Document text
Principal Investigator: Charles Langelier
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $662,381
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Sepsis is a leading cause of death in hospitalized patients and involves a dysregulated host inflammatory
response to infection. Despite decades of clinical trials, no new, effective treatments have been identified, and
mortality rates remain unacceptably high. Several factors have contributed to this impasse, starting with the
complex challenge of accurately detecting the microbial pathogens precipitating sepsis. Heterogeneity across
patient populations is a second key barrier to the development of effective treatment strategies, given that sepsis
can be caused by a broad diversity of microbes, and immune responses vary widely between patients. In
addition, while disease trajectories and interventional needs differ dramatically between individuals, no
prognostic tools exist that account for both the host response and pathogen, the two primary drivers of sepsis
pathobiology. Here we seek to address key gaps in our understanding and treatment of sepsis by leveraging
blood and plasma specimens collected from 1563 patients enrolled across 60 medical centers in the CLOVERS
trial, the largest study of septic shock to date. Aim 1 seeks to identify known and novel pathogens responsible
for septic shock using metagenomic sequencing of host and microbe, a novel culture-independent method for
studying sepsis. Aim 2 will combine host gene expression and microbial metagenomic data to discover novel
sepsis subphenotypes and evaluate their associations with clinical outcomes. Aim 3 will use machine learning
to develop a multiomic classifier that predicts sepsis mortality by incorporating host transcriptomic, microbial
metagenomic, and clinical data. Together, these aims will accelerate our understanding of sepsis pathogenesis,
and could redefine our diagnostic, therapeutic, and prognostic strategies, ultimately improving patient outcomes.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acceleration><Accident and Emergency department><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Automobile Driving><Biologic Characteristic><Biological><Biological Characteristics><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood Tests><Blood specimen><C auris><C. auris><COVID-19 virus><COVID19 virus><Candida auris><Caring><Causality><Cause of Death><Cessation of life><Circulatory Collapse><Clinical><Clinical Data><Clinical Trials><Cluster Analyses><Cluster Analysis><CoV-2><CoV2><Complex><Critical Care><Critical Illness><Critically Ill><Culture-independent methods><Da Nang Lung><Data><Data Set><Death><Death Rate><Detection><Development><Diagnostic><Disease><Disorder><Dysfunction><Emergency Department><Emergency room><Enrollment><Etiology><Failure><Functional Metagenomics><Functional disorder><Gene Expression><General Taxonomy><Goals><Hematologic Tests><Hematological Tests><Hematology Testing><Heterogeneity><Hospital Admission><Hospital Mortality><Hospitalization><Hospitals><Hour><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulators><In-house Mortalities><Individual><Infection><Inflammatory><Inflammatory Response><Inhospital Mortality><Intervention><Intervention Strategies><Life><Machine Learning><Measurement><Medical center><Metagenomics><Methods><Microbe><Miscellaneous Antibiotic><Molecular><NHLBI><National Heart, Lung, and Blood Institute><Organism><Outcome><Pathogenesis><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Physiopathology><Plasma><Plasma Serum><Prognosis><Protein Analysis><Randomized><Research Specimen><Resource Allocation><Resuscitation><Reticuloendothelial System, Serum, Plasma><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sepsis><Septic Shock><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shock><Shock Lung><Specimen><Stiff lung><Subgroup><Taxonomy><Techniques><Testing><Therapeutic><Triage><United States><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Whole Blood><Work><Wuhan coronavirus><adjudication><adjudicative process and procedure><bio-markers><biologic><biologic marker><biomarker><blood infection><bloodstream infection><causation><circulatory shock><cohort><coronavirus disease 2019 virus><coronavirus disease-19 virus><crystalloid><culture-independent analyses><culture-independent approaches><culture-independent molecular techniques><culture-independent techniques><customized therapy><customized treatment><developmental><disease causation><driving><effective therapy><effective treatment><emergent virus><emerging pathogen><emerging virus><enroll><hCoV19><host response><immune modulators><immune system response><immunoresponse><improved><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><interventional strategy><living system><machine based learning><metagenome sequencing><metagenomic sequencing><microbe pathogen><microbial><microbial pathogen><molecular phenotype><mortality><mortality rate><mortality ratio><multiomics><multiple omics><nCoV2><new pathogen><novel><novel pathogen><outcome prediction><panomics><participant enrollment><pathogen><pathogenic microbe><pathophysiology><patient enrollment><patient oriented outcomes><patient population><patient specific therapies><patient specific treatment><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><precision medicine><precision-based medicine><prognostic><prognostic tool><protein biomarkers><protein markers><randomisation><randomization><randomly assigned><response to therapy><response to treatment><risk stratification><sepsis patients><septic patients><shocks><social role><stratify risk><surveillance study><tailored medical treatment><tailored therapy><tailored treatment><therapeutic response><therapy response><tool><trait><transcriptomics><treatment response><treatment responsiveness><treatment strategy><unique treatment><unsupervised clustering><vasopressor><viral emergence><wet lung>