Christian Østergaard

Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial.

Objective:For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival. Design:Randomized controlled open-label trial. Setting:Nine multidisciplinary intensive care units across Denmark. Patients:A total of 1,200 critically ill patients were included after meeting the following eligibility requirements: expected intensive care unit stay of ≥24 hrs, nonpregnant, judged to not be harmed by blood sampling, bilirubin <40 mg/dL, and triglycerides <1000 mg/dL (not suspensive). Interventions:Patients were randomized either to the “standard-of-care-only arm,” receiving treatment according to the current international guidelines and blinded to procalcitonin levels, or to the “procalcitonin arm,” in which current guidelines were supplemented with a drug-escalation algorithm and intensified diagnostics based on daily procalcitonin measurements. Measurements and Main Results:The primary end point was death from any cause at day 28; this occurred for 31.5% (190 of 604) patients in the procalcitonin arm and for 32.0% (191 of 596) patients in the standard-of-care-only arm (absolute risk reduction, 0.6%; 95% confidence interval [CI] −4.7% to 5.9%). Length of stay in the intensive care unit was increased by one day (p = .004) in the procalcitonin arm, the rate of mechanical ventilation per day in the intensive care unit increased 4.9% (95% CI, 3.0–6.7%), and the relative risk of days with estimated glomerular filtration rate <60 mL/min/1.73 m2 was 1.21 (95% CI, 1.15–1.27). Conclusions:Procalcitonin-guided antimicrobial escalation in the intensive care unit did not improve survival and did lead to organ-related harm and prolonged admission to the intensive care unit. The procalcitonin strategy like the one used in this trial cannot be recommended.

Bacteremia causes hippocampal apoptosis in experimental pneumococcal meningitis.

BackgroundBacteremia and systemic complications both play important roles in brain pathophysiological alterations and the outcome of pneumococcal meningitis. Their individual contributions to the development of brain damage, however, still remain to be defined.MethodsUsing an adult rat pneumococcal meningitis model, the impact of bacteremia accompanying meningitis on the development of hippocampal injury was studied. The study comprised of the three groups: I. Meningitis (n = 11), II. meningitis with attenuated bacteremia resulting from iv injection of serotype-specific pneumococcal antibodies (n = 14), and III. uninfected controls (n = 6).ResultsPneumococcal meningitis resulted in a significantly higher apoptosis score 0.22 (0.18-0.35) compared to uninfected controls (0.02 (0.00-0.02), Mann Whitney test, P = 0.0003). Also, meningitis with an attenuation of bacteremia by antibody treatment resulted in significantly reduced apoptosis (0.08 (0.02-0.20), P = 0.01) as compared to meningitis.ConclusionsOur results demonstrate that bacteremia accompanying meningitis plays an important role in the development of hippocampal injury in pneumococcal meningitis.

Clinical presentation and prognostic factors of Streptococcus pneumoniae meningitis according to the focus of infection

BackgroundWe conducted a nationwide study in Denmark to identify clinical features and prognostic factors in patients with Streptococcus pneumoniae according to the focus of infection.MethodsBased on a nationwide registration, clinical informations was prospectively collected from all reported cases of pneumococcal meningitis during a 2-year period (1999–2000). Clinical and laboratory findings at admission, clinical course and outcome of the disease including follow-up audiological examinations were collected retrospectively. The focus of infection was determined according to the clinical diagnosis made by the physicians and after review of the medical records.Results187 consecutive cases with S. pneumoniae meningitis were included in the study. The most common focus was ear (30%), followed by lung (18%), sinus (8%), and other (2%). In 42% of cases a primary infection focus could not be determined. On admission, fever and an altered mental status were the most frequent findings (in 93% and 94% of cases, respectively), whereas back rigidity, headache and convulsion were found in 57%, 41% and 11% of cases, respectively. 21% of patients died during hospitalisation (adults: 27% vs. children: 2%, Fisher Exact Test, P < 0.001), and the causes of death were due to neurological – and systemic complications or the combination of both in 8%, 5% and 6% of cases, respectively. Other causes (e.g. gastrointestinal bleeding, incurable cancer) accounted for 2% of cases. 41% of survivors had neurological sequelae (hearing loss: 24%, focal neurological deficits: 16%, and the combination of both: 1%). The mortality varied with the focus of the infection (otogenic: 7%, sinusitic: 33%, pneumonic: 26%, other kind of focus: 50%, no primary infection focus: 21%, Log rank test: P = 0.0005). Prognostic factors associated with fatal outcome in univariate logistic regression analysis were advanced age, presence of an underlying disease, history of headache, presence of a lung focus, absence of an otogenic focus, having a CT-scan prior to lumbar puncture, convulsions, requirement of assisted ventilation, and alterations in various CSF parameters (WBC <500 cells/μL, high protein levels, glucose levels<1 mmol/L, low CSF/blood glucose levels), P < 0.05. Independent prognostic factor associated with fatal outcome in multivariate logistic regression analysis was convulsions (OR: 4.53, 95%CI: (1.74–11.8), p = 0.002), whereas presence of an otogenic focus was independently associated with a better survival (OR: 6.09, 95%CI: (1.75–21.2), P = 0.005).ConclusionThese results emphasize the prognostic importance of an early recognition of a predisposing focus to pneumococcal meningitis.

The changing epidemiology of Staphylococcus aureus bloodstream infection: a multinational population-based surveillance study

Although the epidemiology of Staphylococcus aureus bloodstream infection (BSI) has been changing, international comparisons are lacking. We sought to determine the incidence of S. aureus BSI and assess trends over time and by region. Population-based surveillance was conducted nationally in Finland and regionally in Canberra, Australia, western Sweden, and three areas in each of Canada and Denmark during 2000-2008. Incidence rates were age-standardized and gender-standardized to the EU 27-country 2007 population. During 83 million person-years of surveillance, 18,430 episodes of S. aureus BSI were identified. The overall annual incidence rate for S. aureus BSI was 26.1 per 100,000 population, and those for methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) were 24.2 and 1.9 per 100,000, respectively. Although the overall incidence of community-onset MSSA BSI (15.0 per 100,000) was relatively similar across regions, the incidence rates of hospital-onset MSSA (9.2 per 100,000), community-onset MRSA (1.0 per 100,000) and hospital-onset MRSA (0.8 per 100,000) BSI varied substantially. Whereas the overall incidence of S. aureus BSI did not increase over the study period, there was an increase in the incidence of MRSA BSI. Major changes in the occurrence of community-onset and hospital-onset MSSA and MRSA BSI occurred, but these varied significantly among regions, even within the same country. Although major changes in the epidemiology of community-onset and hospital-onset MSSA and MRSA BSIs are occurring, this multinational population-based study did not find that the overall incidence of S. aureus BSI is increasing.

Serum Level of YKL-40 is Elevated in Patients with Streptococcus pneumoniae Bacteremia and is Associated with the Outcome of the Disease

YKL-40 is secreted by activated macrophages and neutrophils. Elevated serum concentrations of YKL-40 are found in patients with diseases characterized by inflammation or ongoing fibrosis. The aim of this study was to evaluate serum YKL-40 levels in patients with Streptococcus pneumoniae bacteremia and to correlate these levels with clinical findings and outcomes. YKL-40 was determined by ELISA and 89 patients were included in the study. Serum YKL-40 levels were significantly higher in patients with S. pneumoniae bacteremia (median 342 μg/l; range 20-20,400 μg/l) than in age-matched healthy subjects (44 μg/l; 20-184; p < 0.001). Serum YKL-40 levels were related to the severity of the infection, with significantly higher serum YKL-40 levels being observed in patients who needed hemodialysis (p < 0.001), pharmacological treatment of hypotension (p < 0.001) and mechanical ventilation (p = 0.003) compared to those in patients who did not need this supportive treatment. Nineteen patients died and these patients had significantly higher serum YKL-40 levels (980 μg/l; 88-20,400 μg/l) than those of survivors (256 μg/l; 20-9,100 μg/l; p < 0.001). Serum YKL-40 level was an independent prognostic factor of survival in logistic multivariate regression analysis (p = 0.002). In conclusion, high serum levels of YKL-40 indicated a poorer prognosis for patients with S. pneumoniae bacteremia.

YKL-40 Is Elevated in Cerebrospinal Fluid from Patients with Purulent Meningitis

ABSTRACT YKL-40, a member of the family 18 glycosyl hydrolases, is secreted by activated neutrophils and macrophages. It is a growth factor for connective tissue cells and a potent migration factor for endothelial cells and may function in inflammation and tissue remodeling. YKL-40 was determined in 134 cerebrospinal fluid (CSF) samples taken on admission from patients suspected of having meningitis (48 with purulent meningitis, 49 with lymphocytic meningitis, 5 with encephalitis, and 32 without evidence of meningitis). YKL-40 levels in CSF were significantly higher in patients with purulent meningitis (median, 663 μg/liter [range, 20 to 8,960]) and encephalitis (5,430 μg/liter [620 to 11,600]) than in patients with lymphocytic meningitis (137 μg/liter [41 to 1,865]) or patients without meningitis (167 μg/liter [24 to 630]) (Kruskal-Wallis and Dunn multiple comparison tests, P < 0.001). CSF YKL-40 levels were also determined for 26 patients with purulent meningitis having a repuncture, and patients who died (n = 5) had significantly higher YKL-40 levels than patients who survived (n = 21) (2,100 μg/liter [1,160 to 7,050] versus 885 μg/liter [192 to 15,400], respectively; Mann-Whitney test, P = 0.018). YKL-40 was most likely locally produced, since patients with infections of the central nervous system had CSF YKL-40 levels that were at least 10-fold higher than the corresponding levels in serum (2,033 μg/liter [470 to 11,600] versus 80 μg/liter [19 to 195]). The CSF neopterin level was the biochemical parameter in CSF and blood that correlated best with CSF YKL-40 levels, indicating that YKL-40 may be produced by activated macrophages within the central nervous system. In conclusion, high levels of YKL-40 in CSF are found in patients with purulent meningitis.

ESCMID guideline: diagnosis and treatment of acute bacterial meningitis

D. van de Beek, C. Cabellos, O. Dzupova, S. Esposito, M. Klein, A. T. Kloek, S. L. Leib, B. Mourvillier, C. Ostergaard, P. Pagliano, H. W. Pfister, R. C. Read, O. Resat Sipahi and M. C. Brouwer, for the ESCMID Study Group for Infections of the Brain (ESGIB) 1) Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands, 2) Department of Infectious Diseases, Hospital Universitari de Bellvitge, Barcelona, Spain, 3) Department of Infectious Diseases, Charles University, Third Faculty of Medicine, Prague, Czech Republic, 4) Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, 5) Department of Neurology, Klinikum Großhadern, Munich, Germany, 6) Institute for Infectious Diseases, University of Bern, Bern, Switzerland, 7) Department of Intensive Care Medicine, Groupe Hospitalier Bichat-Claude Bernard, Paris, France, 8) Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, 9) Department of Infectious Diseases, “D. Cotugno” Hospital, Naples, Italy, 10) Department of Infectious Diseases, Southampton General Hospital, Southampton, United Kingdom and 11) Department of Infectious Diseases and Clinical Microbiology, Ege University, Izmir, Turkey

Inhibition of Leukocyte Entry into the Brain by the Selectin Blocker Fucoidin Decreases Interleukin-1 (IL-1) Levels but Increases IL-8 Levels in Cerebrospinal Fluid during Experimental Pneumococcal Meningitis in Rabbits

ABSTRACT The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte recruitment into the cerebrospinal fluid (CSF) during experimental pneumococcal meningitis. In the present study, the effect of fucoidin treatment on the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-8 into the CSF was investigated. Rabbits (n = 7) were treated intravenously with 10 mg of fucoidin/kg of body weight every second hour starting 4 h after intracisternal inoculation of ∼106 CFU of Streptococcus pneumoniae type 3 (untreated control group, n = 7). CSF samples were obtained every second hour during a 16-h study period. Treatment with fucoidin caused a consistent and significant decrease in CSF IL-1 levels (in picograms per milliliter) between 12 and 16 h (0 versus 170, 0 versus 526, and 60 versus 1,467, respectively;P < 0.02). A less consistent decrease in CSF TNF-α levels was observed in the fucoidin-treated group, but with no significant difference between the two groups (P > 0.05). In contrast, there was no attenuation in CSF IL-8 levels. Indeed, there was a significant increase in CSF IL-8 levels (in picograms per milliliter) in the fucoidin-treated group at 10 and 12 h (921 versus 574 and 1,397 versus 569, respectively;P < 0.09). In conclusion, our results suggest that blood-derived leukocytes mainly are responsible for the release of IL-1 and to some degree TNF-α into the CSF during pneumococcal meningitis, whereas IL-8 may be produced by local cells within the brain.

Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome.

The urokinase-type plasminogen activator system has been suggested to play a pathophysiological role in brain damage. The aim of this study was to evaluate CSF levels of suPAR in 183 patients clinically suspected of having meningitis on admission. Of these, 54 patients were found to have purulent meningitis, 63 had lymphocytic meningitis, 12 had encephalitis, and 54 patients were suspected of, but had no evidence of, meningitis. There was a significant difference in suPAR levels among patient groups (Kruskal Wallis test, p<0.0001) with significantly higher CSF suPAR levels in patients with CNS infection (purulent meningitis: median suPAR 2.41 μg/l (range 0.12–35), lymphocytic meningitis: 1.10 μg/l (0.15–5.31), and encephalitis (1.77 μg/l (0.17–11.7)) than in patients without meningitis (0.64 μg/l (0–5.34) (Dunns multiple comparison test, p<0.05). Also, patients with purulent meningitis had significantly higher CSF suPAR levels than patients with lymphocytic meningitis (p<0.001). Patients with purulent meningitis who died (n=8, 4.9 μg/l(1.3–35) had significantly higher CSF levels of suPAR than patients who survived (n=46, 2.1 μg/l (0.1–24), Mann Whitney, p=0.046). Employing a cut-off point of 3.1 and above, the OR (95%CI) for fatal outcome was 11.9 (1.4–106), univariate logistic regression analysis, p=0.026. In conclusion, CSF suPAR levels may be an important predictor for fatal outcome in purulent meningitis.

Differences in survival, brain damage, and cerebrospinal fluid cytokine kinetics due to meningitis caused by 3 different Streptococcus pneumoniae serotypes: Evaluation in humans and in 2 experimental models

BACKGROUND Experimental meningitis with Streptococcus pneumoniae serotypes 1, 3, and 9 has resulted in pronounced differences in disease severity, but clinical meningitis studies addressing serotype-related differences in case-fatality rates are lacking. METHODS Study subjects were Danish patients with pneumococcal meningitis due to serotype 1 (n=38), 3 (n=69), or 9V (n=59) during 1990-2002 for whom clinical information was available. The 3 serotypes were tested for brain damage and cerebrospinal fluid (CSF) inflammatory kinetics in 2 experimental models of meningitis. RESULTS Patients with serotype 1 had a significantly lower case-fatality rate (3%), compared with patients with serotypes 3 (23%) and 9V (32%) (P=.0047, log-rank test). Age and serotype were independent prognostic factors for fatal outcome. In experimental meningitis, the median number of areas per brain slide with brain damage was significantly lower in rats infected with serotype 1 than in rats infected with serotypes 3 and 9V. Three distinct patterns of brain damage were observed: serotype 1, cortical hemorrhage; serotype 3, cortical necrosis and abscess formation; and serotype 9V, subcortical (callosal) abscess formation. Serotype 1 caused the poorest bacterial growth and lowest CSF levels of white blood cells, tumor necrosis factor- alpha, and interleukin-8 (P<.05). CONCLUSION Case-fatality rates of patients with pneumococcal meningitis, the degree and pattern of brain damage, and CSF cytochemical alterations in experimental pneumococcal meningitis differ according to serotype.