Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort

Meningitis Clinical Trial

— PDAID  

Official title:

Clinical Implementation of Metagenomic Next-Generation Sequencing for Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02910037
• Other study ID #: P0509948
• Status: Completed
• Phase: N/A
• Start date: June 1, 2016
• Est. completion date: July 31, 2017

Study information

• Verified date: May 2021
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to use a clinically validated metagenomic next-generation sequencing (mNGS) assay to provide a demonstration of precision medicine for diagnosis of acute infectious disease in hospitalized patients. From June 2016 to June 2017, 200 patients will be enrolled from multiple hospitals in California and outside of California. Patients will be evaluated to determine the impact on the mNGS assay on diagnostic yield, hospital costs and clinical outcomes.

Description:

This study aims to use a clinically validated metagenomic next-generation sequencing (mNGS) assay to provide a demonstration of precision medicine for diagnosis of acute infectious disease in hospitalized patients, with the goal of directly impacting clinical care and improving patient mortality. This diagnostic test has been previously validated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, the University of California, San Francisco Clinical Microbiology Laboratory. From June 2016 to June 2017, investigators will prospectively enroll 200 patients from multiple hospitals in California (University of California, San Francisco; University of California, Los Angeles; University of California, Davis; Children's Hospital Los Angeles) and outside California (Children's National Medical Center, Children's Hospital Colorado, St. Jude Children's Research Hospital) for mNGS testing, and evaluate the impact on the assay on diagnostic yield, hospital costs and clinical outcomes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 214
• Est. completion date: July 31, 2017
• Est. primary completion date: July 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 110 Years

Eligibility

Exclusions:

• Patients on a 5150 or 5250 psychiatric hold

• Prisoners

• University of California employees / students or close associates of any of the key personnel on the study

• Outpatients and/or patients with chronic illness

Inclusion:

Demographic Criteria

1. Age: any (no age limit)

2. Language: any (with the use of interpreting services for obtaining consent)

For the following, the infectious syndromes include meningitis, encephalitis, fever, sepsis, and pneumonia:

Clinical Criteria

1. Hospital admission or transfer with diagnosis of an presumed infectious syndrome or clinical presentation consisting with an infectious syndrome, as defined below:

• Meningitis: fever >38°C and abnormal imaging or CSF pleocytosis (CSF white blood cell count (WBC) > 5 /mm^3) +/- stiff neck, +/- headache, +/- seizure

• Encephalitis: pleocytosis and at least one of the following: altered mental status, seizures, new onset of focal neurologic findings, abnormal EEG, acute brain abnormalities on neuroimaging

2. No known diagnosis of non-infectious etiology responsible for symptoms

3. Time of enrollment: within 7 days of onset of symptoms, either initial presentation or acute exacerbation of presumed infectious syndrome.

Specimen Criteria

1. cerebrospinal fluid available within 7 days of symptom onset AND within 3 days of hospital admission or transfer unless evidence for acute exacerbation as defined by abrupt decline in clinical status, worsening pleocytosis or other laboratory parameters

2. Minimum of 600 microliters (uL) of clinical sample, stored at 4 degrees Celsius (C) no more than 5 days (ideally frozen in -70 degrees Celsius within 24 hours of collection)

3. No more than 3 freeze-thaw cycles

Related Conditions & MeSH terms

• Communicable Diseases
• Encephalitis
• Infection
• Meningitis

Intervention

Device:
• mNGS for pathogen detection
This assay is a laboratory-validated metagenomic test for comprehensive detection of viruses, bacteria, fungi, and parasites in clinical samples.

Locations

Country	Name	City	State
United States	University of California, Davis Medical Center	Davis	California
United States	Children's Hospital Colordao	Denver	Colorado
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of California, Los Angeles Medical Center	Los Angeles	California
United States	St. Jude Children's Research Hospital	Nashville	Tennessee
United States	University of California, San Francisco Medical Center	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (14)

Lead Sponsor

Collaborator

University of California, San Francisco

Bowes Foundation, California Initiative to Advance Precision Medicine, Charles and Helen Schwab Foundation, Children's Hospital Colorado, Children's Hospital Los Angeles, Children's National Research Institute, DNAnexus, Inc., Sandler Foundation, St. Jude Children's Research Hospital, Syapse, Inc., University of California, Berkeley, University of California, Davis, University of California, Los Angeles

Country where clinical trial is conducted

United States, 

References & Publications (9)

Chiu CY, Coffey LL, Murkey J, Symmes K, Sample HA, Wilson MR, Naccache SN, Arevalo S, Somasekar S, Federman S, Stryke D, Vespa P, Schiller G, Messenger S, Humphries R, Miller S, Klausner JD. Diagnosis of Fatal Human Case of St. Louis Encephalitis Virus In — View Citation

Greninger AL, Messacar K, Dunnebacke T, Naccache SN, Federman S, Bouquet J, Mirsky D, Nomura Y, Yagi S, Glaser C, Vollmer M, Press CA, Kleinschmidt-DeMasters BK, Dominguez SR, Chiu CY. Clinical metagenomic identification of Balamuthia mandrillaris encephalitis and assembly of the draft genome: the continuing case for reference genome sequencing. Genome Med. 2015 Dec 1;7:113. doi: 10.1186/s13073-015-0235-2. Erratum in: Genome Med. 2016;8(1):1. Klenschmidt-DeMasters, Bette K [corrected to Kleinschmidt-DeMasters, Bette K]. — View Citation

Greninger AL, Naccache SN, Messacar K, Clayton A, Yu G, Somasekar S, Federman S, Stryke D, Anderson C, Yagi S, Messenger S, Wadford D, Xia D, Watt JP, Van Haren K, Dominguez SR, Glaser C, Aldrovandi G, Chiu CY. A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study. Lancet Infect Dis. 2015 Jun;15(6):671-82. doi: 10.1016/S1473-3099(15)70093-9. Epub 2015 Mar 31. — View Citation

Murkey JA, Chew KW, Carlson M, Shannon CL, Sirohi D, Sample HA, Wilson MR, Vespa P, Humphries RM, Miller S, Klausner JD, Chiu CY. Hepatitis E Virus-Associated Meningoencephalitis in a Lung Transplant Recipient Diagnosed by Clinical Metagenomic Sequencing. — View Citation

Naccache SN, Federman S, Veeraraghavan N, Zaharia M, Lee D, Samayoa E, Bouquet J, Greninger AL, Luk KC, Enge B, Wadford DA, Messenger SL, Genrich GL, Pellegrino K, Grard G, Leroy E, Schneider BS, Fair JN, Martínez MA, Isa P, Crump JA, DeRisi JL, Sittler T, Hackett J Jr, Miller S, Chiu CY. A cloud-compatible bioinformatics pipeline for ultrarapid pathogen identification from next-generation sequencing of clinical samples. Genome Res. 2014 Jul;24(7):1180-92. doi: 10.1101/gr.171934.113. Epub 2014 Jun 4. — View Citation

Naccache SN, Peggs KS, Mattes FM, Phadke R, Garson JA, Grant P, Samayoa E, Federman S, Miller S, Lunn MP, Gant V, Chiu CY. Diagnosis of neuroinvasive astrovirus infection in an immunocompromised adult with encephalitis by unbiased next-generation sequencing. Clin Infect Dis. 2015 Mar 15;60(6):919-23. doi: 10.1093/cid/ciu912. Epub 2015 Jan 7. — View Citation

Wilson MR, Naccache SN, Samayoa E, Biagtan M, Bashir H, Yu G, Salamat SM, Somasekar S, Federman S, Miller S, Sokolic R, Garabedian E, Candotti F, Buckley RH, Reed KD, Meyer TL, Seroogy CM, Galloway R, Henderson SL, Gern JE, DeRisi JL, Chiu CY. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med. 2014 Jun 19;370(25):2408-17. doi: 10.1056/NEJMoa1401268. Epub 2014 Jun 4. — View Citation

Wilson MR, Sample HA, Zorn KC, Arevalo S, Yu G, Neuhaus J, Federman S, Stryke D, Briggs B, Langelier C, Berger A, Douglas V, Josephson SA, Chow FC, Fulton BD, DeRisi JL, Gelfand JM, Naccache SN, Bender J, Dien Bard J, Murkey J, Carlson M, Vespa PM, Vijaya — View Citation

Wilson MR, Shanbhag NM, Reid MJ, Singhal NS, Gelfand JM, Sample HA, Benkli B, O'Donovan BD, Ali IK, Keating MK, Dunnebacke TH, Wood MD, Bollen A, DeRisi JL. Diagnosing Balamuthia mandrillaris Encephalitis With Metagenomic Deep Sequencing. Ann Neurol. 2015 Nov;78(5):722-30. doi: 10.1002/ana.24499. Epub 2015 Aug 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Number of Cases With at Least One Provider Response	Investigators will evaluate impact of mNGS assay by clinician surveys and Clinical Microbial Sequencing Board (CMSB) feedback and discussion as measured by at least 1 provider response per case.	within 1 month of patient enrollment in study
Secondary	Clinical Outcomes: Time From Cerebrospinal Fluid Collection to mNGS Results	Investigators will review medical records to determine time of initial presentation and measure the time to mNGS results.	from admission to 1 month post discharge for each patient during the enrollment period of study
Secondary	Clinical Outcomes: Length of Stay	Investigators will review medical records to determine length of stay including discharge to rehab facilities.	from admission to 1 month post discharge for each patient during the enrollment period of study
Secondary	Clinical Outcomes: Final Diagnosis Category	Investigators will review medical records to determine final diagnosis after all diagnostic testing has been performed including metagenomic Next-Gen sequencing and autopsy where applicable.	from admission to time of final case review (1 month post discharge or up to one year)
Secondary	Clinical Outcomes: Concordance of mNGS With Other Molecular Testing on Cerebrospinal Fluid Pathogens	mNGS findings were compared to conventional testing for concordance. Conventional testing included both tests that were ordered as part of each patients workup and those order to confirm mNGS findings on cerebrospinal fluid (CSF).	from admission to 1 month post discharge for each patient during the enrollment period of study

External Links

•   brief description of PDAID study and referral link
•   summary of the PDAID project, sponsored by the California Initiative to Advance Precision Medicine
•   The UCSF Center for Next-Gen Precision Diagnostics
•   video describing metagenomic next-generation sequencing and its use for diagnosis of infections