Strategies to improve clinical management of community-acquired pneumonia

Abstract

Despite advances during the last few decades in the prevention, diagnosis and treatment of community-acquired pneumonia (CAP), its incidence remains high. In this thesis, strategies are described for improvement of the quality of clinical management in patients with pneumonia and for the reduction of the healthcare burden. The focus is on the prevention of pneumonia, a better understanding of the immune response in CAP, further development of biomarkers, and adjunctive therapies. Recent studies have suggested that gastric acid-suppressive medication may increase the risk of CAP. In Chapter 2, a population-based case-control study is presented on the relationship between proton pump inhibitor (PPI) treatment and CAP. In Chapter 3, the cytokine response in a cohort of 201 non-immunocompromised patients with CAP is described. In addition to the inflammatory response as discussed in Chapter 3, the complement system is an important component of the innate immune system. In Chapter 4, the role of polymorphisms in the genes of these two lectins in patients with S. aureus peritonitis on continuous ambulatory peritoneal dialysis (CAPD) is studied. This led to the study described in Chapter 5 in which binding to the pneumococci of MBL, ficolin-2 and subsequently MASP-2 was explored. This study showed that pneumococci can bind MASP-2 and that ficolin-2 seems to be the overriding MASP-2 activator.In Chapter 6, a quantitative multiplex immunoassay for the measurement of serotype-specific antibody concentrations after the onset of CAP is described. The estimated contribution of the pneumococcus in patients with an unidentified causative agent of CAP was calculated to be 57%. In Chapter 7, the usefulness of serum angiotensin I-converting enzyme (ACE) activity at the time of hospital admission as a prognostic marker is assessed. Serum ACE activity can become useful for the identification of bacteremia before the outcome of blood cultures is known. In Chapter 8, the incidence and predictive value of proteinuria as a biomarker for outcome in patients with CAP is presented. Proteinuria on admission was independently associated with increased length of hospital stay in CAP patients.In Chapter 9, the current literature concerning the various options for supportive therapy of patients treated with otherwise effective antibiotics is reviewed. In Chapter 10, a randomised placebo-controlled trial (RCT) using corticosteroids as an adjunctive treatment to antibiotics in patients with CAP is described. The median length of stay was 6.5 days for patients in the dexamethasone group and 7.5 days in the placebo group (p= 0.048).To further elucidate which patients benefit most from corticosteroids, the cytokine response of 304 patients in an RCT was evaluated in Chapter 11. The overall decrease in cytokine levels was more rapid in patients with CAP treated with dexamethasone in addition to antibiotic treatment than in patients without dexamethasone. In Chapter 12, it is shown that in patients with CAP, a cortisol level <10 µg/dL was not found to be associated with poor outcomes. Furthermore, patients with high cytokine responses and unexpectedly low cortisol levels (<50% of the patients with high cytokine responses) were shown to benefit more from dexamethasone therapy