A Systematic Review of Biomarkers Multivariately Associated With Acute Respiratory Distress Syndrome Development and Mortality

Philip van der Zee; Wim Rietdijk; Peter Somhorst; Henrik Endeman; Diederik Gommers


Crit Care. 2020;24(243) 

In This Article

Abstract and Introduction


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


The acute respiratory distress syndrome (ARDS) is a major problem in the intensive care unit (ICU) with a prevalence of 10% and an in-hospital mortality rate of 40%.[1,2] ARDS pathophysiology is based on a triad of alveolar-capillary membrane injury, high permeability alveolar oedema, and migration of inflammatory cells.[3] This triad is not routinely measured in clinical practice. Therefore, arterial hypoxemia and bilateral opacities on chest imaging following various clinical insults are used as clinical surrogates in the American European Consensus Conference (AECC) definition and the newer Berlin definition of ARDS.[4,5]

Histologically, ARDS is characterized by diffuse alveolar damage (DAD). The correlation between a clinical and histological diagnosis of ARDS is poor.[6] Only half of clinically diagnosed patients with ARDS have histological signs of DAD at autopsy.[7–10] The number of risk factors for ARDS and consequently the heterogeneous histological substrates found in patients with clinical ARDS have been recognized as a major contributor to the negative randomized controlled trial results among patients with ARDS.[11]

It has been suggested that the addition of biomarkers to the clinical definition of ARDS could reduce ARDS heterogeneity by the identification of subgroups.[12–15] A retrospective latent class analysis of large randomized controlled trials identified two ARDS phenotypes largely based on ARDS biomarkers combined with clinical parameters.[16,17] These phenotypes responded differently to the randomly assigned intervention arms. Prospective studies are required to validate these ARDS phenotypes and their response to interventions. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established.

Numerous biomarkers and their pathophysiological role in ARDS have been described.[12,18] In an earlier meta-analysis, biomarkers for ARDS development and mortality were examined in univariate analysis.[19] However, pooling of univariate biomarker data may result in overestimation of the actual effect. For this reason, we conducted a systematic review and included all biomarkers that were multivariately associated with ARDS development or mortality. This study provides a synopsis of ARDS biomarkers that could be used for future research in the identification of ARDS phenotypes.