Clinical Characteristics and Risk Prediction Score in Patients With Mild-to-Moderate Coronavirus Disease 2019 in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, causing widespread mortality. Many patients with COVID-19 have been treated in homes, hotels, and medium-sized hospitals where doctors were responsible for assessing the need for critical care hospitalization. This study aimed to establish a severity prediction score for critical care triage. METHOD: We analyzed the data of 368 patients with mild-to-moderate COVID-19 who had been admitted to Fussa Hospital, Japan, from April 2020 to February 2022. We defined a high-oxygen group as requiring ≥4 l/min of oxygen. Multivariable logistic regression was used to construct a risk prediction score, and the best model was selected using a stepwise selection method. RESULTS: Multivariable analysis showed that older age (≥70 years), elevated creatine kinase (≥127 U/L), C-reactive protein (≥2.19 mg/dL), and ferritin (≥632.7 ng/mL) levels were independent risk factors associated with the high-oxygen group. Each risk factor was assigned a score ranging from 0 to 4, and we referred to the final overall score as the Fussa score. Patients were classified into two groups, namely, high-risk (total risk factors, ≥2) and low-risk (total risk score, <2) groups. The high-risk group had a significantly worse prognosis (low-risk group, undefined vs. high-risk group, undefined; P< 0.0001). CONCLUSIONS: The Fussa score might help to identify patients with COVID-19 who require critical care hospitalization.

Hyperoxia exaggerates bacterial dissemination and lethality in Pseudomonas aeruginosa pneumonia.

Effects of hyperoxia on lethality in mice with Pseudomonas aeruginosa pneumonia were defined, and protective roles of macrolides were examined both in vitro and in vivo. Sub-lethal hyperoxia accelerated lethality of mice with P. aeruginosa pneumonia. Bacterial number was not different in the lungs, but higher in the liver of mice in hyperoxic conditions. Filter-sterilized culture supernatants of bacteria induced loss of viability of alveolar epithelial cells, which was exaggerated in hyperoxia. Metalloprotease blocking by inhibitor or gene-disruption in bacteria resulted in partial reduction of cytotoxic activity in culture supernatants. Co-culture of bacteria with sub-inhibitory concentrations of macrolides, such as azithromycin, reduced cytotoxic activity in the culture supernatants. Azithromycin provided significant survival benefit in hyperoxia-pneumonia model, which was associated with suppression of bacterial dissemination to extra-pulmonary organs. These results suggest that hyperoxia serves as an important cofactor for bacterial dissemination and lethality of P. aeruginosa pneumonia. Our data identify the potential of macrolides to protect individuals with P. aeruginosa pneumonia in the setting of hyperoxia.

Paradoxically high resistance of natural killer T (NKT) cell-deficient mice to Legionella pneumophila: another aspect of NKT cells for modulation of host responses.

In the present study, we examined the roles of natural killer T (NKT) cells in host defence against Legionella pneumophila in a mouse model. The survival rate of NKT cell-deficient Jalpha281 knock-out (KO) mice was significantly higher than that of wild-type mice. There was no bacterial overgrowth in the lungs, but Jalpha281 KO mice showed enhanced pulmonary clearance at a later stage of infection, compared with their wild-type counterparts. The severity of lung injury in L. pneumophila-infected Jalpha281 KO mice was less, as indicated by lung permeability measurements, such as lung weight and bronchoalveolar lavage fluid albumin concentration. Recruitment of inflammatory cells in the lungs was approximately twofold greater in Jalpha281 KO mice on day 3. Interestingly, higher values of interleukin (IL)-1beta and IL-18, and increased caspase-1 activity were noted in the lungs of Jalpha281 KO mice from an early time point (6 h). Exogenous alpha-galactosylceramide, a ligand of NKT cells, induced IL-12 and gamma interferon at 6 h, but suppressed IL-1beta at later time points in wild-type, whereas no effects were evident in Jalpha281 KO mice, as expected. Systemic administration of heat-killed L. pneumophila, but not Escherichia coli LPS, reproduced exaggerated production of IL-1beta in the lungs of Jalpha281 KO mice. These results demonstrate that NKT cells play a role in host defence against L. pneumophila, which is characterized by enhanced lung injury and decreased accumulation of inflammatory cells in the lungs. The regulation of IL-1beta, IL-18 and caspase-1 may be associated with the modulating effect of host responses by NKT cells.

[Evaluation of the usefulness of a rapid immunochromatographic membrane test to detect Streptococcus pneumoniae antigen in the early diagnosis of pneumococcal respiratory tract infections and the relationship to the severity of pneumonia].

We evaluated the usefulness of a rapid immunochromatographic membrane test (Binax NOW Streptococcus pneumoniae kit; ICT) to detect Streptococcus pneumoniae antigen in early diagnosis of pneumococcal respiratory tract infections and the relationship to the severity of pneumonia. We diagnosed 155 of 592 samples, which were performed by ICT, as S. pneumoniae respiratory tract infections. Sixty-three samples (40.6%) exhibited mixed infection. We evaluated the severity of infection using the A-DROP system and compared positive rates. Pneumococcal antigen was detected in patients with severe or most severe pneumococcal infections as frequently as in those with mild or moderate infections. Meanwhile sputum gram staining yielded a lower detection rate in patients with severe or most severe infections than those with mild or moderate infections (P = 0.0046). Serum C-reactive protein levels increased in patients with severe penumococcal infection, but decreased in those with the most severe pneumococcal infection (P<0.0001). The test revealed a sensitivity of 67.7% and a specificity of 98.8%, and the diagnostic yield of pneumococcal pneumonia increased by 7.7% using ICT combined with conventional methods. In conclusion, ICT is a useful test for the early diagnosis of pneumococcal respiratory infections especially in adult patients with severe or most severe infections for whom demonstrative results of a sputum Gram stain is unavailable, even after commencement of antibiotic treatment.

Response of a thymic mucoepidermoid carcinoma to combination chemotherapy with cisplatin and irinotecan: a case report.

A chemotherapeutic regimen for advanced thymic carcinoma has not yet been established. We describe a patient with advanced thymic mucoepidermoid carcinoma who achieved a complete response to combination chemotherapy with cisplatin (Randa) and irinotecan hydrochloride (Campto). A 74-year-old man was admitted to our hospital because of chest pain, general fatigue, appetite loss and weight loss. Chest computed tomography examinations revealed an anterior mediastinal tumour (5.5cmx3.5cmx9.5cm) that had invaded the subcutis through the sternum. The patient was treated with three courses of cisplatin and irinotecan hydrochloride followed by radiotherapy; he has since exhibited a complete response for 3 months.

[Predictive factors for treatment incompletion in elderly patients with newly diagnosed pulmonary tuberculosis].

BACKGROUND: To identify predictive factors of treatment incompletion in elderly patients with newly diagnosed pulmonary tuberculosis. MATERIALS AND METHODS: In elderly patients of more than 65-years old and with newly diagnosed pulmonary tuberculosis, a retrospective study was conducted. A total of 88 patients were admitted in International Medical Center of Japan with pulmonary tuberculosis between June 2000 and February 2002. The relationships between several clinical parameters, including patients' performance status (PS) scale proposed by the Eastern Cooperative Oncology Group, laboratory data, or, radiological findings on admission and treatment incomeletion were assessed by univariate and multivariate logistic regression analyses. RESULTS: Ten patients could not complete their treatment; including nine patients who died during hospitalization and one who refused tuberculosis treatment. Preliminary analysis indicated that the treatment incompletion was related with twelve factors including PS. On univariate analyses, 9 factors were associated with incomplete treatment. The best model was built up by using 5 independent factors, that is, diabetes mellitus, PS, hypoxemia, duration of sleep, drug resistant strain. On multivariate analysis, only the PS was significantly related to treatment incompletion in elderly patients with pulmonary tuberculosis (odds ratio: 0.41, 95% confidence interval: 0.17-0.98, p=0.04). CONCLUSION: High PS showed a strong association with treatment incompletion in elderly patients with pulmonary tuberculosis. The PS is considered to be a useful clinical indicator.

Role of Toll-like receptor 2 in recognition of Legionella pneumophila in a murine pneumonia model.

Legionella pneumophila is an intracellular organism and the major aetiological agent of Legionnaires' disease. Although recent progress has identified Toll-like receptors (TLRs) as receptors for recognition of pathogen-associated molecular patterns in a variety of micro-organisms, understanding the contribution of TLRs to the host response in L. pneumophila infection is still limited. This study examined the roles of TLR2 and TLR4 in murine L. pneumophila pneumonia and an in vitro infection model using bone-marrow-derived macrophages. TLR2-deficient mice, but not TLR4-deficient mice, demonstrated higher lethal sensitivity to pulmonary challenge with L. pneumophila than wild-type mice (P<0.05). Although no differences in pulmonary bacterial burden were observed among the mouse strains examined, lower values of macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived cytokine and interleukin (IL)-6 and higher IL-12 levels were noted in lung homogenates of TLR2-deficient mice compared with the wild-type control and TLR4-deficient mice. Recruitment of inflammatory cells, particularly neutrophils, was severely disturbed in the lungs of TLR2-deficient mice. Reduced MIP-2 production was demonstrated in bone-marrow-derived macrophages from TLR2-deficient mice in response to live L. pneumophila and purified LPS of this strain, but not Escherichia coli LPS. These data highlight the involvement and importance of TLR2 in the pathogenesis of L. pneumophila pneumonia in mice. The results showed that TLR2-mediated recognition of Legionella LPS and subsequent chemokine-dependent cellular recruitment may be a crucial host innate response in L. pneumophila pneumonia.

[Evaluation of ImmnoCard mycoplasma for diagnosis of Mycoplasma pneumoniae infection].

We compared the differences of two tests, for the diagnosis of Mycoplasma pneumoniae infection a rapid detection kit for Mycoplasma pneumoniae-specific IgM antibody, ImmunoCard (IC) Mycoplasma test (Meridian Bioscience-USA), and a particle agglutination (PA) test in a retrospective study among 57 patients. They were all suspected to be suffering from atypical bacterial respiratory infection and were checked by the IC test at the Fukuroi Municipal Hospital from January 2004 to January 2006. In this study, the concordance of IC and PA results showed a great difference in children and adults. All children, whose IC test was positive, showed positive PA results. It was particularly difficult to obtain convalescent serum samples in children and IC was useful for children because it was judged by acute phase serum. On the other hand, some in 20% (7/35) of adults, results of the IC test were not concordant with that of the PA test, therefore, diagnosis in adults should be made based on 4-fold rises in titers between paired sera for serological diagnosis of Mycoplasma pneumoniae infection.

Immunization with 3-oxododecanoyl-L-homoserine lactone-protein conjugate protects mice from lethal Pseudomonas aeruginosa lung infection.

Quorum-sensing systems have been reported to play a critical role in the pathogenesis of several bacterial infections. Recent data have demonstrated that Pseudomonas N-3-oxododecanoyl-L-homoserine lactone (3-oxo-C12-homoserine lactone, 3-oxo-C12-HSL), but not N-butanoyl-L-homoserine lactone (C4-HSL), induces apoptosis in macrophages and neutrophils. In the present study, the effects of active immunization with 3-oxo-C12-HSL-carrier protein conjugate on acute P. aeruginosa lung infection in mice were investigated. Immunization with 3-oxo-C12-HSL-BSA conjugate (subcutaneous, four times, at 2-week intervals) elaborated significant amounts of specific antibody in serum. Control and immunized mice were intranasally challenged with approximately 3 x 10(6) c.f.u. P. aeruginosa PAO1, and survival was then compared. All control mice died by day 2 post bacterial challenge, while 36 % of immunized mice survived to day 4 (P<0.05). Interestingly, bacterial numbers in the lungs did not differ between control and immunized groups, whereas the levels of pulmonary tumour necrosis factor (TNF)-alpha in the immunized mice were significantly lower than those of control mice (P<0.05). Furthermore, the extractable 3-oxo-C12-HSL levels in serum and lung homogenate were also significantly diminished in the immunized mice. Immune serum completely rescued reduction of cell viability by 3-oxo-C12-HSL-mediated apoptosis in macrophages in vitro. These results demonstrated that specific antibody to 3-oxo-C12-HSL plays a protective role in acute P. aeruginosa infection, probably through blocking of host inflammatory responses, without altering lung bacterial burden. The present data identify a promising potential vaccine strategy targeting bacterial quorum-sensing molecules, including autoinducers.

Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.

To restrict infection by Legionella pneumophila, mouse macrophages require Naip5, a member of the nucleotide-binding oligomerization domain leucine-rich repeat family of pattern recognition receptors, which detect cytoplasmic microbial products. We report that mouse macrophages restricted L. pneumophila replication and initiated a proinflammatory program of cell death when flagellin contaminated their cytosol. Nuclear condensation, membrane permeability, and interleukin-1beta secretion were triggered by type IV secretion-competent bacteria that encode flagellin. The macrophage response to L. pneumophila was independent of Toll-like receptor signaling but correlated with Naip5 function and required caspase 1 activity. The L. pneumophila type IV secretion system provided only pore-forming activity because listeriolysin O of Listeria monocytogenes could substitute for its contribution. Flagellin monomers appeared to trigger the macrophage response from perforated phagosomes: once heated to disassemble filaments, flagellin triggered cell death but native flagellar preparations did not. Flagellin made L. pneumophila vulnerable to innate immune mechanisms because Naip5+ macrophages restricted the growth of virulent microbes, but flagellin mutants replicated freely. Likewise, after intratracheal inoculation of Naip5+ mice, the yield of L. pneumophila in the lungs declined, whereas the burden of flagellin mutants increased. Accordingly, macrophages respond to cytosolic flagellin by a mechanism that requires Naip5 and caspase 1 to restrict bacterial replication and release proinflammatory cytokines that control L. pneumophila infection.