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      Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine

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          Abstract

          Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for “lumping and splitting” are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939).

          Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-related genes in sepsis-induced and influenza-induced ARDS, but whole blood expression does not give a robust diagnostic test for ARDS.

          Despite improvements in management of ARDS on the critical care unit, this complex disease continues to be a major life-threatening event. Clinical trials of β 2-agonists, statins, surfactants and keratinocyte growth factor (KGF) have been disappointing. In addition, monoclonal antibodies (anti-TNF) and TNFR fusion protein have also been unconvincing. However, there have been major advances in methods of mechanical ventilation, a neuromuscular blocker (cisatracurium besilate) has shown some benefit, and stem cell therapy is being developed. In the future, by understanding the role of biomarkers in the pathophysiology of ARDS and lung injury, it is hoped that this will provide rational therapeutic targets and ultimately improve clinical care (Seymour CW, Gomez H, Chang CH, Clermont G, Kellum JA, Kennedy J, Yende S, Angus DC, Crit Care 2017, 21:257).

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          Most cited references56

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          Acute Respiratory Distress Syndrome

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            Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome.

            The novel influenza A(H1N1) pandemic affected Australia and New Zealand during the 2009 southern hemisphere winter. It caused an epidemic of critical illness and some patients developed severe acute respiratory distress syndrome (ARDS) and were treated with extracorporeal membrane oxygenation (ECMO). To describe the characteristics of all patients with 2009 influenza A(H1N1)-associated ARDS treated with ECMO and to report incidence, resource utilization, and patient outcomes. An observational study of all patients (n = 68) with 2009 influenza A(H1N1)-associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand between June 1 and August 31, 2009. Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival. Sixty-eight patients with severe influenza-associated ARDS were treated with ECMO, of whom 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8), representing an incidence rate of 2.6 ECMO cases per million population. An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs. The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) Pao(2)/fraction of inspired oxygen (Fio(2)) ratio of 56 (48-63), positive end-expiratory pressure of 18 (15-20) cm H(2)O, and an acute lung injury score of 3.8 (3.5-4.0). The median (IQR) duration of ECMO support was 10 (7-15) days. At the time of reporting, 48 of the 68 patients (71%; 95% confidence interval [CI], 60%-82%) had survived to ICU discharge, of whom 32 had survived to hospital discharge and 16 remained as hospital inpatients. Fourteen patients (21%; 95% CI, 11%-30%) had died and 6 remained in the ICU, 2 of whom were still receiving ECMO. During June to August 2009 in Australia and New Zealand, the ICUs at regional referral centers provided mechanical ventilation for many patients with 2009 influenza A(H1N1)-associated respiratory failure, one-third of whom received ECMO. These ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.
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              Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury.

              β₂-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies. This clinical trial was designed to test the hypothesis that an aerosolized β₂-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI). We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P = 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95%confidence interval for the difference,-4.0 to 14.7%;P = 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of β₂-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).
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                Author and article information

                Contributors
                spdsvn@unife.it
                mirae.park@nhs.net
                cecilia.turrini@hotmail.com
                Tanushree.tunstall@lshtm.a.c.uk
                r.thwaites@imperial.ac.uk
                tommaso.mauri@unimi.it
                rgc@unife.it
                plrugger@unime.it
                t.hansel@imperial.ac.uk
                gcaramori@unime.it
                0039-0532236451 , vlc@unife.it
                Journal
                J Inflamm (Lond)
                J Inflamm (Lond)
                Journal of Inflammation (London, England)
                BioMed Central (London )
                1476-9255
                15 January 2019
                15 January 2019
                2019
                : 16
                : 1
                Affiliations
                [1 ]ISNI 0000 0004 1757 2064, GRID grid.8484.0, Department of Morphology, Surgery and Experimental Medicine, Intensive Care Section, , University of Ferrara, ; 44121 Ferrara, Italy
                [2 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Faculty of Medicine, , National Heart and Lung Institute, Imperial College London, ; London, UK
                [3 ]ISNI 0000 0004 1757 8749, GRID grid.414818.0, Department of Anesthesia, Critical Care and Emergency, , Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ; Milan, Italy
                [4 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Unità Operativa Complessa di Pneumologia, Dipartimento di Scienze Biomediche, , Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, ; Messina, Italy
                Author information
                http://orcid.org/0000-0003-3533-6121
                Article
                202
                10.1186/s12950-018-0202-y
                6332898
                30675131
                a8e9bd91-1ac9-453a-8275-d1527ab84728
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 11 August 2018
                : 22 November 2018
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Immunology
                acute respiratory distress syndrome,biomarkers,inflammatory
                Immunology
                acute respiratory distress syndrome, biomarkers, inflammatory

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