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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

Should we be using biomarkers to tailor sepsis treatment to the individual?

Take-home messages
  • Sepsis is characterised, paradoxically, by both inflammation and immunosuppression
  • A 'one size fits all' treatment approach may be too simplistic, as different mechanisms appear to drive individual pathology
  • Using biomarkers to tailor treatment could therefore improve outcomes
“We should enter the area of personalised medicine”

Tom van der Poll, Professor of Medicine and Chair of the Department of Medicine, Amsterdam UMC, University of Amsterdam

Should we redefine sepsis based on the individual, as defined by biomarkers? Tom van der Poll, Professor of Medicine and Chair of the Department of Medicine, Amsterdam UMC, University of Amsterdam, thinks so. He explored the prospect of tailored sepsis treatment at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 13-16 April 2019, in the symposium ‘Focus on sepsis and septic shock: new data’.

Professor van der Poll started by explaining the multifaceted host response to sepsis. “In sepsis, the immune response becomes unbalanced, and is characterised by both hyperinflammation and concurrent immune suppression. The hyperinflammation is considered to cause early mortality, with organ damage, whereas the immunosuppression may render the host more vulnerable to secondary infections, as we all see in the intensive care unit.”

Hyperinflammatory responses may include the activation of leukocytes, complement and coagulation, as well as necrotic cell death. “This has received the most attention in literature over the past decades,” he added, explaining that immunosuppressive agents, such as TNF-alpha, TLR4, or IL-RA inhibitors have therefore been investigated in this setting. Most of these trials have been negative.

On the other hand, the immunosuppressive responses may include T cell, B cell and dendritic cell death, and inhibition of proinflammatory gene transcription. “More recently, the immunosuppressive state of patients has received more attention, and there are now advocates out there in the sepsis field that tell us to stimulate the immune system rather than to inhibit inflammation,” he said, stating that several studies have trialled this, but the sample sizes have been too small to be conclusive.

“This is what we believe is occurring in patients with sepsis: there’s both persistent inflammation and immune suppression - they are not mutually exclusive - you can actually find them in the same patient.” This may mean that the ‘one size fits all’ treatment approach does not necessarily apply to sepsis, as different biological mechanisms may drive individual pathology. “We should enter the area of personalised medicine,” Professor van der Poll stated, pointing out how this is common practice for many diseases, such as cancer and diabetes, but not for sepsis.

Several small-scale prospective and retrospective studies on leukocyte transcriptomics have supported this theory. The studies showed that patients with sepsis have distinct response signatures, and that these can predict patient outcomes, such as 28-day mortality, or can be linked to their response to treatment, such as corticosteroids.

This theory could also mean that previous trials of immunosuppressive agents may not have strictly ‘failed’, but that the blanket approach did not work for all patients. One case that illustrates this point well is a phase III trial for IL-RA inhibitor anakinra in sepsis, conducted in the late 90s. Though the initial results appeared to be negative, a recent re-analysis (2016) showed that anakinra improved survival versus placebo when focusing on patients with macrophage activation syndrome. In this subgroup, 28-day survival was 65.4% with anakinra vs 35.3% with placebo, with a hazard ratio for death of 0.28 (0.11-0.71; P=0.0071).

This suggests that sepsis trials may need to be approached differently; selection is generally based on severity of disease, such as high APACHE score or septic shock, as opposed to a patient’s immunological profile. “In the future, we should identify not only the [therapeutic] target, but we should develop biomarkers to provide insight in real life, in patients.”

As the fields of proteomics, lipidomics, and transcriptomics develop, he says, “this might be used for stratification of patients into more homogeneous groups, and, finally, it might help to identify patients that are more likely to benefit from a certain immunotherapy.”

This evidence could settle the debate over whether the immune system should be dampened or enhanced in the treatment of sepsis and septic shock. Clearly, the link between the two is blurrier than we previously thought, and the use of biomarkers may sharpen our focus.

Based on van der Poll T. Sepsis: redefining the syndrome based on biomarkers (symposium S0893). Presented on Monday 15 April 2019.

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