Metagenomic Sequencing Enhanced Diagnosis of Meningitis and Encephalitis Infections

MedicalResearch.com Interview with:

Dr. Charles Chiu, M.D./Ph.D. Professor, Laboratory Medicine and Medicine / Infectious Diseases Director, UCSF-Abbott Viral Diagnostics and Discovery Center Associate Director, UCSF Clinical Microbiology Laboratory UCSF School of Medicine

Dr. Chiu

Dr. Charles Chiu, M.D./Ph.D.
Professor, Laboratory Medicine and Medicine / Infectious Diseases
Director, UCSF-Abbott Viral Diagnostics and Discovery Center
Associate Director, UCSF Clinical Microbiology Laboratory
UCSF School of Medicine

MedicalResearch.com: What is the background for this study? Would you describe what is meant by metagenomic sequencing?

Response: Metagenomic next-generation sequencing (mNGS) is the use of technology to generate millions of sequence reads to diagnose infection sin patients by characterizing the full range of potential pathogens (bacteria, viruses, fungi, and parasites) in a single sample. Although shown to be a promising diagnostic tool for  infectious diseases in case reports and limited case series (Chiu and Miller Nature Reviews Genetics 20, 341-355 (2019)), to date the “real-life” utility of this approach for patient care has hitherto not been demonstrated.  This study is the first prospective, multi-center study of clinical mNGS testing for the diagnosis of neurological infections in acutely ill hospitalized patients presenting with meningitis and/or encephalitis.

MedicalResearch.com: What are the main findings? 

Response: Our main findings are that in a prospective cohort of 204 enrolled patients, mNGS testing of patient cerebrospinal fluid (CSF) was needed to identify 13 of the 58 neurological infections (22.4%), with the highest diagnostic yield resulting from combining mNGS testing and conventional clinical microbiological testing (culture, serology, polymerase chain reaction (PCR), and antigen testing).  Evaluated head-to-head for direct detection of pathogens in CSF, mNGS testing alone yielded more diagnoses than conventional testing with culture, PCR, and antigen-based testing.  Among the 13 infections diagnosed only by clinical mNGS, 7 of the 13 (>50%) led to targeted and appropriate antibiotic treatment for the patient. An example is the diagnosis of hepatitis E virus infection in a patient with meningoencephalitis using mNGS; the infection was treatable with ribavirin and likely spared the patient from having to undergo a liver transplant. 

MedicalResearch.com: What should readers take away from your report?

Response: Key take-home points from the report are that clinical mNGS testing is a promising new gene sequencing approach to diagnose infections, with the advantage that nearly all potential pathogens – viruses, bacteria, fungi, and parasites – can be identified in a single test. Over the next several years, we will likely be seeing increasing adoption of clinical mNGS testing for diagnosis of infections in patients.  A key limitation of mNGS testing is that it is a “direct direction” method, like culture and PCR  If nucleic acid from the causative pathogen is not present in the clinical sample at the time of collection, mNGS testing will not be able to diagnose the infection.  However, the availability of mNGS  testing adds another powerful diagnostic tool for doctors to make earlier and more accurate infectious disease diagnoses, especially in critically ill hospitalized patients with mysterious infections. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: As a result of this study, we are planning to expand the scope of mNGS testing to other sample types and other kinds of infections, such as mNGS testing of plasma to diagnose fever and sepsis and of respiratory secretions to diagnose pneumonia. The current mNGS test has a laboratory turnaround time of 48-72 hours; we anticipate moving forward even faster sequencing technologies, such as nanopore sequencing, for real-time analysis of sequencing data and diagnosis of infections in <6 hours. Finally, we are leverage the human RNA sequences that are generated in the clinical mNGS assay to interrogate the human (patient) host response.  In the future, we may be able to provide both pathogen and host response data to doctors to help inform clinical management and treatment for their patients.

MedicalResearch.com: Is there anything else you would like to add?

Response: We have only explored the tip of the iceberg with respect to metagenomic sequencing. As sequencing costs continue to decrease and reference databases continue to grow, the accuracy, speed, and cost-effectiveness of clinical mNGS testing will only improve over time. I envision that in the near future we will see this test being performed routinely for diagnosis of infections.

Disclosures: Dr. Charles Chiu’s research laboratory and this work is supported by the California Initiative to Advance Precision Medicine, NIH grant R01HL105704, a UC Center for Accelerated Innovation grant funded by NIH grant U54HL119893 and NIH/NCATS UCSF-CTSI grant UL1TR000004, Charles and Helen Schwab Foundation, the George and Judy Marcus Innovation Fund, and the Sandler and William K. Bowes, Jr. Foundations. Dr. Chiu is the director of the UCSF-Abbott Viral Diagnostics and Discovery Center and receives research support from Abbott Laboratories Inc.  Dr. Chiu is an inventor on a patent application related  to algorithms used in analysis of clinical metagenomic data titled “Pathogen Detection using Next-Generation Seuqencing” (PCT/US/16/52912).

Citation:

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis

Michael R. Wilson, M.D., M.A.S. Hannah A. Sample, B.S., Kelsey C. Zorn, M.H.S., Shaun Arevalo, B.S., C.L.S., Guixia Yu, B.S., John Neuhaus, Ph.D., Scot Federman, B.A., Doug Stryke, B.S., Benjamin Briggs, M.D., Ph.D., Charles Langelier, M.D., Ph.D., Amy Berger, M.D., Ph.D.,  Vanja Douglas, M.D., et al.
June 13, 2019
N Engl J Med 2019; 380:2327-2340
DOI: 10.1056/NEJMoa1803396

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1803396

 

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