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-19infected 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.

Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress

“…In addition to LPSs and TNF-α, excessive mechanical stress from mechanical ventilation also contributes to the development of severe inflammatory lung injury and vascular leakage driving the severity of ARDS/VILI [ 36 ]. Based on calculations, high tidal volume ventilation resulting in ∼40–50% increases in lung alveolar surface is reflected in vitro by exposure to 18% CS [ 30 , 37 ].…”

Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury

“…Acknowledging the difficulty in identifying specific ARDS sub-phenotypes, due to heterogeneity in host responses to SARS-CoV-2 infection, we also highlight the unmet need for biomarkers predictive of a pathologic hyperinflammatory viral host response versus a physiologic host response. 21 , 22 , 23 Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.…”

“…In addition to dysregulated cytokine release, excessive secretion of proteases and generation of reactive oxygen species (ROS) by infiltrating immune cells contribute to the hyperinflammation characteristic of severe COVID-19 disease ( Figure 2 ). The role of circulating levels of these proteins as diagnostic or prognostic biomarkers has been extensively investigated in non-COVID-19 ARDS 21 , 54 , 55 but to date have not yet been utilized in clinical decision-making. 55 In COVID-19 ARDS, the utility of plasma biomarkers as important diagnostic or prognostic biomarkers and as targets for therapeutics remains under investigation.…”

The Association Between the Baseline and the Change in Neutrophil-to-Lymphocyte Ratio and Short-Term Mortality in Patients With Acute Respiratory Distress Syndrome

“…Although many studies have assessed the prognosis of ARDS patients, none of the biomarkers is perfect (31). NLR is the ratio of neutrophil count to lymphocyte count that can be obtained through routine blood tests without any additional cost, which may make it more convenient for clinical use.…”