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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 < 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., Journal of Fungi, 8(5), art. no. 436; 2022

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 immunocomp, BMC Infectious Diseases, 21(1), art. no. 573; 2021

The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who underwent bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan–Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia., Journal of Clinical Medicine, 10(16), art. no. 3552; 2021

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., International Journal of Environmental Research and Public Health, 18(18), art. no. 9630; 2021

Targeted intrapulmonary delivery of drugs may reduce systemic toxicity and improve treatment efficacy. In the current study, we evaluated the effects of a combination treatment consisting of inhalation of aerosolized liposomal amphotericin B (L-AMB) with intraperitoneal administration of micafungin (MCFG) against murine invasive pulmonary aspergillosis. The combination of aerosolized L-AMB with intraperitoneal MCFG significantly improved the survival rate, and the fungal burdens and histopathology findings after this treatment were superior to those of the control and both monotherapy groups., identifier:Antimicrobial agents and chemotherapy, 53(8), pp.3508-3510; 2009

Severe pneumonia is found in simultaneous influenza pneumonia and bacterial infection, and suggests a relationship with immunological mechanisms. Here, we performed two-dimensional gel electrophoresis to detect immunological molecules related to the fulminant pneumonia caused by influenza virus and Streptococcus pneumoniae co-infection in mice. We found two spots that were expressed strongly in co-infected mouse lungs, compared with S. pneumoniae or influenza virus singly infected mouse lungs. The spots were analysed by mass spectrometry, and identified as alpha-1 anti-trypsin (A1AT), known as an anti-protease for neutrophil-derived proteolytic enzymes, and creatine kinase, which reflects a greater degree of lung damage and cell death. A1AT expression was increased significantly, and proteolytic enzymes from neutrophils, such as neutrophil elastase, myeloperoxidase and lysozyme, were also secreted abundantly in influenza virus and S. pneumoniae co-infected lungs compared with S. pneumoniae or influenza virus singly infected lungs. These data suggest that A1AT may play a central role as a molecule with broad anti-inflammatory properties, and regulation of the neutrophil-mediated severe lung inflammation is important in the pathogenesis of co-infection with influenza virus and bacteria., identifier:Clinical and Experimental Immunology, 152(2), pp.364-371; 2008

Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, ]although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination., Pathogens, 10(1), art.no.23; 2021

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., International Journal of Infectious Diseases, 103, pp.33-36: 2020

Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections., Scientific Reports, 10(1), art.no.3814; 2020

BACKGROUND: Vacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man. CASE PRESENTATION: A 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared. CONCLUSION: This report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART., AIDS research and therapy, 17(1), art.no.38; 2020

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 infect, BMC infectious diseases, 20(1), art.no.281; 2020

Candida peritonitis is a crucial disease, however the optimal antifungal therapy regimen has not been clearly defined. Peritoneal fibrosis (PF)can be caused by abdominal surgery, intra-abdominal infection, and malignant diseases, and is also widely recognized as a crucial complication of long-term peritoneal dialysis. However, the influence of PF on Candida peritonitis prognosis remains unknown. Here, we evaluated the severity of Candida peritonitis within the context of PF and the efficacy of micafungin using mice. A PF mouse model was generated by intraperitoneally administering chlorhexidine gluconate. Candida peritonitis, induced by intraperitoneal inoculation of Candida albicans, was treated with a 7-day consecutive subcutaneous administration of micafungin. Candida infection caused a higher mortality rate in the PF mice compared with the control mice on day 7. Proliferative Candida invasion into the peritoneum and intra-abdominal organs was confirmed pathologically only in the PF mice. However, all mice in both groups treated with micafungin survived until day 20. Micafungin treatment tends to suppress inflammatory cytokines in the plasma 12 h after infection in both groups. Our results suggest that PF enhances early mortality in Candida peritonitis. Prompt initiation and sufficient doses of micafungin had good efficacy for Candida peritonitis, irrespective of the underlying PF., Scientific Reports, 9(1), art.no.9331; 2019

Background: Rapid diagnosis and appropriate treatment of Munchausen syndrome is important not only for the patient but also for health care workers because a delay in diagnosis can worsen patients' clinical outcomes, and result in a substantial medical cost. Case presentation: A young and previously healthy 24-year-old Japanese woman, a nurse, presented with complaints of refractory abscess on her left upper limb for 3 months. A physical examination on admission revealed low-grade fever and a subcutaneous abscess in her left forearm. Laboratory data suggested mild systemic inflammation and liver dysfunction, but no abnormalities of the immune system, including changes in the number of lymphocytes and neutrophils, neutrophil phagocytic capacity, and natural killer (NK) cell activity, were observed. A human immunodeficiency virus test was also negative. Multiple modalities, including positron emission tomography-computed tomography, failed to detect any cause and focus of infection except her left upper limb. Streptococcus mitis and Prevotella buccae were detected from the wound, but no microorganisms were detected in a blood culture. The cellulitis promptly resolved; however, exacerbation of the subcutaneous abscess with polymicrobial bacteremia repeatedly occurred unexpectedly. Because of this puzzling clinical course, the possibility of self-injury was finally suspected. Three syringes with needles, with a turbid liquid, were found in our patient's bag. Enterobacter cloacae and Enterococcus faecalis were detected in the liquid, and an analysis via repetitive element sequence-based polymerase chain reaction determined that Enterococcus faecalis in the wound and syringe contents were genetically identical. She was diagnosed as having Munchausen syndrome and treated with the collaboration of a psychiatrist. She finally confessed that she had injected her own saliva and toilet water into the drip line and wound. Conclusions: This case report is valuable in that it is t, Journal of Medical Case Reports, 13(1), art.no.287; 2019

The Open Microbiology Journal, 12, pp.321-322; 2018

Background: There is conflicting evidence regarding the benefit of adjunctive corticosteroid therapy in patients with Mycoplasma pneumoniae pneumonia. We hypothesised that corticosteroid therapy could reduce mortality and length of stay (LOS) in such patients. Methods: Adult patients with M. pneumoniae pneumonia from January 2010 to December 2013 were identified from the Japanese Diagnosis Procedure Combination inpatient database. The effects of low-dose and high-dose corticosteroid therapies on mortality, LOS, drug costs and hyperglycaemia requiring insulin treatment were evaluated using propensity score analyses. Results: Eligible patients (n=2228) from 630 hospitals were divided into no-corticosteroid (n=1829), low-dose corticosteroid (n=267) and high-dose corticosteroid (n=132) groups. The propensity score-matched pairs were generated from no-corticoid and low-dose corticoid groups (251 pairs), or no-corticoid and high-dose corticosteroid groups (120 pairs). Adjunctive corticosteroid therapy did not decrease 30-day mortality. In addition, both low-dose and high-dose corticosteroid therapies were associated with increases in LOS. Furthermore, hyperglycaemia requiring insulin treatment and drug cost increased with corticosteroid use. Conclusions: Adjunctive treatment with low-dose or high-dose corticosteroids may not be beneficial in M. pneumoniae pneumonia., BMC Pulmonary Medicine, 17, 219; 2017

Background Mycoplasma pneumoniae strains with resistance to macrolides have been spreading worldwide. Here, we aimed to clarify which antimicrobial agent is a better treatment for patients with M. pneumoniae pneumonia in a setting with large epidemics of macrolide resistance. Methods Adult patients hospitalized with laboratory-confirmed M. pneumoniae pneumonia from 2010 to 2013 were identified from the Japanese Diagnosis Procedure Combination national database. Drug switching, length of stay (LOS), 30-day mortality, and total costs for patients who underwent macrolide, quinolone, and tetracycline therapy were compared using propensity score analyses. Results Eligible patients (N = 1650) from 602 hospitals were divided into the macrolide group (n = 508), quinolone group (n = 569), or tetracycline group (n = 573). We found that 52.8%, 21.8%, and 38.6% of patients in the macrolide, quinolone, and tetracycline groups, respectively, had to switch drugs (P <.0001). There was no significant difference in the LOS and the 30-day mortality rates among these 3 groups. Cost was highest in the quinolone group (P =.0062). The propensity score-matched pairs (n = 487×2) generated from the quinolone and tetracycline groups also showed a lower proportion of patients who require switches in the quinolone group than in the tetracycline group (21.2% vs 39.6%, P <.0001) but not in the LOS, mortality, and cost. Conclusions There were no significant differences in the LOS and mortality among any antimycoplasmal drugs as initial treatment for hospitalized M. pneumoniae pneumonia patients despite the lower switching rate in the quinolone group., Clinical Infectious Diseases, 65(11), pp.1837-1842; 2017

Background: Macrolides have antibiotic and immunomodulatory activities, which may have a favorable effect on the clinical outcome of patients with infections, including influenza. This study aimed to evaluate the effects of combination therapy with an anti-influenza agent, oseltamivir, and a single-dose formulation of azithromycin (AZM), which has been used for influenza-related secondary pneumonia, on influenza patients. The primary endpoint was a change in the expression levels of inflammatory cytokines. Secondary endpoints were the time required for resolution of influenza-related symptoms, incidence of complications, and adverse reactions. Methods: Patients with seasonal influenza were enrolled in this multicenter, open-label, randomized study. Patients were stratified according to the presence of a high risk factor and were randomized to receive combination therapy with oseltamivir plus an extended-release formulation of AZM (combo-group) or oseltamivir monotherapy (mono-group). Results: We enrolled 107 patients and randomized them into the mono-group (56 patients) or the combo-group (51 patients). All patients were diagnosed with influenza A infection, and none of the patients had comorbid pneumonia. Statistically significant differences were not observed in the expression levels of inflammatory cytokines and chemokines between the 2 groups. The maximum temperature in the combo-group was lower than that in the mono-group on day 3 through day 5 (p = 0.048), particularly on day 4 (p = 0.037). Conclusion: To our knowledge, this is the first prospective, randomized, clinical trial of oseltamivir and AZM combination therapy for influenza. Although the difference in inflammatory cytokine expression level was not statistically significant, combination therapy showed an early resolution of some symptoms. Name of registry: University hospital Medical Information Network (UMIN). Trial Registration no.: UMIN000005371., PLoS ONE, 9(3), e91293; 2014

Daptomycin is inactivated by pulmonary surfactant, but its effectiveness in hematogenous pulmonary infection has been poorly studied. The potential therapeutic application was evaluated in a methicillin-resistant Staphylococcus aureus (MRSA) hematogenous pulmonary infection mouse model. Compared with control results, daptomycin improved survival (P<0.001) and decreased the number of abscesses and bacteria in the lungs (P<0.01). Daptomycin may be an effective therapeutic option for MRSA hematogenous pulmonary infection., Antimicrobial Agents and Chemotherapy, 57(6), pp.2841-2844; 2013

Aspergillus udagawae and A. fumigatus share similar morphological features but they differ genetically. There is also an important clinical distinction as A. udagawae is less sensitive to amphotericin B than A. fumigatus. We encountered a rare case of bronchial infection due to A. udagawae that was successfully treated with voriconazole. An 82-year-old woman with diabetes mellitus complained of bloody sputum. Bronchoscopy revealed a white plugged region at the origin of the right bronchi B5. Cytological study revealed a clot composed of filamentous fungi and Aspergillus spp. was detected by culture. Molecular analysis revealed that the causative agent was A. udagawae, and voriconazole was used for the treatment. In comparison to A. fumigatus, the A. udagawae strain isolated in this case was less sensitive to amphotericin B, less virulent in immunosuppressed mice, and more sensitive to hydrogen peroxide, features that are almost identical to those of the previously reported isolates of the fungus. We should be aware of the emergence of new Aspergillus species that might pose a clinical threat., Medical Mycology, 50(6), pp.631-636; 2012

Diagnosing chronic pulmonary aspergillosis (CPA) is complicated, and there are limited data available regarding the identification of galactomannan (GM) in clinical specimens to assist the detection of this infection. The purpose of this study was to evaluate the detection of GM in bronchoalveolar lavage fluid (BALF) and serum and to assess its utility for diagnosing CPA. We retrospectively reviewed the diagnostic and clinical characteristics of 144 patients, with and without CPA, in Nagasaki University Hospital, Japan, whose BAL and serum specimens were examined for the presence of GM. The Platelia Aspergillus enzyme immunoassay (PA EIA) was performed according to the manufacturer's instructions. The mean values of BALF GM antigen were 4.535 (range, 0.06214.120) and 0.430 (range, 0.0629.285) in CPA (18) and non-CPA (126) patients, respectively. The mean values of serum GM antigen were 1.557 (range, 0.2325.397) and 0.864 (range, 0.0288.956) in CPA and non-CPA patients, respectively. PA EIA of BALF is superior to the test with serum, with the optimal cut-off values for BALF and serum of 0.4 and 0.7, respectively. The sensitivity and specificity of PA EIA in BALF at a cut-off of 0.4 were 77.2% and 77.0%, respectively, whereas with serum at a cut-off of 0.7, they were 66.7% and 63.5%, respectively. GM testing using BALF showed reasonable sensitivity and specificity as compared to that using serum. Thus, assessing GM levels in BALF may enhance the accuracy of diagnosing CPA., Medical Mycology, 50(8), pp.811-817; 2012

The utility of active surveillance cultures (ASCs) in respiratory wards, that do not have an associated intensive care unit (ICU), and the usefulness of the BD GeneOhm MRSA™ system for rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) have not been previously evaluated in Japan. ASCs using conventional culture methods and the BD GeneOhm MRSA™ assay were conducted in adult inpatients between May 11, 2009 and November 10, 2009 in a respiratory ward, without an associated ICU, in Nagasaki University Hospital. The infection and colonization rates of MRSA acquired in this respiratory ward were both investigated. A total of 159 patients were investigated. Of these, 12 (7.5%) were found positive for MRSA by the BD GeneOhm MRSA™ assay and 9 (5.7%) were found positive by a conventional culture test upon admission. All cases were MRSA-colonized cases and crosstransmission was not found to occur during hospitalization. The BD GeneOhm MRSA™ assay had a sensitivity of 100% and a specificity of 98%. ASCs in our respiratory ward revealed that MRSA was brought in from other sites in some cases, and that current infection control measures in Nagasaki University Hospital are effective. The BD GeneOhm MRSA™ assay was proven to be a useful and rapid detection tool for MRSA., Japanese Journal of Infectious Diseases, 65(1), pp.33-36; 2012

Although the diagnostic significance of isolating Aspergillus spp. from respiratory cultures has been studied in immunocompromised hosts with invasive pulmonary aspergillosis (IPA), little is known of such infections in immunocompetent patients with other forms of aspergillosis. In this study of adult pneumology ward patients, we examined the association between Aspergillus spp. and disease prevalence. Laboratory records from April 1998 to March 2009 were reviewed to identify patients with Aspergillus spp. in respiratory samples. Correlations between the isolated species and clinical characteristics of patients were evaluated. During the study period, 165 Aspergillus spp. isolates were detected in the respiratory cultures of 139 patients. Of these patients, 62 (45%) were colonized with Aspergillus spp. and displayed no clinical symptoms of aspergillosis, while 77 (55%) had a form of pulmonary aspergillosis, characterized as either chronic necrotizing pulmonary aspergillosis (CNPA) (48%), aspergilloma (29%), IPA (13%), or allergic bronchopulmonary aspergillosis (ABPA) (10%). The dominant species were Aspergillus fumigatus (41%), A. niger (32%), and A. versicolor (12%). A. fumigatus was most commonly isolated in patients with IPA, aspergilloma, and CNPA, whereas A. niger was the dominant species in colonized patients and those with ABPA. Isolation of an Aspergillus spp. from respiratory samples does not confirm it as the etiologic pathogen because airway colonization by Aspergillus spp. is a common feature in several chronic lung diseases. Repeated isolation of the identical Aspergillus species and detection of anti-Aspergillus antibodies and/or Aspergillus antigens in sera are needed to determine the isolate represents the etiologic agent of disease., Medical Mycology, 49(6), pp.581-587; 2011

The mechanisms of severe pneumonia caused by co-infection of bacteria and influenza A virus (IAV) have not been fully elucidated. We examined apoptosis and inflammatory responses in a murine model for pneumococcal pneumonia during IAV infection. Inflammation, respiratory epithelium apoptosis, and inflammatory-cell infiltration increased in a time dependent manner in the lungs of mice co-infected with Streptococcus pneumoniae and IAV, in comparison with those infected with either S. pneumoniae or IAV. According to appearance of terminal deoxynucleotidyl transferase dUTPmediated nick-end labeling positive cells, caspase-3 and -8 were activated 24 h after S. pneumoniae infection, and caspase-3 activation decreased after 48 h, whereas inflammatory cytokine levels continued to increase in co-infected mice. In contrast, in mice infected with either IAV or S. pneumoniae, apoptosis and activation of factors related to caspase-3 peaked at 48 h. Furthermore, Fas-associated death domain was significantly expressed in the lungs of co-infected mice 24 h after S. pneumoniae infection. These data suggest that early onset of apoptosis and its related factors play important roles in fulminant pneumonia resulting from bacterial pneumonia complicated by co-infection with influenza virus., Japanese Journal of Infectious Diseases, 64(6), pp.451-457; 2011

A 58-year-old woman was admitted with refractory fever despite receiving broad-spectrum antibiotics. She had hypoxemia, severe anemia, elevated levels of serum lactic dehydrogenase and soluble interleukin-2 receptor, and a positive direct Coombs test, which suggested an underlying autoimmune hemolytic anemia (AIHA). Chest computed tomography (CT) showed no abnormal findings, but she had hypoxia, and her alveolar-arterial oxygen difference (A-aDO2) was increased. A random transbronchial lung biopsy (TBLB) was performed, and pathological analysis showed massive proliferation of tumor cells in the lumina of the small vessels. Intravascular large B-cell lymphoma (IVLBCL) was diagnosed, and her general status improved after chemotherapy., Internal Medicine, 49(24), pp.2697-2701; 2010

We evaluated the potency of garenoxacin in selecting resistant Streptococcus pneumoniae mutants by determining its mutant prevention concentration, using strains with and without topoisomerase gene mutations, and compared its potency to that of other quinolones. Garenoxacin had a significantly greater potency against pneumococci, including strains containing topoisomerase mutations. Genetic analysis of the S. pneumoniae mutants created by garenoxacin revealed that the gyrA gene was a primary target of garenoxacin., Antimicrobial agents and chemotherapy, 53(8), pp.3572-3575; 2009

Lemierre's syndrome is characterized by a primary oropharyngeal infection in a young healthy person who subsequently develops septic thrombophlebitis of the internal jugular vein and metastatic abscesses. We here report an uncommonly severe case of Lemierre's syndrome with acute respiratory distress syndrome (ARDS), in which polymyxin B-immobilized fiber (PMX) was used as supportive therapy. A 30-year-old, previously healthy man presented with sore throat, fever, rigor, and dyspnea. Chest computed tomography scan revealed multiple bilateral peripheral pulmonary nodules with small bilateral pleural effusions. The patient's condition rapidly deteriorated into ARDS after admission. Intubation followed by mechanical ventilation was required, and hemoperfusion with PMX was useful in alleviating the patient's condition. Isolation of Fusobacterium necrophorum from the blood culture and the contrast-enhanced scan revealed thrombosis and thrombophlebitis in the left internal jugular vein. The patient was diagnosed with Lemierre's syndrome, and an alternative treatment regimen with prolonged administration of ampicillin, clindamycin, and metronidazole resulted in improvement of the patient's respiratory function and general condition. Our case indicated that PMX might be an effective supportive therapy in severe cases of Lemierre's syndrome with ARDS that possessed no indication of surgical interventions., Japanese Journal of Infectious Diseases, 62(2), pp. 133-136; 2009

It is important to conserve the effectiveness of antifungal agents because the options for currently available agents are limited. Although echinocandins, which have been developed in recent decades, are highly active against a broad spectrum of fungi, one concern is their reduced activity against Candida albicans at high drug concentrations, which is known as the paradoxical effect. To date, resistance related to the paradoxical effect has not been reported in clinical situations, but some in vivo data suggest that the paradoxical effect potentiates the emergence of resistance. It is valuable to investigate the underlying mechanisms of as well as strategies against this paradoxical resistance. Previous reports imply that the paradoxical effect might be related to stress responses. In this study, we report that radicicol, a heat shock protein 90 (Hsp90) inhibitor, reduces the paradoxical effect of micafungin. We also confirm that radicicol reduces the tolerance to voriconazole, one of the new azoles, which is consistent with a previous report. Our results may therefore imply that common stress responses might exist in the paradoxical resistance to micafungin and also the tolerance to voriconazole, and may suggest that inhibiting Hsp90-related stress responses could help to avoid potential resistances., Japanese Journal of Infectious Diseases, 62(5), pp. 392-393; 2009

Platelet-activating factor (PAF) is a critical mediator of severe inflammatory diseases such as pneumonia, and the PAF-receptor (PAFR) is known to be an anchor for Streptococcus pneumoniae attachment to lung epithelial cells. We conducted a DNA microarray analysis to detect critical factors that mediate fulminant pneumonia due to influenza virus and S. pneumoniae co-infection in mice. Among the factors detected, levels of PAF-acetyl hydrolase (PAF-AH), which functions as inactivated PAF, were significantly increased, and PAFR was expressed in co-infected mouse lungs, as compared to the respective levels in mice infected with either S. pneumoniae or virus alone. Significantly elevated PAF-AH enzymatic activity was observed in the co-infected mouse lung, suggesting that co-infection activated PAF-related factors. These findings suggest that PAF and related molecules play important roles in fulminant pneumonia due to influenza virus infection, especially when severe bacterial pneumonia is complicated by co-infection with influenza virus., Japanese Journal of Infectious Diseases, 62(1), pp.6-10; 2009

We report a rare case of Legionella pneumophila pneumonia followed by invasive aspergillosis (IA). Legionellosis was ameliorated by the administration of ciprofloxacin, erythromycin, and corticosteroid as adjunctive therapy. Although intravenous administration of the corticosteroid was effective at reducing severe inflammation due to legionellosis, IA occurred at 12 days after admission. Combination therapy with micafungin and voriconazole was effective in this case; however, it remains necessary to exercise caution when making decisions regarding indications for corticosteroid use and observation in the treatment of severe pneumonia patients., Japanese Journal of Infectious Diseases, 61(5), pp.379-381; 2008