Immunomodulation in community-acquired pneumonia

Abstract

Community-acquired pneumonia (CAP) is a common disease with considerable morbidity and mortality, despite effective antibiotic treatment. In this thesis, we showed that the major causative microorganisms in CAP trigger distinct inflammatory response profiles in the host. While an inflammatory response as such is required to combat invading pathogens, an excessive inflammatory response may contribute to adverse clinical outcome. Modulation of the immune response could therefore offer promising new treatment options in CAP. In this thesis, we focused on the immunomodulatory properties of corticosteroids, macrolide antibiotics and vitamin D, and their potential role in prevention and treatment of CAP. A randomised placebo-controlled trial in hospitalised, non-immunocompromised patients with CAP showed that administration of dexamethasone adjuvant to antibiotics reduced length of hospital stay by one day. In addition, our data indicate that certain subgroups of patients might benefit in particular from dexamethasone treatment. Differences in dexamethasone effect were found for different microbial aetiologies. Next, in patients with a high pro-inflammatory cytokine response, but a discrepantly low cortisol, adjuvant dexamethasone was associated with a significant decrease in mortality/intensive care unit admission (combined endpoint). In a literature review, we provided an overview of the existing evidence from in vitro and in vivo studies on the immunomodulatory effects of macrolides in CAP. Macrolides have been shown to change the nature of the immune response during acute inflammation in three ways: by suppression of the cytokine response, by changing the behaviour of inflammatory cells to a more anti-inflammatory nature and by affecting structural cells of the respiratory tract. However, experimental and clinical studies on the immunomodulatory effects of macrolides when given adjuvant to β-lactam antibiotics, are lacking. In order to further elucidate the mechanisms of immunomodulation by macrolides during acute inflammation, in particular when given in combination with β-lactam antibiotics, we designed an in vitro model of acute infection with Streptococcus pneumoniae. We found that macrolides, alone or adjuvant to β-lactam antibiotics, attenuated the pro-inflammatory cytokine response in whole blood stimulated with heat-killed S. pneumoniae. This suggests an immunomodulatory effect. However, this effect was not observed in subsequent series of experiments with viable S. pneumoniae (either macrolide-susceptible or -resistant). Vitamin D has pleiotropic immunomodulatory properties, apart from its function in calcium and bone homeostasis. Vitamin D deficiency is common worldwide. In our cohort of patients with CAP, 53% of the patients was vitamin D deficient. We showed that vitamin D deficiency is associated with adverse clinical outcome in CAP. Vitamin D status at the time of hospital admission appeared to be an independent predictor for 30-day mortality, adding prognostic value to other biomarkers and prognostic scores, in particular the Pneumonia Severity Index (PSI) score. In former studies, vitamin D deficiency has been associated with an increased susceptibility to respiratory tract infections. Whether this association is based on a causal relationship is unknown.Three parallel large independent case-control studies showed no preventive association between vitamin D supplementation and pneumonia in adults. This suggests that there is no causal relation between vitamin D deficiency and the risk of pneumonia