Corina N. D'Alessandro-Gabazza

Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial

Objective To determine the efficacy of a 23-valent pneumococcal polysaccharide vaccine in people at high risk of pneumococcal pneumonia. Design Prospective, randomised, placebo controlled double blind study. Setting Nursing homes in Japan. Participants 1006 nursing home residents. Interventions Participants were randomly allocated to either 23-valent pneumococcal polysaccharide vaccine (n=502) or placebo (n=504). Main outcome measures The primary end points were the incidence of all cause pneumonia and pneumococcal pneumonia. Secondary end points were deaths from pneumococcal pneumonia, all cause pneumonia, and other causes. Results Pneumonia occurred in 63 (12.5%) participants in the vaccine group and 104 (20.6%) in the placebo group. Pneumococcal pneumonia was diagnosed in 14 (2.8%) participants in the vaccine group and 37 (7.3%) in the placebo group (P<0.001). All cause pneumonia and pneumococcal pneumonia were significantly more frequent in the placebo group than in the vaccine group: incidence per 1000 person years 55 v 91 (P<0.0006) and 12 v 32 (P<0.001), respectively. Death from pneumococcal pneumonia was significantly higher in the placebo group than in the vaccine group (35.1% (13/37) v 0% (0/14), P<0.01). The death rate from all cause pneumonia (vaccine group 20.6% (13/63) v placebo group 25.0% (26/104), P=0.5) and from other causes (vaccine group 17.7% (89/502) v placebo group (80/504) 15.9%, P=0.4) did not differ between the two study groups. Conclusion The 23-valent pneumococcal polysaccharide vaccine prevented pneumococcal pneumonia and reduced mortality from pneumococcal pneumonia in nursing home residents. Trial registration Japan Medical Association Center for Clinical Trials JMA-IIA00024.

A prospective comparison of nursing home-acquired pneumonia with hospital-acquired pneumonia in non-intubated elderly

There are no prospective comparison of the etiology and clinical outcome between hospital-acquired pneumonia (HAP) and nursing home-acquired pneumonia (NHAP) in non-intubated elderly. This study prospectively evaluated the etiology of HAP and NHAP in non-intubated elderly. A prospective cohort study was carried out in a rural region of Japan where the population over 65 years of age represents 30% of the population. A total of 108 patients were enrolled. There were 33 patients with HAP and 75 with NHAP. Etiologic diagnosis was established in 78.8% of HAP and in 72% of NHAP patients. The most frequent pathogens were Chlamydophila pneumoniae followed by Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus. The frequency of Streptococcus pneumoniae and Influenza virus was significantly higher, whereas the frequency of Staphylococcus aureus and Enterobacteriaceae was significantly lower in NHAP compared to HAP. Performance and nutritional status were significantly worse in patients with HAP than in those with NHAP. Hospital mortality was significantly lower in patients with NHAP compared to those with HAP. This study demonstrated that C. pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus are frequent causative agents of pneumonia in non-intubated elderly and that the responsible pathogens and clinical outcome differ between NHAP and HAP.

Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse

Tenascin C (TN‐C) is an extracellular matrix glycoprotein whose expression is increased in several inflammatory diseases of the lung, including bronchial asthma. However, the exact function of TN‐C in the pathogenesis of lung inflammation remains unclear. In the present study, we compared the degree of bronchial asthma in wild‐type and TN‐C‐deficient (–/–) BALB/c mice. Bronchial asthma was induced by sensitization and challenge with ovalbumin. Littermates treated with saline were used as controls. Cytokines in bronchoalveolar lavage fluid and plasma were measured by enzyme immunoassays. The number of eosinophils in the lung was significantly increased in wild‐type mice compared with TN‐C‐knockout mice. Airway hyperreactivity, NF‐κB activation and concentrations of monocyte chemoattractant protein‐1, IL‐5, IL‐13, metalloproteinase‐9 and immunoglobulin‐E in the bronchoalveolar lavage fluid were significantly decreased in ovalbumin‐sensitized/challenged TN‐C‐knockout mice compared with their wild‐type counterparts. In vitro experiments disclosed that TN‐C significantly stimulates the secretion of IL‐5, IL‐13, IFN‐γ and immunoglobulin‐E from spleen lymphocytes. These observations suggest that TN‐C is involved in the pathogenesis of bronchial asthma.

Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients

The rapid increase in the elderly population is leading to a corresponding increase in the number of people requiring medical care. To date no comparative study between community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) has been reported in the very elderly non-intubated patients. The present study was undertaken to compare the clinical characteristics and microbial etiology between CAP and NHAP in elderly patients >/=85-years old. There were 54 patients with NHAP and 47 with CAP. Performance status was significantly worse in the NHAP than in the CAP group. Among all patients, the most frequent pathogens were Chlamydophilia pneumoniae followed by Streptococcus pneumoniae, Mycoplasma pneumoniae influenza virus and Staphylococcus aureus. The frequency of S. peumoniae was significantly higher in NHAP patients than in CAP patients after adjusting for age and sex. Physical activity, nutrition status and dehydration were significant prognostic factors of pneumonia among all patients. In-hospital mortality was significantly higher in NHAP than in CAP after adjusting for age and sex. This study demonstrated that the etiology and clinical outcome differ between CAP and NHAP patients in the very elderly non-intubated population.

Inhibition of Allergic Bronchial Asthma by Thrombomodulin Is Mediated by Dendritic Cells

RATIONALE bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available. OBJECTIVES to test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs). METHODS the protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure. MEASUREMENTS AND MAIN RESULTS treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM(+)) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM(+) DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs. CONCLUSIONS the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.

Decreased expression of aquaporin-5 in bleomycin-induced lung fibrosis in the mouse

The expression of aquaporin‐5, the major water channel expressed in alveolar, tracheal, and upper bronchial epithelium, is significantly down‐regulated during acute lung injury. In the present study, the expression of aquaporin‐5 in two different mouse models of lung fibrosis was evaluated. Lung fibrosis was induced by intratracheal and by subcutaneous infusion of bleomycin. The expression of aquaporin‐5 was investigated by immunohistochemical studies and by polymerase chain reaction. There were many cells with loss of aquaporin‐5 immunoreactivity in type I alveolar epithelial cells in the mouse models of lung fibrosis. Immunohistochemistry of lung tissue in aquaporin‐5 knockout mice revealed a fibrotic phenotype with increased deposition of extracellular collagen type I in thickened alveolar walls. Semiquantitative analysis of aquaporin‐5 mRNA expression showed more abundant content of aquaporin‐5 in the lung of the normal mouse compared to the mouse with lung fibrosis. The results of this study showed, for the first time, that chronic lung injury and lung fibrosis is associated with decreased protein and mRNA expression of aquaporin‐5 in the lung.

Role of the coagulation system in allergic inflammation in the upper airways

Thrombin has been detected and demonstrated to play a role in the airways of patients with bronchial asthma, but its role in the upper airways including during allergic rhinitis is unknown. This study was conducted to explore whether thrombin is presence in the upper airways and, if so, whether it affects mucin secretion. Fifteen patients with allergic rhinitis were enrolled in the clinical study; primary nasal septum epithelial cells and normal bronchial epithelial cells were used for in vitro evaluation, and rats as animal models. Significant concentrations of thrombin were found in nasal secretion after allergic provocation in allergic patients, and thrombin and its agonistic receptor peptide induced significant secretion of mucin in primary nasal cells and normal bronchial epithelial cells as compared to non-stimulated cells. Increased mucosubstance secretion in septum epithelial cells was also induced after nasal instillation of thrombin in rats. Further, the anticoagulant, activated protein C, significantly inhibited thrombin-induced mucin secretion from septum epithelial cells in rats. The results of this study suggest that activation of the coagulation system occurs during the allergic response and that thrombin plays a crucial role in the regulation of mucin production in the upper airways.

Efficacy of a novel class of RNA interference therapeutic agents.

RNA interference (RNAi) is being widely used in functional gene research and is an important tool for drug discovery. However, canonical double-stranded short interfering RNAs are unstable and induce undesirable adverse effects, and thus there is no currently RNAi-based therapy in the clinic. We have developed a novel class of RNAi agents, and evaluated their effectiveness in vitro and in mouse models of acute lung injury (ALI) and pulmonary fibrosis. The novel class of RNAi agents (nkRNA®, PnkRNA™) were synthesized on solid phase as single-stranded RNAs that, following synthesis, self-anneal into a unique helical structure containing a central stem and two loops. They are resistant to degradation and suppress their target genes. nkRNA and PnkRNA directed against TGF-β1mRNA ameliorate outcomes and induce no off-target effects in three animal models of lung disease. The results of this study support the pathological relevance of TGF-β1 in lung diseases, and suggest the potential usefulness of these novel RNAi agents for therapeutic application.

Eosinophils Promote Epithelial to Mesenchymal Transition of Bronchial Epithelial Cells

Eosinophilic inflammation and remodeling of the airways including subepithelial fibrosis and myofibroblast hyperplasia are characteristic pathological findings of bronchial asthma. Epithelial to mesenchymal transition (EMT) plays a critical role in airway remodelling. In this study, we hypothesized that infiltrating eosinophils promote airway remodelling in bronchial asthma. To demonstrate this hypothesis we evaluated the effect of eosinophils on EMT by in vitro and in vivo studies. EMT was assessed in mice that received intra-tracheal instillation of mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils freshly purified from healthy individuals or with eosinophilic leukemia cell lines. Intra-tracheal instillation of eosinophils was associated with enhanced bronchial inflammation and fibrosis and increased lung concentration of growth factors. Mice instilled with eosinophils pre-treated with transforming growth factor(TGF)-β1 siRNA had decreased bronchial wall fibrosis compared to controls. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and it was associated with increased expression of TGF-β1 and Smad3 phosphorylation in the bronchial epithelial cells. Treatment with anti-TGF-β1 antibody blocked EMT in bronchial epithelial cells. Eosinophils induced EMT in bronchial epithelial cells, suggesting their contribution to the pathogenesis of airway remodelling.

Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 Short Interfering RNAs for Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans.