Towards personalized medicine in sepsis: Quest for Shangri-La?

EXPANDED ABSTRACT: CITATION: Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS: Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011, 306:2594-2605. BACKGROUND: Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyper-inflammatory phase is followed by immunosuppression is a subject of controversy. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. METHODS: OBJECTIVES: To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. DESIGN: Rapid prospective postmortem spleen and lung tissue harvest and analysis within 120 minutes of death. SETTING: Intensive care units (ICUs) of academic medical centers. SUBJECTS: A convenience sample of 40 patients who died with active severe sepsis was taken over the course of 2 years to characterize their immune status at the time of death. 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. INTERVENTIONS: None. OUTCOMES: 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 (standard deviations) of patients with sepsis and controls were 71.7 (15.9) and 52.7 (15.0) years, respectively. Patients with sepsis were in the ICU for a median of 8 days (range of 1 to 195 days), whereas control patients were in the ICU for not more than 4 days. The median duration of sepsis was 4 days (range of 1 to 40 days). Anti-CD3/anti-CD28-stimulated splenocytes from patients with sepsis, compared with those from controls, had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5,361 (95% confidence interval (CI) 3,327 to 7,485) pg/mL versus 418 (95% CI 98 to 738) pg/mL; interferon-gamma, 1,374 (95% CI 550 to 2,197) pg/mL versus 37.5 (95% CI -5 to 80) pg/mL; interleukin-6, 3,691 (95% CI 2,313 to 5,070) versus 365 (95% CI 87 to 642) pg/mL; and interleukin-10, 633 (95% CI -269 to 1,534) versus 58 (95% CI -39 to 156) pg/mL (P < 0.001 for all). There were similar reductions in 5-hour lipopolysaccharidestimulated cytokine secretion. Cytokine secretion in patients with sepsis was generally less than 10% of that in controls, independently of age, duration of sepsis, corticosteroid use, and nutritional status. Despite differences 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 patients with sepsis versus patients with cancer and versus 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 non-sepsis etiologies have bio-chemical, flow cytometric, and immunohistochemical findings consistent with those of immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.