scientific rationale for policies on ending the isolation of SARS-CoV-2-infected individuals.
DOI： 10.7554/eLife.69340
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Nabeshima T, Takazono T, Ashizawa N, Miyazaki T, Inoue S, Ngwe Tun MM, Izumikawa K, Mukae H, Moi ML, Morita K.
Lancet Reg Health West Pac 7 100104 2021.2
Language：English Publishing type：Research paper (scientific journal) Publisher：The Lancet Regional Health - Western Pacific
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Honda M., Tsubouchi H., Inomata R., Yanagi S., Sakai K., Shiomi K., Nakazato M., Miyazaki T.
Peptides 196 2026.3
Publishing type：Research paper (scientific journal) Publisher：Peptides
Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by reduced muscle mass and strength, leading to adverse outcomes such as frailty and increased mortality. Pneumonia can accelerate the progression of sarcopenia, particularly in older adults, by promoting systemic inflammation, reducing physical activity, and impairing respiratory and swallowing muscle function. No effective therapeutic interventions for sarcopenia have been established. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced primarily in the stomach and is known to stimulate appetite, suppress inflammation, and prevent muscle catabolism. Here, we showed that intraperitoneal ghrelin given every 12 h attenuated skeletal-muscle atrophy in aged mice with lipopolysaccharide (LPS)-induced lung injury. Ghrelin treatment preserved muscle weight and mass, suppressed the FoxO1-dependent expression of muscle-specific E3 ubiquitin ligases, muscle RING-finger protein-1, and F-Box protein 32 in the gastrocnemius muscle, and improved the muscle contractile force and voluntary wheel-running activity. In parallel, ghrelin treatment attenuated histological lung injury and was associated with lower levels of inflammatory cytokines in bronchoalveolar lavage fluid. In vitro, ghrelin treatment of LPS-stimulated C2C12 myotubes suppressed reactive oxygen species accumulation and increased the expression of redox-regulating genes including peroxisome proliferator-activated receptor gamma coactivator 1-α and superoxide dismutase 2. Ghrelin also downregulated the LPS-induced expression of muscle-specific ubiquitin ligases in C2C12 cells. These findings suggest that ghrelin has a protective role against inflammation-associated skeletal-muscle atrophy and may have potential as a therapeutic agent for respiratory sarcopenia in the elderly.
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Stratification of viral shedding patterns in saliva of COVID-19 patients. Reviewed
Park H, Raiki Y, Iwanami S, Kim K, Ejima K, Nakamura N, Aihara K, Miyazaki Y, Umeyama T, Miyazawa K, Morita T, Watashi K, Brooke CB, Ke R, Iwami S, Miyazaki T.
Elife. 13 RP96032. 2026.1
Publishing type：Research paper (scientific journal)
DOI： 10.7554/eLife.96032.
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Clinical features of Mycobacterium abscessus complex and Mycobacterium kansasii pulmonary disease in Kyushu, Japan. Reviewed
Takeda K, Takazono T, Ide S, Yoshida M, Iwanaga N, Hosogaya N, Tsukamoto Y, Irifune S, Suyama T, Umemura A, Mihara T, Kondo A, Kobayashi T, Sasaki E, Sawai T, Higashiyama Y, Hashiguchi K, Hanaka M, Ii T, Fukushima K, Komiya K, Miyazaki T, Yatera K, Izumikawa K, Furumoto A, Yanagihara K, Mukae H.
Respir Investig. 64 ( 1 ) 101358. 2026.1
Publishing type：Research paper (scientific journal)
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"Upper Limb Ataxia Among Residents With Chronic Inorganic Arsenic Exposure: A Quantitative Pilot Study. " Reviewed
Sato Y, Ishii N, Sugiyama T, Shiomi K, Miyazaki T, Mochizuki H
Cureus 2025.12
Language：English Publishing type：Research paper (scientific journal)
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Miyazaki T., Shimamura S., Nagayoshi Y., Nakayama H., Morita A., Tanaka Y., Matsumoto Y., Inamine T., Nishikawa H., Nakada N., Sumiyoshi M., Hirayama T., Kohno S., Mukae H.
Nature Communications 16 ( 1 ) 1023 2025.12
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications
Multidrug resistance in the pathogenic fungus Candida glabrata is a growing global threat. Here, we study mechanisms of multidrug resistance in this pathogen. Exposure of C. glabrata cells to micafungin (an echinocandin) leads to the isolation of a mutant exhibiting resistance to echinocandin and azole antifungals. The drug-resistant phenotype is due to a non-synonymous mutation (R70H) in gene IPI1, which is involved in pre-rRNA processing. Azole resistance in the ipi1R70H mutant depends on the Pdr1 transcription factor, which regulates the expression of multidrug transporters. The C. glabrata Ipi1 protein physically interacts with the ribosome-related chaperones Ssb and Ssz1, both of which bind to Pdr1. The Ipi1-Ssb/Ssz1 complex inhibits Pdr1-mediated gene expression and multidrug resistance in C. glabrata, in contrast to Saccharomyces cerevisiae where Ssz1 acts as a positive regulator of Pdr1. Furthermore, micafungin exposure reduces metabolic activity and cell proliferation in the ipi1R70H mutant, which may contribute to micafungin tolerance.
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Response to Letter to the Editor: Efficacy and Safety of Nintedanib in Japanese Patients With Early-Stage Idiopathic Pulmonary Fibrosis: A One-Year Interim Analysis From a Multicenter Observational Study in Kyushu and Okinawa, Japan. Reviewed
Sakamoto N, Okamoto M, Tobino K, Ichiyasu H, Ichikado K, Ishii H, Hamada N, Yatera K, Miyazaki T, Ishimoto H, Kido T, Miyramura T, Morimoto S, Hosogaya N, Mukae H.
Clin Ther. 8 S0149-2918(25)00351-0. 2025.11
Publishing type：Research paper (scientific journal)
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呼吸器感染症の動向と外来診療の実践的アプローチ
宮崎泰可
日本内科学会雑誌 114 ( 11 ) 2053 - 2055 2025.11
Publishing type：Part of collection (book)
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Response to Letter to the Editor: Efficacy and Safety of Nintedanib in Japanese Patients With Early-Stage Idiopathic Pulmonary Fibrosis: A One-Year Interim Analysis From a Multicenter Observational Study in Kyushu and Okinawa, Japan. Reviewed
Sakamoto N, Okamoto M, Tobino K, Ichiyasu H, Ichikado K, Ishii H, Hamada N, Yatera K, Miyazaki T, Ishimoto H, Kido T, Miyramura T, Morimoto S, Hosogaya N, Mukae H.
Clin Ther. 8 S0149-2918(25)00351-0. 2025.11
Publishing type：Research paper (scientific journal)
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MRSA早期診断のための遺伝子検査の活用
力武雄幹、宮崎泰可
感染症対策ICTジャーナル 20 ( 4 ) 271 - 275 2025.10
Publishing type：Part of collection (book)
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OMT-28, a synthetic analog of 17,18-epoxyeicosatetraenoic acid, mitigates lipopolysaccharide-induced lung injury in mice. Reviewed
Tsubouchi H, Inomata R, Yanagi S, Honda M, Sakai K, Konkel A, Lossie J, Schunck WH, Nakazato M, Miyazaki T.
Eur J Pharmacol. 10 1007:178238. 2025.10
Publishing type：Research paper (scientific journal)
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Cerebral radiation necrosis successfully treated with high-dose bevacizumab. Reviewed
Kugimiya K, Tsubouchi H, Saito K, Kadota Y, Azuma M, Sakai K, Oda Y, Sumiyoshi M, Yanagi S, Miyazaki T.
Respir Med Case Rep. 58 102282. 2025.9
Publishing type：Case report
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Multicentre retrospective observational study for development and validation of MAC prognostic score model. Reviewed
Takeda K, Takazono T, Ide S, Yoshida M, Iwanaga N, Hosogaya N, Tsukamoto Y, Irifune S, Suyama T, Mihara T, Kondo A, Kobayashi T, Fukuda Y, Sasaki E, Sawai T, Higashiyama Y, Hashiguchi K, Hanaka M, Ii T, Fukushima K, Komiya K, Miyazaki T, Yatera K, Izumikawa K, Furumoto A, Yanagihara K, Mukae H.
Sci Rep. 15 ( 1 ) 28539 2025.8
Publishing type：Research paper (scientific journal)
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Efficacy and Safety of Nintedanib in Japanese Patients With Early-Stage Idiopathic Pulmonary Fibrosis: A One-Year Interim Analysis from a Multicenter Observational Study in Kyushu and Okinawa, Japan. Reviewed
Sakamoto N, Okamoto M, Tobino K, Ichiyasu H, Ichikado K, Ishii H, Hamada N, Yatera K, Miyazaki T, Ishimoto H, Kido T, Miyramura T, Morimoto S, Hosogaya N, Mukae H.
Clin Ther. 47 ( 8 ) 587 - 597 2025.8
Publishing type：Research paper (scientific journal)
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Risk Factors and Long-Term Prognosis for Coinfection of Nontuberculous Mycobacterial Pulmonary Disease and Chronic Pulmonary Aspergillosis: A Multicentre Observational Study in Japan. Reviewed
Tanaka Y, Ide S, Takazono T, Takeda K, Iwanaga N, Yoshida M, Hosogaya N, Tsukamoto Y, Irifune S, Suyama T, Mihara T, Kondo A, Kobayashi T, Fukuda Y, Sasaki E, Sawai T, Higashiyama Y, Hashiguchi K, Hanaka M, Ii T, Fukushima K, Komiya K, Miyazaki T, Yatera K, Izumikawa K, Furumoto A, Yanagihara K, Mukae H.
Mycoses. 68 (6):e70083. 2025.6
Publishing type：Research paper (scientific journal)
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Whole-Genome Sequencing and Comparative Genomic Analysis of Three Clinical Bloodstream Infection Isolates of Trichosporon austroamericanum. Reviewed
Horiguchi T, Umeyama T, Tomuro H, Otani A, Shinohara T, Abe M, Takatsuka S, Miyazawa K, Nagi M, Muraosa Y, Hoshino Y, Sakoh T, Araoka H, Uchida N, Kaneko T, Nagano Y, Tsukada H, Miyazaki T, Miyazaki Y.
J Fungi (Basel). 11 ( 5 ) 401 2025.5
Publishing type：Research paper (scientific journal)
DOI： 10.3390/jof11050401.
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Pitt candidaemia score as an assessment tool for mortality in patients with candidaemia caused by Candida tropicalis and other Candida species: a multicentre study conducted in Japan. Reviewed
Ueda T, Kakeya H, Yoshida K, Hisato A, Ukimura A, Ogawa T, Nakajima K, Iijima K, Nagao M, Tsuchido Y, Kawamura H, Shigemi A, Hotomi M, Kono M, Kasahara K, Imakita N, Kaneko Y, Niki M, Yamada K, Kakuno S, Miyazaki T, Sumiyoshi M, Murakami Y, Doi M, Yoshioka M, Miyazaki Y, Takesue Y.
JAC Antimicrob Resist. 7 ( 3 ) dlaf078 2025.5
Publishing type：Research paper (scientific journal)
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Analysis of risk factors for long COVID after mild COVID-19 during the Omicron wave in Japan Reviewed
Namie H., Takazono T., Kawasaki R., Yano H., Ito Y., Nakada N., Hirayama T., Yoshida M., Takeda K., Ide S., Takemoto S., Iwanaga N., Tashiro M., Hosogaya N., Ishimoto H., Sakamoto N., Obase Y., Sawai T., Hashiguchi K., Fukuda Y., Kobayashi T., Matsumoto N., Norimura D., Kawano T., Hanaka T., Watanabe T., Komiya K., Miyazaki T., Ishii H., Yatera K., Yanagihara K., Nishino T., Mukae H., Izumikawa K.
Respiratory Investigation 63 ( 3 ) 303 - 310 2025.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Respiratory Investigation
Background: Post-COVID-19 syndrome, referred to as “long COVID,” is characterized by persistent symptoms that develop during or after SRAS-CoV-2 infection lasting for ≥12 weeks, which cannot be explained by factors other than COVID-19. Previous studies before the Omicron pandemic have identified female sex, older age (≥50 years), severity of illness, obesity, diabetes, and smoking as risk factors for long COVID. However, data on long COVID following the emergence of the Omicron variants are limited. Methods: An online survey was conducted among outpatients diagnosed with mild COVID-19 at 14 participating institutions in Japan between July 30, 2022, and December 31, 2023. Results: Of the included 246 cases, 76 (35.5%) experienced at least one long COVID symptom 12 weeks after onset. Logistic regression analysis revealed that age ≥40 years was significantly associated with an increased risk of respiratory (odds ratio [OR]: 3.80, 95% confidence interval [CI]: 1.67–8.65) and neurologic symptoms (OR: 4.53, 95% CI: 1.84–11.13). Conversely, antiviral drug use was associated with a decreased risk of respiratory symptoms (OR: 0.31, 95% CI: 0.11–0.93). Conclusion: Caution is warranted when treating patients over 40 years of age with mild COVID-19 due to their higher susceptibility to developing long COVID. Antiviral drugs may be beneficial in managing respiratory symptoms and mitigating disease severity.
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Volume Rendering画像支援により塞栓に成功した 肺動脈仮性動脈瘤の一例 Reviewed
久保田瑠璃、原卓也、新地康規、増田梨絵、古小路英二、榮建文、末原照大、坪内拡伸、宮崎泰可、東美菜子
宮崎県医師会医学会誌 49 ( 1 ) 29 - 33 2025.3
Publishing type：Research paper (scientific journal)
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Hirayama T., Miyazaki T., Tanaka R., Kitahori N., Yoshida M., Takeda K., Ide S., Iwanaga N., Tashiro M., Takazono T., Izumikawa K., Yanagihara K., Makimura K., Tsukamoto K., Mukae H.
Antimicrobial Agents and Chemotherapy 69 ( 2 ) e0150824 2025.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Antimicrobial Agents and Chemotherapy
Candida auris is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of Candida species to manogepix have been reported previously, those of C. auris are yet to be studied. To investigate the resistance mechanisms of C. auris, we exposed a clinical isolate (clade I) to manogepix in vitro and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in TAC1b. We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high CDR1 expression. Moreover, we generated a strain deficient in CDR1 and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the TAC1b mutation in C. auris upregulates CDR1 expression and decreases its susceptibility to manogepix.
DOI： 10.1128/aac.01508-24
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Mechanisms of multidrug resistance caused by an Ipi1 mutation in the fungal pathogen Candida glabrata. Reviewed
Miyazaki T, Shimamura S, Nagayoshi Y, Nakayama H, Morita A, Tanaka Y, Matsumoto Y, Inamine T, Nishikawa H, Nakada N, Sumiyoshi M, Hirayama T, Kohno S, Mukae H.
Nat Commun. 16 ( 1 ) 1023 2025.1
Publishing type：Research paper (scientific journal)
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Mitsutome E., Yanagi S., Uchida T., Horiguchi T., Tsubouchi H., Sumiyoshi M., Kitamura A., Oda Y., Ueno H., Yamaguchi H., Miyazaki T.
Journal of Infection and Chemotherapy 31 ( 1 ) 102482 2025.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Most cases of nontuberculous mycobacterial pulmonary disease (NTM-PD) have a progressive clinical course, and initiation of treatment is recommended rather than watchful waiting. The NTM-PD medications are frequently associated with adverse reactions, occasionally serious. Optimization of the methods for monitoring and managing adverse events in NTM-PD treatment is thus an important medical issue. Here we report a first case of postprandial hypoglycemia caused by the combination of clarithromycin (CAM) and rifampicin (RFP) in a patient with NTM-PD. A 73-year-old Japanese woman with NTM-PD was hospitalized for treatment with a combination of oral CAM, RFP, and ethambutol. She took the first doses of antibiotics before breakfast, and 3 h later went into a hypoglycemic state. Postprandial hypoglycemia occurred with high reproducibility and was accompanied by relative insulin excess. Continuous glucose monitoring with or without food and in combination with various patterns of medication revealed that the combination of CAM and RFP specifically induced postprandial hypoglycemia. Shifting the timing of administration of the CAM and RFP combination from morning to before sleep corrected the hypoglycemia and enabled continuation of the antimicrobial treatment. In conclusion, our report suggests the importance of introducing NTM-PD medication under inpatient management in order to closely monitor and early detect postprandial hypoglycemia and other serious adverse events.
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Kawaguchi T., Kitamura A., Kimura M., Rikitake Y., Iwao C., Iwao K., Sumiyoshi M., Kariya Y., Matsuda M., Umekita K., Takajo I., Moriguchi-Goto S., Yamashita A., Matsumoto K., Miyazaki T.
Journal of Infection and Chemotherapy 31 ( 1 ) 102534 2025.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Treating disseminated cryptococcosis in people with human immunodeficiency virus (HIV) is challenging due to the limited availability of effective antifungals. Although isavuconazole has antifungal activity against Cryptococcus neoformans, clinical evidence is sparse because this new drug has not been approved for the treatment of cryptococcosis in the US or Europe. Here, we report a case of HIV-associated cryptococcal meningitis that relapsed during maintenance therapy with fluconazole. A Japanese man in his 20s was diagnosed with HIV-1 infection and cryptococcal meningitis. The patient was intolerant to flucytosine and was treated with liposomal amphotericin B monotherapy for 2 weeks as induction therapy, followed by fluconazole (400 mg/day) for 3 months as consolidation therapy. Four months after starting maintenance therapy with fluconazole (200 mg/day), the patient presented with fever and cough, leading to readmission to our hospital. Biopsies of a nodule in the left lung and a left cervical lymph node led to the diagnosis of disseminated cryptococcosis (pulmonary cryptococcosis and cryptococcal lymphadenitis). Although a combination of fluconazole and liposomal amphotericin B was ineffective, the patient was successfully treated with an induction therapy combining isavuconazole and liposomal amphotericin B, followed by a maintenance therapy with isavuconazole. The patient received isavuconazole orally except for loading doses, achieving stable blood concentration levels. Moreover, we observed that blood levels of amphotericin B increased gradually with repeated administration. Therefore, isavuconazole may have a potential role in the treatment of cryptococcosis, and clinical trials involving larger numbers of cases are needed to confirm its efficacy and safety.
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Successful treatment of disseminated cryptococcosis with liposomal amphotericin B and isavuconazole in an adult living with HIV. Reviewed
Kawaguchi T, Kitamura A, Kimura M, Rikitake Y, Iwao C, Iwao K, Sumiyoshi M, Kariya Y, Matsuda M, Umekita K, Takajo T, Moriguchi-Goto S, Yamashita A, Matsumoto K, Miyazaki T.:
J Infect Chemother. 31 ( 1 ) 102534. 2025.1
Publishing type：Case report
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Human granulocytic anaplasmosis with rash and rhabdomyolysis: A case report Reviewed
Kawaguchi T., Rikitake Y., Rikitake M., Kimura M., Iwao C., Iwao K., Aizawa A., Sumiyoshi M., Kariya Y., Matsuda M., Miyauchi S., Umekita K., Takajo I., Ohashi N., Miyazaki T.
Journal of Infection and Chemotherapy 30 ( 12 ) 1309 - 1314 2024.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Human granulocytic anaplasmosis (HGA) is a tick-borne infection caused by Anaplasma phagocytophilum. Only seven cases of HGA have been reported in Japan to date. We report the case of a 61-year-old female farmer who developed HGA with rash and rhabdomyolysis. The patient had fever and erythema covering the entire body, including the palms. An induration with an eschar was observed on the right leg, indicating that the patient had been bitten by a tick. Elevated serum creatinine and creatinine kinase levels and hematuria indicated rhabdomyolysis. We suspected Japanese spotted fever, a tick-borne illness caused by Rickettsia Japonica, and administered minocycline and ciprofloxacin for a week. Transient neutropenia and thrombocytopenia were observed, but the symptoms improved. Polymerase chain reaction (PCR) and antibody tests for R. japonica and Orientia tsutsugamushi, which causes scrub typhus, were both negative. The PCR test for severe fever with thrombocytopenia syndrome virus was also negative. Antibodies against A. phagocytophilum–related proteins were detected by western blotting, indicating seroconversion of IgG with paired serum samples, and the patient was diagnosed with HGA. HGA should be suspected in acute febrile patients with a history of outdoor activity and cytopenia, with or without a rash. A testing system and the accumulation of cases in Japan are necessary for the early diagnosis and appropriate treatment of HGA.
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Human granulocytic anaplasmosis with rash and rhabdomyolysis: A case report. Reviewed
Kawaguchi T, Rikitake Y, Rikitake M, Kimura M, Iwao C, Iwao K, Aizawa A, Sumiyoshi M, Kariya Y, Matsuda M, Miyauchi S, Umekita K, Takajo I, Ohashi N, Miyazaki T.
J Infect Chemother. 30 ( 12 ) 1309 - 1314 2024.12
Publishing type：Case report
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Takazono T., Namie H., Nagayoshi Y., Imamura Y., Ito Y., Sumiyoshi M., Ashizawa N., Yoshida M., Takeda K., Iwanaga N., Ide S., Harada Y., Hosogaya N., Takemoto S., Fukuda Y., Yamamoto K., Miyazaki T., Sakamoto N., Obase Y., Sawai T., Higashiyama Y., Hashiguchi K., Funakoshi S., Suyama N., Tanaka H., Yanagihara K., Izumikawa K., Mukae H.
Respirology 29 ( 8 ) 722 - 730 2024.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Respirology
Background and Objective: The identification of factors associated with long-term prognosis after community-onset pneumonia in elderly patients should be considered when initiating advance care planning (ACP). We aimed to identify these factors and develop a prediction score model. Methods: Patients aged 65 years and older, who were hospitalized for pneumonia at nine collaborating institutions, were included. The prognosis of patients 180 days after the completion of antimicrobial treatment for pneumonia was prospectively collected. Results: The total number of analysable cases was 399, excluding 7 outliers and 42 cases with missing data or unknown prognosis. These cases were randomly divided in an 8:2 ratio for score development and testing. The median age was 82 years, and there were 68 (17%) deaths. A multivariate analysis showed that significant factors were performance status (PS) ≥2 (Odds ratio [OR], 11.78), hypoalbuminemia ≤2.5 g/dL (OR, 5.28) and dementia (OR, 3.15), while age and detection of antimicrobial-resistant bacteria were not associated with prognosis. A scoring model was then developed with PS ≥2, Alb ≤2.5, and dementia providing scores of 2, 1 and 1 each, respectively, for a total of 4. The area under the curve was 0.8504, and the sensitivity and specificity were 94.6% and 61.7% at the cutoff of 2, respectively. In the test cases, the sensitivity and specificity were 91.7% and 63.1%, respectively, at a cutoff value of 2. Conclusion: Patients meeting this score should be considered near the end of life, and the initiation of ACP practices should be considered.
DOI： 10.1111/resp.14752
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Kawaguchi T., Matsuda M., Umekita K., Miyazaki T.
Respirology Case Reports 12 ( 7 ) e01428 2024.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Respirology Case Reports
Nintedanib has been demonstrated to inhibit the rate of forced vital capacity decline in patients with progressive fibrosing interstitial lung diseases (PF-ILD) at a dose of 200 or 300 mg/day in the INBUILD trial. Although concomitant use of nintedanib with P-glycoprotein inhibitors reportedly increases the plasma concentrations of the former, tacrolimus, a P-glycoprotein inhibitor, is often used to treat connective tissue diseases-related interstitial lung diseases. The optimal dose of nintedanib in combination with tacrolimus for the treatment of PF-ILD with connective tissue disease is unknown. We herein present two patients with PF-ILD with anti-aminoacyl-tRNA synthetase antibody-positive dermatomyositis who were successfully treated with low-dose nintedanib (<200 mg/day) in combination with tacrolimus.
DOI： 10.1002/rcr2.1428
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Resolvin D4 mitigates lipopolysaccharide-induced lung injury in mice Reviewed
Inomata R., Tsubouchi H., Takao T., Kurokawa M., Yanagi S., Sakai K., Miyazaki T.
Prostaglandins Leukotrienes and Essential Fatty Acids 203 102652 2024.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Prostaglandins Leukotrienes and Essential Fatty Acids
Acute respiratory distress syndrome (ARDS) is a life-threatening condition involving severe lung inflammation. The excessive oxidative stress and persistent inflammation that occur in ARDS lead to decreased epithelial integrity and hypoxemia due to pulmonary edema via increased vascular permeability. Resolvin D4 (RvD4) is one of the lipid mediators that is biosynthesized from omega-3 polyunsaturated fatty acids. It plays a role in the resolution of inflammation and reduces oxidative stress and cell death. We investigated the therapeutic potential of the administration of RvD4 in a murine model of lipopolysaccharide (LPS)-induced ARDS. Concurrent with the intratracheal administration of LPS, RvD4 or saline was administered to mice via the caudal vein every 12 h. This treatment with RvD4 alleviated the LPS-induced infiltration of inflammatory cells in lungs, inhibited increased pulmonary vascular permeability, decreased the levels of IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF), and suppressed the reduction of the expression levels of the tight junction protein, Zonula occludens-1 (Zo-1) and the NAD+-dependent deacetylase, Sirtuin-3 (Sirt3). In vitro experiments revealed that in LPS-stimulated BEAS-2B cells, treatment with RvD4 suppressed the increases in the expressions of pro-inflammatory cytokines and maintained the epithelial cell barrier function and cell viability. The silencing of SIRT3 abolished both the anti-inflammatory effect and the retention of cell integrity in BEAS-2B cells. Together these results indicate that treatment with RvD4 can (i) protect against LPS-induced lung injury by inhibiting inflammation, and (ii) maintain epithelial barrier function via a reduction in the downregulation of SIRT3.
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Kimura M., Umekita K., Iwao C., Kawano K., Hashikura Y., Hashiba Y., Hidaka T., Sugata K., Satou Y., Miyazaki T.
Frontiers in Immunology 15 1480506 2024
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Immunology
Background: T-SPOT.TB®, one of the screening tests for latent tuberculosis infection (LTBI), yields invalid results in human T-cell leukemia virus type 1 (HTLV-1)-positive patients with rheumatoid arthritis. However, the detailed mechanisms behind this invalidation are unclear. Additionally, it remains unclear whether T-SPOT.TB® or QuantiFERON-TB (QFT) is more useful in HTLV-1-positive patients with rheumatic disease (RD). Method: Among all of the HTLV-1-positive RD patients who visited our department between August 2012 and December 2022, 44 patients who were screened using T-SPOT.TB® were included in the analysis. QFT testing was performed in 33 of the 44 patients, and the results were compared with that of T-SPOT.TB®. Furthermore, we performed a culture experiment mimicking T-SPOT.TB® using peripheral blood mononuclear cells (PBMCs) obtained from HTLV-1-positive patients with RD. Additionally, T-cell subsets with autonomous product IFN-γ were analyzed using a flow cytometer. Results: Of the included patients, 13 (29.5%) were invalid for T-SPOT.TB® because of the increased number of negative control spots. The median HTLV-1 proviral load in the invalid group was higher than that in the valid group (2.45 vs. 0.49 copies/100 PBMCs, respectively, p = 0.002). QFT was performed in all 33 patients, including 13 patients who were invalid in T-SPOT.TB®. The main source of IFN-γ production was CD8+ T-cells in the T-SPOT.TB® mimic experiment. Furthermore, Tax-expressing CD4+ T-cells and Tax-specific cytotoxic CD8+ T-cells were more frequently observed in patients with invalid results than in patients with valid results. CD4+ T-cell depletion in the T-SPOT.TB® mimic experiment reduced the population of IFN-γ producing CD8+ T cells. Conclusion: T-SPOT.TB® may be invalidated by the interaction between Tax-expressing CD4+ T-cells and cytotoxic CD8+ T-cells. Moreover, HTLV-1-associated immune reactions due to contact between these cells may be unlikely to occur in QFT using whole blood. Therefore, our results reveal the superiority of QFT over T-SPOT.TB® as a screening test for LTBI in HTLV-1-positive patients with RD.
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Kitamura A., Yanagi S., Shide K., Sato Y., Kamiunten A., Yamanari Y., Kitamura A., Sumiyoshi M., Oda Y., Tsubouchi H., Shimoda K., Miyazaki T.
American Journal of Case Reports 25 e945804 2024
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Case Reports
Patient: Male, 32-year-old Final Diagnosis: B-acute lymphoblastic leukemia Symptoms: Dyspnea • face swelling Clinical Procedure: — Specialty: Oncology Objective: Unknown etiology Background: Fibrosing mediastinitis (FM) is a rare, fibroproliferative disorder within the mediastinum. It is extremely rare for hematologic malignancies to develop as FM. Case Report: A 32-year-old Japanese man with a 1-month history of headache and 2-week history of facial swelling underwent chest computed tomography (CT); a diffuse mass-like lesion was revealed in the anterior mediastinum with severe stenosis of vital mediastinal organs. After a surgical biopsy, an initial diagnosis of idiopathic FM was made. The FM lesions responded mildly to corticosteroids but recurred repeatedly. Sixteen months after the treatment initiation, blasts appeared in the peripheral blood (PB), and the patient was diagnosed with B-acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL). Chemotherapy led to complete remission of the B-ALL/LBL and almost complete disappearance of FM-like lesions. Immunohistochemistry of the mediastinal biopsy specimen taken before the blasts’ appearance in PB demonstrated a CD34/CD7/terminal deoxynucleotidyl transferase-positive population, an identical pattern of expression common to the blasts in the patient’s PB and bone marrow. Conclusions: This is the first case report of B-ALL/LBL presenting as FM. This case underscores the importance of considering the possibility of latent hematologic malignancy even in the absence of new symptoms other than those caused by FM lesions for a long period of time. This is the first demonstration that leukemia cells may be present in the FM lesions from the initial stage of disease onset. Even if a diagnosis of idiopathic FM is confirmed, continued suspicion of the presence of hematologic malignancy is vital for improving patient outcomes.
DOI： 10.12659/AJCR.945804
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EL3-1 侵襲性カンジダ症の病態と治療
宮崎 泰可
日本医真菌学会総会プログラム・抄録集 65.Suppl1 ( 0 ) 71 2024
Authorship：Lead author Language：Japanese Publishing type：Research paper (other academic) Publisher：日本医真菌学会
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Miyazaki T., van der Linden M., Hirano K., Maeda T., Kohno S., Gonzalez E.N., Zhang P., Isturiz R.E., Gray S.L., Grant L.R., Pride M.W., Gessner B.D., Jodar L., Arguedas A.G.
Frontiers in Microbiology 15 1458307 2024
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers in Microbiology
Streptococcus pneumoniae is an important cause of community-acquired pneumonia (CAP) in Japan. Here, we report the serotype distribution and antimicrobial susceptibility of cultured pneumococcal isolates from Japanese adults aged ≥18 years with CAP. This was a prospective, population-based, active surveillance study conducted in Goto City, Japan from December 2015 to November 2020. Pneumococcal isolates from sterile sites (blood and pleural fluid) and non-sterile sites (sputum and bronchoalveolar lavage) were cultured as part of the standard of care. S. pneumoniae were serotyped using the Quellung reaction. Antimicrobial susceptibility was tested using microdilution and interpreted according to the Clinical and Laboratory Standards Institute criteria. Isolates resistant to erythromycin were phenotyped using the triple-risk test and genotyped by polymerase chain reaction. A total of 156 pneumococcal isolates were collected (138 from sputum, 15 from blood, and 3 from bronchoalveolar lavage) from 1992 patients. Of these, 142 were non-duplicate isolates from unique patients and were included in the analyses. Serotypes contained within the 13-valent pneumococcal conjugate vaccine (PCV13) (including 6C), PCV15 (including 6C), and PCV20 (including 6C and 15C) were detected in 39 (27%), 45 (32%), and 80 (56%) of 142 isolates, respectively. The most common serotypes were 35B (12%), 11A (11%), and 3 (11%). Multidrug resistance (MDR) was detected in 96/142 (68%) isolates. Of the 96 MDR isolates, 31, 32, and 59% were PCV13, PCV15, and PCV20 serotypes, respectively; the most common MDR serotypes were 35B (16%), 6C, 10A, and 15A (9% each), and 3 and 11A (8% each). A total of 119 isolates were resistant to macrolides; 41 (35%) had an M phenotype, 53 (45%) had an iMcLS phenotype, and 25 (21%) had a cMLS phenotype. In conclusion, pneumococcal serotypes 35B, 11A and 3 were most frequently associated with pneumonia and antimicrobial resistance was common among pneumococcal isolates from adults with CAP in Goto City, Japan. Implementing higher-valency PCVs May help reduce vaccine-type CAP among Japanese adults.
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Luteibacter jiangsuensis blood stream infection: a first case report Reviewed
Horiguchi T., Sumiyoshi M., Nagatomo E., Sakamoto K., Ogawa S., Ichinari N., Yamada A., Rikitake Y., Iwao C., Kawaguchi T., Umekita K., Takajo I., Yamamoto S., Miyazaki T.
BMC Infectious Diseases 23 ( 1 ) 863 2023.12
Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Infectious Diseases
Background: Luteibacter jiangsuensis is a gram-negative aerobic bacillus that was first isolated from soil samples at a pesticide factory in China and reported in 2011. Here, we describe the first case of L. jiangsuensis infection in human. Case presentation: A 59-year-old Japanese woman undergoing treatment for Crohn’s disease was admitted to our hospital with fever. Clinical examination indicated catheter-related bloodstream infection. The catheter was removed and meropenem was initiated. Morphologically identical glucose non-fermentative gram-negative bacilli were detected from two sets of aerobic blood culture and catheter-tip cultures. MALDI-TOF mass spectrometry failed to identify the bacterium, which was later identified as L. jiangsuensis by 16 S rRNA gene sequencing. Antimicrobial susceptibility test revealed that the isolate was resistant to carbapenem, therefore meropenem was switched to intravenous levofloxacin (500 mg/day). After 14 days of treatment with levofloxacin, the patient was discharged. Conclusions: This is the first case of L. jiangsuensis infection in human. The strain was identified by 16 S rRNA gene sequence analysis.
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II. Community-acquired Pneumonia
Sumiyoshi Makoto, Miyazaki Taiga
Nihon Naika Gakkai Zasshi 112 ( 11 ) 2053 - 2058 2023.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine
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特集 呼吸器感染症のアンメットニーズを探る Ⅳ.COVID-19 コロナ禍での深在性真菌症の疫学と病態 Reviewed
住吉 誠, 宮崎 泰可
呼吸器ジャーナル 71 ( 4 ) 560 - 566 2023.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：株式会社 医学書院
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Coronavirus disease 2019 in a patient with pulmonary fibrosis and emphysema: An autopsy report Reviewed
Kudo R., Kawaguchi T., Kimura M., Rikitake Y., Iwao C., Rikitake M., Iwao K., Aizawa A., Kariya Y., Matsuda M., Miyauchi S., Takajo I., Sato Y., Asada Y., Miyazaki T., Umekita K.
Heliyon 9 ( 11 ) e22221 2023.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Heliyon
Various diseases (e.g., hypertension and diabetes) are risk factors for the exacerbation of coronavirus 2019 (COVID-19). Patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) tend to develop severe COVID-19. Patients with severe COVID-19 present with acute respiratory distress syndrome (ARDS), and many COVID-19-related ARDS survivors eventually develop fibrosis. However, the appropriate management of patients with COVID-19 and ILD and post-COVID-19 ILD remains unclear. Thus, a better understanding of the pathology that exacerbates COVID-19 in patients with ILD is needed. We report the autopsy results of a patient with COVID-19 and combined pulmonary fibrosis and emphysema, whose lung organization and fibrosis progressed after the acute phase of infection. Histopathological findings suggest that fatal pulmonary fibrosis persists after the negative conversion of SARS-CoV-2. Elucidating the cause of death by autopsy may help determine therapeutic strategies in patients with COVID-19 and ILD. Vaccination and early administration of anti-inflammatory drugs or antifibrotic agents may be crucial for preventing disease progression and fatal lung fibrosis. This report aims to clarify the histopathological features of COVID-19 in patients with ILD via autopsy and discuss treatment strategies.
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A high α1-antitrypsin/interleukin-10 ratio predicts bacterial pneumonia in adults with community-acquired pneumonia: a prospective cohort study. Reviewed
Miyazaki T, Fukushima K, Hashiguchi K, Ide S, Kobayashi T, Sawai T, Yatera K, Kohno Y, Fukuda Y, Futsuki Y, Matsubara Y, Koga H, Mihara T, Sasaki E, Ashizawa N, Hirayama T, Takazono T, Yamamoto K, Imamura Y, Kaku N, Kosai K, Morinaga Y, Yanagihara K, Mukae H
Pneumonia (Nathan Qld.) 15 ( 1 ) 16 2023.10
Language：English Publishing type：Research paper (scientific journal)
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Oda Y, Tsubouchi H, Ishii N, Kitamura A, Moriyama E, Mitsutome E, Sakai K, Shiomi K, Yanagi S, Miyazaki T.
Respir Med Case Rep. 49 101930 2023.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Respiratory Medicine Case Reports
Small cell lung carcinoma (SCLC) is a neuroendocrine carcinoma with a poor prognosis and is a common cause of paraneoplastic syndromes. Paraneoplastic syndromes are characterized by neurological and endocrinological problems in patients with malignancy and are often associated with difficulty in induction of chemotherapy. Here we report the case of a patient with SCLC concomitant with two paraneoplastic syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Lambert–Eaton myasthenic syndrome (LEMS), who was treated with a platinum-doublet chemotherapy regimen. A 66-year-old male patient presented with a 1-month history of progressive proximal muscle weakness, ataxia gait and 5 kg of body weight loss. The laboratory tests revealed hyponatremia due to SIADH and the existence of antibodies against P/Q-type voltage-gated calcium channels. The nerve conduction study showed a low amplitude of compound muscle action potential (0.38 mv), a 34% decrement on 3-Hz stimulation, and a 1939% increment after maximum voluntary contraction in 10 seconds (7.75 mv). The endobronchial ultrasound transbronchial needle aspiration biopsy revealed the pathological findings of SCLC. A 2-cycle chemotherapy regimen of irinotecan plus cisplatin resulted in temporary tumor shrinkage that lasted 2 months, but the improvement of proximal muscle weakness and hyponatremia were maintained over the tumor re-progression period after chemotherapy. Although paraneoplastic syndromes accelerate the decrease in performance status, chemotherapy for SCLC may improve symptoms related to paraneoplastic syndromes and could be considered in similar cases.
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ARAKI KENJI, MATSUMOTO NOBUHIRO, TOGO KANAE, YONEMOTO NAOHIRO, OHKI EMIKO, XU LINGHUA, HASEGAWA YOSHIYUKI, INOUE HIROFUMI, TAKEMOTO RYOTA, MIYAZAKI TAIGA
Japan Journal of Medical Informatics 43 ( 4 ) 137 - 147 2023.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Association for Medical Informatics
We generated methods for evaluating clinical outcomes including treatment response in oncology using the unstructured data from electronic health records (EHR). This retrospective analysis used medical record database of University of Miyazaki Hospital and the Life Data Initiative EHR database of multiple hospitals in patients with lung cancer who are treated with anticancer therapy. For assessing key terms to describe treatment response (objective response [OR], stable disease [SD] or progressive disease [PD]) adjudicated by evaluators, natural language processing (NLP) rules were created. The most common key terms to describe OR were “reduction/shrink”, “(limited) effect”, “remarkable change”, “improvement”, etc., and “reduction/shrink” showed high sensitivity and specificity. These key terms were also found in the EHR database of multiple hospitals by a systematic review approach. This indicates that assessing response to anticancer therapy in patients with lung cancer using unstructured data of EHRs is feasible.
DOI： 10.14948/jami.43.137
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Screening and Synthesis of Tetrazole Derivatives that Inhibit the Growth of Cryptococcus Species Reviewed
Nakada N., Miyazaki T., Mizuta S., Hirayama T., Nakamichi S., Takeda K., Mukae H., Kohno S., Tanaka Y.
ChemMedChem 18 ( 18 ) e202300157 2023.9
Language：English Publishing type：Research paper (scientific journal) Publisher：ChemMedChem
Cryptococcosis has become a major health problem worldwide and caused morbidity and mortality in immunocompromised patients, especially those infected with human immunodeficiency virus (HIV). Despite the global distribution of cryptococcosis, the number and types of the available antifungals are limited, and the treatment outcomes in HIV patients are generally poor. In this study, we screened a compound library and identified one tetrazole derivative as an efficient inhibitor of Cryptococcus neoformans and Cryptococcus gattii. We further designed and synthesized a series of tetrazole derivatives and determined their structure-activity relationship, demonstrating that tetrazole backbone-containing compounds could be developed as novel antifungal drugs with distinct mechanisms against Cryptococcus spp. Our findings provide a starting point for novel target identification and structural optimization to develop a distinct class of therapeutics for patients with cryptococcosis.
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Miyazaki T., Hirano K., Ichihara K., Gonzalez E., Gessner B.D., Isturiz R.E., Zhang P., Gray S., Pride M., van der Linden M., Jodar L., Maeda T., Kohno S., Arguedas A.
CHEST Pulmonary 1 ( 2 ) 2023.9
Language：English Publishing type：Research paper (scientific journal) Publisher：CHEST Pulmonary
Background: Few studies have measured the burden of community-acquired pneumonia (CAP) and pneumococcal vaccine-type CAP in Japan after the introduction of the 23-valent pneumococcal polysaccharide vaccine into the adult national immunization program for individuals aged ≥ 65 years in 2014. In this study, we estimated the incidences of CAP and Streptococcus pneumoniae CAP among Japanese adults between 2015 and 2020. Research Question: What are the incidences of CAP and S pneumoniae CAP among Japanese adults? What are the common pneumococcal serotypes detected in patients with S pneumoniae CAP? Study Design and Methods: This prospective population-based multicenter active surveillance study enrolled adults ≥ 18 years of age with clinically and radiologically confirmed CAP in Goto City, Japan. S pneumoniae was detected using standard-of-care blood and sputum cultures, BinaxNOW (Abbott), and serotype-specific urinary antigen detection assays. Results: A total of 2,103 patients with CAP were enrolled; 84% were aged ≥ 65 years and 6.7% died during the study. The annual CAP, S pneumoniae CAP, 13-valent pneumococcal conjugate vaccine (PCV13) serotype CAP, and 20-valent pneumococcal conjugate vaccine (PCV20) serotype CAP incidences per 100,000 population were 1,280, 227, 63, and 110, respectively. S pneumoniae was detected in 17.8% of all patients with CAP by any detection method, with 4.9%, 5.5%, and 8.6% of cases of CAP resulting from PCV13, 15-valent pneumococcal conjugate vaccine, and PCV20 serotypes, respectively. Applying Goto's incidence and case fatality rate to the Japanese population, assuming PCV20 has the same vaccine efficacy and duration of protection as PCV13 and if licensed in Japan for the prevention of CAP, the inclusion of PCV20 in the national immunization program for adults ≥ 65 years of age could prevent 29,036 cases of CAP and 2,275 CAP-related deaths per year. Interpretation: Given the substantial burden of preventable pneumococcal disease, introduction of pneumococcal conjugate vaccines in Japanese adults may be of merit.
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Tanaka T., Tashiro M., Ota K., Fujita A., Sawai T., Kadota J., Fukuda Y., Sumiyoshi M., Ide S., Tachikawa N., Fujii H., Hibino M., Shiomi H., Izumida M., Matsui K., Yamauchi M., Takahashi K., Yamanashi H., Sugimoto T., Akabame S., Umeda M., Shimizu M., Hosogaya N., Kosai K., Takeda K., Iwanaga N., Ashizawa N., Hirayama T., Takazono T., Yamamoto K., Imamura Y., Miyazaki T., Kobayashi Y., Ariyoshi K., Mukae H., Yanagihara K., Kita K., Izumikawa K.
Medicine (United States) 102 ( 34 ) 2023.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Medicine (United States)
Background: 5-aminolevulinic acid (5-ALA), a natural amino acid that is marketed alongside sodium ferrous citrate (SFC) as a functional food, blocks severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proliferation in vitro and exerts anti-inflammatory effects. In this phase II open-label, prospective, parallel-group, randomized trial, we aimed to evaluate the safety and efficacy of 5-ALA in patients with mild-to-moderate coronavirus disease 2019. Methods: This trial was conducted in patients receiving 5-ALA/SFC (250/145 mg) orally thrice daily for 7 days, followed by 5-ALA/SFC (150/87 mg) orally thrice daily for 7 days. The primary endpoints were changes in SARS-CoV-2 viral load, clinical symptom scores, and 5-ALA/SFC safety (adverse events [AE] and changes in laboratory values and vital signs). Results: A total of 50 patients were enrolled from 8 institutions in Japan. The change in SARS-CoV-2 viral load from baseline was not significantly different between the 5-ALA/SFC (n = 24) and control (n = 26) groups. The duration to improvement was shorter in the 5-ALA/SFC group than in the control group, although the difference was not significant. The 5-ALA/SFC group exhibited faster improvement rates in "taste abnormality,""cough,""lethargy,"and "no appetite"than the control group. Eight AEs were observed in the 5-ALA/SFC group, with 22.7% of patients experiencing gastrointestinal symptoms (decreased appetite, constipation, and vomiting). AEs occurred with 750/435 mg/day in 25.0% of patients in the first phase and with 450/261 mg/day of 5-ALA/SFC in 6.3% of patients in the second phase. Conclusion: 5-ALA/SFC improved some symptoms but did not influence the SARS-CoV-2 viral load or clinical symptom scores over 14 days. The safety of 5-ALA/SFC in this study was acceptable. Further evaluation using a larger sample size or modified method is warranted.
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Kiyohara M, Miyazaki T, Okamoto M, Hirayama T, Makimura K, Chibana H, Nakada N, Ito Y, Sumiyoshi M, Ashizawa N, Takeda K, Iwanaga N, Takazono T, Izumikawa K, Yanagihara K, Kohno S, Mukae H
Journal of fungi (Basel, Switzerland) 9 ( 5 ) 2023.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Fungi
Outbreaks of invasive infections, with high mortality rates, caused by multidrug-resistant Candida auris have been reported worldwide. Although hotspot mutations in FKS1 are an established cause of echinocandin resistance, the actual contribution of these mutations to echinocandin resistance remains unknown. Here, we sequenced the FKS1 gene of a caspofungin-resistant clinical isolate (clade I) and identified a novel resistance mutation (G4061A inducing R1354H). We applied the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to generate a recovered strain (H1354R) in which only this single nucleotide mutation was reverted to its wild-type sequence. We also generated mutant strains with only the R1354H mutation introduced into C. auris wild-type strains (clade I and II) and analyzed their antifungal susceptibility. Compared to their parental strains, the R1354H mutants exhibited a 4- to 16-fold increase in caspofungin minimum inhibitory concentration (MIC) while the H1354R reverted strain exhibited a 4-fold decrease in caspofungin MIC. In a mouse model of disseminated candidiasis, the in vivo therapeutic effect of caspofungin was more closely related to the FKS1 R1354H mutation and the virulence of the strain than its in vitro MIC. The CRISPR-Cas9 system could thus aid in elucidating the mechanism underlying drug resistance in C. auris.
DOI： 10.3390/jof9050529
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Hirayama T, Miyazaki T, Sumiyoshi M, Ito Y, Ashizawa N, Takeda K, Iwanaga N, Takazono T, Yamamoto K, Izumikawa K, Yanagihara K, Makimura K, Tsukamoto K, Kohno S, Mukae H
Antimicrobial agents and chemotherapy 67 ( 4 ) e0124322 2023.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Antimicrobial agents and chemotherapy
Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro.
DOI： 10.1128/aac.01243-22
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Araki K., Matsumoto N., Togo K., Yonemoto N., Ohki E., Xu L., Hasegawa Y., Satoh D., Takemoto R., Miyazaki T.
Advances in Therapy 40 ( 3 ) 934 - 950 2023.3
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Advances in Therapy
Introduction: A framework that extracts oncological outcomes from large-scale databases using artificial intelligence (AI) is not well established. Thus, we aimed to develop AI models to extract outcomes in patients with lung cancer using unstructured text data from electronic health records of multiple hospitals. Methods: We constructed AI models (Bidirectional Encoder Representations from Transformers [BERT], Naïve Bayes, and Longformer) for tumor evaluation using the University of Miyazaki Hospital (UMH) database. This data included both structured and unstructured data from progress notes, radiology reports, and discharge summaries. The BERT model was applied to the Life Data Initiative (LDI) data set of six hospitals. Study outcomes included the performance of AI models and time to progression of disease (TTP) for each line of treatment based on the treatment response extracted by AI models. Results: For the UMH data set, the BERT model exhibited higher precision accuracy compared to the Naïve Bayes or the Longformer models, respectively (precision [0.42 vs. 0.47 or 0.22], recall [0.63 vs. 0.46 or 0.33] and F1 scores [0.50 vs. 0.46 or 0.27]). When this BERT model was applied to LDI data, prediction accuracy remained quite similar. The Kaplan–Meier plots of TTP (months) showed similar trends for the first (median 14.9 [95% confidence interval 11.5, 21.1] and 16.8 [12.6, 21.8]), the second (7.8 [6.7, 10.7] and 7.8 [6.7, 10.7]), and the later lines of treatment for the predicted data by the BERT model and the manually curated data. Conclusion: We developed AI models to extract treatment responses in patients with lung cancer using a large EHR database; however, the model requires further improvement.
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Araki K., Matsumoto N., Togo K., Yonemoto N., Ohki E., Xu L., Hasegawa Y., Inoue H., Yamashita S., Miyazaki T.
Health and Technology 13 ( 2 ) 253 - 262 2023.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Health and Technology
Purpose: We generated methods for evaluating clinical outcomes including treatment response in oncology using the unstructured data from electronic health records (EHR) in Japanese language. Methods: This retrospective analysis used medical record database and administrative data of University of Miyazaki Hospital in Japan of patients with lung/breast cancer. Treatment response (objective response [OR], stable disease [SD] or progressive disease [PD]) was adjudicated by two evaluators using clinicians’ progress notes, radiology reports and pathological reports of 15 patients with lung cancer (training data set). For assessing key terms to describe treatment response, natural language processing (NLP) rules were created from the texts identified by the evaluators and broken down by morphological analysis. The NLP rules were applied for assessing data of other 70 lung cancer and 30 breast cancer patients, who were not adjudicated, to examine if any difference in using key terms exist between these patients. Results: A total of 2,039 records in progress notes, 131 in radiology reports and 60 in pathological reports of 15 patients, were adjudicated. Progress notes were the most common primary source data for treatment assessment (60.7%), wherein, the most common key terms with high sensitivity and specificity to describe OR were “reduction/shrink”, for SD were “(no) remarkable change/(no) aggravation)” and for PD were “(limited) effect” and “enlargement/grow”. These key terms were also found in other larger cohorts of 70 patients with lung cancer and 30 patients with breast cancer. Conclusion: This study demonstrated that assessing response to anticancer therapy using Japanese EHRs is feasible by interpreting progress notes, radiology reports and Japanese key terms using NLP.
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肺炎球菌感染症に対する予防戦略 −宮崎県の現状と今後の展望を含めて−
宮崎泰可
宮崎県医師会医学会誌 47 ( 1 ) 7 - 11 2023.3
Language：Japanese Publishing type：Research paper (scientific journal)
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Kohno S, Izumikawa K, Takazono T, Miyazaki T, Yoshida M, Kamei K, Ogawa K, Taniguchi S, Akashi K, Tateda K, Mukae H, Miyazaki Y, Okada F, Kanda Y, Kakeya H, Suzuki J, Kimura SI, Kishida M, Matsuda M, Niki Y
J Infect Chemother 29 ( 2 ) 163 - 170 2023.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Objectives: Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses. Patients and methods: In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT). Results: A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole. Conclusions: Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.
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ELS4 侵襲性真菌感染症の予防と治療―新規アゾール系薬の使い分けを含めて―
宮崎 泰可
日本医真菌学会総会プログラム・抄録集 64.Suppl1 ( 0 ) 91 2023
Authorship：Lead author Language：Japanese Publishing type：Research paper (other academic) Publisher：日本医真菌学会
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ES2-2 多様化する抗真菌薬をどう使うか？
宮崎 泰可
日本医真菌学会総会プログラム・抄録集 64.Suppl1 ( 0 ) 95 2023
Authorship：Lead author Language：Japanese Publishing type：Research paper (other academic) Publisher：日本医真菌学会
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S1-1 新規アゾール系薬の“ 適正使用” をどう判断するか
宮崎 泰可
日本医真菌学会総会プログラム・抄録集 64.Suppl1 ( 0 ) 50 2023
Authorship：Lead author Language：Japanese Publishing type：Research paper (other academic) Publisher：日本医真菌学会
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S10-4 尿検体を用いたアスペルギルス症診断の開発～網羅的蛋白質断片解析技術を用いたアプローチ～
坪内 拡伸, 宮崎 泰可
日本医真菌学会総会プログラム・抄録集 64.Suppl1 ( 0 ) 68 2023
Authorship：Lead author Language：Japanese Publishing type：Research paper (other academic) Publisher：日本医真菌学会
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Prospective multicenter survey for Nursing and Healthcare-associated Pneumonia in Japan Reviewed
Imamura Y., Miyazaki T., Watanabe A., Tsukada H., Nagai H., Hasegawa Y., Tomono K., Ito I., Teramoto S., Ishida T., Kadota J.i., Kohno S., Mukae H.
Journal of Infection and Chemotherapy 28 ( 8 ) 1125 - 1130 2022.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Introduction: Nursing and healthcare-associated pneumonia (NHCAP) was proposed by the Japanese Respiratory Society in 2011. However, the clinical characteristics of NHCAP are still unclear. Thus, this study aimed to clarify its clinical characteristics. Methods: This multicenter prospective observational study included 596 patients with NHCAP from 73 centers in Japan between May 2014 and February 2016. Results: Patient background was characterized by an older age (81.5 ± 10.1 years), most patients had complications (94.1%), and many patients had a high probability of aspiration pneumonia (68.6%). Among the isolates, Streptococcus pneumoniae was the most common (12.7%), while Pseudomonas aeruginosa was also isolated at 10.8%. The overall 30-day mortality rate for patients was 11.9%, and the factors affecting mortality were non-ambulatory status, high blood urea nitrogen level, impaired consciousness, and low albumin level. Sulbactam/ampicillin was the most commonly administered antibiotic, including in groups with high severity of illness and high risk of multidrug-resistant (MDR) pathogens. Both the A-DROP and I-ROAD scores were useful in predicting the prognosis of NHCAP. Confirmation of intention to provide do not attempt resuscitation (DNAR) instructions was given to 333 patients (55.9%), and 313 patients agreed to DNAR instructions. Conclusions: NHCAP tends to occur in elderly patients with underlying diseases. The risk of MDR pathogens and the mortality rate are intermediate for community-acquired pneumonia and hospital-acquired pneumonia. As NHCAP is considered an important concept in an aging society, such as in Japan, establishing a treatment strategy that considers not only prognosis but also quality of life would be beneficial.
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Kaku N, Sasaki D, Ota K, Miyazaki T, Yanagihara K
The Journal of antimicrobial chemotherapy 77 ( 8 ) 2130 - 2141 2022.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Antimicrobial Chemotherapy
Objectives: Some single-centre studies have reported that MRSA carrying the staphylococcal cassette chromosome mec (SCCmec) type IV has been increasing in bloodstream infections (BSIs) in Japan. Therefore, we conducted nationwide surveillance for MRSA BSIs to investigate the extent of such change across Japan. Methods: We recruited 51 Japanese hospitals from the Japanese Association for Infectious Diseases. MRSA isolates detected in two or more sets of blood cultures were collected between January and September 2019 and subjected to antimicrobial susceptibility testing. WGS was also performed to determine SCCmec and MLST types and detect drug-resistance and virulence genes. Results: Two hundred and seventy MRSA isolates were collected from 45 hospitals. The major combination types were ST8 with SCCmec type IV (ST8-IV) (30.7%), ST1-IV (29.6%), ST2725-IV (9.5%), ST764-II (8.1%) and ST5-II (7.8%). However, there were regional differences among the major types. The most common types in eastern, western and northern Japan were ST1-IV, ST8-IV, and ST5-II and ST764-II, respectively. ST8-IV, ST1-IV and ST2725-IV exhibited greater susceptibility to clindamycin and minocycline than ST764-II and ST5-II, but erm(A) was detected in 93.8% and 100.0% of ST1-IV and ST2725-IV, respectively. Based on drug-resistance and virulence genes, characteristics of ST8-IV were different from those of ST1-IV and ST2725-IV. In addition, there were two major ST8-IV types with different characteristics. Conclusions: This study revealed that SCCmec type IV replaced SCCmec type II in MRSA BSIs. In addition, SCCmec type IV was divided into several types with different characteristics.
DOI： 10.1093/jac/dkac154
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75歳以上のインフルエンザ患者に対するバロキサビル マルボキシルの有効性，安全性：CAPSTONE-2部分集団分析. Reviewed
髙園貴弘、宮崎泰可、吉田祐樹、小嶋悟史、細萱直希、迎 寛
感染症学雑誌 95 ( 1 ) 1 - 8 2022.2
Language：Japanese Publishing type：Research paper (scientific journal)
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A case of Lemierre's syndrome with double vision as the first symptom. Reviewed
Fukushima K, Takazono T, Ashizawa N, Hara S, Kitaoka K, Ideguchi R, Miyazaki T, Hirayama T, Yamamoto K, Imamura Y, Miyazaki T, Izumikawa K, Mukae H.
J Infect Chemother 28 ( 2 ) 286 - 289 2022.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Lemierre's syndrome is a serious disease that typically causes oropharyngeal infection with internal jugular vein thrombosis, followed by distant infection focus, such as septic pulmonary embolism. The main causative organisms are anaerobic bacteria in the oral cavity, namely Fusobacterium necrophorum. We encountered an extremely rare case of Lemierre's syndrome, where double vision was found to be the first symptom. The patient's blood culture results showed the presence of F. nucleatum, which spread from the sphenoid sinus to the skull base because of chronic sinusitis; the patient presented with longus colli abscess, clivus osteomyelitis, venous thrombosis, and hematogenous infection. Antibiotic treatment with sulbactam/ampicillin was continued for 14 weeks, and no recurrence has been observed so far. Lemierre's syndrome can be complicated with atypical symptoms such as double vision if the cranial nerves are involved. It might be important to consider this disease in the differential diagnosis in the presence of cranial nerve symptoms of unknown origin with fever or inflammatory findings.
DOI： 10.1016/j.jiac.2021.09.008. Epub 2021 Sep 29. PMID: 34598877.
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Tanida R., Tsubouchi H., Yanagi S., Saito Y., Toshinai K., Miyazaki T., Takamura T., Nakazato M.
Biochemical and Biophysical Research Communications 589 260 - 266 2022.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr−/−) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr−/− mice survived longer than controls after LPS-induced lung injury. Ghsr−/− mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr−/− mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.
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Tashiro M., Obata Y., Takazono T., Ota Y., Wakamura T., Shiozawa Y., Tsuyuki A., Miyazaki T., Nishino T., Izumikawa K.
Renal Failure 44 ( 1 ) 282 - 292 2022
Language：English Publishing type：Research paper (scientific journal) Publisher：Renal Failure
Acute kidney injury (AKI) often develops during the administration of liposomal amphotericin B (L-AMB), a broad-spectrum antifungal drug. However, clinical recovery approaches for AKI patients administered L-AMB are not well established. This retrospective analysis used the data obtained from hospitals throughout Japan. AKI was defined as a ≥ 1.5-fold increase within 7 days or ≥0.3 mg/dL increase within 2 days in serum creatinine. AKI recovery was defined as a return to creatinine levels below or equal to those recorded before AKI onset. Ninety patients were assessed for recovery from AKI as per the three stages. The incidence of recovery from AKI regardless of its stage was higher, though not significant, in patients administered ≥10 mL/kg/day fluid for 7 consecutive days from AKI onset (63%) than in those who did not (35%, p = 0.053). However, if limited to AKI stage 1 patients, the former group had a significantly higher incidence of recovery (91%) than the latter group (50%, p = 0.017), even after adjusting for confounding factors (odds ratio: 10.135, 95% confidence interval: 1.148–89.513, p = 0.037). The daily fluid volume administered during the 7 consecutive days from AKI onset positively correlated with the recovery from AKI of all stages (p = 0.043). Daily consecutive fluid infusion from AKI onset may be associated with recovery from stage 1 AKI in patients administered L-AMB, with daily fluid volume positively correlating with the incidence of AKI recovery.
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Hosogaya N., Miyazaki T., Fukushige Y., Takemori S., Morimoto S., Yamamoto H., Hori M., Kurokawa T., Kawasaki Y., Hanawa M., Fujii Y., Hanaoka H., Iwami S., Watashi K., Yamagoe S., Miyazaki Y., Wakita T., Izumikawa K., Yanagihara K., Mukae H., Kohno S., Yotsuyanagi H., Kato Y., Matsumoto T., Tarumoto N., Shiraishi S., Ishii H., Ohno H., Yatera K., Yamamoto Y., Kakeya H.
Trials 22 ( 1 ) 2021.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Trials
Objectives: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. Trial design: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. Participants: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria:(1)Japanese male or female patients aged ≥ 20 years(2)SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent(3)Provide informed consent Exclusion criteria:(1)Symptoms developed ≥ 8 days prior to enrolment(2)SpO2 < 96 % (room air)(3)Any of the following screening criteria:a)ALT or AST ≥ 5 × upper limit of the reference rangeb)Child-Pugh class B or Cc)Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min(4)Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment)(5)Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator(6)Hemophiliac or patients with a marked hemorrhagic tendency(7)Severe diarrhea(8)Hypersensitivity to the investigational drug(9)Breastfeeding or pregnancy(10)With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug(11)Receiving rifampicin within the previous 2 weeks(12)Participated in other clinical trials and received drugs within the previous 12 weeks(13)Undergoing treatment for HIV infection(14)History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2(15)Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator Intervention and comparator: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). Main outcomes: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. Randomization: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). Blinding (masking): Only the assessors of the primary outcome will be blinded (blinded outcome assessment). Numbers to be randomized (sample size): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman’s equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. Trial Status: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. Trial registration: This trial was registered in Japan Registry of Clinical Trials (jRCT) (jRCT2071200023) on 21 July 21, 2020. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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Ito Y., Takazono T., Koga S., Nakano Y., Ashizawa N., Hirayama T., Tashiro M., Saijo T., Yamamoto K., Imamura Y., Miyazaki T., Yanagihara K., Izumikawa K., Mukae H.
BMC Infectious Diseases 21 ( 1 ) 2021.12
Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Infectious Diseases
Background: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. Case presentation: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. Conclusions: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.
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Tashiro M., Takazono T., Ota Y., Wakamura T., Takahashi A., Sato K., Miyazaki T., Obata Y., Nishino T., Izumikawa K.
Journal of Infection and Chemotherapy 27 ( 10 ) 1471 - 1476 2021.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Introduction: Liposomal amphotericin B (L-AMB), a broad spectrum anti-fungicidal drug, is often administered to treat invasive fungal infections (IFIs). However, the most suitable time to initiate treatment in septic shock patients with IFI is unknown. Methods: Patients with septic shock treated with L-AMB were identified from the Japanese Diagnosis Procedure Combination national database and were stratified according to L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) to determine their survival rates following septic shock onset and the shock cessation period. Results: We identified 141 patients administered L-AMB on the day of or after septic shock onset: 60 patients received early treatment, whereas 81 patients received delayed treatment. Survival rates after septic shock onset were higher in the early L-AMB group than in the delayed L-AMB group (4 weeks: 68.4% vs 57.9%, P = 0.197; 6 weeks: 62.2% vs 44.5%, P = 0.061; 12 weeks: 43.4% vs 35.0%, P = 0.168, respectively). The septic shock cessation period was shorter in the early L-AMB group than in the delayed L-AMB group (7.0 ± 7.0 days vs 16.5 ± 15.4 days, P < 0.001), with a significant difference confirmed after adjusting for confounding factors with propensity score matching (7.1 ± 7.2 days vs 16.7 ± 14.0 days, P = 0.001). Conclusion: Early L-AMB administration at septic shock onset may be associated with early shock cessation.
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Irifune S., Ashizawa N., Takazono T., Mutantu P., Nabeshima T., Ngwe Tun M.M., Ota K., Hirayama T., Fujita A., Tashiro M., Tanaka T., Yamamoto K., Imamura Y., Miyazaki T., Sawai T., Izumikawa K., Yanagihara K., Morita K., Mukae H.
Journal of Infection and Chemotherapy 27 ( 10 ) 1525 - 1528 2021.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is necessary for confirming a diagnosis of Coronavirus disease 2019 (COVID-19). Here we present a COVID-19 case of an elderly woman whose SARS-CoV-2 PCR tests showed false negative repeatedly by evaluating with different sampling sites and procedures. Nasopharyngeal swabs, suctioned sputum, and tongue swabs were collected for SARS-CoV-2-PCR. As for tongue swabs, we compared between two different sample conditions; one obtained with dry condition and the other obtained with moistened condition inside the oral cavity. SARS-CoV-2-PCR showed positive for an extended period with suctioned sputum samples compared with nasopharyngeal swabs and tongue swabs. No SARS-CoV-2 from a nasopharyngeal swab sample obtained on day 46 after symptoms onset was isolated despite high viral load (183740.5 copies/5μL). An adequate production of neutralizing antibody in a serum sample on day 46 was also confirmed. The number of RNA copies of the tongue swab samples was higher with moistened condition than with dry condition. The present case suggests that the difference of sampling site or sample condition can affect PCR results. High loads viral RNA detection does not always correlate with infectivity.
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Komeda T., Takazono T., Hosogaya N., Miyazaki T., Ogura E., Iwata S., Miyauchi H., Honda K., Fujiwara M., Ajisawa Y., Watanabe H., Kitanishi Y., Hara K., Mukae H.
Clinical Infectious Diseases 73 ( 5 ) E1181 - E1190 2021.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Infectious Diseases
Background: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. Methods: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. Results: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). Conclusions: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir.
DOI： 10.1093/cid/ciaa1870
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Infectious pneumonia and lower airway microorganisms in patients with rheumatoid arthritis Reviewed
Ideguchi S., Yamamoto K., Tahara M., Koga T., Ide S., Hirayama T., Takazono T., Imamura Y., Miyazaki T., Sakamoto N., Morimoto S., Izumikawa K., Yanagihara K., Ashizawa K., Aoki T., Kawakami A., Yatera K., Mukae H.
Journal of Clinical Medicine 10 ( 16 ) 2021.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Medicine
The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who under-went bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan–Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia.
DOI： 10.3390/jcm10163552
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Kaku N., Hashiguchi K., Akamatsu N., Wakigawa F., Matsuda J., Komaru K., Nakao T., Harada Y., Hara A., Uno N., Sakamoto K., Morinaga Y., Kitazaki T., Hasegawa H., Miyazaki T., Fukuda M., Izumikawa K., Mukae H., Yanagihara K.
European Journal of Clinical Microbiology and Infectious Diseases 40 ( 8 ) 1743 - 1748 2021.8
Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Clinical Microbiology and Infectious Diseases
We evaluated a novel transcription-reverse transcription concerted reaction (TRC) assay that can detect influenza A and B within 15 min using nasopharyngeal swab and gargle samples obtained from patients with influenza-like illness, between January and March 2018 and between January and March 2019. Based on the combined RT-PCR and sequencing results, in the nasal swabs, the sensitivity and specificity of TRC for detecting influenza were calculated as 1.000 and 1.000, respectively. In the gargle samples, the sensitivity and specificity of TRC were 0.946 and 1.000, respectively. The TRC assay showed comparable performance to RT-PCR in the detection of influenza viruses.
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One-Year Quality of Life Post-Pneumonia Diagnosis in Japanese Adults Reviewed
Glick H.A., Miyazaki T., Hirano K., Gonzalez E., Jodar L., Gessner B.D., Isturiz R.E., Arguedas A., Kohno S., Suaya J.A.
Clinical Infectious Diseases 73 ( 2 ) 283 - 290 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Infectious Diseases
Background: Pneumonia is a common, serious illness in the elderly, with a poorly characterized long-term impact on health-related quality of life (HRQoL). The Japanese Goto Epidemiology Study is a prospective, active, population-based surveillance study of adults with X-ray/CT scan-confirmed community-onset pneumonia, assessing the HRQoL outcome quality-adjusted life-years (QALYs). We report QALY scores and losses among a subset of participants in this study. Methods: QALYs were derived from responses to the Japanese version of the EuroQol-5D-5L health-state classification instrument at days 0, 7, 15, 30, 90, 180, and 365 after pneumonia diagnosis from participants enrolled from June 2017 to May 2018. We used patients as their own controls, calculating comparison QALYs by extrapolating EuroQol-5D-5L scores for day -30, accounting for mortality and changes in scores with age. Results: Of 405 participants, 85% were aged ≥65 years, 58% were male, and 69% were hospitalized for clinically and radiologically confirmed pneumonia. Compliance with interviews by patients or proxies was 100%. Adjusted EuroQol-5D-5L scores were 0.759, 0.561, 0.702, and 0.689 at days -30, 0 (diagnosis), 180, and 365, respectively. Average scores at all time points remained below the average day -30 scores (P ≤. 001). Pneumonia resulted in a 1-year adjusted loss of 0.13 QALYs (∼47.5 quality-adjusted days) (P <. 001). Conclusions: Substantial QALY losses were observed among Japanese adults following pneumonia diagnosis, and scores had not returned to prediagnosis levels at 1 year postdiagnosis. QALY scores and cumulative losses were comparable to those in US adults with chronic heart failure, stroke, or renal failure.
DOI： 10.1093/cid/ciaa595
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Evaluation of four commercial severe acute respiratory coronavirus 2 antibody tests. Reviewed
Ashizawa N, Takazono T, Ohyama K, Nagasaki Y, Okamoto M, Hirayama T, Takahashi K, Yamanashi H, Tashiro M, Hosogaya N, Tanaka T, Yamamoto K, Fukuda Y, Imamura Y, Kawanami T, Miyazaki T, Sawai T, Fukushima K, Yatera K, Yanagihara K, Izumikawa K, Mukae H.
J Infect Chemother 27 ( 7 ) 1033 - 1038 2021.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Introduction: Numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests exists commercially; however, their performance using clinical samples is limited. Although insufficient to detect SARS-CoV-2 in the early phase of infection, antibody assays can be of great use for surveillance studies or for some coronavirus disease 2019 (COVID-19) patients presenting late to the hospital. Methods: This study evaluated the sensitivity and specificity of four commercial SARS-CoV-2 lateral flow antibody tests using 213 serum specimens from 90 PCR-positive confirmed COVID-19 patients. Of 59 negative control sera, 50 were obtained from patients with other respiratory infectious diseases before COVID-19 pandemic began while nine were from patients infected with other respiratory viruses, including two seasonal coronaviruses. Results: The varied sensitivities for the four commercial kits were 70.9%, 65.3%, 45.1%, and 65.7% for BioMedomics, Autobio Diagnostics, Genbody, and KURABO, respectively, between sick days 1 and 155 in COVID-19 patients. The sensitivities of the four tests gradually increased over time after infection before sick day 5 (15.0%, 12.5%, 15.0%, and 20.0%); from sick day 11–15 (95.7%, 87.2%, 53.2%, and 89.4%); and after sick day 20 (100%, 100%, 68.6%, and 96.1%), respectively. For severe illness, the sensitivities were quite high in the late phase after sick day 15. The specificities were over 96% for all four tests. No cross-reaction due to other pathogens, including seasonal coronaviruses, was observed. Conclusions: Our results demonstrated the large differences in the antibody test performances. This ought to be considered when performing surveillance analysis.
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Ideguchi S., Yamamoto K., Hirayama T., Takazono T., Imamura Y., Miyazaki T., Sakamoto N., Izumikawa K., Yanagihara K., Morimoto S., Mukae H.
Medical Mycology 59 ( 6 ) 616 - 623 2021.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Medical Mycology
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic and life-threatening pulmonary infection with an increasing prevalence among individuals who are human immunodeficiency virus (HIV)-negative. Evidence regarding diagnostic testing of PCP in this patient population is insufficient. We evaluated the performance of serum (1, 3)-β-d-glucan (BDG) using the Fungitec G-test MK kit for diagnosing PCP in non-HIV patients. We retrospectively analyzed data from 219 non-HIV adult patients who underwent bronchoscopy and were tested for P. jirovecii DNA by PCR using lavage samples from the lower respiratory tract. Fifty PCP patients and 125 non-PCP patients were included. The most common underlying diseases were malignancies and systemic autoimmune diseases. Using the serum BDG Fungitec G-test MK test to diagnose PCP, the area under the receiver operating characteristic curve (AUC) was 0.924, whereas the modified cut-off value of 36.6 pg/mL had a sensitivity and specificity of 92.0% and 84.8%, respectively. The AUC for patients with systemic autoimmune diseases was 0.873, and the accuracy of serum BDG test declined when using methotrexate (MTX). In conclusion, the serum BDG test was useful for diagnosing PCP in non-HIV patients; however, the results should be carefully interpreted in case of MTX administration.
DOI： 10.1093/mmy/myaa101
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Ejima K, Kim KS, Iwanami S, Fujita Y, Li M, Zoh RS, Aihara K, Miyazaki T, Wakita T, Iwami S.
J R Soc Interface 18 ( 177 ) 20200947 2021.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the Royal Society Interface
Viral tests including polymerase chain reaction (PCR) tests are recommended to diagnose COVID-19 infection during the acute phase of infection. A test should have high sensitivity; however, the sensitivity of the PCR test is highly influenced by viral load, which changes over time. Because it is difficult to collect data before the onset of symptoms, the current literature on the sensitivity of the PCR test before symptom onset is limited. In this study, we used a viral dynamics model to track the probability of failing to detect a case of PCR testing over time, including the presymptomatic period. The model was parametrized by using longitudinal viral load data collected from 30 hospitalized patients. The probability of failing to detect a case decreased toward symptom onset, and the lowest probability was observed 2 days after symptom onset and increased afterwards. The probability on the day of symptom onset was 1.0% (95% CI: 0.5 to 1.9) and that 2 days before symptom onset was 60.2% (95% CI: 57.1 to 63.2). Our study suggests that the diagnosis of COVID-19 by PCR testing should be done carefully, especially when the test is performed before or way after symptom onset. Further study is needed of patient groups with potentially different viral dynamics, such as asymptomatic cases.
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Taniguchi H, Takemoto S, Ozasa M, Honda N, Suyama T, Umeyama Y, Dotsu Y, Nakao T, Tomohito K, Gyotoku H, Yamaguchi H, Miyazaki T, Sakamoto N, Obase Y, Fukuda M, Fukuoka J, Mukae H.
Thorac Cancer 12 ( 7 ) 1126 - 1130 2021.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Thoracic Cancer
Pulmonary sarcomatoid carcinoma (SC) is an aggressive subtype of lung cancer that exhibits resistance to cytotoxic chemotherapy. Although programmed cell death 1 (PD-1) inhibitors have been reported to show antitumor effects in patients with high programmed death-ligand 1 (PD-L1) expressing SC, the efficacy of combined therapy with PD-1 inhibitor plus cytotoxic chemotherapy has not previously been clarified. We herein report a case of SC with low expression of PD-L1 and few pre-existing tumor-infiltrating lymphocytes which showed a remarkable response to pembrolizumab plus cytotoxic chemotherapy as first-line treatment. Our findings suggest that combined treatment might enhance the immunogenic response, even in immunologically ignored SCs.
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Correction to: The clinical usage of liposomal amphotericin B in patients receiving renal replacement therapy in Japan: a nationwide observational study. Reviewed
Obata Y, Takazono T, Tashiro M, Ota Y, Wakamura T, Takahashi A, Sato K, Miyazaki T, Nishino T, Izumikawa K.
Clin Exp Nephrol 25 ( 3 ) 288 2021.3
Language：English Publishing type：Research paper (scientific journal)
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Obata Y, Takazono T, Tashiro M, Ota Y, Wakamura T, Takahashi A, Sato K, Miyazaki T, Nishino T, Izumikawa K.
Clin Exp Nephrol 25 ( 3 ) 279 - 287 2021.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical and Experimental Nephrology
Background: Liposomal amphotericin B (L-AMB), a broad-spectrum antifungicidal drug, is often used to treat fungal infections. However, clinical evidence of its use in patients with renal dysfunction, especially those receiving renal replacement therapy (RRT), is limited. Therefore, we evaluated the usage and occurrence of adverse reactions during L-AMB therapy in patients undergoing RRT. Methods: Using claims data and laboratory data, we retrospectively evaluated patients who were administered L-AMB. The presence of comorbidities, mortality rate, treatment with L-AMB and other anti-infective agents, and the incidence of adverse reactions were compared between patients receiving RRT, including continuous renal replacement therapy (CRRT) and maintenance hemodialysis (HD), and those that did not receive RRT. Results: In total, 900 cases met the eligibility criteria: 24, 19, and 842 cases in the maintenance HD, CRRT, and non-RRT groups, respectively. Of the patients administered L-AMB, mortality at discharge was higher for those undergoing either CRRT (15/19; 79%) or maintenance HD (16/24; 67%) than for those not receiving RRT (353/842; 42%). After propensity score matching, the average daily and cumulative dose, treatment duration, and dosing interval for L-AMB were not significantly different between patients receiving and not receiving RRT. L-AMB was used as the first-line antifungal agent for patients undergoing CRRT in most cases (12/19; 63%). Although the number of subjects was limited, the incidence of adverse events did not markedly differ among the groups. Conclusion: L-AMB may be used for patients undergoing maintenance HD or CRRT without any dosing, duration, or interval adjustments.
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Takazono T, Ito Y, Tashiro M, Nakano Y, Hirayama T, Hosogaya N, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Kohno S, Mukae H, Izumikawa K.
J Infect Chemother 27 ( 3 ) 537 - 539 2021.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Objective: To evaluate the annual variation in the frequency of patient-acquired azole-resistant Aspergillus fumigatus (ARAf), and correlate it to the amount of oral triazole prescribed, in Nagasaki, Japan. Methods: A. fumigatus isolates from respiratory specimens collected in the Nagasaki University Hospital (NUH) between 1996 and 2017 were included in the study. The amount of oral triazole prescribed in NUH since 2001 was obtained from the medical ordering system. Mutations in cyp51A, hmg1, and erg6 genes of ARAf were also analysed. Results: From a total of 240 ARAf strains, 12 (5%), 6 (2.5%), 15 (6.25%), and 3 (1.25%) strains were resistant to itraconazole (ITC), voriconazole (VRC), to either ITC or VRC, and both triazoles, respectively. The amount of prescribed VRC increased annually, and was three times as large as that of ITC in 2017. All eleven patients harbouring ITC-resistant strains had a history of prior ITC treatment, while only one of six patients harbouring VRC-resistant strains had a history of prior VRC treatment. cyp51A mutations were recorded in 10 strains; however, tandem repeat mutations of the promoter region of cyp51A were not observed. Several azole-resistant strains had non-cyp51A mutations. Conclusions: The frequency of patient-acquired ARAf is not increasing in Nagasaki, Japan. Furthermore, the prevalence of VRC-induced ARAf was rare despite the remarkable increase in the amount of prescribed VRC. Mutations in genes other than cyp51A should also be considered when ARAf strains are obtained from patients treated with azole antifungals.
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Iriki J, Yamamoto K, Senju H, Nagaoka A, Yoshida M, Iwasaki K, Ashizawa N, Hirayama T, Tashiro M, Takazono T, Imamura Y, Miyazaki T, Izumikawa K, Yanagihara K, Tsujino A, Fukuoka J, Uetani M, Satoh M, Mukae H.
Int J Infect Dis 103 33 - 36 2021.2
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Infectious Diseases
A 60-year-old Japanese woman presented with subacute progressive muscle pain and weakness in her proximal extremities. She was diagnosed with influenza A (H3N2) infection a week before the onset of muscle pain. At the time of admission, she exhibited weakness in the proximal muscles of the upper and lower limbs, elevated serum liver enzymes and creatinine kinase, and myoglobinuria. She did not manifest renal failure and cardiac abnormalities, indicating myocarditis. Electromyography revealed myogenic changes, and magnetic resonance imaging of the upper limb showed abnormal signal intensities in the muscles, suggestive of myopathy. Muscle biopsy of the biceps revealed numerous necrotic regeneration fibers and mild inflammatory cell infiltration, suggesting immune-mediated necrotizing myopathy (IMNM). Necrotized muscle cells were positive for human influenza A (H3N2). Autoantibody analysis showed the presence of antibodies against the signal recognition particle (SRP), and the patient was diagnosed with anti-SRP-associated IMNM. She was resistant to intravenous methylprednisolone pulse therapy but recovered after administration of oral systemic corticosteroids and immunoglobulins. We speculate that the influenza A (H3N2) infection might have triggered her IMNM. Thus, IMNM should be considered as a differential diagnosis in patients with proximal muscle weakness that persists after viral infections.
DOI： doi:10.1016/j.ijid.2020.11.153. Epub 2020 Nov 18. PMID: 33217572.
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Okuno D., Oshima K., Miyazaki T., Ashizawa N., Hirayama T., Takazono T., Saijo T., Yamamoto K., Imamura Y., Yamaguchi H., Sakamoto N., Obase Y., Izumikawa K., Yanagihara K., Mukae H.
Clinical Case Reports 9 ( 2 ) 707 - 710 2021.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Case Reports
The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.
DOI： 10.1002/ccr3.3628
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Ota Y, Obata Y, Takazono T, Tashiro M, Wakamura T, Takahashi A, Shiozawa Y, Miyazaki T, Nishino T, Izumikawa K.
BMC Nephrol 22 ( 1 ) 240 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Nephrology
Background: Hypokalemia and acute kidney injury (AKI) occur in patients administered liposomal amphotericin B (L-AMB), a wide-spectrum anti-fungicidal drug. However, the association between potassium supplementation and the occurrence of AKI in patients with hypokalemia who were administered L-AMB is not well understood. Methods: Using nationwide claims data and laboratory data, the occurrence of AKI during L-AMB treatment was retrospectively compared between patients with hypokalemia who were or were not supplemented with potassium and between those adequately or inadequately supplemented with potassium (serum potassium levels corrected to ≥3.5 mEq/L or remained < 3.5 mEq/L, respectively) before or after L-AMB treatment initiation. Results: We identified 118 patients who developed hypokalemia before L-AMB treatment initiation (43 received potassium supplementation [25 adequate and 18 inadequate supplementation] and 75 did not receive potassium supplementation), and 117 patients who developed hypokalemia after L-AMB initiation (79 received potassium supplementation [including 23 adequate and 15 inadequate supplementation] and 38 did not receive potassium supplementation). The occurrence of any stage of AKI was similar between patients with hypokalemia, regardless of potassium supplementation (i.e., before L-AMB treatment initiation [supplementation, 51%; non-supplementation, 45%; P = 0.570] or after L-AMB initiation [supplementation, 28%; non-supplementation, 32%; P = 0.671]). After adjusting for confounding factors, we found that the occurrence of any stage of AKI was not associated with potassium supplementation before L-AMB initiation (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 0.584–2.852, P = 0.528) or after L-AMB initiation (OR: 0.954, 95% CI: 0.400–2.275, P = 0.915). The occurrence of any stage of AKI tended to decline in patients with hypokalemia who were adequately supplemented with potassium (44%) before, but not after, L-AMB initiation relative to that in patients inadequately supplemented with potassium (61%), however this result was not significant (P = 0.358). Conclusion: Potassium supplementation was not associated with any stage of AKI in patients with hypokalemia who were administered L-AMB.
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Ota K, Yanagihara K, Sasaki D, Kaku N, Uno N, Sakamoto K, Kosai K, Miyazaki T, Hasegawa H, Fujita A, Tashiro M, Tanaka T, Izumikawa K, Ariyoshi K, Mukae H, Yasuda J, Morita K, Kohno S.
PLoS One 16 ( 6 ) e0252964 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
Objectives The accurate detection of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is essential for the diagnosis of coronavirus disease 2019 (COVID-19). We compared the quantitative RT-PCR results between nasopharyngeal swabs and saliva specimens. Methods A COVID-19 outbreak occurred on a cruise ship at Nagasaki port, Japan. We obtained 123 nasopharyngeal swabs and saliva each from asymptomatic or mild patients in the late phase of infection. Results The intervals from the diagnosis to the sampling were 25.5 days for nasopharyngeal swabs and 28.9 days for saliva. The positive rate was 19.5% (24/123) for nasopharyngeal swabs and 38.2% (47/123) for saliva (P = 0.48). The quantified viral copies (mean ± SEM copies/ 5 μl) were 9.3±2.6 in nasopharyngeal swabs and 920±850 in saliva (P = 0.0006). Conclusions The advantages of saliva specimens include positive rate improvement and accurate viral load detection. Saliva may be used as a reliable sample for SARS-CoV-2 detection.
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Dotsu Y, Fukuda M, Honda N, Gyotoku H, Kohno Y, Suyama T, Umeyama Y, Taniguchi H, Takemoto S, Yamaguchi H, Miyazaki T, Sakamoto N, Obase Y, Ikeda H, Ashizawa K, Mukae H.
Thorac Cancer 12 ( 2 ) 272 - 276 2021.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Thoracic Cancer
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this “oldest old” elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
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Hirayama T., Miyazaki T., Sumiyoshi M., Ashizawa N., Takazono T., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Pathogens 10 ( 1 ) 1 - 9 2021.1
Authorship：Corresponding author Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pathogens
Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.
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Okuno D., Kido T., Muramatsu K., Tokutsu K., Moriyama S., Miyamura T., Hara A., Ishimoto H., Yamaguchi H., Miyazaki T., Sakamoto N., Obase Y., Ishimatsu Y., Fujino Y., Yatera K., Matsuda S., Mukae H.
Journal of Clinical Medicine 10 ( 3 ) 1 - 10 2021
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Clinical Medicine
Influenza pneumonia, which causes acute respiratory distress syndrome and multiple organ failure, has no established management protocol. Recently, corticosteroid therapy was used to treat coronavirus disease 2019 with respiratory failure; however, its effectiveness as a treatment for influenza pneumonia remains controversial. To investigate the impact of corticosteroid therapy for the early phase of severe influenza pneumonia, we compared influenza pneumonia patients with respiratory failure treated with or without corticosteroids within 7 days after hospital admission using a Japanese nationwide administrative database. The primary endpoint was the mortality rate. The secondary endpoints were duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability weighting method with estimated propensity scores was used to minimize the data collection bias. We included 3519 patients with influenza pneumonia with respiratory failure. Of these, 875 were treated with corticosteroids. There was no significant difference between the groups regarding 30-day and 90-day mortality, duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. However, the in-hospital mortality rate was higher in the corticosteroid group. The use of systematic corticosteroid therapy in patients with influenza pneumonia was associated with a higher in-hospital mortality rate.
DOI： 10.3390/jcm10030494
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Klionsky D.J., Abdel-Aziz A.K., Abdelfatah S., Abdellatif M., Abdoli A., Abel S., Abeliovich H., Abildgaard M.H., Abudu Y.P., Acevedo-Arozena A., Adamopoulos I.E., Adeli K., Adolph T.E., Adornetto A., Aflaki E., Agam G., Agarwal A., Aggarwal B.B., Agnello M., Agostinis P., Agrewala J.N., Agrotis A., Aguilar P.V., Ahmad S.T., Ahmed Z.M., Ahumada-Castro U., Aits S., Aizawa S., Akkoc Y., Akoumianaki T., Akpinar H.A., Al-Abd A.M., Al-Akra L., Al-Gharaibeh A., Alaoui-Jamali M.A., Alberti S., Alcocer-Gómez E., Alessandri C., Ali M., Alim Al-Bari M.A., Aliwaini S., Alizadeh J., Almacellas E., Almasan A., Alonso A., Alonso G.D., Altan-Bonnet N., Altieri D.C., Álvarez É.M.C., Alves S., Alves da Costa C., Alzaharna M.M., Amadio M., Amantini C., Amaral C., Ambrosio S., Amer A.O., Ammanathan V., An Z., Andersen S.U., Andrabi S.A., Andrade-Silva M., Andres A.M., Angelini S., Ann D., Anozie U.C., Ansari M.Y., Antas P., Antebi A., Antón Z., Anwar T., Apetoh L., Apostolova N., Araki T., Araki Y., Arasaki K., Araújo W.L., Araya J., Arden C., Arévalo M.A., Arguelles S., Arias E., Arikkath J., Arimoto H., Ariosa A.R., Armstrong-James D., Arnauné-Pelloquin L., Aroca A., Arroyo D.S., Arsov I., Artero R., Asaro D.M.L., Aschner M., Ashrafizadeh M., Ashur-Fabian O., Atanasov A.G., Au A.K., Auberger P., Auner H.W., Aurelian L.
Autophagy 17 ( 1 ) 1 - 382 2021
Language：English Publishing type：Research paper (scientific journal) Publisher：Autophagy
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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Takazono T., Tashiro M., Ota Y., Obata Y., Wakamura T., Miyazaki T., Nishino T., Izumikawa K.
Scientific Reports 10 ( 1 ) 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Liposomal amphotericin B (L-AMB) is a broad-spectrum antifungal drug that is used to treat fungal infections. However, clinical evidence of its use in patients with renal failure is limited. Here, we aimed to identify factors associated with acute kidney injury (AKI) in patients administered L-AMB. We retrospectively utilized a combination of Diagnosis Procedure Combination data and laboratory data obtained from hospitals throughout Japan between April 2008 and January 2018. In total, 507 patients administered L-AMB were identified. After L-AMB treatment initiation, AKI, which was defined as a ≥ 1.5-fold increase within 7 days or ≥ 0.3 mg/dL increase within 2 days in serum creatinine according to the KDIGO criteria, was recognized in 37% of the total patients (189/507). The stages of AKI were stage 1 in 20%, stage 2 in 11%, and stage 3 in 7%. Five factors were associated with AKI of all stages: prior treatment with angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or carbapenem; concomitant administration of catecholamines or immunosuppressants; and ≥ 3.52 mg/kg/day of L-AMB dosing. Serum potassium < 3.5 mEq/L before L-AMB therapy was associated with severe AKI of stage 2 and 3. Altogether, these factors should be carefully considered to reduce the occurrence of AKI in patients administered L-AMB.
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Hirayama T., Miyazaki T., Ito Y., Wakayama M., Shibuya K., Yamashita K., Takazono T., Saijo T., Shimamura S., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.
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Roles of Elm1 in antifungal susceptibility and virulence in Candida glabrata Reviewed
Ito Y., Miyazaki T., Tanaka Y., Suematsu T., Nakayama H., Morita A., Hirayama T., Tashiro M., Takazono T., Saijo T., Shimamura S., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.
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Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria Reviewed
Sumiyoshi M., Miyazaki T., Makau J.N., Mizuta S., Tanaka Y., Ishikawa T., Makimura K., Hirayama T., Takazono T., Saijo T., Yamaguchi H., Shimamura S., Yamamoto K., Imamura Y., Sakamoto N., Obase Y., Izumikawa K., Yanagihara K., Kohno S., Mukae H.
Scientific Reports 10 ( 1 ) 2020.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-d-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.
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Nagayoshi Y., Yamamoto K., Sato S., Suyama N., Izumikawa T., Izumikawa K., Miyazaki T., Izumikawa K., Yanagihara K., Mukae H.
Geriatrics and Gerontology International 20 ( 12 ) 1138 - 1144 2020.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Geriatrics and Gerontology International
Aim: Clostridioides difficile infection worsens the outcome of older hospitalized patients; thus, its diagnosis is necessary for the nosocomial infection control. The standard diagnostic test's limited sensitivity for Clostridioides difficile infection, an enzyme immunoassay for Clostridioides difficile toxins, is of clinical concern. Glutamate dehydrogenase detection is usually tested combined with Clostridioides difficile toxins. However, the clinical significance of a positive glutamate dehydrogenase result is unclear. We evaluated the association between positive glutamate dehydrogenase results, in-hospital mortality and hospital stay length among older patients with suspected Clostridioides difficile infection. Methods: In this retrospective cohort study, we examined the data of patients who received antibiotics (except for Clostridioides difficile infection treatment) after admission and tested for Clostridioides difficile infection using an enzyme immunoassay for Clostridioides difficile toxins and glutamate dehydrogenase in a secondary care hospital located in a rural region with high aging rate, between 2015 and 2018. Results: In total, 188 patients were included (83.5% of them aged >75 years). Glutamate dehydrogenase positivity was independently associated with in-hospital mortality (adjusted odds ratio 2.19, 95% confidence interval 1.14–4.21) and hospital stay length (regression coefficient 16.0, 95% confidence interval 5.15–26.9). Clostridioides difficile toxin positivity was independently associated with hospital stay duration (regression coefficient 14.5, 95% confidence interval 0.04–29.1), unlike in-hospital mortality. Conclusions: Glutamate dehydrogenase was closely related to in-hospital mortality and prolonged hospitalization compared with Clostridioides difficile toxin. Clinicians should not neglect glutamate dehydrogenase-positive patients, even when they are Clostridioides difficile toxin-negative, and consider them as having poor prognostic potential. Geriatr Gerontol Int 2020; 20: 1138–1144.
DOI： 10.1111/ggi.14054
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Takazono T., Imamura Y., Kawakami K., Yamasaki N., Shimizu H., Usuki K., Kiyohara M., Hirayama T., Tashiro M., Hosogaya N., Saijo T., Yamamoto K., Miyazaki T., Yanagihara K., Izumikawa K., Mukae H.
Respiratory Investigation 58 ( 6 ) 488 - 494 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Respiratory Investigation
Background: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. Methods: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. Results: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients’ families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. Conclusions: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.
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Hayashi F., Kido T., Sakamoto N., Zaizen Y., Ozasa M., Yokoyama M., Yura H., Hara A., Ishimoto H., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Eishi Y., Fukuoka J., Mukae H.
Medicina (Lithuania) 56 ( 11 ) 1 - 12 2020.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Medicina (Lithuania)
Background: Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. Case presentation: A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5-12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. Conclusion: The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology. Additionally, our case suggests that cessation of dust exposure may contribute to improvement under the aforementioned conditions.
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Yoshida M., Tashiro M., Nishi K., Mishima M., Kawano K., Takazono T., Saijo T., Yamamoto K., Imamura Y., Miyazaki T., Kudo T., Yanagihara K., Mukae H., Izumikawa K.
Medical Mycology 58 ( 7 ) 965 - 972 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Medical Mycology
There is an urgent need for development of better diagnostic strategies to improve outcomes in patients with invasive pulmonary aspergillosis (IPA). We hypothesized that lung perfusion single-photon emission computed tomography (SPECT) may be more sensitive and specific than computed tomography (CT) of the chest for detection of IPA because it is an angioinvasive pulmonary infection with characteristics that are different from those of bacterial pneumonia. We used SPECT with injection of technetium-99m-labeled macroaggregated albumin ([99mTc]MAA) to measure pulmonary perfusion in noninfected mice, mice with IPA, and mice with bacterial pneumonia. Histopathologic analysis was performed to evaluate the correlation between the perfusion defect and mould invasion. We also attempted to quantitatively evaluate the SPECT images to identify differences in decreased perfusion levels in affected areas in the mouse lung. Histopathologic analysis in the IPA mouse model showed a clear match between areas with a perfusion defect and the presence of mold, indicating that the location of the perfusion defect on a SPECT image reflects angioinvasion of the mould in the lungs. Some of these perfusion defects could be seen before appearance of the infiltrate of CT images. Quantitative analysis confirmed that perfusion in the affected areas was significantly decreased in the IPA model but not in the bacterial pneumonia model (P < .0001). This imaging method may be preferable to the alternative methods presently used to identify the presence of mold in a patient’s lungs.
DOI： 10.1093/mmy/myz131
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Nakano Y., Tashiro M., Urano R., Kikuchi M., Ito N., Moriya E., Shirahige T., Mishima M., Takazono T., Miyazaki T., Izumikawa K.
Journal of Infection and Chemotherapy 26 ( 10 ) 1021 - 1025 2020.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Due to the increase in the number of azole-resistant Aspergillus fumigatus, there is an urgent need of data to predict future trends and prevent further spreading. The intercountry transfer of resistant A. fumigatus on plant bulbs have been reported. We investigated existence and characteristics of resistant isolates attached to agricultural products imported to Japan. We purchased 292 samples in Japan. All samples were screened for the existence of azole-resistant A. fumigatus. For positive isolates, minimum inhibitory concentrations of the drugs were determined. We also analyzed Cyp51A, Hmg1, and Erg6 mutations of these isolates and conducted microsatellite genotyping. Fourteen azole-resistant isolates were detected, of which 13 were cultured from flower bulbs imported from the Netherlands. Among them 5 were from 11 bulbs of Hippeastrum (45.5%), 5 were from 24 bulbs of Gladiolus (20.8%), 2 were from 4 bulbs of Ixia (50.0%), and 1 was from 22 bulbs of Tulipa (4.5%). Only 1 resistant isolate was cultured from the 10 bulbs of Narcissus (10.0%) originating in Japan. Various novel mutations including Y121F/T289A in Cyp51A with no tandem repeat in promoter region were discovered from imported strains. Our study provides important data showing that agricultural imports provide a possible route for their intercontinental spread and raises the concern that strains harboring highly diverse Cyp51A mutations might increase in clinical settings in the future.
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Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro Reviewed
Miyamura T., Sakamoto N., Kakugawa T., Taniguchi H., Akiyama Y., Okuno D., Moriyama S., Hara A., Kido T., Ishimoto H., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Tanaka Y., Mukae H.
Biochemical and Biophysical Research Communications 530 ( 3 ) 561 - 565 2020.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-β1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-β1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.
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Miyamura T., Sakamoto N., Ishida K., Kakugawa T., Taniguchi H., Akiyama Y., Okuno D., Hara A., Kido T., Ishimoto H., Miyazaki T., Matsumoto K., Tsuchiya T., Yamaguchi H., Miyazaki T., Obase Y., Ishimatsu Y., Nagayasu T., Mukae H.
Respiratory Research 21 ( 1 ) 2020.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Respiratory Research
Background: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association. Methods: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma. Results: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042). Conclusion: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.
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Hamada Y., Ueda T., Miyazaki Y., Nakajima K., Fukunaga K., Miyazaki T., Nakada-Motokawa N., Nagao M., Kawamura H., Shigemi A., Ebihara F., Kimura T., Ikegame K., Uchino M., Ikeuchi H., Takesue Y.
Mycoses 63 ( 8 ) 779 - 786 2020.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Mycoses
Background: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. Objective: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. Methods: The target voriconazole trough concentration (Cmin) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut-offs for AEs. Results: A total of 401 patients were included. Among 108 patients with high initial Cmin, voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin, voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut-offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. Conclusions: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.
DOI： 10.1111/myc.13129
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Akagi K., Yamamoto K., Umemura A., Ide S., Hirayama T., Takazono T., Imamura Y., Miyazaki T., Sakamoto N., Shiraishi H., Takahata H., Zaizen Y., Fukuoka J., Morikawa M., Ashizawa K., Teruya K., Izumikawa K., Mukae H.
AIDS Research and Therapy 17 ( 1 ) 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：AIDS Research and Therapy
Background: Vacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man. Case presentation: A 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared. Conclusion: This report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART.
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Yamashita C., Takesue Y., Matsumoto K., Ikegame K., Enoki Y., Uchino M., Miyazaki T., Izumikawa K., Takada T., Okinaka K., Ueda T., Miyazaki Y., Mayumi T.
Journal of Infection and Chemotherapy 26 ( 6 ) 596 - 603 2020.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Empirical antifungal therapy is recommended in high-risk patients who have persistent febrile neutropenia (FN) despite broad-spectrum antibiotic therapy. Based on high-quality evidence, most guidelines recommend caspofungin. The aim of this study was to clarify whether echinocandins, including micafungin, are associated with improved clinical outcomes in patients with persistent FN. We conducted a meta-analysis of randomized controlled trials (RCTs) of empirical therapy with echinocandins and non-echinocandins for FN in patients with hematological disease. The primary outcome was all-cause mortality within 7 days after completion of therapy. Secondary outcomes included treatment success, and discontinuation of therapy because of adverse events. For subgroup analysis, we compared RCTs of echinocandins with liposomal amphotericin B. Six RCTs (four that evaluated caspofungin and two that evaluated micafungin) were included in the meta-analysis. Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with non-echinocandins [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.49–0.99; RR 0.48, 95% CI 0.33–0.71, respectively]. There was no significant difference in treatment success (RR 1.09, 95% CI 0.87–1.36). Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with liposomal amphotericin B (RR 0.68, 95% CI 0.46–0.99; RR 0.53, 95% CI 0.37–0.74, respectively). In conclusion, patients with persistent FN treated with echinocandins had decreased risk of death and adverse events. Both caspofungin and micafungin may be recommended as first-line empirical antifungal therapy in these patients. However, the small number of enrolled patients and the lack of RCTs involving pediatric patients should be considered when using micafungin.
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Takazono T., Imamura Y., Kitamura M., Furugen R., Hirayama T., Tashiro M., Saijo T., Yamamoto K., Miyazaki T., Saito T., Izumikawa K., Yanagihara K., Mukae H.
Respiratory Investigation 58 ( 3 ) 212 - 215 2020.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Respiratory Investigation
Endobronchial volatile sulfur compounds in patients with lung abscess or lung cancer were measured using the Oral Chroma™ gas chromatograph. High levels of hydrogen sulfide and methyl mercaptan were observed in some patients with lung abscess but not in patients with lung cancer. Measuring endobronchial volatile sulfur compounds could be useful for the rapid diagnosis of lung abscess caused by obligate anaerobes.
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Akagi K., Miyazaki T., Oshima K., Umemura A., Shimada S., Morita K., Senju H., Tashiro M., Takazono T., Saijo T., Kurihara S., Sekino M., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Uda A., Morikawa S., Yoshikawa T., Kurosu T., Shimojima M., Saijo M., Mukae H.
BMC Infectious Diseases 20 ( 1 ) 2020.4
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Infectious Diseases
Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that commonly has a lethal course caused by the tick-borne Huaiyangshan banyang virus [former SFTS virus (SFTSV)]. The viral load in various body fluids in SFTS patients and the best infection control measure for SFTS patients have not been fully established. Case presentation: A 79-year-old man was bitten by a tick while working in the bamboo grove in Nagasaki Prefecture in the southwest part of Japan. Due to the occurrence of impaired consciousness, he was referred to Nagasaki University Hospital for treatment. The serum sample tested positive for SFTSV-RNA in the genome amplification assay, and he was diagnosed with SFTS. Furthermore, SFTSV-RNA was detected from the tick that had bitten the patient. He was treated with multimodal therapy, including platelet transfusion, antimicrobials, antifungals, steroids, and continuous hemodiafiltration. His respiration was assisted with mechanical ventilation. On day 5, taking the day on which he was hospitalized as day 0, serum SFTSV-RNA levels reached a peak and then decreased. However, the cerebrospinal fluid collected on day 13 was positive for SFTSV-RNA. In addition, although serum SFTSV-RNA levels decreased below the detectable level on day 16, he was diagnosed with pneumonia with computed tomography. SFTSV-RNA was detected in the bronchoalveolar lavage fluid on day 21. By day 31, he recovered consciousness completely. The pneumonia improved by day 51, but SFTSV-RNA in the sputum remained positive for approximately 4 months after disease onset. Strict countermeasures against droplet/contact infection were continuously conducted. Conclusions: Even when SFTSV genome levels become undetectable in the serum of SFTS patients in the convalescent phase, the virus genome remains in body fluids and tissues. It may be possible that body fluids such as respiratory excretions become a source of infection to others; thus, careful infection control management is needed.
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Tashiro M., Takazono T., Saijo T., Yamamoto K., Imamura Y., Miyazaki T., Kakeya H., Ando T., Ogawa K., Kishi K., Tokimatsu I., Hayashi Y., Fujiuchi S., Yanagihara K., Miyazaki Y., Ichihara K., Mukae H., Kohno S., Izumikawa K.
Clinical Infectious Diseases 70 ( 5 ) 835 - 842 2020.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Infectious Diseases
Background. There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). Methods. We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. Results. Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively). Conclusions. Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients. Clinical Trials Registration: UMIN000007055.
DOI： 10.1093/cid/ciz287
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Miyazaki T., Yanagihara K., Kakeya H., Izumikawa K., Mukae H., Shindo Y., Yamamoto Y., Tateda K., Tomono K., Ishida T., Hasegawa Y., Niki Y., Watanabe A., Soma K., Kohno S.
Journal of Infection and Chemotherapy 26 ( 2 ) 242 - 251 2020.2
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Infection and Chemotherapy
Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31–14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35–7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26–9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.
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Nakada-Motokawa N., Miyazaki T., Mizuta S., Tanaka Y., Hirayama T., Takazono T., Saijo T., Yamamoto K., Imamura Y., Izumikawa K., Yanagihara K., Makimura K., Takeda K., Kohno S., Mukae H.
ChemistrySelect 5 ( 3 ) 1140 - 1145 2020.1
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ChemistrySelect
Invasive fungal infections are growing causes of morbidity and mortality in immunocompromised patients. However, only one antifungal drug class has been developed in the last 30 years, extremely limiting current therapeutic options. To address unmet medical needs, we performed high-throughput screening of 9600 chemical compounds and identified an aminohydrazone derivative as a novel and potent antifungal compound. We then designed and synthesized a series of aminohydrazone derivatives, and demonstrated that 1-[(E)-[4-(3′,4′-dichlorobenxyloxy)phenyl methylidene]amino]-guanidine had the most potent inhibitory activity and exhibited a broad spectrum of antifungal activities against Candida species (including multidrug resistant C. auris), Aspergillus species, Cryptococcus neoformans, and Rhizopus oryzae. Against C. albicans, the leading cause of Candida infections, the compound had fungicidal activity for planktonic cells at 8 μg mL−1 (25 μM) and anti-biofilm activity at 34 μg mL−1 (100 μM). This study provides new insights for the development of a new drug class for the treatment of invasive fungal infections which are often refractory to conventional therapies.
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Tanaka Y., Yamamoto K., Fukuda Y., Umemura A., Yoshida M., Ideguchi S., Ashizawa N., Hirayama T., Tashiro M., Takazono T., Imamura Y., Miyazaki T., Izumikawa K., Yanagihara K., Chang B., Mukae H.
Emerging Microbes and Infections 9 ( 1 ) 2266 - 2268 2020.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Emerging Microbes and Infections
A 68-year-old Japanese man was admitted to our hospital for an acute febrile illness with shivering and impaired consciousness. He was a previous smoker and had a history of chronic obstructive pulmonary disease, for which he inhaled steroid with a long-acting bronchodilator. He had received a 23-valent pneumococcal polysaccharide vaccination 2 years previously. He was intubated and placed on a ventilator in intensive care unit because of acute respiratory failure and hypercapnia. Streptococcus pneumoniae was grown from his blood, sputum, and urine cultures, and he was diagnosed with invasive pneumococcal disease with acute renal failure. He was treated with intravenous beta-lactam and macrolide with continuous hemodiafiltration and was discharged 3 months later. The pneumococcus was identified as serotype 12F, and his serotype-specific IgG and opsonophagocytic index against serotype 12F indicating a lack of protection from IPD among PPV23 serotypes. This case highlights that some individuals may have a serotype-specific polysaccharide antibody failure that makes them susceptible to serotype 12F invasive pneumococcal disease. This case also illustrates the need for serotype-specific IgG and opsonophagocytic index titre cut-offs for each specific pneumococcal serotype in available vaccines to understand the vaccination protection for individual patients better.
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Izumikawa K., Kakeya H., Sakai F., Shibuya K., Sugita T., Takazono T., Takata T., Tashiro M., Teruya K., Nakamura S., Noguchi H., Hiruma M., Makimura K., Miyazaki T., Miyazaki Y., Yamagishi Y., Yoshida K., Watanabe A.
Medical Mycology Journal 61 ( 4 ) 61 - 89 2020
Language：English Publishing type：Research paper (scientific journal) Publisher：Medical Mycology Journal
DOI： 10.3314/mmj.20.001