Towards a biological definition of ARDS: are treatable traits the solution?

Abstract

The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses.

Keywords: ARDS; Biomarker; Definition; Diagnosis; Pathophysiology; Phenotype.

Fig. 1

There are many ways to parse ARDS into subgroups. Different ways to parse the ARDS population into subgroups some of which are subphenotypes. One patient can, therefore, belong to many different subgroups simultaneously, each of which could be a treatable trait. Top row from left to right: unselected ARDS; Berlin severity with mild, moderate and severe ARDS based on PaO2/FiO2 (light to dark blue); pulmonary (dark blue) and non-pulmonary (light orange) causes for ARDS; Focal (green) and non-Focal (yellow) ARDS based on chest CT. Bottom row from left to right: patients with (red) and without (yellow) apparent endothelial dysfunction; with (dark blue) and without (light blue) apparent epithelial injury; hyperinflammatory (orange) and hypoinflammatory systemic host response; hyperinflammatory (dark purple) and hypoinflammatory (light purple) alveolar host response

Fig. 2

Biological integration of potential treatable traits. The described domains of biological variation do not exist in isolation of each other (Fig. 1). An individual patient could, therefore, be classified according to a conceptional framework that evaluates the three major components of an alveolar unit (endothelium, interstitium with extra-cellular matrix, and epithelium) and the balance of host response between alveolar and blood compartment [71]. We speculate that the position of an individual, based on information pertaining to these component parts in alveolar fluid relative to the circulation, becomes critical in understanding a patient’s biological signature and may inform targeted treatment at a given moment in time. Finally, insights of mechanistic signatures through integration of biological data from other progressive pulmonary pathologies could offer opportunities for drug repurposing in different phases of ARDS, for instance, from interstitial pulmonary fibrosis to ARDS fibrosis [70]