INTRODUCTION
Traumatic injury represents the leading cause of death in children outside the neonatal period in the United States (http://www.cdc.gov/nchs ). In addition to the risks critically injured children face from their primary injuries, they also face substantial morbidity due to nosocomial infection (1 ). These hospital-acquired infections contribute to longer intensive care unit (ICU) stays and increase health care costs by tens of thousands of dollars per infection (2 ).
Host immune function likely contributes importantly to infection risk in the critically injured patient. Impairment of the innate immune system is common and measurable in the setting of critical illness and is characterized by a reduced ability of whole blood to produce the proinflammatory cytokine, tumor necrosis factor α (TNF-α), in response to ex vivo stimulation with lipopolysaccharide (LPS) (3 ). In critically injured adults, ex vivo LPS-induced TNF-α production capacity is reduced following trauma with a greater degree of reduction being associated with increased risks of nosocomial infection and death (4, 5 ). In children, lower ex vivo LPS-induced TNF-α production capacity has been associated with adverse outcomes in the settings of multiple organ dysfunction syndrome (MODS) (6 ), influenza infection (7 ), and cardiopulmonary bypass (8 ), but these relationships have not been previously evaluated following critical trauma. Identifying these relationships is particularly important given that emerging evidence suggests that critical illness–induced immune suppression may be reversible, with beneficial effects on outcomes (6, 9 ). We therefore designed a single-center, prospective, longitudinal, observational study to test the hypothesis that reduced innate immune function will be associated with increased nosocomial infection risk in severely injured pediatric patients.
MATERIALS AND METHODS
Setting
Nationwide Children’s Hospital is a freestanding, quaternary-care pediatric referral center with a level I pediatric trauma designation. The pediatric ICU (PICU ) is a 40-bed multidisciplinary unit that sees more than 2,000 admissions annually. Trauma patients admitted to the PICU are collaboratively managed by trauma and critical care physicians. This study was approved by the institutional review board at Nationwide Children’s Hospital. Written informed consent, and subject assent when appropriate, was obtained for all subjects prior to study participation.
Subjects
Patients 18 years or younger admitted to the PICU at Nationwide Children’s Hospital with an admitting primary diagnosis of trauma and/or burn injury were included. Patients with a preexisting limitation of care order and those with a weight of less than 3.3 kg were excluded (for blood volume reasons). Healthy control subjects were recruited from the outpatient phlebotomy area. Healthy subjects were excluded if they had subjective or objective fever within the past 24 h, current receipt of antibiotics, use of nonsteroidal anti-inflammatory drugs within the past 48 h, history of systemic corticosteroid administration within the past month, or history of a chronic inflammatory disease, malignancy, or transplantation.
Measurements
Subjects were enrolled on the earliest possible weekday following ICU admission and underwent blood sampling at the time of enrollment and every Monday, Wednesday, and Friday thereafter until ICU discharge. Blood was collected in heparinized tubes (Becton Dickinson, Franklin Lakes, NJ) and placed on ice.
To quantify innate immune function, LPS-induced TNF-α production capacity was measured as follows: Within 30 min of collection, 50 μL of whole blood was added to 500 μL of highly standardized stimulation solution containing 500 pg/mL of LPS (phenol-extracted from Salmonella abortus equii [Sigma, St Louis, Mo]) and incubated for 4 h at 37°C. After 4 h, the supernatant was collected and stored at −80°C for batch analysis of TNF-α. Stimulation assays were performed in duplicate for each blood sample, and values reported are the average values from each set of duplicates. Stimulation solution was manufactured monthly and quality controlled such that the intrabatch coefficient of variation for TNF-α production from healthy donor replicates was less than 10%. Plasma from unstimulated whole blood was collected at each sampling point and stored at −80°C for batch analysis of the proinflammatory cytokine interleukin 6 (IL-6) and the anti-inflammatory cytokine IL-10. Tumor necrosis factor α, IL-6, and IL-10 were quantified by chemiluminescence using the Immulite automated chemiluminometer (Siemens Healthcare Diagnostics, Deerfield, Ill). Complete blood cell counts were obtained at the discretion of the treatment team. Absolute cell counts were calculated when present.
In order to evaluate reversibility of trauma-induced innate immune suppression, samples from three children were coincubated at 37°C for 4 h with LPS +/− granulocyte-macrophage colony-stimulating factor (GM-CSF, 1,000 pg/mL) with TNF-α production capacity measured as described above.
Clinical Data and Definitions
Clinical data including age, gender, type of injury(ies), transfusion history, medications, treatments, and outcomes were gathered from the electronic medical record. Nosocomial infection was defined as a new bacterial or fungal infection diagnosed more than 48 h from hospital admission according to the Centers for Disease Control and Prevention (CDC) criteria (10 ), although the decision to obtain cultures was left to the discretion of the treatment team. Of note, nosocomial lung infections in this report could represent “lower respiratory tract infection,” “ventilator-associated pneumonia,” or “ventilator-associated tracheitis” per CDC definitions. Severity of injury within 24 h of admission was measured by Injury Severity Score (ISS) (11, 12 ). Severe traumatic brain injury (TBI) was defined as intracranial pathology with an admission Glasgow Coma Scale score of 8 or less. Nonsevere TBI was defined as any intracranial pathology with an admission Glasgow Coma Scale score of greater than 8. For multiply transfused subjects, storage age of transfused red blood cells (RBCs) was defined as the storage age of the oldest unit transfused. Hospital and ICU lengths of stay were calculated based on physical admission to and discharge from the hospital and ICU, respectively. Patients transferred to inpatient rehabilitation were considered to be discharged from the hospital. Although there were no specific extubation or ICU discharge criteria in place during the study period, there were no systematic changes in those practices over that period. Mortality was defined as death during the hospitalization.
Statistical Analyses
Our primary outcome variable was the development of nosocomial infection within 14 days after injury. We also evaluated time to development of nosocomial infection. Because of the intermittent nature of our weekday sampling regimen, immune function and cytokine data were analyzed using 48-h time windows (e.g., posttrauma days [PTDs] 1–2, 3–4, 5–6, 7–8). Posttrauma day 1 was defined as the first calendar day after the day of injury. Because many subjects were discharged from the PICU within 48 h of injury, we undertook separate analyses for PTDs 1–2 data and data from subjects who had more longitudinal sampling. Given the reduced number of subjects at later time points, we concluded our immunologic analyses by PTDs 7–8. Comparisons between groups were made with Mann-Whitney U test for continuous variables or Fisher exact test for categorical variables. Two-way analyses of variance with Bonferroni posttest analyses were performed to determine differences between groups over time. A receiver operating characteristic curve was constructed, and area-under-the-curve analysis was performed to evaluate the relationships between the lowest ex vivo LPS-induced TNF-α production capacity at any point in time and development of secondary infection within 14 days after injury. In addition, recursive partitioning algorithms were used to assess an “optimal” cutpoint of TNF-α production in relation to development of infection. Kaplan-Meier plotting and log-rank test were used to evaluate time to infection between groups determined by immune function cutpoint. Logistic regression analyses were used to assess the impact of various factors (e.g., gender, age, ISS, injury type, RBC transfusion, innate immune function) on incidence of nosocomial infection. All-subsets logistic regression models were also explored to assess optimal modeling in the multivariable setting; however, given the inherent limitations with these analyses with the relatively limited number of infection events, these were used to guide generation and evaluation of two-covariate multivariable models in relation to incidence of nosocomial infection. Data were log transformed for analyses as appropriate. Analyses were performed using Prism6 (GraphPad Inc, La Jolla, Calif) and the Mac version of the statistical program R version 3.0.1 GUI 1.61 (The R Foundation for Statistical Computing, Vienna, Austria). P = 0.05 was considered significant throughout. Data are presented as median and interquartile range (IQR).
RESULTS
Seventy-six critically injured patients were enrolled between November 2007 and October 2010. All trauma subjects were admitted directly to the PICU from the emergency department or operating room. The median PTD for the first sampling event was PTD 2 (IQR, 1–3), with 67% of patients (n = 51) having their first samples collected within 48 h of injury. Demographic information for enrolled subjects can be found in Table 1 . Sixty-two subjects (81%) had blunt trauma, whereas two subjects (3%) had penetrating trauma, 10 subjects (13%) had burns (median total body surface area, 30%), and two subjects (3%) had asphyxial injury. Thirty-five subjects (46%) had TBI (either isolated or in the setting of polytrauma), of whom 10 had severe TBI. The most common mechanisms of injury were motor vehicle crash (49%), fall (13%), thermal injury (6% scald, 6% flame), and assault (11%). Injury Severity Score data suggested moderate to severe injury (17 [IQR, 10–26]), and RBC transfusion was given in 45% of subjects. No subjects were managed with therapeutic hypothermia, and three patients were treated with methylprednisolone on PTDs 0–1 for treatment of spinal cord injury. No subjects were known to be immunocompromised at baseline, including the use of immunosuppressive medications prior to injury.
Table 1: Clinical data
Twenty-one healthy control subjects were enrolled, 52% of whom were male. The healthy control cohort was not significantly different from the trauma cohort as a whole with respect to age (11.4 [IQR, 8.2–13.3] vs. 9.9 [IQR, 4.5–14.5] years, P = 0.7). Healthy control subjects demonstrated robust ex vivo TNF-α production capacity (1,297 [IQR, 1,088–1,739] pg/mL), and all had undetectable plasma levels of IL-6 and IL-10.
As expected, critically injured children had higher plasma IL-6 levels on PTDs 1–2 compared with control subjects (44 [IQR, 15–156] vs. <5 pg/mL). At the same time, critically injured children also demonstrated slightly higher levels of the anti-inflammatory cytokine IL-10 (5 [IQR, 5–14] vs. <5 pg/mL). Lastly, critically injured subjects had reduced ex vivo TNF-α production capacity compared with control subjects (908 [IQR, 506–1,193] vs. 1,297 [IQR, 1,088–1,739] pg/mL, P = 0.0002).
Overall, 16 patients developed nosocomial infection within 14 days of injury (Table 2 ). The median time from injury to infection in these 16 patients was 4.5 days (range, 3–13 days). In the 51 children with PTDs 1–2 samples available, those who developed nosocomial infection (n = 7) had significantly lower ex vivo TNF-α production capacity on PTDs 1–2 compared with children who did not develop infection (342 vs. 956 pg/mL, P = 0.006; Fig. 1 A). Plasma levels of both IL-6 (P = 0.02) and IL-10 (P = 0.0005) were higher on PTDs 1–2 in the subjects who went on to develop nosocomial infection (Fig. 1 , E and F). Among subjects for whom CBC data were available (n = 33), there were no significant differences in absolute cell counts between groups (Fig. 1 , B–D).
Table 2: Characteristics of subjects with infection within 14 days of injury
Fig. 1: Among subjects with PTDs 1–2 data available, innate immune function (A) was lower in critically injured children compared with control subjects, but was lowest in children who went on to develop nosocomial infection . Among those with CBC data (n = 33), there were no differences in absolute cell counts between groups (B–D). Posttrauma days 1–2 plasma IL-6 (E) and plasma IL-10 (F) levels were bother higher in critically injured children who went on to develop nosocomial infection. Lines and boxes represent median and IQR, with whiskers representing range throughout. NI indicates nosocomial infection; HC, healthy control. **P < 0.01, ***P < 0.001.
For those patients who remained in the PICU and underwent longitudinal sampling, ex vivo TNF-α production capacity remained significantly lower over time in patients who developed infection (Fig. 2 A). Innate immune function returned to near-normal levels in patients who remained infection-free. Interestingly, absolute monocyte and neutrophil counts were also lower over time in patients who developed nosocomial infection (Fig. 2 , B and D), although none were frankly leukopenic or neutropenic beyond PTDs 3–4.
Fig. 2: In critically injured children who underwent longitudinal sampling, those who went on to develop nosocomial infection (gray squares) demonstrated lower innate immune function (A) over time compared with those who did not develop infection (open circles) . The dotted line and shaded area represent median and IQR for control subjects. Absolute monocyte counts (B) and absolute neutrophil counts (D), but not absolute lymphocyte counts (C), were lower over time in the group that developed nosocomial infection. There were no differences in plasma IL-6 (E) or IL-10 (F) levels over time. Data represent median and IQR. NI indicates nosocomial infection.
Receiver operating characteristic curve analysis revealed that the lowest value of LPS-induced TNF-α production capacity in the first week after injury was strongly associated with the development of nosocomial infection (Fig. 3 A). Recursive partitioning algorithm analyses showed that having an ex vivo TNF-α production capacity of less than 520 pg/mL on PTDs 1–2 was an optimum cutpoint for identifying those who would develop nosocomial infection within 14 days of trauma; infection rates in those with PTDs 1–2 ex vivo TNF-α levels of less than 520 were 43% vs. 3% in those with 520 pg/mL or greater (P = 0.004; sensitivity 86% [95% CI, 42%–100%]; specificity 82% [95% CI, 67%–92%]; positive predictive value 43% [95% CI, 18%–71%]; negative predictive value 97% [95% CI, 86%–100%]). This was still a highly significant cutpoint even when evaluating the minimum TNF-α production capacity levels across all patients within the first week of trauma (48% vs. 8%, P = 0.0002; sensitivity 78% [95% CI, 66%–88%]; specificity 75% [95% CI, 48%–93%]; positive predictive value 48% [95% CI, 28%–69%]; negative predictive value 92% [95% CI, 81%–98%]). Overall, 25 patients in the cohort (33%) had at least one ex vivo LPS-induced TNF-α production capacity value below this threshold. Time-to-event analysis shows that having a TNF-α production capacity of less than 520 pg/mL in the first week is highly significantly associated with time to development of infection as well (Fig. 3 B). Multivariable modeling also supported using a cutpoint for ex vivo TNF-α to predict development of nosocomial infection in children after trauma. By univariate logistic regression modeling, higher ISS, presence of severe TBI, burn injury, RBC transfusion during the first week, and an ex vivo LPS-induced TNF-α production capacity of less than 520 pg/mL on days 1–2 or at any time during the PTDs 1–8 were all predictive of the development of nosocomial infection (Table 3 ). All-subsets logistic regression modeling showed that ex vivo TNF-α production capacity of less than 520 pg/mL at any time in the first week after injury was the strongest predictor for infection and remained significant even when adjusting for other factors such as ISS, incidence and severity of TBI, age, gender, and mechanism of injury. In all of the two-covariate logistic regression models, ex vivo TNF-α levels of less than 520 pg/mL was the best predictor of nosocomial infection (Table 3 ).
Table 3: Univariate and two-covariate analyses of risk factors for nosocomial infection
Fig. 3: A, Receiver operating characteristic curve analysis suggests that ex vivo TNF-α production capacity is predictive of nosocomial infection with an optimal cutoff value of 520 pg/mL (sensitivity 75% [95% CI, 48%–93%], specificity 81% [95% CI, 69%–90%]) . B, Time-to-event analysis suggests a strong association between an ex vivo TNF-α production capacity of less than 520 pg/mL and development of nosocomial infection, particularly in the first week following injury (P < 0.0001, log-rank test).
Thirty-four subjects received at least one RBC transfusion following injury, with 29 (85%) of 34 subjects receiving RBCs within 72 h of injury. As an exploratory analysis, we determined relationships between early RBC transfusion and innate immune function over time. Among those transfused within the first 72 h after injury, the median number of donor exposures was 2 (range, 1–3), with a median volume of 15 mL/kg (range, 11–24 mL/kg) transfused and a median RBC storage duration of 16 days (range, 5–42 days). In these patients, we found no association between total volume of RBCs transfused and innate immune function over time (Fig. 4 A). However, children who received RBCs that had been stored for 14 days or longer had lower ex vivo TNF-α production capacity over time (Fig. 4 B) compared with those who received fresher RBCs.
Fig. 4: A, Among children transfused with RBCs within the first 72 h after injury (n = 29), there was no difference in innate immune function between those who received less than 20 mL/kg of RBCs (n = 16, open circles) and those who received 20 mL/kg or more (n = 13, gray squares) . B, Immune function was lower over in time, however, in transfused children whose RBC storage age was 14 days or longer (n = 20, gray squares) versus those receiving fresher RBCs (n = 9, open circles). Data represent median and IQR. The dotted line and shaded area represent median and IQR for control subjects. C, Whole-blood samples from three critically injured children were concurrently incubated with LPS alone and with LPS + GM-CSF (1,000 pg/mL). Coincubation with GM-CSF resulted in increased ex vivo TNF-α production capacity in these samples, suggesting reversibility of trauma-induced innate immune suppression.
Lastly, to evaluate the reversibility of trauma-induced innate immune suppression, whole-blood samples from three critically injured subjects were incubated with LPS alone or LPS + GM-CSF (1,000 pg/mL). Ex vivo coincubation of subjects’ whole blood with LPS + GM-CSF resulted in higher TNF-α production capacity than that seen with LPS alone in all three samples (Fig. 4 C).
DISCUSSION
This is the first study to document innate immune responsiveness in critically injured children. In our cohort, innate immune suppression as measured by reduced ex vivo LPS-induced TNF-α production capacity was common among critically injured children and was significantly associated with the subsequent development of nosocomial infection. Using a highly standardized assay, we found an ex vivo LPS-induced TNF-α production capacity of less than 520 pg/mL at any time in the first week following injury to be predictive of the development of nosocomial infection.
The immunosuppressive nature of critical illness and injury is increasingly recognized as an important feature of ICU pathophysiology. In recent years, innate immune suppression has been described following the onset of sepsis, MODS, influenza, and cardiopulmonary bypass in adults and children (6–8, 13–15 ). It should be noted, however, that this phenomenon was described by Polk et al. (16 ) more than 25 years ago, with impaired antigen presentation capacity demonstrated in innate immune cells from severely injured adults. Much of the literature in this field has continued to focus on antigen-presenting capacity, as measured by reduction (or recovery) of expression of the cell surface marker HLA-DR (a class II major histocompatibility complex molecule) on circulating monocytes. Severe or persistent loss of monocyte HLA-DR expression has been consistently associated with increased sepsis risk following major trauma in adults (17, 18 ).
Another approach to innate immune monitoring is the quantitation of the ability of whole blood to make the proinflammatory cytokine TNF-α upon ex vivo stimulation with LPS. While TNF-α is typically absent from the circulating plasma, whole blood from immunocompetent individuals should readily produce TNF-α when challenged ex vivo . Indeed, we observed robust TNF-α production capacity in our samples from healthy children. Impairment of cytokine production capacity has been reported in adults following severe injury, with an associated increase in risk for infection-related mortality (4 ). We have previously demonstrated a relationship between reduced TNF-α production capacity and adverse outcomes in critically ill children with MODS (6 ), influenza (7 ), and cardiopulmonary bypass (8 ), but this had not been previously studied in the setting of pediatric critical injury. This population is of particular interest because of our ability to clearly elucidate temporal relationships between injury and immune function, something that is more challenging with sepsis, for example, whose onset can be difficult to pinpoint.
Our findings suggest that innate immune suppression occurs as early as the first 48 h following severe trauma, with the depth of suppression being predictive of subsequent nosocomial infection risk even at this early time point. Elevations in plasma biomarkers of both the proinflammatory (IL-6) and anti-inflammatory (IL-10) responses occurred along with innate immune suppression. This finding is consistent with our prior work, which demonstrated high levels of plasma cytokines alongside impaired innate immune responsiveness in other forms of pediatric critical illness (6, 7 ). The association of elevations in early plasma IL-6 levels with adverse outcomes is also consistent with the adult trauma literature (18, 19 ). It is notable that impairment of TNF-α production capacity was not associated with reduced innate immune cell numbers among subjects with absolute cell counts available on PTDs 1–2. This is suggestive of impaired cellular function rather than leukopenia as an explanation for the reduced TNF-α response.
The longitudinal time course of the innate immune response was also of interest in our study. Among subjects who underwent serial immune monitoring, recovery of TNF-α production capacity was slower in children who went on to develop nosocomial infection, with infection typically occurring toward the end of the first week after injury. In these analyses, we did see a relationship between lower innate immune cell numbers and lower TNF-α production capacity, although none of the subjects were frankly leukopenic or neutropenic.
One of the problems in the field of innate immune monitoring has been the lack of standardization of LPS stimulation procedures. Our highly standardized reagents and approach have now been used in single-center and multicenter studies with consistent prediction of adverse outcomes (6–8 ) and are consistent with results obtained in adults using a similar approach (20 ). Whereas we have repeatedly demonstrated a threshold of TNF-α production capacity of around 250 pg/mL to be associated with mortality in critically ill children (6, 7 ), a higher threshold of 520 pg/mL was highly predictive of nosocomial infection risk in our trauma cohort. This still represents marked depression of innate immune responsiveness compared with healthy children, whose values were typically greater than 1,000 pg/mL. This also suggests that different immune function thresholds may be relevant for different outcomes or clinical contexts. We were unable to evaluate a mortality threshold due to the low incidence of death in our study population.
Mechanisms of innate immune suppression in the PICU remain poorly understood. It is likely that these mechanisms are multifactorial and include patient-related factors as well as unintended immunomodulation by treatments provided in the ICU. Very few of our subjects (3/76) received overtly immunosuppressive medications, such as glucocorticoids. A growing body of evidence suggests that RBC transfusion may be immunosuppressive. Several retrospective analyses have shown RBC transfusion to be an independent risk factor for mortality and nosocomial infection in critically ill adult patient populations, including trauma (21–23 ). Receipt of RBCs with longer storage duration has been shown to be associated with increased risks of adverse outcomes in critically ill adults and children (24–27 ). While exact mechanisms underlying these observations remain uncertain, studies from our laboratory indicate that stored RBCs suppress monocytes in vitro as a function of RBC storage duration (28 ). These findings suggest that RBC transfusion, particularly with RBCs of longer storage duration, may be immunosuppressive. In our current study, the receipt of an RBC transfusion was associated with a strong trend toward increased infection risk even after adjusting for immune function. In addition, receipt of RBCs with longer storage duration was associated with a failure to recover innate immune function, supporting the hypothesis that RBC storage–related factors may contribute to posttraumatic innate immune suppression.
Our observed nosocomial infection rate of 21% is comparable to previously published studies of critically injured children (1 ). It should be noted that these infections included all nosocomial infections by the CDC criteria, not just ventilator-associated pneumonia or catheter-associated bloodstream infections. The majority of patients who developed nosocomial infection in our cohort had either severe TBI or burn injury. This is in keeping with higher rates of infectious complications reported in the literature for each of these two mechanisms of injury (29, 30 ). This increased susceptibility to infection may be due to severity of illness and increased need for invasive support (central venous catheters and mechanical ventilation), but evidence suggests that immune suppression following these injuries may be particularly problematic (31, 32 ). Indeed, burn injury and severe TBI are likely to be immunologically distinct from other forms of trauma and warrant independent study.
Our data provide additional evidence that trauma-induced innate immune suppression may be reversible, given that coculture of whole blood from critically injured children with the stimulant GM-CSF was capable of restoring LPS-induced TNF-α production capacity. These findings are in agreement with similar studies in injured adults that suggest that suppressed innate immune cells can be pharmacologically reactivated ex vivo (33, 34 ) and in vivo (35 ). Granulocyte-macrophage colony-stimulating factor has been Food and Drug Administration approved since 1991 for the reconstitution of bone marrow following chemotherapy and bone marrow transplantation in adults and children. Limited evidence also suggests that it may reverse critical illness–induced innate immune suppression (6, 9 ). We are currently conducting a National Institutes of Health–funded clinical trial of GM-CSF therapy for the reversal of trauma-induced innate immune suppression in critically injured children (NCT01495637, R01GM094203).
There are important limitations to our study. First, as a single-center study of critically injured children, we had a limited sample size including a relatively small number of children who went on to develop nosocomial infection. As such, we were limited in the number of covariables that could be included in multivariable regression models, and it is possible that other confounding variables may have contributed to our results. Given the study logistics of weekday testing, not all patients had samples available on PTDs 1–2, and many of the patients had left the ICU by day PTDs 7–8. Despite this, we present the largest cohort of critically injured children to undergo immune monitoring to date and were able to show robust associations between immune function and outcome. Second, our patient population was heterogeneous, representing the spectrum of critical injuries throughout the pediatric age range. For the purposes of this observational study, we intentionally cast a wide net in hopes of evaluating a diverse group of injured children. For subsequent multicenter and/or interventional trials, it will likely be important to stratify for the presence or absence of important confounders such as severe TBI and burns. Third, we used a single method of quantitation of innate immune function. It is not clear if ex vivo LPS-induced TNF-α production capacity is superior to monocyte HLA-DR expression in predicting risk of adverse outcomes following trauma. Our approach offers the advantage of standardization along with measurement of a functional output (cytokine production capacity). Multiple approaches for HLA-DR quantitation by flow cytometry exist (e.g., % positive, molecules/cell), and it is not clear which approach is optimal. Furthermore, flow cytometric approaches all have some potential to be affected by lot-to-lot variability in reagents and cytometer settings. Head-to-head comparison of all of these measures of innate immune function is badly needed in a large cohort of critically injured patients.
In summary, suppression of the innate immune response in the first week following trauma is common and is predictive of the development of nosocomial infection in critically injured children. Further multicenter work is warranted to determine mechanisms of innate immune suppression following trauma, including the effects of stored RBCs, and to determine the efficacy of immunomodulatory treatments in preventing adverse outcomes in pediatric trauma patients.
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