295 General discussion inflammatory features, resulting in damage to the host [1]. This general description immediately indicates that it remains difficult to properly define sepsis - there is no gold standard for the diagnosis [2]. Hyperinflammation is characterized by activation of genes coding for proinflammatory cytokines (leukocyte activation), injurious triggering of the complement system, activation of the coagulation system and concurrent downregulation of anticoagulant mechanisms, and necrotic cell death. Features of immune suppression are massive apoptosis and thereby depletion of immune cells, reprogramming of monocytes and macrophages to a state of a decreased capacity to release pro-inflammatory cytokines, and a disturbed balance in cellular metabolic processes. Much progress has been made in understanding the pathogenesis of sepsis, but translation of this knowledge into effective novel sepsis therapies has been unsuccessful [3]. This failure has for a large part been ascribed to the heterogeneity of the clinical syndrome captured by the current sepsis definition. Sepsis researchers and critical care physicians now aim to stratify patients into more homogeneous groups with shared biological features, for instance based on leukocyte derived mRNA, to develop a consensus sepsis subclassification system [4]. Biomarkers can reflect or represent such biological features and thereby identify sepsis subgroups with common (patho) physiological processes. In an ideal world, clinicians can use these biomarkers at the bedside for quick decision making when confronted with an ill patient. In Chapter 3 we discussed the literature on biomarkers in sepsis. Biomarkers can be of diagnostic, prognostic or theragnostic value, the latter meaning to aid in selection and monitoring of therapy. The clinical use of biomarkers in sepsis and pneumonia is still at its infancy, especially when compared to other fields, such as vascular medicine and oncology. To use the field of oncology as an example to explain the relation between personalized medicine and biomarkers: several decades ago, a patient would be diagnosed with breast cancer and receive standard treatment. One knew that the outcomes of treatment varied widely, and that it was difficult to predict whether treatment would be successful at all. Currently, we know that breast cancer, on the molecular level, is a heterogeneous disease. Molecular features include activation of human epidermal growth factor receptor 2 (HER2), activation of hormone receptors (oestrogen and progesterone receptor) and/or BRCA mutations, each come with their own line of treatment [5]. Thus far biomarker research in sepsis has primarily focused on discrimination between infectious and non-infectious causes of critical illness, and sepsis prognosis. Ideally, biomarkers could also be used to stratify the heterogeneous group of patients with sepsis according to biochemical and/or immunological profiles, associating expression at RNA, protein and metabolite levels with specific complications and outcomes, which can provide insight into the main pathophysiological mechanisms in individual patients and in pathways that can potentially be targeted [6]. The challenge will be to find a set of biomarkers that can be measured in easily obtained samples such as blood or urine, but that also mirrors the complex pathophysiology of sepsis or pneumonia in its totality. In Chapter 4 we studied a proposed biomarker associated with increased mortality in patients with sepsis - ferritin [7] – in the context of pneumonia. High circulating levels of ferritin, hyperferritinemia, can be found in patients as a response to infection or other inflammatory conditions. Four out of five patients admitted to the Intensive 12
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