306 Chapter 13 Pneumonia is an acute lower respiratory tract infection that imposes a substantial disease burden, as evidenced by its high morbidity and mortality rates. When pneumonia progresses to sepsis, it becomes a life-threatening condition for which no universal treatment exists. As personalized approaches to pneumonia and sepsis care gain momentum, it is becoming clear that understanding the factors influencing each patient’s disease progression is essential for tailoring effective treatments. This thesis focusses on the pathogenesis of pneumonia, the host response of patients with pneumonia, and the diagnosis and clinical management of pneumonia. The overall objective was to contribute to the goal of tailored, individualized treatment of patients with severe pneumonia and sepsis. In Part I, the thesis delves into the pathogenesis of pneumonia and sepsis, focusing on the host immune response. Pneumonia arises when a pathogen successfully evades the body’s defences, leading to infection in the lower respiratory tract. The severity of pneumonia varies widely, influenced by factors such as the patients’ age, comorbidities, and immune status. This part aims to contribute to the question why some individuals recover easily while others progress to severe illness, including sepsis. Chapter 2 provides a foundational overview of sepsis, exploring the dual immune responses—pro-inflammatory and anti-inflammatory—that occur during severe infection. This chapter lays the groundwork for the thesis, as pneumonia is a leading cause of sepsis. The complexity of sepsis is emphasized, with no «gold standard» for diagnosis due to the diverse clinical presentations among patients. The current sepsis definition captures patients with heterogeneous host response aberrations. The role of biomarkers is central in Chapter 3, where the thesis discusses their potential in diagnosing, predicting, and guiding therapy in sepsis. Biomarkers can provide insight into the host’s immune response, offering a way to stratify patients into more homogeneous groups with shared biological features that might respond better to treatments targeted at specific pathophysiological mechanisms; that is to say, if we can overcome the challenge to develop an easy-to-use quick biomarker assay with real time analysis of host response data. Ferritin, a marker of inflammation, is explored further in Chapter 4. Hyperferritinemia in patients with pneumonia admitted to a general ward was associated with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. Ferritin may serve as a readily accessible biomarker for future diagnostic and therapeutic applications in specific subgroups of pneumonia patients. Chapter 5 concerns an observational study conducted on 30 Intensive Care Units (ICU) in 11 European countries that tested the hypothesis that ICUacquired pneumonia is associated with broad host immune aberrations in the trajectory to pneumonia. We indeed showed that patients who acquired a new pneumonia while on the ICU had plasma biomarker concentrations suggestive of enhanced inflammation and a more disturbed endothelial barrier function, both at study enrolment and in the path to pneumonia diagnosis, as compared to ICU patients who did not develop pneumonia. Part II shifts focus to the gut microbiome and its relationship with pneumonia and sepsis. The gut microbiome plays a crucial role in modulating immune responses, and disruptions in the microbiota can influence infection outcomes.
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