Towards Precision Medicine in Sepsis Patients: Are We Close? CRRT San Diego 2018 Peter Pickkers Department of Medicine Radboud university medical centre, Nijmegen
No LPS circulating (n=55) P < 0.05 LPS circulating (n=198) Opal SM, Infect Dis 1999
Relation cytokine levels and development of AKI No AKI Mild AKI No AKI Mild AKI SevereAKI SevereAKI
Relation cytokine levels and development of AKI IL-6 IL-10 TNF
The original idea Net immunological response in sepsis TNF-α Hotchkiss et al. Nat Med, 2009
And the results are.
Negative
Dozens of interventions Thousands of patients Billons of dollars
Current situation There is no specific sepsis-treatment
Current situation There is no specific sepsis-treatment
In all these trials: the cytokine/endotoxin to be inhibited was not measured Inhibiting the immune response IN ALL PATIENTS is not beneficial
In all these trial: the cytokine/endotoxin to be inhibited was not measured Inhibiting the immune response IN ALL PATIENTS is not beneficial New compound 30% Placebo 30%
In all these trial: the cytokine/endotoxin to be inhibited was not measured Inhibiting the immune response IN ALL PATIENTS is not beneficial New compound 40% 20% 30% Placebo 30% 30% 30%
Activated protein C for sepsis PAI-1 hyper-responders Normals apc effective More bleedings
Making personalized medicine reality in acute care
Another example: Transfusion policy
Transfusion trigger in sepsis Hb 7 g/dl = 4.3 mmol/l Hb 9 g/dl = 5.4 mmol/l
Physiological trigger?
Tolerance to anemia differs between organs Meier, CCM 2013
Use of O 2 ER as a transfusion trigger ER normal ER normal ER high ER high Hb O 2 ER Orlov Transfusion 2009
Tool to measure O 2 tension in the cell Oxygen measurements in blood, cellular level Mik, Nature Methods 2006
Mitochondrial oxygen tension in healthy individuals Harms F, Stolker RJ, Mik E (2016). Cutaneous Respirometry as Novel Technique to Monitor Mitochondrial Function: A Feasibility Study in Healthy Volunteers. PLoS ONE 11(7): e0159544.
MitoPO 2 can predict O 2 reserve in hemodilution Mik, Anesthesiology 2016
Another example: ARDS JAMA 2012
Reactive Uninflamed
Back to immunomodulation in sepsis patients
Sepsis induces profound suppression of immune cell function (<5-10% compared to non-septic patients!) Both innate (monocytes) and adaptive (T-cell) immune cell function is depressed
Death Proinflammatory response A Homeostasis Antiinflammatory response Time (days) Proinflammation Bacterial load Antiinflammation Proinflammatory response Homeostasis B Survival Antiinflammatory response Time (days) Proinflammatory response C Death Death Homeostasis Antiinflammatory response Leentjens et al. Am J Resp Crit Care Med, 2013 Time (days)
Sometimes inhibition may be needed IL-1 receptor blockade does not imporove outcome in sepsis patients Opal SM,et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997;25:1115 1124 Re-analysis of data, focus on sepsis patients with features of macrophage activation syndrome (5.6% of total study group) Patients with MAS defined as sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation
No MAS Anakinra No MAS Placebo MAS Anakinra MAS Placebo
Other times immunostimulating agents may be needed IL-7 IFN-y GM-CSF Anti-PD-1
Immunosuppressive mechanisms in cancer and sepsis are comparable! Immunotherapy that is effective in cancer, could be useful in sepsis patients!!
How can we measure it? Wu et al. Critical Care 2011 15:R220
4 y/o leukemia patient Refractory disseminated candidiasis
Fungal sepsis (invasive mucormycosis). Interferon-γ restores monocyte function and has been used as rescue therapy for life-threatening fungal infections in patients not responding to conventional treatment. Nivolumab binds to PD-1, blocks interaction with its ligands, PD-L1 and PD-L2, and releases PD-1 pathwaymediated inhibition of T-cell proliferation and cytokine production
Immunotherapy with IFN-γ may be considered as adjuvant salvage therapy
Conclusions We finally realize that sepsis patients are a heterogeneous bunch! A more personalized approach is valid Stop conducting trials in which the pathway to be inhibited/stimulated is not determined and all patients are treated the same Immune suppression might be beneficial in a subgroup Immune stimulation might be beneficial in a subgroup Are we close? No Optimal biomarker needs to be established Effects of interventions on clinical outcome parameters need to be determined
Thanks for your attention