Review
Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach

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Summary

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.

Introduction

The failure of several high-profile clinical trials in sepsis has led researchers to state that sepsis studies need new direction.1, 2, 3, 4, 5, 6 Experts have discussed important reasons for the failures of new investigative drugs and highlighted problems in design and conduct of sepsis trials.1, 2, 3, 4, 5, 6 However, there might also be inadequate understanding of key pathophysiological mechanisms that operate in sepsis. Post-mortem studies of patients who died of sepsis have provided important insights into why septic patients die, and highlighted key immunological defects that impair host immunity.7, 8 Several small phase 2 clinical trials of immune-enhancing drugs have shown benefit, thereby substantiating the concept that immunosuppression has a central role.9, 10 Findings from studies of clinically relevant animal models of sepsis that mimic the protracted nature of the disease also support the premise that boosting immunity improves survival.11 Sepsis and cancer share many immunological defects, and therefore the recent successes of several immunomodulatory drugs in cancer provide hope for and insight into potential immunostimulatory therapies in sepsis.12, 13, 14

Section snippets

Sepsis as a cytokine storm

Patients with sepsis often present with high spiking fevers, shock, and respiratory failure. Partly because of this striking presentation, the prevailing theory of sepsis for many years was that it represented an uncontrolled inflammatory response.15 The discovery that various potent cytokines, including tumour necrosis factor (TNF) and interleukin 1, are at increased concentrations in patients with sepsis, and when injected into animals reproduced many clinical and laboratory features of

Why do patients with sepsis die?

Whereas some patients rapidly succumb to massive proinflammatory cytokine-driven inflammation as occurs, for example, in toxic shock syndrome and meningococcaemia, improved treatment algorithms have resulted in most patients surviving the early hyperinflammatory phase of sepsis and entering a more protracted phase.22, 23 More than 70% of deaths in sepsis occur after the first 3 days of the disorder, with many deaths occurring weeks later. In a post-mortem study, Torgersen and colleagues7

Sepsis as an immunosuppressive disorder

Although both proinflammatory and anti-inflammatory processes begin promptly after sepsis initiation, in general there is predominance of an initial hyperinflammatory phase, the scale of which is determined by many factors including pathogen virulence, bacterial load, host genetic factors, age, and host comorbidities. For example, a previously healthy young adult who develops meningococcaemia will likely have a profound hyperinflammatory cytokine-storm-mediated response, that causes shock, high

Post-mortem and gene-expression clinical studies

Results from an important post-mortem study showed that sepsis-induced immunosuppression occurred in major organs, not just within circulating leucocytes.8 Rapid post-mortem spleen and lung harvest was done 30–180 min after death in 40 patients with sepsis. Cytokine secretion studies and immunophenotyping of cell-surface receptor or ligand expression profiles were done to discover potential mechanisms of immunosuppression. A striking finding was that lipopolysaccharide-stimulated splenocytes

New approaches: immunomodulatory therapy

Sepsis can be thought of as a race to the death between the invading microbes and the host immune response, and the pathogens seek an advantage by incapacitating various aspects of host immunity. Most previous sepsis drug trials used compounds that blocked the host response to pathogens or limited inflammation. There is likely a role for drugs that block inflammatory cytokines in sepsis; however, such agents should be shortacting, applied early in sepsis, and used only in patients who have

Conclusion

In the future, immunomodulatory therapies in sepsis will be personalised on the basis of particular laboratory and clinical findings, or both—eg, the use of GM-CSF dependent on monocyte HLA-DR expression (table).1, 9, 10 Similarly, flow cytometry quantitation of circulating immune cell expression of PD-1/PD-L1 or rapid whole-blood stimulation assays of cytokine secretion could be used to guide immunotherapy. Finally, patients with infections caused by opportunistic pathogens (eg, Enterococcus

Search strategy and selection criteria

References for this Review were identified through searches of PubMed for articles published from Jul, 1976, to Oct, 2012 by use of the terms “sepsis”, “immunosuppression”, “immunoparalysis”, and “immunotherapy”. Only papers published in English were used.

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