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Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 in Children

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ClinicalTrials.gov Identifier: NCT05576714
Recruitment Status : Recruiting
First Posted : October 12, 2022
Last Update Posted : October 14, 2022
Sponsor:
Collaborators:
Chang Gung Medical Foundation
National Cheng-Kung University Hospital
Chi Mei Medical Hospital
Mackay Memorial Hospital
Tri-Service General Hospital
National Health Research Institutes, Taiwan
National Science and Technology Council
Information provided by (Responsible Party):
National Taiwan University Hospital

Brief Summary:

Background and objective From this April, there was a COVID-19 outbreak in Taiwan. The first fatal case of pediatric COVID-19 encephalitis was reported on April 19, 2022 and fatal fulminant cerebral edema in other 4 children with COVID-19 encephalitis was reported within 1 month from Taiwan CDC registry. To date, around 700,000 children got COVID-19 recently. Several children developed MIS-C (multi-system inflammatory syndrome in children)-related shock about 2-6 weeks after COVID-19. Since both COVID-19 associated encephalopathy/ encephalitis and MIS-C are life-threatening, it is urgent to delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis.

Methods Pediatricians will enroll cases of both COVID-19 associated encephalopathy/ encephalitis and MIS-C from several hospitals and medical centers. Their clinical manifestations, lab findings, severity and outcomes will be collected. Clinical assessment of all the systems will be performed. Blood, nasopharyngeal swab and stool will be collected at acute, subacute and convalescent stages for whole exome sequencing, immunopathogenesis including chemokine/cytokine, T/B lymphocyte subset, SARS-CoV2 specific Ab/T/B cell, T and B cell repertoire, viral pathogenesis including multiple viral detection, persistence of fecal SARS-COVID-2 as well as respiratory and gut microbiota. We will establish the animal models for COVID-19 associated encephalopathy/encephalitis and MIS-C, based on the K18-hACE2 or R26R-AGP mouse models established in NTU animal center. Moreover, specific viral or host factors involved in regulating the pathogenesis and immune responses can be investigated, to optimize the protocol for further improvement of the animal models and also to help identify the putative therapeutic targets.

Expected results We will delineate the clinical and laboratory characteristics of COVID-19 associated encephalopathy and encephalitis, the role of immune, virology, genetics mechanism in pathophysiology, and will optimize the treatment algorithm based on the result of this study. We also expect that the important biomarkers and risk factors associated with clinical outcome and severity, the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.


Condition or disease Intervention/treatment
COVID-19-Associated Encephalitis Multisystem Inflammatory Syndrome in Children Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 300 participants
Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration: 1 Year
Official Title: Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 Associated Encephalopathy/Encephalitis and Multi-systemic Inflammatory Syndrome in Children
Actual Study Start Date : August 1, 2022
Estimated Primary Completion Date : July 2025
Estimated Study Completion Date : July 2025

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
encephalopathy/encephalitis
Children will be classified as the following four diagnoses: 1. Encephalopathy (MERS, ANEC, ASED); 2. Acute encephalitis; 3. ADEM; 4. Fulminant cerebral edema. The classification will be adjudicated and discussed by neurology and critical care experts on the NTUH and CGMH study team (W.T.L, J.J.L, and K.L.L.)
Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis
We will delineate the clinical and laboratory characteristics of COVID-19 associated encephalopathy and encephalitis, the role of immune, virology, genetics mechanism in pathophysiology, and will optimize the treatment algorithm based on the result of this study. We also expect that the important biomarkers and risk factors associated with clinical outcome and severity, the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.

MIS-C
The following 6 criteria for MIS-C have to be met: age 0 to 19 years, fever for ≥3 days, clinical signs of multisystem involvement (at least 2 systems), elevated markers of inflammation (e.g., CRP, procalcitonin or ferritin), evidence of SARS-CoV-2 infection and no other obvious microbial cause of inflammation.
Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis
We will delineate the clinical and laboratory characteristics of COVID-19 associated encephalopathy and encephalitis, the role of immune, virology, genetics mechanism in pathophysiology, and will optimize the treatment algorithm based on the result of this study. We also expect that the important biomarkers and risk factors associated with clinical outcome and severity, the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.

control group
Age and gender matched healthy control children or mild COVID-19 cases without MIS-C will be also included for further comparison
Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis
We will delineate the clinical and laboratory characteristics of COVID-19 associated encephalopathy and encephalitis, the role of immune, virology, genetics mechanism in pathophysiology, and will optimize the treatment algorithm based on the result of this study. We also expect that the important biomarkers and risk factors associated with clinical outcome and severity, the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.




Primary Outcome Measures :
  1. clinical and laboratory characteristics of COVID-19 associated encephalitis/encephalopathy [ Time Frame: 2 year ]
    for example: fever, poor consciousness, persistent lethargy, persistent headache, persistent vomiting, muscle twitching, convulsions, unsteady gait, etc.

  2. biomarkers and risk factors of MIS-C [ Time Frame: 2 year ]
    the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.


Biospecimen Retention:   Samples With DNA
blood, nasopharyngeal swab, stool


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Active surveillance will be performed nationally to identify children and adolescents (age≤18 years) with COVID-19 related illness hospitalized from July 01, 2022, to February 28, 2023. The data will registry to the public database hold by NTUH and CGMH.
Criteria

Inclusion Criteria:

  1. Age less than 18 years old.
  2. A positive SARS-CoV-2 test result (reverse transcriptase-polymerase chain reaction and/or antibody)。
  3. Hospitalized children.
  4. Clinical diagnostic criteria for encephalitis.

Major criteria:

1). Altered mental status greater than 24 hours without alternative cause identified Minor criteria: need at least 2 minor criteria for encephalitis

  1. Fever
  2. Seizures
  3. Focal neurologic signs
  4. CSF: pleocytosis
  5. EEG: abnormal slow background or epileptiform discharge
  6. Neuroimaging: abnormal brain inflammation on MRI *****Major+2 minor: possible encephalitis; Major+3 minor: probable encephalitis; Brain biopsy: confirmed encephalitis

The following 6 criteria for MIS-C have to be met: age 0 to 19 years, fever for ≥3 days, clinical signs of multisystem involvement (at least 2 systems), elevated markers of inflammation (e.g., CRP, procalcitonin or ferritin), evidence of SARS-CoV-2 infection and no other obvious microbial cause of inflammation.

Exclusion Criteria:

  1. Age more than 18 years old
  2. Previous history of encephalopathy, acute encephalopathy caused by other etiology, not COVID-19, development delay, autism, ADHD, epilepsy and febrile seizure
  3. Non-hospitalized children

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05576714


Contacts
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Contact: Tsui-Yien Fan, RA +886 2312 3456 ext 71730 twffccy@gmail.com

Locations
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Taiwan
National Taiwan University Hospital Recruiting
Taipei, Chung Cheng District, Taiwan, 100
Contact: Tsui-Yien Fan, RA    +886 2312 3456 ext 711730    twffccy@gmail.com   
Sponsors and Collaborators
National Taiwan University Hospital
Chang Gung Medical Foundation
National Cheng-Kung University Hospital
Chi Mei Medical Hospital
Mackay Memorial Hospital
Tri-Service General Hospital
National Health Research Institutes, Taiwan
National Science and Technology Council
Investigators
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Study Chair: Luna-Yin Chang, professor National Taiwan University Hospital
Publications:
Payne AB, Gilani Z, Godfred-Cato S, Belay ED, Feldstein LR, Patel MM, Randolph AG, Newhams M, Thomas D, Magleby R, Hsu K, Burns M, Dufort E, Maxted A, Pietrowski M, Longenberger A, Bidol S, Henderson J, Sosa L, Edmundson A, Tobin-D'Angelo M, Edison L, Heidemann S, Singh AR, Giuliano JS Jr, Kleinman LC, Tarquinio KM, Walsh RF, Fitzgerald JC, Clouser KN, Gertz SJ, Carroll RW, Carroll CL, Hoots BE, Reed C, Dahlgren FS, Oster ME, Pierce TJ, Curns AT, Langley GE, Campbell AP; MIS-C Incidence Authorship Group; Balachandran N, Murray TS, Burkholder C, Brancard T, Lifshitz J, Leach D, Charpie I, Tice C, Coffin SE, Perella D, Jones K, Marohn KL, Yager PH, Fernandes ND, Flori HR, Koncicki ML, Walker KS, Di Pentima MC, Li S, Horwitz SM, Gaur S, Coffey DC, Harwayne-Gidansky I, Hymes SR, Thomas NJ, Ackerman KG, Cholette JM. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open. 2021 Jun 1;4(6):e2116420. doi: 10.1001/jamanetworkopen.2021.16420.
Sacco K, Castagnoli R, Vakkilainen S, Liu C, Delmonte OM, Oguz C, Kaplan IM, Alehashemi S, Burbelo PD, Bhuyan F, de Jesus AA, Dobbs K, Rosen LB, Cheng A, Shaw E, Vakkilainen MS, Pala F, Lack J, Zhang Y, Fink DL, Oikonomou V, Snow AL, Dalgard CL, Chen J, Sellers BA, Montealegre Sanchez GA, Barron K, Rey-Jurado E, Vial C, Poli MC, Licari A, Montagna D, Marseglia GL, Licciardi F, Ramenghi U, Discepolo V, Lo Vecchio A, Guarino A, Eisenstein EM, Imberti L, Sottini A, Biondi A, Mato S, Gerstbacher D, Truong M, Stack MA, Magliocco M, Bosticardo M, Kawai T, Danielson JJ, Hulett T, Askenazi M, Hu S; NIAID Immune Response to COVID Group; Chile MIS-C Group; Pavia Pediatric COVID-19 Group; Cohen JI, Su HC, Kuhns DB, Lionakis MS, Snyder TM, Holland SM, Goldbach-Mansky R, Tsang JS, Notarangelo LD. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med. 2022 May;28(5):1050-1062. doi: 10.1038/s41591-022-01724-3. Epub 2022 Feb 17.

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Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT05576714    
Other Study ID Numbers: 202207201RIND
First Posted: October 12, 2022    Key Record Dates
Last Update Posted: October 14, 2022
Last Verified: October 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Taiwan University Hospital:
COVID-19
encephalitis
MIS-C
Additional relevant MeSH terms:
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COVID-19
Encephalitis
Syndrome
Disease
Pathologic Processes
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases