Impaired Immune Response in Elderly Burn Patients: New Insights Into the Immune-senescence Phenotype

Abstract

Objective: Comparing the inflammatory and immunological trajectories in burned adults versus burned elderly patients to gain novel insights and better understanding why elderly have poor outcomes.

Summary background data: Despite receiving the same treatment and clinical consideration as all other burn patients, elderly patients continue to have substantially poorer outcomes compared with adults. In light of an aging population, gaining a better understanding of their susceptibility to complications and creating new treatment strategies is imperative.

Methods: We included 130 burn patients (94 adults: <65 years old and 36 elderly: ≥65 years old) and 10 healthy controls in this study. Immune activity and expression was assessed using bioplex at various time points. Clinical outcomes such as infection, sepsis, and mortality were prospectively collected.

Results: Elderly burn patients had significantly lower burn size but significantly higher Baux scores. Morbidity and mortality was significantly increased in the elderly cohort. Immune biomarkers indicated that elderly are immune compromised and unable to respond with the expected inflammatory response during the early phase after injury. This trajectory changes to a hyperinflammatory pattern during the later phase after burn. These findings are even more pronounced when comparing sepsis versus nonsepsis patients as well as survivors versus nonsurvivors in the elderly.

Conclusions: Elderly burned patients mount a delayed immune and dampened inflammatory response early after burn injury that changes to an augmented response at later time points. Late-onset sepsis and nonsurvivors had an immune exhaustion phenotype, which may represent one of the main mediators responsible for the striking mortality in elderly.

Figure 1

Elderly patients showed decrease survival relative to adult thermally injured with divergence occurring beyond 30 days (n = 410). ***Significant difference was found between adults and elderly burns (Kaplan-Meier = 14.94, p<0.0001).

Figure 2

Plasma cytokine profiling of healthy controls (n = 10), adult (n = 94) and elderly (n = 36) groups over the course of hospital stay (0–6, 7–14, 15–30, 30+ days post burn) showed dramatic alterations relative to healthy controls. The emergence of a delayed immune response in the older group becomes apparent beyond the second week after injury. Comparing both burn groups, pro-inflammatory cytokines were increased in elderly beyond 14-days after injury for IL-6 (A), TNF-α (B), IL-1α (C), IL-13 (D) and IL-3 (E). FMS-like tyrosine kinase 3 ligand (FLT-3L) (F), Granulocyte-colony stimulating factor (G-CSF) (G), Granulocyte-macrophage colony-stimulating factor (GM-CSF) (H), interferon gamma-induced protein 10 (IP-10) (I) and monocyte chemotactic protein 1 (MCP-1) (J) showed similar delayed upregulation. Other significant alterations were observed in MIP-1α (K), MCP-3 (L), IL-15 (M), IL-12p40 (N). Dashed red lines represent healthy control mean values and data is represented as mean ± SEM, *p<0.05, **p<0.01 and ***p<0.001 relative to adult burn group.

Figure 3

Immunological profile of adult and elderly septicemia patients. Comparing adult non-sepsis and sepsis burn patient’s showed significant increases in inflammatory (IL-6, TNF-α, IL-10), chemokine (MCP-1, IP-10, GM-CSF) and other immune mediators (FLT-3L, IL-2) early after injury (0–6 & 7–14 days). Elderly non-sepsis and sepsis patients showed very similar cytokine expression over time with early significance found for IL-6, IL-10, FLT-3L and later (>14 days) for TNF-α, and IP-10. (A). Kaplan-Meier survival curves for early and late onset sepsis and for both adult and elderly groups. Early-onset sepsis for both age group resulted in approximately 80% survival, however a striking difference was observed when comparing late-onset sepsis with elderly supporting a 30% survival (B). Extending the comparison of sepsis onset to cytokine analysis, early (0–14 days) versus late (>14 days) sepsis onset was compared for various immune mediators. All cytokine presented were found to be significant and the lower concentration of late-onset sepsis elderly suggest a dampened response contributing to mortality (C). Dashed red lines represent healthy control mean values and sepsis data is represented as mean ± SEM, *p<0.05, **p<0.01 and ***p<0.001 relative to non-sepsis for each respective burn age group.

Figure 4

Cytokine distribution of survivors and non-survivors over time showed an early (<14 days) elevated expression in adult non-survivors for IL-6, TNF-α, IL-1α, IFN-γ, IL-1RA & IFN-α2. They further supported immune exhaustion in this group with IL-1α, IFN-γ, IFN-α2 & IL-4 showing lower expression than survivors and healthy controls beyond 14-days after injury. Elderly survivors and non-survivors showed near-indistinguishable difference for all cytokines over the coarse of time and further proposed a non-responsive immune profile compared to adults for inflammation (TNF-α, IL-1RA, IFN-γ, IL-4). Dashed red lines represent healthy control mean values and non-survivor data is represented as mean ± SEM, *p<0.05, **p<0.01 and ***p<0.001 relative to survivors for each respective burn age group.