Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

Abstract

Context Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009–2011). Control spleens (n=29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n=20) were obtained from transplant donors or from lung cancer resections. Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1–195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1–40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327–7485) pg/mL vs 418 (95% CI, 98–738) pg/mL; interferon γ, 1374 (95% CI, 550–2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313–5070) vs 365 (95% CI, 87–642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P<.001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent ...

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…If sepsis persists, the failure of crucial elements of both the innate and the adaptive immune system occurs, such that patients enter a marked immunosuppressive state 10. We have shown that patients who die of sepsis have marked immunosuppression11 (Figure 1). Deaths are the result of an inability of patients to clear their primary infections, as well as the development of secondary infections.…”

“…The prolonged duration of sepsis is characterized by high antigen load and high levels of proinflammatory and anti‐inflammatory cytokines, which induces T‐cell exhaustion. Boomer et al11 reported that spleens that were obtained rapidly after the death of patients with sepsis showed evidence that is highly consistent with the occurrence of T‐cell exhaustion; profound suppression of the production of IFN‐γ by stimulated T cells; increased expression of programmed cell death‐1 (PD‐1) on CD4 + T cells and programmed cell death 1 ligand 1 (PD‐L1) on macrophages. An association between T‐cell exhaustion and mortality in sepsis was provided by studies showing that the increased expression of PD‐1 in circulating T cells from patients with sepsis correlated with decreased T‐cell proliferative capacity and mortality 40…”

“…PD‐1, which is a negative costimulatory molecule expressed on immune effector cells, is upregulated along with its cognate ligand PD‐L1 during chronic HIV infection. PD‐1 impairs immunity by inducing apoptosis, increasing the production of IL‐10, preventing T‐cell proliferation, and causing T cells to become nonresponsive 11. Thus, PD‐1 affects immunosuppression through its effect on IL‐10 expression.…”

“…Boomer et al showed that PD‐1 expression was increased in CD4 and CD8 T cells, whereas PD‐L1 expression was increased in antigen‐presenting cells as well as in the spleen and lungs of septic patients. This indicates that the PD‐1/PD‐L1 axis is present and may be dysregulated in human sepsis 11, 48. In oncology, anti‐PD‐1 and anti‐PD‐L antibody therapy have been used successfully to treat various tumors 49.…”

Mucosal associated invariant T (MAIT) cell: a novel cellular mechanism participating in post-aggressive immunodepression

“…Among these mechanisms, the concept of immunodepression has emerged and would seem to have a central role, as recently reviewed [2]. This has been substantiated by clinical results [3][4][5][6]. Early immunodepression involves both innate and adaptive immunity [7] with a reduction in monocyte human leukocyte antigens (HLA)-DR expression [4,6], ''exhaustion'' of T cells with induced apoptosis and reduced functional activity of almost all T-lymphocyte subsets [2], with the exception of CD25(?)Fox(-)P3(?)…”