Injuries continue to be the fifth leading cause of death overall and the leading cause of death for persons less than 45 years of age in the U.S. Multiorgan failure (MOF) and death remain unacceptably common in severely injured patients. In our recent Glue Grant study, 19% of severe trauma patients died, 41% developed MOF and the average time to recovery was 16 days. Despite an improved understanding of the basic pathophysiology of severe trauma and its sequelae, there are essentially no biological response modifiers that have proven successful in prospective, randomized clinical trials. We propose that a significant proportion of patients who would generally meet the inclusion criteria for a study of severely injured patients, are not in need of immunomodulatory therapy and are not only unlikely to benefit but also suffer direct toxicity from such therapies. In contrast, there exists subset of patients who are going to have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. The most important challenge today is to identify prospectively the subset of patients who are going to have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. We believe that we have developed such a prospective genomic test. Therefore, the overall goal of this proposal is to prospectively validate a rapid genomic test obtained from blood leukocyte subpopulations of severely traumatized patients in the first 24 hrs after admission that can be used to discriminate those patients who will have a complicated clinical trajectory and would, therefore, be good candidates for interventional, immunomodulatory therapies. Based on our preliminary data, we have developed several genomic models based on total leukocyte and enriched blood neutrophils that retrospectively can identify patients who will have a poor clinical outcome and would benefit from interventional immunological therapies. Here, we propose to validate this approach in 200 severely traumatized patients enrolled at two geographically-distinct institutions. These genomic tests will be compared for their precision to standard anatomical and physiological scoring systems, and models based on plasma cytokine concentrations. If successful, these studies would dramatically alter how clinical trials in severely traumatized patients would be conducted in the future. A successful, rapid, prognostic genomic test would reduce the size, cost and time required to evaluate new drugs in this population by identifying individuals at risk of a complicated outcome. Personalized medicine"""""""" would be one step closer to reality.
Clinical trials of immunomodulation therapy for severely traumatized patients have been hindered by the large inherent variation in clinical response to trauma, potential direct toxicity of therapy, and subsequent outcomes. Here we propose the prospective validation of a novel genomic test obtained in the first 24 hours after admission that can identify those patients who will have a protracted clinical course and would benefit from interventional therapies. These studies will introduce 'personalized genomic medicine'in critically ill patients.
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|Moldawer, Lyle L; Efron, Philip A; Brakenridge, Scott et al. (2017) The authors reply. Crit Care Med 45:e740-e741|
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