The acute respiratory distress syndrome biomarker pipeline: crippling gaps between discovery and clinical utility

Abstract

Recent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into "personalized" medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. The unmet need for biomarkers in acute respiratory distress syndrome (ARDS) is for reliable and validated biomarkers that minimize heterogeneity and allow for stratification of subject selection for enrollment in clinical trials of tailored therapies. This unmet need is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. The unprecedented numbers of COVID-19-induced ARDS cases has strained health care systems across the world and exposed the need for biomarkers that would accelerate drug development and the successful phenotyping of COVID-19-infected patients at risk for development of ARDS and ARDS mortality. Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies.

Fig 1

ARDS biomarkers by category. The majority of candidate ARDS biomarkers involve dysregulation of the following pathways: endothelial injury, epithelial injury, inflammatory cascade, coagulation cascade, or fibrosis and apoptosis. Studies have mostly assessed the diagnostic and prognostic performance of these candidate biomarkers. Ang-2, angiopoietin 2; HMGB1, high mobility group box nuclear protein 1; IL-1β, interleukin 1 beta; IL-1RA, interleukin 1 receptor antagonist; IL-6, interleukin 6; IL-8, interleukin 8; MIP-1α, macrophage inflammatory protein-1α; eNAMPT, extracellular nicotinamide phosphoribosyltransferase; sRAGE, soluble receptor for advanced glycation end products; VEGF, vascular endothelial growth factor.

Fig 2

Steps in the biomarker development pipeline. There are 4 phases in the biomarker development pipeline. Biomarker discovery is the initial preclinical description of an association with a disease process. Analytical validation involves the assessment of the performance of the assay in specific samples. How reliably does the test measure the analytes of interest in the patient specimen? Clinical validation assesses how robustly and reliably is the test result correlated with the clinical phenotype or outcome of interest. Regulatory qualification and approval is required prior to clinical implementation of a biomarker. The FDA regulates initial biomarker qualification in the USA. IVD, in vitro diagnostic products are classified by the FDA to determine the appropriate premarket process. The FDA does not enforce premarket review of LDT – laboratory developed test – in vitro diagnostic test designed, manufactured and used within a single laboratory. CLIA, Clinical Laboratory Improvement Amendments, regulate laboratory testing and require clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing. CPT, Common Procedural Terminology.

Fig 3

ARDS biomarkers in the development continuum. The majority of the current candidate biomarkers have laboratory developed or commercially available assays that have undergone some form of analytical validation. No biomarker has cleared the threshold for robust and reliable clinical validation. Biomarkers are listed by type of dysregulated pathway. Ang-2, angiopoietin 2; CC16, Clara cell secretary protein; HGF, hepatocyte growth factor; HTI₅₆, human alveolar type I cell protein; KL-6, Krebs von den Lungen-6; HMGB1, high mobility group box nuclear protein 1; iCAM-1, intracellular adhesion molecule 1; IL-1β, interleukin 1 beta; IL-1RA, interleukin 1 receptor antagonist; IL-6, interleukin 6; IL-8, interleukin 8; KGF*, keratinocyte growth factor; MMP, matrix metalloproteinase; MIF, macrophage migration inhibitory factor; MIP-1α, macrophage inflammatory protein-1α; eNAMPT, extracellular nicotinamide phosphoribosyltransferase; PAI-1, plasminogen activator inhibitor-1; S1PR3, sphingosine-1phosphate receptor 3; SP-D, surfactant protein D; sRAGE, soluble receptor for advanced glycation end products; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor. Elastin*, Laminin*. *No evidence of analytical validation.