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

Shigeaki Inoue,Sadaki Inokuchi,Kyoko Suzuki-Utsunomiya,Yukiko Morishita,Takehito Sato,Kodai Suzuki,Yukako Komori,Katsuto Hozumi

doi:10.1186/cc13941

Abstract

IntroductionSepsis 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.MethodsFifty-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.ResultsThe 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).ConclusionsPersistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

Highlights

Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression
To evaluate the impact of comorbidities on severe sepsis, we performed sensitivity analysis by excluding patients with comorbidities that were more prevalent in elderly patients than in adult patients; we compared the outcomes between the remaining adult and elderly patients with sepsis
Decreased survival and persistent inflammation in severe sepsis in elderly patients and in aged septic mice Fifty-five patients with severe sepsis and thirty healthy donors (HDs) were enrolled in the current study (Figure 1)

Summary

Introduction

Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Inflammation is characterized by excessive production of pro-inflammatory mediators [7], and immunosuppression is characterized by disturbed phagocytosis, antigen presentation by monocytes with decreased expression of HLA-DR and dysfunction, and apoptosis of lymphocytes, leading to shutdown of innate and adaptive immunity [8]. This phenomenon has recently been identified as an important cause of mortality during late-stage sepsis [6,9]. The purpose of this study was to further investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis

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