Bacteraemia and sepsis are major causes of mortality worldwide. Individual subjects seem to have different risks of developing bacteraemia and sepsis, individual organ failures and death. Despite novel options in the treatment of sepsis, the course of disease in individuals remains unpredicted and the mortality rate high. The lack of knowledge of sepsis pathogenesis and the heterogeneity of patients with bacteraemia and sepsis make risk stratification difficult. The main purpose of this study was to elucidate the role of host genetic factors, living habits, and underlying diseases in bacteraemia outcome, to study the effect of genetic factors on susceptibility to bacteraemia, and to find new approaches in understanding the pathogenesis and prognostication in bacteraemia. This prospective cohort study involved 149 in-hospital patients (79 male and 70 female) with bacteraemia caused by Staphylococcus aureus (S. aureus) (41 patients), Streptococcus pneumoniae (Str. pneumoniae) (42 patients), ß-haemolytic streptococcus (ß-hml str.) (23 patients) and Escherichia coli (E. coli) (43 patients) recruited in Tampere University Hospital during the years 1999-2004. Nineteen (12.8%) bacteraemic patients died.
Mannose-binding lectin (MBL) insufficiency caused by point mutations in the MBL2 gene has been associated with increased susceptibility to infections, but the data are controversial. To study the effect of MBL2 polymorphisms on susceptibility to and the clinical course of bacteraemia, 145 patients with bacteraemia and 400 controls were examined. In study I, MBL2 structural polymorphisms at codons 52, 54 and 57, and promoter region polymorphisms at position -221 were determined. No difference in MBL2 genotype frequencies was detected between bacteraemic patients and controls, and MBL2 genotype had no independent effect on mortality. However, smoking proved a significant risk factor for gram-positive (S. aureus, Str. pneumoniae or ß-hml. str.) bacteraemia among carriers of the variant O allele, while it had no effect on those homozygous for the A allele.
Nitric oxide (NO) is a crucial element in the pathogenesis of sepsis. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular NO production. The eNOS gene polymorphism at position 894 (G>T, Glu298Asp), resulting in the T allele, has been studied in the context of vascular diseases, but its role in sepsis is unclear. In study II, the polymorphism of the eNOS gene, G894T, was genotyped in patients with bacteraemia. Carriage of the T allele was associated with hypotension and severe disease in patients suffering from E. coli bacteraemia, but not in bacteraemia caused by a gram-positive organism. The Glu298Asp polymorphism had no effect on case fatality. In study III, the major underlying conditions associated with case fatality in bacteraemia were studied. Obesity (body mass index (BMI ≥30)) and smoking were independently associated with case fatality in a multivariate model adjusted for the effect of potential confounders. The median BMI was significantly higher among those who died compared to survivors (33 vs. 26, p=0.003) Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. IDO degrades tryptophan (trp) to its metabolite kynurenine (kyn), constituting a suppressor of T-cells. However, the precise role of IDO in different disease processes is largely unknown. In study IV, serum tryptophan and kynurenine concentrations were determined by high-performance-liquid chromatography (HPLC) in bacteraemic patients. The kyn/trp ratio, reflecting the activity of the IDO enzyme, was calculated. Maximum IDO activity 1-4 days after blood culture was significantly higher in nonsurvivors compared to survivors. High IDO activity remained an independent predictor of case fatality in the multivariate model.
In summary, this study showed that obese patients and smokers had significantly higher case fatality rates in bacteraemia compared to their normal-weight and non-smoking counterparts. Smoking also increased the risk of gram-positive bacteraemia in patients carrying the MBL2 gene structural variant O allele, this constituting a novel example of gene-environment interaction. Carriage of the eNOS gene T allele at nucleotide position 894 was associated with hypotension in patients with E. coli bacteraemia. A high kyn/trp ratio, reflecting IDO activity was strongly associated with case fatality in patients with bacteraemia. The present findings provide evidence of fundamental differences between gram-negative and gram-positive sepsis and interindividual differences in predisposition to bacteraemia relating to genetic and smoking interactions, and of lifestyle effects on outcome. The contribution of the eNOS gene, a gene regulating vascular tone, on disease severity in bacteraemia is shown. IDO may constitute a novel key to the understanding of sepsis pathogenesis.
