Precision Diagnosis of Acute Infectious Diseases
Principal InvestigatorsCharles Chiu, MD, PhD
Associate Professor of Laboratory Medicine and Medicine/Infectious Diseases, UC San Francisco
Diagnosing a disease quickly and accurately is essential for patients with acute infections. As many infectious diseases present similar signs and symptoms, laboratory tests have been developed to detect particular microbes that cause a patient’s illness. Physicians commonly test the blood, urine, and other fluids and subject the patient’s sample to microbiology laboratory tests for specific disease agents based on the patient’s symptoms and history, such as recent travels. With tens of thousands of possible disease agents known, a physician must prioritize which disease agents are more likely to be responsible and select the appropriate diagnostic tests.
Infectious agents like bacteria, viruses, fungi, and parasites come in many forms and are therefore only detected by different diagnostic tests. Despite advances in diagnostics, many patients with suspected infections are prescribed antimicrobial therapies, such as antibiotics, rather than thoroughly tested, diagnosed, and treated for the underlying, specific disease agent. As a result, the current stock of available antimicrobial therapies are overused, increasing the risk of antimicrobial resistance.
For critically ill patients, when initial diagnostic tests do not reveal the cause of illness, additional testing is often costly and time-consuming, and may only provide vague or contradictory results. Health care decisions for hospitalized patients must therefore often be made on the basis of limited and imperfect information, with an increased likelihood of death as many therapeutics may be tried without success.
In California, it has been estimated that 240,000 infections are annually contracted from hospital stays alone, costing the health care system approximately $3.1 billion. Many more infections are acquired in community settings.
Metagenomic next generation sequencing
To help address this problem, the research team pioneered an approach that has the potential to identify thousands of disease agents in a single minimally invasive test. The state-of-the-art genome analysis approach is called metagenomic next generation sequencing (mNGS), where 'meta' represents all organisms, 'genome' encapsulates the entire genetic (DNA) material of an organism, and 'sequencing' refers to genome analysis. The technique can detect almost all known infectious agents in a single sample from a patient, quickly revealing the cause of bacterial, viral, fungal, and parasitic infections, many of which routinely elude physicians. Such information is also highly useful for ruling out an infection, as in the case of an autoimmune disease that may present similar symptoms.
This data-driven precision medicine test works by analyzing the genomic information present in a patient’s sample, such as cerebrospinal fluid (CSF) or blood. Because bacteria, viruses, fungi, and parasites also have DNA-based genomes and can be recognized by unique genetic signatures, infectious agents may be detected among total genomic information in a sample, which is mostly human.
DNA sequencing technologies have advanced at an exponential pace, dramatically lowering both speed and cost. While a genome analysis approach for diagnosing infections has long been theoretically possible, the process would have taken months and cost millions of dollars to diagnose a single patient one decade ago. The research team has so far optimized their system to offer the mNGS diagnostic test for $2,200, providing results within a few days of sample collection. Just prior to the awarding of funds, the research team and its collaborators had obtained evidence that supported the life-saving potential of the technique for critically ill patients. The mNGS test radically sped up the diagnostic process and led to a diagnosis when conventional tests had failed. For example, the team was presented with a case of a 14-year-old boy who was near death with brain inflammation that remained undiagnosed despite months of lab tests, expensive imaging technologies, and invasive procedures, such as brain biopsy. The mNGS test was able to identify the infectious agent, and the boy quickly recovered after targeted treatment.
The research team previously developed a genome-based test for infectious disease diagnostics and obtained evidence that this comprehensive test can accelerate identification of infectious agents in previously difficult-to-diagnose cases. The test has the potential to save the lives of critically ill patients by enabling appropriate treatments in a timely fashion.
The goals of this project were to expand the use of metagenomic next generation sequencing mNGS for diagnostic tests of meningitis, encephalitis, sepsis, and pneumonia from a research lab to a routine clinical setting and to collect evidence for its clinical and economic utility as compared to conventional testing. Moving a diagnostic test into clinical practice is a complex process that includes 1) developing procedures that ensure accurate and reliable test results and confirming the performance of the test in a licensed diagnostic laboratory that is certified to federal standards (Clinical Laboratory Improvement Amendments, CLIA); 2) determining the test’s clinical validity, that is, how well it identifies, measures, or predicts the presence or absence of a clinical condition; 3) creating processes for ordering, billing, and reimbursing the test; 4) educating the medical profession about the utility and use of the test; and 5) scaling the test to allow for large volume testing.
Toward their ultimate goal of ensuring accessibility, the team has also initiated a cost effectiveness analysis and made progress on multiple technical, logistical, and regulatory steps.
With additional third-party funding in place, the team is well positioned to complete the project and, if successful, transform clinical diagnosis for infectious diseases.
The team will continue to expand precision diagnostic tests for infectious diseases by completing the CLIA standard confirmation of the test for diagnosing blood infections and by initiating a clinical study for patients with blood infections. Work is ongoing to increase the speed of the tests, attempt to study the determinants of antibiotic resistance, and to harness AI to better diagnose infectious or non-infectious causes of illness. Additionally, the team is working to complete an economic analysis to further demonstrate the value of their assays compared to the current standard of practice.
Research Team and Collaborators
University of California, San Francisco
- Charles Chiu, MD, PhD
- Steve Miller, MD, PhD
- Joseph DeRisi, PhD
- Eric Chow, PhD
- Steven Hauser, MD
- Michael Wilson, MD
- Michael Geschwind, MD, PhD
- Jeffrey Gelfand, MD
- Felicia Chow, MD
- Jacob Appelbaum, MD, PhD
- Chaz Langelier, MD, PhD
- Kristen McCaleb, PhD
University of California, Los Angeles
- Romney Humphries, PhD. D(ABMM)
- Jeffrey Klausner, MD, MPH
- Tara Vijayan, MD
University of California, Davis
- Christopher Polage, MD
- Stuart Cohen, MD
University of California, Berkeley
- Brent Fulton, PhD, MBA
California Department of Public Health
- James Watt, MD
- Dongxiang Xia, MD, PhD
- Sharon Messenger, PhD
- Debra Wadford, PhD
- Jonathan Hirsch, PhD
- Laurie Gomer, MBA
- Davis Shaywitz, MD, PhD
- Omar Serang, BS
Quest Diagnostics, Inc.
- Rick Pesano, MD, PhD
- John Leake, MD, MPH
- Mostafa Ronaghi, PhD
- Sri Madabushi, PhD
Abbott Laboratories, Inc.
American Tissue Culture Collection
Children’s Hospital Colorado / University of Colorado in Denver, CO
Children’s Hospital Los Angeles
Children’s National Medical Center at Washington D.C.
Oxford Nanopore Technologies, Inc.
Quest Diagnostics, Inc.
St. Jude Children’s Research Hospital in Vanderbilt, TN
University of California, San Diego
University of Maryland
U.S. Food and Drug Administration
Zuckerberg San Francisco General Hospital and Trauma Center
L to R, Front Row: Michael Geschwind, MD, PhD; Joe DeRisi, PhD; Michael Wilson, MD, MAS; Charles Chiu, MD, PhD; Steve Miller, MD, PhD; Kelsey Zorn, MHS; Back Row: Jeffrey Gelfand, MD, MAS; Hannah Sample, BS; Scot Federman, BA; Eric Chow, PhD; Wei Gu, MD, PhD; Allan Gopez, CLS; Walter Lorizio, CLS; Crystal Chan, CLS Specialist; Lydia Dang, CLS
In order to achieve its goals, the PDAID project requires additional funds beyond those provided by CIAPM. The state’s contribution to the project is significantly leveraged by generous donations from the Sandler and the William F. Bowes, Jr., foundations for a total of $2.4 million, and by additional funding from the Charles and Helen Schwab foundation and a $400,000 award from the Marcus Program in Precision Medicine Innovation at UCSF. In addition, PDAID is funded by research awards that, together, amount to close to $400,000.
- UCSF provided in-kind support through administrative fees and faculty time.
- In-kind contributions from Quest, CDPH and UCSF in the form of patient samples for the validation of the sequencing assay.