Clinical characteristics and innate immunity in patients with community-acquired pneumonia

Abstract

Community-acquired pneumonia (CAP) is the most common infectious disease requiring hospitalisation in the Western world. In spite of improving antibiotic regiments, CAP still has significant mortality. In non-immune compromised patients, Streptococcus pneumoniae is the most frequently isolated micro-organism in CAP, followed by the Gram-negative bacterium Haemophilus influenzae There are many known risk factors for CAP caused by a specific pathogen. Nevertheless, many patients, especially young patients, do not contain any of these risk factors for CAP. A possible explanation could be that these patients are at risk for CAP caused by a specific micro-organism due to genetic variations within their immune system. The outline of this thesis is to identify such variations within a part of the immune system: innate immunity. As expected, we found Streptococcus pneumoniae and Haemophilus influenzae to be the most frequently identified micro-organisms in CAP. Patient characteristics (medical history of hypertension), clinical characteristics (low C-reactive protein) and a history of prior antibiotic use, contribute to the failure of identifying the pathogens and the causative micro-organisms in CAP. In this thesis a three-step diagnostic protocol is presented, in which by the time the first two steps are completed all clinical relevant micro-organisms are identified within 48h after patient admission through sputum and blood cultures, urine antigen test and PCR of the sputum for Chlamydophila species, Legionella pneumophila and Mycoplasma pneumoniae. The role of the ACE I/D polymorphism is limited in CAP. Low levels of ACE in serum are associated with the disease severity, which is reflected by the clinical scores. Within innate immunity, there are many genetic variations that are associated with the susceptibility to and outcome from pathogen-specific CAP. IL-6 and IL-10 polymorphisms are associated with an increased susceptibility of acquiring severe CAP or CAP in young patients. IL-6 and IL-10 are markers as well as predictors of disease severity. The TLR2 2477 A allele and the Fcgamma-RIIa R131 genotype are associated with an increased susceptibility to Haemophilus influenzae CAP, while TLR5 392stop and Fcgamma-RIIa R131 are associated with an increased susceptibility to (severe) pneumococcal pneumonia. Fc?-RIIa H131 (wild type) and MBL sufficient genotypes are associated with an increased susceptibility to CAP caused by Legionella pneumophila or Mycoplasma pneumoniae. MBL genotypes code for MBL serum levels, and MBL deficiency is associated with an increased susceptibility for acquiring additional viral infections in patients with existing CAP. Thus, the answer to the central question of this thesis - are variations in innate immunity are associated with the susceptibility to and outcome of CAP - is yes, but only in a pathogen-specific manner.