Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies

Abstract

With improvements in personnel and vehicular body armor, robust casualty evacuation capabilities, and damage control resuscitation strategies, more combat casualties are surviving to reach higher levels of care throughout the casualty evacuation system. As such, medical centers are becoming more accustomed to managing the deleterious late consequences of combat trauma related to the dysregulation of the immune system. In this review, we aim to highlight these late consequences and identify areas for future research and therapeutic strategies. Trauma leads to the dysregulation of both the innate and adaptive immune responses, which places the injured at risk for several late consequences, including delayed wound healing, late onset sepsis and infection, multi-organ dysfunction syndrome, and acute respiratory distress syndrome, which are significant for their association with the increased morbidity and mortality of wounded personnel. The mechanisms by which these consequences develop are complex but include an imbalance of the immune system leading to robust inflammatory responses, triggered by the presence of damage-associated molecules and other immune-modifying agents following trauma. Treatment strategies to improve outcomes have been difficult to develop as the immunophenotype of injured personnel following trauma is variable, fluid and difficult to determine. As more information regarding the triggers that lead to immune dysfunction following trauma is elucidated, it may be possible to identify the immunophenotype of injured personnel and provide targeted treatments to reduce the late consequences of trauma, which are known to lead to significant morbidity and mortality.

Keywords: Compensatory anti-inflammatory response syndrome; Immune dysfunction; Persistent inflammation-immunosuppression and catabolism syndrome; Sepsis; Trauma.

Fig. 1

Temporal association of immune dysfunction syndromes. After an initial combat-related injury, there is the development of a hyper-inflammatory response, termed the systemic inflammatory response syndrome (SIRS), and an immune suppressing response, termed the compensatory anti-inflammatory response syndrome (CARS). These two responses happen within minutes to days, occurring nearly simultaneously, and it is during these initial inflammatory phases that death from early multi-organ dysfunction syndrome (MODS) may occur. As both the pro-inflammatory and anti-inflammatory responses resolve, there is a period of resolution, typically within days to weeks, that allows for the return to homeostasis and survival after the injury. However, in a percentage of injured patients, the pro-inflammatory and/or anti-inflammatory responses never resolve, leading to a period of chronic critical illness termed persistent inflammatory-immunosuppressive and catabolic syndrome (PICS). This occurs in patients who have been critically ill for longer than 14 days with significant lymphopenia and chronic inflammation. PICS may persist for months and lead to the risk of developing later MODS and secondary infections with subsequent morbidity and late mortality

Fig. 2

Interactions of the innate and adaptive immune systems in response to trauma. Immediately following injury, damaged tissues release damage-associated molecular patterns (DAMPs) and in response, residing innate immune cells release pro-inflammatory cytokines. These signals help recruit other innate immune cells to the site of injury in an attempt to contain the deleterious effects of the injury. However, in severe injuries, the immune response goes beyond the local site of injury and leads to systemic inflammation. To reduce the impact of systemic inflammation, the adaptive immune system, primarily through the suppression of regulatory T cells (T_reg), releases anti-inflammatory cytokines and other signals that impede the immune system as it tries to continue the pro-inflammatory response. This manifests as apoptosis of innate immune cells and decreased antigen presentation (HLA-DR on monocytes), as well as apoptosis and the anergy of helper T cells causing leukopenia. In the maladaptive state, preponderance of this anti-inflammatory, immune suppressing phenotype leads to the consequences of CARS and PICS. The general effect of a chronic inflammatory state on immune systems in response to injury is listed below their respective cell types. For a general review of the immune system and inflammation, the reader is referred to a review by Spiering [37]