Prospective multicenter study of the causative organisms of community-acquired pneumonia in adults in Japan.

Although a wide variety of recognized pathogens causes community-acquired pneumonia, the precise etiology in Japan remains unknown. We prospectively investigated the etiology in 232 patients with community-acquired pneumonia who visited 20 community-general hospitals. New diagnostic methods, using polymerase chain reaction (PCR) assays and urinary antigen tests were employed, in addition to conventional methods. The frequency of identification of causative pathogens was high (73.3%), and the leading organism was Streptococcus pneumoniae (24.6%), followed by Haemophilus influenzae (18.5%), viruses (16.4%), Chlamydia pneumoniae (6.5%), Mycoplasma pneumoniae (5.2%), and Legionella spp. (3.9%). S. pneumoniae and M. pneumoniae were the most prevalent pathogens in younger patients, and S. pneumoniae and H. influenzae were the most prevalent in elderly patients. Multiple or mixed infections were found in 25.9% of all patients and in 35.3% with a causal diagnosis. The results have important practical implications for the initial treatment of adult patients with community-acquired pneumonia.

Redox-active protein thioredoxin prevents proinflammatory cytokine- or bleomycin-induced lung injury.

Thioredoxin (TRX) is a multifunctional redox (reduction/oxidation)-active protein that scavenges reactive oxygen species by itself or together with TRX-dependent peroxiredoxin. TRX also has chemotaxis-modulating functions and suppresses leukocyte infiltration into sites of inflammation. Leukocyte infiltration and oxidative stress may be involved in the pathogenesis of several diseases, including interstitial lung diseases (ILD). We examined the effects of TRX in two mouse models of human ILD. Recently, we established a new mouse model for human ILD in which daily administration of proinflammatory cytokine interleukin (IL)-18 with IL-2 induces lethal lung injury accompanied by acute interstitial inflammatory responses. Administration of recombinant TRX suppressed IL-18/IL-2-induced interstitial infiltration of cells and prevented death and lung tissue damage. TRX-transgenic mice also showed resistance to lethal lung injury caused by IL-18/IL-2. Administration of bleomycin induces the infiltration of polymorphonuclear and mononuclear leukocytes in the pulmonary interstitium, followed by progressive fibrosis. Wild-type mice given recombinant TRX treatment and TRX-transgenic mice demonstrated a decrease in bleomycin-induced cellular infiltrates and fibrotic changes in the lung tissue. These results suggest that TRX modulates pulmonary inflammatory responses and acts to prevent lung injury. TRX may have clinical benefits in human ILD, including lung fibrosis, for which no effective therapeutic strategy currently exists.

Community-acquired Chlamydia pneumoniae pneumonia in Japan: a prospective multicenter community-acquired pneumonia study.

OBJECTIVE: To investigate the clinical features of Chlamydia pneumoniae pneumonia in Japan and to evaluate the newly created Japanese community-acquired pneumonia (CAP) guidelines. PATIENTS AND METHODS: A multicenter CAP surveillance study was carried out in 20 hospitals between December 1999 and March 2000. The diagnosis of C. pneumoniae infection was based on isolation in cell culture, the polymerase chain reaction and serologic testing of antibodies by the microimmunofluorescence test. RESULTS: Among 232 CAP cases, C. pneumoniae was identified as the etiologic agent in 15 cases (6.5%). C. pneumoniae was the only pathogen identified in nine of these cases, while one or more additional etiological agents were found in the other six cases. Of the present and previously reported single agent C. pneumoniae pneumonia cases, about 50% were more than 60 years old and had underlying diseases. A relatively slow pulse rate in relation to fever was not seen in these patients. The mean WBC count of all patients was normal. No patient required respiratory support or admission to an intensive care unit and no deaths occurred among these patients. CONCLUSION: The clinical pictures of C. pneumoniae pneumonia as a single agent were mild to moderate and were remarkably different from those of cases of C. pneumoniae pneumonia concomitant with other bacteria. If the patient is less than 60 years old and some guideline headings are excluded, we think it would be possible to distinguish between C. pneumoniae and bacterial pneumonia.

Bacteremic and leukopenic pneumococcal pneumonia: successful treatment with antibiotics, pulse steroid, and continuous hemodiafiltration.

We describe a case of bacteremic, leukopenic pneumococcal pneumonia with respiratory failure, accompanied by diabetic ketoacidosis and hypothermia. Pulmonary leukostasis may play a role in the pathogenesis of the acute respiratory distress syndrome (ARDS) in pneumococcal pneumonia. The patient recovered with mechanical ventilation, intravenous antibiotics, pulse-steroid therapy, and continuous hemodiafiltration (CHDF). In particular, administration of steroid and the use of CHDF may improve the status of pulmonary leukostasis in leukopenic pneumococcal infection.

Phase 1 clinical study of cyclophilin B peptide vaccine for patients with lung cancer.

Cyclophilin B (CypB) possesses two antigenic epitopes (CypB(84-92) and CypB(91-99) ) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). To determine the safety of CypB-derived peptides and its ability to generate antitumor immune responses, patients with advanced lung cancer received subcutaneous vaccinations of these peptides or their modified peptides. All 16 patients were vaccinated with CypB(91-99) or its modified peptide, whereas only two patients were vaccinated with the modified CypB(84-92), as immediate-type hypersensitivity to CypB(84-92) or its modified peptide was observed in the remaining patients. No severe adverse events were associated with the vaccination. No significant increase in cellular responses to either peptides or tumor cells was observed in the postvaccination PBMCs by the conventional CTL assays in any patients tested. These results suggest that the vaccination of CypB(91-99) peptide was safe, but failed to induce objective immune responses at this regimen.

[A three-year review of acute respiratory tract infections caused by Streptococcus milleri group].

The objective of our study is to understand the clinical features of patients with acute respiratory tract infection associated with Streptococcus milleri group (SMG). Fifteen patients with SMG respiratory tract infection visited our hospital from July, 1997 through May, 2000. There were seven cases of pneumonia, two pulmonary abscess, three thoracic empyema and three acute bronchitis. The mean age of the patients was 57.8 years (range 16-87), twelve were males, and seven were smokers. The moderately to severe underlying diseases existed in thirteen patients (86.7%) and included the following: respiratory diseases (20.0%), history of the esophageal or gastric surgery (26.7%), central nerve system diseases (13.3%), alcohol intake (60.0%), hepatitis and pancreatitis (33.3%), diabetes mellitus (13.3%) and malignancy (6.7%). The species of SMG detected were as follows: S. constellatus, 8, S. anginosus, 6 and S. intermedius, 1. Anaerobic organism and other microorganisms were detected in five patients. A patient with SMG nosocominal pneumonia who previously had thoracic surgery for esophageal cancer died. Antibiotics therapy with carbapenem or combination therapy, drainage and no surgery, were successful in 14 of the 15 cases (93.3%). The number of intermediately or complete resistant strains against penicillin G, ampicillin and cefmetazole were 5 (33.3%), 8 (53.3%) and 12 (80.0%), respectively in this series. Recently, it is seemed that acute respiratory tract infections caused by SMG are increasing in the patients with moderately to severe underlying diseases, and several clinical strains of SMG are acquiring a tolerance to antibiotics.

Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia.

Interleukin 18 (IL-18) was discovered as an interferon-gamma (IFN-gamma)-inducing factor and plays important roles in natural killer (NK) cell activation. IL-18 also induces proinflammatory cytokines; chemokines; helper T-cell 2 (T(H)2) cytokines (eg, IL-4, IL-13); and immunoglobulin E (Ig-E) and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 up-regulates IFN-gamma gene expression and NK cytotoxicity and has synergistic antitumor activity in vivo and in vitro. Here it is reported that daily administration of IL-18 with IL-2, but not of IL-18 or IL-2 alone, induces lethal lung injury in normal mice, but not in IL-18 receptor alpha (IL-1 receptor-related protein)-deficient (IL-18 receptor alpha(-/-)) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells, was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-18/IL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited tumor necrosis factor-alpha and Fas-ligand release. While IFN-gamma(-/-) mice were partially resistant to the treatment, IL-4(-/-), IL-13(-/-), IL-4/IL-13(-/-), and Stat6(-/-) mice were sensitive to IL-18/IL-2, indicating that these genes were not involved in the host response. The lethal effect by IL-18/IL-2 was completely eliminated in severe combined immunodeficient mice pretreated with antiasialo-GM1 antibody and normal mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8, monoclonal antibody. These results suggest that specific cytokines, chemokines, and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences.

Antiphospholipid syndrome and multiple ischemic strokes in a patient with myasthenia gravis.

Little is known about ischemic stroke occurrence in patients with myasthenia gravis (MG), although antiphospholipid antibodies are detectable in many MG patients. A 47-year-old woman with a 20-year history of generalized MG had an acute onset of right hemiparesis. She had undergone thymectomy 10 years previously and was treated for phlebothrombosis of the lower extremity 3 years previously. Computed tomography (CT) demonstrated an old infarct in the left frontal lobe and a new lesion in the right parietal lobe. Multiple small cortical and subcortical infarcts were demonstrated on fluid attenuated inversion recovery (FLAIR) images. Thrombocytopenia (5.9 x 10(4)/microL), a prolonged activated partial thromboplastin time (aPTT; 50.2 sec), and an elevation of beta 2-IgG-glycoprotein I anticardiolipin antibodies (beta 2-GPIaCL; 55.7 U/mL) were observed. Neurological defects improved significantly over 2 weeks. She then was treated with oral prednisolone (30 mg/day) for 18 months, with resolution of laboratory abnormalities and no new cerebrovascular events or findings on imaging. We believe that our patient's multiple infarcts are caused by antiphospholipid antibodies and recommend glucocorticoid therapy to prevent recurrent of ischemic stroke in similar case.

Clinical evaluation methods for new antimicrobial agents to treat respiratory infections: Report of the Committee for the Respiratory System, Japan Society of Chemotherapy.

The present report constitutes an attempt to improve and modify the existing clinical evaluation method for new antimicrobial agents to treat respiratory infections. One year ago, a general guideline on the clinical evaluation of antimicrobial agents to treat respiratory infections was drafted in Japanese, leaving scope for critical discussion, and this has been translated into English, as there were no major changes. In this report, respiratory infections have been discussed under the headings "acute respiratory tract infection" and pneumonia and acute exacerbation of chronic pulmonary diseases. Standardized criteria were set for the assessment of severity of infection and effectiveness of the antimicrobial agent in question. Severity was evaluated on the basis of a combined assessment of the severity of infection and severity of the clinical condition of the patients. Clinical effectiveness of the antimicrobial agent used was evaluated on the basis of clinical outcome as well as microbiological outcome of the trial. Body temperature, local pain, cough, change in sputum quality, peripheral white blood cell count, C-reactive protein level, and chest radiograph were used as the parameters for the evaluation. To maintain the quality of specimens to be examined, Geckler's classification of specimens was used. This report was constructed based on the analysis of large amounts of material collected over the years, incorporating internal and external factors concerning the present evaluation methods. The newly suggested standardized criteria for clinical evaluation of the new antimicrobial drugs are expected to be practiced properly hereupon and subjected to further improvement if necessary.