Janne Aittoniemi

Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study.

Huttunen R, Syrjänen J, Vuento R, Hurme M, Huhtala H, Laine J, Pessi T, Aittoniemi J (Tampere University Hospital; University of Tampere Medical School, University of Tampere; Centre for Laboratory Medicine, Pirkanmaa Hospital District; University of Tampere Medical School; School of Health Sciences, University of Tampere; and Medical School, University of Tampere; Tampere, Finland) Plasma level of soluble urokinase‐type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study. J Intern Med 2011; 270: 32–40.

Age‐dependent variation in the serum concentration of mannan‐binding protein

Mannan‐binding protein (MBP) is an acute phase reactant, and its deficiency is associated with the common opsonic defect and suspectibility to infections and atopic constitution. The aim of this study was to investigate the changes occurring in the serum level of MBP in infancy and during later childhood. We studied the serum concentration of MBP in 611 Finnish children of different ages and 110 adults by using an enzyme immunoassay. In an analysis of successive serum samples from infants at the day of birth and at the ages of 1 and 5 months, and at 1 and 2 years, the serum concentration of MBP increased significantly after birth, and was at its highest (the mean and median were 8.13 and 8.49 mg1−1, respectively) at the age of 1 month. After that, it declined to the initial level until the age of 5 months. The MBP concentration continued to decrease during childhood, and after the age of 12 years the MBP values reached the adult level. In Finnish adults the mean and median concentrations of MBP were 4.48 and 4.02 mg 1−1, respectively, which seem to be higher than those reported previously in other populations. The high concentration of MBP in infants may best be explained by exposure to novel environmental antigens in early childhood, which suggests a protective role for MBP during the period of immaturity of the immunosystem. In older children the high level of MBP can probably be explained by childhood infections and the ensuing need of MBP.

Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia

We investigated responses to vaccination against pneumococcal polysaccharide, Haemophilus influenzae b (Hib) conjugate and tetanus toxoid antigens in 31 patients with chronic lymphocytic leukaemia (CLL) and 25 controls. While in the control group all antibody responses against different antigens were highly significant, in the patient group clear evidence for responsiveness was detected only in the case of Hib polysaccharide antigen. Certain CLL patient subgroups showed low reactivity against tetanus toxoid antigen. In conclusion, plain polysaccharide vaccines seem to be ineffective in patients with CLL. Conjugate vaccines, in turn, are immunogenic and may offer protection against infections caused by encapsulated bacteria in these patients. Further studies concerning an optimal vaccination scheme and clinical efficiency are warranted.

High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients.

Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan (trp) catabolism, may play a critical role in various inflammatory disorders. Recent studies on trauma patients have suggested that the degradation of trp is associated with the development of sepsis. The role of IDO activity in bacteremic patients is unclear. We studied IDO activity in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, &bgr;-hemolytic streptococcae, or Eschericia coli. The serum concentrations of trp and its metabolite kynurenine (kyn) were measured by reverse-phase high-performance liquid chromatography 1 to 4 days after the positive blood culture and on recovery. The kyn-to-trp ratio (kyn/trp), reflecting the activity of the IDO enzyme, was calculated. The maximum value in the ratio for every patient during 1 to 4 days after positive blood culture was used in analysis. The maximum kyn/trp ratio was significantly higher in nonsurvivors versus those who survived (193.7 vs. 82.4 &mgr;mol/mmol; P = 0.001). The AUCROC of maximal kyn/trp in the prediction of case fatality was 0.75 (95% confidence interval, 0.64-0.87), and the kyn/trp ratio at a cutoff level of 120 &mgr;mol/mmol showed 83% sensitivity and 69% specificity for fatal disease. A kyn/trp ratio greater than 120 &mgr;mol/mmol was associated with increased risk of death versus low (≤120 &mgr;mol/mmol) ratios (odds ratio, 10.8; confidence interval, 3.0-39.8). High IDO activity also remained an independent risk factor for case fatality in a multivariate model adjusted for potential confounders. The data in this report demonstrate that IDO activity is markedly increased in bacteremia patients, constituting an independent predictor of severe disease and case fatality.

Fatal Outcome in Bacteremia is Characterized by High Plasma Cell Free DNA Concentration and Apoptotic DNA Fragmentation: A Prospective Cohort Study

Introduction Recent studies have shown that apoptosis plays a critical role in the pathogenesis of sepsis. High plasma cell free DNA (cf-DNA) concentrations have been shown to be associated with sepsis outcome. The origin of cf-DNA is unclear. Methods Total plasma cf-DNA was quantified directly in plasma and the amplifiable cf-DNA assessed using quantitative PCR in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-hemolytic streptococcae or Escherichia coli. The quality of cf-DNA was analyzed with a DNA Chip assay performed on 8 survivors and 8 nonsurvivors. Values were measured on days 1–4 after positive blood culture, on day 5–17 and on recovery. Results The maximum cf-DNA values on days 1–4 (n = 132) were markedly higher in nonsurvivors compared to survivors (2.03 vs 1.26 ug/ml, p<0.001) and the AUCROC in the prediction of case fatality was 0.81 (95% CI 0.69–0.94). cf-DNA at a cut-off level of 1.52 ug/ml showed 83% sensitivity and 79% specificity for fatal disease. High cf-DNA (>1.52 ug/ml) remained an independent risk factor for case fatality in a logistic regression model. Qualitative analysis of cf-DNA showed that cf-DNA displayed a predominating low-molecular-weight cf-DNA band (150–200 bp) in nonsurvivors, corresponding to the size of the apoptotic nucleosomal DNA. cf-DNA concentration showed a significant positive correlation with visually graded apoptotic band intensity (R = 0.822, p<0.001). Conclusions Plasma cf-DNA concentration proved to be a specific independent prognostic biomarker in bacteremia. cf-DNA displayed a predominating low-molecular-weight cf-DNA band in nonsurvivors corresponding to the size of apoptotic nucleosomal DNA.

High Plasma Level of Long Pentraxin 3 (PTX3) Is Associated with Fatal Disease in Bacteremic Patients: A Prospective Cohort Study

Introduction Long pentraxin 3 (PTX3) is an acute-phase protein secreted by various cells, including leukocytes and endothelial cells. Like C-reactive protein (CRP), it belongs to the pentraxin superfamily. Recent studies indicate that high levels of PTX3 may be associated with mortality in sepsis. The prognostic value of plasma PTX3 in bacteremic patients is unknown. Methods Plasma PTX3 levels were measured in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic streptococcae and Escherichia coli, using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). Values were measured on days 1–4 after positive blood culture, on day 13–18 and on recovery. Results The maximum PTX3 values on days 1–4 were markedly higher in nonsurvivors compared to survivors (44.8 vs 6.4 ng/ml, p<0.001) and the AUCROC in the prediction of case fatality was 0.82 (95% CI 0.73–0.91). PTX3 at a cut-off level of 15 ng/ml showed 72% sensitivity and 81% specificity for fatal disease. High PTX3 (>15 ng/ml) was associated with hypotension (MAP <70 mmHg)(OR 7.9;95% CI 3.3–19.0) and high SOFA score (≥4)(OR 13.2; 95% CI 4.9–35.4). The CRP level (maximum value on days 1 to 4) did not predict case fatality at any cut-off level in the ROC curve (p = 0.132). High PTX3 (>15 ng/ml) remained an independent risk factor for case fatality in a logistic regression model adjusted for potential confounders. Conclusions PTX3 proved to be a specific independent prognostic biomarker in bacteremia. PTX3 during the first days after diagnosis showed better prognostic value as compared to CRP, a widely used biomarker in clinical settings. PTX3 measurement offers a novel opportunity for the prognostic stratification of bacteremia patients.

New concepts in the pathogenesis, diagnosis and treatment of bacteremia and sepsis

Bacteremia and sepsis are major health concerns. Despite intensive research, there are only a limited number of successful treatment options, and it is difficult to see the forest for the trees when considering the pathogenesis of this condition. Studies in the last decade have shown that a major pathophysiologic event in sepsis is the progression from proinflammation to an immunosuppressive state. However, recent genome-based data indicate that sepsis-related inflammatory responses are highly variable, which calls in question the classic two-phase model of sepsis. Adequate and timely antimicrobial treatment is a cornerstone for survival in patients with bacteremia and sepsis. However, microbial resistance has emerged as an increasing challenge for clinicians and with an increasing number of resistant pathogens causing infections, selection of empiric antimicrobial treatment has become difficult. Treatment options currently under way are targeted to enhance immune responses, rebalance the regulation of the dysregulated immune system, remove endotoxin and block/inhibit apoptosis.

Vaccination Against Infections in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a well-defined mature B-cell neoplasm associated with increased susceptibility to infections. Two major options in prevention of infections in CLL, intravenous gammaglobulin treatment and antimicrobial chemoprophylaxis, have not resulted in satisfactory outcome. A third strategy, antimicrobial vaccination, is the topic of this minireview. We collected articles and their references concerning CLL vaccination from the Medline database starting from 1966 and thirteen relevant studies were found. Plain bacterial polysaccharide vaccines would seem to be ineffective in antibody formation in patients with CLL. However, protein and conjugate vaccines appear to be more immunogenic and their responses may be further enhanced with ranitidine adjuvant treatment. New well-designed investigations are needed to develop appropriate vaccination strategies and evaluate vaccination efficacy in infection morbidity and mortality in CLL.

Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study

Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima‐media thickness, carotid artery distensibility and brachial artery flow‐mediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24–39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow‐mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow‐mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow‐mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age.

Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics

BackgroundThe liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved.MethodsRelative ratios of major commensal bacterial communities (Bacteroides spp., Bifidobacterium spp., Clostridium leptum group, Enterobactericaea and Lactobacillus spp.) were determined in faecal samples from post mortem examinations performed on 42 males, including cirrhotic alcoholics (n = 13), non-cirrhotic alcoholics (n = 15), non-alcoholic controls (n = 14) and in 7 healthy male volunteers using real-time quantitative PCR (RT-qPCR). Translocation of bacteria into liver in the autopsy cases and into the ascites of 12 volunteers with liver cirrhosis was also studied with RT-qPCR. CD14 immunostaining was performed for the autopsy liver samples.ResultsRelative ratios of faecal bacteria in autopsy controls were comparable to those of healthy volunteers. Cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers (p = 0.011). Enterobactericaea were also the most common bacteria translocated into cirrhotic liver, although there were no statistically significant differences between the study groups. Of the ascites samples from the volunteers with liver cirrhosis, 50% contained bacterial DNA from Enterobactericaea, Clostridium leptum group or Lactobacillus spp.. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression (p = 0.045). CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p = 0.004).ConclusionsOur results suggest that translocation of intestinal bacteria into liver may be involved as a one factor in the pathogenesis of alcoholic liver cirrhosis.