Mikael Gencay

Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial

BACKGROUND Lower respiratory tract infections are often treated with antibiotics without evidence of clinically relevant bacterial disease. Serum calcitonin precursor concentrations, including procalcitonin, are raised in bacterial infections. We aimed to assess a procalcitonin-based therapeutic strategy to reduce antibiotic use in lower respiratory tract infections with a new rapid and sensitive assay. METHODS 243 patients admitted with suspected lower respiratory tract infections were randomly assigned standard care (standard group; n=119) or procalcitonin-guided treatment (procalcitonin group; n=124). On the basis of serum procalcitonin concentrations, use of antibiotics was more or less discouraged (<0.1 microg/L or <0.25 microg/L) or encouraged (> or =0.5 microg/L or > or =0.25 microg/L), respectively. Re-evaluation was possible after 6-24 h in both groups. Primary endpoint was use of antibiotics and analysis was by intention to treat. FINDINGS Final diagnoses were pneumonia (n=87; 36%), acute exacerbation of chronic obstructive pulmonary disease (60; 25%), acute bronchitis (59; 24%), asthma (13; 5%), and other respiratory affections (24; 10%). Serological evidence of viral infection was recorded in 141 of 175 tested patients (81%). Bacterial cultures were positive from sputum in 51 (21%) and from blood in 16 (7%). In the procalcitonin group, the adjusted relative risk of antibiotic exposure was 0.49 (95% CI 0.44-0.55; p<0.0001) compared with the standard group. Antibiotic use was significantly reduced in all diagnostic subgroups. Clinical and laboratory outcome was similar in both groups and favourable in 235 (97%). INTERPRETATION Procalcitonin guidance substantially reduced antibiotic use in lower respiratory tract infections. Withholding antimicrobial treatment did not compromise outcome. In view of the current overuse of antimicrobial therapy in often self-limiting acute respiratory tract infections, treatment based on procalcitonin measurement could have important clinical and financial implications.

ERK1/2 and p38 MAP kinase control MMP-2, MT1-MMP, and TIMP action and affect cell migration: a comparison between mesothelioma and mesothelial cells

Pleural malignant mesothelioma is a locally aggressive tumor of mesothelial cell origin. In other tumor types high expression of matrix metalloproteinase (MMP)‐2, together with membrane‐type1‐MMP (MT1‐MMP), and low levels of the tissue inhibitor of MMP (TIMP)‐2 have been correlated with aggressive tumor progression and low survival rates. Therefore, we compared the expression and activation of these three factors and their regulation by two mesothelioma associated growth factors, platelet‐derived growth factor (PDGF)‐BB, and transforming growth factor (TGF)‐β1 in six human mesothelioma and one mesothelial cell line. Polymerase chain reaction (PCR), immnuoblotting, zymography, and small inhibitory RNAs (siRNA) were used to study gene expression, protein activation, and signal transduction. To proof the relevance of our in vitro data immunohistochemistry was performed in tissue sections. PDGF‐BB induced, while TGF‐β1 inhibited cell proliferation. PDGF‐BB was a chemoattractant for mesothelial cells, and its effect was increased in the presence of TGF‐β1. TGF‐β1 stimulated the de novo synthesis of pro‐MMP‐2 in both cell types. Pro‐MMP‐2 synthesis involved p38 MAP kinase. In cell culture and tissue sections only mesothelial cells expressed MT1‐MMP. Migration of mesothelioma cells was dependent on the presence of MT1‐MMP. Migration, but not proliferation of mesothelioma cells was inhibited by oleoyl‐N‐hydroxylamide, TIMP‐2, and siRNA for MT1‐MMP. Our data suggest that in mesothelioma cells the phosphorylation of p38 MAP kinase is deregulated and is involved in pro‐MMP‐2 expression. Mesothelioma progression depends on an interaction with mesothelial cells that provide MT1‐MMP necessary to activate pro‐MMP‐2 to facilitate migration through an extracellular matrix (ECM) layer. J. Cell. Physiol. 207: 540–552, 2006.

Chlamydia pneumoniae Activates Epithelial Cell Proliferation via NF-κB and the Glucocorticoid Receptor

ABSTRACT Chlamydia pneumoniae is an obligate intracellular eubacterium and a common cause of acute and chronic respiratory tract infections. This study was designed to show the effect of C. pneumoniae on transcription factor activation in epithelial cells. The activation of transcription factors by C. pneumoniae was determined in human epithelial cell lines (HL and Calu3) by electrophoretic DNA mobility shift assay, Western blotting, and luciferase reporter gene assay. The activation of transcription factors was further confirmed by immunostaining of C. pneumoniae-infected HL cells and mock-infected controls. The effect of transcription factors on C. pneumoniae-induced host cell proliferation was assessed by [3H]thymidine incorporation and direct cell counting in the presence and absence of antisense oligonucleotides targeting transcription factors or the glucocorticoid receptor (GR) antagonist RU486. The activation of the GR, CCAAT-enhancer binding protein (C/EBP), and NF-κB was induced within 1 to 6 h by C. pneumoniae. While the interleukin-6 promoter was not activated by C. pneumoniae, the GR-driven p21(Waf1/Cip1) promoter was increased 2.5- to 3-fold over controls 24 h after infection. C. pneumoniae dose-dependently increased the DNA synthesis of the host cells 2.5- to 2.9-fold, which was partly inhibited either by RU486 or by NF-κB antisense oligonucleotides. Furthermore, we provide evidence that heat-inactivated C. pneumoniae does not cause a significant increase in cell proliferation. Our results demonstrate that C. pneumoniae activates C/EBP-β, NF-κB, and the GR in infected cells. However, only NF-κB and the GR were involved in C. pneumoniae-induced proliferation of epithelial cells.

Airway epithelium-derived transforming growth factor-beta is a regulator of fibroblast proliferation in both fibrotic and normal subjects.

Background In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately.

Single and Multiple Viral Infections in Lower Respiratory Tract Infection

Background: Lower respiratory tract infection (LRTI) often leads to hospitalization, and it was indicated that causative viral infections are underestimated. Objectives: It was our aim to compare the frequency of 8 relevant viruses in 109 hospitalized LRTI patients and 144 healthy controls. Methods: Virus infection was determined by seroconversion and ELISA for anti-virus antibodies in repeated serum samples. Bacterial infection was diagnosed in respiratory specimens, blood cultures and urine. Results: The LRTI patient cohort consisted of 49 patients with community-acquired pneumonia, 30 patients with acute bronchitis and 30 chronic obstructive pulmonary disease patients with acute exacerbation. Viral infection was detected in 89 (82%) LRTI patients compared with 32 (22%) in healthy controls (relative risk 3.42, 95% confidence interval 2.48–4.72; p < 0.0001). The most frequent viral pathogens were: influenza B (23%), adenovirus (16%) and parainfluenza virus 3 (12%). Importantly, infections with more than 1 virus were detected in 63% (n = 57) of LRTI patients with viral infection, which represents 52% of all LRTI patients. No multiple virus infection was detected in the healthy controls. Patients with community-acquired pneumonia were more often infected with adenovirus and respiratory syncytial virus as compared with the other LRTI patients (p = 0.046 and 0.0009, respectively). Conclusions: There is a high incidence of single and multiple viral infections in LRTI patients requiring hospitalization. The data indicate the need for regular virus diagnosis and the development of point of care tools that enables a fast diagnosis of the most common viruses and bacteria. The data also imply the need to consider antiviral therapy in positive LRTI cases.

Fast beneficial systemic anti-inflammatory effects of inhaled budesonide and formoterol on circulating lymphocytes in asthma.

Inhaled glucocorticoids and long acting β2‐agonists reduce airway inflammation. It is unclear if this effect is based on the local action of the drugs or is due to a systemic effect on circulating peripheral blood lymphocytes. We assessed whether inhaled budesonide and/or formoterol modify the activity of circulating peripheral blood lymphocytes.

Adenovirus-specific IgG maturation as a surrogate marker in acute exacerbations of COPD.

BACKGROUND B cells in airways and lung parenchyma may be involved in COPD evolution; however, whether their pathogenic role is beneficial or harmful remains controversial. The objective of this study was to investigate the maturation of adenovirus-specific immunoglobulins in patients with COPD with respect to clinical outcome. METHODS The presence of adenovirus-specific immunoglobulins during acute exacerbation of COPD (AECOPD) was analyzed at exacerbation and 2 to 3 weeks later. Patients with detectable adenovirus-specific IgM and low IgG avidity were grouped into fast and delayed IgG maturation. The clinical outcome of both groups was evaluated. RESULTS Of 208 patients, 43 (20.7%) had serologic evidence of recent adenovirus infection and were grouped by fast IgG maturation (26 patients) and delayed IgG maturation (17 patients). Baseline characteristics, AECOPD therapy, and duration of hospitalization were similar in both groups, but the AECOPD recurrence rate within 6 months was higher (P = .003), and there was a trend for earlier AECOPD-related rehospitalizations (P = .061) in the delayed IgG maturation group. The time to rehospitalization or death within 2 years was shorter in patients with delayed IgG maturation (P = .003). Adenovirus-specific IgG maturation was an independent predictor of the number of AECOPD recurrences within 6 months (P = .001) and the occurrence of hospitalization or death within 2 years (P = .005). CONCLUSIONS Delayed immunoglobulin avidity maturation following COPD exacerbation is associated with worse outcomes. TRIAL REGISTRY ISRCTN Register; No.: ISRCTN77261143; URL: www.isrctn.org.