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      Upregulated pneumococcal adhesion molecule (platelet-activating factor receptor) may predispose COPD patients to community-acquired pneumonia

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          Abstract

          Dear editor We read with great interest the recent paper by Braeken et al which analyzed the associations between COPD and community-acquired pneumonia (CAP), published in your journal.1 In this large population-based study, the authors have concluded that the risk of CAP increases fourfold in patients with COPD, independent of smoking status. The authors briefly discuss potential smoking-induced mechanisms leading to increased risk of CAP in COPD, such as host physiological and structural changes, increased bacterial virulence and impaired host immunity. The authors also stress the need for further mechanistic studies on the cause of this increased risk of CAP in COPD patients.1 We believe that some of our recent work is relevant to these findings. We have published several studies that have found increased respiratory tract epithelial expression of specific bacterial adhesion factors in COPD, in particular platelet-activating factor receptor (PAFr) which is the major pneumococcal and Haemophilus influenzae adhesion molecule.2,3 This could well be one important mechanism that the authors did not mention that could significantly increase the risk of Streptococcus pneumoniae respiratory infection in COPD. Pack-years of smoking were strongly related to epithelial PAFr protein levels in COPD patients.2 Notably, S. pneumoniae expresses phosphorylcholine in its cell wall that specifically binds to PAFr, leading to initial attachment and subsequent translocation of bacteria into deeper tissue. In addition, cultured respiratory epithelial cells exposed to cigarette smoke extract exhibited significantly increased PAFr protein expression and greater S. pneumoniae adhesion. Notably, blocking PAFr by specific PAFr-antagonist (WEB-2086) reduced adherence of S. pneumoniae to the levels seen in control cells.4 This opens the possibility that PAFr could be targeted therapeutically in COPD patients to limit chronic bacterial adhesion and potentially acute exacerbations, but also CAP in this vulnerable population. Translational research in this area of bacterial–epithelial interactions is still in its infancy but has huge potential to provide novel insights into COPD pathogenesis and its natural history, as well as new therapeutic targets. Blocking the initial stages of bacterial adhesion and colonization in already activated epithelium in COPD patients could emerge as a promising target for the development of alternate, non-antibiotic pharmacotherapies for the management of the disease and its infective complication.5 Preliminary data in both in vitro and in vivo models is so promising that further clinical research on anti-PAFr therapies is now warranted to ascertain their efficacy in preventing and treating bacterial infections in COPD. There may be broader application to other chronic respiratory diseases, such cystic fibrosis, given that Pseudomonas aeruginosa is the third “common respiratory pathogen” that also adheres to PAFr. Indeed, there seems to be no other obvious mechanism that links these three quite disparate organisms, making them so dangerous to the respiratory tract in very particular circumstances.

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          Most cited references 6

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          Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.

          Inhaled corticosteroids (ICS) are anti-inflammatory drugs that have proven benefits for people with worsening symptoms of chronic obstructive pulmonary disease (COPD) and repeated exacerbations. They are commonly used as combination inhalers with long-acting beta2-agonists (LABA) to reduce exacerbation rates and all-cause mortality, and to improve lung function and quality of life. The most common combinations of ICS and LABA used in combination inhalers are fluticasone and salmeterol, budesonide and formoterol and a new formulation of fluticasone in combination with vilanterol, which is now available. ICS have been associated with increased risk of pneumonia, but the magnitude of risk and how this compares with different ICS remain unclear. Recent reviews conducted to address their safety have not compared the relative safety of these two drugs when used alone or in combination with LABA. To assess the risk of pneumonia associated with the use of fluticasone and budesonide for COPD. We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), clinicaltrials.gov, reference lists of existing systematic reviews and manufacturer websites. The most recent searches were conducted in September 2013. We included parallel-group randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies were included if they compared the ICS budesonide or fluticasone versus placebo, or either ICS in combination with a LABA versus the same LABA as monotherapy for people with COPD. Two review authors independently extracted study characteristics, numerical data and risk of bias information for each included study.We looked at direct comparisons of ICS versus placebo separately from comparisons of ICS/LABA versus LABA for all outcomes, and we combined these with subgroups when no important heterogeneity was noted. After assessing for transitivity, we conducted an indirect comparison to compare budesonide versus fluticasone monotherapy, but we could not do the same for the combination therapies because of systematic differences between the budesonide and fluticasone combination data sets.When appropriate, we explored the effects of ICS dose, duration of ICS therapy and baseline severity on the primary outcome. Findings of all outcomes are presented in 'Summary of findings' tables using GRADEPro. We found 43 studies that met the inclusion criteria, and more evidence was provided for fluticasone (26 studies; n = 21,247) than for budesonide (17 studies; n = 10,150). Evidence from the budesonide studies was more inconsistent and less precise, and the studies were shorter. The populations within studies were more often male with a mean age of around 63, mean pack-years smoked over 40 and mean predicted forced expiratory volume of one second (FEV1) less than 50%.High or uneven dropout was considered a high risk of bias in almost 40% of the trials, but conclusions for the primary outcome did not change when the trials at high risk of bias were removed in a sensitivity analysis.Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I(2) = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate. Budesonide also increased non-fatal serious adverse pneumonia events compared with placebo, but the effect was less precise and was based on shorter trials (OR 1.62, 95% CI 1.00 to 2.62; six more per 1000 treated over nine months; moderate quality). Some of the variation in the budesonide data could be explained by a significant difference between the two commonly used doses: 640 mcg was associated with a larger effect than 320 mcg relative to placebo (subgroup differences: I(2) = 74%, P value 0.05).An indirect comparison of budesonide versus fluticasone monotherapy revealed no significant differences with respect to serious adverse events (pneumonia-related or all-cause) or mortality. The risk of any pneumonia event (i.e. less serious cases treated in the community) was higher with fluticasone than with budesonide (OR 1.86, 95% CI 1.04 to 3.34); this was the only significant difference reported between the two drugs. However, this finding should be interpreted with caution because of possible differences in the assignment of pneumonia diagnosis, and because no trials directly compared the two drugs.No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to permit conclusions to be drawn. Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison.Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations such as fluticasone furoate, for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings.
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            Platelet-activating factor receptor (PAFr) is upregulated in small airways and alveoli of smokers and COPD patients.

            PAFr is a cell adhesion site for specific bacteria, notably non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae. We previously published that PAFr expression is significantly upregulated in the large airways of smokers, especially in COPD. We have now investigated PAFr expression in the epithelium and Rbm of small airways and in the alveolar compartment in smokers and patients with both COPD and small airway disease.
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              An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke

              Background COPD is emerging as the third largest cause of human mortality worldwide after heart disease and stroke. Tobacco smoking, the primary risk factor for the development of COPD, induces increased expression of platelet-activating factor receptor (PAFr) in the lung epithelium. Nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae adhere to PAFr on the luminal surface of human respiratory tract epithelial cells. Objective To investigate PAFr as a potential drug target for the prevention of infections caused by the main bacterial drivers of acute exacerbations in COPD patients, NTHi and S. pneumoniae. Methods Human bronchial epithelial BEAS-2B cells were exposed to cigarette smoke extract (CSE). PAFr expression levels were determined using immunocytochemistry and quantitative polymerase chain reaction. The epithelial cells were challenged with either NTHi or S. pneumoniae labeled with fluorescein isothiocyanate, and bacterial adhesion was measured using immunofluorescence. The effect of a well-evaluated antagonist of PAFr, WEB-2086, on binding of the bacterial pathogens to BEAS-2B cells was then assessed. In silico studies of the tertiary structure of PAFr and the binding pocket for PAF and its antagonist WEB-2086 were undertaken. Results PAFr expression by bronchial epithelial cells was upregulated by CSE, and significantly associated with increased bacterial adhesion. WEB-2086 reduced the epithelial adhesion by both NTHi and S. pneumoniae to levels observed for non-CSE-exposed cells. Furthermore, it was nontoxic toward the bronchial epithelial cells. In silico analyses identified a binding pocket for PAF/WEB-2086 in the predicted PAFr structure. Conclusion WEB-2086 represents an innovative class of candidate drugs for inhibiting PAFr-dependent lung infections caused by the main bacterial drivers of smoking-related COPD.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2017
                24 October 2017
                : 12
                : 3111-3113
                Affiliations
                [1 ]School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan
                [2 ]Hunter Medical Research Institute, New Lambton Heights, NSW
                [3 ]School of Medicine, University of Tasmania, Hobart, TAS, Australia
                [1 ]Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht
                [2 ]Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands
                [3 ]Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
                [4 ]Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht
                [5 ]Department of Research and Education, CIRO, Horn, the Netherlands
                [6 ]Department of Health eResearch, University of Manchester, Manchester, UK
                Author notes
                Correspondence: Eugene Haydn Walters, School of Medicine, University of Tasmania, 17 Liverpool Street, Private Bag 23, Hobart, TAS 7000, Australia, Email haydn.walters@ 123456utas.edu.au
                Correspondence: Frank de Vries, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO box 80082, 3508 TB Utrecht, the Netherlands, Tel +31 30 253 7324, Fax +31 30 253 9166, Email f.devries@ 123456uu.nl
                Article
                copd-12-3111
                10.2147/COPD.S151142
                5661495
                © 2017 Shukla et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Letter

                Respiratory medicine

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