Paving the way for precision medicine v2.0 in intensive care by profiling necroinflammation in biofluids

Abstract

Current clinical diagnosis is typically based on a combination of approaches including clinical examination of the patient, clinical experience, physiologic and/or genetic parameters, high-tech diagnostic medical imaging, and an extended list of laboratory values mostly determined in biofluids such as blood and urine. One could consider this as precision medicine v1.0. However, recent advances in technology and better understanding of molecular mechanisms underlying disease will allow us to better characterize patients in the future. These improvements will enable us to distinguish patients who have similar clinical presentations but different cellular and molecular responses. Treatments will be able to be chosen more "precisely", resulting in more appropriate therapy, precision medicine v2.0. In this review, we will reflect on the potential added value of recent advances in technology and a better molecular understanding of necrosis and inflammation for improving diagnosis and treatment of critically ill patients. We give a brief overview on the mutual interplay between necrosis and inflammation, which are two crucial detrimental factors in organ and/or systemic dysfunction. One of the challenges for the future will thus be the cellular and molecular profiling of necroinflammation in biofluids. The huge amount of data generated by profiling biomolecules and single cells through, for example, different omic-approaches is needed for data mining methods to allow patient-clustering and identify novel biomarkers. The real-time monitoring of biomarkers will allow continuous (re)evaluation of treatment strategies using machine learning models. Ultimately, we may be able to offer precision therapies specifically designed to target the molecular set-up of an individual patient, as has begun to be done in cancer therapeutics.

Fig. 1

Schematic simplification of different modes of parenchymal and immune cell death. Organismal homeostasis is based on a balance between cell renewal and death, which is mediated by apoptosis. Apoptotic blebbing allows quick phagocytic uptake and recycling, which prevents leakage of the cellular content and subsequent inflammation (Arrow 1). In the absence or lack of sufficient phagocytic capacity (Arrow 2), apoptotic caspases cleave Gasdermin E (GSDME) resulting in cell rupture, referred to as secondary necrosis. Similarly, inflammatory caspases cleave Gasdermin D (GSDMD) to induce pyroptosis. Necroptosis is executed by the concerted action of RIPK3 kinase activity and the pseudokinase MLKL, whereas ferroptosis is fulfilled by free radical-induced lipid peroxidation catalyzed by Fe(II). Neutrophils typically die by netosis along expelling neutrophil extracellular traps (NETs), which is dependent on autophagy processes and PAD4-mediated citrullination. Different molecular mechanisms execute plasma membrane rupture, resulting in cellular leakage, defined as necrosis. Release of damage-associated molecular patterns (DAMPs) and inflammatory signaling by necrotic cells subsequently induce inflammation

Fig. 2

Hypothetical model representing major detrimental factors in multiple organ dysfunction syndrome (MODS). MODS mostly develops by the concerted action of four factors: (1) infection, (2) inflammation, (3) parenchymal necrosis (apoptosis, necroptosis, and ferroptosis), and (4) immune cell necrosis (pyroptosis and netosis). These features are responsible for the release of biomolecules (MAMPs, DAMPs, chemokines, and cytokines) in biofluids and the activation of immune cells, which both are often biohazardous worsening tissue damage. Monitoring this in biofluids will be crucial to stratify patients and identify novel potential biomarkers with predictive value. Ultimately, combined intervention strategies controlling infection, inflammation, and necrosis might be the key to effective treatment of MODS. MAMPs, microbe-associated molecular patterns; DAMPs, damage-associated molecular patterns

Fig. 3

Schematic roadmap toward precision medicine v2.0 in critical care. Critical care mostly implies life-threatening situations involving systemic infection, inflammation, and organ dysfunction. Biofluids are an easily accessible source of liquid biopsies that can be used to monitor the evolution of the patient’s critical illness. To date, a clinical diagnosis is typically based on a combination of approaches including physiologic and/or genetic parameters, high-tech diagnostic medical imaging and an extended list of laboratory values determined in biofluids. Blood, urine, saliva, lymphatics, semen, mucus and cerebral spinal fluid (CSF), pleural, peritoneal, and bone marrow fluid are easily accessible biofluids. The cellular and molecular profiling of necrosis and inflammation in biofluids using cutting-edge technologies such as real-time immunodiagnostics, next-generation sequencing, and mass spectrometry will pave the way for precision medicine v2.0 in critical care. This is needed for data-mining approaches to allow patient-clustering, identify novel biomarkers, and develop novel intervention strategies controlling necrosis and inflammation. The real-time monitoring of biomarkers will allow continued (re)evaluation of treatment strategies using machine-learning models