There is a need to develop a better understanding of the role of cytochrome P450 as a protective system against multiple organ dysfunction syndrome (MODS).
A more clear understanding of the molecular mechanisms involved in Pathogen Associated Molecular Pattern (PAMP) / Damage Associated Molecular Pattern (DAMP) mediated cytokine release in MODS; such insight may result in the ultimate development of DAMP and PAMP modulators to prevent and ameliorate MODS.
The evolution and mechanisms of mitochondrial dysfunction and recovery in MODS are not completely established; deficits in mitochondrial metabolic pathways including electron transport system, citric acid cycle, and β oxidation of fatty acids require more evaluation. The ability to assess and monitor relatively rapid changes in mitochondrial function in a clinically relevant time frame is needed such that commonly used drugs which can inhibit / damage mitochondria during MODS may be assessed.
A clear understanding of the molecular mechanisms of macrophage activation in MODS is lacking.
The influence of genetic, epigenetic and environmental factors in determining the risk for immunoparalysis, thrombocytopenia associated MOF (TAMOF), sequential MOF (SMOF), and macrophage activation syndrome (MAS) is not completely understood. Additionally, the impact of intensive care interventions such as medications, transfusions, and mechanical support on the development of immunoparalysis, TAMOF, SMOF, and MAS also requires further elucidation.
The development of standardized immune function testing (e.g. HLA-DR expression, ex vivo lipopolysaccharide (LPS)-stimulated TNF-α production capacity) that can be performed in the clinical laboratory in a clinically relevant time frame is needed.
There is a need to identify strategies for restoring immunologic balance in MODS, potentially including immune modulation medications that target innate and / or adaptive immune function.
The role of FasL and defective activated immune cell death in MODS including liver injury and lymphoproliferation is not completely understood.
Further definition of the role of NK and CD8 cytolytic pathways in normal immune down regulation and in hyper-ferritinemic MODS with macrophage activation syndrome may help advance the field.
The genetic overlap in perforin and granzyme signaling (multiple oligogenic heterozygotes versus homozygous mutants) in pediatric MODS is not clearly elucidated.
There is a need for targeted therapies which control persistent hyper-ferritinemic hyper-inflammatory states without inducing immune suppression.
There is also a need for the development of a rapid and feasible biomarker assay for the identification of TAMOF such as ADAMTS13, vWF and complement activities.
The therapeutic value of plasma exchange in the treatment of TAMOF needs to be better elucidated.
A better understanding of the common mechanistic pathways among various MODS phenotypes is needed.
The role of growth factors and regenerative response in reprogramming after MODS is not well elucidated.
