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      Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC)

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          Abstract

          Asthma prevalence in Italy is on the rise and is estimated to be over 6% of the general population. The diagnosis of asthma can be challenging and elusive, especially in children and the last two decades has brought evidences that asthma is not a single disease but consists of various phenotypes. Symptoms can be underestimated by the patient or underreported to the clinician and physical signs can be scanty. Usual objective measures, like spirometry, are necessary but sometimes not significant. Despite proper treatment, asthma can be a very severe condition (even leading to death), however new drugs have recently become available which can be very effective in its control. Since asthma is currently thought to be caused by inflammation, a direct measure of the latter can be of paramount importance. For this purpose, the measurement of Fractional Exhaled Nitric Oxide (FE NO) has been used since the early years of the current century as a non-invasive, easy-to-assess tool useful for diagnosing and managing asthma. This SIP-IRS/SIAAIC Position Paper is a narrative review which summarizes the evidence behind the usefulness of FE NO in the diagnosis, management and phenotypization of asthma.

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          Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

          Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

            Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.
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              A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

              Breath tests cover the fraction of nitric oxide in expired gas (FeNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FeNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FeNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.
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                Author and article information

                Journal
                Multidiscip Respir Med
                MRM
                Multidisciplinary Respiratory Medicine
                PAGEPress Publications, Pavia, Italy
                1828-695X
                2049-6958
                19 February 2020
                28 January 2020
                : 15
                : 1
                : 36
                Affiliations
                [1 ]Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS , Rozzano (MI)
                [2 ]Department of Biomedical Sciences, Humanitas University , Pieve Emanuele (MI)
                [3 ]Department of Medical and Surgical Sciences, University of Foggia; Section of Respiratory Diseases , Hospital d'Avanzo , Foggia
                [4 ]Department of Medicine-DIMED, Immunological and Respiratory Rare Disease, Allergologic Clinic Ca’ Foncello Hospital , Treviso
                [5 ]Allergy and Pneumology Unit, A.O. S. Croce e Carle , Cuneo
                [6 ]Respiratory Rehabilitation Unit, ICS Maugeri, Institute of Telese Terme IRCCS
                [7 ]Institute of Biomolecular Chemistry , National Research Council , Pozzuoli (NA)
                [8 ]Allergy and Clinical Immunology, University of Turin and A.O. Mauriziano , Turin
                [9 ]Department of Woman's and Child's Health, University Hospital of Padua
                [10 ]Department of Woman, Child and of General and Specialized Surgery, University of Campania "Luigi Vanvitelli" , Naples
                [11 ]Paediatric Section, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona
                [12 ]Italian Respiratory Society-Società Italiana di Pneumologia , Milan, Italy
                Author notes
                Italian Respiratory Society-Societa Italiana di Pneumologia, Milan, Italy. snardini.pneumologo@ 123456gmail.com

                Contributions: All the authors made a substantive intellectual contribution, read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

                Conflict of interest: EH, SN are consultants of Circassia AB; SN is Coordinator of the Associate Editors of the Editorial Board of Multidisciplinary Respiratory Medicine. The remaining authors have no conflict of interest to declare.

                Ethics approval and consent to participate: Not applicable.

                Article
                10.4081/mrm.2020.36
                7137762
                32269772
                77933ea3-e234-40cf-8ac8-6430410fc113
                ©Copyright: the Author(s), 2020

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                History
                : 04 December 2019
                : 05 February 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 259, Pages: 20
                Funding
                Funding: This position paper jointly produced by the Italian Society of Asthma, Allergy and Clinical Immunology (SIAAIC) and the Italian Respiratory Society (SIP-IRS) has been made possible thank to an unconditioned educational grant of Circassia AB, Hansellisgatan 13, SE-754 50 Uppsala, Sweden.
                Categories
                Position Paper

                Respiratory medicine
                asthma diagnosis,asthma management,fractional exhaled nitric oxide (feno)

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