SURGICAL INFECTIONS Volume 15, Number 6, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/sur.2013.235
The Geriatric Cytokine Response to Trauma: Time To Consider a New Threshold Mary E. Ottinger,1 Sean F. Monaghan,1 Stefan Gravenstein,2 William G. Cioffi,1 Alfred Ayala,1 and Daithi S. Heffernan1
Abstract
Background: Inflammatory responses to trauma, especially if exaggerated, drive mortality and morbidities including infectious complications. Geriatric patients are particularly susceptible to profound inflammation. Age-related declines in inflammatory and immune systems are known to occur. Geriatric patients display dampened inflammatory responses to non-critical disease processes. Specific inflammatory responses in critically ill geriatric trauma patients, and how the inflammatory profile associated with subsequent infections or mortality, remain unknown. Methods: Geriatric ( ‡ 65 y) and young (18–50 y old) critically ill blunt trauma intensive care unit (ICU) patients were enrolled prospectively. Blood was drawn within 36 h of presentation to measure circulating cytokines including interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), and tumor necrosis factor (TNF)-a (pg/mL) levels. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE II) score and outcomes were reviewed. Results: Twenty-one young and 29 geriatric critically ill patients were recruited. Groups were comparable in male gender and age-adjusted APACHE II score, but geriatric patients had higher mortality (38% versus 9.5%; p = 0.04). Within geriatric trauma patients, the development of a secondary infection was associated with significantly lower presenting IL-6 and IL-10 levels and no difference in TNF-a levels. Furthermore, geriatric patients who died had elevated IL-6 and IL-10 and decreased TNF-a levels compared with geriatric patients who lived. Compared with the young cohort, IL-6 and IL-10 levels were similar between geriatric patients who died and young patients who lived. However, geriatric patients who lived, compared with young patients who lived, had significantly lower IL-6 and IL-10. There was no such relation noted with TNF-a. Conclusions: A lowered inflammatory response in geriatric patients is associated with the development of a subsequent infection. However, geriatric patients exhibiting inflammatory responses as robust as their younger counterparts have increased mortality. Redefining our understanding of an appropriate geriatric inflammatory response to trauma will help future therapy, thereby improving morbidity and mortality.
T
rauma remains a leading cause of death worldwide and within geriatric patients specifically. By 2050, geriatric patients are estimated to comprise more than 20% of the population [1]. With this increasingly active and independent aging population, defined as individuals greater than age 65, there will be an ever-increasing number of geriatric patients presenting after traumatic injury [2]. Both minor and severe illness and injury clearly affect young and geriatric patients differently. Both human and animal studies have demonstrated age-related increases in mortality after trauma/ systemic inflammatory response system (SIRS) and sepsis
events. The inflammatory response to traumatic injuries is a large determinant of mortality [3]. There are several theories regarding the aging immune system as it affects the progression of disease and injury [4– 6]. Geriatric patients have baseline age-related decline in both the innate and acquired immune response [7]. Geriatric patients are noted to have a lowered immune response to illness, as well as higher mortality with more exaggerated and prolonged inflammatory stimulation [8,9]. Geriatric patients are particularly susceptible to the effects of inflammation [10]. It has been postulated that a dampening
1 Division of Surgical Research, Department of Surgery, 2Division of Geriatrics, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island.
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GERIATRIC CYTOKINE RESPONSE TO TRAUMA
of an inflammatory response may indeed be protective with respect to less cardiopulmonary inflammation. An exaggerated inflammatory response can lead to end-organ dysfunction such as acute respiratory distress syndrome (ARDS). However, an inappropriately dampened immune response is also associated with poor bacterial clearance and slowed resolution after an inciting event [11]. An attenuated immune response is associated with an increased susceptibility to secondary infections, which is also believed to drive outcomes following trauma. Only a paucity of literature pertains to the specific inflammatory components among critically ill geriatric trauma patients [12] and how the inflammatory profile affects secondary infections and/or mortality. We postulate that critically ill geriatric trauma patients with a dampened immune response will be at increased risk for secondary infection. Also, we hypothesize that a robust geriatric inflammatory response comparable to young patients will have increased mortality compared with geriatric patients who display a more dampened response. Patients and Methods
Critically ill blunt trauma intensive care unit (ICU) patients were enrolled prospectively. Exclusion criteria included patients who died within 48 h and any patient with a known history of lymphoma or leukemia. Geriatric patients were defined as those aged 65 y and older. Young patients were defined as those aged 18 to 50 y. At the time of the morning blood draws in the ICU blood was also collected for this study. All blood draws occurred within 36 h of presentation to the ICU. Interleukin (IL)-6 was chosen to represent the proinflammatory response and IL-10 was chosen to represent the anti-inflammatory response in these patients. Cytokines measured were IL-6 (pg/mL), IL-10 (pg/mL), and tumor necrosis factor (TNF)-a (pg/mL). Flow cytometry using Cytometric Bead Array (CBA; BD Biosciences, San Jose, CA) was used to measure the cytokines according to the manufacturer’s specifications. The two primary end points were development of a secondary infection and death. A secondary infection was defined as an infection occurring after the third day. Charts were reviewed for age, gender, APACHE II score, all microbiology data, hospital length of stay, and mortality. Clinical and laboratory data from the day of the laboratory draw were extracted to calculate the APACHE II score at the time of the blood draw. The white blood cell (WBC) count was reviewed from the daily laboratory data from the day of the study blood draw. For the sake of comparison between the young and the geriatric groups, we then noted the age-adjusted APACHE II score by removing the age component of the APACHE II score [13]. Results are expressed as mean – standard error of the mean. w2 was used for categorical data. Mann-Whitney U was used for continuous data when comparing two groups. One-way analysis of variance (ANOVA) with Holm-Sidak post-hoc analysis was used when comparing continuous data across multiple groups. Significance was set at p < 0.05. Institutional Review Board approval was obtained for this study. Results
We recruited 21 young and 29 geriatric critically ill blunt trauma patients. Mean age of the young patients was 38 ( – 2.5) years and of the geriatric patients was 76 ( – 1.6) years. Geriatric and young patients were matched with respect to male
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Table 1. Demographics Young n = 21 Age Male gender (%) Age-adjusted APACHE II White blood cell count Overall mortality (%)
Geriatric n = 29
p
38 ( – 1.56) 76 ( – 2.49) < 0.001 15 ( 71.5%) 16 ( 55%) 0.038 13.5 12.7 0.70 13.8 ( – 1.4) 2
(
12.1 ( – 0.64)
9.5%) 11
( 38%)
0.24 0.04
APACHE II = Acute Physiology and Chronic Health Evaluation.
gender distribution (55% versus 71%; p = 0.38), age-adjusted APACHE II score (12.7 versus. 13.5; p = 0.7), and WBC count at the time of laboratory draw (12.1 – 0.64 versus 13.8 – 1.4; p = 0.24). Overall, geriatric patients had higher mortality compared with young patients (38% versus 9.5%; p = 0.04; Table 1). Although not statistically different, of those who died, time to death was different between geriatric and young patients (24.3 – 3.1 versus 15.7 – 4.4; p = 0.28). Over the course of the study, seven of the 29 geriatric patients (24%) developed an infection after admission. Geriatric patients who later developed a subsequent secondary infection during their hospital stay had significantly lower early IL-6 levels (41.1 – 13.8 versus 189.6 – 37.9 pg/mL; p = 0.04) as well as significantly lower early IL-10 concentrations (5.3 – 0.14 versus 12.34 – 1.7 pg/mL; p = 0.03) compared with geriatric patients who did not develop a secondary infection during their hospital course. There was, however, no difference in TNF-a concentrations (2.8 – 0.4 versus 2.5 – 0.2 pg/mL; p = 0.42) between geriatric patients who did and did not develop a secondary infection during their hospital stay (Fig. 1A, 1B, and 1C). With respect to mortality within the geriatric group there was no difference in age in patients who lived versus those who died (76.1 – 2.2 versus 77.1 – 2.5 years; p = 0.9), WBC count (11.9 – 0.8 versus 12.5 – 1.2 · 109/L; p = 0.6) or hospital length of stay (38.1 – 2.4 versus 34.8 – 2.7 days; p = 0.34). However, geriatric patients who died had significantly higher age-adjusted APACHE II scores (16.5 – 1.4 versus 10.7 – 1.1; p = 0.004; Table 2). Compared with geriatric patients who lived, geriatric patients who died had significantly elevated IL-6 (278.9 – 63 versus. 77.2 – 16 pg/mL; p = 0.002) and IL-10 (15.2 – 3.04 versus 7.83 – 0.9 pg/mL; p = 0.02) as well as decreased TNF-a (1.79 – 0.25 versus 3.03 – 0.2 pg/mL; p = 0.03) concentrations. Using one-way ANOVA, the early cytokine concentrations of both the geriatric patients who lived and the geriatric patients who died were then compared with the early cytokine concentrations of young patients who lived. Intriguingly, geriatric patients who died had similar IL-6 (278.6 – 63 versus 277.5 – 34 pg/mL; p = 0.98) and IL-10 (15.2 – 3.04 versus 14.3 – 1.5 pg/mL; p = 0.74) concentrations to young patients who survived. However, geriatric patients who lived, compared with young patients who lived, had significantly lower IL-6 (77.2 – 16 versus 277.5 – 34; p < 0.001) and IL-10 7.83 – 0.9 versus 14.3 – 1.5; p = 0.005) concentrations. We found was no such relation noted with TNF-a between geriatric and young patients (Fig. 2A, 2B, and 2C).
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OTTINGER ET AL.
Table 2. Geriatric Patients Who Lived versus Those who Died Geriatriclived Age White blood cell count Hospital length of stay Age-adjusted APACHE II
76.1 11.9 38.1 10.7
( – 2.2) ( – 0.8) ( – 2.4) ( – 1.1)
Geriatricdied 77.1 12.5 34.8 16.5
( – 2.5) ( – 1.2) ( – 2.7) ( – 1.4)
p 0.9 0.6 0.34 0.004
APACHE II = Acute Physiology and Chronic Health Evaluation.
FIG. 1. (A) Significantly lower presenting interleukin (IL)-6 concentrations noted in geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.04. (B) Significantly lower presenting interleukin (IL)-10 concentrations noted in geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.03. (C) No differences in presenting tumor necrosis factor (TNF)-a concentrations between geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.42. Discussion
The inflammation and immune system to trauma represents a complex balance between pro- and anti-inflammatory mediators. The SIRS is the consequence of myriad disturbances to normal homeostasis, ranging from traumatic injury
to infectious etiologies [14]. The opposing compensatory anti-inflammatory response syndrome (CARS) [3], plays a similar role in the resolution of inflammation and outcomes after insult. Our understanding has evolved to recognize that a simultaneous activation of pro- and anti-inflammatory mediators at the time of injury and the failure of expedient resolution of both contributes to a more complicated outcome [3,15]. A perturbation of this balance results in either an insufficient immune response rendering the host susceptible to infectious complications, or an excessively robust response with end-organ failure and death. A limitation of many of the studies on trauma-induced inflammation is the predominant inclusion of young patients with a scarcity of geriatric patients. Geriatric patients represent a unique population wherein age-related changes in underlying immunity [4,16] and the response to physiologic insults have a profound effect on morbidity and mortality [9]. Immune senescence, or agerelated immune decline, is a well-described entity that is believed to contribute to the noted increased susceptibility to infections in geriatric patients [4,17–19]. Immune senescence affects cell-mediated immunity more than humoralmediated immunity. Professional antigen presenting cells such as dendritic cells, and especially plasmacytoid dendritic cells, from geriatric individuals show considerable functional decline with aging, especially in relation to phagocytosis [20]. A full understanding of trauma-induced inflammation in an aged population has yet to be elucidated despite a relatively extensive knowledge of inflammatory cascade in young patients [4,21]. Older patients have less effective neutrophil activity [7], decreased natural killer cell cytotoxicity, and decreased macrophage function [22,23]. There is also an age-related decrease in cytokine production by monocytes, particularly the pro-inflammatory mediators IL-6 and TNF-a, as well as decreased macrophage production of IL-10 [4,7,8,19,23]. It is postulated that this contributes to older subjects’ increased risk of infectious complications. We herein have demonstrated that geriatric trauma patients who developed a secondary infection, compared with those who did not develop an infection, were noted to have a relatively blunted presenting IL-6 (28.6 versus 179.8 pg/mL) and IL-10 (5.30 versus 12.34 pg/mL) response to the traumatic injuries. Our data offers a unique insight into the geriatric aspect of the immuno-paralysis that is often observed in trauma patients. Multiple animal studies have demonstrated a difference in the initial inflammatory response to injury in elderly mice compared with their younger counterparts [7,9,24]. Our data are in keeping with several murine models noting the importance of IL-6 in the response to bacterial pathogens.
GERIATRIC CYTOKINE RESPONSE TO TRAUMA
FIG. 2. (A) One-way analysis of variance (ANOVA) analysis of interleukin (IL)-6 concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p < 0.001; #p = 0.002. (B) One-way ANOVA analysis of IL-10 concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p = 0.005; #p = 0.02. (C) One-way ANOVA analysis of tumor necrosis factor (TNF)-a concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p = 0.03. Interleukin-6 knockout mice were noted to have alterations in the recruitment of inflammatory cells, impaired microbial clearance, and ultimately were more susceptible to infection [25]. Moreover, Boyd et al. [26] demonstrated an age-related macrophage functional decline in a Streptococcus pneumoniae pneumonia model. They noted that IL-6 levels were markedly lower in aged mice and this lowered IL-6 was associated with diminished bacterial clearance. Thus, for
803
geriatric patients, an impaired IL-6 response may play a key role in modulating the risk of developing an infection. The finding of lowered IL-10 concentrations being associated with the development of a subsequent infection is surprising. Interleukin-10 is believed to be an anti-inflammatory and immunosuppressant cytokine. Multiple murine studies have demonstrated improved survival from sepsis after IL-10 antibody administration [27]. However, blocking of a single cytokine does not affect the other effector functions of the cell(s) of origin. We contend that our data demonstrating lower IL-10 concentrations being associated with increased risk of subsequent infection represents an immune system with limited abilities to respond to critical injury and illness. The dampened immune response to critical illness observed in immuno-aging does not merely represent a robust anti-inflammatory pathway suppressing the pro-inflammatory response to trauma. We believe that our finding of a dampened initial post-trauma pro- and anti-inflammatory cytokine response corresponding to the development of a subsequent infection represents a global state of immune depression, dysfunction and inefficacy. Our study did not demonstrate a correlation between presenting TNF-a concentrations and subsequent infection in geriatric patients. Tumor necrosis factor-alpha is known to show a considerable lag time in geriatric individuals with respect to its role in bacterial, viral, or vaccine regulation [4,9,28]. We believe that this lag time to TNF-a peak occurred outside of our observation window. Further work is needed to assess whether later time points show a correlation. With respect to mortality and cytokine profiles, we demonstrated an intriguing relation between dampened IL-6 and IL-10 concentrations and survival in geriatric patients. Interleukin-6 has been associated with mortality after trauma in human and animal studies [14,15,29]. The predominance of this work has focused on young patients, with little examination of the applicability of these findings to geriatric patients. Most intriguingly, we demonstrated that geriatric patients who displayed a cytokine response as robust as their younger counterparts were noted to have a significantly higher mortality compared with geriatric patients with a more blunted response. Our data challenges the theory that geriatric patients’ survival is negatively impacted by an inability to mount an appropriate pro-inflammatory response. If patients survive the early post-injury period, it is believed that subsequent mortality is driven by inflammation induced end-organ failure. The initial inflammatory response to critical illness, including traumatic injuries, sets the stage for the ongoing dysregulated systemic immune and inflammatory cascade. It has been shown that the magnitude of IL-6 production corresponds to the magnitude of injury in trauma patients. Giannoudis et al. [30] demonstrated that IL-6 concentrations corresponded with both the presence of a SIRS response to trauma, and ultimately to mortality. Biffl et al. [29] demonstrated that increasing concentrations of IL-6 correlated with increasing severity of insult as well as increasing risk of mortality. Furthermore, Gebhard et al. [31] demonstrated that this correlation was independent of mechanism of trauma. Similarly, elevated IL-10 concentrations have been associated with increased mortality following traumatic injuries. An early elevated IL-10 response to trauma has been shown to be associated with the development of end-organ failure, specifically ARDS [32]. Furthermore, IL-10 is an independent
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biomarker for mortality in patients with severe traumatic brain injury. Rather than the specific effects of the single cytokine, our data more likely represent the global excessive cellular response to trauma that leads to tissue damage and end-organ failure, known drivers of trauma-related mortality. We contend that geriatric trauma patients, with less physiologic reserve, suffer greater effects from this inflammationinduced end-organ failure, potentially leading to their higher mortality rates. To this effect, the use of APACHE II accounts for the myriad of clinical presentations, resuscitations, and organ dysfunction of varying populations. Furthermore, APACHE II is a better Injury Severity Scale (ISS) predictor of mortality than ISS in trauma patients once admitted to the ICU [13]. It is becoming increasingly clear that inflammation tolerated by younger trauma patients exceeds the threshold tolerated by the aging trauma population. The old paradigm leads us to believe that a dysfunctional inflammatory response after traumatic injuries begets infection and this subsequent infection directly leads to death. However in the context of modern ICU care, this paradigm needs to be reassessed. Although there remains an association between the inflammatory response and both mortality and infection, these end effects are not interlinked closely. Conclusion
The inflammatory response to critical illness often influences outcomes. Geriatric patients who exhibit an inflammatory response as robust as their younger counterparts appear to have dramatically increased mortality. Redefining our definition of inflammation in the geriatric patient may help future therapy modulate inflammation and improve morbidity and mortality. Author Disclosure Statement
No competing financial interests exist. References
1. Manini T. Development of physical disability in older adults. Curr Aging Sci 2011;4:184–191. 2. Callaway DW, Wolfe R. Geriatric trauma. Emerg Med Clin North Am 2007;25:837–860. 3. Hietbrink F, Koenderman L, Rijkers GT, Leenen LPH. Trauma: The role of the innate immune system. World J Emer Surg 2006;1:15. 4. Shaw AC, Joshi S, Greenwood H, et al. Aging of the innate immune system. Curr Opin Immunol 2010;22:507–513. 5. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol 2008;43:718–728. 6. Nomellini V, Gomez CR, Gamelli RL, Kovacs EJ. Aging and animal models of systemic insult: Trauma, burn, and sepsis. Shock 2009;31:11–20. 7. Valente SA, Fallon WF, Alexander TS, et al. Immunologic function in the elderly after injury—The neutrophil and innate immunity. J Trauma 2009;67:968–974. 8. Bruunsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 2003;23:15–39. 9. Turnbull IR, Clark AT, Stromberg PE, et al. Effects of aging on the immunopathological response to sepsis. Crit Care Med 2009;37:1018–1023.
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10. De Martinis M, Fancheschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol 2006;80:219–227. 11. Kahlke V, Angele MK, Ayala A, et al. Immune dysfunction following trauma-haemorrhage: Influence of gender and age. Cytokine 2000;12:69–77. 12. Smith, RM. Immunity, trauma and the elderly. Injury 2007;38:1401–1404. 13. Dossett LA, Redhage LA, Sawyer RG, May AK. Revisiting the validity of Apache II in the trauma ICU: Improved risk stratification in critically injured adults. Injury 2009;40: 993–998. 14. Robertson CM, Coopersmith CM. The systemic inflammatory response syndrome. Microbe Infect 2006;8:1382– 1389. 15. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med 2011;208:2581–2590. 16. Sarkar D, Fisher PB. Molecular mechanisms of aging-associated inflammation. Cancer Lett 2006;236:13–26. 17. Mahbub S, Deburghgraeve CR, Kovacs EJ. Advanced age impairs macrophage polarization. J Interferon Cytokine Res 2012;32:18–26. 18. Boyd AR, Orihuela CJ. Dysregulated inflammation as a risk factor for pneumonia in the elderly. Aging Dis 2011;2:487– 500. 19. Weng NP. Aging of the immune system: How much can the adaptive immune system adapt? Immunity 2006;24: 495–499. 20. Agrawal A, Agrawal S, Cao JN, et al. Altered innate immune functioning of dendritic cells in elderly humans: A role of phosphoinositide 3-kinase-signaling pathway. J Immunol 2007;178:6912–6922. 21. Butcher SK, Lord JM. Stress responses and innate immunity: Aging as a contributory factor. Aging Cell 2004; 3:151–160. 22. Jing Y, Shaheen E, Drake RR, et al. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol 2009;70:777–784. 23. Gomez CR, Karavitis J, Palmer JL, et al. Interleukin-6 contributes to age-related alteration of cytokine production by macrophages. Mediators Inflamm 2010;2010:475139. 24. Gomez CR, Goral J, Ramirez L, et al. Aberrant acute-phage response in aged interleukin-6 knockout mice. Shock 2006;25:581–585. 25. Hoge J, Yan I, Janner N, et al. IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling J Immunol. 2013;190:703–11. 26. Boyd AR, Shivshankar P, Jiang S, Berton MT, Orihuela CJ. Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. Exp Gerontol 2012;47:507–518. 27. Lyons A, Goebel A, Mannick JA, Lederer JA. Protective effects of early interleukin 10 antagonism on injuryinduced immune dysfunction. Arch Surg 1999;134:1317– 1323. 28. Hayden FG, Fritz R, Lobo MC, et al. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defence. J Clin Invest 1998;101:643–649. 29. Biffl, WE, Moore EE, Moore MD, Peterson VM. Interleukin-6 in the injured patient: Marker of injury or mediatory of inflammation? Ann Surg 1996;224:647–664.
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30. Giannoudis PV, Harwood PJ, Loughenbury P, et al. Correlation between IL-6 levels and the systemic inflammatory response score: Can an IL-6 cutoff predict a SIRS state? Trauma 2008;65:646–652. 31. Gebhard F, Pfetsch H, Steinbach G, et al. Is interleukin 6 an early marker of injury severity following major trauma in humans? Arch Surg 2000;135:291–295. 32. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with traumatic injuries: Utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010;68:1121–1127.
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Address for correspondence: Dr. Daithi S. Heffernan Division of Trauma and Surgical Critical Care Department of Surgery 435 APC Bldg., 4th Fl. 593 Eddy St. Rhode Island Hospital Providence, RI 02903 E-mail: [email protected]
The Geriatric Cytokine Response to Trauma: Time To Consider a New Threshold Mary E. Ottinger,1 Sean F. Monaghan,1 Stefan Gravenstein,2 William G. Cioffi,1 Alfred Ayala,1 and Daithi S. Heffernan1
Abstract
Background: Inflammatory responses to trauma, especially if exaggerated, drive mortality and morbidities including infectious complications. Geriatric patients are particularly susceptible to profound inflammation. Age-related declines in inflammatory and immune systems are known to occur. Geriatric patients display dampened inflammatory responses to non-critical disease processes. Specific inflammatory responses in critically ill geriatric trauma patients, and how the inflammatory profile associated with subsequent infections or mortality, remain unknown. Methods: Geriatric ( ‡ 65 y) and young (18–50 y old) critically ill blunt trauma intensive care unit (ICU) patients were enrolled prospectively. Blood was drawn within 36 h of presentation to measure circulating cytokines including interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), and tumor necrosis factor (TNF)-a (pg/mL) levels. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE II) score and outcomes were reviewed. Results: Twenty-one young and 29 geriatric critically ill patients were recruited. Groups were comparable in male gender and age-adjusted APACHE II score, but geriatric patients had higher mortality (38% versus 9.5%; p = 0.04). Within geriatric trauma patients, the development of a secondary infection was associated with significantly lower presenting IL-6 and IL-10 levels and no difference in TNF-a levels. Furthermore, geriatric patients who died had elevated IL-6 and IL-10 and decreased TNF-a levels compared with geriatric patients who lived. Compared with the young cohort, IL-6 and IL-10 levels were similar between geriatric patients who died and young patients who lived. However, geriatric patients who lived, compared with young patients who lived, had significantly lower IL-6 and IL-10. There was no such relation noted with TNF-a. Conclusions: A lowered inflammatory response in geriatric patients is associated with the development of a subsequent infection. However, geriatric patients exhibiting inflammatory responses as robust as their younger counterparts have increased mortality. Redefining our understanding of an appropriate geriatric inflammatory response to trauma will help future therapy, thereby improving morbidity and mortality.
T
rauma remains a leading cause of death worldwide and within geriatric patients specifically. By 2050, geriatric patients are estimated to comprise more than 20% of the population [1]. With this increasingly active and independent aging population, defined as individuals greater than age 65, there will be an ever-increasing number of geriatric patients presenting after traumatic injury [2]. Both minor and severe illness and injury clearly affect young and geriatric patients differently. Both human and animal studies have demonstrated age-related increases in mortality after trauma/ systemic inflammatory response system (SIRS) and sepsis
events. The inflammatory response to traumatic injuries is a large determinant of mortality [3]. There are several theories regarding the aging immune system as it affects the progression of disease and injury [4– 6]. Geriatric patients have baseline age-related decline in both the innate and acquired immune response [7]. Geriatric patients are noted to have a lowered immune response to illness, as well as higher mortality with more exaggerated and prolonged inflammatory stimulation [8,9]. Geriatric patients are particularly susceptible to the effects of inflammation [10]. It has been postulated that a dampening
1 Division of Surgical Research, Department of Surgery, 2Division of Geriatrics, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island.
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GERIATRIC CYTOKINE RESPONSE TO TRAUMA
of an inflammatory response may indeed be protective with respect to less cardiopulmonary inflammation. An exaggerated inflammatory response can lead to end-organ dysfunction such as acute respiratory distress syndrome (ARDS). However, an inappropriately dampened immune response is also associated with poor bacterial clearance and slowed resolution after an inciting event [11]. An attenuated immune response is associated with an increased susceptibility to secondary infections, which is also believed to drive outcomes following trauma. Only a paucity of literature pertains to the specific inflammatory components among critically ill geriatric trauma patients [12] and how the inflammatory profile affects secondary infections and/or mortality. We postulate that critically ill geriatric trauma patients with a dampened immune response will be at increased risk for secondary infection. Also, we hypothesize that a robust geriatric inflammatory response comparable to young patients will have increased mortality compared with geriatric patients who display a more dampened response. Patients and Methods
Critically ill blunt trauma intensive care unit (ICU) patients were enrolled prospectively. Exclusion criteria included patients who died within 48 h and any patient with a known history of lymphoma or leukemia. Geriatric patients were defined as those aged 65 y and older. Young patients were defined as those aged 18 to 50 y. At the time of the morning blood draws in the ICU blood was also collected for this study. All blood draws occurred within 36 h of presentation to the ICU. Interleukin (IL)-6 was chosen to represent the proinflammatory response and IL-10 was chosen to represent the anti-inflammatory response in these patients. Cytokines measured were IL-6 (pg/mL), IL-10 (pg/mL), and tumor necrosis factor (TNF)-a (pg/mL). Flow cytometry using Cytometric Bead Array (CBA; BD Biosciences, San Jose, CA) was used to measure the cytokines according to the manufacturer’s specifications. The two primary end points were development of a secondary infection and death. A secondary infection was defined as an infection occurring after the third day. Charts were reviewed for age, gender, APACHE II score, all microbiology data, hospital length of stay, and mortality. Clinical and laboratory data from the day of the laboratory draw were extracted to calculate the APACHE II score at the time of the blood draw. The white blood cell (WBC) count was reviewed from the daily laboratory data from the day of the study blood draw. For the sake of comparison between the young and the geriatric groups, we then noted the age-adjusted APACHE II score by removing the age component of the APACHE II score [13]. Results are expressed as mean – standard error of the mean. w2 was used for categorical data. Mann-Whitney U was used for continuous data when comparing two groups. One-way analysis of variance (ANOVA) with Holm-Sidak post-hoc analysis was used when comparing continuous data across multiple groups. Significance was set at p < 0.05. Institutional Review Board approval was obtained for this study. Results
We recruited 21 young and 29 geriatric critically ill blunt trauma patients. Mean age of the young patients was 38 ( – 2.5) years and of the geriatric patients was 76 ( – 1.6) years. Geriatric and young patients were matched with respect to male
801
Table 1. Demographics Young n = 21 Age Male gender (%) Age-adjusted APACHE II White blood cell count Overall mortality (%)
Geriatric n = 29
p
38 ( – 1.56) 76 ( – 2.49) < 0.001 15 ( 71.5%) 16 ( 55%) 0.038 13.5 12.7 0.70 13.8 ( – 1.4) 2
(
12.1 ( – 0.64)
9.5%) 11
( 38%)
0.24 0.04
APACHE II = Acute Physiology and Chronic Health Evaluation.
gender distribution (55% versus 71%; p = 0.38), age-adjusted APACHE II score (12.7 versus. 13.5; p = 0.7), and WBC count at the time of laboratory draw (12.1 – 0.64 versus 13.8 – 1.4; p = 0.24). Overall, geriatric patients had higher mortality compared with young patients (38% versus 9.5%; p = 0.04; Table 1). Although not statistically different, of those who died, time to death was different between geriatric and young patients (24.3 – 3.1 versus 15.7 – 4.4; p = 0.28). Over the course of the study, seven of the 29 geriatric patients (24%) developed an infection after admission. Geriatric patients who later developed a subsequent secondary infection during their hospital stay had significantly lower early IL-6 levels (41.1 – 13.8 versus 189.6 – 37.9 pg/mL; p = 0.04) as well as significantly lower early IL-10 concentrations (5.3 – 0.14 versus 12.34 – 1.7 pg/mL; p = 0.03) compared with geriatric patients who did not develop a secondary infection during their hospital course. There was, however, no difference in TNF-a concentrations (2.8 – 0.4 versus 2.5 – 0.2 pg/mL; p = 0.42) between geriatric patients who did and did not develop a secondary infection during their hospital stay (Fig. 1A, 1B, and 1C). With respect to mortality within the geriatric group there was no difference in age in patients who lived versus those who died (76.1 – 2.2 versus 77.1 – 2.5 years; p = 0.9), WBC count (11.9 – 0.8 versus 12.5 – 1.2 · 109/L; p = 0.6) or hospital length of stay (38.1 – 2.4 versus 34.8 – 2.7 days; p = 0.34). However, geriatric patients who died had significantly higher age-adjusted APACHE II scores (16.5 – 1.4 versus 10.7 – 1.1; p = 0.004; Table 2). Compared with geriatric patients who lived, geriatric patients who died had significantly elevated IL-6 (278.9 – 63 versus. 77.2 – 16 pg/mL; p = 0.002) and IL-10 (15.2 – 3.04 versus 7.83 – 0.9 pg/mL; p = 0.02) as well as decreased TNF-a (1.79 – 0.25 versus 3.03 – 0.2 pg/mL; p = 0.03) concentrations. Using one-way ANOVA, the early cytokine concentrations of both the geriatric patients who lived and the geriatric patients who died were then compared with the early cytokine concentrations of young patients who lived. Intriguingly, geriatric patients who died had similar IL-6 (278.6 – 63 versus 277.5 – 34 pg/mL; p = 0.98) and IL-10 (15.2 – 3.04 versus 14.3 – 1.5 pg/mL; p = 0.74) concentrations to young patients who survived. However, geriatric patients who lived, compared with young patients who lived, had significantly lower IL-6 (77.2 – 16 versus 277.5 – 34; p < 0.001) and IL-10 7.83 – 0.9 versus 14.3 – 1.5; p = 0.005) concentrations. We found was no such relation noted with TNF-a between geriatric and young patients (Fig. 2A, 2B, and 2C).
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Table 2. Geriatric Patients Who Lived versus Those who Died Geriatriclived Age White blood cell count Hospital length of stay Age-adjusted APACHE II
76.1 11.9 38.1 10.7
( – 2.2) ( – 0.8) ( – 2.4) ( – 1.1)
Geriatricdied 77.1 12.5 34.8 16.5
( – 2.5) ( – 1.2) ( – 2.7) ( – 1.4)
p 0.9 0.6 0.34 0.004
APACHE II = Acute Physiology and Chronic Health Evaluation.
FIG. 1. (A) Significantly lower presenting interleukin (IL)-6 concentrations noted in geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.04. (B) Significantly lower presenting interleukin (IL)-10 concentrations noted in geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.03. (C) No differences in presenting tumor necrosis factor (TNF)-a concentrations between geriatric trauma patients who developed a subsequent infection (Infxn) and those who did not develop a subsequent infection (No Infxn); *p = 0.42. Discussion
The inflammation and immune system to trauma represents a complex balance between pro- and anti-inflammatory mediators. The SIRS is the consequence of myriad disturbances to normal homeostasis, ranging from traumatic injury
to infectious etiologies [14]. The opposing compensatory anti-inflammatory response syndrome (CARS) [3], plays a similar role in the resolution of inflammation and outcomes after insult. Our understanding has evolved to recognize that a simultaneous activation of pro- and anti-inflammatory mediators at the time of injury and the failure of expedient resolution of both contributes to a more complicated outcome [3,15]. A perturbation of this balance results in either an insufficient immune response rendering the host susceptible to infectious complications, or an excessively robust response with end-organ failure and death. A limitation of many of the studies on trauma-induced inflammation is the predominant inclusion of young patients with a scarcity of geriatric patients. Geriatric patients represent a unique population wherein age-related changes in underlying immunity [4,16] and the response to physiologic insults have a profound effect on morbidity and mortality [9]. Immune senescence, or agerelated immune decline, is a well-described entity that is believed to contribute to the noted increased susceptibility to infections in geriatric patients [4,17–19]. Immune senescence affects cell-mediated immunity more than humoralmediated immunity. Professional antigen presenting cells such as dendritic cells, and especially plasmacytoid dendritic cells, from geriatric individuals show considerable functional decline with aging, especially in relation to phagocytosis [20]. A full understanding of trauma-induced inflammation in an aged population has yet to be elucidated despite a relatively extensive knowledge of inflammatory cascade in young patients [4,21]. Older patients have less effective neutrophil activity [7], decreased natural killer cell cytotoxicity, and decreased macrophage function [22,23]. There is also an age-related decrease in cytokine production by monocytes, particularly the pro-inflammatory mediators IL-6 and TNF-a, as well as decreased macrophage production of IL-10 [4,7,8,19,23]. It is postulated that this contributes to older subjects’ increased risk of infectious complications. We herein have demonstrated that geriatric trauma patients who developed a secondary infection, compared with those who did not develop an infection, were noted to have a relatively blunted presenting IL-6 (28.6 versus 179.8 pg/mL) and IL-10 (5.30 versus 12.34 pg/mL) response to the traumatic injuries. Our data offers a unique insight into the geriatric aspect of the immuno-paralysis that is often observed in trauma patients. Multiple animal studies have demonstrated a difference in the initial inflammatory response to injury in elderly mice compared with their younger counterparts [7,9,24]. Our data are in keeping with several murine models noting the importance of IL-6 in the response to bacterial pathogens.
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FIG. 2. (A) One-way analysis of variance (ANOVA) analysis of interleukin (IL)-6 concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p < 0.001; #p = 0.002. (B) One-way ANOVA analysis of IL-10 concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p = 0.005; #p = 0.02. (C) One-way ANOVA analysis of tumor necrosis factor (TNF)-a concentrations between young patients who lived versus geriatric patients who died and geriatric patients who lived. *p = 0.03. Interleukin-6 knockout mice were noted to have alterations in the recruitment of inflammatory cells, impaired microbial clearance, and ultimately were more susceptible to infection [25]. Moreover, Boyd et al. [26] demonstrated an age-related macrophage functional decline in a Streptococcus pneumoniae pneumonia model. They noted that IL-6 levels were markedly lower in aged mice and this lowered IL-6 was associated with diminished bacterial clearance. Thus, for
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geriatric patients, an impaired IL-6 response may play a key role in modulating the risk of developing an infection. The finding of lowered IL-10 concentrations being associated with the development of a subsequent infection is surprising. Interleukin-10 is believed to be an anti-inflammatory and immunosuppressant cytokine. Multiple murine studies have demonstrated improved survival from sepsis after IL-10 antibody administration [27]. However, blocking of a single cytokine does not affect the other effector functions of the cell(s) of origin. We contend that our data demonstrating lower IL-10 concentrations being associated with increased risk of subsequent infection represents an immune system with limited abilities to respond to critical injury and illness. The dampened immune response to critical illness observed in immuno-aging does not merely represent a robust anti-inflammatory pathway suppressing the pro-inflammatory response to trauma. We believe that our finding of a dampened initial post-trauma pro- and anti-inflammatory cytokine response corresponding to the development of a subsequent infection represents a global state of immune depression, dysfunction and inefficacy. Our study did not demonstrate a correlation between presenting TNF-a concentrations and subsequent infection in geriatric patients. Tumor necrosis factor-alpha is known to show a considerable lag time in geriatric individuals with respect to its role in bacterial, viral, or vaccine regulation [4,9,28]. We believe that this lag time to TNF-a peak occurred outside of our observation window. Further work is needed to assess whether later time points show a correlation. With respect to mortality and cytokine profiles, we demonstrated an intriguing relation between dampened IL-6 and IL-10 concentrations and survival in geriatric patients. Interleukin-6 has been associated with mortality after trauma in human and animal studies [14,15,29]. The predominance of this work has focused on young patients, with little examination of the applicability of these findings to geriatric patients. Most intriguingly, we demonstrated that geriatric patients who displayed a cytokine response as robust as their younger counterparts were noted to have a significantly higher mortality compared with geriatric patients with a more blunted response. Our data challenges the theory that geriatric patients’ survival is negatively impacted by an inability to mount an appropriate pro-inflammatory response. If patients survive the early post-injury period, it is believed that subsequent mortality is driven by inflammation induced end-organ failure. The initial inflammatory response to critical illness, including traumatic injuries, sets the stage for the ongoing dysregulated systemic immune and inflammatory cascade. It has been shown that the magnitude of IL-6 production corresponds to the magnitude of injury in trauma patients. Giannoudis et al. [30] demonstrated that IL-6 concentrations corresponded with both the presence of a SIRS response to trauma, and ultimately to mortality. Biffl et al. [29] demonstrated that increasing concentrations of IL-6 correlated with increasing severity of insult as well as increasing risk of mortality. Furthermore, Gebhard et al. [31] demonstrated that this correlation was independent of mechanism of trauma. Similarly, elevated IL-10 concentrations have been associated with increased mortality following traumatic injuries. An early elevated IL-10 response to trauma has been shown to be associated with the development of end-organ failure, specifically ARDS [32]. Furthermore, IL-10 is an independent
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biomarker for mortality in patients with severe traumatic brain injury. Rather than the specific effects of the single cytokine, our data more likely represent the global excessive cellular response to trauma that leads to tissue damage and end-organ failure, known drivers of trauma-related mortality. We contend that geriatric trauma patients, with less physiologic reserve, suffer greater effects from this inflammationinduced end-organ failure, potentially leading to their higher mortality rates. To this effect, the use of APACHE II accounts for the myriad of clinical presentations, resuscitations, and organ dysfunction of varying populations. Furthermore, APACHE II is a better Injury Severity Scale (ISS) predictor of mortality than ISS in trauma patients once admitted to the ICU [13]. It is becoming increasingly clear that inflammation tolerated by younger trauma patients exceeds the threshold tolerated by the aging trauma population. The old paradigm leads us to believe that a dysfunctional inflammatory response after traumatic injuries begets infection and this subsequent infection directly leads to death. However in the context of modern ICU care, this paradigm needs to be reassessed. Although there remains an association between the inflammatory response and both mortality and infection, these end effects are not interlinked closely. Conclusion
The inflammatory response to critical illness often influences outcomes. Geriatric patients who exhibit an inflammatory response as robust as their younger counterparts appear to have dramatically increased mortality. Redefining our definition of inflammation in the geriatric patient may help future therapy modulate inflammation and improve morbidity and mortality. Author Disclosure Statement
No competing financial interests exist. References
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Address for correspondence: Dr. Daithi S. Heffernan Division of Trauma and Surgical Critical Care Department of Surgery 435 APC Bldg., 4th Fl. 593 Eddy St. Rhode Island Hospital Providence, RI 02903 E-mail: [email protected]
