Precision Medicine in Sepsis

Transcription

1 Precision Medicine in Sepsis Jean-Daniel Chiche, MD PhD MICU & Dept Infection, Immunity & Inflammation Hôpital Cochin & Institut Cochin, Paris-F

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3 Sepsis 2017: a litany of failed clinical trials? l The dark side: RCTs l The bright side Improved ICU outcomes (better general care, less iatrogenic harm) Even positive outcome RCTs from doing less (ventilation, sedation, ) l Starting to understand what may be good for populations l Still strugling to make decisions for the individual

4 Sepsis & Precision Medicine Pharmacogenomics Hemodynamics Immune modulation Steroids Antibiotics

5 The «Omics» revolution

6 The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future

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8 What drives septic phenotypes?

9 Casanova JL et al. Nat Rev Immunol 2004 Waterer GW et al. ARCCM 2011

10 The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future

11 Proof of concept

12 Intranasal challenge, 10 6 cfu S. pneumoniae strain D39

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14 Cause of Death (Parent Dead before 50 y.o.) All causes Biologic Adoptive Infection Biologic Adoptive Vascular Biologic Adoptive Relative risk for adoptee to die from the same cause

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17 TNF2 & Mortality of Septic Shock % Mortality TNF1 TNF Total Septic Shock (SS) SS + Comorbidities n Age SAPS ±16 59±15 59±16 56±14 63±16 53±18 54±21 52±17 52±21 54± ±15 56±19 Comorbidities: cirrhosis, heart failure, cancer & immunosuppressive agents

18 l l l l l l l l Good candidate genes Strong case for the genetic variants typed Appropriate sample phenotyping Sample size Good genotyping Appropriate analysis Appropriate interpretation Replication

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20 More breakthroughs coming? 7 millions of human genomes sequenced by 2020

21 l From community-acquired pneumonia, peritonitis and meningococcal sepsis to septic shock, organ failure and death l Objective: 2000 patients l Genome-wide analysis

22 The SNP rs in the FER gene is associated with a survival advantage in pts with pneumonia

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24 The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future

25 Find Your Patients on Sepsis Pathways

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27 l l l Weight loss Anorexia Abdominal mass Fever Tachycardia Hypotension Cancer Sepsis Chemotherapy? Surgery? Radiotherapy? Anti-CD.? Markers Antibiotics? Surgery? Corticosteroids? Adjunctive treatments?

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29 Improving diagnosis with biomarkers

30 RT-PCR based 21-gene assay developed specifically for patients with ER positive breast cancer

31 Indolent Hormone therapy sensitive No chemo benefit Aggressive Less sensitive to hormone Large chemo benefit

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35 Cytomics Chemogenomics Peptidomics Pharmacogenomics Epigenomics Metabolomics hits Omics + Sepsis Omics + Cancer Omics Proteomics Transcriptomics Genomics Bioinformatics

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37 Whole Genome Transcriptomics - Advancing the science of medicine-

38 Evaluation of gene expression for 100 «class-defining genes». Color & intensity indicate increased / decreased gene expression

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40 A predictive set of 7 genes enables classification of pts in 2 distinct sepsis response signatures (SRS1/SRS2) 265 pts with CAP, sepsis & organ dysfunction Peripheral blood leucocyte transcriptomics

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42 New Paradigm for Sepsis Mortality Hotchkiss R et al. Nat Rev Immunol. 2013;13(12):862 74

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44 l 30 y.o woman victim of terrorist bombing in Brussels in 03/2016 Pelvic & femur fractures Extensive soft-tissue abdominal &pelvic damage Pulmonary contusion Second-degree burns l Early complications Sepsis Femur osteomyelitis Deep wound infections with multi-drug-resistant Enterobacteriaceae

45 Immuno adjuvant therapy Interferon-γ (100 μg x3/week, 5 doses Nivolumab 250 mg D7 D15 D22 D27 D36 D43 D50 Invasive mucormycosis Liposomal ampho-b + posaconazole Gastrectomy + splenectomy Therapeutic success ì lymphocyte, CD8 T-cell counts & monocyte HLA-DR expression î T-cell PD-1 expression

46 The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future

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48 Identified 4 blood gene expression endotypes Mars1 associated with 28d- & 1-yr mortality Combining APS IV & endotypes improves pt risk stratification

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51 The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future

52 Molecular Systems Biology (2012) 8: 612

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56 A translational research study with n=1

57 ipop: towards the integrative Personal Omics Profile l Combines biological profiles from a single individual over a 14 month period Genomic Transcriptomic Proteomic Metabolomic Autoantibodies l Monitor omics to study molecular complexity & dynamic changes in physiologic & disease states

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61 v Can a genome sequence be used to estimate disease risk in a healthy individual? v Can the disease be detected by monitoring traits and markers associated with that disease?

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63 l Many unaddressed challenges Interpreting regulatory/non protein coding regions DNA Methylation Microbiome Exposome

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65 I think the biggest innovations of the 21 st century will be at the intersection of biology and technology. A new era is beginning