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

Early apoptosis of blood monocytes in the septic host: is it a mechanism of protection in the event of septic shock?

INTRODUCTION: Based on the central role of the triggering of monocytes for the initiation of the septic cascade, it was investigated whether apoptosis of blood monocytes in septic patients is connected to their final outcome. METHODS: Blood monocytes were isolated from 90 patients with septic syndrome due to ventilator-associated pneumonia on days 1, 3, 5 and 7 from the initiation of symptoms. Apoptosis was defined after incubation with annexin-V-fluorescein isothiocyanate and propidium iodine and reading by a flow cytometer. The function of first-day monocytes was evaluated from the concentrations of tumour necrosis factor alpha (TNFα) and IL-6 in supernatants of cell cultures after triggering with endotoxins. TNFα, IL-6 and IL-8 were estimated in serum by an enzyme immunoassay. RESULTS: Mortality rates of patients with apoptosis ≤50% compared with patients with apoptosis >50% were 49.12% and 15.15%, respectively (P < 0.0001). Kaplan-Meier analysis showed a 28-day survival benefit in patients with septic shock and monocyte apoptosis >50% compared with those patients with apoptosis ≤50% (P = 0.0032). Production of IL-6 by monocytes on the first day by patients with apoptosis ≤50% was similar compared with monocytes isolated from healthy controls. Serum concentrations of TNFα were higher in patients with monocyte apoptosis ≤50% and septic shock compared with patients with apoptosis >50% on day 7; similar findings occurred for serum IL-6 on days 1 and 7 and for serum IL-8 on days 1 and 5. CONCLUSION: Early apoptosis of monocytes upon presentation of clinical signs of sepsis is connected to a favourable outcome. These findings are of particular importance for the patient with septic shock, where they might constitute a mechanism of pathogenesis

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

Clarithromycin is an effective immunomodulator when administered late in experimental pyelonephritis by multidrug-resistant Pseudomonas aeruginosa

BACKGROUND: To apply clarithromycin as an immunomodulatory treatment in experimental urosepsis by multidrug-resistant Pseudomonas aeruginosa. METHODS: Acute pyelonephritis was induced in 40 rabbits after inoculation of the test isolate in the renal pelvis. Therapy was administered upon signs of sepsis in four groups: A, controls; B, intravenous clarithromycin; C, amikacin; and D, both agents. Survival and vital signs were recorded; blood was sampled for culture and estimation of pro-inflammatory mediators; monocytes were isolated for determination of apoptotic rate and ex vivo TNFα secretion. Quantitative cultures and biopsies of organs were performed after death. RESULTS: Increased rectal temperature and oxygen saturation were found in groups B and D compared to A and C. Mean survival of groups A, B, C and D was 2.65, 7.15, 4.25 and 8.70 days respectively. No differences were noted between groups concerning bacterial load in blood and tissues and serum endotoxins. Serum MDA and total caspase-3 activity of monocytes of group D decreased following treatment compared to other groups. Negative correlation was detected between cytoplasmic caspase-3 and ex vivo secretion of TNFα of blood monocytes of group A; similar correlation was not found for any other group. Pathology scores of liver and lung of group B were lower than group A. CONCLUSION: Clarithromycin administered late in experimental urosepsis by multidrug-resistant P. aeruginosa prolonged survival and ameliorated clinical findings. Its effect is probably attributed to immunomodulatory intervention on blood monocytes

Clarithromycin as immunomodulation therapy: administration on onset of experimetnal sepsis by multidrug resistant pseudomonas aeruginosa

Background To apply clarithromycin as an immunomodulatory treatment in experimental urosepsis by multidrug-resistant Pseudomonas aeruginosa. Methods Acute pyelonephritis was induced in 40 rabbits after inoculation of the test isolate in the renal pelvis. Therapy was administered upon signs of sepsis in four groups: Α, controls; B, intravenous clarithromycin; C, amikacin; and D, both agents. Survival and vital signs were recorded; blood was sampled for culture and estimation of pro-inflammatory mediators; monocytes were isolated for determination of apoptotic rate and ex vivo TNFα secretion. Quantitative cultures and biopsies of organs were performed after death. Results Increased rectal temperature and oxygen saturation were found in groups B and D compared to A and C. Mean survival of groups A, B, C and D was 2.65, 7.15, 4.25 and 8.70 days respectively. No differences were noted between groups concerning bacterial load in blood and tissues and serum endotoxins. Serum MDA and total caspase-3 activity of monocytes of group D decreased following treatment compared to other groups. Negative correlation was detected between cytoplasmic caspase-3 and ex vivo secretion of TNFα of blood monocytes of group A; similar correlation was not found for any other group. Pathology scores of liver and lung of group B were lower than group A. Conclusions Clarithromycin administered late in experimental urosepsis by multidrug-resistant P.aeruginosa prolonged survival and ameliorated clinical findings. Its effect is probably attributed to immunomodulatory intervention on blood monocytes.Σκοπός Η εφαρμογή της κλαριθρομυκίνης ως ανοσοτροποποιητική θεραπεία στην πειραματική ουροσήψη από πολυανθεκτική Pseudomonas aeruginosa. Μέθοδοι Πρόκληση οξείας πυελονεφρίτιδας σε 40 κονίκλους μετά ενοφθαλμισμό του μικροβίου στη νεφρική πύελο. Η θεραπεία χορηγήθηκε κατά την εμφάνιση σημείων σήψης σε τέσσερις ομάδες: Α: μάρτυρες, B: ενδοφλέβιας κλαριθρομυκίνης, C: αμικασίνης και D: και των δύο φαρμάκων. Καταγράφηκε η επιβίωση και τα ζωτικά σημεία, έγινε συλλογή αίματος για καλλιέργεια και υπολογισμό προφλεγμονωδών μεσολαβητών, απομονώθηκαν μονοκύτταρα για καθορισμό του ρυθμού απόπτωσης και της ex vivo έκκρισης TNFα. Έγιναν ποσοτικές καλλιέργειες και βιοψίες οργάνων μετά τον θάνατο των πειραματικών προτύπων. Αποτελέσματα Βρέθηκαν αυξημένη θερμοκρασία ορθού και κορεσμός οξυγόνου στις ομάδες B και D συγκριτικά με τις A και C. Η μέση επιβίωση των ομάδων A, B, C και D ήταν 2.65, 7.15, 4.25 και 8.70 ημέρες αντίστοιχα. Δεν παρατηρήθηκαν διαφορές μεταξύ των ομάδων όσον αφορά το βακτηριακό φορτίο στο αίμα και τους ιστούς και τις ενδοτοξίνες στον ορό. Η MDA του ορού και η δραστικότητα της ολικής κασπάσης-3 των μονοκυττάρων της ομάδας D ελαττώθηκε μετά τη θεραπεία συγκριτικά με τις άλλες ομάδες. Διαπιστώθηκε αρνητική συσχέτιση μεταξύ της κυτταροπλασματικής κασπάσης-3 και της ex vivo έκκρισης TNFα των μονοκυττάρων του αίματος της ομάδας A, ενώ ανάλογη συσχέτιση δεν βρέθηκε για καμία άλλη ομάδα. Η ιστοπαθολογική ταξινόμηση του ήπατος και των πνευμόνων της ομάδας B ήταν χαμηλότερη από της ομάδας A. Συμπεράσματα Η όψιμη χορήγηση κλαριθρομυκίνης στην πειραματική ουροσήψη από πολυανθεκτική P.aeruginosa παρέτεινε την επιβίωση και βελτίωσε τα κλινικά ευρήματα. Η αποτελεσματικότητά της πιθανώς αποδίδεται σε ανοσοτροποποιητική παρέμβαση στα μονοκύτταρα του αίματος

Langerhans cell histiocytosis following treatment for testicular cancer. A case report and literature review

A 35 year old male patient received treatment for testicular cancer of pure seminoma histology. He underwent initially a right inguinal orchiectomy and afterwards he received 3 cycles of BEP chemotherapy, as his imaging studies showed enlarged para-aortic lymph nodes. Five months after completion of chemotherapy treatment, a thoracic CT revealed multiple micronodular lesions in both lungs. The patient was advised about the need of salvage chemotherapy, but he opted to undergo further investigation. A lung lesion biopsy was performed, and histology was compatible with diagnosis of Langerhans cell histiocytosis (LCH)

Long-term efficacy of etanercept in hidradenitis suppurativa: results from an open-label phase II prospective trial

Objective: To evaluate the long-term efficacy of etanercept for the management of hidradenitis suppurativa. Methods: Analysis was based on the long-term follow-up (weeks 24-144) of 10 patients enrolled in a prospective open-label phase II study; etanercept was initially administered subcutaneously 50 mg once weekly for 12 weeks in 10 patients. Disease recurrence and the need to restart etanercept were recorded. Results: Three patients did not report any disease recurrence. A second course of treatment with etanercept was needed in seven patients. Favourable responses were found in five; two patients failed treatment. Conclusions: The first treatment course achieved long-term disease remission in almost one-third of patients. The remaining needed a second treatment course but even in that case, their disease severity at restart was significantly lower compared with baseline

The importance of fever as a predictive symptom for the potency of host&apos;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 alpha), interleukin (IL)-6, IL-10, and malondialdehyde (MDA) were estimated in supernatants. Patients were divided into three groups: group A: &lt; 12 hours, group B: 12 -24 hours, and group C: &gt; 24 hours between initiation of fever and blood sampling. Results. TNFa 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, andMDA 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. Copyright (C) 2008 Magdalini Kyriakopoulou et al