Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

Abstract

Context-Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. 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)(2010)(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 with immuno...

Defective cytokine production early after multiple traumas: Modulation in severe sepsis

“…In this setting isolated PBMCs within the first 24 h from sepsis onset provide suppressed cytokine responses [13]. Boomer et al [14] isolated the macrophage population from the spleen of fresh cadavers from severe sepsis and found that cytokine stimulation was defective compared to the respective cell population of cadavers from multiple trauma. Our study provides a novel finding compared to the results by Boomer et al; severe sepsis developing in the field of multiple trauma is associated with increased production of TNFa.…”

Macrophage polarization in pathology

“…Using an in vitro model of LPS-induced tolerance, we demonstrated that the SIRS to CARS transition underlies an M1-M2 switch of polarized monocyte/macrophage activation [92]; according a distinct M2 gene expression profile was confirmed in endotoxin tolerant human mononuclear phagocytes [93]. Although this functional reprogramming represents a protective mechanism to counteract overwhelming inflammation, it also associates with increased risk of relapse and susceptibility to secondary infections and mortality [94,95].…”

Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α

“…The early phase is characterized by leukocyte activation, cytokine storm, and a systemic inflammatory response, while the later phase is characterized by immunosuppression, leukocyte deactivation, increased risks of secondary infection, and high mortality (Boomer et al, 2011;Hotchkiss et al, 2009). The scenario might be even more complicated with the overlapping co-existence of inflammatory and immunosuppressive processes, as suggested by some (AdibConquy and Cavaillon, 2009;Xiao et al, 2011).…”