Anti-Cytokine Therapy (p55-IgG) in Severe Sepsis
ABSTRACT & COMMENTARY
Synopsis: This randomized, control trial demonstrated that p55 TNF receptor fusion protein decreased 28-day all-cause mortality in patients with severe sepsis without refractory shock, but further questions need to be answered before anti-cytokine therapy can be recommended routinely for sepsis.
Source: Abraham E. JAMA 1997 (May 21);277: 1531-1538.
A randomized, controlled, multicenter, clinical trial was conducted to evaluate the efficacy of p55 TNF receptor fusion protein (p55-IgG) in the treatment of severe sepsis and septic shock. Patients diagnosed as having severe sepsis or septic shock following the standard criteria were prospectively randomized to receive a single infusion of either p55-IgG, in doses of 0.083 mg/kg, 0.042 mg/kg, 0.008 mg/kg, or placebo. All patients received standard intensive care, and 28-day all-cause mortality was used as an outcome. After 201 patients had been enrolled in the study, the treatment dose of 0.008 mg/kg was discontinued, because no significant difference in mortality between this arm and placebo was seen. Subsequently, the remaining two doses were continued, and the study was completed in a total of 498 patients (0.008 mg/kg [n = 54]; 0.042 mg/kg [n = 145]; 0.083 mg/kg [n = 159]; and placebo [n = 140]).
There was no statistically significant difference in mortality between the overall patients who received p55-IgG and those who received the placebo. There was no significant increase in survival in patients with septic shock. However, in patients with severe sepsis (n = 247), therapy with a dose of 0.083 mg/kg of p55-IgG tended to decrease the 28-day all-cause mortality by 36% in comparison with the placebo, although this did not reach statistical significance (P = 0.07). When predicted mortality and plasma IL-6 levels were included as continuous covariates in a logistic regression analysis, a trend toward reduced mortality by p55-IgG became significant at day 28.
COMMENT BY JUN TAKEZAWA, MD
First, this paper demonstrated the clinical feasibility of anti-cytokine therapy in severe sepsis. However, the conclusion that this therapy improves patient outcome appears to be premature at this point, since the decrease in mortality in severely septic patients given p55-IgG in a single dose of 0.083 mg/kg in comparison with placebo did not reach a statistical significance. Subsequently, Abraham had to include the APACHE III score and IL-6 level in order to find a statistically significant effect (P < 0.01) using a prospectively planned logistic regression analysis on mortality between the patients with 0.083 mg/kg of p55-IgG and the patients receiving the placebo. To confirm that all potential confounders were equally distributed in both groups (which incidentally was not accomplished in this study), another large-scale RCT would be required.
Although it is reasonable to expect that p55-IgG would improve the outcome of severe sepsis, the previous RCTs using a monoclonal antibody to TNFa failed to demonstrate decreased mortality in sepsis or septic shock (Abraham E, et al. JAMA 1995;273:934-941; Dhainaut, JF, et al. Crit Care Med 1995;23:1461-1469; Reinhart K, et al. Crit Care Med 1996;24:733-742; Cohen J, Carlet, J. Crit Care Med 1996;24:1431-1440; Sprung CL, et al. Crit Care Med 1996;24:1441-1447). The discrepancy between the present study and previous studies using a monoclonal antibody to TNFa can be attributed to the following reasons: first, an antibody bound to TNFa may not inactivate the bioactive site of TNFa, and antibody-TNFa complex may rather activate targets cells via receptor clustering while 55p-IgG is bound to the bioactive site of TNFa, resulting in the prevention of signal transduction to the target cells. To confirm the blood TNF level, a bioassay using a mouse L929 cell line is required, because TNF bound to the antibody or receptor fusion protein can be identified and measured by the ELISA method, while TNF bound to p55-IgG may not produce bioactivity. Second, a single infusion of antibody is insufficient to reduce TNFa to the nontoxic level throughout the duration of sepsis. p55-IgG has a long pharmacokinetic half-life and a higher binding affinity for TNFa than anti-TNFa antibody. A continuous infusion or sequential administration of p55-IgG might further improve the outcome. Finally, of course, TNFa may not play a significant role in affecting the outcome of sepsis. Again, a large scaled RCT would be required to prove that p55-IgG therapy improves the outcome of severe sepsis.