A systematic review of biomarkers multivariately associated with acute respiratory distress syndrome development and mortality

BACKGROUND: Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established. OBJECTIVE: To provide an overview of the biomarkers that were multivariately associated with ARDS development or mortality. DATA SOURCES: We performed a systematic search in Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar from inception until 6 March 2020. STUDY SELECTION: Studies assessing biomarkers for ARDS development in critically ill patients at risk for ARDS and mortality due to ARDS adjusted in multivariate analyses were included. DATA EXTRACTION AND SYNTHESIS: We included 35 studies for ARDS development (10,667 patients at risk for ARDS) and 53 for ARDS mortality (15,344 patients with ARDS). These studies were too heterogeneous to be used in a meta-analysis, as time until outcome and the variables used in the multivariate analyses varied widely between studies. After qualitative inspection, high plasma levels of angiopoeitin-2 and receptor for advanced glycation end products (RAGE) were associated with an increased risk of ARDS development. None of the biomarkers (plasma angiopoeitin-2, C-reactive protein, interleukin-8, RAGE, surfactant protein D, and Von Willebrand factor) was clearly associated with mortality. CONCLUSIONS: Biomarker data reporting and variables used in multivariate analyses differed greatly between studies. Angiopoeitin-2 and RAGE in plasma were positively associated with increased risk of ARDS development. None of the biomarkers independently predicted mortality. Therefore, we suggested to structurally investigate a combination of biomarkers and clinical parameters in order to find more homogeneous ARDS phenotypes. PROSPERO IDENTIFIER: PROSPERO, CRD42017078957