CHAPTER 16: Molecular Biomarkers in Critical Care Medicine

KEY POINTS

• All biomarker measurements must be actionable, that is, they must direct action/decisions leading to improved patient outcomes. A limited number of actionable biomarkers have been developed in critical care medicine.

• Common functions of biomarkers include diagnostic, to follow response to therapy, to subphenotype, to identify patients who will likely respond to a specific therapy (theragnostic), to decrease heterogeneity in clinical trial cohorts, and prognostic.

• Measurements of single proteins have been the most common type of molecular biomarkers but miRNAs, gene expression arrays, DNA assays, other metabolites, and multiplex “omics” panels combining clinical variables with a variety of these molecular biomarkers are becoming common.

• Critical care medicine syndromes such as sepsis, shock, ARDS, and AKI result from diverse pathophysiological processes and disease states, so molecular biomarkers, which arise from specific (not diverse) metabolic pathways, are often insensitive and nonspecific. Using arrays of biomarkers to subphenotype critical illness syndromes into specific pathophysiologic processes or disease states is likely to greatly enhance the value of molecular biomarkers in directing therapeutic action targeted at the underlying pathophysiologic mechanisms.

INTRODUCTION

Bedside clinical examination and typical laboratory and radiologic assessment are often insensitive and nonspecific for identifying and characterizing critical illnesses since a clinical presentation can arise from a variety of very different pathophysiologic processes and disease states. Therefore, the addition of biomarkers to our armamentarium holds great promise.

The Problem

Biomarkers have been highly successful in transforming care in cardiology, oncology, and other fields. In critical care medicine, the development and use of biomarkers is increasing. However, progress has not been as rapid in part because most critical care illnesses are syndromes (eg, sepsis, shock, acute respiratory distress syndrome [ARDS], acute kidney injury [AKI], etc.) rather than diagnostic entities having specific underlying pathophysiological mechanisms. Furthermore, many critical illnesses prominently affect multiple organ systems, each one differently, and often involve an inflammatory response. Inflammatory responses are highly heterogeneous, generally involving many inflammation-associated pathways, thousands of genes and their transcripts, and hundreds to thousands of proteins and other metabolites.¹ As a result, individual DNA, RNA, protein, or metabolite measurements are typically neither sufficiently sensitive nor specific to provide firm information to confidently direct changes in clinical management of critically ill patients.

In discussing biomarkers, it is also important to recognize the almost paradoxical truth that many standard, useful, actionable biomarkers in other fields of medicine are neither sensitive nor specific in critically ill patients. Troponin, D-dimer, thyroid stimulating hormone (TSH), thyroxine, ferritin, a cosyntropin stimulation test, brain natriuretic peptide (BNP), etc., are no longer as diagnostic and actionable as they are in noncritically ill patients.

Promise of Molecular Biomarkers

Nevertheless, the potential for a beneficial role for molecular biomarkers in critical illnesses is very high for precisely the same reasons that make biomarker development challenging in critical illnesses. That ...