title: Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach.
abstract: Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion-a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis.
authors: Department of Anesthesiology, Medicine, and Surgery; Washington University School of Medicine, St Louis, MO, USA. hotch@wustl.edu
authors: Richard S
authors: RS
authors: Hotchkiss
authors: Guillaume
authors: G
authors: Monneret
authors: Didier
authors: D
authors: Payen
mesh_terms: D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000097:blood*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors / Q000627:therapeutic use; D056747:Immunomodulation; D015851:Interleukin-7 / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D018805:Sepsis / Q000276:immunology* / Q000628:therapy*
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines; D007155:Immunologic Factors; D015851:Interleukin-7; D061026:Programmed Cell Death 1 Receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor