294 Chapter 12 Pneumonia is an acute infection of the lower respiratory tract with a significant burden of disease reflected in its high morbidity and mortality. Two factors contribute strongly to the development of pneumonia: the immune defence system of the human at risk and the virulence of the invading pathogen. When a pathogen successfully escapes the first line of defence (such as the human’s skin or mucosa), the human and the pathogen enter a complicated relationship in which both parties give and take to achieve a final balance. From the human’s perspective, he or she ultimately hopes to be the stronger one in this relationship by eradicating or at least suppressing the pathogen. From the pathogen’s perspective, it is essential for his or her survival to circumvent host defence mechanisms of the human as much as possible. This thesis studies the relation between human and pathogen from the human perspective. In its various studies, it describes the pathogenesis of pneumonia, the host response of patients with pneumonia, and the diagnosis and clinical management of this potentially deadly disease. When pneumonia deteriorates into sepsis, it becomes a life-threatening condition where currently science is yet to deliver on the golden therapy that fits all patients. Advancing insight drives home the realization that a one size fits all solution is very unlikely. Yet, personalized approaches in pneumonia and sepsis care are rapidly emerging. To personalize healthcare, one first must understand which factors contribute to the individual course of a disease. The overall objective of this thesis was to contribute to the understanding and improved management of pneumonia. There are several overarching themes and insights that I will discuss here on the basis on this dissertation. Pathogenesis and host response It appears simple: the person next to you coughs, contaminated droplets are transferred through the air and are lucky enough to reach the mucosa of your nose, where – in the upper airways - the interplay with pre-existing colonizing micro-organisms and mucosal defence mechanisms eventually determines the fate of the newly introduced microbial agent: eradication, colonization or multiplication with invasion of lower airways. In the latter instance, you start to cough, develop a fever, and are diagnosed with pneumonia - the pathogenesis of pneumonia briefly described. However, why do some patients only require oral antibiotics, do others fall severely ill and require hospital admission, and do some become so sick that doctors talk about sepsis and discuss end-of-life wishes with your partner or relatives? From the human perspective, many factors play a part in the development of pneumonia, such as age, comorbidities, and smoking status. These are easily measured features and are used for as long as the medical profession exists to estimate the risk of disease progression of an individual patient. But these features are not all-encompassing. I regularly encounter a patient, about 50 years old, who is in the hospital with a serious pneumonia, and talks with some indignation about his 84-year-old father who has smoked all his life, hardly plays sports, but has never experienced anything like this. Why me and not him? Chapter 2 was written for educational purposes and explains the pathogenesis of sepsis as we understand it now. This chapter is a relevant basis for the rest of the thesis, as sepsis is most often caused by pneumonia. Sepsis is best described as the occurrence of two opposite immune reactions to severe infection, with proinflammatory and anti-
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