13 General introduction higher diagnostic sensitivity of ultra-low-dose chest CT to detect pneumonia would affect clinical management and patients’ outcomes in patients suspected of communityacquired pneumonia. Furthermore, we designed a biomarker study where blood samples were taken from over 600 patients included in this large multicentre cohort to investigate the pathophysiology of pneumonia. In this biomarker study, we aimed to study the association of hyperferritinemia in patients with community-acquired pneumonia with their clinical presentation, outcome and aberrations in key host response pathways implicated in the immunopathology of pneumonia and sepsis. Second, we performed a study as part of the “Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in EuRopE - Intensive Care Units” (ASPIRE-ICU) project, a study of 1997 adult ICU patients at 30 hospitals in 11 European countries aimed to report the incidence density and the risk factors of S. aureus and Ps. aeruginosa ICU pneumonia in Europe [21]. Presented in this thesis, our project was designed as a nested case-control study within the ASPIRE-ICU population aimed to obtain insight into host response protein differences between cases (patients who developed an ICU-acquired pneumonia) and controls (patients who did not develop an ICU-acquired pneumonia). We studied the host response prior to and during ICUacquired pneumonia, and the host response trajectory, i.e. the changes in host response over time. Last, to study gut microbiota-related immunological processes and its relation to pulmonary immunity, we designed and performed a proof-of-concept human intervention trial to address the question whether modulation of the gut microbiome of adults with allergic asthma influences lung inflammation in a house dust mite provocation model. Twenty patients with asthma and house dust mite allergy were recruited and randomized into two groups, receiving either broad-spectrum antibiotics orally for 7 days to disrupt the intestinal microbiota, or no treatment. After a wash-out period of antibiotics, all patients were challenged through house dust mite installation in one lung segment by bronchoscopy. Bronchoalveolar lavage fluid was obtained during a second bronchoscopy several hours later. The primary outcome was the influx of inflammatory cells into the bronchoalveolar space as a measure of pulmonary inflammation. Outline thesis Pneumonia remains a major cause of mortality globally, and its incidence is rising due to an aging population, increased use of immunosuppressive drugs, and antibiotic resistance. Bearing the complex pathophysiology of pneumonia and the potentially serious progression to sepsis in mind, the overall objective of this thesis is to contribute, if only modestly, to the understanding and improved management of this lifethreatening condition that continues to challenge the global healthcare community. Part I of this thesis focuses on the pathogenesis and host response in pneumonia and sepsis. Chapter 2 is a book chapter from the Handbook of Sepsis, written for educational purposes, to summarize the current understanding of the pathogenesis of sepsis. In 1
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