11 General introduction Biomarkers Biomarkers, which are naturally occurring molecules, genes, or other characteristics reflecting physiological or pathological processes, hold great promise for personalized medicine in pneumonia and sepsis [16]. Not all patients with pneumonia develop sepsis. Patient characteristics, clinical signs and disease severity scores only partly explain the variation in the course of disease. Biomarkers can shed light on the pathophysiological mechanisms underlying pneumonia and help us better understand how this disease evolves and why this varies amongst individuals. Biomarkers can be of diagnostic, prognostic or theragnostic value; the latter being the use of a biomarker to select and evaluate specific therapies. Biomarkers can be useful tools for clinicians, as additional information to the clinical evaluation, aiding in optimized patient care at the bedside [17]. They can help stratify patients into subgroups for targeted therapy and personalize follow-up of response to treatment. In recent years, there has been a surge of interest in biomarkers in the sepsis field. The challenge lies in the intricate nature of sepsis pathophysiology, making it unlikely that a single biomarker can accurately capture the complexity of the host response. In this context, novel technologies focussing on panels of biomarkers, biomarker trajectories over time, and the “omics” field of system biology hold promise in the management of patients with sepsis [16,17]. Microbiome The human gut microbiota, comprising diverse microbial communities in the intestine, plays a crucial role in protecting against harmful agents. Gut micro-organisms and their derived metabolites are associated with the susceptibility to sepsis as well as outcomes of sepsis [18]. The interaction between sepsis and the microbiome is a complex, bidirectional relationship. The disease state of sepsis can disrupt the microbiota, while clinical interventions, particularly antimicrobial therapy, can also affect microbial composition [18]. Furthermore, disruptions in gut microbiota-related immunological processes have been linked to pulmonary disease severity and treatment responses. Mechanistic data supporting this so-called gut-lung-axis are scarce but would offer potential in future management of patients with pulmonary diseases. Clinical trials This thesis describes research on the pathogenesis, host response, diagnostics, and clinical management of patients with pneumonia. Two large clinical trials, the OPTIMACT trial and the ASPIRE-ICU trial, and one smaller human proof-of-concept intervention trial, provided the infrastructure for our research questions and were the backbone of the studies discussed in this thesis (Figure 1). 1
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