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      Bacterial regulation of macrophage bacterial recognition receptors in COPD are differentially modified by budesonide and fluticasone propionate

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          Abstract

          Rationale

          Patients with COPD have an increased risk for community-acquired pneumonia, which is further increased by inhaled corticosteroids.

          Objective

          To assess effects of the corticosteroids, budesonide and fluticasone propionate, on macrophage bacterial responses in COPD.

          Methods

          Monocyte-derived macrophages (MDMs) generated from blood monocytes from 10 non-smoker controls (NoS), 20 smokers without COPD (Sm), and 40 subjects with moderate to severe COPD (21 ex-smokers (COPD-ES) and 19 current smokers (COPD-S)) were pre-treated with budesonide or fluticasone (10 nM—1 μM) and challenged with live non-typeable Haemophilus influenzae (NTHI) or Streptococcus pneumoniae (SP). Cell surface bacterial recognition receptor expression (flow cytometry) and cytokine release (bead array) were analyzed.

          Results

          NTHI and SP reduced bacterial recognition receptor expression on MDMs from COPD and Sm, but not NoS (except TLR4). SR-AI and MARCO were reduced by both NTHI and SP, whereas other receptors by either NTHI or SP. Among COPD subjects, COPD-ES demonstrated a greater number of reductions as compared to COPD-S. NTHI reduced SR-AI, MARCO, CD11b, CD35 and CD206 in COPD-ES while only SR-AI and CD11b in COPD-S. SP reduced SRA-1, CD1d, TLR2 and TLR4 in both COPD-ES and COPD-S, and reduced MARCO and CD93 only in COPD-ES. All receptors reduced in COPD by NTHI and most by SP, were also reduced in Sm. Budesonide counteracted the receptor reductions induced by both NTHI (CD206 p = 0.03, MARCO p = 0.08) and SP (SR-AI p = 0.02) in COPD-ES. Fluticasone counteracted only SP-induced reductions in TLR2 (p = 0.008 COPD-ES and p = 0.04 COPD-S) and TLR4 (p = 0.02 COPD-ES). Cytokine release was equivalently reduced by both corticosteroids.

          Conclusions

          Reduction in macrophage bacterial recognition receptors during bacterial exposure could provide a mechanism for the increased pneumonia risk in COPD. Differential effects of budesonide and fluticasone propionate on macrophage bacterial recognition receptor expression may contribute to the higher pneumonia incidence reported with fluticasone propionate.

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          Most cited references35

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          Defective macrophage phagocytosis of bacteria in COPD.

          Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasing cause of hospitalisations and are associated with accelerated progression of airflow obstruction. Approximately half of COPD exacerbations are associated with bacteria and many patients have lower airways colonisation. This suggests that bacterial infection in COPD could be due to reduced pathogen removal. This study investigated whether bacterial clearance by macrophages is defective in COPD. Phagocytosis of fluorescently labelled polystyrene beads and Haemophillus influenzae and Streptococcus pneumoniae by alveolar macrophages and monocyte-derived macrophages (MDM) was assessed by fluorimetry and flow cytometry. Receptor expression was measured by flow cytometry. Alveolar macrophages and MDM phagocytosed polystyrene beads similarly. There was no difference in phagocytosis of beads by MDM from COPD patients compared with cells from smokers and nonsmokers. MDM from COPD patients showed reduced phagocytic responses to S. pneumoniae and H. influenzae compared with nonsmokers and smokers. This was not associated with alterations in cell surface receptor expression of toll-like receptor (TLR)2, TLR4, macrophage receptor with collagenous structure, cluster of differentiation (CD)163, CD36 or mannose receptor. Budesonide, formoterol or azithromycin did not suppress phagocytosis suggesting that reduced responses in COPD MDM were not due to medications. COPD macrophage innate responses are suppressed and may lead to bacterial colonisation and increased exacerbation frequency.
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            Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results.

            Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.
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              Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.

              The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo, budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In a 12-month, randomised, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 yrs, mean forced expiratory volume in one second (FEV1) 36% predicted normal), patients received two inhalations twice daily of either budesonide/formoterol (Symbicort) 160/4.5 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg or placebo. Severe exacerbations and FEV1 (primary variables), peak expiratory flow (PEF), COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta2-agonist and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. FEV1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day 1 versus placebo and budesonide; after 1 week, morning PEF was improved versus placebo, budesonide and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta2-agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Investigation
                Role: ConceptualizationRole: Writing – review & editing
                Role: Formal analysis
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 January 2019
                2019
                : 14
                : 1
                : e0207675
                Affiliations
                [1 ] Veterans Health Administration, Veterans Affairs Western New York Healthcare System at Buffalo, Division of Pulmonary, Critical Care and Sleep Medicine, Buffalo, New York, United States of America
                [2 ] University at Buffalo, State University of New York, Jacobs School of Medicine and Biomedical Sciences, Division of Pulmonary, Critical Care and Sleep Medicine, Buffalo, New York, United States of America
                [3 ] Respiratory GMed, AstraZeneca Gothenburg, Mölndal, Sweden
                [4 ] University at Buffalo, State University of New York, Jacobs School of Medicine and Biomedical Sciences, Department of Medicine, Buffalo, New York, United States of America
                University of Torino, ITALY
                Author notes

                Competing Interests: Author Karin Provost received research grant funding from: 1. Pulmatrix, LLC that immediately preceded the work 2. Pfizer, ASPIRE Awards in Adult Vaccine Research that followed the data collection and overlapped with analysis 3. Clinical Advisory Board, ARSANIS, starting 2017. Author Sanjay Sethi received research grant funding from: 1. AstraZeneca for a separate project on the presence and role of biofilms that overlapped the time frame of the research. 2. National Center for Advancing Translational Science (National Institutes of Health (NIH), CTSA Award) 3. National Institute of Allergy and Infectious Disease (NIAID) (NIH) (co-PI) 4. National Heart, Lung, Blood Institute (NHLBI) Subcontract (NIH). Author Anna Miller-Laarson was a full-time employee at AstraZeneca AB. Author Miyuki Smith, the lab technician, received salary support from the grant funding of AstraZeneca AB, provided by the Buffalo Institute of Medical Research. AstraZeneca AB was allowed, by the VA-approved research CRADA, to review the data and provide comments, but were not allowed to influence the data presented or withhold any parts from publication. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-1735-4046
                Article
                PONE-D-18-13104
                10.1371/journal.pone.0207675
                6345465
                30677037
                31c4f1bb-8e1d-4934-acc7-c989b46f8b95

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 1 May 2018
                : 5 November 2018
                Page count
                Figures: 5, Tables: 2, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100004325, AstraZeneca;
                Award ID: D589BN00039
                Award Recipient :
                The funding from AstraZeneca was provided under the Investigator Initiated Grant mechanism (D589BN00039), which was administered by the Buffalo Institute of Medical Research, the non-profit organization associated with the VA Western New York Healthcare System to administer non-VA grant funding. Sponsor had no role in the data collection, analysis, or the decision to publish. Author Miyuki Smith, the lab technician, received support in the form of a salary from the grant funding. Author Anna Miller-Larsson was a full-time employee of AstraZeneca, and participated in the initial study design, particularly with focus on drug solubility and ensuring equal and appropriate drug concentrations for the experimental design. She did not have any additional role in the study design, data collection and analysis or decision to publish the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Custom metadata
                We will follow the Veterans Affairs Data Management and Access Plan (DMAP): A de-identified, anonymized dataset will be created and shared. As recommended by the VA Office of Research Oversight (ORO), such sharing will take place under a written, fully executed data use agreement (DUA) that adheres to any applicable Informed Consent provisions and prohibits the recipient from identifying or re-identifying (or taking steps to identify or re-identify) any individual whose data are included in the dataset. The de-identified, anonymized dataset will include the dataset used to reach the conclusions drawn in the manuscript. Methods are completely described within the Manuscript body and Supporting Information. De-identified, anonymized datasets for clinical and demographic data (metadata) can also be provided upon request and approval of the local Institutional Review Board. Requests can be made directly to the first author (Dr. Provost) or Dr. Provost and the Research Office at the VA Western New York Healthcare System at Buffalo, Human Research Protections Program administrator Ms. Jill Madden ( jill.madden@ 123456va.gov ).

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