M. E. Wakeley1, S. F. Monaghan1, W. G. Cioffi1, A. Ayala1, D. S. Heffernan1 1Brown University School Of Medicine,Surgery,Providence, RI, USA
Introduction: Trauma induces significant immune-deficiency associated with secondary infection, long term organ dysfunction and an increased risk of death. Lymphocyte loss and dysfunction plays a central role in adverse trauma related outcomes, and co-inhibitory molecules have emerged as key drivers of immune dysfunction in critical illness. HVEM, a TNF family transmembrane receptor is known to mediate host immunity at mucosal barriers in both stimulatory and inhibitory ways. Altered expression of HVEM and one of its ligands BTLA, are associated with poor outcomes and increased nosocomial infections in critically ill septic patients. Given infections are a driving force in poor long-term trauma outcomes, we hypothesize critically ill trauma patients will display increased blood lymphocyte HVEM expression and that such alteration should be predictive of secondary infectious events.
Methods: Critically ill trauma patients prospectively enrolled from the Trauma ICU were compared with healthy controls. Leukocytes were isolated from whole blood, stained for CD3 (lymphocytes) and HVEM by flow cytometry. Charts were reviewed for injuries sustained, APACHE II score, and hospital course including secondary infections.
Results: Trauma patients (N=31) compared with healthy controls (N=10) were slightly older (46.7 +/-2.4 vs 36.8+/- 2.1 years; p=0.03) but matched for male sex (74% vs 60%; p=0.4). Trauma patients had higher presenting White Cell Count (13.9 +/- 1.3 vs 5.6 +/-0.5 x106/ml; p=0.002), lower percentage of CD3+ lymphocytes (7.5% +/-0.8 vs 22.5% +/-0.9; p<0.001), but significantly greater expression of HVEM+/CD3+ lymphocytes (89.6% +/-1.46 vs 67.3% +/-1.7; p<0.001). The most common source of infection was ventilator associated pneumonia. Among trauma patients, those who developed a secondary infection during the hospitalization had a higher APACHE II score (20.6 +/- 1.6 vs 13.6 +/-1.4; p=0.03) and markedly lower HVEM expression on CD3+ lymphocytes (75% +/-2.6 vs 93% +/-0.7; p<0.01).
Conclusion: In keeping with prior observations on critically ill septic patients, we demonstrate that HVEM expression is increased on CD3+cells after trauma. However, patients who develop an infection during their hospital stay have a lower percentage HVEM+ CD3+ cells circulating. This suggests that HVEM signaling in lymphocytes plays a role in maintaining host defense to infection in critically injured trauma patients. Given the expanding availability of check-point protein mediators, HVEM expression may play the roles of a marker of risk for infection as well as a potential therapeutic target to modulate the immune response to trauma, offering a means for preventing trauma related complications.