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Interferon-gamma (IFN-gamma) has shown promise in treatment of injured patients. However, reactive states marked by immunologic and inflammatory responses constitute a potential deleterious effect of IFN-gamma administration. IFN-gamma therapy has been associated with high levels of tumor necrosis factor-alpha (TNF-alpha), with potential enhancement of coagulopathy after injury. This study evaluated TNF-alpha production and markers of hemostatic activation in patients receiving IFN-gamma therapy. Seventy-three patients, part of a larger multicenter trial, with severe injuries were randomized to IFN-gamma (100 microg/day s.c. for 21 days) or placebo treatment. Enrollment criteria included injury severity score (ISS) > or = 25 or significant bacterial contamination with ISS > or = 20. TNF-alpha and other cytokine production was assessed at baseline and on days 3, 8, and 22 following injury. Markers of coagulation activation and fibrinolysis were also evaluated. Plasma TNF-alpha and interleukin-6 (IL-6) levels were higher in IFN-treated relative to placebo-treated patients before and after IFN administration. Markers of coagulation and fibrinolysis were elevated at all times studied following injury in both treatment and control groups but did not differ between patients receiving IFN and those receiving placebo. Activation of coagulation and fibrinolysis diminished in a time-related manner following injury. We conclude that (1) IFN-gamma therapy at the dose employed was not associated with a significant increase in TNF-alpha or other inflammatory cytokine production beyond that seen in patients receiving placebo, (2) coagulation and fibrinolytic markers were increased following injury but decreased significantly in surviving patients, and (3) no changes in coagulation and fibrinolytic parameters were noted in relation to IFN-gamma therapy. These findings support previous observations that trauma is associated with hemostatic activation and that treatment of patients at the dose of IFN-gamma studied is safe in the setting of injury.

Objective: The efficacy of interferon gamma therapy in reducing infection and improving outcome from infection in patients sustaining major injury was examined., Design: Randomized double-blind placebo control trial, Setting: Nine level one university affiliated trauma centers in the United States., Patients and Participants: Four hundred sixteen patients with injury severity score (ISS) > or = 25 or ISS > or = 20 with evidence of wound contamination., Intervention: Recombinant human interferon gamma 100 ug or placebo was given subcutaneously daily for up to 21 days in addition to standard antibiotic therapy., Measurements and Results: Comparable rates of major and minor infections were observed. Among the patients treated with interferon gamma there were fewer deaths related to major infection regardless of type [7-(3%) vs 18-(9%)]. The results, however, were dominated by one center which had the highest enrollment, infection and death rates., Conclusions: Further studies are warranted to investigate the role of interferon gamma therapy in improving outcome with major infection.

Two recent studies have examined the efficacy of interferon-gamma in reducing infection and death in patients sustaining severe injury. Both included multi-center, randomized, double-blinded placebo-control design. The first trial, conducted at four university trauma centers, enrolled 213 patients, while the second trial involved nine university trauma centers and 416 subjects. Recombinant human interferon-gamma (100 micrograms) was administered subcutaneously daily for 10 days in the first trial and 21 days in the second, in addition to standard supportive therapy. In both trials infection rates were similar in the treatment arms. Although the death rate related to infection was not affected in the first study, the second trial suggested an improved outcome from this complication. The outcome of the larger trial was flawed by dominant findings at one center that had the highest enrollment, infection, and death rates. Confounding variable analysis presented here explains much of the difference between center findings in the larger trial. Thus, the benefit of interferon-gamma as an immune adjuvant in severe injury is clouded by study design flaws evaluating its use and by the inability to identify appropriate subjects using clinical criteria.

Objective: To assess the efficacy of interferon gamma in reducing infection and death in patients sustaining severe injury., Design: Multicenter, randomized, double-blind, placebo-controlled trial with observation for 60 days and until discharge for patients with major infection on day 60., Setting: Nine university-affiliated level 1 trauma centers., Patients: Four hundred sixteen patients with severe injuries, assessed by Injury Severity Score and degree of contamination., Intervention: Recombinant human interferon gamma, 100 micrograms, was administered subcutaneously once daily for 21 days (or until patient discharge if prior to 21 days) as an adjunct to standard antibiotic and supportive therapy., Main Outcome Measures: Incidence of major infection, death related to infection, and death., Results: Infection rates were similar in both treatment groups; however, patients treated with interferon gamma experienced fewer deaths related to infection (seven [3%] vs 18 [9%]; P = .008) and fewer overall deaths (21 [10%] vs 30 [14%]; P = .17). While 12 early deaths (days 1 through 7) occurred in each treatment group, late death occurred in 18 placebo-treated patients and nine in interferon gamma-treated patients. The results were dominated by findings at one center, which had the highest enrollment and higher infection and death rates. Statistical analysis did not eliminate the possibility of an unidentified imbalance between arms as an explanation for the results., Conclusion: Further evaluation is required to determine the validity of the observed reduction in infection-related deaths in patients treated with interferon gamma.

Interferon-gamma (IFN-gamma) has been demonstrated to improve outcome following localized infection and hemorrhagic shock in experimental studies. We sought to determine the effects of IFN-gamma in a clinically relevant murine model of intra-abdominal polymicrobial sepsis. Fifty male BDF1 mice, each weighing 23-28 g, underwent cecal ligation and puncture (CLP) followed by administration of subcutaneous injections of IFN-gamma 100-22,500 U or vehicle control immediately post-CLP and then daily. In a second set of experiments, 60 mice underwent daily injections of vehicle control or 100 U IFN-gamma 24, 48, or 72 hours prior to CLP. Interferon-gamma administered following CLP led to increased mortality and earlier deaths in a dose-dependent fashion (p < 0.05). Interferon-gamma given 24, 48, or 72 hours prior to CLP resulted in no demonstrable benefit when compared with animals that did not receive IFN-gamma (p = 0.14, p = 0.94, and p = 0.97, respectively). While IFN-gamma has been reported to be of value in selected clinical situations by improving resistance to infection, it may not be capable of conferring protection following surgery or trauma with intra-abdominal sepsis, and in fact may be detrimental.

Interferon-gamma (IFN-gamma), a cytokine that has been shown to upregulate macrophage function, has recently been demonstrated to improve outcome when exogenously administered in several animal models of injury. Because the macrophage is also important in the events that govern wound healing, we evaluated the effects of IFN-gamma upon wound healing in a murine model. IFN-gamma was administered in doses of 937.5-22,500 u synchronous with the creation of a left paraspinous wound and then daily. At Day 10, wounds were harvested, evaluated for wound disruption strength (WDS), and subjected to morphometric analysis. Wounds were also subjected to 36-hr formalin fixation to maximally cross-link collagen fibrils and retested for WDS. We found that IFN-gamma impaired wound healing at all doses relative to control, and WDS was impaired in a dose-dependent fashion. Our highest dose of IFN-gamma (22,500 u) produced a WDS only 65% of the control. Morphometric studies demonstrated less collagen deposition and a lower degree of neovascularity in IFN-gamma-treated animals. In addition, formalin fixation studies suggested that IFN-gamma may impair collagen cross-linking. The potential benefits of IFN-gamma in the multiply injured patient must be weighed against the possibility that IFN-gamma might deleteriously effect events fundamental to wound healing.