The Importance of Fever as a Predictive Symptom for the Potency of Host's Monocytes to Release Pro- and Anti-Inflammatory Mediators

Objective. To clarify whether time lapsing from advent of fever as a first sign of sepsis may be indicative of the potency of monocytes for the release of pro- and anti-inflammatory mediators. Methods. Monocytes were isolated from blood of 51 septic patients and 9 healthy donors. Monocytes were incubated in the absence and presence of patients' serum and concentrations of tumour necrosis factor-alpha (TNF α), interleukin (IL)-6, IL-10, and malondialdehyde (MDA) were estimated in supernatants. Patients were divided into three groups: group A: <12 hours; group B: 12—24 hours, and group C: >24 hours between initiation of fever and blood sampling. Results. TNF α of supernatants of groups B and C was higher than controls, as also were IL-6 of A and C, IL-10 of A and B, and MDA of A. IL-6 of group A was increased after addition of patients serum. A negative correlation was found between time from initiation of symptoms and IL-6 of monocyte supernatants incubated in the presence of patients serum. Median IL-6 of survivors was higher than nonsurvivors. Conclusion. Monocytes are potent for the release of pro- and anti-inflammatory mediators within the first 24 hours upon advent of fever related to sepsis; serum stimulates further release of IL-6 within the first 12 hours

Effect of Clarithromycin in Patients with Sepsis and Ventilator-Associated Pneumonia

Background. Because clarithromycin provided beneficiary nonantibiotic effects in experimental studies, its efficacy was tested in patients with sepsis and ventilator-associated pneumonia (VAP). Methods. Two hundred patients with sepsis and VAP were enrolled in a double-blind, randomized, multicenter trial from June 2004 until November 2005. Clarithromycin (1 g) was administered intravenously once daily for 3 consecutive days in 100 patients; another 100 patients were treated with placebo. Main outcomes were resolution of VAP, duration of mechanical ventilation, and sepsis-related mortality within 28 days. Results. The groups were well matched with regard to demographic characteristics, disease severity, pathogens, and adequacy of the administered antimicrobials. Analysis comprising 141 patients who survived revealed that the median time for resolution of VAP was 15.5 days and 10.0 days among placebo- and clarithromycin-treated patients, respectively (P=.011); median times for weaning from mechanical ventilation were 22.5 days and 16.0 days, respectively (P=.049). Analysis comprising all enrolled patients showed a more rapid decrease of the clinical pulmonary infection score and a delay for advent of multiple organ dysfunction in clarithromycin-treated patients, compared with those of placebo-treated patients (P=.047). Among the 45 patients who died of sepsis, time to death was significantly prolonged in clarithromycin-treated compared with placebo-treated patients (P=.004). Serious adverse events were observed in 0% and 3% of placebo- and clarithromycin-treated patients, respectively (P=.25). Conclusions. Clarithromycin accelerated the resolution of VAP and weaning from mechanical ventilation in surviving patients and delayed death in those who died of sepsis. The mortality rate at day 28 was not altered. Results are encouraging and render new perspectives on the management of sepsis and VA

Effect of the Novel Influenza A (H1N1) Virus in the Human Immune System

BACKGROUND: The pandemic by the novel H1N1 virus has created the need to study any probable effects of that infection in the immune system of the host. METHODOLOGY/PRINCIPAL FINDINGS: Blood was sampled within the first two days of the presentation of signs of infection from 10 healthy volunteers; from 18 cases of flu-like syndrome; and from 31 cases of infection by H1N1 confirmed by reverse RT-PCR. Absolute counts of subtypes of monocytes and of lymphocytes were determined after staining with monoclonal antibodies and analysis by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from patients and stimulated with various bacterial stimuli. Concentrations of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-18, interferon (FN)-alpha and of IFN-gamma were estimated in supernatants by an enzyme immunoassay. Infection by H1N1 was accompanied by an increase of monocytes. PBMCs of patients evoked strong cytokine production after stimulation with most of bacterial stimuli. Defective cytokine responses were shown in response to stimulation with phytohemagglutin and with heat-killed Streptococcus pneumoniae. Adaptive immune responses of H1N1-infected patients were characterized by decreases of CD4-lymphocytes and of B-lymphocytes and by increase of T-regulatory lymphocytes (Tregs). CONCLUSIONS/SIGNIFICANCE: Infection by the H1N1 virus is accompanied by a characteristic impairment of the innate immune responses characterized by defective cytokine responses to S.pneumoniae. Alterations of the adaptive immune responses are predominated by increase of Tregs. These findings signify a predisposition for pneumococcal infections after infection by H1N1 influenza

Immunomodulatory effect of three-day continuous administration of clarithromycin for experimental sepsis due to multidrug-resistant Pseudomonas aeruginosa

Based on former animal studies showing the immunomodulatory effect of clarithromycin in experimental sepsis by multidrug-resistant Pseudomonas aeruginosa following administration of single doses, the significance of its administration for three consecutive days was evaluated. Acute pyelonephritis was induced in 30 rabbits after inoculation of the test isolate in the renal pelvis. Therapy was administered upon signs of sepsis in three groups: A, controls,B, intravenous clarithromycin for one day,and C, intravenous clarithromycin for three days. Survival was recorded and blood was sampled for culture and estimation of pro-inflammatory mediators, monocytes were isolated for determination of ex vivo TNFα secretion. Quantitative cultures and biopsies of organs were performed after death. Mean survival of groups A, B and C was 2.65, 7,15 and 7.95 days respectively. Death occurred in all controls(mortality 100%) and in 15 animals treated with either one-or three-day regimen of clarithromycin ( mortality 75%, p:0,033). At 24 hours, serum malondialdehyde of group C, which is an index of the oxidant status in serum, was lower than A. Ex vivo release of TNFalpha by the isolated monocytes of group B and C was lower than A .Ex vivo release of TNFα by the isolated monocytes of group C was lower than A on all times of sampling. Total pathology scores of liver of group B were lower than A and C. It is concluded that administration of clarithromycin for three days than one day had superior immunomodulatory effects in experimental sepsis by multidrug-resistant P.aeruginosa. Its action was exerted on blood monocytes.Με βάση προηγούμενες μελέτες σε ζωικά πρότυπα που ανέδειξαν την ανοσοτροποποιητική δράση της κλαριθρομυκίνης στην πειραματική σήψη μετά χορήγηση μιας δόσης φαρμάκου,ακολούθησε η μελέτη χορήγησης φαρμάκου για τρεις διαδοχικές μέρες στην πειραματική σήψη από πολυανθεκτική P. aeruginosa. Οξεία πυελονεφρίτιδα προκλήθηκε σε 30 κονίκλους μετά ενοφθαλμισμό του παθογόνου στη νεφρική πύελο.Τα ζωικά πρότυπα διαιρέθηκαν σε τρεις ομάδες μελέτης Α, μάρτυρες, Β, ζώα στα οποία χορηγήθηκε κλαριθρομυκίνη για μια μέρα και C, ζώα στα οποία χορηγήθηκε θεραπεία για τρεις μέρες. Ακολούθησε παρακολούθηση της επιβίωσης και αιμοληψίες για καλλιέργειες και προσδιορισμό προφλεγμονωδών μεσολαβητών.Επίσης έγινε απομόνωση μονοκυττάρων για προσδιορισμό της ex vivo παραγωγής TNFα.Μετά το θάνατο κάθε ζώου ακολουθούσε νεκροτομή με ποσοτικές καλλιέργειες και βιοψίες των οργάνων.Η μέση επιβίωση των ομάδων Α,Β και C ήταν 2.65, 7.15, και 7.95 μέρες αντίστοιχα. Όλοι οι μάρτυρες απεβίωσαν (θνητότητα 100%), ενώ από τα ζώα που έλαβαν αγωγή με κλαριθρομυκίνη ,είτε για μια μέρα είτε για τρεις,απεβίωσαν 15 (θνητότητα 75%,p:0;033). Στις 24 ώρες,η μαλονοδιαλδεύδη ορού της ομάδας C ήταν χαμηλότερη από την αντίστοιχη της ομάδας A. Επίσης, στις 48 ώρες ο παράγοντας ΤΝFα των ομάδων B και C, ήταν χαμηλότερος από την ομάδα Α. Η ex vivo παραγωγή του TNFα, από τα απομονωμένα μονοκύτταρα της ομάδας C, κυμαινόταν ομοίως σε χαμηλότερα επίπεδα από την ομάδα Α, σε όλες τις δειγματοληψίες.Total pathology scores του ήπατος της ομάδος Β, ήταν χαμηλότερα από τα αντίστοιχα των ομάδων Α και C. Συμπεραίνεται ότι η χορήγηση κλαριθρομυκίνης για τρεις μέρες υπερτερεί της μονοήμερης χορήγησης,όσον αφορά στην ανοσοτροποποιητική της δράση στην πειραματική σήψη από πολυανθεκτική P.aeruginosa

Large vessel vasculitis in a patient with acute Q-fever: A case report

Q fever is a zoonosis caused by the rickettsial organism Coxiella burnetii. Infection has an acute course, usually with a self-limited febrile illness and the possibility of the evaluation to a chronic course with endocardial involvement. The presence of autoantibodies and various autoimmune disorders have also been associated with C. burnetii infection. We report a case of acute Q fever in which the patient developed large vessel vasculitis. The FDG-PET/CT scan detected inflammation of the thoracic aortic wall, suggesting an unusual immunologic host response to acute Q fever infection

Portal and systemic endotoxemia in abdominal operations: The significance of acute abdomen

Little evidence is available for the implication of bacterial translocation in cases of acute abdomen. Intraoperative endotoxemia in both portal and systemic circulation was studied in 20 surgical patients with acute abdomen and in 36 controls undergoing elective abdominal surgery. Blood was sampled simultaneously from a mesenteric vein immediately after opening the peritoneum and from a peripheral vein. Endotoxin was measured by a colorimetric Limulus amebocyte lysate assay and malondialdehyde (MDA) was measured by the thiobarbiturate assay and passage through a high-performance liquid chromatography (HPLC) system as a marker of the oxidative status. LPS concentrations (mean +/- SE) in portal vein blood from patients with acute abdomen was 5.69 +/- 1.58 and from patients with chronic diseases 1.05 +/- 0.07 EU/ml (P &lt; 0.0001). Respective values for the systemic circulation were 4.98 +/- 1.47 and 1.36 +/- 0.31 EU/ml (P &lt; 0.0001). Concentrations of MDA (mean SE) in portal vein blood from patients with acute abdomen was 11.16 +/- 4.00 and from patients with chronic diseases was 10.56 +/- 2.39 mu M, (P NS). Positive correlations were observed between endotoxin and MDA in both portal and systemic circulation. These results indicate increased levels of endotoxin in acute abdominal conditions pointing to the gut as the site of origin of the bacterial products. (c) 2006 Elsevier Inc. All rights reserved

Metabolite Profiles in Sepsis: Developing Prognostic Tools Based on the Type of Infection∗

Objectives: Currently used biomarkers insufficiently discriminate between patients with systemic inflammatory response syndrome of non-infectious origin and sepsis. The aim of this study was to identify surrogate markers that distinguish between systemic inflammatory response syndrome and sepsis as well as the underlying type of infection by targeted metabolomics. Design: Retrospective analysis. Settings: Six sites of the Hellenic Sepsis Study Group and at Jena University Hospital. Patients: A total of 406 patients were analyzed: 66 fulfilling criteria for diagnosis of systemic inflammatory response syndrome, 100 for community-acquired pneumonia, 112 for urinary tract infection, 83 for intra-abdominal infection and 45 for bloodstream infection. Patients were divided into test cohort (n = 268) and confirmation cohort (n = 138). Interventions: A total of 186 metabolites were determined by liquid chromatography tandem mass spectrometry. Measurements and Main Results: Serum concentrations of most acylcarnitines, glycerophospholipids and sphingolipids were altered in sepsis compared to systemic inflammatory response syndrome. A regression model combining the sphingolipid SM C22:3 and the glycerophospholipid lysoPCaC24:0 was discovered for sepsis diagnosis with a sensitivity of 84.1% and specificity of 85.7%. Furthermore, specific metabolites could be used for the discrimination of different types of infection. The glycerophospholipid lysoPCaC26:1 identified patients with community-acquired pneumonia in sepsis or severe sepsis/septic shock. Within severe sepsis/septic shock, patients with bloodstream infection could be discriminated by a decrease of acetylornithine. Changes of metabolites between sepsis and severe sepsis/septic shock also varied according to the underlying type of infection, showing that putrescine, lysoPCaC18:0 and SM C16:1 are associated with unfavorable outcome in community-acquired pneumonia, intra-abdominal infections and bloodstream infections, respectively. Conclusions: Using a metabolomics approach, single metabolites are identified that allow a good, albeit at about 14% false positive rate of sepsis diagnosis. Additionally, metabolites might be also useful for differentiation and prognosis according to the type of underlying infection. However, confirmation of the findings in ongoing studies is mandatory before they can be applied in the development of novel diagnostic tools for the management of sepsis. Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved