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Journal of Trauma and Acute Care Surgery:
doi: 10.1097/TA.0b013e3182ab1ab5
AAST 2013 Plenary Papers

Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma

Vanzant, Erin L. MD; Lopez, Cecilia M. BS; Ozrazgat-Baslanti, Tezcan PhD; Ungaro, Ricardo BS; Davis, Ruth RN; Cuenca, Alex G. MD, PhD; Gentile, Lori F. MD; Nacionales, Dina C. MD; Cuenca, Angela L. MPH; Bihorac, Azra MD; Leeuwenburgh, Christiaan PhD; Lanz, Jennifer MSH; Baker, Henry V. PhD; McKinley, Bruce PhD; Moldawer, Lyle L. PhD; Moore, Frederick A. MD; Efron, Philip A. MD

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Author Information

From the Departments of Surgery (E.L.V., R.U., R.D., A.G.C., L.F.G., D.C.N., A.L.C., J.L., B.M., L.L.M., F.A.M., P.A.E.), Molecular Genetics and Microbiology (C.M.L., H.V.B.), and Anesthesia (T.O-B., A.B.), and Institute on Aging (C.L.), University of Florida College of Medicine, Gainesville, Florida.

Submitted: August 2, 2013, Revised: October 11, 2013, Accepted: October 11, 2013.

This study was presented at the 72nd annual meeting of the American Association for the Surgery of Trauma, September 18–21, 2013, in San Francisco, California.

The work represents a secondary use of this public database, and the conclusions and discussion are the authors and do not necessarily represent the views of either the Glue Grant, Massachusetts General Hospital, or the National Institute of General Medical Sciences.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site ( www.jtrauma.com).

Address for reprints: Philip A. Efron, MD, Department of Surgery, University of Florida College of Medicine, PO Box 10019, Gainesville, FL 32610-0019; email: philip.efron@surgery.ufl.edu.

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Abstract

BACKGROUND

We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level.

METHODS

We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14.

RESULTS

Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings.

CONCLUSION

Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS.

LEVEL OF EVIDENCE

Epidemiologic study, level III.

Even with advances in care during the last three decades, severe blunt trauma causes significant long-term morbidity and mortality.1,2 In the last decade, in-hospital mortality has improved markedly, and late multiple-organ failure (MOF) deaths are disappearing.3,4 Regardless, long-term mortality and functional recovery have essentially remained unchanged.2,5 Severe trauma causes an early systemic inflammatory response syndrome (SIRS), which can result in early MOF in the absence of infection. SIRS has been linked to a compensatory anti-inflammatory response (CARS), reflecting defects in adaptive immunity.6 Recently, observations from multiple sources have led to a single-stage model of SIRS/CARS.

Xiao et al.7 demonstrated early in the leukocyte transcriptome that there is a simultaneous increase in the expression of innate immunity genes (i.e., SIRS) and suppression of adaptive immunity genes (i.e., CARS). Furthermore, patients with “complicated” clinical courses versus uncomplicated patients had an increased magnitude and duration of these genomic changes (i.e., failure to restore homeostasis).7

Study of these complicated patients5,8 led to the recognition of several clinical patterns in patients who remained critically ill in the intensive care unit (ICU). From these observations, we recently proposed a new model of chronic critical illness (CCI) (Fig. 1) where the phenotype of “late MOF” is replaced with a new syndrome termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS).9 These patients generally proceed along a complicated course requiring transfer to long-term acute care facilities (LTACs), where they ultimately experience indolent deaths. Unlike previous paradigms on CCI, this syndrome offers a unique and unifying pathogenic hypothesis that persistent low-level inflammation induces immune suppression and progressive protein catabolism.

Figure 1
Figure 1
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Current evidence suggests that trauma patients experience a systemic immunologic dysregulation central to organ injury and places them at an increased risk for PICS.10–12 To examine this, we analyzed the clinical data, outcomes, and genomic profiles of leukocyte cell populations previously obtained from the Inflammation and Host Response to Injury Glue Grant (GG) database (TRDB). The goal of this study was to determine whether genomic and clinical data from patients with complicated clinical outcomes after severe blunt trauma have ongoing evidence of PICS, supporting our hypothesis that PICS represents a predominant phenotype of CCI after injury and sepsis.

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PATIENTS AND METHODS

Approval was obtained from the University of Florida Institutional Review Board to analyze deidentified human data obtained from the GG TRDB.13

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Data Source and Study Population

GG data were derived from eight US designated Level 1 trauma centers that enrolled blunt trauma patients in the TRDB from 2001 to 2011.4

The enrolled patients were divided into two distinct cohorts defined as complicated or uncomplicated based on a new metric found to correlate with injury severity and critical illness after trauma, time to recovery from multiple-organ injury (TTR). Patients with TTR of greater than 14 days were considered to have complicated clinical courses and those with TTR of less than 5 days were classified as uncomplicated (i.e., rapid recovery). The description of how TTR was calculated can be found in previously published literature.7,13 Of the 1,989 patients, 369 uncomplicated and 785 complicated patients met the predetermined criteria; 835 were classified as intermediate, not meeting either criterion.

In the initial phase of the GG, 167 of the 1,989 trauma patients enrolled, 18 years to 55 years of age, agreed to blood sampling for total leukocyte genomics and were matched by age, sex, and ethnicity to 37 healthy control subjects.14 Blood sampling for T-cell, monocyte, and neutrophil (PMN) genomic analysis was obtained from a second set of 244 severe trauma patients, 16 years to 90 years of age and compared with 21 matched controls. Since we define PICS as patients with persistent inflammation, immunosuppression, and catabolism, the complicated patients with TTR in excess of 14 days would most likely include those who meet our PICS criteria.9

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Clinical Outcomes and Laboratory Analysis

Demographics and outcomes recorded included age, sex, mortality, maximum Marshall and Denver scores, New Injury Severity Score (NISS), Acute Physiology and Chronic Health Evaluation II (APACHE II), total days on mechanical ventilation, and disposition. Clinical parameters were recorded at admission, worst value over hospital course, and on Days 7 and 14 for the following parameters: Marshall and Denver scores, creatinine, bilirubin, alkaline phosphatase, white blood cell (WBC) count, lymphocyte count, PMN count, platelet count, international normalized ratio (INR), albumin, and Pao2/FiO2 (P/F) ratio.

Clinical values were compared among the different cohorts grouped in six different analyses as follows: (1) complicated patients’ values at each time point vs. uncomplicated patients’ worst values over their hospital course; (2) complicated patients’ values at each time point vs. uncomplicated patients’ values at admission; (3) uncomplicated patients’ worst values recorded over their hospital course vs. complicated and intermediate patients values combined at each time point; (4) uncomplicated patients’ worst recorded values over their hospital course combined with intermediate patients’ values at each time point vs. complicated patients’ values at each time point; (5) uncomplicated patients’ values on admission vs. complicated and intermediate patients’ values combined at each time point; and finally, (6) uncomplicated patients’ values on admission combined with intermediate patients’ values at each time point vs. complicated patients’ values at each time point. Patients without recorded data at the time point analyzed were excluded from the total number of patients for analysis at those time points.

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Gene Chip Validation

Four individual chips were used for analysis over the study (Affymetrix HU133+v2, GGh1, GGh2, and GGh3).15 For the second set of patients, principle component analysis (PCA) was performed using Robust Multi-array. Averages for overall RNA production between the individual GeneChips in an attempt to address the concerns in variability of data production among the GGh chips. PCA is a multivariate statistical technique used for the visual representation of the patterns of similarity between variables and observations.16

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Gene Expression Profiles

Blood samples were drawn within 12 hours of injury and at 1, 4, 7, 14, 21, and 28 days after injury. For the first 167 patients, whole blood nucleated cells were isolated, and genome-wide expression analyses of 54,675 probe sets were performed after RNA extraction and hybridization onto Affymetrix U133+v2 GeneChip.17,18 Individual leukocyte subpopulations were isolated either by negative selection (monocytes and T-cells) or by positive selection (PMN) using microfluidics cassettes.17 Genome-wide expression analyses were performed after RNA extraction and hybridization to the GGh GeneChips as mentioned earlier. Full detailed descriptions of the protocols and specific methodologies can be found in previously published reports and their supporting text.17

BRB tools and Ingenuity Systems (Ingenuity Pathways Analysis) were used to identify gene expression differences as well as compare functional pathways, ontologies, and individual gene fold changes between the cohorts and controls. Significant genes were selected by identifying trauma responsive genes in both uncomplicated and complicated patients versus human control subjects (p < 0.001, f test). For genes that were represented by multiple probe sets, the probe set with the highest expression value was used for analysis. A distance from reference (DFR) metric (natural log) was calculated for assessing the overall perturbation in gene expression as previously described.19 Leave-one-out cross-validation was performed to compute the misclassification rate, and a Monte Carlo simulation was conducted to test statistical significance.

Once significant genes were identified, fold changes were calculated between each of the cohorts and control samples. These fold changes in magnitude were significant at p values of 0.001. Functional pathway analysis in Ingenuity Pathways Analysis identified pathways that were overrepresented or underrepresented in terms of the observed numbers of genes whose expression significantly changed on cohort analysis. The Z score was used to test for significance at a 95% confidence interval (less than −2 or greater than 2).20

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Statistical Analysis

Categorical variables were reported as frequencies and percentages. Pearson χ2 or Fisher’s exact tests were used to test independence between categorical variables as appropriate. Normality of distribution was tested using the Kolmogorov-Smirnov test, and continuous variables that did not satisfy the normality assumptions were reported as medians (25th and 75th percentiles). Bootstrap method, a nonparametric method in which data are resampled and replaced a large number of times to compute adjusted p value, was used for adjustments for multiple comparisons.

Mixed-model analysis of longitudinal changes in clinical laboratory data was used to account for correlations among repeated measurements for each patient. For each variable, we modeled change over time by including time, recovery class, and their interaction adjusting for Abbreviated Injury Scale (AIS), NISS, age, and sex.

All significance tests were two sided, with a 0.05 α level. Statistical analyses were performed with SAS (version 9.3, Cary, NC).

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RESULTS

Patient Demographics, Clinical Data, and Mixed-Model Analysis

Complicated patients were significantly older, with longer days on mechanical ventilation, as well as higher Marshall MOF, NISS, Denver, and APACHE II scores, when comparing complicated and intermediate patients combined to uncomplicated patients. This was also true when comparing complicated patients to the combined cohort of intermediate and uncomplicated patients (Table 1). Complicated patients were noted to have lower lymphocyte counts, P/F ratios, and albumin levels as well as higher PMN counts, leukocytosis, and creatinine concentrations when compared with both admission and worst values for uncomplicated patients. These changes often persisted to Day 14 (Table 2). Results for all cohorts compared can be found in Supplemental Table 1, Supplemental Digital Content 1, at http://links.lww.com/TA/A334. Mixed-model analysis demonstrated that recovery class (complicated, intermediate, uncomplicated), time, and their interaction were significant for all clinical variables, except for alkaline phosphatase for which only time was significant. For complicated recoveries, there was a significant change for all variables from admission to Day 7, except for the P/F ratio, and from admission to Day 14, except for albumin. The difference between admission and worst values were different for Marshall score, bilirubin, WBC, PMN, lymphocyte count, INR, and creatinine (Table 3).

TABLE 1
TABLE 1
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TABLE 2
TABLE 2
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TABLE 3
TABLE 3
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Microarray Data on Whole Blood Leukocytes

The genome-wide expression patterns for complicated patients were more aberrant from control subjects than those of uncomplicated patients (DFR: 11.8 ± 0.4 vs. 11.6 ± 0.4, respectively, p < 0.001). Comparison of the transcriptome of the uncomplicated, complicated, and control patients on Day 7 revealed 30,351 probe sets (14,262 genes) that were significant in differentiating among groups after trauma (p < 0.001). Moreover, the overall pattern of gene expression was significantly different, as determined by leave-one-out cross-validation (91% to nearest first neighbor). Comparison of complicated with uncomplicated patients on Day 7 showed that 415 genes could differentiate between the two (p < 0.001). Similarly, comparison among complicated, uncomplicated, and control cohorts on Day 14 demonstrated 26,842 probe sets (13,189 genes) were expressed differently among the groups (p < 0.001) (see Supplemental Figure 1A, Supplemental Digital Content 2, at http://links.lww.com/TA/A335).

Next, we evaluated individual genes whose fold changes from control were significantly different between complicated and uncomplicated patients. We found that complicated patients had an increased magnitude of alterations in specific genes involved in increased inflammation, up-regulation of myeloid-derived suppressor cells (MDSCs), decreased chemotaxis, and defective innate immunity compared with uncomplicated patients on Days 7 and 14 (Table 4).

TABLE 4
TABLE 4
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Using Gene Ontology and Biocarta, we found that complicated patients had significant differences in their gene expression patterns from pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity on Day 7. Furthermore, multiple-comparison analysis demonstrated that complicated patients had significant differences in pathways involved in the suppression of adaptive immunity (i.e., regulation of Th1 immune response and CD4+/CD25+alpha-beta regulation of T-cell differentiation pathways, and increased inflammation (i.e., interleukin 22 [IL-22] signaling) compared with uncomplicated patients on Day 7. On Day 14, genome-wide expression illustrated continued increases in the pathways involved in adaptive immunity suppression (i.e., suppression of myeloid cell differentiation) (p < 0.05) (see Supplemental Table 2, Supplemental Digital Content 3, at http://links.lww.com/TA/A336).

Evaluation of functional pathways on Day 7 revealed over-representation of pathways involved in increased hematopoiesis (T-cell development, differentiation in mononuclear cells, differentiation of myeloid cells), inflammatory response (activation of leukocytes), and immune cell trafficking (activation of leukocytes) in uncomplicated patients compared with control, as would be expected after traumatic injury. On Day 14, uncomplicated patients also illustrated over-representation of pathways involved in hematologic system development (T-cell and blood cell development, differentiation of blood cells and monocytes, and quantity of leukocytes), and hematopoiesis (T-cell differentiation, development of leukocytes and blood cells), immune cell trafficking (activation of lymphocytes). Similar pathways failed to reach significance in complicated patients.

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Isolated Leukocyte Subpopulations

PCA and unsupervised cluster analysis of probe sets in control subjects for isolated leukocyte subpopulations demonstrated that their expression was consistent despite the variant of GGh GeneChip used (see Supplemental Figure 1B, Supplemental Digital Content 1, at http://links.lww.com/TA/A334) and that each cell line (monocytes, PMNs, and T-cells) exhibited cell-specific gene expression. A total of 4,614 probe sets (4,399 genes) were significant in differentiating between individual leukocyte subsets (p < 0.001) (see Supplemental Figure 1C, Supplemental Digital Content 1, at http://links.lww.com/TA/A334).

Evaluation of individual gene fold changes (from controls) showed different expression patterns between complicated and uncomplicated patients in each leukocyte subset. Monocyte and PMN subpopulations from complicated patients on Day 7 had significant alterations in the expression of genes involved in decreased chemotaxis, pathogen-associated molecular pattern (PAMP) recognition, and antigen presentation. In addition, they demonstrated changes associated with increased inflammation and up-regulation of MDSCs as compared with controls and often in increased magnitude of change as compared with uncomplicated patients. Several of these changes persisted out to Day 14 after injury. T-cells from complicated patients had alterations in genes involved in increased T-reg’s, Th1-Th2 skewing, and inflammation, as well as decreased PAMP recognition and chemotaxis on Day 7. Gene expression changes involving increased inflammation persisted out to Day 14 (see Supplemental Table 3, Supplemental Digital Content 4, at http://links.lww.com/TA/A337).

Gene Ontology and Biocarta analysis on Day 7 in complicated patients (PMN and monocyte subsets) showed up-regulation in proinflammatory pathways (examples include IL-1 signaling and chronic inflammatory response pathways), down-regulation of pathways involved in adaptive immunity (examples include IL-4 and antigen processing and presentation pathways) as compared with uncomplicated patients. Similar changes were present on Day 14. T-cells from complicated patients on Day 7 were noted to have increased expression of pathways involved in the modulation of T-cell activity and the inflammatory response (examples include IL-2 and T-cell receptor signaling and chronic inflammatory response pathways) (Fig. 2).

Figure 2
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Functional pathway analysis of the leukocyte subpopulations on Day 7 revealed under-representations of pathways involved in increased cell line viability, differentiation of leukocytes and blood cells, inflammatory response, hematologic system development, cell movement and immune cell trafficking for PMNs, chemotaxis of phagocytes in monocytes, and increased cell viability in T-cells in uncomplicated patients. There was also under-representation (PMNs) of pathways involved in cell death of leukocyte and myeloid cell lines as well as homing and chemotaxis of neutrophil pathways. Uncomplicated patients on Day 14 had under-representation in pathways involved in the proliferation of hematopoietic progenitor cells (PMNs) and apoptosis of the lymphoid system as well as an overrepresentation in the cell viability pathway in T cells, which did not reach similar significance in complicated patient cell lines.

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DISCUSSION

The concept of CCI can be found in the literature since the early 1990s under different terms used to describe patients who survived their initial episode of critical illness but remained dependent on ICU care and not fully recovering.21–23 Recently, it was estimated that there are at least 100,000 of these CCI patients in the United States at any one time, incurring a tremendous burden on the already taxed health care system.24 Although in-hospital mortality has decreased, the overall 1-year mortality remains unchanged, and substantially more patients are being discharged to LTACs. In fact, 41% of complicated patients discharged in the GG went to rehabilitation or LTAC facilities.13

The underlying immunologic and inflammatory response of this new phenotype of CCI is a matter of considerable controversy. Most investigators have focused on prolonged adaptive immune suppression, but immune suppression alone cannot explain the persistent acute phase response, protein catabolism, malnutrition, and reduced functional and cognitive abilities.

Genome-wide leukocyte expression analysis can be used to assess simultaneously the inflammatory status and adaptive immune functions at the level of gene regulation. Past studies have strongly suggested that information contained in the leukocyte transcriptome after trauma could be used to identify families of genes involved in inflammation, antigen presentation, and T-cell responses as being discriminatory. Thus, we sought clinical and genomic evidence of a persistent inflammatory and immunosuppressive response in leukocytes from patients with different clinical trajectories.

We found that trauma patients who experienced complicated outcomes had overall genome-wide expression patterns that were more aberrant from controls, consistent with previous reports.19 On evaluation, the global genome-wide expression in complicated patients on Day 7 was significantly increased from uncomplicated patients, indicating that gene expression was still more perturbed in patients who had complicated clinical outcomes. We identified multiple genes whose expressions were significantly different in magnitude and duration in trauma patients with complicated clinical courses compared with those with an uncomplicated clinical trajectory and to healthy subjects. Importantly, changes in gene expression consistent with PICS can be seen as early as 7 days after injury in patients with complicated courses.

Gene Ontology and Biocarta evaluation between cohorts 7 days after injury demonstrated that complicated patients had significant changes in pathways involved in increased inflammation and suppression of adaptive immunity, especially those pathways involved in T-cell function and hematopoiesis. Analysis of functional pathways on Day 7 supported these findings. Patients with uncomplicated outcomes were found to have significant increases in pathways essential to innate and adaptive immunity compared with control, as one would expect after severe injury. Failure of complicated patients to reach similar significance may indicate defects in these functions, leading to depressed innate immunity, despite increased inflammatory responses.

Of note, we found that the changes in genomic expression in complicated trauma patients were reflected by the patients’ clinical data. Complicated patients were found to exhibit persistent inflammation supported by elevated WBC counts, immunosuppression with lymphopenia, and signs of ongoing protein catabolism (low albumin levels) over their course. In a mixed-model analysis adjusted for AIS, NISS, age, and sex, having a complicated outcome was independently associated with this leukocytosis, immunosuppression, and ongoing protein catabolism over time.

In conclusion, our data support a novel paradigm that in trauma patients with complicated outcomes, there is increased inflammation, concordant defects of adaptive immunity, and signs of host protein catabolism that persist over their hospital course at increased levels. This provides some validation on the genomic and clinical level that trauma patients with complicated outcomes are indeed exhibiting PICS. It is still unclear why certain patients develop PICS, while others seem to recover relatively quickly after injury. Attempts to determine why these differences exist are important for improving outcomes in this expanding CCI population.

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AUTHORSHIP

E.L.V. drafted the manuscript. F.A.M., P.A.E., H.V.B., C.L., and L.L.M. contributed in the study concept and design. A.B. and T.O.-B. performed the statistical analysis. C.M.L., H.V.B., and E.L.V. preformed the acquisition of data. T.O.-B, L.L.M., P.A.E., E.L.V., C.M.L., F.A.M. performed the analysis and interpretation of data. R.U., R.D., A.G.C., L.F.G., D.C.N., A.L.C., L.F.G., J.L., L.L.M., F.A.M., and P.A.E. provided the critical revision of the article.

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DISCLOSURE

The Glue Grant database was supported by the Inflammation and the Host Response to Injury Large Scale Collaborative Research Program (Glue Grant U54 GM062119), awarded to Dr. Ronald G. Tompkins, Massachusetts General Hospital, by the National Institute of General Medical Sciences. A.B. was supported by NIH NIGMS Grant K23 GM087709. A.G.C. and L.F.G. were supported by a training grant in burn and trauma research (T32 GM-08431). This study was supported in part by grants R01 GM-40586-24, R01 GM-081923-06, and T32GM-008721-15 awarded by the National Institute of General Medical Science, U.S.P.H.S.

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DISCUSSION

Dr. David Hoyt (Chicago, Illinois): Dr. Malangoni, Dr. Livingston, members and guests. I’d like to congratulate Erin on an excellent presentation and a very complicated set of studies. This is like a Dostoevsky novel. And I’m going to try and give you the Cliff Notes version here.

This study analyzes the so-called Glue Grant or Inflammation and Host Response to Injury" database against three clinical trajectories to determine if the syndrome PICS (persistent inflammation, immunosuppression and catabolism) has replaced multiple organ failure as a predominant phenotype in chronic surgical illness.

The characterization of the endpoint is of great interest and importance to us as trauma surgeons. This study, in particular, is important because it will drive research in our attempt to understand what causes this state.

Current evidence suggests that trauma patients experience a systemic immunologic dysregulation that is central to organ injury and places them at increased risk for PICS.

The study presented today looks at clinical values and compares these amongst six different cohorts. The analysis is very comprehensive.

Trauma patients who experience so-called complicated outcomes have an overall genome-wide expression pattern which is more aberrant from controls. You saw that summarized at the end.

Complicated patients, so-called, are found to have persistent inflammation supported by increase in white blood cell counts, immunosuppression with lymphopenia and signs of ongoing protein catabolism expressed as low albumin.

In the mixed model analysis, which adjusts for AIS, NISS, age and sex, and other co-variables that you would think might influence this, the complex outcome or complicated outcome independently is associated with leukocytosis, immunosuppression and ongoing protein catabolism. This does seem to be a real entity.

I have several questions for the authors.

You alluded to the original description in the paper. Can you help us better understand the clinical definition of complicated recovery? Is there a specific type of organ injury that particularly correlates with this syndrome of PICS?

Second, the state of PICS that correlates with complicated recovery must be driven by some mechanism. Could you speculate what this might be? Is it driven by ongoing peripheral hypoxia?

Are the inflammatory changes seen late simply a failure to down regulate over time? Or is there some other unexplained mechanism that explains this inflammatory state? Please comment.

And, finally, Dr. Fred Moore yesterday in a discussion on another paper suggested that as we evaluate therapeutic intervention, the ability of a patient to avoid this kind of syndrome could be an alternative to mortality and as an outcome for clinical trial design. Could you comment on that as well.

Again, thank you for the opportunity to review and comment on your excellent study. It’s studies like these that are essential to advancing our understanding of critical illness in trauma patients.

Thank you.

Dr. Eileen Bulger (Seattle, Washington): Thank you. Very interesting paper. Just one quick question, do you know if there is any relationship between age and the development of PICS? It appeared that the complicated group was older in general and I wonder if we’re starting to see this now because we are seeing a lot more elderly trauma patients. Perhaps older trauma patients can’t restore homeostasis of their inflammatory response as well as younger patients. And I think it would be very interesting to look at. So I’m just interested if you have any observations on that issue.

Dr. Michael T. White (Detroit, Michigan): You know, some of this reminds me of a large burn injury that has persistent changes in inflammation even after several months of recovery.

The one question I have is to continue studies have you thought about looking at this long-term, out farther than 14 days? You say that these patients often go months out with these changes. Have you thought about looking at these changes longer term on the patients that develop this?

And my other question is, what do we do with this data? Is this going to be something that we can use to look for these patients particularly in terms of clinically identifying them as high risk for problems down the line?

I guess that leads to a lot of clinical questions also in terms of what we’re going to do. If we identify them is there some way we can intervene on them to avoid this prolonged changes in inflammation and final poor outcome?

Dr. Matthew Delano (Seattle, Washington): That was a very nice presentation. The number of cytokines, paracrines, autocrines, and then gene changes you found is relatively small compared to the total number in the human body. How do you know that those gene changes, which control significantly disparate processes if you compare CD-86, FLIT-3, IL-1, are actually the gene changes that translate into proteins that then translate into effective functions that are accounting for PICS? Are these just observations that occur along with PICS and may be true and unrelated?

Dr. Erin Vanzant (Gainesville, Florida): I will start with Dr. Hoyt’s questions. The first one is the clinical definition of complicated recovery. I think I actually said that in my slide but uncomplicated and complicated were separated by less than 5 days and then greater than 14 days with a time to organ recovery.

But as far as our definition of the complicated patients would be those that remain in the ICU greater than 14 days with signs of persistent inflammation and signs of continued immunosuppression.

As far as is there a specific organ failure type, the best preliminary data is there is a possibility of acute kidney patients is similar phenotype as that.

And then the question about whether or not PICS is driven by a specific mechanism, what we can guess is it is more than likely this low level of inflammation that persists that leads to the development of immunosuppression and then the cells I just talked about earlier just briefly, the suppressor cells increased. But as far as what one specifically drives another, again, we are not really sure yet.

As far as evaluating a therapy in a clinical trial and expecting a treatment of the syndrome, if we can prevent the syndrome, would it improve mortality, yes, that’s what we would expect. Dr. Moore actually just submitted an NIH grant to start studying this.

As far as whether PICS is related to a specific age, could the elderly population that was in our complicated subgroup explain this? We started analyzing the Glue Grant based on age and by clinical course but I don’t have the data yet.

And then Dr. White, regarding long-term changes, the Glue Grant actually studied out to 30 days but we attempted to analyze 21 and 28 [days]. The number of samples collected were so small in the uncomplicated group that it wasn’t really worth presenting. But, once again, hopefully we will have that data whenever this study goes.

And then Dr. Delano, we have not actually studied or analyzed the protein translation. So in theory the gene products could-despite the changes seen here-they might not relate to actual protein products. But I believe the data is collected and can be analyzed. It is just not there yet.

Thank you.

Keywords:

Genomics; microarray; multiple-organ failure (MOF); trauma; PICS

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