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

Ayan Sen, Sachin Yende

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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: 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.

Original languageEnglish (US)
Article number303
JournalCritical Care
Volume17
Issue number1
DOIs
StatePublished - Feb 11 2013
Externally publishedYes

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Precision Medicine
Sepsis
Confidence Intervals
Cytokines
Lung
Immunosuppression
Ligands
Interleukin-3
HLA-DR Antigens
Nutritional Status
Interleukin-10
Interferon-gamma
Interleukin-6
Adrenal Cortex Hormones
Spleen
Tumor Necrosis Factor-alpha
Epithelial Cells
Tissue Donors
Staining and Labeling

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Towards personalized medicine in sepsis : Quest for Shangri-La? / Sen, Ayan; Yende, Sachin.

In: Critical Care, Vol. 17, No. 1, 303, 11.02.2013.

Research output: Contribution to journalArticle

Sen, Ayan ; Yende, Sachin. / Towards personalized medicine in sepsis : Quest for Shangri-La?. In: Critical Care. 2013 ; Vol. 17, No. 1.
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abstract = "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: 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.",
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N2 - 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: 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.

AB - 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: 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.

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