Another concept not well understood is the exact threshold that determines when and how an immune response transitions from local to systemic. This is important because, once the response becomes systemic, the risk of developing subsequent organ failure increases significantly (14). The ability to predict how and when the response will systemically affect the host is necessary to understand the mechanisms involved in what we currently describe as a “dysregulated” response. Importantly, there has been a major paradigm change in the description of the systemic response to injury or infection, as initially described by Bone et al. (15). This has necessitated a shift in our understanding of the process of inflammation as a whole. The original theory was that the systemic inflammatory response syndrome (SIRS) initiates the response to injury or infection, characterized by the release of a cascade of pro-inflammatory mediators and activation of immune cells. The inflammatory mediators in SIRS allowed for the removal of invading pathogens or cellular debris. The killing mechanisms implicated in SIRS, however, are nonspecific and could cause local tissue destruction if left unchecked, leading to early death due to multiple organ failure. Once the SIRS response diminishes in this paradigm, there is a subsequent compensatory anti-inflammatory response syndrome (CARS) that not only downregulates the destructive mechanisms of innate immune cells, but also promotes tissue healing and repair (4, 16). If this phase becomes imbalanced or prolonged and certain signals are not turned off appropriately, patients are at risk of developing ongoing inflammation, which ultimately leads to lymphocyte depletion and immunosuppression. If the inflammatory response is either insufficient or too excessive in this model, both the responses activated simultaneously, creating a mixed antagonist response syndrome (17). Recent studies have challenged Bone's sequential articulation of inflammatory responses. Instead, it appears that the CARS-type response often occurs simultaneous to the SIRS-type response, providing a concurrent reaction to injury and infection from the onset of the insult (18). The mechanisms involved with maintaining the balance between the SIRS and CARS responses, however, are not clear. Therefore, future studies investigating which individuals do not resolve the inflammatory response and eventually progress to a state of immunosuppression are essential (2).
It remains unclear whether one specific mediator or a medley of mediators are sensitive or specific enough to identify which patients will progress to PICS. IL-6 and IL-8 consistently seem to have the greatest sensitivity and specificity to prognosticate infection in critically ill patients in the ICU (31, 32). A number of studies have shown that certain genetic polymorphisms of cytokine genes are associated with worse outcomes in critically ill patients (33, 34) and with aging (35). In particular, individuals predisposed to generating higher levels of pro-inflammatory cytokines have decreased longevity and worse outcomes in response to an insult (36). None of these studies evaluates whether there are certain genetic predispositions to the development of chronic critical illness or PICS. While many biomarkers are associated with predictors of prolonged hospitalizations or increased infectious complications, perhaps measuring the absolute value of these markers does not accurately portray the course of the immune response. For instance, while elevated IL-6 correlates with worse outcomes in a number of clinical scenarios, it is unclear which is more harmful: the release of very high levels of IL-6 followed by a quick return to baseline or a protracted release of moderate levels of IL-6. Some have suggested that, rather than focusing on an absolute level of biomarker release, perhaps tracking the change in biomarker levels over time would allow one to predict a patient's course (11). Such studies could better identify which patients are at risk of developing prolonged critical illness and who would potentially benefit from early intervention.
Although activation of the inflammatory response is excessive or prolonged in conditions leading to persistent inflammation, the immune cells themselves appear markedly dysfunctional. In the normal inflammatory response, innate immune cells become activated upon recognizing pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (29). PAMPs are peptides or DNA fragments derived from foreign pathogens at a site of infection, whereas DAMPs are released from host cells following tissue damage and are primarily implicated in the inflammatory response to injury. Pathogen-recognition receptors (PRRs) on the surface of innate immune cells then recognize these molecular fragments. The most commonly known group of PRRs is the toll-like receptor family (27).
Once the PAMPs or DAMPs bind to the PRRs, a series of host defense responses are activated. These responses include the elaboration of reactive oxygen species, the generation of reactive nitrogen species, and the phagocytosis of pathogens. In response to local tissue damage or infection, surrounding cells release chemokines to promote trafficking of additional immune cells toward the site of the insult. The robustness of this response is integral to the efficient and timely clearance of pathogens. Furthermore, the ability of innate immune cells to present antigens on their cell surface is imperative for activation and clonal expansion of T cells, which provide a complimentary pathway to eradicating pathogens and clearing damaged tissue.
Various states of systemic inflammation are also associated with a depletion of CD4+ and CD8+ T cells in the blood, bone marrow, spleen, and secondary lymphoid organs (53, 54). This loss is directly related to increased apoptosis of T cells. Therapies that prolong prosurvival signals for lymphocytes have demonstrated increased bacterial clearance in various models of infection (55). The significance of this suppressed adaptive response is exemplified in studies showing the reactivation of latent viruses that occurs even in nonimmunocompromised individuals suffering from prolonged inflammatory states (53, 56). While the respective roles of the innate and adaptive immune systems in the development of persistent inflammation are not clear, some show that a Gr-1+ CD11b+ suppressor cell population, termed myeloid-derived suppressor cells (MDSC), are significantly elevated in severe sepsis and other prolonged inflammatory states. These cells can significantly induce T-cell suppression, which decreases microbial clearance, and may be a contributing factor to persistent inflammation (57, 58).
Overall, an increased or prolonged release of immune mediators leading to the state of ongoing inflammation and immunosuppression is characterized by decreased activation of innate immune cells, as well as depletion and decreased activation of lymphocytes. This dysfunctional process leads to global immune suppression, resulting in decreased clearance of any remaining tissue debris or bacteria, generating a cycle that is difficult to resolve. It is unclear what determines which individuals will progress to this state; however, it is likely a combination of the size and type of the initial insult and the ability of the patient to respond, as determined by their genetics and current clinical state. Further investigation of the various states associated with the progression to PICS may help clarify this process.
Those most at risk for progressing to a state of chronic critical illness are patients with multiple medical comorbidities, the elderly, those with severe injury or septic shock, and the malnourished (59). While these clinical states are seemingly unrelated, they can all present with prolonged states of inflammation. This section, as summarized in Figure 3, examines each of these clinical states and evaluates the divergent yet similar pathways to develop persistent inflammation and immune suppression.
Advanced age is perhaps the most studied state of chronic inflammation. A number of diseases associated with aging, such as atherosclerosis, rheumatoid arthritis, osteoporosis, and cancer, are classically thought to be the etiology of the chronic inflammation seen in this population (25, 60). However, aging alone is associated with elevated levels of pro-inflammatory mediators in systemic circulation, even in the absence of illness or injury. This phenomenon has suitably been termed, “inflamm-aging” (60–62). Since these individuals exist in a state of chronic, low-grade inflammation already, the response to any secondary insult tends to be significantly diminished. This is thought to be the reason why the elderly are significantly more susceptible to infection and injury, even when they are thought to be healthy otherwise.
This chronic inflammatory state of the elderly is associated with a gradual accumulation of oxidative stress to DNA, proteins, and lipids, leading to alterations in overall cellular function over time (63, 64). Normally, cells can protect themselves against mild degrees of oxidant damage by activating catalase and superoxide dismutase to eliminate peroxide and superoxide, respectively (6). With excessive or prolonged stress, however, cells can be overwhelmed with oxidative stress. In addition, the ability to manage this overwhelming response is significantly decreased with aging due to a decrease in the endoplasmic reticulum stress response and decreased mitochondrial metabolism (63, 65). With an ongoing source of cellular damage, paired with an inability for the innate and adaptive immune system to function properly, the elderly are primed to remain in a persistent inflammatory state. For these patients, encountering even mild insults can be devastating.
Many have corroborated that the more significant the insult in patients suffering from severe injury or septic shock, the greater the immune dysfunction (12, 26). In young, healthy patients with only mild injury or infection, activation of a robust inflammatory response, followed by rapid source control and resolution of the response, correlates with a relatively quick clinical recovery (18). In these patients, cell surface receptor expression and downstream signaling occur in a predictable and expected fashion (18). After a more severe insult, such as a large burn or significant traumatic injury, the immune system is tasked with a greater mission, potentially requiring increased or prolonged activation. Certainly, many factors contribute to poor outcomes in young patients with severe trauma or sepsis, such as dysregulation of the neuro-endocrine system, abnormal insulin utilization, and the secondary effects of multiple organ dysfunction. However, an uncontrolled inflammatory response is a major contributor to poor outcomes in this population as well (12, 26, 66). Without a definition of “excessive” inflammation in these patients, however, it is difficult to determine which individuals will progress to a persistent inflammatory state. More clear definitions of what threshold is “too excessive” for each individual patient may help determine which therapeutic interventions to employ throughout their clinical course.
Obesity is strongly associated with chronic, low grade inflammation which is thought to be an important underlying cause for obesity-related diseases, such as atherosclerosis, nonalcoholic steatohepatitis, and diabetes (67). The chronic inflammation noted in severe obesity is principally driven by the interplay of excess adipose tissue and the gut (67). However, severe protein-calorie malnutrition is also associated with immune dysfunction (39, 42, 45, 54). When further delineating between different classes of obesity, it appears that class 1 obesity (body mass index [BMI] between 30 and 34.9) yields the greatest survival benefit in sepsis compared with malnourished, nonobese, or morbidly obese individuals (68). Higher leptin levels in class 1 obese individuals are thought to confer this immune protection (69).
As opposed to the gradual accumulation of oxidative stress that occurs with aging or the acute stress that accompanies severe injury and septic shock, the mechanisms of persistent inflammation in malnutrition are even less understood. It is possible that the lack of substrate and cofactor availability during starvation leads to a decrease in the ability to perform cellular respiration, thus decreasing global cellular function (30). Others have suggested that, during starvation, disruption in the mucosal integrity and immunity of the gastrointestinal tract is the driving mechanism of systemic immune dysfunction (70–72). In this theory, mucosal disruption can lead to bacterial translocation, which alters systemic immune function. Consequently, when faced with an actual injury or infection, the response in these individuals is blunted. Regardless of the cause, defects in both the innate and adaptive immune systems can occur in malnourished individuals, as evidenced by poor wound healing, increased susceptibility to infection, decreased memory T-cell expansion, and anergy (53, 66). When studying the effect of nutritional states, however, it is imperative to differentiate the two extremes—malnourished versus BMI >35—since the mechanisms of immune dysfunction are different.
There are a bewildering array of animal studies which suggest that blocking pro-inflammatory mediators diminishes the severity of the inflammatory response (73, 74). For example, administration of anti-IL-6 antibody, anti-TNFα antibody, antichemokine antibodies, IL-1 receptor antibody, or soluble TNF receptor in various animal models is associated with a significant reduction in the degree of systemic inflammation after either sepsis or injury (46, 75, 76). Modulation of bioactive lipid mediators through manipulation of the arachidonic acid pathway has also been examined. Specifically, treatment with nonsteroidal antiinflammatory drugs or inhibitors of prostaglandin in sepsis appears to confer a survival advantage in animal models (28, 77). Although many studies aimed at blocking inflammatory mediators have been attempted in humans, none of them has demonstrated a clinical benefit after injury or infection as they have in animal studies (78).
The administration of anti-inflammatory mediators to diminish a prolonged inflammatory response has also been studied, but this intervention also shows no clinical benefit. Preliminary animal studies offered great promise for the antithrombotic and anti-inflammatory protein, activated protein C, prompting the PROWESS trial in humans. In this trial, the administration of activated protein C in patients with severe sepsis or septic shock significantly improved mortality (79). However, subsequent studies failed to confirm the benefit of this modulator and instead suggested an increased bleeding risk. As a result, activated protein C as a treatment for sepsis was withdrawn from the market altogether (80).
Given that oxidative stress is associated with aging, severe injury, and sepsis, the administration of various antioxidants has also been extensively explored (81). The effects of antioxidants in aging show some benefit, but the results in sepsis or severe trauma have not been promising. In particular, selenium, zinc, vitamin A, vitamin C, and vitamin E have been studied in adult critically ill patients. It appears that, although there is significant depletion of these essential cofactors in the critically ill, supplementation alone does not affect overall outcomes or improve infectious complications and may even cause some harm (82).
Although targeting single mediators within the inflammatory response has largely been successful in animal models, this has not translated to durable success in human trials. Part of the reason for this lack of success is not only related to the inability to perfectly model these responses in the laboratory, but also because the redundancy in the inflammatory response prevents the ability to target one single molecule (83–85). Some also suggest that the trials evaluating the effect of anti-inflammatory agents were unsuccessful because they did not first evaluate the variability in individual responses (11, 86). Retrospective and confirmatory studies by Eichacker et al. indicate that anti-inflammatory agents minimally effect individuals who are at a high risk of dying. This study instead suggests that evaluating individual immune responses will allow us to risk-stratify patients and identify those who would actually benefit from anti-inflammatory agents. For instance, while elevated TNFα and IL-1β tend to correlate with worse outcomes in sepsis and injury, others have shown that not all septic patients have elevated levels of these cytokines in circulation (66). Therefore, administration of anti-TNFα or anti-IL-1β antibodies to all patients presenting with sepsis may not show significant clinical benefit. Future trials in which patients’ immune profiles are assessed prior to therapeutic intervention would be very impactful.
Another reason why administration of medications that block the inflammatory response has not shown clinical benefit is that conditions associated with ongoing inflammation exhibit decreased immune cell function. Therefore, administration of anti-inflammatory agents may further exacerbate this immunosuppressed state. On the other hand, attempting to reactivate immune cells to improve their function may provide some benefit. Restoration of HLA-DR expression on monocytes using interferon-γ, stimulating neutrophils with granulocyte colony-stimulating factor, restoring the ability for T and B cell proliferation with IL-7, or improving costimulation between T cells and antigen presenting cells significantly improves immune cell function (11, 87, 88). Regulatory immune cells are also being investigated as a way to manipulate the immune response as a therapeutic target (89). A host of regulatory cells have been investigated in these clinical fields, ranging from T- and B-regulatory cells to MDSCs (59). In theory, expanding MDSCs may help reverse the persistent inflammation that occurs after injury or sepsis by preventing excessive inflammation (90). However, MDSCs are also thought to suppress T-cell responses and may perhaps exacerbate the immunosuppression that occurs (4, 91).
Since stress is a potent activator of the hypothalamic-pituitary-adrenal axis, modulating hormonal pathways could theoretically counterbalance the inflammatory and catabolic state of critically ill patients. Although corticosteroids were previously recommended to reduce the inflammation of severe sepsis, large clinical trials have failed to show improved outcomes (92, 93). Currently, the Surviving Sepsis Campaign recommends using corticosteroids as an intervention in sepsis only when patients develop septic shock that is refractory to fluids and vasopressors (94). This subset of patients is in septic shock because of relative adrenal insufficiency leading to vascular collapse. Here, corticosteroid therapy acts to restore endogenous catecholamines, not necessarily to provide anti-inflammatory effects. In fact, the anti-inflammatory effects of corticosteroids in sepsis are potentially detrimental due to the increased risk of infectious complications that can occur.
The supplemental administration of oxandrolone, testosterone, or DHEA as methods to modulate the response to severe injury or sepsis also fails to improve outcomes (95–97). In fact, supplementation of aged or critically ill patients with certain anabolic hormones, such as growth hormone, does not improve muscle mass or strength and is associated with adverse side effects, such as increased insulin resistance and increased mortality (98, 99). The failure to achieve beneficial outcomes using anabolic hormones may be an age-related or injury-specific phenomenon, since oxandrolone improves muscle strength, preserves bone mineral content, and minimizes changes in height in pediatric burn patients (100).
Many studies show that females have a survival advantage in sepsis and trauma and that estrogen may be protective in these settings (19, 20). Therefore, administration of estrogen after severe injury or sepsis may be beneficial, regardless of patient gender. Topical estrogen accelerates cutaneous wound healing in aged humans by decreasing the inflammatory response (101). Others have shown that systemic administration of estrogen is particularly beneficial in aged animals after injury by acting as an anti-inflammatory agent (102). Trials examining the effect of estrogen in critically ill patients, however, have yet to be performed.
Lastly, since the ghrelin/leptin system has profound effects on the innate immune system, some have explored its effect on critically ill patients. Ghrelin and leptin are the main mediators of hunger and appetite, working in concert to regulate metabolism. Targeting this hormone pathway in critical illness has yielded mixed results (103, 104). Higher levels of leptin, as seen in mildly obese patients, seem to be protective in sepsis, leading to stabilization of body temperature, reduction in the overwhelming pro-inflammatory cytokine response, and improved survival (69). In other models of critical illness, ghrelin supplementation actually leads to improvement in systemic inflammation. In these studies, it is unclear whether ghrelin administration improves outcomes because of direct modulation of the inflammatory response or from the secondary benefits of improved enteral nutrition through stimulation of appetite (104). Further investigation on modulating this pathway is required to determine the mechanisms involved in injury or infection.
Early enteral nutrition may be one of the most potent strategies to improve outcomes after injury or infection. Administration of enteral nutrition is associated with a significant reduction in mortality, remote organ damage, and infectious complications after injury and sepsis compared with total parenteral nutrition in both animals and humans (105, 106). When the gastrointestinal tract is starved for multiple days, mucosal breakdown can occur, making the host vulnerable to the bacteria within the lumen of the gut (107). This breakdown decreases the natural defensins and other antimicrobial mediators within the lining of the gut, which weakens its innate defense system. This weakness is also associated with decreased lymphocytes in the lining of the gut, leading to increased susceptibility to systemic inflammation (107).
Initiation of enteral nutrition in the starved state results in almost immediate normalization of the gut mucosal barrier, restoration of mucosal immunity, and decreased neutrophil sequestration within the gastrointestinal tract (70, 107). In fact, early enteral nutrition has consistently demonstrated to improve outcomes after injury or sepsis (45, 70, 72, 106, 108, 109). Some have also shown that glutamine-enriched diets in severely injured and septic patients enhance the immune system by providing the small intestine with their primary source of energy. Accordingly, both the Society for Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition recommend a glutamine supplemented diet for enteral nutritional support in severely injured trauma and septic patients (110).
Since the inflammatory response is one of the most powerful modulators of energy expenditure, persistent inflammation is associated with a prolonged catabolic state (5–7). For those who are already malnourished, even mild challenges to the immune system may be devastating (111). However, restoration of immune function in the malnourished patient can occur by initiating early enteral nutrition. Importantly, neither aging, severe injury, nor sepsis demonstrate such rapid reversibility of a dysregulated inflammatory state. Therefore, establishing malnutrition as a model to investigate potential measures to abrogate PICS or chronic critical illness is essential.
Employing early exercise and resistance training in critically ill patients is another adjunctive strategy that accompanies early enteral nutrition. Regardless of how it is clinically measured, frailty (and not age per se) serves as a robust predictor of mortality, ICU and hospital length of stay, readmission rate, and complication rate after major surgery or injury (112, 113). The persistent inflammation and accompanying catabolic state that characterizes chronic critical illness is thought to be responsible for the exaggerated loss of lean body mass and the concomitant development of clinical frailty (4, 25, 30). As such, early physical therapy and resistance training has been shown to impede frailty development and significantly improve outcomes for critically ill patients (114). In a landmark paper, patients who were mechanically ventilated in the ICU for greater than 72 h were randomized either to early mobilization with physical therapy or standard ICU therapy. Early mobilization resulted in decreased delirium, more ventilator-free days, and enhanced functional outcomes over the 28-day follow-up period (114). While the link between exercise and reduced inflammation has been recognized for some time, the effects of early mobilization and physical therapy on mitigating the development of immune dysfunction in critically ill patients have yet to be studied (115, 116).
Given the observations that not all individuals respond to the same insult in a similar manner, perhaps individualized genomic or immune cell profiling may provide a more comprehensive analysis of the patient's clinical state to provide some insight into which treatment modalities could work best for them. This concept is not novel, in fact. Early studies of sepsis employed the idea of categorizing patient in terms of their Predisposition to having worse outcomes, Infection or injury type, the Response to the insult, and the Organ dysfunction that could increase the risk of complications further (117). This PIRO staging system was initially suggested as another tool for helping predict which septic patients would have poor outcomes. Given how cumbersome this score is to generate and the fact that more simplified scoring systems were generated, the PIRO staging system has fallen by the wayside. Perhaps studying the similarities and difference between aging, injury, infection, and malnutrition may uncover better strategies to risk stratify critically ill patients. With this risk stratification, clinical trials tailoring the therapy to the individual patient could significantly change outcomes and potentially advance our understanding of the response to significant injury or infection. Furthermore, with better definitions of “persistent” or “excessive” inflammation and immunosuppression, the ability to risk stratify patients will be even more robust. Further investigation into these mechanisms along with new insights from investigators evaluating the role of energy expenditure, mitochondrial dysfunction, and the effects of bioactive lipid molecules on immune cell signaling will be promising. In the meantime, multimodal regimens that include early enteral nutrition and mobilization are useful adjuncts to improving immune function in states of persistent inflammation.
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