LAUSR

N ecrotizing soft tissue infections represent a tremendously challenging clinical problem with a significant mortality and morbidity. These challenges arise for several reasons. First, delays in diagnosis are common because of the need for both a high clinical suspicion and the need for an incision to make the diagnosis. Once the diagnosis is made, the surgeon is confronted with decisions about how much tissue to debride. Extensive debridement of infected, necrotic tissue is essential for resolution of the infection, yet the greater the extent of debridement, the greater the morbidity for survivors. Meanwhile, the surgeon is faced with the pressures of making timely decisions regarding the extent and frequency of debridement in the context of a critically ill patient with a profound systemic inflammatory response leading to progressive organ dysfunction. This inflammatory response is driven by endotoxin mediated T-cell activation in gram negative infections or diffuse T-cell activation caused by superantigens in the context of gram-positive infections. The severity of organ dysfunction and the extent of soft tissue infection are major drivers of mortality and morbidity, with the former likely playing the larger role. It is for this reason why Dr. Bulger and colleagues elected to study the immunomodulator, reltecimod, which binds to the CD28 co-stimulatory receptor on T-cells to modulate the hostderived inflammatory response. Their welldesigned phase III multicenter randomized controlled trial in this issue of Annals of Surgery was developed on a strong foundation of prior work including animal studies, prospective cohort studies and a phase II trial. This trial evaluated the utility of reltecimod administered within 6 hours of surgical confirmation of the diagnosis of a necrotizing soft tissue infection. They performed a modified intent to treat analysis, accepting the possibility that some patients would be randomized and at surgery, would be found to have something other than a necrotizing soft tissue infection (NSTI). The investigators also performed a per protocol analyses, where patients were evaluated according to