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Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

Vanzant EL, Hilton RE, Lopez CM, Zhang J, Ungaro RF, Gentile LF, Szpila BE, Maier RV, Cuschieri J, Bihorac A, Leeuwenburgh C, Moore FA, Baker HV, Moldawer LL, Brakenridge SC, Efron PA, Inflammation and Host Response to Injury Investigato - Crit Care (2015)

Bottom Line: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts.Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities.As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Molecular Genetics and Microbiology, University of Florida, PO Box 100245, Gainesville, FL, 32610-0245, USA. erin.vanzant@surgery.ufl.edu.

ABSTRACT

Introduction: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.

Methods: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.

Results: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.

Conclusions: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

No MeSH data available.


Related in: MedlinePlus

Heat map and calculated difference from distance from reference (DFR) for polymorphonuclear neutrophil (PMN) genome-wide expression. Using a false discovery adjusted probability of <0.001 and a two-fold difference in expression, the temporal pattern of the expression of the trauma responsive genes that differed between the matched aged (≥55 years) and young (<55 years old) trauma cohorts with complicated outcomes, as well as healthy controls, is presented. (A) Cluster analysis of the cohorts 0.5 days after injury showed that there were 3,121 probe sets (2,095 genes) with expression that was significant expressed among groups (F-test, P <0.001). In addition, the overall pattern of gene expression was significantly different in each cohort, as determined by leave one out cross-validation. (B) Summary of the DFR score calculated for each patient in the complicated aged and young cohorts at days 0.5, one and four days after injury. Analysis revealed significant differences in the DFRs at all the post trauma time points between the two cohorts when compared to controls. In addition, the advanced age cohort had significantly more aberrant gene expression as compared to the young patients on day 4 (Newman-Keuls multiple comparison test, *P <0.05).
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Fig1: Heat map and calculated difference from distance from reference (DFR) for polymorphonuclear neutrophil (PMN) genome-wide expression. Using a false discovery adjusted probability of <0.001 and a two-fold difference in expression, the temporal pattern of the expression of the trauma responsive genes that differed between the matched aged (≥55 years) and young (<55 years old) trauma cohorts with complicated outcomes, as well as healthy controls, is presented. (A) Cluster analysis of the cohorts 0.5 days after injury showed that there were 3,121 probe sets (2,095 genes) with expression that was significant expressed among groups (F-test, P <0.001). In addition, the overall pattern of gene expression was significantly different in each cohort, as determined by leave one out cross-validation. (B) Summary of the DFR score calculated for each patient in the complicated aged and young cohorts at days 0.5, one and four days after injury. Analysis revealed significant differences in the DFRs at all the post trauma time points between the two cohorts when compared to controls. In addition, the advanced age cohort had significantly more aberrant gene expression as compared to the young patients on day 4 (Newman-Keuls multiple comparison test, *P <0.05).

Mentions: As our epidemiological analysis illustrated that aged patients had a worse outcome to severe trauma, we wished to determine if there were differences due to age in the transcriptomic response to injury and shock, while trying to exclude the confounders of the magnitude of the injury, gender, the hospital course, and treatment. Thus, we compared the genome-wide expression patterns of matched (for the variables of: complicated outcome; gender; AIS; number of samples isolated at the same time points; and whether the patient died during hospitalization) patients with complicated outcomes. This revealed 3,121 probe sets (2,095 genes) that were differentially expressed between the two age groups at 12 hours after trauma (F-test, P <0.001). Leave one out cross-validation was used to confirm that the differences in PMN gene expression between young and aged patients could not be explained by chance alone (Figure 1A).Figure 1


Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

Vanzant EL, Hilton RE, Lopez CM, Zhang J, Ungaro RF, Gentile LF, Szpila BE, Maier RV, Cuschieri J, Bihorac A, Leeuwenburgh C, Moore FA, Baker HV, Moldawer LL, Brakenridge SC, Efron PA, Inflammation and Host Response to Injury Investigato - Crit Care (2015)

Heat map and calculated difference from distance from reference (DFR) for polymorphonuclear neutrophil (PMN) genome-wide expression. Using a false discovery adjusted probability of <0.001 and a two-fold difference in expression, the temporal pattern of the expression of the trauma responsive genes that differed between the matched aged (≥55 years) and young (<55 years old) trauma cohorts with complicated outcomes, as well as healthy controls, is presented. (A) Cluster analysis of the cohorts 0.5 days after injury showed that there were 3,121 probe sets (2,095 genes) with expression that was significant expressed among groups (F-test, P <0.001). In addition, the overall pattern of gene expression was significantly different in each cohort, as determined by leave one out cross-validation. (B) Summary of the DFR score calculated for each patient in the complicated aged and young cohorts at days 0.5, one and four days after injury. Analysis revealed significant differences in the DFRs at all the post trauma time points between the two cohorts when compared to controls. In addition, the advanced age cohort had significantly more aberrant gene expression as compared to the young patients on day 4 (Newman-Keuls multiple comparison test, *P <0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4404112&req=5

Fig1: Heat map and calculated difference from distance from reference (DFR) for polymorphonuclear neutrophil (PMN) genome-wide expression. Using a false discovery adjusted probability of <0.001 and a two-fold difference in expression, the temporal pattern of the expression of the trauma responsive genes that differed between the matched aged (≥55 years) and young (<55 years old) trauma cohorts with complicated outcomes, as well as healthy controls, is presented. (A) Cluster analysis of the cohorts 0.5 days after injury showed that there were 3,121 probe sets (2,095 genes) with expression that was significant expressed among groups (F-test, P <0.001). In addition, the overall pattern of gene expression was significantly different in each cohort, as determined by leave one out cross-validation. (B) Summary of the DFR score calculated for each patient in the complicated aged and young cohorts at days 0.5, one and four days after injury. Analysis revealed significant differences in the DFRs at all the post trauma time points between the two cohorts when compared to controls. In addition, the advanced age cohort had significantly more aberrant gene expression as compared to the young patients on day 4 (Newman-Keuls multiple comparison test, *P <0.05).
Mentions: As our epidemiological analysis illustrated that aged patients had a worse outcome to severe trauma, we wished to determine if there were differences due to age in the transcriptomic response to injury and shock, while trying to exclude the confounders of the magnitude of the injury, gender, the hospital course, and treatment. Thus, we compared the genome-wide expression patterns of matched (for the variables of: complicated outcome; gender; AIS; number of samples isolated at the same time points; and whether the patient died during hospitalization) patients with complicated outcomes. This revealed 3,121 probe sets (2,095 genes) that were differentially expressed between the two age groups at 12 hours after trauma (F-test, P <0.001). Leave one out cross-validation was used to confirm that the differences in PMN gene expression between young and aged patients could not be explained by chance alone (Figure 1A).Figure 1

Bottom Line: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts.Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities.As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Molecular Genetics and Microbiology, University of Florida, PO Box 100245, Gainesville, FL, 32610-0245, USA. erin.vanzant@surgery.ufl.edu.

ABSTRACT

Introduction: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.

Methods: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.

Results: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.

Conclusions: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

No MeSH data available.


Related in: MedlinePlus