Shintaro Kurihara

The First Identification and Retrospective Study of Severe Fever With Thrombocytopenia Syndrome in Japan

Abstract Background. Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV), a novel bunyavirus reported to be endemic in central and northeastern China. This article describes the first identified patient with SFTS and a retrospective study on SFTS in Japan. Methods. Virologic and pathologic examinations were performed on the patients samples. Laboratory diagnosis of SFTS was made by isolation/genome amplification and/or the detection of anti-SFTSV immunoglobulin G antibody in sera. Physicians were alerted to the initial diagnosis and asked whether they had previously treated patients with symptoms similar to those of SFTS. Results. A female patient who died in 2012 received a diagnosis of SFTS. Ten additional patients with SFTS were then retrospectively identified. All patients were aged ≥50 years and lived in western Japan. Six cases were fatal. The ratio of males to females was 8:3. SFTSV was isolated from 8 patients. Phylogenetic analyses indicated that all of the Japanese SFTSV isolates formed a genotype independent to those from China. Most patients showed symptoms due to hemorrhage, possibly because of disseminated intravascular coagulation and/or hemophagocytosis. Conclusions. SFTS has been endemic to Japan, and SFTSV has been circulating naturally within the country.

Correlation between triazole treatment history and susceptibility in clinically isolated Aspergillus fumigatus

ABSTRACT This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154 Aspergillus fumigatus clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (r = 0.5700, P < 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 μg/ml (0.5 μg/ml versus 2 μg/ml, P = 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (r = 0.5237, P < 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 μg/ml (0.25 μg/ml versus 0.5 μg/ml, P = 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r = −0.2627, P = 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant A. fumigatus. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the cyp51A gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant A. fumigatus if itraconazole is used for extended periods.

Antifungal Susceptibilities of Aspergillus fumigatus Clinical Isolates Obtained in Nagasaki, Japan

ABSTRACT We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.

Comparison of usefulness of plasma procalcitonin and C-reactive protein measurements for estimation of severity in adults with community-acquired pneumonia.

Although procalcitonin (PCT) measurement has been performed in patients with infectious diseases, there are few reports on its usefulness in community-acquired pneumonia (CAP) associated with systemic inflammatory response syndrome (SIRS). We investigated 88 patients who visited the internal medicine departments of Nagasaki University Hospital, Nagasaki, Japan, and its 11 affiliated hospitals in Japan because of CAP with or without SIRS. Of the 88 patients, 15 (17.0%), 43 (48.9%), and 30 (34.1%) were judged to have severe, moderate, and mild CAP, respectively. Although 87 patients (98.9%) had C-reactive protein (CRP) levels exceeding 0.3 mg/dL, only 30 patients (34.1%) had PCT levels more than 0.5 ng/mL. In addition, 93.3% (28/30) of patients with mild CAP had negative PCT, and 48.3% (28/58) of patients positive for PCT had moderate or severe CAP. Our findings suggest that PCT level might be more useful for estimating CAP severity than CRP level at the 1st visit.

Clinical features, risk factors and treatment of fulminant Mycoplasma pneumoniae pneumonia: A review of the Japanese literature

Mycoplasma pneumoniae (MP) is one of the most common causes of community-acquired pneumonia in children and young adults. Although MP sometimes causes self-limiting pneumonia, severe and fulminant cases with hypoxia occur, but their clinical features have rarely been reported. This study aimed to reveal the clinical manifestations, risk factors, and treatment of fulminant MP pneumonia (MPP). Using PubMed and abstracts from the proceedings of several domestic Japanese academic societies, we reviewed the Japanese and English literature for cases of fulminant or severe MPP reported in Japan. All clinical information such as sex, age, underlying diseases, clinical symptoms, clinical course, laboratory and radiological findings, and treatment was collected and analyzed. In total, 52 fulminant MPP cases were reported between September, 1979 and February, 2010. The dominant population of fulminant MPP was young adults without severe underlying diseases. Cough (97.3%), fever (100.0%), and dyspnea (83.3%) with diffuse abnormal findings in radiological examinations were noted. Antibiotics without anti-mycoplasmal activity were used in 32 cases (61.5%) as initial treatment prior to the onset of hypoxia. Anti-mycoplasmal drugs were appropriately used in 41 cases (78.8%) after onset of respiratory failure with steroids (23 cases, 45.1%) and effective. The majority of patients improved within 3-5 days after steroid administration. There were only 2 fatal cases. Although this small retrospective study did not reveal the apparent risk factors of fulminant MPP, initial inappropriate use of antibiotics may be a risk factor, and early administration of appropriate anti-mycoplasmal drugs with steroids as a cellular immune suppressor is required.

Bronchoalveolar lavage galactomannan for the diagnosis of chronic pulmonary aspergillosis

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 manufacturers instructions. The mean values of BALF GM antigen were 4.535 (range, 0.062-14.120) and 0.430 (range, 0.062-9.285) in CPA (18) and non-CPA (126) patients, respectively. The mean values of serum GM antigen were 1.557 (range, 0.232-5.397) and 0.864 (range, 0.028-8.956) 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.

Elevated levels of high mobility group box chromosomal protein-1 (HMGB-1) in sera from patients with severe bacterial pneumonia coinfected with influenza virus.

Plasma levels of high mobility group box chromosomal protein-1 (HMGB-1), as well as of other inflammatory molecules such as interleukin-6 (IL-6), regulated on activation normal T-cell expressed and secreted (RANTES), and soluble intercellular adhesion molecule-1 (sICAM-1), were determined in patients with bacterial pneumonia coinfected with influenza virus. HMGB-1 levels were significantly elevated in these patients compared to patients undergoing mild bacterial pneumonia alone (p<0.01). Among cases of coinfection, we found a significant correlation between the concentration of HMGB-1 and white blood cell counts (p<0.05, r=0.612). Levels of IL-6 were also higher in these patients than in patients with bacterial pneumonia alone (p<0.05), despite similar levels of RANTES and sICAM-1 in the 2 groups. These data suggest that HMGB-1 is involved in the pathogenesis of severe bacterial pneumonia coinfected with influenza virus.

The risk factors for developing of chronic pulmonary aspergillosis in nontuberculous mycobacteria patients and clinical characteristics and outcomes in chronic pulmonary aspergillosis patients coinfected with nontuberculous mycobacteria

Patients with chronic pulmonary aspergillosis (CPA) have a poor prognosis and CPA occurs in patients with various underlying diseases. Recently, the number of patients with CPA complicated by nontuberculous mycobacteria (NTM) has increased. Additionally, complications of both diseases have several problems like drug interactions. Since the impact of NTM on the outcome of CPA is not well understood, we investigated the risk factors for developing CPA and the clinical characteristics of CPA patients with or without NTM. We retrospectively investigated the medical records of NTM and CPA patients who were admitted to Nagasaki University Hospital between April 2008 and September 2013. Comorbid diseases, causative microorganisms, radiological findings, and outcomes were evaluated. During the study period, 82 and 41 patients were diagnosed as having NTM and CPA, respectively. Nine patients were coinfected with NTM and CPA, and cavitary type NTM and steroid usage were independent risk factors of development of CPA. Mortality rates in the coinfection group were significantly higher than those of the NTM without CPA group (P = .003, log-rank test). The rate of treatment initiation in the co-infection group (33.3%) was significantly lower than in the CPA without NTM group (84.4%) (P = .006). However, there were no significant differences in cumulative survival rate between both groups (P = .760, log-rank test). Cavity formation and steroid usage were the independent risk factors for NTM patients to develop CPA within long observation period, and development of CPA made outcomes poor. It is important to diagnose the development of CPA early and initiate treatment for CPA.

Efficacy of Combination Therapy with Oseltamivir Phosphate and Azithromycin for Influenza: A Multicenter, Open-Label, Randomized Study

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

The effect of intravenous peramivir, compared with oral oseltamivir, on the outcome of post-influenza pneumococcal pneumonia in mice.

BACKGROUND Pneumococcal pneumonia often occurs secondary to influenza infection and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. Peramivir is a novel, intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. We investigated the efficacy of peramivir for modulating the severity of secondary pneumococcal pneumonia. METHODS CBA/JNCrlj mice, infected with influenza virus and superinfected with Streptococcus pneumoniae, were treated with either intravenous peramivir (single or multiple doses of 60 mg/kg/day) or oral oseltamivir at doses of 10 or 40 mg/kg/day in divided doses. The survival rate, viable bacterial count and virus titre in the lungs, as well as cytokine/chemokine concentration and histopathological findings were compared between both groups. RESULTS The median duration of survival of coinfected mice was significantly prolonged by treatment with multiple doses of peramivir, relative to mice treated with oseltamivir at either dose. Viable bacterial counts and virus titres in the lungs were significantly reduced by intravenous peramivir treatment compared with no treatment or oral oseltamivir treatment. The production of inflammatory cytokines/chemokines was also significantly suppressed by multiple dosing of peramivir compared with oseltamivir. Increased survival appeared to be mediated by decreased inflammation, manifested as lower levels of inflammatory cells and proinflammatory cytokines in the lungs and less severe histopathological findings. The lungs of mice treated with multiple doses of peramivir showed mild inflammatory changes compared to oseltamivir. CONCLUSIONS This study demonstrated that a multiple-dose regimen of intravenous peramivir was more efficacious than a single peramivir dose or multiple doses of oseltamivir for improving outcomes in pneumococcal pneumonia following influenza virus infection in mice.