Towards Precision Medicine in Sepsis Patients: Are We Close?

Transcription

1 Towards Precision Medicine in Sepsis Patients: Are We Close? CRRT San Diego 2018 Peter Pickkers Department of Medicine Radboud university medical centre, Nijmegen

2

3 No LPS circulating (n=55) P < 0.05 LPS circulating (n=198) Opal SM, Infect Dis 1999

4

5 Relation cytokine levels and development of AKI No AKI Mild AKI No AKI Mild AKI SevereAKI SevereAKI

6 Relation cytokine levels and development of AKI IL-6 IL-10 TNF

7 The original idea Net immunological response in sepsis TNF-α Hotchkiss et al. Nat Med, 2009

8 And the results are.

9

10 Negative

11 Dozens of interventions Thousands of patients Billons of dollars

12

13 Current situation There is no specific sepsis-treatment

14 Current situation There is no specific sepsis-treatment

15 In all these trials: the cytokine/endotoxin to be inhibited was not measured Inhibiting the immune response IN ALL PATIENTS is not beneficial

16 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%

17 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%

18

19 Activated protein C for sepsis PAI-1 hyper-responders Normals apc effective More bleedings

20 Making personalized medicine reality in acute care

21

22

23

24

25

26 Another example: Transfusion policy

27 Transfusion trigger in sepsis Hb 7 g/dl = 4.3 mmol/l Hb 9 g/dl = 5.4 mmol/l

28 Physiological trigger?

29 Tolerance to anemia differs between organs Meier, CCM 2013

30 Use of O 2 ER as a transfusion trigger ER normal ER normal ER high ER high Hb O 2 ER Orlov Transfusion 2009

31 Tool to measure O 2 tension in the cell Oxygen measurements in blood, cellular level Mik, Nature Methods 2006

32

33 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): e

34 MitoPO 2 can predict O 2 reserve in hemodilution Mik, Anesthesiology 2016

35 Another example: ARDS JAMA 2012

36

37 Reactive Uninflamed

38

39 Back to immunomodulation in sepsis patients

40 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

41 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)

42 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: 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

43 No MAS Anakinra No MAS Placebo MAS Anakinra MAS Placebo

44 Other times immunostimulating agents may be needed IL-7 IFN-y GM-CSF Anti-PD-1

45

46

47

48 Immunosuppressive mechanisms in cancer and sepsis are comparable! Immunotherapy that is effective in cancer, could be useful in sepsis patients!!

49

50 How can we measure it? Wu et al. Critical Care :R220

51

52 4 y/o leukemia patient Refractory disseminated candidiasis

53 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

54 Immunotherapy with IFN-γ may be considered as adjuvant salvage therapy

55

56 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

57 Thanks for your attention