Treating sepsis – have we got it the wrong way round?

In our understanding of the pathophysiology of sepsis, we often attribute organ damage and death to the excessive host response to infection, including the popular phrase ‘cytokine storm’. This has been nicely described as ‘friendly fire’ by Prof Derek Angus, who points out that this central tenet of sepsis understanding may in some cases be flawed1; it has led to research on drugs that suppress parts of these inflammatory pathways, although none have yet proven effective. An elegant study on patients dying from sepsis showed clear evidence of immunosuppression compared with controls2.

Editorialist Peter Ward3 proposes an area for future research: whether such derangements can be reversed by treatment with agents such as interleukins 7 or 15, which might combat the T-cell depletion state in sepsis.
The authors point out that all the patients included in the study died on ICU, some after a considerable duration of illness, and they emphasise that early deaths from sepsis in previously healthy patients with infections of highly virulent organisms are associated with an extremely exuberant immunoinflammatory response.
1.The Search for Effective Therapy for Sepsis: Back to the Drawing Board?
JAMA December 21, 2011, Vol 306, No. 23, pp 2614-5
2.Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure
JAMA December 21, 2011, Vol 306, No. 23, pp 2594-2605
[EXPAND 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 (2009-2011). 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 immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

3.Immunosuppression in Sepsis
JAMA December 21, 2011, Vol 306, No. 23, pp 2618-9

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