Precision Medicine in Sepsis Jean-Daniel Chiche, MD PhD jean-daniel.chiche@aphp.fr MICU & Dept Infection, Immunity & Inflammation Hôpital Cochin & Institut Cochin, Paris-F
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
Sepsis & Precision Medicine Pharmacogenomics Hemodynamics Immune modulation Steroids Antibiotics
The «Omics» revolution
The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future
What drives septic phenotypes?
Casanova JL et al. Nat Rev Immunol 2004 Waterer GW et al. ARCCM 2011
The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future
Proof of concept
Intranasal challenge, 10 6 cfu S. pneumoniae strain D39
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 1.71 0.71 5.8 0.73 4.5 3.1
TNF2 & Mortality of Septic Shock % Mortality 60 50 40 30 20 60 50 40 30 20 60 50 40 30 20 TNF1 TNF2 10 10 10 Total Septic Shock (SS) SS + Comorbidities n Age SAPS2 440 151 212 88 228 61±16 59±15 59±16 56±14 63±16 53±18 54±21 52±17 52±21 54±20 63 64±15 56±19 Comorbidities: cirrhosis, heart failure, cancer & immunosuppressive agents
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
More breakthroughs coming? 7 millions of human genomes sequenced by 2020
l From community-acquired pneumonia, peritonitis and meningococcal sepsis to septic shock, organ failure and death l Objective: 2000 patients l Genome-wide analysis
The SNP rs4957796 in the FER gene is associated with a survival advantage in pts with pneumonia
The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future
Find Your Patients on Sepsis Pathways
l l l Weight loss Anorexia Abdominal mass Fever Tachycardia Hypotension Cancer Sepsis Chemotherapy? Surgery? Radiotherapy? Anti-CD.? Markers Antibiotics? Surgery? Corticosteroids? Adjunctive treatments?
Improving diagnosis with biomarkers
RT-PCR based 21-gene assay developed specifically for patients with ER positive breast cancer
Indolent Hormone therapy sensitive No chemo benefit Aggressive Less sensitive to hormone Large chemo benefit
Cytomics Chemogenomics Peptidomics Pharmacogenomics Epigenomics Metabolomics 2 35 0 25 0 35 33 3521 6 1323 71 1693 hits Omics + Sepsis Omics + Cancer Omics Proteomics Transcriptomics 153 14 394 10894 Genomics Bioinformatics 292 368 20734 23308 0 20000 40000 60000 80000 100000 120000 140000 160000
Whole Genome Transcriptomics - Advancing the science of medicine-
Evaluation of gene expression for 100 «class-defining genes». Color & intensity indicate increased / decreased gene expression
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
New Paradigm for Sepsis Mortality Hotchkiss R et al. Nat Rev Immunol. 2013;13(12):862 74
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
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
The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future
Identified 4 blood gene expression endotypes Mars1 associated with 28d- & 1-yr mortality Combining APS IV & endotypes improves pt risk stratification
The Sepsis / Precision Medicine Agenda 1l Molecular microbiology 2l Personal genomics l 3 Disease characterization l 4 Defining endotypes l 5 The future
Molecular Systems Biology (2012) 8: 612
A translational research study with n=1
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
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?
l Many unaddressed challenges Interpreting regulatory/non protein coding regions DNA Methylation Microbiome Exposome
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I think the biggest innovations of the 21 st century will be at the intersection of biology and technology. A new era is beginning