Weil Institute Researchers Developing New Methods of Managing Pediatric Sepsis
A new study integrating biomolecular immune response data, machine learning and rapid pathogen detection could pave the way for improved methods of diagnosing and treating sepsis in developing immune systems.
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ANN ARBOR, MI —University of Michigan Professor of Emergency Medicine and Pediatrics Dr. Prashant Mahajan is leading a prospective observational study aimed at improving care and outcomes in pediatric sepsis. Supported by a $3.3M grant from the Eunice Kennedy National Institute of Child Health and Human Development (NICHD), the study is being conducted by the U-M Max Harry Weil Institute for Critical Care Research and Innovation and Michigan Medicine in collaboration with Nationwide Children’s Hospital of Ohio.
"Currently, we do not understand how a child will respond to infection, and we also cannot predict who is going to survive or respond to treatment."
Prashant Mahajan, MD, MPH, MBA
Professor, Emergency Medicine, Pediatrics
Vice Chair, Emergency Medicine
Division Chief, Pediatric Emergency Medicine, CS Mott Children's Hospital
Sepsis is a major cause of morbidity and mortality in children, accounting for over 75,000 inpatient admissions each year in the United States with an associated mortality rate of 5 to 20%. Despite this critical illness’s overwhelming burden, current understanding of sepsis is limited. Pediatric sepsis cannot be diagnosed accurately and in a timely manner at emergency department (ED) presentation with existing tools, and management of the disease is guided by evidence derived from studies of adults.
According to Dr. Mahajan, a Weil Institute member who also serves as the Vice-Chair for the Department of Emergency Medicine and Division Chief of Pediatric Emergency Medicine at Michigan’s CS Mott Children's Hospital, much of the difficulty lies in the fact that children’s immune systems are still developing. As a result, they respond differently from adults to infectious agents and potential therapies. “Currently,” he says, “we do not understand how a child will respond to infection, and we also cannot predict who is going to survive or respond to treatment.”
A major focus of the team’s study is on defining “sepsis signatures” to improve disease diagnosis and prognosis. The team hypothesizes that patients who have pediatric sepsis at ED presentation possess unique biomolecular indications of disruptions in their immune responses which, when analyzed, could provide clinicians with a comprehensive picture or “signature” of the disease and inform them of complications that could develop.
Defining these signatures requires monitoring and capturing a host of data including changes in the patients’ vital signs and in their physiologic (electronic health record), immunologic (lab tests), and transcriptomic (changes in cell RNA molecules) profiles. The study team is working with the Weil Institute’s Data Science core, led by co-investigator and Research Assistant Professor of Emergency Medicine Dr. Sardar Ansari, to gather these datasets and use them to train machine learning models capable of producing sepsis signatures for future clinical use. The Weil Institute Analytic Platform they are leveraging gathers continuous, high-resolution data from every Emergency Department and ICU patient at the University of Michigan Hospital, with datatypes including physiologic waveforms (e.g., EKG, arterial catheter waveforms), radiographic studies, medication administration, and laboratory results.
The team will also utilize an optical microtechnology developed by Dr. Ryan Bailey, Robert A. Gregg Professor of Chemistry at U-M and a member of the Weil Institute, to detect levels of multiple inflammatory biomarkers that could indicate patient prognosis when integrated with other biosignatures. The rapidity of Dr. Bailey’s detection technology may allow the team to monitor dynamic signature changes that reflect a patient’s response to clinical interventions and provide actionable information to help guide treatment.
“Having a detailed picture of a patient’s unique sepsis signature at ED presentation could help caregivers diagnose sepsis quicker than is possible with existing scores,” said Dr. Octavio Ramilo, Chief of Infectious Diseases at Nationwide Children’s Hospital and the principal investigator leading the transcriptomic profile focus of the study. “We also believe that changes occurring in a patient’s sepsis signature over time will allow us to reliably predict which child is more at risk for developing complications and death very early in the disease course.”
In tandem with defining pediatric patients’ unique immune responses to sepsis, the team will also apply novel rapid pathogen detection technologies to better identify the root cause of the infection. Standard methods in the ED require one-size-fits-all approaches to treating sepsis that may not be appropriate—and can even cause harm—depending on whether a case is bacterial or nonbacterial (e.g., viral) in origin. However, current culture-based pathogen detection methods have a twenty-four-hour turnaround that makes them unavailable for use in the ED.
To overcome this limitation, the study team will use a rapid, ultrasensitive assay developed by Dr. Scott VanEpps, U-M Assistant Professor of Emergency Medicine and Biomedical Engineering, and an Associate Director of the Weil Institute. Called Nanorod-PCR, the assay utilizes nanotechnology to dramatically improve its sensitivity and specificity in detecting bacteria in whole blood without culture. The team anticipates the device will have even greater benefit for pediatric patients, where large sample volumes cannot be obtained, compared to standard culture-based methods where sensitivity increases with sample volume.
Despite advances in understanding patients’ immune responses in sepsis, in pathogen detection, and in applying bioinformatics to detect sepsis, substantial knowledge gaps persist. This is partly because each of these approaches has been evaluated in isolation and have all been largely unexplored in pediatric sepsis. The project team hopes that by demonstrating the methods’ combined value in this unique patient population, future iterations will be able to move forward to clinical implementation.
“We believe our comprehensive, integrative analysis approach to defining the host immune response to sepsis and pairing it with pathogen detection will address current gaps in pediatric sepsis and will be poised for translation into practice,” said Dr. Mahajan. “Our project is the first step towards precision medicine to improve diagnosis, guide appropriate therapies and reliably prognosticate patient outcomes.”
Project Team
Prashant Mahajan, MD, MPH, MBA (PI, Emergency Medicine and Pediatrics, Weil Institute Member, Michigan Medicine); Octavio Ramilo, MD, MPH (PI, Infectious Diseases and Pediatrics, Nationwide Children’s Hospital, Ohio State University College of Medicine); Sardar Ansari, PhD (Co-I, Emergency Medicine, Weil Institute Data Science Team Lead, Michigan Medicine); Ryan Bailey, PhD (Co-I, Chemistry, University of Michigan and Weil Institute Member); Scott VanEpps, MD, PhD, FACEP (Co-I, Emergency Medicine, Biointerfaces Institute, Weil Institute Associate Director, Michigan Medicine); Zhaohui Xu, PhD (Co-I, Pediatrics, Nationwide Children’s Hospital, Ohio State University College of Medicine); Asuncion Mejias, MD, PhD (Co-I, Pediatrics and Pediatric Infectious Diseases, Nationwide Children’s Hospital, Ohio State University College of Medicine)
Disclosures
The Nanorod-PCR technology used in this study was developed by Dr. Scott VanEpps, who is a co-investigator on this study as well as an Associate Director at the Weil Institute. The Nanorod-PCR technology was previously supported through the Weil Institute’s Sepsis Grand Challenge program.
The photonic sensor technology used in this study is developed by co-investigator Dr. Ryan Bailey and is being commercialized by Genalyte, Inc., a company that Bailey helped found, and in which he holds an equity interest.
About the Weil Institute, formerly MCIRCC
The team at the Max Harry Weil Institute for Critical Care Research and Innovation (formerly the Michigan Center for Integrative Research in Critical Care) is dedicated to pushing the leading edge of research to develop new technologies and novel therapies for the most critically ill and injured patients. Through a unique formula of innovation, integration and entrepreneurship that was first imagined by Weil, their multi-disciplinary teams of health providers, basic scientists, engineers, data scientists, commercialization coaches, donors and industry partners are taking a boundless approach to re-imagining every aspect of critical care medicine. For more information, visit weilinstitute.med.umich.edu.