Publications: Acute Infections and Sepsis

Mayhew M, et al. “Optimization of genomic classifiers for clinical deployment: evaluation of Bayesian optimization for identification of predictive models of acute infection and in-hospital mortality.” arXiv. Mar 2020.
Currently, detection of acute infection as well as assessment of a patient’s severity of illness are based on imperfect (and often superficial) measures of patient physiology. Characterization of a patient’s immune response by quantifying expression levels of key genes from blood represents a potentially more timely and precise means of accomplishing both tasks. Machine learning methods provide a platform for development of deployment-ready classification models robust to the smaller, more heterogeneous datasets typical of healthcare.

Mayhew M, et al. “A generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections.” Nature Communications. Mar 2020.
Improved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Severe acute infections and sepsis are globally associated with substantial mortality (nearly half of all inpatient deaths) and dollars spent ($24 billion annually in the US). An alternative to testing for pathogens is to examine the host immune response to infection, and thereby infer the presence and type of infection. Recent advances in machine learning and artificial intelligence offer the promise both of improved generalizability and of solving non-binary problems, such as distinguishing between bacterial, viral, and non-infectious inflammation.

Sweeney TE, Schultz B, Khatri P, et al. “Pilot study of a novel serum mRNA gene panel for diagnosis of acute septic arthritis” World Journal of Orthopedics. Dec 2019.
Septic arthritis is an orthopedic emergency requiring immediate surgical intervention. Current diagnostic standard of care is an invasive joint aspiration. Aspirations provide information about the inflammatory cells in the sample within a few hours, but there is often ambiguity about whether the source is infectious (e.g. bacterial) or non-infectious (e.g. gout). Cultures can take days to result, so decisions about surgery are often made with incomplete data. Novel diagnostics are thus needed. The “Sepsis MetaScore” (SMS) is an 11-mRNA host immune blood signature that can distinguish between infectious and non-infectious acute inflammation. It has been validated in multiple cohorts across heterogeneous clinical settings.

Sweeney TE, Liesenfeld O, May L. “Diagnosis of bacterial sepsis: why are tests for bacteremia not sufficient?” Expert Review of Molecular Diagnostics. Aug 2019.
Rapid diagnosis of sepsis, and its underlying causes, is of great interest. With pathogen detection techniques showing a multitude of limitations for clinical utility in early sepsis workflow, probing the host immune response to infection has gained increased interest. This editorial explores the belief that the initial treatment of patients with sepsis will be best supported by ultra-rapid tools that can inform on the ‘two axes’ of sepsis (diagnosis of infection and estimate of severity) at the time of initial presentation.

Gunsolus I, Sweeney TE, et al. “Diagnosing and managing sepsis by probing the host response to infection: Advances, opportunities, and challenges.” Journal of Clinical Microbiology. Jul 2019.
Sepsis is a major source of mortality and morbidity globally. Accurately diagnosing sepsis remains challenging due to the heterogeneous nature of the disease, and delays in diagnosis and intervention contribute to high mortality rates. Measuring the host response to infection enables more rapid diagnosis of sepsis than is possible through direct detection of the causative pathogen, and recent advances in host response diagnostics and prognostics hold promise for improving outcomes.

Sweeney, TE, et al. “Unsupervised analysis of transcriptomics in bacterial sepsis across multiple datasets reveals three robust clusters.” Critical Care Medicine. Mar 2018.  
A 33 gene expression test has identified three sepsis subtypes (Inflammopathic, Adaptive, and Coagulopathic), developed and validated via advanced informatics methods. The Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. These findings may enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit.

Sweeney TE, et al. “A community approach to mortality prediction in sepsis via gene expression analysis.” Nature Communications. Feb 2018.
The HostDx Sepsis severity gene set, exclusively licensed from Stanford by Inflammatix, when combined with clinical severity scores (the current standard of care), demonstrated a substantial increase in prognostic power for 30-day mortality (i.e., an AUC increase of 10 percent, from 77 percent to 87 percent). This would translate to an ability to rule out approximately 20 percent more sepsis cases, compared to clinical severity scores alone. Such findings suggest this approach could help save substantial resources by avoiding unnecessary care.

Sweeney TE, Khatri P. “Generalizable biomarkers in critical care: toward precision medicine.” Critical Care Medicine. Jun 2017.
Many critical illnesses, like sepsis, are defined syndromically. These syndromes typically have clear, though changing, clinical criteria. Assuming the clinical spectrum of a disease has a common molecular pathophysiology, then a molecular biomarker should exist that is generalizable to the disease. Once a disease is clearly defined, then we can begin dividing it into subtypes, which allows for a “precision medicine” approach to medical care.

Sweeney TE, et al. “Validation of the Sepsis MetaScore for diagnosis of neonatal sepsis.” J Ped Infect Dis Soc. Apr 2017.
Neonates are at increased risk for developing sepsis, but this population often exhibits ambiguous clinical signs that complicate the diagnosis of infection. Until now, no biomarker has yet shown enough diagnostic accuracy to rule out sepsis at the time of clinical suspicion.

Sweeney TE, Khatri P. “Benchmarking sepsis gene expression diagnostics using public data.” Critical Care Medicine. Jan 2017.
In response to a need for better sepsis diagnostics, several new gene expression classifiers have been recently published, including the 11-gene “Sepsis MetaScore” (exclusively licensed by Inflammatix), the “FAIM3-to-PLAC8” ratio, and the Septicyte Lab. We performed a systematic search for publicly available gene expression data in sepsis and tested each gene expression classifier in all included data sets. The Inflammatix classifier was shown to be superior.

Sweeney TE, Wong HR, Khatri P. “Robust classification of bacterial and viral infections via integrated host gene expression diagnostics.” Science Translational Medicine. Jul 2016.
It can be difficult to distinguish patients with noninfectious inflammation from those with bacterial and viral infections, and only those with bacterial sepsis derive any benefit from antibiotics. We have created an integrated score that not only identifies infected patients but also classifies their infection as bacterial or viral, suggesting appropriate treatment.

Sweeney TE, Shidham A, Wong HR, Khatri P. “A Comprehensive time-course-based meta-analysis of sepsis and sterile inflammation reveals a robust discriminatory gene set.” Science Translational Medicine. May 2015.
Although several dozen studies of gene expression in sepsis have been published, distinguishing sepsis from a sterile systemic inflammatory response syndrome (SIRS) is still largely up to clinical suspicion. We hypothesized and demonstrated that a multicohort analysis of the publicly available sepsis gene expression data sets would yield a robust set of genes for distinguishing patients with sepsis from patients with sterile inflammation.

Selected Abstracts: Acute Infections and Sepsis

Rawling D, et al. “An Ultra-Rapid Host Response Assay to Discriminate Between Bacterial and Viral Infections Using Quantitative Isothermal Gene Expression Analysis.” 2019 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 13-16, 2019.

Mayhew M, et al. “Diagnosis of acute bacterial and viral infections using a 29-mRNA neural network.” 2019 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 13-16, 2019.

Rawling D, et al. “Multiplex RT-qPCR for diagnosis and risk stratification of acute infection and sepsis using a 30-mRNA host response signature.” 2019 European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 13-16, 2019.

Rawling, D. et al. “Rapid Host mRNA-Based Discrimination Between Bacterial and Viral Infection.” SAEM Western Regional Meeting, March 21‐22, 2019.

Nie, W. et al. “Multiplexing of an 18-Host-Gene Signature Using Rapid PCR for Better Antibiotics Decision.” SAEM Western Regional Meeting, March 21‐22, 2019.

Rawling, D, et al. “An Ultra-Rapid Host Response Assay to Discriminate Between Bacterial and Viral Infections Using Quantitative Isothermal Gene Expression Analysis.” 2018 IDWeek, October 3-7, 2018.

Nie, W, et al. “Rapid multiplex host gene expression profiling to discriminate bacterial from viral infections.” 2018 IDWeek, October 3-7, 2018.

Stojanovic, I., et al. “Cost Effectiveness of Emergency Department Use of a Novel Multi-mRNA Assay for Diagnosis and Risk Assessment of Acute Respiratory Tract Infections and Sepsis.” International Sepsis Forum 2018, Oct 1-3, 2018.

Sweeney TE, et al, “Dual-cohort independent validation of a novel 12-mRNA score for sepsis prognosis.” International Sepsis Forum 2018, Oct 1-3, 2018.

Schultz, et al. “Survey-based assessment of emergency room physician practices for patients with suspected infection and sepsis.” EUSEM 2018, September 8-12, 2018.

Liesenfeld, O, et al. “A host gene signature for diagnosis and risk stratification of acute infection and sepsis at hospital admission: HostDxTM Sepsis.” EUSEM 2018, September 8-12, 2018.

Cheng H, et al. “Integration of Next-Generation Sequencing, Viral Sequencing, and Host-Response Profiling for the Diagnosis of Acute Infections” ID Week 2017, October 7, 2017.

Sweeney TE, Azad TD, Donoto M, et al, “The derivation and validation of three novel sepsis molecular subtypes to help guide precision therapies.” Sepsis 2017, Sept 11-13, 2017.

Sweeney TE, Khatri P, “Host-response biomarkers for diagnosing acute infections.” MHSRS, August 28-29, 2017.

Sweeney TE, Mansur A, Hinz J, Khatri P, “Prospective validation of the Sepsis MetaScore for diagnosis of infections post traumatic injury.” American Surgical Congress, Feb 7-9, 2017.

Other Applications: Publications, Reviews and Abstracts

Robinson M, Sweeney TE, et al. “A 20-gene set predictive of progression to severe dengue.” Cell Reports. Jan 2019.
Early detection and treatment of patients with severe dengue reduces mortality, but there are currently no usable prognostics to accurately predict which patients will progress to severe dengue. A multicohort analysis framework revealed a generalizable 20-gene set to predict severe dengue. The results present potential implications for the development of a host response-based dengue prognostic assay.

Warsinke HC, et al. “Assessment of validity of a blood-based 3-gene signature score for progression and diagnosis of tuberculosis, disease severity and treatment response.” Journal of the American Medical Association Network Open. Oct 2018.
The purpose of this study is to validate that the previously identified 3-gene TB score can be a diagnostic tool throughout the course of TB disease, from latency to diagnosis to treatment response, and post-treatment residual inflammation. Across 3 independent prospective cohorts, the 3-gene TB score approaches the WHO target product profile benchmarks for a non-sputum based triage test and is now shown to distinguish patients with ATB from those with LTBI, other diseases, and healthy controls.

Azad TD, et al. “Inflammatory macrophage-associated 3-gene signature predicts subclinical allograft injury and graft survival.” Journal of Clinical Investigation. Jan 2018.
The incomplete understanding of graft failure pathophysiology limits the development of new treatments that may enable long term transplant success. The development of effective treatments is hindered because of a lack of early markers of graft injury and failure, which requires that patients must be followed long term to understand whether a new treatment is effective. A 3-gene signature enriched in inflammatory macrophages was identified that is capable of diagnosing AR, recognizing subclinical injury, and risk-stratifying renal transplant patients.

Aditya R, Sweeney TE, Khatri P. “A robust host-based gene expression diagnostic for malaria versus other infectious diseases.” 27th ECCMID, Vienna Austria. April 22-25, 2017.
While early diagnosis of malaria can lead to rapid treatment and cure, the similarity of symptoms to other infectious diseases and the long incubation time causes delayed and incorrect diagnoses. The authors show that a small set of host genes can be used to form a robust classifier for malaria versus other infectious diseases that are within the differential diagnosis for malarial symptoms.

Sweeney TE, et al. “Methods to increase reproducibility in differential gene expression via meta-analysis.” Nucleic Acid Research. Jan 2017.
The authors performed large scale meta-analysis to create a silver standard of true positives, and then compared meta-analysis methods on data set subsets to determine the relative reproducibility of the results. They show that for a given aggregate sample size in gene expressions meta-analysis, higher accuracy with fewer false positives is attained when those samples are divided among more independent data sets.

Lofgren S, et al. “Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity.” Journal of Clinical Investigation. Dec 2016.
Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by inter-clinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. The authors identified and validated a 415-gene signature composed of differentially expressed genes in skin biopsies from systemic sclerosis (SSc) patients compared with healthy control subjects. They further defined a disease severity measure called 4S using the signature. Their results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.

Sweeney TE, et al. “Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis.” Lancet Respiratory Medicine. Feb 2016.
Active pulmonary tuberculosis is difficult to diagnose and treatment response is difficult to effectively monitor. A WHO consensus statement has called for new non-sputum diagnostics. The aim of this study was to use an integrated multicohort analysis of samples from publicly available data sets to derive a diagnostic gene set in the peripheral blood of patients with active tuberculosis. The authors identified and validated a three-gene set that is robustly diagnostic for active tuberculosis versus healthy controls, latent tuberculosis, and other diseases.

Andres-Terre M, et al. “Integrated multicohort analysis identifies conserved transcriptional signatures across multiple respiratory viruses.” Immunity. Dec 2015.
In light of the large unmet need for novel antiviral strategies, an efficient solution would be to repurpose currently approved drugs as broad-spectrum, host-centered antivirals that could impair viral transmission and prevent clinical pathology by identifying host factors that are targeted by existing drugs and required for viral growth. The authors identified host transcriptional responses common to multiple respiratory viruses (MVS) or specific to influenza (IMS) by leveraging heterogeneity present in public data sets. Both signatures distinguish viral from bacterial infections and IMS also distinguishes influenza from other viral infections.

Khatri P, et al. “A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.” Journal of Experimental Medicine. Oct 2013.
There is a need for novel, more targeted therapeutics in transplantation. Given the escalating costs of drug discovery, and the relatively greater impact of these costs on smaller disease markets such as organ transplantation, we believe that it is important to find common injury pathways across multiple solid organ transplants. Targeting the CRM genes is a novel approach to repositioning available FDA-approved drugs and identifying new drug targets for all solid organ transplants. The authors identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

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