Perioperative treatment with human recombinant interferon-gamma: a randomized double-blind clinical trial.
In spite of proven immunoregulatory effects in vitro of recombinant human interferon-gamma (rhIFN-gamma) in trauma, clinical trials remain inconclusive in such patients. To investigate the in vivo effect of rhIFN-gamma perioperatively in surgical patients we did a pilot study in 46 patients termed anergic by negative delayed-type hypersensitivity (DTH) skin test, who were undergoing major surgery (22 women and 24 men). They received 100 micrograms of rhIFN-gamma subcutaneously (treated [T]; n = 24) in a double-blind, placebo- (control [C]; n = 22) controlled manner on preoperative days -7, -5, and -3. Whole-blood cultures were stimulated on days -7, -1, 4, 7, and 10 for 12 h with or without LPS (1 microgram/mL). Mild side effects such as fever, headache, or chills were observed in 7/24 patients. No major complications occurred and no significant effect of rhIFN-gamma on HLA-DR, IL-1, and IL-8 was demonstrated. PGE2, TNF-alpha and IL-6 levels were elevated perioperatively in T. versus C. Neopterin, a metabolite of activated monocytes and macrophages, was significantly activated on days -1 (C: 7.6 +/- 1.2 versus T: 20.5 +/- 2.4 nmol/mL; P < 0.001), day 1 (C: 8.3 +/- 1.4 nmol/mL versus T: 24.9 +/- 2.8 nmol/mL; P < 0.001), and day 4 (C: 9.5 +/- 1.1 nmol/mL versus T: 16.0 +/- 1.8 nmol/mL; P < 0.05). Due to the overall lack of infectious complications during the investigation, no clinical effect was shown for rhIFN-gamma treatment. DTH skin testing failed to detect high-risk individuals in the patient population studied. In conclusion, we demonstrated in our pilot study that pre-operative immunomodulation with rhIFN-gamma in surgical anergic patients did not show severe side effects and modulated in vitro immunoresponse. A larger clinical trial in better-defined high-risk patients may show whether a reduction of infectious complications can be achieved.
Schinkel
C
C
Department of Surgery, Ludwig-Maximilians University Munich, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany.
Licht
K
K
Zedler
S
S
Schinkel
S
S
Fuchs
D
D
Faist
E
E
D015703:Antigens, CD / Q000032:analysis; D004311:Double-Blind Method; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010865:Pilot Projects; D011994:Recombinant Proteins; D012882:Skin Tests; D013514:Surgical Procedures, Operative; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D006684:HLA-DR Antigens; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma