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Fungi are categorized into Risk or Hazard Groups, depending on their potential to harm humans, with groupings ranging from 1 (least risky) to 4 (most risky). Similarly, Biosafety or Containment Levels ranging from 1 to 4 denote the level of control over microorganisms in laboratories. This review focuses on fungi categorized as Risk Group 3 by the Biosafety Committee of the Japanese Society for Medical Mycology. One such fungus is Blastomyces dermatitidis, which is primarily found in North America and causes blastomycosis, a condition that can result in a pulmonary or disseminated disease. It is classified as Risk Group 3, as substantiated by 11 laboratory-acquired infections and two fatalities. Cladophialophora bantiana, commonly found in Asia, causes brain abscesses and is also classified as Risk Group 3 due to a high mortality rate of 65.2%. Coccidioides immitis/posadasii, found in the Americas, can cause severe respiratory conditions with the potential for dissemination. Their Risk Group 3 classification is substantiated by a history of laboratory-acquired infections. Histoplasma capsulatum, which is found globally, causes a range of infections, from asymptomatic to fatal. Its classification as Risk Group 3 is substantiated by 81 laboratory-acquired infections and one fatality. Rhinocladiella mackenziei, which primarily affects the nervous system, has a mortality rate of 92.5% and is also classified as Risk Group 3. These fungi necessitate strict containment measures in laboratories owing to their high mortality rates or reported cases of laboratory-acquired infections and fatalities, emphasizing the critical need for heightened awareness and stringent safety protocols.

DOI： 10.3314/mmj.24.008

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BACKGROUND: Mucormycosis is a potentially fatal fungal infection, and there is limited information on its precise epidemiology and treatment practices, including the optimal dosage of liposomal amphotericin B. METHODS: A retrospective, multicenter, nationwide analysis of 82 proven and probable cases of mucormycosis was performed. Cases between 2015 and 2022 were collected from 51 hospitals in Japan by hematologists and infectious disease specialists. The study included the epidemiology, treatment details, and association between the dose of liposomal amphotericin B and the outcome. RESULTS: The lungs were the most commonly involved organ (70.7% of cases), and 35.4% of patients had disseminated disease. Rhizopus spp., Cunninghamella spp., and Mucor spp. were the most common organisms. Mortality at 4 weeks was 41.5%. The survivors had a shorter duration of neutropenia (P = .006) and less persistent hyperglycemia (P = .023). The site of infection and species of Mucorales had no detectable effect on survival. Survival did not differ between patients receiving liposomal amphotericin B at 5 mg/kg/d relative to those receiving >5 mg/kg/d (P = .625). Using Cox proportional hazards models and adjusting for confounders, the hazard ratio for the influence of >5 mg/kg/d liposomal amphotericin B on 4-week survival was 0.86 (95% CI, 0.28-2.68; P = .796) compared with 5 mg/kg/d. CONCLUSIONS: This study provides important insights into the precise epidemiology and treatment practices of mucormycosis. Treatment with liposomal amphotericin B at doses higher than 5 mg/kg/d did not improve outcomes relative to 5 mg/kg/d.

DOI： 10.1093/ofid/ofad480

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Association for Infectious Diseases  

DOI： 10.11150/kansenshogakuzasshi.r23001

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

The effectiveness of population-wide compliance to personal precautions (mask-wearing and hand hygiene) in preventing community-acquired pneumonia has been unknown. In Japan, different types of non-pharmaceutical interventions from personal precautions to containment and closure policies (CACPs, e.g. stay-at-home requests) were sequentially introduced from late January to April 2020, allowing for separate analysis of the effects of personal precautions from other more stringent interventions. We quantified the reduction in community-acquired pneumonia hospitalizations and deaths and assessed if it coincided with the timing of increased public awareness of personal precautions before CACPs were implemented. A quasi-experimental interrupted time series design was applied to non-COVID-19 pneumonia hospitalization and 30-day death data from April 2015 to August 2020 across Japan to identify any trend changes between February and April 2020. We also performed a comparative analysis of pyelonephritis and biliary tract infections to account for possible changes in the baseline medical attendance. These trend changes were then compared to multiple indicators of public awareness and behaviors related to personal precautions, including keyword usage in mass media coverage and sales of masks and hand hygiene products. Hospitalizations and 30-day deaths from non-COVID-19 pneumonia dropped by 24.3% (95% CI 14.8–32.8) and 16.1% (5.5–25.5) respectively in February 2020, before the implementation of CACPs, whereas pyelonephritis and biliary tract infections did not suggest a detectable change. These changes coincided with increases in indicators related to personal precautions rather than those related to contact behavior changes. Community-acquired pneumonia could be reduced by population-wide compliance to moderate precautionary measures.

DOI： 10.1093/pnasnexus/pgad153

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The Malassezia species are dimorphic fungi that require lipids such as olive oil for their growth. They are constituents of the normal human skin microbiota and can affix to the host or other surfaces through the establishment of biofilms. Malassezia species are accountable for superficial mycoses like folliculitis. Additionally, they are capable of causing invasive infections, such as of the bloodstream, in neonates and immunocompromised patients, albeit infrequently. Catheter-associated bloodstream infections in neonates are the most commonly reported invasive cases. Remarkably, unlike other invasive fungal infections, neutropenia and the use of broad-spectrum antibiotics do not seem to contribute to the risk of invasive Malassezia infections. Nosocomial outbreaks of Malassezia infections have been reported. While most cases of invasive Malassezia infection are fungemia, they seldom give rise to disseminated lesions in various organs. The diagnosis can be confirmed by the visualization of characteristic yeasts through histologic or cytologic examination of a biopsy or needle aspiration specimen, or via positive culture results from sterile sites. The prognosis for invasive Malassezia infection is generally favorable, with few reports of treatment failure. Nevertheless, due to the limited number of cases, evidence-based treatment recommendations are wanting. Management of invasive Malassezia infections linked to central venous catheters includes removal of the catheter, cessation of intravenous lipid emulsion, and intravenous administration of appropriate antifungal agents.

DOI： 10.3314/mmj.23-003

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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.

DOI： 10.1080/0886022X.2022.2036618

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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.

DOI： 10.1016/j.jiac.2021.06.013

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Chronic disseminated candidiasis (CDC) is a type of invasive candidiasis. CDC commonly appears in the neutrophil recovery phase after chemotherapy in patients with hematologic malignancies, and immune reconstitution inflammatory syndrome (IRIS) is thought to play a major role in CDC development. This report describes the case of a 33-year-old man with CDC as a complication of acute myeloid leukemia. We describe the clinical course, body temperature, therapy, and (1,3)-β-D-glucan (BDG) levels over the course of 22 months. He was initially treated with antifungals, but corticosteroids were added because of a persistently elevated body temperature, which we attributed to IRIS. After starting corticosteroids, his clinical condition improved, but his BDG levels became markedly elevated. We hypothesize that the suppression of the excessive immune response by corticosteroids lead to granuloma collapse, fungal release, and hematogenous dissemination, resulting in elevated BDG levels. The patient's condition gradually improved over the course of follow-up.

DOI： 10.1016/j.jiac.2021.05.005

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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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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.

DOI： 10.1016/j.jiac.2020.05.008

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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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DOI： 10.1186/s12890-017-0566-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

DOI： 10.1093/cid/cix695

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医真菌学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J05794&link_issn=&doc_id=20171122550008&doc_link_id=1390282680374743168&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282680374743168&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医真菌学会  

DOI： 10.3314/mmj.16.001

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DOI： 10.1186/s12890-016-0199-z

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DOI： 10.1016/j.diagmicrobio.2014.09.019

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DOI： 10.1128/AAC.00514-12

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DOI： 10.3109/13693786.2011.610037

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DOI： 10.1128/AAC.05394-11

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本感染症学会  

DOI： 10.11150/kansenshogakuzasshi.84.187

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本呼吸器学会  

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DOI： 10.1620/tjem.216.77

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：国立病院機構長崎医療センター  

67歳男.患者は呼吸困難を主訴とした.非小細胞肺癌Stage IIIBと診断され,イリノテカンとシスプラチンによる胸部放射線同時分割併用療法を施行して部分寛解となった.治療終了直後と,終了1年後に間質性肺炎を繰返したが,ステロイドパルス療法で軽快した.更に治療終了2年後,白質脳症,IgA腎症を併発して血管炎が疑われ,ステロイドパルス療法を行い軽快した.しかし治療終了3年後には発熱,SpO2 88%,傾眠傾向を認め入院となった.間質性肺炎,細菌性肺炎を疑い,ステロイドパルス療法,抗菌剤投与を開始するも軽快せず,細菌感染および真菌感染等の重症感染症を併発して呼吸状態は徐々に悪化し,患者は最終的に死亡となった.剖検の結果,本症例は間質性肺炎の主な原因として,放射線肺臓炎の存在と薬剤性肺炎の存在が示唆された

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BACKGROUND: The precise mechanisms of respiratory infection caused by oral anaerobic bacteria remain elusive. Unexpectedly, bacterial microbiota analysis using 16S rRNA revealed "hidden" mixed infections of anaerobic bacteria and commensal oral Streptococcus species in patients with community-acquired pneumonia (CAP). The study aimed to elucidate the mechanisms by which Prevotella intermedia exacerbates oral streptococcal pneumonia. METHODS: Oral streptococci were oropharyngeally administered with the culture supernatants of P. intermedia (PiSup) in mice to assess survival, microbial burden, inflammatory responses, and host response using unbiased bulk RNA sequencing. Additionally, genetically engineered strains of P. intermedia were used to identify pathogenic factors. RESULTS: Seven-week-old female C57BL/6J mice treated with the combination of Streptococcus spp. and PiSup exhibited significantly worse survival and increased microbial burden in the lungs and spleen compared to Streptococcus spp. and control medium. RNA sequencing of whole lung revealed disruption of neutrophilic bactericidal activity due to NADP downregulation, accompanied by reduced myeloperoxidase production in mixed infections, leading to dysfunctional neutrophil accumulation in the lungs. Notably, PiSup from strains bearing mutations in the type IX secretion pathway (ΔporT or ΔporK) failed to worsen the mixed infection. CONCLUSIONS: Prevotella intermedia exacerbates pneumonia caused by commensal oral streptococci by inducing neutrophilic dysfunction in mixed infection. Products of type IX secretion system should be investigated as novel targets independent of reported virulence factors.

DOI： 10.1093/infdis/jiaf278

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BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a severe complication of COVID-19 with a poor prognosis. In this study, we aimed to analyze the nationwide epidemiology of CAPA in Japan. METHODS: This nationwide retrospective study involved data of 98 patients with CAPA reported in 221 hospitals in Japan between January 2020 and August 2023, using both online and paper-based questionnaires. We investigated the clinical characteristics of CAPA, assessed outcomes using Kaplan-Meier curves, and identified independent predictors of 90-day mortality using Cox proportional hazards analysis. RESULTS: The median age of the patients with CAPA was 71 years, and 71.4% were men. The positivity rates for β-D-glucan and serum galactomannan antigen were 59.1% and 68.4%, respectively, while chest computed tomography revealed cavities in 25.5% of patients. The 30-day and 90-day mortality rates were 50.0% and 55.1%, respectively. Kaplan-Meier analysis showed that the mortality rate of patients treated with echinocandin monotherapy was significantly higher than that of patients treated with other antifungals (log-rank test, p=0.04). Multivariate analysis identified a neutrophil count of ≥10,000/μL (hazard ratio [HR]: 2.67, 95% confidence interval [CI]: 1.49-4.89) and echinocandin monotherapy (HR: 2.06, 95% CI: 1.01-3.93) as independent predictors of 90-day mortality. Patients treated with echinocandin monotherapy were older, and Aspergillus spp. was not isolated in half of these patients. CONCLUSION: This study provides a comprehensive overview of CAPA in Japan. Appropriate antifungal therapy is essential to improve the prognosis of patients with CAPA.

DOI： 10.1016/j.jiac.2025.102739

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

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.

DOI： 10.1016/j.resinv.2025.02.008

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Chronic pulmonary aspergillosis (CPA) is a refractory infectious disease that occurs in patients with mildly compromised immunity or an underlying pulmonary disease. The mortality rate associated with pulmonary aspergillosis has also increased. In the diagnosis and management of CPA, numerous challenges persist. The Aspergillus IgG antibody test is a highly accurate adjunctive diagnostic method for CPA that has been approved in Japan since 2024. However, the diagnostic accuracy for non-fumigatus species is not as high as that for Aspergillus fumigatus. The development of an auxiliary diagnostic method for non-fumigatus CPA is a pressing concern. Azole-resistant strains, related species, and challenges in long-term therapy are significant issues. Currently, most azole-resistant strains in Japan are patient-route strains that harbor CYP51A mutations. Although the prevalence of azole-resistant strains transmitted via environmental routes remains limited, ongoing surveillance and monitoring are essential. Furthermore, the lack of health insurance coverage for drug susceptibility testing is another critical issue. The recommended treatment duration for CPA is a minimum of 6-12 months; however, maintaining long-term therapy is challenging because of the higher incidence of adverse events associated with antifungal agents than with other antimicrobial medications. Additionally, CPA co-infection in patients with non-tuberculosis mycobacteria has recently become a concern owing to poor prognosis and drug-drug interactions between antifungal and antimycobacterial agents. Therefore, the development of treatment agents with improved safety profiles and fewer drug-drug interactions is highly desirable.

DOI： 10.1016/j.resinv.2025.04.005

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INTRODUCTION: Despite the ongoing efforts to refine treatment durations and methods for patients with chronic pulmonary aspergillosis, the clinical use of antifungal agents remains unclear. This study aimed to describe the treatment practices, trajectories, and prognoses of newly diagnosed patients with chronic pulmonary aspergillosis. METHODS: Data from a longitudinal database from hospitals in Japan was used. The target population included patients who started antifungal treatment following their initial diagnosis of pulmonary aspergillosis, pulmonary aspergilloma, or chronic necrotizing pulmonary aspergillosis between October 2015 and September 2017. We described patient characteristics and treatment practices. RESULTS: Of the 680 patients analyzed, 253 (37.2%), 231 (34.0%), 155 (22.8%), 31 (4.6%), and 10 (1.5%) patients received the initial treatment with voriconazole, itraconazole, micafungin, caspofungin, and liposomal amphotericin B, respectively. Over 50% of the patients initially treated with micafungin or caspofungin switched to azoles within a month. Of the patients treated with antifungal agents, only 46.8% continued treatment for 6 months, indicating a lower retention rate. The overall mortality rate at 1 year was 24.7%. The median treatment duration of initial treatment until switching was 83 days (interquartile range [IQR], 159) for voriconazole and 162 days (IQR, 310) for itraconazole, indicating a significant variation in treatment duration. Notably, 15.7% (76/484) of the patients underwent a treatment switch between voriconazole and itraconazole in the initial azole treatment group. CONCLUSIONS: Our findings highlight the challenges associated with sustaining long-term antifungal treatment.

DOI： 10.1007/s40121-024-01094-y

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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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BACKGROUND: Azithromycin has favorable effects on critical respiratory diseases owing to its antimicrobial and anti-inflammatory properties. During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, azithromycin was frequently administered before specific treatments were developed. However, the efficacy of this treatment has not been verified. We retrospectively investigated the effects of its intravenous (IV) administration in patients with severe/critical COVID-19 using the National Administrative Database of Japan during the first wave (February-April 2020). METHODS: Patients were categorized based on whether they received IV azithromycin within three days of hospitalization. An overlap weighting method with estimated propensity scores was used to reduce bias. RESULTS: Among the 830 patients with severe/critical COVID-19, 148 (17.8 %) received azithromycin, and 682 (82.2 %) did not. After adjustment, the use of azithromycin was associated with a shorter duration of intensive care unit (ICU) management (-3.48 days, 95 % confidence interval [CI]: 4.59 to -2.38). However, other endpoints, including mortality rate, duration of mechanical ventilation, and duration of hospital stay, did not suggest any associations. Furthermore, of the 115 ICU patients, 27 (23.5 %) were treated with IV azithromycin and 88 (76.5 %) were not. After adjustment, azithromycin was associated with favorable outcomes, including reduced in-hospital mortality (odds ratio [OR], 0.45, 95 % CI: 0.22 to 0.92), 30-day mortality (OR, 0.46, 95 % CI: 0.22 to 0.94), and a shorter duration of ICU management (-2.94 days, 95 % CI: 5.15 to -0.73). CONCLUSION: We verified that IV azithromycin was associated with favorable impact in patients with COVID-19 requiring ICU management.

DOI： 10.1016/j.rmed.2024.107834

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Exophiala dermatitidis is an emerging black fungus that causes pulmonary infections that may be underestimated by conventional culture methods. We encountered one case that initially appeared to be yeast and was misidentified as Rhodotorula spp. using a commercial identification kit. Thus, genetic identification and clinical background investigations were conducted on 46 strains of Rhodotorula spp. The sequences of the internal transcribed spacer and large-subunit RNA genes (D1/D2 regions) of 43 isolates, excluding two environmental isolates and one difficult-to-culture isolate, were determined and genetically identified. Notably, 22 isolates were identified as E. dermatitidis and misidentified as Rhodotorula spp. using the conventional method. Based on the exclusion criteria, the clinical information of 11 patients was retrospectively reviewed. Five cases (definite) had definite exacerbation of pulmonary infections due to E. dermatitidis, and six cases (possible) had undeniable infections. Of the 11 cases of pulmonary infection suggested to be caused by E. dermatitidis, comorbidities included two cases of chronic pulmonary aspergillosis (CPA), three cases of pulmonary non-tuberculous mycobacterial (NTM) infection and one case of pulmonary nocardiosis, suggesting a trend towards simultaneous detection of chronic pulmonary infections. Steroid and immunosuppressive drug use was observed in five cases, and β-D-glucan elevation was observed in three of five definite cases of pulmonary infections due to E. dermatitidis. The possibility of E. dermatitidis infection should be considered when Rhodotorula spp. are isolated from cultures of airway-derived specimens, and, in addition to CPA and NTM, identification of E. dermatitidis may be important in chronic pulmonary infections.

DOI： 10.1111/myc.13804

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Objectives: In the present study, we aimed to clarify the mechanisms by which periodontal pathogens, particularly Prevotella intermedia, induce severe neutrophilic inflammation. In addition, we aimed to test the efficacy of macrolides, which has not been resolved in the neutrophilic inflammation induced by P. intermedia. Methods: NCl-H292 human airway epithelial cells were pre-incubated with clarithromycin for 2 h before incubation with P. intermedia supernatants. Then, C-X-C motif chemokine ligand 8 (CXCL8) transcription and interleukin (IL)-8 production were measured. To elucidate the signaling pathway, mitogen-activated protein kinase inhibitors were added to the cell culture, and the cells were subjected to Western blotting. Results:P. intermedia supernatants promoted CXCL8 transcription and IL-8 production, and the reactions were significantly suppressed by clarithromycin pretreatment. Only trametinib, the selective mitogen-activated extracellular signal-regulated kinase inhibitor, downregulated CXCL8 transcription and IL-8 production. Furthermore, Western blotting revealed that stimulation with P. intermedia supernatants specifically induces extracellular signal-regulated kinases (ERK) 1/2 phosphorylation, which is suppressed by clarithromycin pretreatment. Notably, the interference analysis revealed that ERK3 might be dispensable for IL-8 production under the stimulation of P. intermedia supernatants. Conclusions: Our results provide new insight into the mechanism underlying P. intermedia-induced production of IL-8 from human airway epithelial cells. Furthermore, macrolides might have therapeutic potential in regulating periodontal pathogen-induced neutrophilic inflammation in the lungs.

DOI： 10.3390/antibiotics13090909

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

INTRODUCTION: The diagnostic tools of nucleic acid amplification tests and antigen tests have been extensively employed for the detection of Coronavirus disease 2019 (COVID-19). Although the reverse-transcriptase polymerase chain reaction (RT)-PCR test has high sensitivity and specificity, it is a time-consuming and labor-intensive process. On the other hand, antigen tests are simple and prompt, however, their low sensitivity and potential for false positives have been identified as limitations. In light of these factors, the development of novel tests that combine speed and clinical dependability is a promising prospect. METHODS: Surface plasmon field-enhanced fluorescence spectroscopy (SPFS) excites chromophores by means of an enhanced electromagnetic field induced on a gold film surface. It enables the highly sensitive measurement of biomarkers in a short and simple 20-min window. In this study, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SPFS-based antigen test targeting the SARS-CoV-2 nucleocapsid protein was performed and evaluated in 25 patients with COVID-19 and 10 non-infected controls. RESULTS: A positive correlation was observed between antigen levels determined by SPFS and RNA levels determined via RT-PCR. The sensitivity values were 100 %, 92 %, and 62.5 %; and the specificity values were 100 %, 90 %, and 100 %; for nasopharyngeal swabs, nasal swabs, and saliva specimens when the cutoff values were set to 65.1, 0.2, and 1.5 pg/mL, respectively. No clinically problematic cross-reactivity with analogous coronaviruses was observed. CONCLUSIONS: The SARS-CoV-2 SPFS antigen test showed excellent clinical diagnostic accuracy for nasopharyngeal and nasal swabs, with a rapid turnaround.

DOI： 10.1016/j.jiac.2024.08.019

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Candida vulturna is a recently discovered and not widely documented ascomycetous yeast phylogenetically related to the outbreak-causing and multidrug-resistant Candida auris. A middle-aged Japanese man with no discernible immunodeficiency was admitted to hospital with ileal diverticulitis. Following laparoscopic right hemicolectomy against abscess formation on postoperative day (POD) 7, continuous fungemia occurred due to Candida haemulonii, identified using a conventional method by confirming the biochemical phenotype. Micafungin was initiated; however, the fungus was persistently isolated from blood cultures. Eventually, the antifungal agent was changed to a combination of liposomal amphotericin B (L-AMB) and caspofungin (CPFG), which cleared the infection, and no pathogens were detected in the blood cultures on POD 31. Contrast-enhanced computed tomography showed septic emboli in the lungs and spleen; however, no evidence of vasculitis was observed. Moreover, sequential echocardiography did not reveal any signs of infectious endocarditis. Finally, CPFG and L-AMB were administered to the patient for 7 and 9 weeks, respectively, during which the patient's symptoms did not relapse. The strain was later genetically identified as C. vulturna. This case report illustrates a clinical presentation of C. vulturna and provides the diagnostic approach and treatment methods for this pathogen.

DOI： 10.1016/j.heliyon.2024.e31464

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UNLABELLED: Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.

DOI： 10.1128/spectrum.03614-23

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background:

Non-acquired immunodeficiency syndrome (AIDS)-defining cancers (NADCs) in patients infected with human immunodeficiency virus (HIV) have recently attracted attention because of the improved survival of this patient population. To obtain accurate data, a longitudinal study is warranted for the nationwide surveillance of the current status and national trend of NADCs in patients infected with HIV in Japan.

Setting:

An annual nationwide surveillance of NADCs in patients infected with HIV-1 in Japan from 1999 to 2021.

Methods:

An annual questionnaire was sent to 378 HIV/AIDS referral hospitals across Japan to collect data (clusters of differentiation 4-positive lymphocytes, time of onset, outcomes, and antiretroviral therapy status) of patients diagnosed with any of the NADCs between 1999and 2021.

Results:

The response and case-capture rates for the questionnaires in 2021 were 37.8% and 81.2%, respectively. The number of reported NADC cases subsequently increased since the beginning of this study. Evaluation of the case counts of NADCs demonstrated a high incidence of lung, colorectal, gastric, and liver cancers as the top four cancers. Pancreatic cancer (0.63), lung cancer (0.49), and leukemia (0.49) had the highest mortality rates among the NADCs. Trends of NADCs in terms of transmission routes were maintained over the years in men who have sex with men compared to heterosexual males and females.

Conclusion:

We demonstrated an increasing trend in the incidence of NADCs over a period of 23 years in Japan. The current data highlighted the importance of raising awareness regarding cancer management for patients infected with HIV in Japan.

DOI： 10.1097/qai.0000000000003389

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A 63-year-old male received a third allogeneic hematopoietic stem cell transplantation with voriconazole prophylaxis for relapsed acute myeloid leukemia. He developed septic arthritis without any typical skin lesions due to fungal infection on day 42. Treatment with liposomal amphotericin B was initiated following surgical debridement; however, he died of progressive fungal infection. Ribosomal DNA sequencing identified Fusarium solani species complex (FSSC) harboring voriconazole resistance. This clinical course indicates that breakthrough invasive fusariosis (azole-resistant FSSC infection) needs to be considered as a pathogen when patients with hematological malignancies develop septic arthritis without typical skin lesions during voriconazole prophylaxis.

DOI： 10.1016/j.lrr.2024.100483

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUND: Pre-transplant vaccination is recommended for patients undergoing solid organ transplantation (SOT). While appropriate vaccination protocols are implemented at some facilities, transplantation is sometimes performed with inadequate preoperative vaccine management. Vaccination rates vary across facilities, but those of SOT centers in Japan have never been investigated. This study aimed to conduct a nationwide questionnaire survey to assess pre- and post-transplant vaccination policies among SOT facilities in Japan. METHODS: The survey was conducted from September to November 2022. All registered (n = 221) solid organ (namely, the lungs, liver, kidneys, pancreas, heart, and small intestine) transplant facilities were asked to complete a web-based survey. RESULTS: The survey response rate was 70.2 %. Live and inactivated vaccines were recommended at 64.9 % and 68.9 % of the responding facilities, respectively. The following vaccines were incorporated into the vaccination protocols of facilities: pneumococcal vaccine, 31.7 % (13-valent pneumococcal conjugate vaccine) and 65.4 % (23-valent pneumococcal polysaccharide vaccine); hepatitis B virus vaccine, 67.3 %; severe acute respiratory syndrome coronavirus 2 vaccine, 73.1 %; influenza vaccine, 73.1 %; and zoster vaccines, 23.1 %. The reasons for unresponsiveness to vaccinations included inadequate time before transplantation (60.3 %), cost burden (41.1 %), high number of vaccinations (21.9 %), no recognition of the need for vaccination (17.9 %), and the requirement to explain the need for vaccination (15.2 %). CONCLUSIONS: Our study revealed gaps in vaccination practices across nationwide facilities in Japan. The findings indicate the importance of promoting scheduled efficiency and encouraging the national health system to reduce vaccine costs with the support of public subsidies.

DOI： 10.1016/j.vaccine.2023.11.033

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Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are diseases caused by Aspergillus infection, and CPA can develop from ABPA in some cases. We herein report a patient with CPA overlapping with ABPA. Serum cytokine levels were evaluated at 4 time points: the ABPA diagnosis, CPA diagnosis, 6 months after the start of voriconazole (VRCZ), and 12 months after re-administration of VRCZ. Interleukin (IL)-13 levels decreased upon glucocorticoid treatment, whereas IL-25 and IL-33 levels decreased rapidly with the initiation of antifungals. Early antifungal therapy may be important to control disease progression and prevent CPA overlap.

DOI： 10.2169/internalmedicine.2234-23

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BACKGROUND: Cryptococcal meningitis (CM) is an invasive fungal infection with a poor prognosis that often occurs in both healthy individuals and compromised hosts, such as patients infected with human immunodeficiency virus (HIV). Unlike CM in HIV patients, evidence regarding CM in non-HIV patients is limited to small retrospective studies. OBJECTIVE: To identify the pretreatment prognostic factors for CM in non-HIV patients. METHODS: We conducted a large retrospective analysis of CM in non-HIV patients using data from a nationwide Japanese database. The study included hospitalized patients diagnosed with CM between 1 April 2010 and 31 March 2017. All-cause mortality was compared between patients with CM with and without HIV infection. Poor diagnostic factors were analysed in the non-HIV CM group. RESULTS: Overall, 533 (64 HIV and 469 non-HIV) patients met the criteria. The mortality rate at 90 days was significantly lower in the HIV group (6.3% vs. 25.4% p = .0002). In a logistic regression analysis of the non-HIV group, age ≥ 65 y (odds ratio [OR] 2.37, 95% CI 1.17-4.78), impaired consciousness (Japan Coma Scale ≥1) (OR 2.25, 95% CI 1.29-3.93), haemodialysis (OR 3.53, 95% CI 1.12-11.20) and previous corticosteroid usage (OR 2.40, 95% CI 1.37-4.19) were associated with poor prognosis at 30 days after diagnosis. CONCLUSION: More caution is suggested when treating non-HIV with CM in older patients with impaired consciousness, previous corticosteroid usage and haemodialysis.

DOI： 10.1111/myc.13658

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Data on antifungal susceptibility of Cryptococcus neoformans are limited in Japan. A total of 89 C. neoformans strains isolated from 83 non-human immunodeficiency virus-infected patients with cryptococcosis between 1997 and 2021 in Nagasaki, Japan, were investigated. Using the reference method M27-Ed4 by the Clinical and Laboratory Standards Institute, the minimum inhibitory concentration for 90% of isolates of fluconazole, itraconazole, voriconazole, amphotericin B, and flucytosine were 4, 0.125, 0.06, 0.5, and 4 µg/ml, respectively, which were below the reported epidemiological cutoff values, without any detectable non-wild-type strains. Our findings imply no increasing trend of antifungal-resistant C. neoformans in Nagasaki, Japan.

DOI： 10.1093/mmy/myad100

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

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.

DOI： 10.1097/md.0000000000034858

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ekir.2023.06.008

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Following endobronchial examination, a young mine supervisor was treated with antibiotics for a pulmonary nontuberculous mycobacterial infection for approximately 1 year. However, a review of the radiological findings, which had not been previously assessed, revealed a different possibility. Accordingly, pulmonary resection was performed, enabling histopathological analysis, which showed numerous yeast-like fungi. Given the history of a stay in the southwestern United States for 2 months in 2009, 8 years previously, coccidioidomycosis was strongly suspected and the diagnosis was subsequently confirmed by serology and polymerase chain reaction testing of the excised specimen. Here, we report an educational case emphasizing the importance of meticulous medical history-taking and awareness of endemic mycoses in other countries in the context of globalization.

DOI： 10.7883/yoken.JJID.2023.073

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Inhaled liposomal antimicrobials are known to cause hypersensitivity pneumonitis. Amikacin liposome inhalation suspension (ALIS) is a promising novel antimicrobial agent against refractory Mycobacterium avium complex infections. The frequency of drug-induced lung injury caused by ALIS is relatively high. To date, no reports of ALIS-induced organizing pneumonia diagnosed by bronchoscopy are available. We report a case of a 74-year-old female patient presenting with non-tuberculous mycobacterial pulmonary disease (NTM-PD). She was treated with ALIS for refractory NTM-PD. Fifty-nine days after starting ALIS, the patient developed a cough, and her chest radiographs indicated deterioration. She was diagnosed with organizing pneumonia based on pathological findings of the lung tissues obtained by bronchoscopy. After switching from ALIS to amikacin infusion, her organizing pneumonia improved. It is difficult to distinguish between organizing pneumonia and an exacerbation of NTM-PD based on chest radiography alone. Therefore, it is essential to perform an active bronchoscopy for diagnosis.

DOI： 10.1016/j.jiac.2023.04.013

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A 65-year-old Japanese woman repeatedly withdrew and resumed antibiotics against pulmonary non-tuberculous mycobacterial infection caused by Mycobacterium intracellulare for more than 10 years. Although she continued to take medications, her respiratory symptoms and chest computed tomography indicated an enlarged infiltrative shadow in the lingular segment of the left lung that gradually worsened over the course of a year or more. Bronchoscopy was performed and mycobacterial culture of the bronchial lavage fluid was negative, whereas Exophiala dermatitidis was detected. After administration of oral voriconazole was initiated, the productive cough and infiltrative shadow resolved. There are no characteristic physical or imaging findings of E. dermatitidis, and it often mimics other chronic respiratory infections. Thus, when confronting refractory non-tuberculous mycobacterial cases, it might be better to assume other pathogenic microorganisms, including E. dermatitidis, and actively perform bronchoscopy.

DOI： 10.1016/j.jiac.2023.03.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：長崎大学医学部  

日本では、免疫クロマトグラフィアッセイとして喀痰を用いるRAPIRUN Streptococcus pneumoniae(RAPIRUN)と尿を用いるBinaxNow Streptococcus pneumoniae(BinaxNow)が使用されている。本研究では、臨床現場における両検査法の有効性を比較した。2011年9月～2015年5月に長崎県内の六つの医療機関で下気道症状のある成人呼吸器感染症患者192例(男性124例、女性68例、平均70.0±14.5歳)を対象とする前向き観察研究を行った。これらの患者から喀痰と尿を採取し、RAPIRUNとBinaxNowおよび喀痰の定量培養を行い、RAPIRUNとBinaxNowの性能比較を行った。主な基礎疾患は慢性呼吸器不全(52.6%)、心疾患(14.1%)、悪性腫瘍(11.5%)、糖尿病(9.4%)であった。192例のうち167例(87.0%)が肺炎であった。192例中86症例(44.8%)の喀痰培養検査で肺炎球菌が証明された。RAPIRUNとBinaxNowの陽性症例数はそれぞれ83例と57例であった。RAPIRUNの感度、特異度はそれぞれ84.9%、90.6%、BinaxNowはそれぞれ55.8%、91.5%であり、RAPIRUNはBinaxNowに比較し感度が有意に優れ、特異度はほぼ同等であった。RAPIRUNは喀痰の定量培養で菌量が増加するに従い、陽性率が増加する傾向にあり、特に10^7CFU/mL以上の菌量が多い症例では98.2%と高い陽性率を示した。さらに、10^3～10^4CFU/mLと比較的低い菌量でも肺炎球菌を検出することができた。喀痰から多くの菌量の肺炎球菌が検出されるような症例では、菌量が多ければ多いほどRAPIRUNがBinaxNowよりもより高い検出能を有することが証明された。BinaxNowでは同様の傾向は認められなかったことから、呼吸器感染症患者で喀痰排出がある患者では、RAPIRUNのより積極的な使用を行うことが患者予後の改善に寄与すると思われた。

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DOI： 10.1016/j.idcr.2023.e01739

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Aspergillus udagawae is a cryptic species of Aspergillus section Fumigati. Here, we report a case of canaliculitis with isolated A. udagawae. Fungal canaliculitis is a rare lacrimal disease, and its clinical features are poorly understood. The causative fungus was initially misclassified as Aspergillus thermomutatus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) but was finally identified as A. udagawae by β-tubulin genetic analysis. The patient showed rapid improvement and did not experience relapse after drainage alone, without antifungal therapy. A. udagawae has low virulence, which may be related to the minimally invasive nature of the infection.

DOI： 10.3314/mmj.23-00004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Tuberculous meningitis is an infectious disease with high mortality. Literature describing intrathecal therapy for tuberculous meningitis is scarce. We herein report a case of refractory tuberculous meningitis in a 52-year-old woman with underlying neuropsychiatric systemic lupus erythematosus. Despite systemic treatment with anti-tuberculosis drugs and dexamethasone, her meningeal irritation deteriorated. Intrathecal isoniazid and prednisolone administration was therefore initiated, and the symptoms of severe meningeal irritation improved along with head magnetic resonance imaging and cerebrospinal fluid findings. This case report highlights the efficacy of intrathecal isoniazid and steroid injections for refractory tuberculous meningitis, particularly in patients with severe meningeal irritation.

DOI： 10.2169/internalmedicine.1917-23

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

It is challenging to diagnose infected aneurysm in the early phase. This study aimed to describe the clinical and microbiological characteristics of infected aneurysm, and to elucidate the difficulties in diagnosing the disease.

Methods

Forty-one cases of infected aneurysm were diagnosed in Nagasaki University Hospital from 2005 to 2019. Information on clinical and microbiological characteristics, radiological findings, duration of onset, and type of initial computed tomography (CT) imaging conditions were collected. Factors related to diagnostic delay were analyzed by Fisher’s exact test for categorical variables or by the Wilcoxon rank-sum test for continuous variables.

Results

Pathogens were identified in 34 of 41 cases; the pathogens were Gram-positive cocci in 16 cases, Gram-negative rods in 13 cases, and others in five cases. Clinical characteristics did not differ in accordance with the identified bacteria. At the time of admission, 16 patients were given different initial diagnoses, of which acute pyelonephritis (n = 5) was the most frequent. Compared with the 22 patients with an accurate initial diagnosis, the 19 initially misdiagnosed patients were more likely to have been examined by plain CT. The sensitivities of plain CT and contrast-enhanced CT were 38.1% and 80.0%, respectively.

Conclusions

In cases of infected aneurysm, diagnostic delay is attributed to non-specific symptoms and the low sensitivity of plain CT. Clinical characteristics of infected aneurysm mimic various diseases. Contrast-enhanced CT should be considered if infected aneurysm is suspected.

DOI： 10.1186/s12879-022-07567-0

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Other Link： https://link.springer.com/article/10.1186/s12879-022-07567-0/fulltext.html

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：長崎医学会  

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Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age &gt; 50 years, body mass index &gt; 25 kg/m2, hypertension, tachycardia with pulse rate &gt; 100/min or blood pressure &gt; 135 mmHg at triage, and &gt;3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization.

DOI： 10.3390/jcm11185444

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Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] &lt; 4000/μL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC &lt; 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF.

DOI： 10.3390/v14081807

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BACKGROUND: Cryptococcal meningitis (CM) is an opportunistic infectious disease that occurs in immunocompromised hosts, not only in patients living with HIV, but also in patients without HIV. The evidence regarding the treatment for CM in patients without HIV is mainly found in small retrospective studies and is extremely limited. OBJECTIVES: In the present study, we compared the efficacy of liposomal amphotericin B (L-AMB) alone and in combination with flucytosine (5-FC) for the induction treatment of CM in patients without HIV. PATIENTS/METHODS: Data was gathered from the Japanese Diagnosis Procedure Combination database obtained from hospitals throughout Japan. The study included 517 patients without HIV but having CM who fulfilled the inclusion and exclusion criteria. We analyzed the average effect of adding 5-FC to L-AMB treatment using the survival time within 14 days of the diagnosis after adjustment of the baseline clinical characteristics with associations with both selections of the treatment and the prognosis. RESULTS: A total of 146 and 217 CM patients received L-AMB and L-AMB with 5-FC, respectively, within 7 days of diagnosis. L-AMB with 5-FC showed better prognosis than L-AMB on day 14 (mortality 6% vs. 11%, hazard ratio, 0.5775; 95% confidence interval, 0.2748-1.213; p = 0.1, Wald test). CONCLUSIONS: From the results of this real-world database study, we revealed that the combination therapy of 5-FC on L-AMB for induction therapy might have an advantage on the survival time of NHNT patients with CM as well as PLHIV patients with CM.

DOI： 10.1111/myc.13493

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Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are important fungal infections caused by Aspergillus species. An overlap of ABPA and CPA has been reported; therefore, it is critical to determine whether the main pathology is ABPA or CPA and whether antifungals are required. In this study, we investigated whether the serum cytokine profile is useful for understanding the pathology and for differentiating between these diseases. We compared the various serum cytokine levels among healthy subjects and patients diagnosed with asthma, ABPA, or CPA at Nagasaki University Hospital between January 2003 and December 2018. In total, 14 healthy subjects, 19 patients with asthma, 11 with ABPA, and 10 with CPA were enrolled. Interleukin (IL) -5 levels were significantly higher in patients with ABPA than in those with CPA, and IL-33 and tumor necrosis factor (TNF) levels were significantly higher in patients with CPA than in those with asthma (p &lt; 0.05, Dunn's multiple comparison test). The sensitivity and specificity of the IL-10/IL-5 ratio (cutoff index 2.47) for diagnosing CPA were 70% and 100%, respectively. The serum cytokine profile is useful in understanding the pathology of ABPA and CPA, and the IL-10/IL-5 ratio may be a novel supplemental biomarker for indicating the pathology of CPA.

DOI： 10.3390/jof8050436

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INTRODUCTION: Nursing facilities are vulnerable to coronavirus disease 2019 (COVID-19) due to the congregate nature of their housing, the older age of the residents, and the variety of their geriatric chronic conditions. Little is known about the impact of nursing facility COVID-19 on the local health system. METHODS: We collected data of COVID-19 cases in Nagasaki city from April 15, 2020 to June 30, 2021. We performed universal screening of the healthcare workers (HCWs) and the users of nursing facilities, once the first case of COVID-19 was detected within that facility. The community-dwelling people received testing if they had symptoms or if they were suspected of having close contact with the positive cases. The epidemiological survey for each COVID-19 case was performed by the public health officers of the local public health center. RESULTS: Out of 111,773 community-dwelling older adults (age ≥ 65 years) and 20,668 nursing facility users in Nagasaki city, we identified 358 and 71 COVID-19 cases, and 33 and 12 COVID-19 deaths, respectively, during the study period. The incidence rate ratios (IRRs) for COVID-19 and its deaths among the nursing facility users were 1.07 (95% confidence interval (CI), 0.82-1.39) and 1.97 (95%CI, 0.92-3.91) compared with the community-dwelling older adults. Four clusters, which had more than 10 COVID-19 cases, accounted for 60% (65/109) of the overall cases by the HCWs and the users. CONCLUSIONS: The prevention of COVID-19 clusters is important to reduce the number of COVID-19 cases and deaths among the nursing facility population.

DOI： 10.1016/j.jiac.2022.04.010

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.

DOI： 10.3390/v14020279

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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.

DOI： 10.1016/j.jiac.2021.07.008

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Real-time RT-PCR is the most commonly used method for COVID-19 diagnosis. However, serological assays are urgently needed as complementary tools to RT-PCR. Hachim et al. 2020 and Burbelo et al. 2020 demonstrated that anti-nucleocapsid(N) SARS-CoV-2 antibodies are higher and appear earlier than the spike antibodies. Additionally, cross-reactive antibodies against N protein are more prevalent than those against spike protein. We developed a less cross-reactive immunoglobulin G (IgG) indirect ELISA by using a truncated recombinant SARS-CoV-2 N protein as assay antigen. A highly conserved region of coronaviruses N protein was deleted and the protein was prepared using an E. coli protein expression system. A total of 177 samples collected from COVID-19 suspected cases and 155 negative control sera collected during the pre-COVID-19 period were applied to evaluate the assay's performance, with the plaque reduction neutralization test and the commercial SARS-CoV-2 spike protein IgG ELISA as gold standards. The SARS-CoV-2 N truncated protein-based ELISA showed similar sensitivity (91.1% vs. 91.9%) and specificity (93.8% vs. 93.8%) between the PRNT and spike IgG ELISA, as well as also higher specificity compared to the full-length N protein (93.8% vs. 89.9%). Our ELISA can be used for the diagnosis and surveillance of COVID-19.

DOI： 10.3390/ijerph18189630

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BACKGROUND: This study aimed to clarify the involvement of anaerobes in aspiration pneumonia by measuring volatile sulfur compounds (VSCs), which are metabolites of anaerobic bacteria in the mouth. METHODS: This study included 84 older adult patients (mean age, 82.5 ± 7.34 years) who had dementia and were hospitalized for more than 6 months. We measured the VSCs in the patient's mouth with Oral Chroma and obtained the data of pneumonia development in the past 6 months. We also evaluated the association or correlation of VSCs and some factors which might be the risk factors of aspiration pneumonia. RESULTS: The development of pneumonia had no significant association with the VSCs in the patient's mouth. CONCLUSION: The present pilot study suggests that anaerobes might not be the main causative pathogens of aspiration pneumonia in older adult patients.

DOI： 10.1016/j.resinv.2021.08.006

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本環境感染学会  

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In April 2020, a coronavirus disease (COVID-19) outbreak occurred on the cruise ship Costa Atlantica in Nagasaki, Japan. Our outbreak investigation included 623 multinational crewmembers onboard on April 20. Median age was 31 years; 84% were men. Each crewmember was isolated or quarantined in a single room inside the ship, and monitoring of health status was supported by a remote health monitoring system. Crewmembers with more severe illness were hospitalized. The investigation found that the outbreak started in late March and peaked in late April, resulting in 149 laboratory-confirmed and 107 probable cases of infection with severe acute respiratory syndrome coronavirus 2. Six case-patients were hospitalized for COVID-19 pneumonia, including 1 in severe condition and 2 who required oxygen administration, but no deaths occurred. Although the virus can spread rapidly on a cruise ship, we describe how prompt isolation and quarantine combined with a sensitive syndromic surveillance system can control a COVID-19 outbreak.

DOI： 10.3201/eid2709.204596

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A 68-year-old woman developed systemic blisters while receiving treatment for nephrotic syndrome. As she also developed marked liver dysfunction and disseminated intravascular coagulation, she was admitted to our hospital. She was diagnosed with varicella zoster virus (VZV) infection. Treatment was administered in the intensive-care unit, but the patient died on day 24 post-admission after severe VZV infection. A post-mortem examination showed micro-abscesses and necrosis caused by varicella zoster infection in multiple organs, including the liver, kidneys, and gastrointestinal tract. Because VZV infection can become severe in immunocompromised patients, careful consideration is needed for the prevention and treatment of the viral infection.

DOI： 10.2169/internalmedicine.7332-21

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Septic shock is characterized by dysregulated vascular permeability. We hypothesized that the vascular permeability of endothelial cells (ECs) would be regulated by serotonin via serotonin-Rho-associated kinase (ROCK) signaling. We aimed to determine the impact of 5-hydroxyindoleacetic acid (5-HIAA) on septic shock as a novel biomarker. Plasma 5-HIAA levels and disease severity indices were obtained from 47 patients with sepsis. The association between 5-HIAA levels and severity indices was analyzed. Permeability upon serotonin stimulation was determined using human pulmonary microvascular ECs. 5-HIAA were significantly higher in septic shock patients than in patients without shock or healthy controls (p = 0.004). These elevated levels were correlated with severity indexes (SOFA score [p < 0.001], APACHE II [p < 0.001], and PaO2:FiO2 [p = 0.02]), and longitudinally associated with worse clinical outcomes (mechanical ventilation duration [p = 0.009] and ICU duration [p = 0.01]). In the experiment, serotonin increased the permeability of ECs, which was inhibited by the ROCK inhibitor (p < 0.001). Serotonin increases vascular permeability of ECs via ROCK signaling. This suggests a novel mechanism by which serotonin disrupts endothelial barriers via ROCK signaling and causes the pathogenesis of septic shock with a vascular leak. Serotonin serves as a novel biomarker of vascular permeability.

DOI： 10.1038/s41598-021-93649-z

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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.

DOI： 10.1016/j.jiac.2021.03.008

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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.

DOI： 10.1186/s12882-021-02450-7

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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.

DOI： 10.1186/s12879-021-06279-1

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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.

DOI： 10.1007/s10157-020-01989-3

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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.

DOI： 10.1016/j.jiac.2020.11.027

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/md9.0000000000000055

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

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： 10.1016/j.ijid.2020.11.153

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Acute respiratory distress syndrome (ARDS) is characterized by dysregulated vascular permeability. The clinical outcomes remain poor, and the disease burden is widespread. We demonstrated that plasma 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, is a pivotal severity indicator of ARDS. Serotonin is an effector of cellular contraction and a modulator of vascular permeability. Plasma 5-HIAA levels were significantly elevated in severe ARDS cases with shock status (p = 0.047) and positively correlated with SOFA (p < 0.0001) and APACHE-II score (p < 0.0001). In the longitudinal analysis, plasma 5-HIAA levels were also a strong independent predictor of mortality rate (p = 0.005). This study indicates that plasma 5-HIAA is a biomarker of ARDS severity and highlights the importance of evaluating vascular leakage levels for ARDS treatment.

DOI： 10.3389/fmed.2021.785409

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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.

DOI： 10.1371/journal.pone.0252964

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OBJECTIVES: The accurate prevalence of acquired immunodeficiency syndrome (AIDS)-defining illnesses (ADIs) in human immunodeficiency virus (HIV)-infected patients has not been well investigated. Hence, a longitudinal nationwide surveillance study analyzing the current status and national trend of opportunistic complications in HIV-infected patients in Japan is warranted. METHODS: A nationwide surveillance of opportunistic complications in HIV-infected patients from 1995 to 2017 in Japan was conducted. An annual questionnaire was sent to 383 HIV/AIDS referral hospitals across Japan to collect information (CD4+ lymphocyte count, time of onset, outcome, and antiretroviral therapy [ART] status) of patients diagnosed with any of 23 ADIs between 1995 and 2017. RESULTS: The response and case capture rates of the questionnaires in 2017 were 53% and 76%, respectively. The number of reported cases of opportunistic complications peaked in 2011 and subsequently declined. Pneumocystis pneumonia (38.7%), cytomegalovirus infection (13.6%), and candidiasis (12.8%) were associated with the cumulative incidence of ADIs between 1995 and 2017. The mortality rate in HIV-infected patients with opportunistic complications substantially decreased to 3.6% in 2017. The mortality rate was significantly higher in HIV patients who received ART within 14 days of diagnosis of complications than in those who received ART 15 days after diagnosis (13.0% vs. 3.2%, p < 0.01). CONCLUSIONS: We have demonstrated a 23-year trend of a newly diagnosed AIDS status in Japan with high accuracy. The current data reveal the importance of Pneumocystis pneumonia as a first-onset illness and that early initiation of ART results in poor outcomes in HIV patients in Japan.

DOI： 10.1371/journal.pone.0256452

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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.

DOI： 10.1080/22221751.2020.1830716

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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.

DOI： 10.1016/j.resinv.2020.05.003

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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.

DOI： 10.1038/s41598-020-72135-y

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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.

DOI： 10.1038/s41598-020-66620-7

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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.

DOI： 10.1016/j.resinv.2020.01.007

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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.

DOI： 10.1186/s12879-020-05012-8

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3314/mmj.20.001

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Severe fever with thrombocytopenia syndrome virus (SFTSV) can be transmitted between humans. We describe a case of severe fever with thrombocytopenia syndrome in which SFTSV RNA was detected in semen after its disappearance from serum. Our findings indicate possible sexual transmission of this emerging virus.

DOI： 10.3201/eid2511.190061

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：九州山口薬学会  

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The Aspergillus-specific lateral-flow device (AspLFD) test is a newly developed point-of-care diagnostic method for invasive pulmonary aspergillosis. However, evidence of the diagnostic performance of the AspLFD for chronic pulmonary aspergillosis (CPA) is limited. Therefore, we conducted a retrospective study to investigate this in comparison with the galactomannan (GM) β-d-glucan (BDG) test. Fifty patients with chronic pulmonary aspergillosis and 65 patients with respiratory disease, as a control, were enrolled in this study. The majority of the CPA disease entities were chronic pulmonary aspergillosis (64.0%, n = 32), followed by subacute invasive pulmonary aspergillosis (IPA) (20.0%, n = 10) and simple pulmonary aspergilloma (SPA) (16.0%, n = 8). The sensitivity and specificity of the AspLFD test in serum samples were 62.0% and 67.7%, respectively. The GM test (cutoff index, 1.54) showed a sensitivity of 22% and a specificity of 92.3%, while the sensitivity and specificity of the BDG test (cutoff, 19.3 pg/ml) were 48% and 90.8%, respectively. In bronchoalveolar lavage fluid samples, the AspLFD test showed a sensitivity of 66.7% and a specificity of 69.2%, while those of the GM test (cutoff index, 0.6) were 72.7% and 83.1%, respectively. The Aspergillus precipitating antibody test had 70% sensitivity. Unlike the Aspergillus precipitating antibody test, the AspLFD on serum samples showed similar sensitivity to non-fumigatus Aspergillus species. Patients with false-positive results for the AspLFD on serum samples were of a significantly higher age and had a higher prevalence of cavitary lesions in chest computed tomography than patients with negative results in the control group. Given the results in this study, the performance of the AspLFD using serum was acceptable as a point-of-care test for the diagnosis of CPA.

DOI： 10.1128/JCM.00095-19

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There have been conflicting reports of false positive galactomannan assay results in patients with systemic cryptococcosis. We sought to determine the frequency of GM positivity in patients with pulmonary cryptococcosis and confirm the source of this cross-reactivity in vitro. We conducted a retrospective study to elucidate the rate of galactomannan (GM) false positivity and cause in a cohort of 29 patients with pulmonary cryptococcal disease. The production of GM cross-reacting substances by clinical isolates and laboratory isolates of C. neoformans was tested in vitro. The mean serum GM index (Platelia Aspergillus) in patients with pulmonary cryptococcosis was 1.06, with 16 (55.2%) of patients having values above the positive cutoff value of 0.5. GM index values significantly decreased after treatment of cryptococcosis. There was no significant correlation between galactomannan and cryptococcal glucuronoxylomannan antigen (Eiken Latex test) results. Culture supernatants from clinical isolates and wild-type C. neoformans did not react in the GM assay; however, growth in the presence of 6% sodium chloride induced the production of cross-reacting GM antigens in culture supernatants from clinical isolates, wild type and a glucuronoxylomannan-deficient mutant of C. neoformans, but not in culture supernatants from a galactoxylomannan-deficient strain. Our results support the cross-reactivity of cryptococcal galactoxylomannan with the serum GM assay in vitro and in patients with pulmonary cryptococcal infection.

DOI： 10.1007/s10096-019-03469-3

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Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a 'self-eating' process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species.

DOI： 10.3389/fmicb.2019.00027

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We clarified the performance of a cryptococcal glucuronoxylomannan (GXM) antigen test using bronchoalveolar lavage fluid (BALF) samples, in an HIV-negative Japanese population. Between March 2008 and December 2014, we examined cryptococcal GXM antigens in both serum and BALF specimens from 429 cases at Nagasaki University hospital. The diagnoses, underlying diseases, chest computed tomography findings, and cryptococcal GXM antigen test results were retrospectively investigated. Twenty-three patients were confirmed to have pulmonary cryptococcosis, another six were clinically diagnosed with cryptococcosis because they were seropositive for the GXM antigen, and five possible cryptococcosis cases had BALF samples that were positive for the GXM antigen and serum samples that were negative. The test's sensitivities for detecting cryptococcal GXM antigens in serum and BALF samples, for confirmed cases, were 73.9% and 82.6%, respectively, and their respective specificities were 98.5% and 97.8%. Three of the five putative patients with cryptococcosis were treated with antifungal agents; the pulmonary lesions decreased in size in all treated patients. Both the BALF and serum GXM antigen titers showed positive correlations with the lesion sizes; however, the serum antigen titers showed a higher correlation (r = 0.490, P = .0033) than did the BALF titres (r = 0.312, P = .0724). The rate of GXM-positive BALF samples was higher than the rate for serum samples, especially for patients with pulmonary lesion diameters ≤25 mm. Testing for the presence of the cryptococcal GXM antigen in BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

DOI： 10.1093/mmy/myx010

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Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but rarely in Japan. In recent years, however, the number of histoplasmosis patients in Japan has increased. In addition, to our knowledge, there are no previous reports of increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with histoplasmosis. We report a case series of histoplasmosis in three Japanese temporary workers in Manzanillo, Mexico. All three patients developed a persistent high fever and general fatigue. Laboratory tests showed increased C-reactive protein levels and mild liver dysfunction. All patients also showed increased soluble interleukin-2 receptor (sIL-2R) levels. Chest computed tomography revealed multiple nodules in both lung fields. All patients were positive for serum anti-Histoplasma antibodies, and two patients were positive for Histoplasma on polymerase chain reaction tests. After treatment that included antifungals, their conditions gradually improved and laboratory data normalized. Although one patient developed respiratory failure, this patient recovered with antifungal therapy in combination with methylprednisolone. Serum sIL-2R levels in all patients gradually declined to normal levels, indicating their recovery from Histoplasma infection. From our experience with these patients, sIL-2R levels may be a useful biomarker for patients with histoplasmosis.

DOI： 10.1016/j.jiac.2017.03.006

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DOI： 10.1093/jac/dkx020

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本化学療法学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.mmcr.2016.11.001

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本移植学会  

症例は60代男性で、アルコール性肝硬変による腹水貯留加療のため5年前から不定期に受診した。入院6ヵ月前頃より腹部膨満、下腿浮腫が増悪し、受診し、体重増加、腹水貯留を認め利尿薬が開始された。CTで肝S3に20mm大、5mm大、S2に10mm大の肝細胞癌(HCC)を認めた。肝予備能不良でHCCに対する肝動脈化学塞栓療法(TACE)、ラジオ波焼灼術(RFA)治療は困難と判断された。長男が肝提供を希望し、6ヵ月以上の断酒期間を経た後、生体肝移植術を行う方針とした。頭部CTで副鼻腔炎の所見を認めクラリスロマイシンを投与した。右咽頭痛を訴え急性咽頭炎と診断しアシクロビルを静脈内投与した。治癒10日後に肝拡大左葉グラフト移植術を施行した。術後は免疫抑制剤減量を行っていない。帯状疱疹の再発予防でバラシクロビル、真菌感染予防でアムホテリシンBを投与した。移植3ヵ月目に自己免疫性溶血性貧血を認めたため免疫抑制を強化し、バラシクロビル投与を継続した。6ヵ月後に減量し、現在も内服継続中である。経過中、咽頭部帯状疱疹再発は認めていない。

DOI： 10.11386/jst.51.2-3_218

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00083&link_issn=&doc_id=20160926360018&doc_link_id=%2Fcl8isoke%2F2016%2F005102%2F019%2F0218-0221%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2016%2F005102%2F019%2F0218-0221%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jiac.2016.04.001

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本環境感染学会  

DOI： 10.4058/jsei.31.241

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DOI： 10.1016/j.jiac.2015.11.012

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DOI： 10.1093/mmy/myv093

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DOI： 10.2169/internalmedicine.55.6787

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DOI： 10.2169/internalmedicine.55.6228

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DOI： 10.2169/internalmedicine.55.6250

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DOI： 10.2169/internalmedicine.55.6969

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：長崎大学医学部保健学科  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：長崎大学医学部保健学科  

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DOI： 10.2169/internalmedicine.54.2292

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DOI： 10.1016/j.jiac.2013.10.016

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DOI： 10.7883/yoken.66.312

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Language：English   Publishing type：Research paper (scientific journal)  

Cryptococcosis is primarily caused by two Cryptococcus species, i.e., Cryptococcus neoformans and C. gattii. Both include several genetically diverse subgroups that can be differentiated using various molecular strain typing methods. Since little is known about the molecular epidemiology of the C. neoformans/C. gattii species complex in Japan, we conducted a molecular epidemiological analysis of 35 C. neoformans isolates from non-HIV patients in Nagasaki, Japan and 10 environmental isolates from Thailand. All were analyzed using URA5-restriction fragment length polymorphism (RFLP) and multilocus sequence typing (MLST). Combined sequence data for all isolates were evaluated with the neighbor-joining method. All were found to be serotype A and mating type MATα. Thirty-two of the 35 clinical isolates molecular type VNI, while the three remaining isolates were VNII as determined through the URA5-RFLP method. Thirty-one of the VNI isolates were identified as MLST sequence type (ST) 5, the remaining one was ST 32 and the three VNII isolates were found to be ST 43. All the environmental isolates were identified as molecular type VNI (four MLST ST 5 and six ST 4). Our study shows that C. neoformans isolates in Nagasaki are genetically homogeneous, with most of the isolates being ST 5.

DOI： 10.3109/13693786.2012.708883

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本化学療法学会  

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DOI： 10.1111/j.1749-6632.2012.06758.x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3109/13693786.2010.548084

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Total pages：204   Responsible for pages：166-172   Book type：Textbook, survey, introduction

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Total pages：xx, 1094p   Responsible for pages：55-59   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：360   Responsible for pages：286-289   Book type：Textbook, survey, introduction

ASIN

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Total pages：vii, 317p   Responsible for pages：p144-146   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：xxvi, 1065p   Responsible for pages：p59-63   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：58, 2151p   Responsible for pages：p231-232   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Responsible for pages：97   Book type：Textbook, survey, introduction

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Total pages：694   Responsible for pages：344-348   Book type：Textbook, survey, introduction

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Responsible for pages：p116-122   Book type：Textbook, survey, introduction

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Responsible for pages：p61-67   Language：Japanese   Book type：Textbook, survey, introduction

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Responsible for pages：p295-301   Book type：Textbook, survey, introduction

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Responsible for pages：p212-216   Book type：Textbook, survey, introduction

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Total pages：117   Responsible for pages：36-38, 64-71   Book type：Textbook, survey, introduction

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Responsible for pages：p41-47   Book type：Textbook, survey, introduction

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Responsible for pages：p199-205   Book type：Textbook, survey, introduction

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Responsible for pages：p210-214   Book type：Textbook, survey, introduction

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Responsible for pages：p72-76   Book type：Textbook, survey, introduction

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Responsible for pages：p53-54   Book type：Textbook, survey, introduction

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Responsible for pages：p43-49   Book type：Textbook, survey, introduction

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Responsible for pages：p187-191   Book type：Textbook, survey, introduction

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Responsible for pages：p131-137   Book type：Textbook, survey, introduction

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Responsible for pages：p58-64   Book type：Textbook, survey, introduction

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Responsible for pages：p129-132   Book type：Textbook, survey, introduction

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Total pages：11, 391p   Responsible for pages：p59-70   Language：Japanese   Book type：Textbook, survey, introduction

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Total pages：xxii, 1198p   Responsible for pages：p761-766   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：xvii, 282p   Responsible for pages：p49-51   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：309p   Responsible for pages：p205-212   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：283p   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：x, 140p   Responsible for pages：p49-51   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：707p   Responsible for pages：p506-514   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Total pages：322p   Responsible for pages：p103-107   Language：Japanese   Book type：Textbook, survey, introduction

CiNii Books

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(株)文光堂  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医歯薬出版(株)  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00060&link_issn=&doc_id=20240501010015&doc_link_id=issn%3D0039-2359%26volume%3D289%26issue%3D4%26spage%3D279&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D289%26issue%3D4%26spage%3D279&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本臨床微生物学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(株)北隆館  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(株)北隆館  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(株)じほう  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：(株)日本医事新報社  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(株)総合医学社  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：(株)エスアールエル  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：(株)近代出版  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：サラヤ(株)  

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Language：Japanese   Publisher：日本感染症学会西日本地方会・日本感染症学会中日本地方会・日本化学療法学会西日本支部  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(公社)日本化学療法学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(一社)日本感染症学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：(有)科学評論社  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：日本感染症学会西日本地方会・日本感染症学会中日本地方会・日本化学療法学会西日本支部  

J-GLOBAL

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J-GLOBAL

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Authorship：Lead author,　Corresponding author  

J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本医真菌学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：日本感染症学会西日本地方会・日本感染症学会中日本地方会・日本化学療法学会西日本支部  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本環境感染学会  

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Language：Japanese   Publisher：(一社)日本病院薬剤師会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04451&link_issn=&doc_id=20210517360004&doc_link_id=%2Fdg4hppha%2F2021%2F005705%2F004%2F0505-0507%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2021%2F005705%2F004%2F0505-0507%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：栄研化学(株)  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)近代出版  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(株)総合医学社  

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Language：Japanese   Publisher：緑膿菌感染症研究会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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Language：Japanese   Publisher：(一社)日本医真菌学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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