Granulocyte Elastase, Tumor Necrosis Factor-α and Urokinase Levels as Prognostic Markers in Severe Infection

Abstract

SummaryWe have examined the prognostic value of the levels in the blood of granulocyte elastase-α1-proteinase inhibitor (E-α1-PI) complex, tumor necrosis factor-α (TNF-α) and urokinase-type plasminogen activator (u-PA) in 35 patients with severe infection upon admission to an Intensive Care Unit. Fourteen patients died.No differences for E-α1-PI complex were found between survivors and nonsurvivors, but in all patients the levels on admission were eight-fold higher than the reference value.TNF-α levels, measured by immunoassay, on admission were four times higher in the nonsurvivors than in the survivors (p = 0.0003) and correlated with the severity of the disease (APACHE II score, r = 0.43, p <0.05). TNF-α was not detectable by bioassay.Total u-PA antigen (u-PA Ag), plasmin-activatable single-chain u-PA (scu-PA) and inactive, nonactivatable u-PA (u-PA#) were on admission all two-fold higher in the nonsurvivors (p = 0.0006, 0.003 and 0.0003, respectively), while normal in the survivors. In both, survivors and nonsurvivors, the ratio between scu-PA and u-PA Ag was significantly decreased (p <0.001, compared to a reference group of healthy volunteers), indicative for enhanced conversion of scu-PA to active two-chain u-PA (tcu-PA) and inactive u-PA# during severe infectious disease. tcu-PA was detected in nine of the 35 patients, while virtually undetectable in controls. scu-PA correlated with the Child-Pugh score on admission (r = 0.42, p <0.05). TNF-α correlated with u-PA Ag (r = 0.38, p <0.05) and with u-PA# (r = 0.47, p <0.01).In a stepwise logistic regression analysis, documentation of infection and plasma levels of u-PA Ag contributed most significantly to prediction of patient outcome. Serum levels of TNF-α did not. These results suggest that, in addition to a number of other clinical and laboratory parameters, u-PA Ag can be used as a prognostic marker in patients with severe infection admitted to an Intensive Care Unit.

Fibrinolytic changes in a patient with toxic shock syndrome; release of active u-PA

“…The appearance of active u-PA in the circulation at a relatively late stage of the evolving disorder was unexpected and has not hitherto been recorded. In 1992 Philippe et al [10] noted increased u-PA antigen in the plasma of septic patients and suggested that conversion of scu-PA to active two-chain u-PA might occur. Our observations indicate that active u-PA was, in fact, present in the plasma of this grossly septic patient, a phenomenon not demonstrable in normal individuals, though occurring in advanced cirrhosis.…”

Time course of cytokine levels in sepsis

“…Although a number of reports [1,2,4,6,8,10] have shown a positive correlation between plasma TNF levels at time of admission or diagnosis and mortality, others have failed to find such an association [3,9,[12][13][14][15]. In the study that included the largest number of patients (n = 97), mean plasma levels of TNF on admission did not differ between survivors and nonsurvivors, but posthoc analysis with categorization of TNF levels demonstrated a positive correlation with mortality [13].…”

“…Highest levels of TNF were observed at the time of admission or diagnosis in several studies, with a more or less progressive decline over the following 24 h [8], 48 h [12] or 5 days [15]. In contrast, Munoz et al [9] usually found higher levels at later points in time and highly variable time courses during observation periods of up to 3 weeks, whereas Philipp6 et al [10] observed no major changes in median levels between admission and day 7 in either survivors or nonsurvivors. Interestingly, in two studies [12,15], median levels did not differ between survivors and nonsurvivors initially but became significantly lower in survivors than in nonsurvivors after 6-12 h. Taken together, these findings seem to indicate that TNF levels, when detectable, are usually higher at the time of admission or diagnosis than during subsequent sampling time, especially in survivors.…”

Role of the urokinase plasminogen activator system in patients with bacterial meningitis

“…A correlation between serum uPA levels and mortality has been reported earlier in patients with sepsis. 34,35 Patients with sepsis show increased serum concentrations of uPA, but also concomitantly marked PAI-1 upregulation. 34,36 It was remarkable that the serum PAI-1 concentrations were not elevated in our patients with bacterial meningitis.…”