Potential Hazards of Combination Immunotherapy in the Treatment of Experimental Septic Shock

• Published in: The Journal of infectious diseases 1996-06, Vol.173 (6), p.1415-1421
• Main Authors: Opal, Steven M., Cross, Alan S., Jhung, Jhung W., Young, Lynnette D., Palardy, John E., Parejo, Nicholas A., Donsky, Curtis
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Bacteremia - blood; Biological and medical sciences; Blood; Carrier Proteins - adverse effects; Carrier Proteins - chemistry; Carrier Proteins - therapeutic use; Colony Count, Microbial; Cyclophosphamide - pharmacology; Cytokines; Drug Therapy, Combination; Emergency and intensive care: infection, septic shock; Endotoxins; Endotoxins - blood; Humans; Immunosuppressive Agents - pharmacology; Immunotherapy; Immunotherapy - adverse effects; Infections; Intensive care medicine; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Major Articles; Medical sciences; Neutropenia - chemically induced; Polyethylene Glycols - chemistry; Pseudomonas aeruginosa; Pseudomonas aeruginosa - growth & development; Pseudomonas Infections - pathology; Pseudomonas Infections - therapy; Rats; Receptors; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Recombinant Proteins - adverse effects; Sepsis; Septic shock; Shock, Septic - pathology; Shock, Septic - therapy; Sialoglycoproteins - adverse effects; Sialoglycoproteins - therapeutic use; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha - analysis; Tumor necrosis factors
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/173.6.1415

Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic rats, the potential utility of a combination anticytokine approach for the treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked with polyethylene glycol was used with recombinant human interleukin-1 receptor antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20). Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo. Disseminated microabscesses in major organs were found in animals treated with combination immunotherapy. Combination anticytokine therapy may exacerbate systemic infection and worsen outcome in experimental sepsis.