Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis

Adrien Carla,Céline Lambert,Manuela De Carvalho,Vincent Sapin,Julie A Bastarache,Raïko Blondonnet ,Patrícia Rieken Macêdo Rocco ,Lieuwe D J Bos ,Nathalie Piñol-Domenech ,Ruoyang Zhai,Michael A Matthay,Nicole P Juffermans,Jules Audard,Lorraine B Ware,John G Laffey,Bruno Pereira,Dominique Morand,Antonio Artigas,Hanifa Boukail,Jean-Michel Constantin,Carolyn S Calfee,Daniel F Mcauley,Matthieu Jabaudon

doi:10.1186/s12931-020-01337-9

Abstract

BackgroundSubphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.MethodsWe will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.DiscussionThis study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.Systematic review registrationPROSPERO (ID: CRD42019157236).

Highlights

Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses
This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation
While benefit has been demonstrated in numerous preclinical studies for many candidate therapies, most have failed to translate to improved patient outcomes in randomized clinical trials (RCTs), suggesting that the appropriate subset of patients to target with the novel therapies may not have been correctly identified [8]

Summary

Introduction

Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits. Various pharmacotherapeutic agents have failed to improve ARDS outcomes and current treatment strategy is largely supportive, based on optimized ventilatory settings [1]. The clinical and biological heterogeneity within syndromes such as sepsis ARDS makes it essential to identify more homogeneous subphenotypes when investigating potential therapies [4, 5]. There has been recent recognition of distinct subphenotypes (on the basis of clinical/biochemical variables, natural history, disease manifestation, and/or treatment response without any implication about mechanism) and endotypes (defined by a distinct functional/pathobiological mechanism) within patients with ARDS [4, 6, 7]. While benefit has been demonstrated in numerous preclinical studies for many candidate therapies, most have failed to translate to improved patient outcomes in randomized clinical trials (RCTs), suggesting that the appropriate subset of patients to target with the novel therapies may not have been correctly identified [8]

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