E Giamarellos-Bourboulis

Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients

PURPOSE To determine the inter-relationships between cytokine levels and physiological scores in predicting outcome in unselected, critically ill patients. METHODS To this end, 127 patients (96 men), having a mean+/-SD age of 45+/-20 years, with a wide range in admission diagnoses (medical, surgical, and multiple trauma patients) were prospectively investigated. Severity of critical illness and organ dysfunction were graded by acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, respectively. Blood samples were drawn on admission in the ICU to determine pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and IL-10. The main outcome measure was 28-day mortality. RESULTS Overall, 88 patients survived and 39 patients died. Univariate logistic regression analysis showed that SOFA, APACHE II, IL-8, IL-6, and IL-10 on admission in the ICU were related to mortality. Multiple logistic regression analysis in the entire cohort of critically ill patients revealed that SOFA (OR=1.341, p<0.001) and IL-6 (OR=1.075, p=0.01) constituted independent outcome predictors. receiver operator characteristics curve analysis showed that SOFA, APACHE II, and IL-6 had the highest area under the curve values. IL-6 correlated with APACHE II (r(s)=0.44, p<0.0001) and SOFA (r(s)=0.40, p<0.0001) scores. CONCLUSIONS In mixed ICU patients cytokine concentrations on admission in the ICU represent independent outcome predictors in the presence of disease severity scores.

Exhaled Breath Condensate in Mechanically Ventilated Brain-injured Patients with No Lung Injury or Sepsis

BACKGROUND The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). METHODS Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1β, 6, 8, and 12p70; and tumor necrosis factor-α. RESULTS EBC pH was lower, whereas IL-1β and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. CONCLUSIONS In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.

Change of annexin binding of monocytes as an expression of cellular response to Candida albicans: down-regulation in severe sepsis

To study the differences of monocyte activation by albicans and non-albicans species of Candida and its change in sepsis, peripheral blood mononuclear cells were isolated from 17 healthy volunteers and 26 patients with severe sepsis/shock, and incubated in the absence/presence of heat-killed (HK) isolates of four different Candida species and purified β-D-glucan from C.albicans. Experiments were repeated in the presence and absence of inhibitors of intracellular activation pathways. Expression of annexin V on cells membranes of monocytes and lymphocytes, cytoplasmic activity of caspase-3, and DNA fragmentation of monocytes were studied. Membrane expression of annexin V on viable monocytes of healthy volunteers decreased significantly after incubation with C.albicans but not with non-albicans species. The decrease was dose-dependent from the Candida inoculum and by the concentration of β-D-glucan. A relationship with inhibition of apoptosis was found as the activity of caspase-3 activity, and the level of DNA fragmentation were also decreased. Incubation in the absence/presence of inhibitors showed that the decrease by annexin V expression resulted by activation of the dectin-1 pathway and Raf-1 by β-D glucan. The decrease of annexin V(+)/PI(−) expression was not shown on monocytes of patients with severe sepsis/shock, where no effect of inhibitors was found. Decrease of annexin V binding on monocytes can be viewed as a selective response to C.albicans partly effected through activation of dectin-1. This response is down-regulated after a septic insult.

Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients

Introduction: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. Methods: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. Results: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1–3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0–3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-&agr; by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. Conclusions: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation.

A circulating factor modulates apoptosis of lymphocytes and monocytes after multiple trauma

The advent of multiple trauma is accompanied by lymphopenia often due to apoptosis. This may be due to the existence of a circulating factor modulating apoptosis. The presence of such a factor in the serum of patients was assessed.

Clarithromycin reverses sepsis-induced immunoparalysis of monocytes

In a recently published double-blind, randomized trial conducted by our study group, clarithromycin was intravenously administered in patients with ventilator-associated pneumonia (VAP) and sepsis for three consecutive days [1]. An earlier resolution of VAP and a fivefold decrease of the risk for death by septic shock and multiple organ failure (MODS) compared with placebo were shown.