Innovative cell death diagnostics allowing stratifying critically ill patients for novel ferroptosis or pyroptosis intervention strategies

The complexity of critical illness in intensive care essentially requires a precision approach. Organ failure and sepsis are key detrimental factors in critical illness, and fundamentally driven by an auto-amplifying loop of cell death and inflammation. This process feeds dynamic disease fluctuations and heterogeneity in critical care, which might partially explain inconsistent translatability. Patients with similar clinical presentations typically have different cellular and molecular responses due to individual differences and co- morbidities. To deal with this form of heterogeneity, innovative biomarkers with predictive value are needed to allow determining subtypes of clinically similar patients. There is a growing list of circulating detrimental biomolecules related to some forms of regulated non-apopoptic cell death (i.e. so-called ferroptotic and pyroptotic cell death), which are druggable and allow stratifying critically ill patients. Actually, we discovered that therapeutic targeting ferroptosis or pyroptosis respectively increased survival in experimental models of multi organ failure or septic shock. To allow follow-up of clinical intervention studies, real-time diagnostics for these detrimental factors are needed. Dynamic monitoring of a panel of cytokines in critically ill patients showed prognostic value for 30-day survival, septic shock and organ injury. To level up our proof of concept, we want to conduct a translational study in critically ill patients by using real-time immunodiagnostics to detect ferroptosis and pyroptosis; which should allow quick stratification for the linked targeted therapies thereby preventing organ/systemic dysfunction and mortality. To detect general tissue injury due to excess cell death, we also optimized a procedure to episequence plasma cell free DNA (cfDNA) using real-time Oxford Nanopore Technology. As a potential future complementary diagnostic tool, we want to determine the diagnostic power of nanopore episequencing to detect tissue specific cell death. To process the clinical and molecular fingerprint of the critically ill determined in biofluids, we additionally use big data mining approaches in these phenotypically well-characterized patients. Precision intervention based on innovative real-time molecular diagnostics and stratification could bring diagnostics in intensive care into the 21st century and pinpoint which patients are likely to benefit from a certain treatment.

Keywords:CELLULAR TOXICITY, INTENSIVE CARE

Disciplines:Diagnostics not elsewhere classified, Intensive care and emergency medicine not elsewhere classified, Biomarker discovery and evaluation not elsewhere classified