Robert C. Read

BTS guidelines for the management of community acquired pneumonia in adults: update 2009

A summary of the initial management of patients admitted to hospital with suspected community acquired pneumonia (CAP) is presented in fig 8. Tables 4 and 5, respectively, summarise (1) the relevant microbiological investigations and (2) empirical antibiotic choices recommended in patients with CAP. Figure 8 Hospital management of community acquired pneumonia (CAP) in the first 4 h. CXR, chest x ray; DBP, diastolic blood pressure; SBP, systolic blood pressure. View this table: Table 4 Recommendations for the microbiological investigation of community acquired pneumonia (CAP) View this table: Table 5 Initial empirical treatment regimens for community acquired pneumonia (CAP) in adults ### Investigations ( Section 5 ) #### When should a chest radiograph be performed in the community? 1. It is not necessary to perform a chest radiograph in patients with suspected CAP unless: 2. #### When should a chest radiograph be performed in hospital? 1. All patients admitted to hospital with suspected CAP should have a chest radiograph performed as soon as possible to confirm or refute the diagnosis. [D] The objective of any service should be for the chest radiograph to be performed in time for antibiotics to be administered within 4 h of presentation to hospital should the diagnosis of CAP be confirmed. #### When should the chest radiograph be repeated during recovery? 1. The chest radiograph need not be repeated prior to hospital discharge in those who have made a satisfactory clinical recovery from CAP. [D] 2. A chest radiograph should be arranged after about 6 weeks for all those patients who have persistence of symptoms or physical signs or who are at higher risk of underlying malignancy (especially smokers and those aged >50 years) whether or not they have been admitted to hospital. [D] 3. Further investigations which may include bronchoscopy should be considered in patients with persisting signs, symptoms …

Guidelines for the management of adult lower respiratory tract infections ‐ Full version

Abstract This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. Background sections and graded evidence tables are also included. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.

Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis

OBJECTIVE Genetic variation in the gene for interleukin-6 (IL-6) contributes to the pathogenesis of inflammatory arthritis, but the role, if any, of epigenetic variability has not been reported. The aims of this study were to compare the DNA methylation status of the IL6 promoter in rheumatoid arthritis (RA) patients and control subjects and to study the effects on gene expression. METHODS Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) obtained from RA patients and healthy controls. Macrophages from healthy controls were isolated and stimulated with lipopolysaccharide (LPS). Methylation status was determined using bisulfite genomic sequencing and IL6 messenger RNA (mRNA) levels by quantitative polymerase chain reaction. Gel shift assays were performed with methylated or unmethylated probes and HeLa cell nuclear extract. RESULTS The proximal CpG motifs (-666 to +27) were predominantly unmethylated and the upstream motifs (-1099 to -1001) were highly methylated in PBMCs from patients and controls. Methylation of individual CpG motifs was similar, except at -1099C, which was less methylated in the patients than in the controls (58% versus 98%; P = 1 x 10(-6)). To test whether this observation might relate to gene regulation, LPS-stimulated macrophages were grouped according to their IL6 mRNA stimulation index (SI). The level of methylation at -1099C was significantly lower in the group with high (SI >75) compared with the group with low (SI <10) induced mRNA levels (71% versus 93%; P = 0.007). Gel shift assays revealed decreased protein binding to the -1099C unmethylated probe. CONCLUSION These data suggest that methylation of a single CpG in the IL6 promoter region may affect IL6 gene regulation and may play a role in the pathogenesis of RA.

A Functional Polymorphism of Toll-like Receptor 4 Is Not Associated with Likelihood or Severity of Meningococcal Disease

Human Toll-like receptor 4 (TLR4) transduces proinflammatory cytokine release by human cells in response to lipopolysaccharide (LPS). This study tested the hypothesis that, if TLR4 is rate limiting for a successful response to bacterial LPS in humans, a human gene polymorphism that results in the amino acid substitution Asp299Gly and causes reduced expression and function of TLR4 should influence susceptibility to or severity of natural gram-negative infection. The allele frequency of the Asp299Gly polymorphism was 5.9% among 879 blood donors, 6.5% among 1047 patients with microbiologically proven meningococcal disease, and 4.1% among 86 patients who died of meningococcal disease. No significant differences were observed, including those analyzed after stratification of the infected population by age and by meningococcal serogroup. Therefore, this functional TLR4 polymorphism does not influence susceptibility to or severity of meningococcal disease.

Mannose-Binding Lectin Regulates the Inflammatory Response of Human Professional Phagocytes to Neisseria meningitidis Serogroup B

The influence of the innate immune protein mannose-binding lectin (MBL) on the response of human phagocytes to Neisseria meningitidis was investigated. MBL increased the association of killed meningococci with neutrophils, monocytes, and macrophages by increasing the proportion of cells that recognized bacteria. MBL down-regulated the normal change in expression of the leukocyte adhesion molecules CD11b and CD62L. In an ex vivo model, the addition of MBL to the blood of MBL-deficient donors influenced the production of monocyte-derived inflammatory cytokines. The addition of high concentrations of MBL (>6 microg/mL) profoundly decreased the production of interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha by monocytes in response to meningococci, whereas lower concentrations enhanced the production of IL-6 and IL-1beta. These results suggest that MBL not only is involved in complement activation but also is a potent regulator of inflammatory pathways and, as such, may affect the severity of meningococcal disease.

Toll-Like Receptors in Health and Disease: Complex Questions Remain

Until recently, the manner in which we respond to pathogens was obscure. It is now clear that a family of proteins, the Toll-like receptors (TLRs),[3][1] contribute to the signal transduction induced by many pathogen-associated molecular patterns (PAMPs), and perhaps also to endogenous damage

Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May–September 2009)

Background During the first wave of pandemic H1N1 influenza in 2009, most cases outside North America occurred in the UK. The clinical characteristics of UK patients hospitalised with pandemic H1N1 infection and risk factors for severe outcome are described. Methods A case note-based investigation was performed of patients admitted with confirmed pandemic H1N1 infection. Results From 27 April to 30 September 2009, 631 cases from 55 hospitals were investigated. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged ≥65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically-confirmed pneumonia and a raised C-reactive protein (CRP) level (≥100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people. Conclusions Pandemic H1N1 infection causes disease requiring hospitalisation of previously fit individuals as well as those with underlying conditions. An abnormal chest x-ray or a raised CRP level, especially in patients who are recorded as obese or who have pulmonary conditions other than asthma or COPD, indicate a potentially serious outcome. These findings support the use of pandemic vaccine in pregnant women, children <5 years of age and those with chronic lung disease.

Identification of In Vivo–Expressed Antigens of Staphylococcus aureus and Their Use in Vaccinations for Protection against Nasal Carriage

A spectrum of in vivo-expressed Staphylococcus aureus antigens was identified by probing bacteriophage expression libraries of S. aureus with serum samples from infected and uninfected individuals. Eleven recombinant antigenic proteins were produced, and specific antibody titers in a large collection of human serum samples were determined. Significantly increased concentrations of reactive immunoglobulin G (IgG) to 7 antigens were found in serum samples from ill individuals, compared with those in healthy individuals. Significantly higher concentrations of reactive IgG to 4 antigens, including iron-responsive surface determinant (Isd) A and IsdH, were found in serum samples from healthy individuals who were not nasal carriers of S. aureus, compared with those in healthy carriers. Vaccination of cotton rats with IsdA or IsdH protected against nasal carriage. Also, IsdA is involved in adherence of S. aureus to human desquamated nasal epithelial cells and is required for nasal colonization in the cotton rat model. Thus, vaccination with these antigens may prevent S. aureus carriage and reduce the prevalence of human disease.

von Willebrand factor is an acute phase reactant in man.

Plasma von Willebrand factor antigen (vWfAg) concentrations in 19 patients with acute infectious illnesses of bacterial, viral or parasitic origin were significantly elevated with a mean greater than 3-fold above normal. In individual patients the elevation of vWf correlated strongly with the elevation of serum C-reactive protein (CRP). When patients were studied longitudinally, vWfAg and CRP concentrations both returned to normal values over 3-4 weeks. Similarly, in 14 volunteers infected with cold virus, vWfAg and CRP levels rose significantly and fell together during the course of infection. VWf is thus an acute phase reactant in man.

Guidelines for the management of adult lower respiratory tract infections - Summary

This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.