Back to resultsPrecision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort (PDAID)
Primary Purpose
Encephalitis, Meningitis
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
mNGS for pathogen detection
Sponsored by
About this trial
This is an interventional diagnostic trial for Encephalitis focused on measuring metagenomic next-generation sequencing, microbiological diagnosis, bacterial infections, viral infections, fungal infections, parasitic infections
Eligibility Criteria
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
- Age: any (no age limit)
- 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
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
- No known diagnosis of non-infectious etiology responsible for symptoms
- Time of enrollment: within 7 days of onset of symptoms, either initial presentation or acute exacerbation of presumed infectious syndrome.
Specimen Criteria
- 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
- 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)
- No more than 3 freeze-thaw cycles
Sites / Locations
- University of California, Davis Medical Center
- Children's Hospital Los Angeles
- University of California, Los Angeles Medical Center
- University of California, San Francisco Medical Center
- Children's Hospital Colordao
- Children's National Medical Center
- St. Jude Children's Research Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
patients enrolled for mNGS testing
Arm Description
Patients with meningitis and/or encephalitis will be enrolled in this study in order to analyze the clinical utility of mNGS for pathogen detection. There is no control group for this study (Investigators will identify historical controls by retrospective chart review and clinical reimbursement documents).
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
Clinical Outcomes: Length of Stay
Investigators will review medical records to determine length of stay including discharge to rehab facilities.
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.
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).
Full Information
NCT ID
NCT02910037
First Posted
September 13, 2016
Last Updated
May 7, 2021
Sponsor
University of California, San Francisco
Collaborators
California Initiative to Advance Precision Medicine, Sandler Foundation, Bowes Foundation, Charles and Helen Schwab Foundation, University of California, Davis, University of California, Los Angeles, Children's Hospital Los Angeles, Children's Hospital Colorado, St. Jude Children's Research Hospital, Children's National Research Institute, University of California, Berkeley, DNAnexus, Inc., Syapse, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02910037
Brief Title
Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort
Acronym
PDAID
Official Title
Clinical Implementation of Metagenomic Next-Generation Sequencing for Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
June 1, 2016 (Actual)
Primary Completion Date
July 31, 2017 (Actual)
Study Completion Date
July 31, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
California Initiative to Advance Precision Medicine, Sandler Foundation, Bowes Foundation, Charles and Helen Schwab Foundation, University of California, Davis, University of California, Los Angeles, Children's Hospital Los Angeles, Children's Hospital Colorado, St. Jude Children's Research Hospital, Children's National Research Institute, University of California, Berkeley, DNAnexus, Inc., Syapse, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Device Product Not Approved or Cleared by U.S. FDA
Yes
Data Monitoring Committee
No
5. Study Description
Brief 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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Encephalitis, Meningitis
Keywords
metagenomic next-generation sequencing, microbiological diagnosis, bacterial infections, viral infections, fungal infections, parasitic infections
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
214 (Actual)
8. Arms, Groups, and Interventions
Arm Title
patients enrolled for mNGS testing
Arm Type
Experimental
Arm Description
Patients with meningitis and/or encephalitis will be enrolled in this study in order to analyze the clinical utility of mNGS for pathogen detection. There is no control group for this study (Investigators will identify historical controls by retrospective chart review and clinical reimbursement documents).
Intervention Type
Device
Intervention Name(s)
mNGS for pathogen detection
Other Intervention Name(s)
Sequence-Based Ultrarapid Pathogen Identification (SURPI)+, UCSF metagenomic next-generation sequencing testing
Intervention Description
This assay is a laboratory-validated metagenomic test for comprehensive detection of viruses, bacteria, fungi, and parasites in clinical samples.
Primary Outcome Measure Information:
Title
Total Number of Cases With at Least One Provider Response
Description
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.
Time Frame
within 1 month of patient enrollment in study
Secondary Outcome Measure Information:
Title
Clinical Outcomes: Time From Cerebrospinal Fluid Collection to mNGS Results
Description
Investigators will review medical records to determine time of initial presentation and measure the time to mNGS results.
Time Frame
from admission to 1 month post discharge for each patient during the enrollment period of study
Title
Clinical Outcomes: Length of Stay
Description
Investigators will review medical records to determine length of stay including discharge to rehab facilities.
Time Frame
from admission to 1 month post discharge for each patient during the enrollment period of study
Title
Clinical Outcomes: Final Diagnosis Category
Description
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.
Time Frame
from admission to time of final case review (1 month post discharge or up to one year)
Title
Clinical Outcomes: Concordance of mNGS With Other Molecular Testing on Cerebrospinal Fluid Pathogens
Description
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).
Time Frame
from admission to 1 month post discharge for each patient during the enrollment period of study
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Minute
Maximum Age & Unit of Time
110 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Age: any (no age limit)
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
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
No known diagnosis of non-infectious etiology responsible for symptoms
Time of enrollment: within 7 days of onset of symptoms, either initial presentation or acute exacerbation of presumed infectious syndrome.
Specimen Criteria
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
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)
No more than 3 freeze-thaw cycles
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charles Y Chiu, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hannah Sample, BS
Organizational Affiliation
University of California, San Francisco
Official's Role
Study Director
Facility Information:
Facility Name
University of California, Davis Medical Center
City
Davis
State/Province
California
ZIP/Postal Code
95616
Country
United States
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
University of California, Los Angeles Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California, San Francisco Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94116
Country
United States
Facility Name
Children's Hospital Colordao
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
All genomic / metagenomic sequencing data from this study will be made available either at NIH Sequence Read Archive or NIH database of Genotypes and Phenotypes (dbGaP), depending on whether human sequence data is included. The investigators intend to make de-identified ancillary clinical, laboratory, and radiographic data available as well upon request.
IPD Sharing Time Frame
The clinical study report will be submitted for publication by June 2018.
IPD Sharing URL
http://nextgendiagnostics.ucsf.edu/our-research/
Citations:
PubMed Identifier
24896819
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.
Results Reference
background
PubMed Identifier
26620704
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].
Results Reference
background
PubMed Identifier
25572898
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.
Results Reference
background
PubMed Identifier
25837569
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.
Results Reference
background
PubMed Identifier
24899342
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, Martinez 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.
Results Reference
background
PubMed Identifier
26290222
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.
Results Reference
background
PubMed Identifier
31189036
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, Vijayan T, Allyn PR, Campeau S, Humphries RM, Klausner JD, Ganzon CD, Memar F, Ocampo NA, Zimmermann LL, Cohen SH, Polage CR, DeBiasi RL, Haller B, Dallas R, Maron G, Hayden R, Messacar K, Dominguez SR, Miller S, Chiu CY. Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis. N Engl J Med. 2019 Jun 13;380(24):2327-2340. doi: 10.1056/NEJMoa1803396.
Results Reference
result
PubMed Identifier
28930022
Citation
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 Infection by Metagenomic Sequencing, California, 2016. Emerg Infect Dis. 2017 Oct;23(10):1964-1968. doi: 10.3201/eid2310.161986.
Results Reference
result
PubMed Identifier
28721353
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. Open Forum Infect Dis. 2017 Jun 13;4(3):ofx121. doi: 10.1093/ofid/ofx121. eCollection 2017 Summer.
Results Reference
result
Links:
URL
http://chiulab.ucsf.edu
Description
brief description of PDAID study and referral link
URL
http://www.ciapm.org/project/precision-diagnosis-acute-infectious-diseases
Description
summary of the PDAID project, sponsored by the California Initiative to Advance Precision Medicine
URL
https://www.youtube.com/watch?v=OFYSEowGfeI
Description
video describing metagenomic next-generation sequencing and its use for diagnosis of infections
URL
http://nextgendiagnostics.ucsf.edu
Description
The UCSF Center for Next-Gen Precision Diagnostics
Learn more about this trial
Precision Diagnosis of Acute Infectious Diseases; Neuroinflammatory Cohort
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