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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

Inoue S, Suzuki K, Komori Y, Morishita Y, Suzuki-Utsunomiya K, Hozumi K, Inokuchi S, Sato T - Crit Care (2014)

Bottom Line: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6.Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation.Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

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ABSTRACT

Introduction: Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis.

Methods: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6-8 weeks) and aged (20-22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

Results: The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased detection of gram-negative bacteria at days 14-16 and 28-32 after sepsis (P < 0.05).

Conclusions: Persistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

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Decreased survival and prolonged elevation of serum pro- and anti-inflammatory cytokines in severe sepsis in elderly patients. (A) Left, survival rates of adult and elderly patients with sepsis; right, serum concentrations of IL-6 after diagnosis. (B) Upper left, survival rates of aged and young mice after cecal ligation and puncture (CLP) (P = 0.015, n = 8 per group); serum concentrations of IL-6 (upper right), monocyte chemoattractant protein-1 (MCP-1) (lower left) and IL-10 (lower right) in young and aged mice after CLP (P <0.01).
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Figure 2: Decreased survival and prolonged elevation of serum pro- and anti-inflammatory cytokines in severe sepsis in elderly patients. (A) Left, survival rates of adult and elderly patients with sepsis; right, serum concentrations of IL-6 after diagnosis. (B) Upper left, survival rates of aged and young mice after cecal ligation and puncture (CLP) (P = 0.015, n = 8 per group); serum concentrations of IL-6 (upper right), monocyte chemoattractant protein-1 (MCP-1) (lower left) and IL-10 (lower right) in young and aged mice after CLP (P <0.01).

Mentions: Fifty-five patients with severe sepsis and thirty HDs were enrolled in the current study (Figure 1). The study participants were divided into two groups based on age: adult (18 to 64 years) and elderly (≥65 years). The clinical characteristics of the respective groups are summarized in Table 1. The 3-month survival of elderly septic patients (60%) was significantly lower than that of adult sepsis patients (93%, P <0.05; Figure 2A). Multivariate analysis using Cox proportional hazard regression showed that age was the strongest predictor of 3-month mortality in the patients (HR, 1.07; 95% CI, 1.01, 1.13; P = 0.02) (Table 2). The serum IL-6 concentration was consistently higher in elderly sepsis patients than in adult sepsis patients; the mean difference between the groups was 354 to 13,095 pg/mL (P <0.01; Figure 2A). We analyzed serum albumin levels at day 1 and day 30 after sepsis in the patients to address the impaired catabolism in the elderly patients. We found decreased serum albumin levels in the septic elderly patients compared to adult patients at both 1 and 30 days after sepsis (P <0.05 in elderly survivors, P <0.01 in elderly non survivors) (Additional file 1).


Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

Inoue S, Suzuki K, Komori Y, Morishita Y, Suzuki-Utsunomiya K, Hozumi K, Inokuchi S, Sato T - Crit Care (2014)

Decreased survival and prolonged elevation of serum pro- and anti-inflammatory cytokines in severe sepsis in elderly patients. (A) Left, survival rates of adult and elderly patients with sepsis; right, serum concentrations of IL-6 after diagnosis. (B) Upper left, survival rates of aged and young mice after cecal ligation and puncture (CLP) (P = 0.015, n = 8 per group); serum concentrations of IL-6 (upper right), monocyte chemoattractant protein-1 (MCP-1) (lower left) and IL-10 (lower right) in young and aged mice after CLP (P <0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230031&req=5

Figure 2: Decreased survival and prolonged elevation of serum pro- and anti-inflammatory cytokines in severe sepsis in elderly patients. (A) Left, survival rates of adult and elderly patients with sepsis; right, serum concentrations of IL-6 after diagnosis. (B) Upper left, survival rates of aged and young mice after cecal ligation and puncture (CLP) (P = 0.015, n = 8 per group); serum concentrations of IL-6 (upper right), monocyte chemoattractant protein-1 (MCP-1) (lower left) and IL-10 (lower right) in young and aged mice after CLP (P <0.01).
Mentions: Fifty-five patients with severe sepsis and thirty HDs were enrolled in the current study (Figure 1). The study participants were divided into two groups based on age: adult (18 to 64 years) and elderly (≥65 years). The clinical characteristics of the respective groups are summarized in Table 1. The 3-month survival of elderly septic patients (60%) was significantly lower than that of adult sepsis patients (93%, P <0.05; Figure 2A). Multivariate analysis using Cox proportional hazard regression showed that age was the strongest predictor of 3-month mortality in the patients (HR, 1.07; 95% CI, 1.01, 1.13; P = 0.02) (Table 2). The serum IL-6 concentration was consistently higher in elderly sepsis patients than in adult sepsis patients; the mean difference between the groups was 354 to 13,095 pg/mL (P <0.01; Figure 2A). We analyzed serum albumin levels at day 1 and day 30 after sepsis in the patients to address the impaired catabolism in the elderly patients. We found decreased serum albumin levels in the septic elderly patients compared to adult patients at both 1 and 30 days after sepsis (P <0.05 in elderly survivors, P <0.01 in elderly non survivors) (Additional file 1).

Bottom Line: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6.Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation.Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis.

Methods: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6-8 weeks) and aged (20-22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

Results: The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased detection of gram-negative bacteria at days 14-16 and 28-32 after sepsis (P < 0.05).

Conclusions: Persistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

Show MeSH
Related in: MedlinePlus